BR122023026537A2 - USE OF ATRASENTAN TO TREAT IGA NEPHROPATHY - Google Patents

Abstract

Provided herein are methods of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Also provided herein are methods to decrease renal inflammation and/or fibrosis, decrease the occurrence of hematuria, stabilize eGFR, decrease the number of disease flares associated with IgA nephropathy, delay the onset of ESRD, decrease proteinuria, and decrease fatigue in a subject with IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure.

Description

CROSS REFERENCE TO RELATED ORDERS

[001] This application claims priority to Provisional Application No. U.S. 62/949,115, filed on December 17, 2019, Provisional Application No. U.S. 63/005,003, filed on April 3, 2020, Provisional Application No. U.S. 63/ 072,699, filed on August 31, 2020, Provisional Application No. U.S. 63/084,739, filed on September 29, 2020 and Provisional Application No. U.S. 63/125,205, filed on December 14, 2020, which are incorporated by way of reference in its entirety.

BACKGROUND

[002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Aberrant glycosylation of IgA1 results in increased serum levels of galactose-deficient IgA1 (Gd-IgA1) that are recognized by glycan-specific IgA and IgG autoantibodies. Immune complex aggregates are formed in situ and/or deposited in the glomerular mesangium. This promotes the proliferation of mesangial cells, increased synthesis of extracellular matrix proteins, cytokines, chemokines, and infiltration of immune cells into the surrounding tissue. Thus, disease progression involves (1) the production of Gd-IgA1; and (2) its recognition by antiglycan autoantibodies; which (3) form immune complexes in the kidney; and (4) activate mesangial cells. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pages 137-148 (2017).

[003] Unlike other progressive kidney diseases, such as diabetic nephropathy, IgAN occurs mainly in individuals between the ages of 20 and 30 who are healthy. Patients present with a range of symptoms, often including micro- or macrohematuria and increased protein excretion in the urine. Patients may also experience hypertension as a result of sustained kidney damage. Current therapeutic approaches only provide supportive care, including administration of the maximum tolerable dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or administration of immunosuppressive drugs, the benefits of which are largely outweighed by adverse reactions. Ultimately, 30-40% of patients will develop end-stage renal disease (ESRD) within 20-30 years of IgAN diagnosis. In the meantime, patients experience numerous symptoms that significantly degrade their quality of life, in addition to declining kidney function. Patients with IgAN often exhibit significantly increased expressions of endothelin 1 (ET-1) and ET-RA in the kidney. Increased expression of endothelins positively correlates with proteinuria, one of the characteristic symptoms of IgAN.

SUMMARY

[004] Atrasentan is a selective endothelin A (ETA) receptor antagonist (ETA Ki ~34 pM; ETB Ki ~63 nm, ETA selectivity ~1800x). See, for example, Wu-Wong et al., Clin. Sci. (London), 103(48), pages 107s-111s (2002). Selective ETA receptor antagonists block ETA function while minimally affecting the ETB receptor, providing beneficial renal effects including vasodilation and reduced inflammation while still allowing ET-1 clearance. See, for example, Jandeleit-Dahm and Watson, Curr. Opinion. Nephrol. Hypertens., 21(1), pages 66-71 (2012); see also, Nakamura, et al., Nephron, Vol. 72, pages 454-460 (1996). Although ETA receptor antagonists increase sodium and water retention by the kidney, this is generally manageable clinically. See, for example, Saleh, et al., J. Pharm. Exp. Ther., 338(1), pages 263-270 (2011). Atrasentan has been shown to be effective in patients with diabetic kidney disease (DKD), significantly reducing the risk of renal events defined as doubling of serum creatinine or end-stage renal disease. See, for example, Heerspink, et al., The Lancet, 393, pages 1937-1947 (2019). DKD is considered a secondary glomerular disease, where kidney disease develops secondary to an identified systemic cause, in the case of DKD as a microvascular complication of long-standing diabetes. See, for example, Dattani and McAdoo, Medicine, 47(10), pages 644-648 (2019). The pathogenesis of DKD is multifactorial and complex. Chronically elevated blood glucose levels due to diabetes, which causes glucose toxicity to kidney cells, especially renal endothelial cells, and systemic and renal hemodynamic factors associated with hypertension that result in the transmission of shear stress to resident glomerular cells are the main factors pathogens of DKD. See, for example, Thomas et al., Nat. Rev. Disease Primers. 1, pages 15018-15026 (2015). Multiple dysregulated factors in the diabetic environment, including metabolic components, such as hyperglycemia, dyslipidemia and oxidative stress, and hemodynamic factors, such as vasoactive substances associated with hypertension, stimulate the formation of renal ET-1. Furthermore, DKD is typically seen in older populations due to the need for long-standing diabetes before DKD manifests, and aging is also associated with increased ET-1 production in the kidney. See, for example, Kohan, Kidney Int., 86(5), pages 896-904 (2014). Combined, all of this provides a solid scientific rationale for treating DKD with the ETA receptor blocker atrasentan. See Dhaun, et al., Hypertension, Vol. 57, pages 772-779 (2011).

[005] In contrast to DKD, IgA nephropathy is considered a primary glomerular disease where localized or intrinsic renal pathology is present. The peak incidence of IgA nephropathy is in young individuals in the second or third decade of life and is a disease of autoimmune origin, unlike DKD. IgA nephropathy results from the pathogenic deposition of IgA immune complex in the glomerular mesangium. See, for example, Lai, et al., Nature Reviews Disease Primers, 2, page 16001, 2016. Definitive diagnosis requires renal biopsy and demonstration of mesangial IgA deposition by immunofluorescence microscopy. Recent advances in understanding the triggering events of IgA nephropathy have revealed that an aberrant mucosal immune response stimulates the production of galactose-deficient IgA1, which is recognized as an autoantigen by circulating antiglycan autoantibodies. Immune recognition results in the formation of nephritogenic immune complexes that are deposited in the kidney and activate mesangial cells. Activated mesangial cells proliferate and produce excessive amounts of extracellular matrix components, cytokines, and chemokines. See, for example, Suzuki, et al., J. Am. Soc. Nephrol., Vol. 22, pages 1795-1803 (2011). Up to 40% of patients with biopsy-proven IgA nephropathy progress to end-stage renal disease at some point during long-term follow-up. The role of ET-1 or the ETA receptor in mesangial cell activation has not been previously reported and atrasentan has not been previously tested in IgA nephropathy. As further described herein, atrasentan can be administered at an effective dose with acceptable toxicity and has the appropriate selectivity to minimize unwanted side effects while still treating the underlying IgAN and improving individuals' quality of life. Some embodiments provide a method for inhibiting the activation of mesangial cells in a subject with IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[006] Some embodiments provide a method for inhibiting PDGF signaling (e.g., decreasing the activity and/or expression of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1 and MAP3K1) in a mesangial cell in a subject having IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan, or a pharmaceutically acceptable salt thereof; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[007] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[008] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject does not have one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[009] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; in which the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[010] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, prostate cancer or acute renal failure.

[011] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure.

[012] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure.

[013] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject is not being treated for one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure.

[014] Some embodiments provide a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject was determined to have controlled serum glucose levels; and where the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure.

[015] Some embodiments provide a method for decreasing renal inflammation and/or fibrosis in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[016] Some modalities provide a method for decreasing the occurrence of hematuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[017] Some embodiments provide a method of stabilizing eGFR in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[018] Some embodiments provide a method for decreasing the number of outbreaks of diseases associated with IgA nephropathy in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need. the same.

[019] Some embodiments provide a method for delaying the onset of ESRD in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[020] Some embodiments provide a method for decreasing proteinuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[021] Some embodiments provide a method for decreasing fatigue in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the subject was determined not to suffer from one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure.

[022] Some embodiments provide a method for inhibiting the activation of mesangial cells, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[023] Some embodiments provide a method for reducing the activation of a mesangial cell in contact with an IgA immune complex, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[024] Some modalities provide a method of treating IgA nephropathy in a subject who requires it, comprising: a) determining that the subject has elevated serum levels of Gd-IgA1; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[025] Some modalities provide a method of treating IgA nephropathy in a subject who requires it, comprising: a) determining that the subject has high levels of mesangial activation; and b) administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to the subject.

[026] Some embodiments provide a method of treating IgA nephropathy in a subject who requires it, comprising: a) determining that the subject has elevated levels of IgA immune complexes in the kidney; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF FIGURES

[027] Figure 1A illustrates that treatment with atrasentan reduces the proliferation of primary human mesangial cells exposed to immune complexes derived from individuals with IgAN.

[028] Figure 1B illustrates the content of galactose-deficient (Gd)-IgA and total IgA after purification of IgAN immune complexes or healthy control serum.

[029] Figure 2A illustrates the decrease in proliferation (after 48 hours) of primary human mesangial cells stimulated with endothelin 1 (ET-1) after treatment with increasing concentrations of atrasentan shown on a logarithmic scale, demonstrating an IC50 of about 5. 1 nm.

[030] Figure 2B illustrates the decrease in proliferation (after 72 hours) of primary human mesangial cells stimulated with endothelin 1 (ET-1) after treatment with increasing concentrations of atrasentan shown on a logarithmic scale, demonstrating an IC50 of about 50, 8nm.

[031] Figure 3A illustrates the increase in IL-6 production by primary human mesangial cells exposed to ET-1 over 48 hours (about a 6-fold increase) and the decrease in IL-6 levels after treatment with increasing concentrations of atrasentan shown on a logarithmic scale, demonstrating an IC50 of about 1 nm.

[032] Figure 3B illustrates the increase in IL-6 production by primary human mesangial cells exposed to ET-1 over 72 hours (about a 2.2-fold increase) and the decrease in IL-6 levels after treatment with increasing concentrations of atrasentan shown on a logarithmic scale, demonstrating an IC50 of about 1 nm.

[033] Figure 4 illustrates UACR levels in g-ddY mice, at baseline, before administration of atrasentan and after approximately 5 days of treatment with atrasentan at 0 (control), 10, 20 or 30 mg/kg /day in drinking water. (*P < 0.05 compared to baseline levels, paired t-test).

[034] Figure 5 illustrates the change in UACR levels (% of baseline) in g-ddY mice, after approximately 5 days of treatment with atrasentan at 0 (control), 10, 20 or 30 mg/kg/day in drinking water. (*P <0.05 compared to control group (0 mg/kg/day), unpaired t-test).

[035] Figure 6 illustrates the top 100 genes differentially expressed in kidney tissue after treatment of g-ddY mice with atrasentan at 0 (control), 10, 20 or 30 mg/kg/day. The heatmap shows z-transformed counts per line per million (CPM) values for each of the top 100 differentially expressed genes.

[036] Figure 7A illustrates differential gene expression in kidney tissue after treatment of g-ddY mice with atrasentan at 0 (control) and 10 mg/kg/day. Black dots indicate genes not significantly differentially expressed. Gray dots above log 0 modulation indicate upregulated genes. Gray dots below log 0 modulation indicate downregulated genes.

[037] Figure 7B illustrates differential gene expression in kidney tissue after treatment of g-ddY mice with atrasentan at 0 (control) and 20 mg/kg/day. Black dots indicate genes not significantly differentially expressed. Gray dots above log 0 modulation indicate upregulated genes. Gray dots below log 0 modulation indicate downregulated genes.

[038] Figure 7C illustrates differential gene expression in kidney tissue after treatment of g-ddY mice with atrasentan at 0 (control) and 30 mg/kg/day. Black dots indicate genes not significantly differentially expressed. Gray dots above log 0 modulation indicate upregulated genes. Gray dots below log 0 modulation indicate downregulated genes.

[039] Figure 8A illustrates genes differentially expressed in kidney tissue in a subset of genes associated with an ET1 gene signature after treatment of g-ddY mice with atrasentan at 0 (control) and 10 mg/kg/day.

[040] Figure 8B illustrates genes differentially expressed in kidney tissue in a subset of genes associated with an ET1 gene signature after treatment of g-ddY mice with atrasentan at 0 (control) and 20 mg/kg/day.

[041] Figure 8C illustrates genes differentially expressed in kidney tissue for a subset of genes associated with an ET1 gene signature following treatment of g-ddY mice with atrasentan at 0 (control) and 30 mg/kg/day.

[042] Figure 9A illustrates the significantly enriched characteristic gene sets (FDR <0.05) after treatment of g-ddY mice with atrasentan 10 mg/kg/day compared to atrasentan treatment at 0 mg/kg/day day (control). Negative normalized enrichment score (NES) indicates underexpression and positive NES indicates overexpression.

[043] Figure 9B illustrates the significantly enriched (FDR <0.05) landmark gene sets following treatment of g-ddY mice with atrasentan 20 mg/kg/day compared to atrasentan treatment at 0 mg/kg/day day (control). Negative normalized enrichment score (NES) indicates underexpression and positive NES indicates overexpression.

[044] Figure 9C illustrates the significantly enriched (FDR <0.05) landmark gene sets following treatment of g-ddY mice with atrasentan 30 mg/kg/day compared to atrasentan treatment at 0 mg/kg/day day (control). Negative normalized enrichment score (NES) indicates underexpression and positive NES indicates overexpression.

[045] Figure 10 illustrates pathway concordance of the set of significantly enriched landmark genes (FDR <0.05) following treatment of g-ddY mice with 10, 20 or 30 mg/kg/day compared to atrasentan at 0 (control), after treatment ET-1 stimulated HRMC with atrasentan at 1 nm and 25 nm, and ET-1 stimulated HRMC compared to untreated HRMC (control).

[046] Figure 11A illustrates the overlap in gene signature between the published human mesangial single cell signature (Lake et al., A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat. Com. , 10(1), 1-15 (2018); labeled as mesangial), genes differentially expressed after treatment of g-ddY mice with atrasentan at 30 mg/kg/day (labeled as g-ddY) and genes differentially expressed after treatment of HRMC with atrasentan at 25 nm in the presence of ET1 (labeled as HRMC).

[047] Figure 11B illustrates the expression levels (z-transformed values per row of log2 counts per million) of 44 genes overlapping between the human mesangial single cell signature and differentially expressed genes following treatment of g-ddY mice with atrasentan at 30 mg/kg/day.

[048] Figure 12A illustrates a comparison between potential human- and mouse-based biomarkers with an “x” indicating translatability and whether the potential biomarker is in plasma/serum and/or urine. Notably, each of the relevant markers is found in humans and mice (e.g., g-ddY mice).

[049] Figure 12B illustrates log2(CPM) for each potential biomarker after treating g-ddY mice with atrasentan at 0 (control), 10, 20 or 30 mg/kg/day.

[050] Table 1 Top 40 DEGs (25 upregulated and 15 downregulated) in the treatment of g-ddY mice with atrasentan at 10 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[051] Table 2 Top 50 DEGs (25 upregulated and 25 downregulated) in the treatment of g-ddY mice with atrasentan at 20 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[052] Table 3 Top 50 DEGs (25 upregulated and 25 downregulated) in the treatment of g-ddY mice with atrasentan at 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[053] Table 4 Signaling pathways enriched after treatment of g-ddY mice with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control). Z score values indicate the magnitude of effect observed at each dosage.

[054] Table 5 Gene Set Enrichment Analysis showing enrichment in characteristic gene sets after treatment of g-ddY mice with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg /day (control). NES is the normalized enrichment score that indicates the representation of DEGs in the gene set and is responsible for the size of the gene set. NES of <-1.5 or >1.5 is considered biologically significant. The adjusted p-value is the estimated probability that the calculated NES of the given enriched gene set is a false positive result.

[055] Table 6 lists upstream regulators grouped by molecular types of cytokine and growth factor. The overlap p-value indicates the significance of enrichment based on the number of overlapping genes between the dataset and the gene targets in IPKB. Activation z-score threshold <-2 or >2 and overlap threshold p-value <0.05 were considered significant.

[056] Table 7 List of upstream regulators grouped by transmembrane receptor, G protein-coupled receptor and molecular types of protein complexes. The overlap p-value indicates the significance of enrichment based on the number of overlapping genes between the dataset and the gene targets in IPKB. Activation z-score threshold <-2 or >2 and overlap threshold p-value <0.05 were considered significant.

[057] Table 8 List of upstream regulators grouped by transcription regulator and molecular types of ligand-dependent nuclear receptors. The overlap p-value indicates the significance of enrichment based on the number of overlapping genes between the dataset and the gene targets in IPKB. Activation z-score threshold <-2 or >2 and overlap threshold p-value <0.05 were considered significant.

[058] Table 9 Gene expression of components of NF-kB signaling pathways after treatment of g-ddY mice with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control ).

[059] Table 10 Gene expression of components of IL6 signaling pathways after treatment of g-ddY mice with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[060] Table 11 Gene expression of components of the PDGF signaling pathways after treatment of g-ddY mice with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[061] Table 12 Gene expression of components of cell proliferation signaling pathways (mitotic spindle and G2M cell cycle checkpoint) after g-ddY treatment with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[062] Table 13 Gene expression of components of the inflammatory response signaling pathways after g-ddY treatment with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

[063] Table 14 Gene expression of the 44 genes associated with the mesangial cell signature after g-ddY treatment with atrasentan at 10, 20 or 30 mg/kg/day compared to atrasentan at 0 mg/kg/day (control).

DETAILED DESCRIPTION A. DEFINITIONS

[064] So that the present disclosure can be more easily understood, certain terms are defined first. As used in this order, except as expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the order.

[065] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by one skilled in the art to which this disclosure relates. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cellular and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide a specialist with a general dictionary of many of the terms used in this disclosure. For purposes of this disclosure, the following terms are defined.

[066] Units, prefixes and symbols are indicated in their form accepted by the Système International de Unites (SI). Numeric ranges include the numbers that define the range. The headings provided herein are not limitations on the various aspects of the disclosure, which may be obtained by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[067] The terms “a”, “an” or “the” used herein not only include aspects with one member, but also include aspects with more than one member. As used in this document, the singular forms “a”, “a”, “the/a” include their plural inflections, unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so on.

[068] The term “or” as used herein should generally be interpreted non-exclusively. For example, a claim to “a composition comprising A or B” would normally present an aspect with a composition comprising A and B. “Or” should, however, be interpreted to exclude those aspects presented that cannot be combined without contradiction (e.g. example, a composition pH that is between 9 and 10 or between 7 and 8).

[069] The group “A or B” is typically equivalent to the group “selected from the group consisting of A and B”.

[070] The term “and/or” when used in this document should be considered as specific disclosure of each of the two specified features or components with or without the other. Therefore, the term “and/or” used in a phrase such as “A and/or B” in this document is intended to include “A and B”, “A or B”, “A” (alone) and “B” (alone) . Likewise, the term “and/or” as used in a phrase such as “A, B and/or C” is intended to encompass each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[071] The terms “about” and “approximately”, as used herein, generally mean an acceptable degree of error for the measured quantity, given the nature or precision of the measurements. Typical and exemplary degrees of error are within 20 percent (%), within 10%, or within 5% of a given value or range of values. Any reference to “about X” specifically indicates at least the values 04X and 1.05X. Thus, “about X” is intended to provide written descriptive support for a claim limitation of, for example, “0.98X.” The terms “about” and “approximately”, particularly in reference to a given quantity, encompass and describe the given quantity itself.

[072] When “about” is applied to the beginning of a numeric range, it applies to both ends of the range. Thus, “from about 5 to 20%” is equivalent to “from about 5% to about 20%”. When “about” is applied to the first value in a set of values, it applies to all values in that set. Thus, “about 0.5, 0.75 or 1.0 mg” is equivalent to “about 0.5, about 0.75 or about 1.0 mg”.

[073] As used herein, the term “about”, when preceding a series of peak positions for powder X-ray diffraction (e.g., 2θ values), means that all peaks of the preceding group are reported in terms of angular positions with a variability of ±0.1°. Thus, for example, the phrase about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2° or 19.5° means 8.3° ± 0 .1°, 9.7° ± 0.1°, 10.0° ± 0.1°, 13.0° ± 0.1°, 15.6° ± 0.1°, 17.2° ± 0 .1° or 19.5°+ 0.1°.

[074] “Treatment” or “therapy” of a subject refers to any type of intervention or process performed or the administration of an active agent to the subject with the aim of reversing, alleviating, improving, inhibiting or delaying the onset, progression , development, severity or recurrence of a symptom, complication, condition or biochemical signs associated with a disease.

[075] “Administer” or “administration” refers to the physical introduction of a therapeutic agent to a subject, using any of several methods and delivery systems known to those skilled in the art. Routes of administration may include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example, by injection or infusion (e.g., intravenous infusion). Administration may also be carried out, for example, once, several times and/or for one or more prolonged periods.

[076] The term “prophylactic” or “prophylactically” refers to any type of intervention or process performed or the administration of an active agent to the subject with the aim of protecting or preventing the development of a disease or condition or, at least , of not developing fully (e.g., to reduce the symptoms or severity of the disease or condition), as in developing a side effect.

[077] A “subject” includes any human or non-human animal. The term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms “subject” and “patient” and “individual” are used interchangeably in this document.

[078] An “effective amount” or “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, delays the onset of a disease or promotes regression of the disease evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods of the disease, or an improvement of an impairment or disability due to the affliction of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled artisan, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by testing the agent's activity in in vitro assays.

[079] The phrase “pharmaceutically acceptable” indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that comprise a formulation and/or the mammal to be treated with it.

[080] As used herein, “polymorphs” refer to distinct solids that share the same molecular formula, but each polymorph may have distinct solid state physical properties. A single compound can give rise to a variety of polymorphic forms in which each form has different and distinct solid-state physical properties, such as different solubility profiles, melting point temperatures, fluidity, dissolution rates, and/or different diffraction peaks. These practical physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which define a particular polymorphic form of a substance. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy, such as X-ray powder diffraction (“XRPD”), and by other methods, such as infrared spectroscopy. Furthermore, polymorphic forms of the same drug substance or active pharmaceutical ingredient can be administered alone or formulated as a drug (pharmaceutical composition) and are well known in the pharmaceutical art to affect, for example, solubility, stability, fluidity, treatability and compressibility of medicinal substances and the safety and efficacy of drugs. For more, see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH 2006.

[081] As used herein, the term “amorphous” means a solid in a solid state that is a non-crystalline state. Amorphous solids generally have short-range molecular arrangement similar to crystals, but not long-range molecular packing order as found in crystalline solids. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those skilled in the art.

[082] As used herein, the term “crystalline” means a solid in a solid state with a regularly repeating arrangement of molecules or external face planes. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those skilled in the art. Accordingly, the term "crystalline purity" as used herein means the percentage of a certain crystalline polymorph of atrasentan or pharmaceutically acceptable salt thereof in a sample that may contain amorphous atrasentan or a pharmaceutically acceptable salt thereof, one or more polymorphs. additional crystalline atrasentan or a pharmaceutically acceptable salt thereof or mixtures thereof. When a crystalline polymorph of atrasentan or a pharmaceutically acceptable salt thereof is described as having “substantial crystalline purity,” it means that the polymorph is substantially free (e.g., contains <10%, <5%, <2%, <1 %, <0.5%, <0.1% or <0.05%) of other polymorphs (amorphous and/or crystalline).

[083] The term “chemical purity”, as used herein, means the percentage of a certain compound (for example, atrasentan or a pharmaceutically acceptable salt thereof) in a sample. Accordingly, atrasentan or a pharmaceutically acceptable salt thereof and compositions comprising or made therefrom may contain one or more impurities, including, but not limited to: water, ethyl acetate, ethanol, acid (2R,3R,4S)- 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R,3R,4S)- 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((N-(n-butyl)-N-ethyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, (2R, 4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine or ethyl(2R,3R,4S )-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate. When a sample of atrasentan or a pharmaceutically acceptable salt thereof is described as having “substantial purity,” the sample is substantially free of impurities (e.g., contains <10%, <5%, <2%, <1%, <0.5%, <0.1% or <0.05%).

[084] The term “diastereomeric excess”, as used herein, means the amount of a diastereomer of a compound (for example, atrasentan or a pharmaceutically acceptable salt thereof) in a mixture that may have other diastereomers of the same compound in the mixture. The term “substantial diastereomeric purity” as used herein means diastereomeric excess greater than about 90%, 95%, 99%, 99.5%, 99.9% or 100%.

[085] As used herein, the term “pharmaceutically acceptable carrier” refers to a substance that assists in the administration of an active agent to a cell, an organism or a subject. “Pharmaceutically acceptable carrier” refers to a carrier or excipient that can be included in the compositions of the disclosure and that does not cause any significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline solutions, Ringer's lactate, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic and absorption delaying agents and the like. The carrier may also be substances to impart stability, sterility and isotonicity to the formulation (e.g. antimicrobial preservatives, antioxidants, chelating agents and buffers), to prevent the action of microorganisms (e.g. antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like) or to provide the formulation with an edible flavor, etc. In some cases, the carrier is an agent that facilitates the delivery of a small drug molecule or antibody to a target cell or tissue. One of skill in the art will recognize that other pharmaceutical carriers are useful in the present disclosure.

[086] The term “expression”, as used herein, refers to the level of protein or mRNA in a mammalian cell.

[087] The term “activity”, as used herein, refers to one or more activities of a protein, such as binding or enzymatic activity (e.g., one or more of phosphorylation, dephosphorylation, nuclear import, transcriptional activation, transcriptional repression and/or binding activity to a substrate or a binding partner).

[088] The term “IL-6 signaling”, as used herein, means the expression and/or activity of one or more proteins in a signaling pathway beginning with the activation of an IL-6 receptor and ending with the expression gene. Non-limiting examples of proteins in a signaling pathway beginning with activation of an IL-6 receptor and ending in gene expression include an IL-6 receptor, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF- kB, MAPK, Ras, Raf, MEK and ERK.

[089] The term “NF-kB signaling”, as used herein, means the expression and/or activity of one or more of IKKα, IKKβ, IkB and NF-kB and/or one or more genes positively regulated by the activity of NF-kB (e.g., one or more of TNF-α, IL-1, CAM, COX-2 and iNOS).

[090] The term “PDGF signaling”, as used herein, means the expression and/or activity of one or more PDGF receptors, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR , NAPDH oxidase, MAPK and cPLA2.

[091] The term “SGLT-2 inhibitor”, as used herein, refers to a compound that inhibits the Sodium Glucose Cotransporter-2 (SGLT-2). SGLT-2 inhibitors stop the reabsorption of glucose by the kidneys and thus exert a glucose-lowering effect. By increasing glycosuria independently of insulin, SGLT-2 inhibitors have been shown to treat type 2 diabetes and improve cardiovascular outcomes. See, Wright, 2001, Am. J. Physiol. Renal Physiol. 280: F10; and Scheen, 2018, Circ. Res. 122: 1439. In some embodiments, the term “SGLT-2 inhibitor” refers to compounds whose primary effect is inhibition of SGLT-2, but is not limited to compounds that only inhibit SGLT-2, including compounds that have activities other than SGLT-2 inhibition (e.g., SGLT-1 inhibition).

[092] In some embodiments, SGLT-2 inhibitors include compounds from a class of drugs known as gliflozins. In some embodiments, SGLT-2 inhibitors include compounds that are approved as SGLT-2 inhibitors by a regulatory agency such as the FDA or EMA. Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin , sergliflozin, licogliflozin, sotagliflozin (ZYNQUISTATM) and tofogliflozin.

[093] In some embodiments, SGLT-2 inhibitors include, but are not limited to dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3-(4- ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate and T-1095 etabonate (((2R,3S,4S ,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran- 2-il).

[094] In some embodiments, SGLT-2 inhibitors include C-glycosides, such as dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin (DWP-16001). In some embodiments, SGLT-2 inhibitors include C-glycosides with a bicyclic or spiropyran group, such as tofogliflozin, ertugliflozin, and henagliflozin (SHR-3824). In some embodiments, SGLT-2 inhibitors include C-glycosides that do not have a bicyclic or spiropyran group, such as dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), and enavogliflozin (DWP-16001).

[095] In some embodiments, SGLT-2 inhibitors include N-glycosides, such as TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole) and indole-N-glucoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole).

[096] In some embodiments, SGLT-2 inhibitors include 2-methylthio-C-glycosides, such as sotagliflozin.

[097] In some embodiments, SGLT-2 inhibitors include thiopyran-C-glycosides, such as luseogliflozin.

[098] In some embodiments, SGLT-2 inhibitors include O-glycosides and O-glycoside prodrugs, such as sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 etabonate ((( 2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro -2H-pyran-2-yl).

[099] In some embodiments, an SGLT-2 inhibitor, as defined herein, includes any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, an SGLT-2 inhibitor is selective for SGLT-2 over SGLT-1, e.g., by having about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold , about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 750 times, about 1,000 times, about 1,250 times, about 1,500 times, about 1,750 times , about 2,000 times, about 2,500 times, or anywhere in between, greater activity against SGLT-2 than against SGLT-1. Exemplary SGLT-2 inhibitors may exhibit inhibitory activity (IC50) against SGLT-2 of less than about 1,000 nm, less than about 500 nm, less than about 200 nm, less than about 100 nm, less than about 50 nm, less than about 25 nm, less than about 10 nm, or less than about 1 nm as measured in an assay as described herein. In some embodiments, SGLT-2 inhibitors may exhibit inhibitory activity (IC50) against SGLT-2 of less than about 25 nm, less than about 10 nm, less than about 5 nm, or less than about 1 nm as per measured in an assay as provided herein. An exemplary assay for determining SGLT-2 inhibitory activity is described in Ryan, et al., Kidney International, Vol. 45, pages 48-57 (1994). Briefly, CHO cells are stably transfected with cDNA encoding human SGLT-2 (GenBank no. M95549). Cells are washed and then incubated with 10 μM [14C]alpha-methyl glucopyranoside (AMG) and 10 μM inhibitor. The uptake of [14C]AMG is quenched with cold buffer containing phlorizin and the cells are lysed. Suitable reagents are then used to quantify [14C]AMG absorption.

[0100] SGLT-2 inhibitors include pharmaceutically acceptable salts, solvates, complexes and solvate salts thereof, for example, "dapagliflozin" includes salts of dapagliflozin (such as the hydrochloride salt) as well as solvates (such as propylene glycol hydrate ); Likewise, “canagliflozin” includes solvates (such as canagliflozin hemihydrate) and salts of solvates (such as the hydrochloride salt of the hydrate). Likewise, henagliflozin (SHR-3824) and dapagliflozin include complexes (such as henagliflozin proline and dapagliflozin proline complexes, respectively).

[0101] As used herein, when a subject is described as having “controlled serum glucose levels,” it means that the subject has a serum glucose level within normal or healthy ranges. In some embodiments, the subject has a fasting serum glucose level between about 70 mg/dl and about 130 mg/dl. For example, the subject was determined to have a fasting serum glucose level below about 130 mg/dl, 125 mg/dl, 120 mg/dl, 115 mg/dl, 110 mg/dl, 105 mg/dl, 100 mg/dl, 95 mg/dl, 90 mg/dl, 85 mg/dl, 80 mg/dl or 75 mg/dl.

[0102] As used in the methods described herein, the term “reduction” refers to a reduction in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in the subject taken prior to the start of administration with atrasentan or with a pharmaceutically acceptable salt thereof, or a reduction in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in a healthy subject (e.g., a subject who does not have IgA nephropathy). Likewise, the term “increase” as used herein refers to an increase in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in the subject taken prior to the start of administration with atrasentan or with a pharmaceutically acceptable salt thereof, or an increase in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in a healthy subject (e.g., a subject who does not have IgA nephropathy).

[0103] The term “glomerular filtration rate (GFR)” is defined as the volume of fluid filtered from the renal glomerular capillaries (kidneys) to the Bowman capsule per unit of time. It is indicative of overall kidney function. Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a constant level in the blood and is filtered freely but is not reabsorbed or secreted by the kidneys. The rate therefore measured is the amount of the substance in the urine that originated from a calculable volume of blood. GFR is normally recorded in units of volume per time, for example milliliters per minute and the formula below can be used: GFR=(Urine Concentration x Urine Volume)/Plasma Concentration. GFR can be determined by injecting inulin into the plasma. Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its excretion rate is directly proportional to the rate of filtration of water and solutes through the glomerular filter. A normal value is: GRF=90-125 ml/min/1.73 m2, in particular GRF=100-125 ml/min/1.73 m2. Other principles for determining GFR involve measuring 51Cr-EDTA, [125I]iothalamate, or iohexol. The “estimated glomerular filtration rate (eGFR)” is defined as derived in screening serum creatinine values based on, for example, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or Modification of Diet in Renal Disease (MDRD), which are all known in the art. “Stabilize eGFR” as used herein means reducing the rate of eGFR decline and/or attenuating the rate of eGFR decline. For example, the rate of eGFR decline can be attenuated by at least about 20%; by at least about 30%; by at least about 40%; by at least about 50%; by at least about 60%; by at least about 70%; by at least about 80%; by at least about 90%; or at least about 95%; or any intermediate value after treatment with atrasentan or a pharmaceutically acceptable salt thereof. This attenuation may be after treatment, for example, for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between. In some embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months and about 1 year.

[0104] “ESRD” is the abbreviation for end-stage renal disease. As used herein, the onset of ESRD is defined as the point in time when the subject has an eGFR of less than about 15 ml/min/1.73 m2 and/or when the subject begins chronic dialysis. When a subject is defined as “at high risk for progression to ESRD,” the subject has >1 g/day of urine protein and/or eGFR <60 for at least about 3 months prior to the first administration of atrasentan or a its pharmaceutically acceptable salt.

[0105] “Disease flares associated with IgA nephropathy,” as used herein, refer to disease flares associated with hematuria, worsening proteinuria, systemic manifestations, and declines in eGFR. Other symptoms associated with disease flares include: increased edema, fatigue, increased hematuria, macroscopic hematuria, and other symptoms that often negatively affect disease progression.

[0106] As used herein, when a subject is described to “maintain a potassium level within the normal physiological range,” the subject has a blood potassium level of about 3.5 mEq/l to about 5.2 mEq/l.

[0107] As used herein, when a subject is described to “maintain a sodium level within the normal physiological range,” the subject has a blood sodium level of about 135 to about 145 mEq/l.

[0108] As used herein, the term “proteinuria” refers to the presence of protein in the urine in excess of normal levels. “Proteinuria” includes “albuminuria” and “microalbuminuria”. Normal human levels of protein appear in urine in the range of about 0 to 30 mg/l, although for any given urine sample, the level can reach about 80 mg/l. For a 24-hour urine collection, normal human urinary protein levels are in the range of about 0 to 150 mg. Proteinuria may be indicated by the urine total protein/creatinine ratio (UPCR), or by the ratio of a specific protein, such as a urinary albumin/creatinine ratio (UPCR) greater than about 30 mg/g. Typically, the urinary UACR value in mg/g is approximately equal to the subject's albumin excretion in mg/day. Proteinuria, including albuminuria and microalbuminuria, often leads to or is indicative of a disease, but is not limited to the production of a disease. Proteinuria is intended to encompass all forms of proteinuria, including but not limited to physiologic proteinuria; functional proteinuria; and athletic proteinuria, which is related to a form of functional proteinuria after excessive muscular effort. Additionally, proteinuria encompasses benign proteinuria (also known as “essential” proteinuria), which refers to types or proteinuria that are not the result of pathological changes in the kidneys. Proteinuria also encompasses pathological proteinuria, for example, protein levels in the urine higher than normal physiological levels.

[0109] As used herein, the term “albuminuria” (also known as “macroalbuminuria”) refers to the presence of albumin in the urine in excess of normal levels. Since urinary protein is predominantly albumin, normal human urinary UACR levels are in the range of about 0 to 30 mg/mmol. As used herein, the term “microalbuminuria” refers to the presence of albumin in urine, excreted at a rate of about 20 to 200 μg/min or at a level of about 30 to 300 mg/l in humans. When defined by urinary ACR, “microalbuminuria” refers to a urinary UACR greater than about 30 mg/g, or a urinary UACR of about 3.5 mg/mmol or greater for women and about 2.5 mg /mmol or higher for men. Microalbuminuria is often an early warning of kidney disease, but it can also be present for other reasons.

[0110] As used herein, the term “hematuria” refers to the presence of blood in the urine. It may present as macroscopic hematuria (visible traces of blood cells) or microscopic hematuria (microscopic traces of blood) in the urine. A confirmed indication of microhematuria is defined as 3 or more red blood cells present per high-power microscopic field (HPF) in a minimum of 3 adequately collected urine samples. Microhematuria can also be detected by urine dipstick (colorimetric comparison estimation) in the clinic. Hematuria (microscopic or macroscopic) can be asymptomatic (no additional symptoms associated with hematuria) or symptomatic. Additional symptoms include dysuria (painful urination), a feeling of incomplete bladder emptying or increased frequency or urination, or flank pain.

[0111] “ALT”, as used herein, refers to alanine transaminase. “AST” as used herein refers to aspartate transaminase.

[0112] The term “synergy” or “synergistic” is used herein to mean that the effect of a combination of two or more therapeutic agents is greater than the sum of the effect of each agent when administered alone. See, for example, Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55. A “synergistically effective amount” is an amount of the combination of two or more therapeutic agents that results in a synergistic effect (as “synergistic” is defined herein). In some embodiments, a synergistically effective amount of a combination may be therapeutically effective even when one or more of the compounds in the combination are administered in a dose that would be subtherapeutic when the compound is administered alone.

[0113] It will be appreciated that different concentrations of each compound can be employed for various factors recognized in the art, for example, height, weight, sex, age and medical history of the patient. Exemplary synergistic effects include, but are not limited to, increased therapeutic efficacy, decreased dosage at equal or increased level of efficacy, reduced or delayed development of drug resistance, and simultaneous increase or equal therapeutic actions (e.g., the same therapeutic effect of at least one of the therapeutic agents) and a reduction in unwanted drug effects (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0114] In some embodiments, "synergistic effect", as used herein, refers to a combination of atrasentan or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents (e.g., an SGLT-inhibitor). 2), producing an effect, e.g., any of the beneficial or desired results, including clinical results as described herein, that is greater than the sum of the effect observed when atrasentan or a pharmaceutically acceptable salt thereof and the atrasentan inhibitor SGLT-2 are administered alone. Such clinical outcomes include, but are not limited to, treatment of IgA nephropathy, decreased renal inflammation and/or fibrosis, decreased hematuria, decreased proteinuria (e.g., albuminuria), stabilization of eGFR, decreased number of disease flares associated with IgA nephropathy, delay in the onset of ESRD, decreasing fatigue, reducing the activation of a mesangial cell.

[0115] In some embodiments, “synergistic effect”, as used herein, refers to a combination of atrasentan or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor, providing a greater reduction in proteinuria, such as as albuminuria, than the sum of the effect observed when atrasentan or a pharmaceutically acceptable salt thereof and the SGLT-2 inhibitor are administered alone.

[0116] In some embodiments, “synergistic effect”, as used herein, refers to a combination of atrasentan or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor, producing a desired therapeutic effect and a reduction on the occurrence and/or severity of an undesirable drug effect, side effect or adverse event. In some embodiments, the undesired drug effect, side effect or adverse event is associated with or observed in monotherapy of atrasentan or a pharmaceutically acceptable salt thereof or an SGLT-2 inhibitor. In some embodiments, the unwanted drug effect, side effect, or adverse event is one or more of fluid retention, anemia, nausea, constipation, thirst, bone fractures, increased urination, urinary tract infection, yeast infection, vaginal itching. , increased LDL cholesterol, increased brain natriuretic peptide (BNP) levels, acute sodium retention, and acute increases in creatinine levels. In some embodiments, fluid retention is associated with weight gain greater than about 3 kg. In some embodiments, the increased BNP levels are greater than about 300 pg/ml.

[0117] As described herein, any concentration range, percentage range, ratio range, or whole number range should be understood to include the value of any whole number within the recited range and, where appropriate, fractions thereof (such as one tenth and one hundredth of a whole number), except where indicated.

[0118] Unless otherwise indicated, any reference to an amount of atrasentan in this disclosure is based on the free equivalent weight of atrasentan. For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan in free form or an equivalent amount of a saline form of atrasentan.

[0119] Various aspects of the disclosure are described in more detail in the following subsections.

B. INTRODUCTION

[0120] Most individuals with IgAN first present with single or episodic macroscopic hematuria, or after detection of microscopic hematuria and/or proteinuria during routine urine testing. In some cases, individuals experience acute kidney injury as a result of increasing IgAN or macroscopic hematuria causing tubular obstruction. The definitive diagnosis of IgAN is typically established by renal biopsy, with immunofluorescence and/or immunoperoxidase studies for IgA deposits. Prominent globular deposits of IgA (sometimes accompanied by C3 and IgG) in the mesangium and less prominent along the glomerular capillary wall are a hallmark of IgAN. Certain histopathologic features that correlate with long-term outcome include mesangial proliferation, endocapillary proliferation, segmental scarring, and tubular atrophy.

C. TREATMENT METHODS

[0121] In a normal, healthy human kidney, ET-1 and ET-RA expressions are more intense in vascular tissue and less intense in glomerular structures. In contrast, individuals with IgAN show increased expressions of ET-1 and ET-RA in the kidney. In this population, ET-1 expression positively correlates with proteinuria, which is at least partially ameliorated by administration of ACE inhibitors. Indeed, current therapy for IgAN is optimization of antihypertensive and antiproteinuric agents (e.g., angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers), along with a course of corticosteroids, to inhibit the disease progression. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pages 137-148 (2017). However, these combinations of agents may have significant dose-limiting side effects, such as hyperkalemia, and additional immunosuppression may be necessary in more severe cases.

[0122] Clinically, IgAN is diagnosed by renal biopsy indicating the presence of mesangial cell proliferation and/or matrix expansion (or focal segmental glomerular sclerosis in advanced stages) with predominant mesangial granular deposits of IgA (2+ or more) in the immunofluorescence. This pathology is distinct from other progressive kidney diseases, such as diabetic nephropathy, which typically presents with diffuse thickening of the capillary basement membrane with peripheral hyaline PAS-positive nodules, with segmental or global glomerular sclerosis in advanced stages and thickened arterioles with hyaline deposits. See, for example, Zanatta, et al., Renal Failure, 34(3), pages 308-315 (2012).

[0123] Accordingly, in one aspect, there is provided herein a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0124] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with HIV/AIDS. In some embodiments, the subject has not been previously diagnosed with HIV-related nephropathy. In some embodiments, the subject has not been previously diagnosed with prostate cancer. In some embodiments, the subject has not been previously diagnosed with acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject has been previously diagnosed with diabetes and has not been previously diagnosed with diabetic nephropathy. In some embodiments, the subject has not been previously diagnosed with type 2 diabetes. In some embodiments, the subject has been previously diagnosed with type 2 diabetes. .

[0125] In some embodiments, the subject is not currently diagnosed with cancer. In some embodiments, the subject is not currently being treated for cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0126] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have diabetic nephropathy. In some embodiments, the subject does not have HIV/AIDS. In some embodiments, the subject does not have HIV-related nephropathy. In some embodiments, the subject does not have cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not have acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject has diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject does not have diabetes (i.e., type 1 or type 2 diabetes). In some embodiments, the subject has diabetes and does not have diabetic nephropathy. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject does not have type 2 diabetes. In some embodiments, the subject has type 2 diabetes and does not have diabetic nephropathy.

[0127] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from diabetic nephropathy. In some embodiments, the subject does not suffer from HIV/AIDS. In some embodiments, the subject does not suffer from HIV-related nephropathy. In some embodiments, the subject does not suffer from cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the subject does not suffer from acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject does not suffer from diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject suffers from diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject suffers from diabetes, such as type 1 diabetes or type 2 diabetes, but does not suffer from diabetic nephropathy. In some embodiments, the subject does not suffer from type 2 diabetes. In some embodiments, the subject suffers from type 2 diabetes. In some embodiments, the subject suffers from type 2 diabetes, but does not suffer from diabetic nephropathy.

[0128] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for HIV/AIDS. In some embodiments, the subject is not being treated for HIV-related nephropathy. In some embodiments, the subject is not being treated for prostate cancer. In some embodiments, the subject is not being treated for acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV/AIDS, HIV-related nephropathy, cancer, or acute renal failure. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the subject is not being treated for diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject is being treated for diabetes (i.e., Type 1 or Type 2 diabetes). In some embodiments, the subject is being treated for diabetes, such as type 1 diabetes or type 2 diabetes, but is not being treated for diabetic nephropathy. In some embodiments, the subject is not being treated for type 2 diabetes. In some embodiments, the subject is being treated for type 2 diabetes. diabetic.

[0129] In certain embodiments, it has been determined that the subject has controlled serum glucose levels. In some embodiments, the subject with controlled serum glucose levels is not being treated for diabetes. In some embodiments, the subject with controlled serum glucose levels is being treated for diabetes. In some embodiments, the subject with controlled serum glucose levels is not being treated for type 2 diabetes. In some embodiments, the subject with controlled serum glucose levels is being treated for type 2 diabetes. that the subject has controlled serum glucose levels; where the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure. For example, the subject was determined to have a fasting serum glucose level below about 130 mg/dl, about 125 mg/dl, about 120 mg/dl, about 115 mg/dl, about 110 mg/dl, about 105 mg/dl, about 100 mg/dl, about 95 mg/dl, about 90 mg/dl, about 85 mg/dl, about 80 mg/dl or about 75 mg /dl or any value in between. In certain embodiments, the subject has not been diagnosed with one or more HIV-related nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein; and the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have controlled serum glucose levels; and the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure.

[0130] In another aspect, provided herein is a method for decreasing renal inflammation and/or fibrosis in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need for the same.

[0131] In some embodiments, renal inflammation in the subject with IgA nephropathy is decreased by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In certain embodiments, renal inflammation in the subject is decreased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0132] In some embodiments, renal fibrosis in the subject with IgA nephropathy is decreased by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In certain embodiments, renal fibrosis in the subject is decreased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0133] In some embodiments, renal fibrosis in the subject with IgA nephropathy is decreased to less than about 50% of the cortical area of the affected kidney(s) after treatment with atrasentan or a pharmaceutically acceptable salt of the same (e.g. after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any amount in between). In certain embodiments, renal fibrosis in the subject is decreased to less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is decreased to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% or any value in between. of the cortical area. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0134] In another aspect, provided herein is a method for decreasing the occurrence of hematuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0135] In some embodiments, the number of urinary red blood cells per high power field (microscope) (rbc/hpf) in the subject with IgA nephropathy is decreased by at least about 10% after treatment with atrasentan or a pharmaceutically available salt. acceptable of the same (e.g. after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks , about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks , about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anywhere in between). In certain embodiments, the urinary rbc/hpf in the subject is decreased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%. , about 90% or about 95% or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0136] In another aspect, provided herein is a method of stabilizing eGFR, in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need.

[0137] In some embodiments, there is provided herein a method for reducing the rate of decrease in eGFR in a subject with IgA nephropathy, the method comprising administering, to a subject in need thereof, a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the rate of decrease in the subject's eGFR is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anywhere in between). In some embodiments, the rate of decrease in the subject's eGFR is reduced by at least about 20%; by at least about 30%; by at least about 40%; by at least about 50%; by at least about 60%; by at least about 70%; by at least about 80%; by at least about 90%; or at least about 95%; or any value in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months and about 1 year.

[0138] In some embodiments, the rate of decrease in eGFR of the subject with IgA nephropathy is reduced to less than about 10 ml/min/1.73 m2 after treatment with atrasentan or a pharmaceutically acceptable salt thereof. For example, after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any intermediate value. In certain embodiments, the rate of decrease in the subject's eGFR is reduced to less than about 9 ml/min/1.73 m2, about 8 ml/min/1.73 m2, about 7 ml/min/1, 73 m2, approximately 6 ml/min/1.73 m2, approximately 5 ml/min/1.73 m2, approximately 4 ml/min/1.73 m2, approximately 3 ml/min/1.73 m2 , about 2 ml/min/1.73 m2, about 1 ml/min/1.73 m2, or about 0.75 ml/min/1.73 m2 or anything in between after treatment with atrasentan or a salt pharmaceutically acceptable thereof, for about 6 months to about 1 year. The typical decline in eGFR with age, for example in a subject between about 20 to about 30 years of age, is about 1 ml/min/1.73 m2 per year.

[0139] In another aspect, provided herein is a method for decreasing the number of outbreaks of diseases associated with IgA nephropathy in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. to a person in need. In some modalities, the method reduces disease attacks associated with hematuria. In some modalities, the method reduces disease outbreaks associated with proteinuria. In some modalities, the method reduces flare-ups of diseases associated with IgA nephropathy that are associated with systemic manifestations. In some embodiments, the method decreases declines in eGFR as described elsewhere herein. In some embodiments, the method decreases one or more of edema, fatigue, hematuria, or gross hematuria. In some modalities, the method positively impacts the progression of the disease.

[0140] In another aspect, provided herein is a method for delaying the onset of ESRD in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0141] In some embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2. In certain embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 10%. For example, in some embodiments, the method increases the time between the subject's diagnosis of IgA nephropathy and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 20%. about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450% or about 500% or anything in between.

[0142] In certain embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 1 year. For example, the method may delay the time at which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 1.5 years, 2 years, 2.5 years, 3 years, 3, 5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5 years, 8 years, 8.5 years, 9 years, 9.5 years , 10 years, 11 years, 12 years, 13 years, 15 years, 15 years, 16 years, 17 years, 18 years, 19 years or 20 years.

[0143] In another aspect, provided herein is a method for decreasing proteinuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need.

[0144] In some embodiments, the amount of proteins (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by at least about 10% following treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks , about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks , about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anywhere in between) . In some embodiments, the amount of protein in the subject's urine is reduced by at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%. %, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95% or any value in between . In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0145] In certain embodiments, the amount of proteins (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by about 20% to about 80% after about 2 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by about 20% to about 80% after about 15 days and about 30 days of treatment with atrasentan or with a pharmaceutically acceptable salt thereof. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%. In the above-mentioned embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before initiating treatment with atrasentan, or one thereof. pharmaceutically acceptable salt.

[0146] In some embodiments, the amount of proteins (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by about 100 mg/dl to about 3000 mg/dl after treatment with atrasentan or a pharmaceutically acceptable salt of the same (e.g. after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value in between). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 2,500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 2000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 1500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 1,000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 400 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 300 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 200 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 2,500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 2,000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 1,500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 1000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 800 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1,000 mg/dl to about 2,000 mg/dl. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In the above-mentioned embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before initiating treatment with atrasentan, or one thereof. pharmaceutically acceptable salt.

[0147] In certain embodiments, the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by about 100 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan, or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 200 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. . In certain embodiments, the amount of protein in the subject's urine is reduced by about 300 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. . In the above-mentioned embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before initiating treatment with atrasentan, or one thereof. pharmaceutically acceptable salt.

[0148] In certain embodiments, the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is reduced by about 500 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan, or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. . In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. . In the above-mentioned embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before initiating treatment with atrasentan, or one thereof. pharmaceutically acceptable salt.

[0149] In some embodiments, the subject with IgA nephropathy has a reduced level of protein (e.g., albumin) in the urine below about 1.0 grams/day following treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g. example, after treatment for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks or 200 weeks). In certain embodiments, the subject has a reduced level of protein in the urine below about 0.9 grams/day. In certain embodiments, the subject has a reduced level of urine protein below about 0.8 grams/day. In certain embodiments, the subject has a reduced level of protein in the urine below about 0.7 grams/day. In certain embodiments, the subject has a reduced level of protein in the urine below about 0.6 grams/day. In certain embodiments, the subject has a reduced level of protein in the urine below about 0.5 grams/day. In certain embodiments, the subject has a reduced level of urine protein below about 0.4 grams/day. In certain embodiments, the subject has a reduced level of protein in the urine below about 0.3 grams/day. In certain embodiments, the subject has a reduced level of protein in the urine below about 0.2 grams/day. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In the above-mentioned embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of the subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before initiating treatment with atrasentan, or one thereof. pharmaceutically acceptable salt.

[0150] In another aspect, provided herein is a method for decreasing fatigue in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, it has been determined that the subject does not suffer from one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In certain embodiments, it has been determined that the subject does not suffer from diabetic nephropathy. In certain embodiments, it has been determined that the subject does not suffer from HIV-related neuropathy. In certain embodiments, it has been determined that the subject does not suffer from prostate cancer. In certain embodiments, it has been determined that the subject does not suffer from acute renal failure.

[0151] In some embodiments, the fatigue of the subject with IgA nephropathy is reduced by about 5% to about 80% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In certain embodiments, fatigue is reduced by about 20% to about 75%. In certain embodiments, fatigue is reduced by about 20% to about 70%. In certain embodiments, fatigue is reduced by about 20% to about 65%. In certain embodiments, fatigue is reduced by about 20% to about 60%. In certain embodiments, fatigue is reduced by about 20% to about 55%. In certain embodiments, fatigue is reduced by about 20% to about 50%. In certain embodiments, fatigue is reduced by about 20% to about 45%. In certain embodiments, fatigue is reduced by about 20% to about 40%. In certain embodiments, fatigue is reduced by about 20% to about 35%. In certain embodiments, fatigue is reduced by about 20% to about 30%. In certain embodiments, fatigue is reduced by about 30% to about 75%. In certain embodiments, fatigue is reduced by about 30% to about 70%. In certain embodiments, fatigue is reduced by about 30% to about 65%. In certain embodiments, fatigue is reduced by about 30% to about 60%. In certain embodiments, fatigue is reduced by about 30% to about 55%. In certain embodiments, fatigue is reduced by about 30% to about 50%. In certain embodiments, fatigue is reduced by about 30% to about 45%. In certain embodiments, fatigue is reduced by about 30% to about 40%. In certain embodiments, fatigue is reduced by about 40% to about 75%. In certain embodiments, fatigue is reduced by about 40% to about 70%. In certain embodiments, fatigue is reduced by about 40% to about 65%. In certain embodiments, fatigue is reduced by about 40% to about 60%. In certain embodiments, fatigue is reduced by about 40% to about 55%. In certain embodiments, fatigue is reduced by about 40% to about 50%. In certain embodiments, fatigue is reduced by about 50% to about 75%. In certain embodiments, fatigue is reduced by about 50% to about 70%. In certain embodiments, fatigue is reduced by about 50% to about 65%. In certain embodiments, fatigue is reduced by about 50% to about 60%. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In certain embodiments, the decrease in fatigue comprises a decrease in scores on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F Subscale, Vigor, and Global Affect, the May and Kline Adjective Checklist, the Pearson-Byars Fatigue Feeling Checklist, the Rhoten Fatigue Scale, the Fatigue and Anergy Chart, the Visual Analog Scale or Checklist of Individual Strength. In the aforementioned embodiments, the reduction in fatigue experienced by the subject with IgA nephropathy is relative to the fatigue experienced by the subject prior to initiation of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in fatigue comprises a decrease in the Brief Fatigue Inventory score.

SUBJECT SELECTION

[0152] The subject with IgA nephropathy as described elsewhere herein can be diagnosed using one or more methods known in the art. Non-limiting examples include: kidney biopsy, detection of galactose-deficient IgA (e.g., Gd-IgA1), detection of anti-glycan antibodies, detection of IgA immune complex deposition in the kidney, or a combination of any of the foregoing. In some embodiments, the diagnosis of IgA nephropathy comprises the detection of deposition of IgA immune complexes in the kidney. In certain embodiments, the diagnosis of IgA nephropathy comprises a renal biopsy. In certain embodiments, the diagnosis of IgA nephropathy comprises the detection of galactose-deficient IgA. In certain embodiments, the diagnosis of IgA nephropathy comprises the detection of antiglycan antibodies (e.g., KM55). In certain embodiments, the diagnosis of IgA nephropathy comprises a renal biopsy followed by detection of IgA immune complex deposition in the kidney (e.g., by light microscopy and/or immunofluorescence microscopy).

[0153] In some embodiments, the presence and/or level of a particular protein in a subject is determined prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, serum levels of Gd-IgA1, serum levels of autoantibodies specific to Gd-IgA1, and/or serum and/or urinary levels of IgA1-containing immune complexes. See, for example, Knoppova, et al., Front. Immunol., Vol. 17, art. 117 (2016), which is incorporated herein by reference in its entirety. In some embodiments, the subject has Gd-IgA levels at or above the 90th percentile prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has Gd-IgA levels at or above the 95th percentile prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Gd-IgA levels decrease below the 90th percentile after treatment with atrasentan or a pharmaceutically acceptable salt thereof, for about 6 months to 1 year.

[0154] In certain embodiments, the subject has mesangial cellularity in about >50% (e.g., about >60%, about >70%, or about >80%) of the glomeruli, wherein mesangial cellularity is defined as more than four mesangial cells in any mesangial area of a glomerulus. In certain embodiments, endocapillary hypercellularity is present in the subject, wherein endocapillary hypercellularity is defined as hypercellularity due to an increased number of cells within the glomerular capillary lumen. In certain embodiments, segmental sclerosis is present in the subject, wherein segmental sclerosis is defined as adhesion or sclerosis (obliteration of the capillary lumen by the matrix) in part but not all of the glomerular tuft. In certain embodiments, the subject has tubular atrophy/interstitial fibrosis of about >50% (e.g., about >60%, about >65%, about >70%, about >75%, or about >80 %) of cortical area, where tubular atrophy/interstitial fibrosis is defined as the estimated percentage of cortical area showing tubular atrophy or interstitial fibrosis. In certain embodiments, the subject has crescents present in the glomeruli. In some such embodiments, the subject has crescents present below about 25% (e.g., below about 20%, about 15%, about 10%, or about 5%) of the glomeruli. In certain embodiments, the subject has a MEST-C score of M1; E1; S1; T1 or T2; and/or C0 or C1 under the Oxford MEST-C classification system. The Oxford MEST-C classification system is defined in Kidney International (2009) 76, 546-556 and Nature Reviews Nephrology (2017) 13, 385-386, each of which is incorporated herein by reference in its entirety (see also: Kidney Research and Clinical Practice (2016) 35, 197-203; and IgA Nephropathy in Medscape (accessed November 4, 2019), each of which is incorporated herein by reference in its entirety).

[0155] In some embodiments, the subject is at high risk of progression to ESRD. In some such embodiments, the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject has a mean eGFR <60 ml/min/1.73 m2 (e.g., about <55, about <50, about <45, about <40, about <35) for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some such embodiments, the subject has eGFR >30 ml/min/1.73 m2 prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months , at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years or at least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may be excreting an average of about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1, 8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams. 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams or 7.5 grams or 10 grams , or any intermediate value, of urine protein per day for at least 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the subject is excreting an average of about 0.3 grams to about 2 grams of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 1.5 years, or at least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may be excreting from about 0.3 grams to 0.5 grams, from about 0.5 grams to 1 gram, from about 0.5 grams to 1.5 grams, from about 1 gram to 1, 5 grams or about 1.5 grams to 2 grams of protein in urine per day for at least 3 months.

[0158] In some embodiments, the subject is excreting at least about 1 gram of protein in urine per day in at least two of three consecutive measurements one year before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may excrete about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1 .9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams. 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams or 7.5 grams or 10 grams of protein, or any intermediate value, in the urine per day in at least two of three consecutive measurements one year before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the subject has a UACR value of at least about 300 mg/g for at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, e.g., 300 mg/g at about 5,000 mg/g. In some embodiments, the subject has a UACR value of about 800 mg/g for at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, e.g., 800 mg/g to about 5,000 mg/g. g. In some embodiments, the subject has a UACR value of at least about 500 mg/g, about 600 mg/g, about 700 mg/g, about 800 mg/g, about 900 mg/g, about of 1,000 mg/g, about 1,500 mg/g, about 2,000 mg/g, about 2,500 mg/g, about 3,000 mg/g, about 3,500 mg/g, about 4,000 mg/g, about 4,500 mg/g or about 5,000 mg/g or any value in between, for at least three months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the subject has a decrease in UACR value of at least about 30% relative to the subject's mean UACR value for at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt of the even, for example, a decrease of about 30% to about 100%, relative to the subject's mean UACR value for at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a decrease in UACR value of at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%. or about 100%, or any intermediate value, relative to the subject's mean UACR value for at least three months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with a decrease in UACR value also does not experience significant sodium retention and/or significant fluid retention. In some embodiments, significant fluid retention may be about 1 kg to about 4 kg over six weeks, e.g., about 4 kg, about 3.5 kg, about 3 kg, about 2 .5kg, about 2kg, about 1.5kg or about 1kg or anywhere in between over 6 weeks. In some embodiments, a subject with significant fluid retention exhibits clinical symptoms of edema.

[0161] In certain embodiments, the subject has an average eGFR of about 20 to about 90 ml/min/1.73 m2 for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. (e.g. about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years or about 2 years). For example, about 20 to about 50 ml/min/1.73 m2; about 30 to about 60 ml/min/1.73 m2; about 40 to about 70 ml/min/1.73 m2; about 50 to about 80 ml/min/1.73 m2; or about 60 to about 90 ml/min/1.73 m2; for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a mean eGFR <60 ml/min/1.73 m2 for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject has an average eGFR <55 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <50 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <45 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <40 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <35 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <25 ml/min/1.73 m2 for at least about 3 months. In certain embodiments, the subject has an average eGFR <20 ml/min/1.73 m2 for at least about 3 months. In some of the above embodiments, the subject has a mean eGFR between about 30 ml/min/1.73 m2 and about 60 ml/min/1.73 m2 for at least 3 months prior to administration of atrasentan or a salt. pharmaceutically acceptable thereof. For example, the subject may have an average eGFR between about 30 ml/min/1.73 m2 and about 55 ml/min/1.73 m2, between about 30 ml/min/1.73 m2 and about 50 ml/min/1.73 m2, between about 30 ml/min/1.73 m2 and about 45 ml/min/1.73 m2 or between about 30 ml/min/1.73 m2 and about 40 ml/min/1.73 m2.

[0162] In certain embodiments, the subject has an average eGFR of about 30 ml/min/1.73 m2 to about 45 ml/min/1.73 m2, e.g., about <45, about <40 , about <35 or about <30, for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years, or at least about 2 years ) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a mean eGFR of about 25 ml/min/1.73 m2 to about 75 ml/min/1.73 m2 for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, about 25 ml/min/1.73 m2, about 30 ml/min/1.73 m2, about 35 ml/min/1.73 m2, about 40 ml/min/1.73 m2 , about 45 ml/min/1.73 m2, about 50 ml/min/1.73 m2, about 55 ml/min/1.73 m2, about 60 ml/min/1.73 m2, about of 65 ml/min/1.73 m2, about 70 ml/min/1.73 m2, about 75 ml/min/1.73 m2 or anything in between for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the subject has an average HbA1c of about 4% to about 6% for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years, or at least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have an average HbA1c of about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5.0%, about 5, 2%, about 5.4%, about 5.6%, about 5.8% or about 6% or anything in between.

[0164] In some embodiments, the subject has an average fasting blood glucose level of about 125 mg/dl or less for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years or at least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have an average fasting blood glucose level of about 120 mg/dl, about 115 mg/dl, about 110 mg/dl, about 105 mg/dl, about 100 mg/dl. dl, about 95 mg/dl, about 90 mg/dl, about 85 mg/dl, about 80 mg/dl or about 75 mg/dl or anything in between.

[0165] In some embodiments, the subject maintains a potassium level within the normal physiological range. In certain embodiments, the subject maintains a potassium level within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years or at least least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject maintains a potassium level within 3.5 to 5.2 mEq/l. For example, the subject maintains an average potassium level of about 3.5 mEq/l, about 3.6 mEq/l, about 3.7 mEq/l, about 3.8 mEq/l, about 3.9, about mEq/l, about 4.0 mEq/l, about 4.1 mEq/l, about 4.2 mEq/l, about 4.3 mEq/l, about 4, 4 mEq/l, about 4.5 mEq/l, about 4.6 mEq/l, about 4.7 mEq/l, about 4.8 mEq/l, about 4.9 mEq/l, about 5.0 mEq/l, about 5.1 mEq/l or about 5.2 mEq/l or anything in between.

[0166] In some embodiments, the subject maintains a sodium level within the normal physiological range. In certain embodiments, the subject maintains a potassium level within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about a year, at least about 1.5 years or at least least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject maintains a sodium level within 135 to 145 mEq/l. For example, the subject maintains an average sodium level of about 135 mEq/l, about 136 mEq/l, about 137 mEq/l, about 138 mEq/l, about 139 mEq/l, about 140 mEq/l, about 141 mEq/l, about 142 mEq/l, about 143 mEq/l, about 144 mEq/l, about or 145 mEq/l, or anywhere in between.

[0167] In some embodiments, the subject has ALT/AST levels during administration of atrasentan or a pharmaceutically acceptable salt thereof that are approximately the same as ALT/AST levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject has ALT/AST levels during administration of atrasentan or a pharmaceutically acceptable salt thereof within about 25%, about 20%, about 15%, about 10%, about 5%. , about or 2.5% or any value between levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the subject has bilirubin levels during administration of atrasentan or a pharmaceutically acceptable salt thereof that are approximately the same as the bilirubin levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. same. For example, the subject has bilirubin levels during administration of atrasentan or a pharmaceutically acceptable salt thereof within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5%, or any amount therebetween, of the levels prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, fluid retention in the subject is manageable with diuretics (e.g., during treatment with atrasentan or a pharmaceutically acceptable salt thereof and/or prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof). ). For example, fluid retention may be less than about 3 kilograms (kg) of weight gain over 6 weeks. In some embodiments, fluid retention is less than about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg or any value between more than 6 weeks.

[0170] In some embodiments, the subject undergoes surgery and/or other regimens before, substantially at the same time or after administration of atrasentan or a pharmaceutically acceptable salt thereof, as disclosed herein. In some embodiments, the subject receives other chemical and/or biological therapeutic agents before, substantially at the same time or after administration of atrasentan or a pharmaceutically acceptable salt thereof as disclosed herein.

[0171] In some embodiments, the subject has received one or more inhibitors of the renin-angiotensin system for at least about 60 weeks prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has received one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 24 weeks, about 48 weeks, or about 60 weeks, or anywhere in between, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the subject has received a maximum tolerated stable dose of one or more inhibitors of the renin-angiotensin system. For example, the subject may be receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks. , about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks or about 50 weeks or anything in between, before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, one or more inhibitors of the renin-angiotensin system are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and aldosterone antagonists. For example, one or more inhibitors of the renin-angiotensin system may be ACE inhibitors, ARB, or a combination thereof, wherein the ACE inhibitor or ARB may be described anywhere herein. For example, the ACE inhibitor can be selected from: quinapril, fosinopril perindopril, captopril, enalapril, enalapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril , rescinamine and pivopril. For example, the ARB can be selected from: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0173] In some embodiments, the subject is also receiving one or more additional agents. In some embodiments, one or more additional agents are selected from calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids. In some embodiments, the dosage of one or more additional agents is decreased after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional agents are immunosuppressants.

[0174] In some embodiments, the subject is not currently receiving one or more additional agents. In certain embodiments, the subject has not used one or more additional agents for two or more weeks in the 6 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, one or more additional agents are selected from calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors and steroids.

[0176] In certain embodiments, one or more additional agents are steroids. For example, one or more additional agents may be selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine, and combinations of any of the foregoing.

[0177] In certain embodiments, one or more additional agents are aminoquinolines. For example, one or more additional agents may be hydroxychloroquine.

[0178] In some embodiments, the subject is receiving one or more additional agents at the time of treatment with atrasentan. In certain embodiments, the dosage of one or more additional agents is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks , 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks or 200 weeks of treatment). In some such embodiments, the dosage of one or more additional agents is decreased after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some of the above embodiments, the dosage of additional agent is decreased by about 10% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 15% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 20% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 25% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 30% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 35% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 40% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 45% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 50% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 55% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 60% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 65% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 70% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 75% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 80% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 85% to about 100%. In certain embodiments, the dosage of additional agent is decreased by about 90% to about 100%. In some of the above embodiments, the dosage of one or more additional agents is decreased after about 15 days to about 30 days (e.g., about 15 days, about 20 days, about 25 days, or about 30 days). treatment with atrasentan, or a pharmaceutically acceptable salt thereof. When the dosage of additional agent is decreased by 100% as described herein, the subject no longer requires additional agent.

[0179] In certain embodiments, the dosage of one or more steroids is decreased after treatment with atrasentan, or a pharmaceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the steroid dosage is decreased by about 10% to about 100% as described herein. In some embodiments, the dosage of prednisone, dexamethasone, hydrocortisone, cyclosporine, or a combination of any of the foregoing is reduced by about 10% to about 100% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0180] In certain embodiments, the dosage of one or more aminoquinolines is decreased after treatment with atrasentan, or a pharmaceutically acceptable salt thereof, for example, after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the aminoquinoline dosage is decreased by about 10% to about 100% as described herein. In some embodiments, the dosage of hydroxychloroquine is reduced by about 10% to about 100% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the subject is concomitantly receiving one or more additional therapeutic agents. The one or more additional therapeutic agents are described herein. For example, the subject is concomitantly receiving an inhibitor of one or more elements of the renin-angiotensin-aldosterone system. In certain embodiments, the subject is concomitantly receiving an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, fish oil, hydroxychloroquine or a combination of any of the above. In some of these embodiments, the subject is concomitantly receiving an SGLT-2 inhibitor. In some of these embodiments, the subject is concomitantly receiving an ACE inhibitor, an ARB, or a combination thereof. In certain embodiments, the subject is concomitantly receiving one or more statins, such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. In certain embodiments, the subject is concomitantly receiving one or more diuretics, such as hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinetazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methylclothiazide bemetanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone and amiloride. In certain embodiments, the subject is concomitantly receiving an SGLT-2 inhibitor, such as canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin. In certain embodiments, the subject is concomitantly receiving one or more ACE inhibitors, such as quinapril, fosinopril, perindopril, captopril, enalapril, enalapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep. , pentopril, moexipril, rescinamine and pivopril. In certain embodiments, the subject is concurrently receiving an ARB, such as candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657. In certain embodiments, the subject is concomitantly receiving a diuretic and an ACE inhibitor or an ARB. In certain embodiments, the subject is concomitantly receiving a diuretic, an ACE inhibitor, and an ARB. In certain embodiments, the subject is concomitantly receiving a diuretic and an SGLT-2 inhibitor and an ACE inhibitor or an ARB. In certain embodiments, the subject is concomitantly receiving a diuretic, an SGLT-2 inhibitor, an ACE inhibitor, and an ARB. In certain embodiments, the subject concomitantly receiving one or more additional therapeutic agents has not previously received one or more therapeutic agents. For example, a subject who is concomitantly receiving an SGLT-2 inhibitor who has not previously received an SGLT-2 inhibitor.

[0182] In some embodiments, the subject has previously received, but is not concomitantly receiving, one or more additional therapeutic agents, such as those described herein. For example, the subject has previously received, but is not concomitantly receiving, an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist, oil of fish, hydroxychloroquine or a combination of any of the above as described herein. In some of these embodiments, the subject has previously received, but is not concomitantly receiving, an SGLT-2 inhibitor.

[0183] In some embodiments, the subject has cellular glomerular crescents present in about <25% of the glomeruli within 6 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have cellular glomerular crescents present in about 25%, about 20%, about 15%, about 10%, about 5% or about 1% or any intermediate amount of glomeruli. In some embodiments, the subject does not have cellular glomerular crescents present in the glomeruli. In certain embodiments, the subject is not under clinical suspicion of rapidly progressive glomerulonephritis (RPGN).

[0184] In some embodiments, the subject has not undergone organ transplantation prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the subject has a systolic blood pressure of less than about 160 mmHg prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have a systolic blood pressure of less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 mmHg. In some embodiments, the subject has a diastolic blood pressure of less than about 100 mmHg prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject may have a diastolic blood pressure of less than about 100 mmHg, less than about 95 mmHg, or less than about 90 mmHg. In some embodiments, the subject has a systolic blood pressure of between about 100 mm Hg and about 130 mm Hg and a diastolic blood pressure of about 70 mm Hg to about 90 mm Hg.

[0186] In some embodiments, the subject has not been diagnosed with heart failure prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not previously been admitted to the hospital for conditions related to fluid overload prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. Non-limiting examples of conditions include uncontrolled peripheral edema, pleural effusion, or ascites. In some embodiments, the subject has not been diagnosed with clinically significant liver disease prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's transaminase or bilirubin values are no more than twice the upper limit of normal prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the subject's ALT level is below about 110 U/l (e.g., below about 100 U/l, below 90 U/l, below about 80 U/l, below about below about 70 U/l, below about 60 U/l, below about 50 U/l, or below about 40 U/l or any value in between). As another example, the subject's AST level is below 100 U/l (e.g., below 90 U/l, below about 80 U/l, below about 70 U/l, below about 60 U/l, below about 50 U/l, or below about 40 U/l or anything in between). As yet another example, the subject's bilirubin level is below about 2.5 mg/dl (e.g., below about 2 mg/dl, below about 1.5 mg/dl, below about 1.4 mg/dl, below about 1.3 mg/dl, below about 1.2 mg/dl, below about 1.1 mg/dl, below about 1.0 mg/dl or below about 0.9 mg/dl or anywhere in between).

[0187] In some embodiments, the subject has a hemoglobin level above about 9 g/dl (e.g., above about 10 g/dl, about 11 g/dl, about 12 g/dl, or about of 13 g/dl or any value between) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not received a blood transfusion for anemia for at least about 3 months (e.g., at least about 4 months, about 5 months, about 6 months, or about a year) before the first administration. of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer (e.g., lung cancer or prostate cancer) for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been diagnosed with cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not have cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject does not suffer from cancer prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, the subject is not being treated for cancer for at least 5 years prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment.

[0188] In some embodiments of the methods, uses or products for uses herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. In some embodiments of the methods, uses, or products for uses herein, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, cancer (e.g., prostate cancer or lung cancer) or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, cancer (e.g., lung cancer or prostate cancer), or acute renal failure. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy. In certain embodiments, the subject has not been previously diagnosed with HIV/AIDS. In certain embodiments, the subject has not been previously diagnosed with acute renal failure. In certain embodiments, the subject has not been previously diagnosed with HIV-related nephropathy. In certain embodiments, the subject has not been diagnosed with cancer. In certain embodiments, the subject has not been diagnosed with prostate cancer. In certain embodiments, the subject has not been diagnosed with lung cancer. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy, HIV/AIDS, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy, HIV/AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject has not been previously diagnosed with diabetic nephropathy, HIV-related nephropathy, and acute renal failure. In some embodiments of the methods, uses, or products for uses herein, the subject has not been previously diagnosed with diabetes. In some embodiments of the methods, uses, or products for uses herein, the subject has not been previously diagnosed with type 2 diabetes. In some of the foregoing embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere in this document.

[0189] In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV/AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not have one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy. In certain embodiments, the subject does not have HIV/AIDS. In certain embodiments, the subject does not have acute renal failure. In certain embodiments, the subject does not have HIV-related nephropathy. In certain embodiments, the subject does not have prostate cancer. In certain embodiments, the subject does not have diabetic nephropathy, HIV/AIDS, and acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy, HIV/AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not have diabetic nephropathy, HIV-related nephropathy, and acute renal failure. In some embodiments, the subject does not have diabetes. In some embodiments, the subject does not have type 2 diabetes. In some of the foregoing embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein.

[0190] In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject does not suffer from one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy. In certain embodiments, the subject does not suffer from HIV/AIDS. In certain embodiments, the subject does not suffer from acute renal failure. In certain embodiments, the subject does not suffer from HIV-related nephropathy. In certain embodiments, the subject does not suffer from prostate cancer. In certain embodiments, the subject does not suffer from diabetic nephropathy, HIV/AIDS, and acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy, HIV/AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject does not suffer from diabetic nephropathy, HIV-related nephropathy, and acute renal failure. In some embodiments, the subject does not suffer from diabetes. In some embodiments, the subject does not suffer from type 2 diabetes. In some of the foregoing embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein.

[0191] In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV/AIDS, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV/AIDS, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure. In some embodiments, the subject is not being treated for one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy. In certain embodiments, the subject is not being treated for HIV/AIDS. In certain embodiments, the subject is not being treated for acute renal failure. In certain embodiments, the subject is not being treated for HIV-related nephropathy. In certain embodiments, the subject is not being treated for prostate cancer. In certain embodiments, the subject is not being treated for diabetic nephropathy, HIV/AIDS, and acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy, HIV/AIDS, prostate cancer, and acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy, HIV-related nephropathy, prostate cancer, and acute renal failure. In certain embodiments, the subject is not being treated for diabetic nephropathy, HIV-related nephropathy, and acute renal failure. In some embodiments, the subject is not being treated for diabetes. In some embodiments, the subject is not being treated for type 2 diabetes. In some of the above embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein.

[0192] In some embodiments, it has been determined that the subject has controlled serum glucose levels; or the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have controlled serum glucose levels. For example, the subject was determined to have a fasting serum glucose level below about 130 mg/dl, about 125 mg/dl, about 120 mg/dl, about 115 mg/dl, about 110 mg/dl, about 105 mg/dl, about 100 mg/dl, about 95 mg/dl, about 90 mg/dl, about 85 mg/dl, about 80 mg/dl or about 75 mg /dl or any value in between. In certain embodiments, the subject has not been diagnosed with one or more HIV-related nephropathy or acute renal failure. In certain embodiments, the subject has been determined to have controlled serum glucose levels as described elsewhere herein; and the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure.

[0193] In some embodiments, the subject has not been previously diagnosed with a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy determined not to be associated with IgA nephropathy. In certain embodiments, the subject has not been previously diagnosed with diabetic kidney disease. In certain embodiments, the subject has not been previously diagnosed with a hypertensive kidney disease. In certain embodiments, the subject has not been diagnosed with a primary glomerulopathy that is determined not to be associated with IgA nephropathy.

[0194] In some embodiments, the subject does not have a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy determined not to be associated with IgA nephropathy. In certain embodiments, the subject does not have diabetic kidney disease. In certain embodiments, the subject does not have hypertensive kidney disease. In certain embodiments, the subject does not have a primary glomerulopathy that is determined not to be associated with IgA nephropathy.

[0195] In some embodiments, the subject does not suffer from a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy determined not to be associated with IgA nephropathy. In certain embodiments, the subject does not suffer from diabetic kidney disease. In certain embodiments, the subject does not suffer from a hypertensive kidney disease. In certain embodiments, the subject does not suffer from a primary glomerulopathy that is determined not to be associated with IgA nephropathy.

[0196] In some embodiments, the subject is not being treated for a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or a primary glomerulopathy determined not to be associated with IgA nephropathy. In certain embodiments, the subject is not being treated for diabetic kidney disease. In certain embodiments, the subject is not being treated for a hypertensive kidney disease. In certain embodiments, the subject is not being treated for a primary glomerulopathy that is determined not to be associated with IgA nephropathy. TREATMENT RESULT

[0197] In some embodiments of the methods, uses or products for uses herein, renal inflammation is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal inflammation in the subject is decreased by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In some embodiments, renal inflammation in the subject is decreased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%. % or about 95% or any value in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0198] In some embodiments, renal fibrosis is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, renal fibrosis in the subject is decreased by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In certain embodiments, renal fibrosis in the subject is decreased by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%. % or about 95% or any value in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0199] In some embodiments, renal fibrosis in the subject is decreased to less than about 50% of the cortical area after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or anywhere in between). In certain embodiments, renal fibrosis in the subject is decreased to less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is decreased to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% or any value in between. of the cortical area. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0200] In some embodiments, the occurrence of hematuria is decreased in a subject after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the number of urinary red blood cells per high power field (microscope) (rbc/hpf) in the subject is decreased by at least about 10% following treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks , about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks , about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks). In certain embodiments, the urinary rbc/hpf in the subject is decreased by at least about 20%. For example, in some embodiments, the urinary rbc/hpf in the subject is decreased by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%. % or about 95% or any value in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0201] In some embodiments, the rate of decrease in the subject's eGFR is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, 2 weeks, 3 weeks , about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks , about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks , about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In certain embodiments, the rate of decrease in the subject's eGFR is reduced by at least about 20%. For example, in some embodiments, the rate of decrease in the subject's eGFR is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months and about 1 year.

[0202] In some embodiments, the rate of decrease in the subject's eGFR is reduced to less than about 10 ml/min per year after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In some embodiments, the rate of decrease in the subject's eGFR is reduced to less than about 9 ml/min per year. For example, in some embodiments, the rate of decrease in the subject's eGFR is reduced to less than about 8 ml/min per year, about 7 ml/min per year, about 6 ml/min per year, about 5 ml/min per year, about 4 ml/min per year, about 3 ml/min per year, about 2 ml/min per year or about 1 ml/min per year or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months and about 1 year.

[0203] In some embodiments, the subject's risk of developing ESRD is reduced by about 20% to about 99% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). For example, the subject's risk of developing ESRD may be reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about of 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 99% or any value in between. In some of the above embodiments, the subject has been treated for about 90 days to about 180 days. In certain embodiments, the subject's risk of developing ESRD is reduced by about 20% to about 99% after between about 90 and about 180 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for about 6 months and about 1 year.

[0204] In some embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below about 15 ml/min/1.73 m2. In certain embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 10%. For example, in some embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below about 15 ml/min/1.73 m2 by at least about 20 %, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100%, about 150 %, about 200%, about 250%, about 300%, about 350%, about 400%, about 450% or about 500% or any value in between.

[0205] In some embodiments, the method increases the time between the diagnosis of IgA nephropathy in the subject and the time in which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 1 year. For example, the method may delay the time at which the subject's eGFR falls below 15 ml/min/1.73 m2 by at least about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about 6.5 years, about 7 years, about 7.5 years, about 8 years, about 8.5 years, about 9 years, about 9.5 years, about 10 years, about 11 years, about 12 years, about 13 years, about 15 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years or about 20 years or anything in between.

[0206] In some embodiments, the method reduces the average rate of decrease in eGFR from about 0.75 ml/min/year to about 6 ml/min/year for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about of 11 months, at least about one year, at least about 1.5 years, or at least about 2 years) before the first administration of atrasentan or a pharmaceutically acceptable salt thereof. For example, the method reduces the average rate of decrease in eGFR by about 0.75 ml/min/year, about 1 ml/min/year, about 1.5 ml/min/year, about 2 ml/year min/year, about 2.5 ml/min/year, about 3 ml/min/year, about 3.5 ml/min/year, about 4 ml/min/year, about 4.5 ml /min/year, about 5 ml/min/year, about 5.5 ml/min/year or about 6 ml/min/year. In some embodiments, the method reduces the average rate of decrease in eGFR from about 4 ml/min/year to about 5 ml/min/year for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically available salt. acceptable of the same. In some embodiments, the method reduces the average rate of decrease in eGFR from about 3 ml/min/year to about 6 ml/min/year for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically available salt. acceptable of the same. In some embodiments, the method reduces the average rate of decrease in eGFR from about 4 ml/min/year to about 5 ml/min/year for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically available salt. acceptable of the same. In some embodiments, the decrease in eGFR in ml/min/year refers to units per 1.73 m2.

[0207] In some embodiments, the method reduces the average rate of decrease in eGFR from about 15% to about 30% after about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decrease in eGFR may be reduced by about 15% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decrease in eGFR may be reduced by about 20% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decrease in eGFR may be reduced by about 25% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the average rate of decrease in eGFR may be reduced by about 30% after about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0208] In another aspect, provided herein is a method for decreasing proteinuria, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0209] In some embodiments, the amount of proteins (e.g., albumin) in the subject's urine is reduced by at least about 10% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or anywhere in between). In some embodiments, the amount of protein in the subject's urine is reduced by at least about 15%. For example, in some embodiments, the amount of protein in the subject's urine is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0210] In certain embodiments, the amount of proteins (e.g., albumin) in the subject's urine is reduced by about 20% to about 80% after between about 15 days and about 30 days of treatment with atrasentan or with a pharmaceutically acceptable salt thereof. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the subject's urine is reduced by about 50% to about 80%.

[0211] In some embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg/dl to about 3000 mg/dl after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g. example, after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any intermediate value). In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 2500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 2000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 1500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 1000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 400 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 300 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 200 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 2500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 2000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 1500 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 1000 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 800 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg/dl to about 900 mg/dl. In certain embodiments, the amount of protein in the subject's urine is reduced by about 1000 mg/dl to about 2000 mg/dl. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0212] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 100 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 200 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. . In certain embodiments, the amount of protein in the subject's urine is reduced by about 300 mg/dl to about 500 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. .

[0213] In certain embodiments, the amount of protein (e.g., albumin) in the subject's urine is reduced by about 500 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of protein in the subject's urine is reduced by about 600 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt of atrasentan. same. In certain embodiments, the amount of protein in the subject's urine is reduced by about 700 mg/dl to about 900 mg/dl after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt of atrasentan. same.

[0214] In some embodiments, the subject has a reduced level of protein (e.g., albumin) in the urine below about 1.0 grams/day following treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., following treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks , about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks , about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks). In some embodiments, the subject has a reduced level of protein in the urine below about 0.9 grams/day. For example, in some embodiments, the subject has a reduced level of protein in the urine below about 0.8 grams/day, about 0.7 grams/day, about 0.6 grams/day, 0.5 grams /day, about 0.4 grams/day, about 0.3 grams/day or about 0.2 grams/day or anything in between. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days.

[0215] In some embodiments, the subject is between about 15 and about 40 years old. In some embodiments, the subject is between about 15 to about 25 years old, about 20 to about 30 years old, about 25 to about 35 years old, about 30 to about 40 years old, or any age in between. In some embodiments, the subject is between about 20 to about 30 years old or any age in between. In some embodiments, the subject is about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old. years old, about 29 years old or about 30 years old.

[0216] In some embodiments, the patient's level of fatigue is reduced after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, fatigue is reduced by about 5% to about 80% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anywhere in between). In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In some of the above embodiments, the subject has been treated with atrasentan or a pharmaceutically acceptable salt thereof for between about 15 days and about 30 days. In certain embodiments, the decrease in fatigue comprises a decrease in scores on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Brief Fatigue Inventory, the FACT-F Subscale, Vigor, and Global Affect, the May and Kline Adjective Checklist, the Pearson-Byars Fatigue Feeling Checklist, the Rhoten Fatigue Scale, the Fatigue and Anergy Chart, or the Individual Strength Checklist.

[0217] Some embodiments provide a method for inhibiting the activation of mesangial cells in a subject with IgA nephropathy, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0218] Some embodiments provide a method for inhibiting PDGF signaling activity (e.g., decreasing the expression and/or activity of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1) in a mesangial cell in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, to the subject; in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0219] Some embodiments provide a method for inhibiting the activation of mesangial cells, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, mesangial activation is induced by IgA immune complexes. In some embodiments, mesangial activation is associated with the presence of IgA immune complexes. The presence and/or amount of IgA immune complexes can be detected by a variety of methods. For example, complexes can be detected in serum or urine and can also be detected in a kidney biopsy sample.

[0221] In some embodiments, inhibition of mesangial cell activation comprises reducing the expression and/or activity of one or more biomarkers indicative of mesangial cell proliferation. In some embodiments, inhibiting mesangial cell activation comprises reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation comprises reducing the expression and/or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation comprises reducing IL-6 expression and/or activity. In some embodiments, the expression and/or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 99% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks , about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks , about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anywhere in between) . In some embodiments, the expression and/or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about from 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99% or anywhere in between. For example, in some of these embodiments, one or more biomarkers may be IL-6.

[0222] In some embodiments, inhibiting mesangial cell activation comprises reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation comprises reducing IL-6 signaling (e.g., reducing expression and/or activity in one or more proteins involved in an IL-6 signaling pathway, e.g., a reduction in the expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8 and Il1r1). In some embodiments, reducing mesanial cell inflammation comprises reducing the expression and/or activity of one or more (e.g., 1, 2, 3, 4, or 5) of: Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1.

[0223] In some embodiments, inhibition of mesangial cell activation comprises reducing the pro-fibrotic response in mesangial cells. In some embodiments, reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of NF-KB, TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis. . In some embodiments, the expression and/or activity of one or more of NF-kB, TGF, PDGF, CTGF, MMP, and TIMPS is reduced by about 25% to about 99% following treatment with atrasentan or a pharmaceutically acceptable salt of the same. (e.g. after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any intermediate value) with respect to expression and/or activity prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and/or activity of one or more of NF-KB, TGF, PDGF, CTGF, MMP and TIMPS is reduced by about 25% to about 50%, about 40% to about 60%. , about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or anything in between.

[0224] In some embodiments, inhibition of mesangial cell activation comprises reducing the pro-fibrotic response in mesangial cells. In some embodiments, reducing the pro-fibrotic response comprises reducing NF-kB signaling. In some embodiments, reducing the pro-fibrotic response comprises reducing the expression and/or activity of one or more (e.g., 1, 2, 3, 4, or 5) of: Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, and/or increasing the expression and/or activity of one or more (e.g., 1, 2, 3, 4, or 5) of: Ehd1, Snn, Tnfaip8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc1 (in cases where the component inhibits NF-kB signaling).

[0225] In some embodiments, reducing the pro-fibrotic response comprises reducing PDGF signaling. In some embodiments, reducing the pro-fibrotic response comprises reducing the expression and/or activity of one or more (e.g., 1, 2, 3, 4, or 5) of: Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, Pdgfb, Nfkb1 and/or increasing the expression and/or activity of one or more (e.g., 1, 2, 3, 4 or 5) of: Hras (in cases where the component inhibits PDGF signaling).

[0226] In some embodiments, the expression and/or activity of NF-kB and/or PDGF expression and/or activity is reduced by about 25% to about 99% after treatment with atrasentan or a pharmaceutically acceptable salt thereof. (e.g. after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any intermediate value), relative to expression and/or activity prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the expression and/or activity of NF-KB and/or PDGF is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%. , about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or anything in between.

[0227] In some embodiments, reducing the pro-fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells comprises reducing the expression and/or activity of one or more excess matrix secretion by mesangial cells.

[0228] Some embodiments provide a method for reducing the activation of a mesangial cell in contact with an IgA immune complex, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reducing the activation of a mesangial cell comprises reducing the expression and/or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0229] In some embodiments, reducing the activation of a mesangial cell comprises reducing inflammation of the mesangial cells. In some embodiments, reducing mesangial cell inflammation comprises reducing the expression and/or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation.

[0230] In some embodiments, reducing the activation of a mesangial cell comprises reducing the pro-fibrotic response in the mesangial cells. In some embodiments, reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0231] In some embodiments, reducing the pro-fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells comprises reducing the expression and/or activity of one or more biomarkers indicative of excess matrix secretion by mesangial cells.

[0232] In some embodiments, reductive activation of a mesangial cell comprises reducing unwanted migration of mesangial cells. In some embodiments, reduction in unwanted mesangial cell migration occurs after about 15 days to about 30 days after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reduction in unwanted mesangial cell migration occurs after about 3 months to about 6 months after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, reductive activation of a mesangial cell comprises reducing unwanted proliferation of mesangial cells. In some embodiments, reduction in unwanted mesangial cell proliferation occurs after about 15 days to about 30 days after treatment with atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, reduction in unwanted mesangial cell proliferation occurs after about 3 months to about 6 months after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 99% after treatment with atrasentan or a pharmaceutically acceptable salt thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between). In some embodiments, unwanted mesangial cell proliferation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99% or anything in between.

[0235] In some embodiments, mesangial cell activation can be assessed by one or more serum analyses, urinalysis, and microscopy of a renal biopsy sample (e.g., light microscopy and/or immunofluorescence microscopy).

[0236] In some embodiments, contact occurs in vitro. In some embodiments, contact occurs in vivo.

[0237] Some modalities provide a method of treating IgA nephropathy in a subject in need thereof, comprising: a) determining that the subject has elevated serum levels of Gd-IgA1; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-related nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0238] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, comprising: a) determining that the subject has high levels of mesangial activation; and b) administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to the subject.

[0239] In some embodiments, determining high levels of mesangial activation comprises obtaining a sample from the subject and evaluating the level of mesangial activation therein. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing.

[0240] In some embodiments, the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition, mesangial cell proliferation, and endocapillary cell proliferation. In some embodiments, the sample exhibits elevated levels of IgA immune complex deposition.

[0241] In some embodiments, the subject has been determined to have proteinuria of at least about 1 g/day in at least two of three consecutive readings over the year prior to administration of a therapeutically effective amount of atrasentan or a salt pharmaceutically acceptable thereof. For example, about 1 g/day, about 1.2 g/day, about 1.4 g/day, about 1.6 g/day, about 1.8 g/day, or about at least 2 g/day.

[0242] In some embodiments, the subject has received a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject concomitantly receives a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0243] In some embodiments, the subject has been determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the hematuria is microhematuria. In some embodiments, the hematuria is gross hematuria.

[0244] In some embodiments, the subject has been determined to have an eGFR of at least 30 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been determined to have an eGFR of about 30 ml/min/1.73 m2 to about 60 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or a salt pharmaceutically acceptable thereof.

[0245] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-related nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0246] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, comprising: a) determining that the subject has elevated levels of IgA immune complexes in the kidney; and b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, determining elevated levels of IgA immune complexes in the kidney comprises obtaining a sample from the subject and evaluating the level of IgA immune complexes therein. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing. In some embodiments, IgA immune complexes are deposited in the mesangium.

[0248] In some embodiments, IgA immune complex levels can be assessed by one or more serum analyses, urinalysis, and microscopy of a kidney biopsy sample (e.g., light microscopy and/or immunofluorescence microscopy).

[0249] In some embodiments, the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition in the mesangium, activation of mesangial cells, proliferation of mesangial cells, and proliferation of endocapillary cells.

[0250] In some embodiments, the subject has been determined to have proteinuria of at least about 1 g/day in at least two of three consecutive readings over the year prior to administration of a therapeutically effective amount of atrasentan or a salt pharmaceutically acceptable thereof. For example, about 1 g/day, about 1.2 g/day, about 1.4 g/day, about 1.6 g/day, about 1.8 g/day, or about at least 2 g/day.

[0251] In some embodiments, the subject has received a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject concomitantly receives a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0252] In some embodiments, the subject has been determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the hematuria is microhematuria. In some embodiments, the hematuria is gross hematuria.

[0253] In some embodiments, the subject has been determined to have an eGFR of at least 30 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been determined to have an eGFR of about 30 ml/min/1.73 m2 to about 60 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or a salt pharmaceutically acceptable thereof.

[0254] In some embodiments, the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. In some embodiments, the subject has not been previously diagnosed with HIV-related nephropathy. In some embodiments, the subject has not been previously diagnosed with cancer. In some embodiments, the cancer is lung cancer or prostate cancer.

[0255] In some embodiments, the methods include determining, in the subject, the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6 and NF-kB. In some embodiments, expression and/or activity are determined prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, expression and/or activity are determined following administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, determination of expression and/or activity is performed prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, determination of expression and/or activity is performed after administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or anything in between.

[0257] In some embodiments, it has been determined that the subject has elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL -6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb. In some embodiments, the subject has been determined to have elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF -kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1. In some embodiments, the subject has been determined to have elevated expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2 , Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra , Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb. In some embodiments, the subject has been determined to have elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF. -kB. In some embodiments, the subject has been determined to have elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19.

[0258] Some embodiments provide a method of treating IgA nephropathy in a subject, comprising: (a) determining that the subject has elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS , IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF- α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb; and (b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0259] Some embodiments provide a method of treating IgA nephropathy in a subject determined to have elevated expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN , ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb, comprising administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

D. ATRASENTAN

[0260] Atrasentan, also known as (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4- phenyl methoxy)pyrrolidine-3-carboxylic acid, ABT-627, A-147627 or A-127722, is a small molecule of the following chemical structure:

[0261] Atrasaentan and its preparation methods are described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. WO 1997/030045 (see, for example, Example 501), each of which is incorporated herein for reference in its entirety.

[0262] In some embodiments, atrasentan is administered as a free base. In some other embodiments, atrasentan is administered as a pharmaceutically acceptable salt as described elsewhere herein.

[0263] Atrasentan is an ETA inhibitor that is about 1860 times more selective for ETA compared to ETB. As used herein, “ETA” is the abbreviation for endothelin receptor A; and “ETB” is the abbreviation for endothelin B receptor. See, for example, Ann Rheum Dis., 66(11), pages 1467-1472 (2007); Eur. Resp. J., 37, pages 475-476 (2011); Plos One, 9, e87548 (2014); J. Clin. Oncol., 10, 31(14), pages 1740-7 (2013); Pharmacol. Rev., 68 (2) pages 357-418 (2016); and Nephrol. Dial. Transplant., 29, pages i69-i73 (2014).

SALTS

[0264] In some embodiments, atrasentan is in the form of a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable salt” as used herein refers to pharmaceutically acceptable organic or inorganic salts of a compound of the disclosure (e.g., atrasentan). Exemplary salts include acid addition salts formed by the reaction between atrasentan and an acid (e.g., organic acid or inorganic acid). Non-limiting examples include: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate , maleate, mandelate (e.g. (S)-mandelate or (R)-mandelate), gentilinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate and p-toluenesulfonate, pamoate salts (i.e. 4,4'-methylene-bis-(2-hydroxy-3-naphthoate)). Exemplary salts also include base addition salts formed by the reaction between atrasentan and a base. Non-limiting examples include: alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., magnesium), and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the original compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions. When referring to atrasentan, the term “salt” or “salts” is understood to mean a salt of atrasentan that may be present alone or in a mixture with free atrasentan.

[0265] In some embodiments, atrasentan is in the form of a hydrochloride salt. Atrasentan hydrochloride salt, also known as atrasentan hydrochloride (CAS Number: 195733-43-8); atrasentan hydrogen chloride; atrasentan hydrochloride salt; atrasentan chloride salt; atrasentan HCl; atrasentan monohydrochloride; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid , monohydrochloride; 3-pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxygenyl)-, hydrochloride (1:1), ( 2R,3R,4S)-; (2R,3R,4S)-1-[(dibutylamino)methyl]-2-(p-methoxyphenyl)-4-[3,4-(methylenedioxy)phenyl]-3-pyrrolidinecarboxylic acid, monohydrochloride; 3-pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl), monohydrochloride, [2R-(2α, 3β , 4α)]; ABT-627; A-147627.1; Abbott-147627.1, has the following structure:

[0266] wherein the molar ratio of atrasentan to chloride is 1:1. Atrasentan hydrochloride and methods of preparation thereof are further described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. WO 1997/030045 (see, e.g., Example 501), each of which is incorporated here for reference in its entirety.

[0267] In some embodiments, atrasentan is in the form of a mandelate salt. In certain embodiments, atrasentan is in the form of a (S)-mandelate salt. In certain embodiments, atrasentan is in the form of an (R)-mandelate salt. In certain embodiments, in the mandelate salt of atrasentan, atrasentan and mandelate have a molar ratio of 1:1. In certain embodiments, in the mandelate salt of atrasentan, atrasentan and mandelate have a molar ratio of 2:1. Atrasentan mandelate salt and methods of preparation thereof are further described in U.S. Patent Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0268] In some embodiments, atrasentan is in the form of a hemisulfate salt. The hemisulfate salt and methods of preparation thereof are further described in U.S. patents 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

[0269] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in anhydrous form. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of a hydrate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the form of a solvate.

STEREOCHEMISTRY

[0270] Atrasentan has three asymmetric centers and can be produced as individual stereoisomers (e.g., enantiomers or diastereomers) or as mixtures thereof as described in U.S. Patent No. 7,208,517 and International Patent Application Publication No. WO 1997/ 030045. In some embodiments, atrasentan as described herein comprises the (2R,3R,4S)-stereoisomer, which is acid (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1- [ 2-(dibutylamino)-2-oxoethyl]-2-(4-methoxy phenyl)pyrrolidine-3-carboxylic acid. In certain embodiments, atrasentan is the (2R,3R,4S)-stereoisomer that is substantially free of the other stereoisomers (e.g., contains <10%, <5%, <2%, <1%, <0.5%, <0.1% or <0.05% of other stereoisomers).

POLYMORPHS

[0271] Atrasentan or a pharmaceutically acceptable salt thereof, as described herein, may be in one or more polymorphic forms. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99, 5% amorphous). In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially crystalline (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99, 5% crystalline).

[0272] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises the Crystalline Form of Atrasentan Hydrochloride 1. In certain embodiments, the atrasentan or a pharmaceutically acceptable salt thereof is substantially the Crystalline Form of Atrasentan Hydrochloride 1 ( e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% of Form 1). The Crystalline Form of Atrasentan 1 Hydrochloride and methods for making the same are described in International Patent Application Publication No. WO 2006/034094, which is incorporated herein by reference in its entirety.

[0273] In some embodiments, the Crystalline Form of Atrasentan 1 Hydrochloride is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with at least three peaks (e.g. , 3, 4, 5, 6 or 7) having respective 2θ values of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2° or 19.5°. In certain embodiments, the Crystalline Form of Atrasentan Hydrochloride 1 is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with at least three peaks having respective 2θ values. of about 8.3°, 9.7°, 10.0°, 13.0°, 15.6°, 17.2°, or 19.5°, and essentially no peaks with 2θ values below about 6.2° and/or between about 6.6° and 8.0°.

[0274] In some embodiments, the Crystalline Form of Atrasentan Hydrochloride 1 is characterized in the orthorhombic crystal system and space group P2l2l2l, when measured at about 25 °C with Cu-Kα radiation, by lattice parameters a, b and c of 1 .7663 nm ± 0.0005 nm, 2.124 nm ± 0.001 nm, and 0.8005 nm ± 0.0002 nm (17.663 A ± 0.005 A, 21.24 A ± 0.01 A, and 8.005 A ± 0.002 A), respectively.

[0275] In some embodiments, the Crystalline Form of Atrasentan Hydrochloride 1 has substantial crystalline purity. In some embodiments, the Crystalline Form of Atrasentan Hydrochloride 1 has substantial chemical purity. In some embodiments, the Crystalline Form of Atrasentan Hydrochloride 1 has substantial diastereomeric purity.

[0276] Representative characteristic peak positions in the powder X-ray diffraction pattern of Crystalline Form of Atrasentan Hydrochloride I, expressed in degrees relative to 2θ, are, when measured at about 25°C with Cu radiation -Ka, about 8.3°((020), 77.35%); 9.7°((120), 76.37%); 10.0°((200), 14.53%); 13.2°((220), 28.03%); 13.6°((130), 16.71%); 14.9°((121), 38.93%); 15.8°((310), 13.11%); 16.2°((230), 18.09%); 17.4°((320), 15.87%); 17.5°((131), 37.80%); 19.6°((240), 28.77%); 20.8°((141), 46.26%); 23.3°((112), 100.0%); 24.3°((151), 52.6%); 25.3°((341), 13.08%); and 25.9°((132), 33.98%). Each peak position is shown with its Miller index (hkl) values and its integrated intensity (peak height). It should be understood that peak heights may vary and will be dependent on variables such as temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintagx2 Diffraction Pattern System. It should also be understood that peak positions may vary when measured with different radiation sources. For example, Cu-Kα1, Mo-Kα, Co-Kα, and Fe-Kα radiation, with wavelengths of 0.15406 nm, 0.07107 nm, 0.17902 nm, and 0.19373 nm (1.54060 A, 0.7107 A, 1.7902 A, and 1.9373 A), respectively, may provide peak positions that differ from those measured with Cu-Kα radiation.

[0277] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises the Crystalline Form of Atrasentan 2 Hydrochloride. In certain embodiments, the atrasentan or a pharmaceutically acceptable salt thereof is substantially the Crystalline Form of Atrasentan 2 Hydrochloride ( e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% of Form 2). The Crystalline Form of Atrasentan 2 Hydrochloride and methods for making the same are described in International Patent Application Publication No. WO 2006/034084, which is incorporated herein by reference in its entirety.

[0278] In certain embodiments, the Crystalline Form of Atrasentan 2 Hydrochloride is characterized, when measured at about 25 °C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective values of 2θ of about 6.7° and 22.05° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6°.

[0279] In certain embodiments, the Crystalline Form of Atrasentan 2 Hydrochloride has substantial crystalline purity and is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6.7° and 22.05° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6°.

[0280] In certain embodiments, the Crystalline Form of Atrasentan 2 Hydrochloride has substantial crystalline purity and substantial chemical purity; and said Crystalline Form of Atrasentan Hydrochloride 2 is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6. 7° and 22.05° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6°.

[0281] In certain embodiments, the Crystalline Form of Atrasentan 2 Hydrochloride has substantial crystalline purity, substantial chemical purity and substantial diastereomeric purity; and said Crystalline Form of Atrasentan Hydrochloride 2 is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6.7 ° and 22.05° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6°.

[0282] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises the Crystalline Form of Atrasentan 3 Hydrochloride. In certain embodiments, the atrasentan or a pharmaceutically acceptable salt thereof is substantially the Crystalline Form of Atrasentan 3 Hydrochloride ( e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% of Form 3). The Crystalline Form of Atrasentan 3 Hydrochloride and methods for making the same are described in International Patent Application Publication No. WO 2006/034234 and U.S. Patent No. 9,051,301, each of which is incorporated herein by reference. in its entirety.

[0283] In certain embodiments, the Crystalline Form of Atrasentan 3 Hydrochloride is characterized, when measured at about 25 °C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective values of 2θ of about 6.7° and 21.95° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6°.

[0284] In certain embodiments, the Crystalline Form of Atrasentan 3 Hydrochloride has substantial crystalline purity and is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6.7° and 21.95° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5° , 19.8° or 20.6°.

[0285] In certain embodiments, the Crystalline Form of Atrasentan 3 Hydrochloride has substantial crystalline purity and substantial chemical purity; and said Crystalline Form of Atrasentan Hydrochloride 3 is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6 .7° and 21.95° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6° .

[0286] In certain embodiments, the Crystalline Form of Atrasentan Hydrochloride 3 has substantial crystalline purity, substantial chemical purity and substantial diastereomeric purity; and said Crystalline Form of Atrasentan Hydrochloride 3 is characterized, when measured at about 25°C with Cu-Kα radiation, by a powder X-ray diffraction pattern with peaks having respective 2θ values of about 6 .7° and 21.95° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0°, 18.5°, 19.8° or 20.6° .

[0287] In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises amorphous atrasentan hydrochloride. In certain embodiments, atrasentan hydrochloride is substantially amorphous (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99.5% amorphous) . Amorphous atrasentan hydrochloride and methods of manufacturing the same are described in International Patent Application Publication No. WO 2006/034085, which is incorporated herein by reference in its entirety.

[0288] In certain embodiments, the amorphous atrasentan hydrochloride has substantial chemical purity. In certain embodiments, the amorphous atrasentan hydrochloride has substantial diastereomeric purity.

[0289] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises a crystalline atrasentan mandelate salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially a crystalline atrasentan mandelate salt (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99% or >99.5% crystalline atrasentan mandelate salt).

[0290] In certain embodiments, the crystalline atrasentan mandelate salt is a crystalline atrasentan (S)-mandelate salt. In certain embodiments, the atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the (S)-mandelate salt of atrasentan is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate salt is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate salt is a hydrated salt. (A) (S)-MANDELATO SALT (1:1 STOCHIOMETRY)

[0291] In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a crystalline atrasentan (S)-mandelate salt in which the molar ratio of atrasentan to (S)-mandelate is about 1:1 . In certain embodiments, the atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the (S)-mandelate salt of atrasentan is a solvated salt. In certain embodiments, the atrasentan (S)-mandelate salt is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the atrasentan (S)-mandelate salt is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99, 5%) a crystalline (S)-mandelate salt of atrasentan in which the molar ratio of atrasentan to (S)-mandelate is about 1:1.

[0292] In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, and 19.4 ± 0 .2 degrees 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, 12.1 ± 0.2, and 19.4 ± 0.2 degrees 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, 12.1 ± 0.2, 18.0 ± 0.2, 18.4 ± 0.2 and 19.4 ± 0.2 degrees 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the powder X-ray diffraction peak values recited in the above various embodiments is ±0.1 degree 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate is about 1:1.

[0293] In certain embodiments, the crystalline (S)-mandelate salt has a type of orthorhombic network. In certain embodiments, the crystalline (S)-mandelate salt has a P212121 space group. In certain embodiments, the crystalline (S)-mandelate salt has unit cell values a, b, and c of about 0.9954 nm (9.954 Å), about 1.1049 nm (11.049 Å), and about 3.0861 nm (30.861 A), respectively. In certain embodiments, the crystalline (S)-mandelate salt has α, β, and Y unit cell values of about 90°, about 90°, and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has at least three or more of the following properties: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) unit cell a, values of b and c of about 0.9954 nm (9.954 A), about 1.1049 nm (11.049 A), and about 3.0861 nm (30.861 A), respectively, and/or (d) unit cell values α, β, and y of about 90°, about 90° and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt has: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) a, b, and c unit cell values of about 0.9954 nm ( 9.954 A), about 1.1049 nm (11.049 A), and about 3.0861 nm (30.861 A), respectively, and (d) α, β, and y unit cell values of about 90°, about 90° and about 90°, respectively. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate is about 1:1. (B) (S)-MANDELATO SALT (2:1 STOCHIOMETRY)

[0294] In certain embodiments, the crystalline (S)-mandelate salt is a crystalline atrasentan (S)-mandelate salt in which the molar ratio of atrasentan to (S)-mandelate is about 2:1. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a solvated salt. In certain embodiments, the crystalline atrasentan (S)-mandelate salt is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99, 5%) a crystalline (S)-mandelate salt of atrasentan in which the molar ratio of atrasentan to (S)-mandelate is about 2:1.

[0295] In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, and 18.1 ± 0 .2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, 18.1 ± 0.2, and 18.7 ± 0.2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline (S)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, 9.1 ± 0.2, 18 .1 ± 0.2 and 18.7 ± 0.2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the powder X-ray diffraction peak values recited in the above various embodiments is ±0.1 degree 2θ. In certain embodiments, the crystalline (S)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline (S)-mandelate salt is a hydrated salt.

[0296] In certain embodiments, the crystalline atrasentan mandelate salt is a crystalline atrasentan (R)-mandelate salt. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a hydrated salt. (C) (R)-MANDELATO SALT (1:1 STOCHIOMETRY)

[0297] In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a crystalline atrasentan (R)-mandelate salt in which the molar ratio of atrasentan to (R)-mandelate is about 1:1 . In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a solvated salt. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99%, or >99, 5%) a crystalline (R)-mandelate salt of atrasentan in which the molar ratio of atrasentan to (R)-mandelate is about 1:1.

[0298] In certain embodiments, the crystalline atrasentan (R)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.7 ± 0.2, 11.8 ± 0.2, and 20.9 ± 0.2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline atrasentan (R)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.7 ± 0.2, 8.2 ± 0.2, 11.8 ± 0, 2 and 20.9 ± 0.2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the crystalline atrasentan (R)-mandelate salt has a powder X-ray diffraction pattern comprising peaks at 5.7 ± 0.2, 8.2 ± 0.2, 8.6 ± 0, 2, 11.8 ± 0.2 and 20.9 ± 0.2 degree 2θ when measured at about 25 °C with monochromatic Kα1 radiation. In certain embodiments, the experimental error associated with the powder X-ray diffraction peak values recited in the above various embodiments is ±0.1 degree 2θ. In certain embodiments, the crystalline atrasentan (R)-mandelate salt is an anhydrous salt.

[0299] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises an amorphous atrasentan mandelate salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially an amorphous atrasentan mandelate salt (e.g., >75%, >80%, >85%, >90%, >95%, >98%, > 99% or >99.5% amorphous atrasentan salt).

[0300] In certain embodiments, the amorphous atrasentan mandelate salt is the amorphous atrasentan (S)-mandelate salt. In certain embodiments, the amorphous atrasentan (S)-mandelate salt is an anhydrous salt. In certain embodiments, the amorphous atrasentan (S)-mandelate salt is a solvated salt. In certain embodiments, the amorphous atrasentan (S)-mandelate salt is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate and a pyridine solvate. In certain embodiments, the amorphous atrasentan (S)-mandelate salt is a hydrated salt. In certain embodiments, in the amorphous (S)-mandelate salt of atrasentan, the molar ratio of atrasentan and (S)-mandelate is about 1:1. In certain embodiments, in the amorphous (S)-mandelate salt of atrasentan, the molar ratio of atrasentan and (S)-mandelate is about 2:1.

[0301] In certain embodiments, the amorphous atrasentan mandelate salt is the amorphous (R)-atrasentan mandelate salt. In certain embodiments, the amorphous atrasentan (R)-mandelate salt is an anhydrous salt. In certain embodiments, the amorphous atrasentan (R)-mandelate salt is a solvated salt. In certain embodiments, the amorphous atrasentan (R)-mandelate salt is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, the amorphous atrasentan (R)-mandelate salt is a hydrated salt. In certain embodiments, in the amorphous (R)-mandelate salt of atrasentan, the molar ratio of atrasentan and (R)-mandelate is about 1:1. In certain embodiments, in the amorphous (R)-mandelate salt of atrasentan, the molar ratio of atrasentan and (R)-mandelate is about 2:1.

[0302] Crystalline and amorphous atrasentan mandelate salts are further described in U.S. Patent Nos. 8,962,675 and 9,637,476, each of which is incorporated herein by reference in its entirety.

E. FORMULATION

[0303] The term “pharmaceutical composition”, as used herein, is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients or from other types of reactions or interactions of one or more of the ingredients. Accordingly, pharmaceutical compositions of the present disclosure encompass any composition made by mixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or salt solvate thereof, and a pharmaceutically acceptable carrier.

[0304] The amount administered depends on the compound formulation, route of administration, etc. and is generally determined empirically, and variations will necessarily occur depending on the target, host and route of administration, etc. Generally, the amount of active compound in a unit dose of preparation can be varied or adjusted from about 0.1 milligram (mg) to about 10 mg or from about 0.5 mg to about 2 mg, according to the particular application. For convenience, the total daily dosage can be divided and administered in portions throughout the day.

[0305] The pharmaceutical compositions of the present disclosure for injection comprise sterile pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants.

[0306] These pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. The compounds can be incorporated into slow-release or targeted-release systems, such as polymeric matrices, liposomes and microspheres. Such formulations can provide more effective delivery of the compounds.

[0307] Pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0308] Solid dosage forms of the present pharmaceutical compositions for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0309] Solid pharmaceutical compositions of a similar type can also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0310] Solid dosage forms of the present pharmaceutical compositions of tablets, tablets, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifying agents and may also be of a formulation that release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of pharmaceutical incorporation compositions that can be used include polymeric substances and waxes.

[0311] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the excipients mentioned above.

[0312] Liquid dosage forms of the present pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, alcohol benzyl, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and its mixtures.

[0313] In addition to inert diluents, oral pharmaceutical compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0314] Suspensions of the present compounds, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Tragacanth and its mixtures.

[0315] The compounds and compositions described herein can, for example, be administered orally or parenterally, with a dosage ranging from about 0.01 milligram per kilogram (mg/kg) to about 0.05 mg/kg, every 4 to 120 hours, or according to the requirements of the particular drug, dosage form and/or route of administration. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219-244 (1966). Body surface area can be determined approximately from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970). In certain embodiments, the compositions are administered by oral administration or injection. The methods herein contemplate administering an effective amount of compound or compound composition to achieve a desired or claimed effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as chronic or acute therapy.

[0316] Lower or higher doses than those mentioned above may be necessary. The specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion. , drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition towards the disease and the judgment of the treating physician.

[0317] Dosage forms include from about 0.01 mg to about 10 mg (including, from about 0.1 mg to about 5 mg, from about 0.2 mg to about 4 mg, from about 0.3 mg to about 3 mg, from about 0.4 mg to about 2 mg, from about 0.5 mg to about 1.5 mg, or from about 0.6 mg to about 1 mg) of an atrasentan compound or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form includes about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg , about 0.65, about 0.7 mg, about 0.75, about 0.8 mg, about 0.85, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg , about 1.9 mg, about 2 mg or any amount therebetween of atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form includes about 0.75 mg of an atrasentan compound or a pharmaceutically acceptable salt thereof.

[0318] Dosage forms may further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

[0319] Appropriate dosage levels can be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less frequently if a drug delivery system is used. However, the actual dosage levels and timing of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a given patient, composition and mode of administration, without being intolerably toxic to the patient. In certain cases, dosages may differ from the indicated amounts, in particular depending on the patient's age, sex, body weight, diet and general health status, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval during which administration occurs. Thus, it may be satisfactory, in some cases, to administer with less than the minimum value mentioned, while in other cases the upper limit indicated may be exceeded. If larger quantities are administered, it may be advisable to divide them into several individual doses distributed throughout the day.

EXEMPLIFICATIVE DOSAGE FORMS OF ATRASENTAN

[0320] In some embodiments, there is provided herein a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in dosage form is from about 0.05 weight percent to about 2.0 weight percent on an equivalent weight basis. Atrasentan free; and (b) a pharmaceutically acceptable diluent.

[0321] In some embodiments, there is provided herein a stable solid pharmaceutical dosage form comprising: (a) about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.05 weight percent to about 2.0 weight percent on a free base equivalent weight basis of delay; (b) a pharmaceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan, or pharmaceutically acceptable salt thereof, is from about 10:1 to about 1:10; and (c) a pharmaceutically acceptable diluent.

[0322] In some of these embodiments, the degradation of atrasentan in the dosage form is less than the degradation of atrasentan in an identical dosage form without the antioxidant when the dosage forms are stored for a storage period of six months to about 40 °C and around 75% relative humidity.

[0323] In some embodiments, the dosage form is stored during the storage period in a semipermeable container or a substantially impermeable container. In some embodiments, the dosage form is stored during the storage period in a sealed HDPE bottle or blister package. In some embodiments, the dosage form is stored during the storage period in a sealed HDPE bottle. In some embodiments, the dosage form is stored during the storage period in a blister package.

(I) ATRASENTAN

[0324] The dosage form may comprise a free base of atrasentan, a pharmaceutically acceptable salt of atrasentan or a combination thereof. In some embodiments, the dosage form comprises an atrasentan-free base. In some embodiments, the dosage form comprises a pharmaceutically acceptable salt of atrasentan. In some embodiments, the dosage form comprises atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride having a polymorphic form selected from the group consisting of amorphous atrasentan hydrochloride, crystalline form of atrasentan hydrochloride 1, crystalline form of atrasentan hydrochloride 2, and crystalline form of atrasentan hydrochloride 3 In some embodiments, the dosage form comprises amorphous atrasentan hydrochloride. In some embodiments, the dosage form comprises the crystalline form of atrasentan hydrochloride 1. In some embodiments, the dosage form comprises the crystalline form of atrasentan hydrochloride 2. In some embodiments, the dosage form comprises the crystalline form of atrasentan hydrochloride of atrasentan 3. In some embodiments, the dosage form comprises atrasentan mandelate. In certain embodiments, the dosage form comprises a crystalline atrasentan mandelate (e.g., a crystalline atrasentan (S)-mandelate and/or a crystalline atrasentan (R)-mandelate). In certain embodiments, the dosage form comprises an amorphous atrasentan mandelate (e.g., an amorphous atrasentan (S)-mandelate and/or an amorphous atrasentan (R)-mandelate). In some of the above embodiments (when the dosage form comprises a crystalline and/or amorphous (S) and/or (R)-mandelate of atrasentan), the molar ratio of atrasentan and mandelate is 1:1. In certain other embodiments, the molar ratio of atrasentan and mandelato is 2:1.

[0325] In certain embodiments, the dosage form comprises amorphous atrasentan hydrochloride; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises the crystalline form of atrasentan 1 hydrochloride; and is substantially free of (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) other forms (e.g., other salts and /or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline form 2 of atrasentan hydrochloride; and is substantially free of other forms (e.g., other salts and/or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises the crystalline form of atrasentan 3 hydrochloride; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline atrasentan (S)-mandelate; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises crystalline atrasentan (R)-mandelate; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises amorphous atrasentan (S)-mandelate; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan. In certain embodiments, the dosage form comprises amorphous atrasentan (R)-mandelate; and is substantially free (e.g., contains <10%, <5%, <1%, <0.5%, <0.1%, <0.05%) in other forms (e.g., other salts and/or or other polymorphs) of atrasentan.

[0326] In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.1 weight percent to about 2.0 weight percent on a weight basis. free base equivalent of atrasentan. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.2 weight percent to about 1.0 weight percent on an equivalent base weight basis. delay-free. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.3 weight percent to about 0.8 weight percent on an equivalent weight basis. delay-free. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.40 weight percent to about 0.45 weight percent on an equivalent weight basis. delay-free. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 0.60 weight percent to about 0.65 weight percent on an equivalent weight basis. delay-free.

[0327] In some embodiments, the dosage form comprises from about 0.40 mg to about 1.00 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.50 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

(II) DILUENT

[0328] Suitable diluents for use in the disclosed dosage forms include, but are not limited to lactose (such as lactose monohydrate, anhydrous lactose and PHARMATOSE® DCL21), sucrose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (such as AVICEL ® PH101 and AVICEL® PH102), silicified microcrystalline cellulose (such as PROSOLV® SMCC 50 and SMCC 90), dicalcium phosphate, starches and combinations thereof. In some embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, microcrystalline cellulose, dicalcium phosphate, and combinations thereof. In some embodiments, the diluent is lactose.

[0329] In some embodiments, the weight percentage of the diluent in the dosage form is from about 70 weight percent to about 99 weight percent. In some embodiments, the weight percentage of the diluent in the dosage form is from about 80 weight percent to about 99 weight percent. In some embodiments, the weight percentage of the diluent in the dosage form is from about 85 weight percent to about 99 weight percent. In some of the above embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, and combinations thereof. As a non-limiting example, the diluent may be lactose.

(III) BINDER

[0330] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder (e.g., polymeric binder). Suitable binders for use in the disclosed dosage forms include, but are not limited to, celluloses such as hydroxypropylmethylcellulose (e.g., Hypromellose E5 (Premium LV)), hydroxypropyl ethylcellulose and hydroxypropylcellulose and other pharmaceutically acceptable substances with cohesive properties. In some embodiments, the binder is selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, and hydroxypropylcellulose. In some embodiments, the binder is hydroxypropylmethylcellulose. In some embodiments, the binder is hydroxypropylcellulose. In some embodiments, the binder is hydroxyethylpropylcellulose.

[0331] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder; and the weight percentage of the binder in the dosage form is from about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percentage of the binder in the dosage form is from about 1.0 weight percent to about 8.0 weight percent. In some embodiments, the weight percentage of the binder in the dosage form is from about 1.0 weight percent to about 5.0 weight percent. In some of the above embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose.

[0332] In some embodiments, the dosage form further comprises a pharmaceutically acceptable binder; and the weight/weight ratio of the binder to atrasentan or pharmaceutically acceptable salt thereof is from about 2:1 to about 25:1 on an equivalent weight basis of atrasentan free base. In some embodiments, the weight/weight ratio of the binder to the atrasentan, or pharmaceutically acceptable salt thereof, is from about 1:1 to about 20:1 on an equivalent weight basis of atrasentan free base. In some embodiments, the weight/weight ratio of the binder to the atrasentan, or pharmaceutically acceptable salt thereof, is from about 1:1 to about 15:1 on an equivalent weight basis of atrasentan free base. In certain embodiments, the binder is a polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose;

(IV) DISINTEGRATING

[0333] In some embodiments, the dosage form optionally comprises a pharmaceutically acceptable disintegrant. Suitable disintegrants for use in the disclosed dosage forms include, but are not limited to, cross-linked polyvinylpyrrolidone (such as POLYPLASDONE™ XL), corn starch, potato starch, corn starch and modified starches (including sodium starch glycolate), agar- agar, alginic acids, microcrystalline cellulose, croscarmellose sodium and combinations thereof. In some embodiments, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, and croscarmellose sodium. In some embodiments, the disintegrant is a cross-linked polyvinylpyrrolidone. In some embodiments, the disintegrant is crospovidone.

[0334] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant. In certain embodiments, the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 4.0 weight percent. In some of the above embodiments, the disintegrant is crospovidone.

[0335] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant and the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or pharmaceutically acceptable salt or ester thereof, is about from 60:1 to about 3:1. In some embodiments, the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or pharmaceutically acceptable salt or ester thereof, is from about 50:1 to about 4:1. In some embodiments, the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine), or pharmaceutically acceptable salt or ester thereof, is from about 35:1 to about 5:1.

(V) ADDITIONAL EXCIPIENTS

[0336] In other embodiments, the dosage form optionally comprises a pharmaceutically acceptable lubricant and/or slider. Lubricants and glidants suitable for use in the disclosed dosage forms include, but are not limited to, silicon dioxide (such as SYLOID® 244FP and AEROSIL® 200), glyceryl behenate (such as COMPRITOL®), talc, stearic acid, solid polyethylene glycols, silica gel and mixtures thereof and other substances with lubricating or sliding properties. In certain embodiments, the lubricant is glyceryl behenate (such as COMPRITOL®). In certain embodiments, the slider is silicon dioxide (such as SYLOID® 244FP). In certain embodiments, the lubricant is glyceryl behenate and the slider is silicon dioxide.

[0337] In some embodiments, the dosage form further comprises a pharmaceutically acceptable slider. In another aspect, the weight percentage of the slider in the dosage form is from about 0.1 weight percent to about 1.5 weight percent. In some embodiments, the weight percentage of the slider in the dosage form is from about 0.1 weight percent to about 1.0 weight percent. In some embodiments, the weight percentage of the slider in the dosage form is from about 0.1 weight percent to about 0.8 weight percent. In some embodiments, the slider is silicon dioxide.

[0338] In some embodiments, the dosage form further comprises a pharmaceutically acceptable lubricant. In some embodiments, the dosage form further comprises a pharmaceutically acceptable hydrophobic lubricant. In some embodiments, the weight percentage of the lubricant in the dosage form is from about 0.05 weight percent to about 5.0 weight percent. In some embodiments, the weight percentage of the lubricant in the dosage form is from about 0.2 weight percent to about 3.0 weight percent. In some embodiments, the weight percentage of the lubricant in the dosage form is from about 0.5 weight percent to about 2.0 weight percent. In certain embodiments, the lubricant is glyceryl behenate.

[0339] In some embodiments, the dosage form further comprises a disintegrant, a glidant and a lubricant.

(VI) ANTIOXIDANT

[0340] Antioxidants suitable for use in the disclosed dosage forms include antioxidants that function as reducing agents and are oxidized to pharmaceutically acceptable reduced products in the dosage form. In some embodiments, the antioxidant has an oxidation reduction potential less than the oxidation reduction potential of atrasentan (i.e., an oxidation reduction potential of less than about 900 mV) and greater than about 550 mV. In some embodiments, the antioxidant has an oxidation reduction potential of less than about 550 mV. In some embodiments, the antioxidant has an oxidation reduction potential of about 1 mV to about 550 mV. In some embodiments, the solubility of the antioxidant in water at about 25 °C is greater than about 24 mg/ml. In some embodiments, the antioxidant is an amino acid, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is cysteine. In some embodiments, the antioxidant is L-cysteine or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is selected from the group consisting of L-cysteine hydrochloride monohydrate, L-cysteine hydrochloride anhydrous, and L-cysteine ethyl ester. In some embodiments, the dosage form comprises L-cysteine hydrochloride monohydrate.

[0341] In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.05 weight percent to about 1.0 weight percent. In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.07 weight percent to about 0.7 weight percent. In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.09 weight percent to about 0.5 weight percent.

[0342] In some embodiments, the molar ratio of the antioxidant to atrasentan or pharmaceutically acceptable salt thereof is from about 10:1 to about 1:10. In some embodiments, the molar ratio of the antioxidant to atrasentan or pharmaceutically acceptable salt thereof in dosage form is from about 5:1 to about 1:5. In some embodiments, the molar ratio of the antioxidant to atrasentan or pharmaceutically acceptable salt thereof is from about 2:1 to about 1:2. In some embodiments, the molar ratio of the antioxidant to atrasentan or pharmaceutically acceptable salt thereof is about 1:1.

[0343] In some embodiments, the antioxidant is L-cysteine or a pharmaceutically acceptable salt thereof. In certain embodiments, the weight percentage of the L-cysteine or pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.05 weight percent to about 1.0 weight percent. In certain embodiments, the weight percentage of the L-cysteine or pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.07 weight percent to about 0.7 weight percent. In certain embodiments, the weight percentage of L-cysteine or pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.09 weight percent to about 0.5 weight percent.

[0344] In certain embodiments, the molar ratio of L-cysteine or pharmaceutically acceptable salt or ester thereof to atrasentan or pharmaceutically acceptable salt thereof in the dosage form is from about 10:1 to about 1:10. In certain embodiments, the molar ratio of L-cysteine or pharmaceutically acceptable salt or ester thereof to atrasentan or pharmaceutically acceptable salt thereof in the dosage form is from about 5:1 to about 1:5. In certain embodiments, the molar ratio of L-cysteine or pharmaceutically acceptable salt or ester thereof to atrasentan or pharmaceutically acceptable salt thereof is from about 2:1 to about 1:2. In certain embodiments, the molar ratio of L-cysteine or pharmaceutically acceptable salt or ester thereof to atrasentan or pharmaceutically acceptable salt thereof is about 1:1.

[0345] In certain embodiments, the antioxidant is selected from the group consisting of L-cysteine hydrochloride monohydrate, L-cysteine hydrochloride anhydrous and L-cysteine ethyl ester. In some embodiments, the dosage form comprises L-cysteine hydrochloride monohydrate.

(VII) ADDITIONAL MODALITIES

[0346] In some embodiments, the dosage form comprises atrasentan or a pharmaceutically acceptable salt thereof and an antioxidant. In some such embodiments, the antioxidant is L-cysteine or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the molar ratio of the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) is from about 5:1 to about 1:5. In some of the foregoing embodiments, the dosage form further comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the molar ratio of antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) to atrasentan or pharmaceutically acceptable salt thereof is from about 5:1 to about 1:5; and the weight/weight ratio of the binder to atrasentan or pharmaceutically acceptable salt thereof is from about 1:1 to about 20:1 on an equivalent weight basis of atrasentan free base. In some embodiments, this dosage form further comprises a disintegrant and the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) is from about 60:1 to about 3:1. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in this dosage form is from about 0.2 weight percent to about 1.0 weight percent on an equivalent weight basis. delay-free. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the molar ratio of antioxidant (e.g., L-cysteine or a pharmaceutically acceptable salt or ester thereof) to atrasentan or pharmaceutically acceptable salt thereof is from about 2:1 to about 1:2; and the weight/weight ratio of binder to atrasentan or pharmaceutically acceptable salt thereof is from about 1:1 to about 15:1 on an equivalent weight basis of atrasentan free base. In some embodiments, the dosage form further comprises a disintegrant and the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine, or a pharmaceutically acceptable salt or ester thereof) is about 50:1 to about 4:1. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in this dosage form is from about 0.2 weight percent to about 1.0 weight percent on an equivalent weight basis. delay-free. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the molar ratio of antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) to atrasentan or pharmaceutically acceptable salt thereof is about 1:1; and the weight/weight ratio of binder to atrasentan or pharmaceutically acceptable salt thereof is from about 1:1 to about 15:1 on an equivalent weight basis of atrasentan free base. In some embodiments, this dosage form further comprises a disintegrant and the weight/weight ratio of the disintegrant to the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) is from about 35:1 to about 5:1. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in this dosage form is from about 0.3 weight percent to about 0.8 weight percent on a free base equivalent weight basis. of delay. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the dosage form comprises from about 0.05 weight percent to about 1.0 weight percent of the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof); and the dosage form comprises from about 1.0 weight percent to about 10.0 weight percent binder. In some embodiments, this dosage form further comprises a disintegrant and the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 10.0 weight percent. In some embodiments, the weight percentage of atrasentan, or pharmaceutically acceptable salt thereof, in this dosage form is from about 0.1 weight percent to about 2.0 weight percent on an equivalent weight basis of atrasentan free base. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the dosage form comprises from about 0.07 weight percent to about 0.70 weight percent of the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof); and the dosage form comprises from about 1.0 weight percent to about 8.0 weight percent binder. In some embodiments, this dosage form further comprises a disintegrant and the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 6.0 weight percent. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in this dosage form is from about 0.2 weight percent to about 1.0 weight percent on an equivalent weight basis. delay-free. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the dosage form comprises a pharmaceutically acceptable polymeric binder selected from the group consisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose and hydroxypropylcellulose; the dosage form comprises from about 0.09 weight percent to about 0.80 weight percent of the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof) and the dosage form comprises from about 1.0 weight percent to about 5.0 weight percent of the binder. In some embodiments, this dosage form further comprises a disintegrant and the weight percentage of the disintegrant in the dosage form is from about 1.0 weight percent to about 4.0 weight percent. In some embodiments, the weight percentage of atrasentan or pharmaceutically acceptable salt thereof in this dosage form is from about 0.3 weight percent to about 0.8 weight percent on a free base equivalent weight basis. of delay. In some embodiments, this dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the dosage form comprises:

[0353] (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0354] (b) about 0.05 weight percent to about 1.0 weight percent of the antioxidant (e.g., L-cysteine or pharmaceutically acceptable salt or ester thereof);

[0355] (c) about 75 weight percent to about 99 weight percent diluent;

[0356] (d) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0357] (e) optionally, about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0358] (f) optionally, about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; It is

[0359] (g) optionally, about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0360] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0361] In some embodiments, the dosage form comprises:

[0362] (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0363] (b) about 0.05 weight percent to about 1.0 weight percent of the antioxidant (L-cysteine or pharmaceutically acceptable salt or ester thereof);

[0364] (c) about 75 weight percent to about 99 weight percent diluent;

[0365] (d) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0366] (e) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0367] (f) optionally, about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; It is

[0368] (g) optionally, about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0369] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0370] In some embodiments, the dosage form comprises:

[0371] (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0372] (b) about 0.07 weight percent to about 0.7 weight percent of the antioxidant (L-cysteine or pharmaceutically acceptable salt or ester thereof);

[0373] (c) about 82 weight percent to about 99 weight percent diluent;

[0374] (d) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0375] (e) optionally, about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0376] (f) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; It is

[0377] (g) optionally, about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0378] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0379] In some embodiments, the dosage form comprises:

[0380] (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0381] (b) about 0.07 weight percent to about 0.70 weight percent L-cysteine or pharmaceutically acceptable salt or ester thereof;

[0382] (c) about 82 weight percent to about 99 weight percent diluent;

[0383] (d) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0384] (e) about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0385] (f) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; It is

[0386] (g) optionally, about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0387] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0388] In some embodiments, the dosage form comprises:

[0389] (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0390] (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine or pharmaceutically acceptable salt or ester thereof;

[0391] (c) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0392] (d) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0393] (e) optionally, about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0394] (f) optionally, about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; It is

[0395] (g) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0396] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0397] In some embodiments, the dosage form comprises:

[0398] (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0399] (b) about 0.09 weight percent to about 0.50 weight percent L-cysteine or pharmaceutically acceptable salt or ester thereof;

[0400] (c) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0401] (d) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0402] (e) about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0403] (f) optionally, about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; It is

[0404] (g) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0405] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0406] In some embodiments, the dosage form comprises:

[0407] (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0408] (b) about 75 weight percent to about 99 weight percent diluent;

[0409] (c) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0410] (d) optionally, about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0411] (e) optionally, about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; It is

[0412] (f) optionally, about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0413] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0414] In some embodiments, the dosage form comprises:

[0415] (a) about 0.1 weight percent to about 2.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0416] (b) about 75 weight percent to about 99 weight percent diluent;

[0417] (c) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable binder;

[0418] (d) about 1.0 weight percent to about 10.0 weight percent of a pharmaceutically acceptable disintegrant;

[0419] (e) optionally, about 0 weight percent to about 1.5 weight percent of a pharmaceutically acceptable glidant; It is

[0420] (f) optionally, about 0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable lubricant;

[0421] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0422] In some embodiments, the dosage form comprises:

[0423] (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0424] (b) about 82 weight percent to about 99 weight percent diluent;

[0425] (c) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0426] (d) optionally, about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0427] (e) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; It is

[0428] (f) optionally, about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0429] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0430] In some embodiments, the dosage form comprises:

[0431] (a) about 0.2 weight percent to about 1.0 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0432] (b) about 82 weight percent to about 99 weight percent diluent;

[0433] (c) about 1.0 weight percent to about 8.0 weight percent of a pharmaceutically acceptable binder;

[0434] (d) about 1.0 weight percent to about 6.0 weight percent of a pharmaceutically acceptable disintegrant;

[0435] (e) optionally, about 0 weight percent to about 1.0 weight percent of a pharmaceutically acceptable glidant; It is

[0436] (f) optionally, about 0 weight percent to about 3.0 weight percent of a pharmaceutically acceptable lubricant;

[0437] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0438] In some embodiments, the dosage form comprises:

[0439] (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0440] (b) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0441] (c) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0442] (d) optionally, about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0443] (e) optionally, about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; It is

[0444] (f) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0445] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0446] In some embodiments, the dosage form comprises:

[0447] (a) about 0.3 weight percent to about 0.8 weight percent atrasentan or pharmaceutically acceptable salt thereof, on an equivalent weight basis of atrasentan free base;

[0448] (b) about 87 weight percent to about 99 weight percent of a pharmaceutically acceptable diluent;

[0449] (c) about 1.0 weight percent to about 5.0 weight percent of a pharmaceutically acceptable binder;

[0450] (d) about 1.0 weight percent to about 4.0 weight percent of a pharmaceutically acceptable disintegrant;

[0451] (e) optionally, about 0 weight percent to about 0.75 weight percent of a pharmaceutically acceptable glidant; It is

[0452] (f) optionally, about 0 weight percent to about 2.0 weight percent of a pharmaceutically acceptable lubricant;

[0453] wherein the cumulative weight percentage for all components of the dosage form equals 100 percent.

[0454] In some embodiments, the dosage form satisfies one or more of the following conditions:

[0455] (a) the diluent is lactose;

[0456] (b) the dosage form comprises a pharmaceutically acceptable binder and the binder is hydroxypropylmethylcellulose;

[0457] (c) the dosage form comprises a pharmaceutically acceptable disintegrant and the disintegrant is crospovidone;

[0458] (d) the dosage form comprises a pharmaceutically acceptable glidant and the glidant is silicon dioxide;

[0459] (e) the dosage form comprises a pharmaceutically acceptable lubricant and the lubricant is glyceryl behenate.

[0460] In some embodiments, the dosage form is a solid pharmaceutical dosage form comprising from about 0.25 mg to about 1.25 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride). on an atrasentan equivalent weight basis. In some embodiments, the pharmaceutical composition comprises from about 0.40 mg to about 1.00 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an equivalent weight basis of atrasentan. In some embodiments, the pharmaceutical composition comprises from about 0.40 mg to about 0.85 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an equivalent weight basis of atrasentan. In some embodiments, the pharmaceutical composition comprises about 0.50 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an equivalent weight basis of atrasentan. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on an equivalent weight basis of atrasentan. In some of the above embodiments, the dosage form is a tablet.

[0461] In some embodiments, the dosage form is a tablet. In some embodiments, the tablet has a weight of about 37.5 mg to about 1500 mg. In some embodiments, the tablet has a weight of about 50 mg to about 750 mg. In some embodiments, the tablet has a weight of about 50 mg to about 250 mg. In some embodiments, the tablet has a weight of about 75 mg to about 500 mg. In some embodiments, the tablet has a weight of about 75 mg to about 150 mg. In some embodiments, the tablet has a weight of about 100 mg to about 250 mg. In some embodiments, the tablet has a weight of about 100 mg to about 230 mg. In some embodiments, the tablet has a water content below about 10%. In certain embodiments, the tablet has a water content of about 4%-6% (e.g., about 4%-5%).

[0462] In general, the tablet may optionally be surrounded or coated with at least one non-rate controlling layer. The non-rate controlling layer may be formed as a single layer, coating or membrane or a plurality of single layers, coatings or membranes. Functions of the non-rate controlling layer may include, for example, providing additional stability for the atrasentan, serving as a process aid and/or as a cosmetic enhancement to the formulation, and/or acting as a masking agent to reduce any unwanted odor associated with the atrasentan. formulation (like the odor commonly associated with L-cysteine).

[0463] When the dosage form comprises a non-rate controlling layer, the non-rate controlling layer may be made of one or more polymers, as well as other ingredients known in the art, such as, but not limited to, plasticizers, pigments/ opacifiers, waxes, etc. Examples of polymers that can be used include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol and polyethylene glycol. Examples of plasticizers that can be used include, but are not limited to, polyethylene glycol(s), glycerin, triacetin, triethyl citrate, diethyl phthalate, L-cysteine, and mineral oils. Examples of pigments/opacifiers that may be used include, but are not limited to, water-soluble dyes (e.g., sunset yellow, quinoline yellow, erythrosine, and tartrazine), pigments (e.g., aluminum lakes, titanium oxides, iron oxides and talc) and natural products (e.g. riboflavin, carotenoids, chlorophyll, anthocyanins and carmine). An example of a wax that can be used includes, but is not limited to, a paraffin wax.

[0464] In some embodiments, the dosage form is a tablet coated with a pharmaceutically acceptable polymer.

[0465] In some embodiments, the dosage form is a capsule.

[0466] In some embodiments, the dosage form is packaged in a semipermeable container. In some embodiments, the semipermeable container is a blister.

[0467] In some embodiments, the dosage form is packaged in a substantially impermeable container.

[0468] In some embodiments, the dosage form is an immediate release dosage form. In some embodiments, the dosage form is an immediate-release tablet and releases at least about 85% of the atrasentan, or pharmaceutically acceptable salt thereof, within about 45 minutes, as determined in an in vitro dissolution test performed using a USP 2 Dissolution Apparatus (Paddle Apparatus), a 0.01 N hydrochloric acid dissolution medium and a 50 RPM paddle rotation. In some embodiments, the dosage form is an immediate-release tablet and releases at least about 75% of the atrasentan, or pharmaceutically acceptable salt thereof, in about 30 minutes.

[0469] In some embodiments, the dosage form comprises less than about 1.0 weight percent of the total impurities resulting from the degradation of atrasentan, or pharmaceutically acceptable salt thereof, after a storage period of six months to about 40 °C and around 75% relative humidity. In some embodiments, degradation of atrasentan or a pharmaceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0470] In some embodiments, the dosage form comprises less than about 0.6 percent by weight of any single impurity resulting from the degradation of atrasentan, or pharmaceutically acceptable salt thereof, after a storage period of six months to about of 40 °C and around 75% relative humidity. In some embodiments, degradation of atrasentan or a pharmaceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0471] In some embodiments, the dosage form comprises less than about 1.0 weight percent of total impurities and less than about 0.6 weight percent of any single impurity resulting from degradation of atrasentan or pharmaceutically acceptable salt thereof, after a storage period of six months at about 40 ° C and about 75% relative humidity. In some embodiments, degradation of atrasentan or a pharmaceutically acceptable salt thereof is analyzed using high performance liquid chromatography.

[0472] In certain embodiments, the dosage form is selected from the group consisting of: aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.35 mg free base x 1.07 = 0.37 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain. aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.50 mg free base x 1.07 = 0.5350 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain. aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.75 mg free base x 1.07 = 0.8025 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain.

[0473] In certain embodiments, the dosage form is selected from the group consisting of: aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.5 mg free base x 1.07 = 0.5350 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain. aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.75 mg free base x 1.07 = 0.8025 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain. aAtrasentan monohydrochloride salt factor = 1.07 (i.e. 0.35 mg free base x 1.07 = 0.37 mg salt). bGranulation suspension medium. Less than 2% in the final product. cBased on 10% solids aqueous solution. dBased on 120 mg tablet weight with a 3% coating weight gain.

[0474] Formulations of atrasentan or a pharmaceutically acceptable salt thereof and methods for making the same are further described in U.S. Patent No. 9,364,458 and U.S. Patent No. 10,016,393, each of which is incorporated herein by reference. reference in its entirety.

F. DOSAGE AND ADMINISTRATION

[0475] In some embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is between about 0.001 mg and 0.1 mg per kg of the subject's body weight (e.g., about 0.001, about 0.002, about 0.003, about 0.004, about 0.005, about 0.006, about 0.007, about 0.008, about 0.009, about 0.01, about 0.015, about 0.02, about 0.025, about 0, 03, about 0.035, about 0.04, about 0.045, about 0.05, about 0.055, about 0.06, about 0.065, about 0.07, about 0.075, about 0, 08, about 0.085, about 0.09, about 0.095, or about 0.10 mg per kg, or any intermediate value of the subject's body weight) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is between about 0.1 mg and 10 mg (e.g., about 0.1, about 0.2, about 0.3 , about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8 about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1, 9, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5 or about 10, 0 mg, or any intermediate value) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 0.75 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 0.25 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 0.35 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 1.0 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 1.25 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 1.5 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is about 1.75 mg (e.g., when administered once daily) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some such embodiments, a dose of atrasentan or a pharmaceutically acceptable salt thereof is 0.75 mg (e.g., 1 x 0.75 mg tablet; or 1.5 x 0.50 mg tablet) of atrasentan. or an equivalent amount of a pharmaceutically acceptable salt thereof, administered once daily.

[0477] In some embodiments, a dose of atrasentan or salt or solvate thereof contains a therapeutically effective amount of atrasentan or salt or solvate thereof. In other embodiments, a dose of atrasentan or salt or solvate thereof contains less than a therapeutically effective amount of atrasentan or salt or solvate thereof, (e.g., when multiple doses are given to achieve the desired clinical or therapeutic effect ).

[0478] In some embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.20 mg to about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof . For example, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof may be about 0.20 mg, about 0.30 mg, about 0.40 mg, about 0.50 mg, about 0.60 mg, about 0.70 mg, about 0.80 mg, about 0.90 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1 3 mg, about 1.4 mg or about 1.5 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. For example, the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof may be about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg or about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. As a non-limiting example, the therapeutically effective amount of atrasentan or pharmaceutically acceptable salt thereof may be about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0479] Atrasentan or salt or solvate thereof can be administered by any suitable route and method. Suitable routes of administration of antibodies and/or antibody-drug conjugate of the present disclosure are well known in the art and can be selected by those skilled in the art. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered parenterally. Parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous , subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In some embodiments, the route of administration of atrasentan is intravenous injection or infusion. In some embodiments, the route of administration of atrasentan is intravenous infusion. In some embodiments, the route of administration of atrasentan is intravenous injection or infusion. In some embodiments, atrasentan is intravenous infusion. In some embodiments, the route of administration of atrasentan is oral.

[0480] In one embodiment of the methods or uses or product for uses provided herein, atrasentan is administered to the subject daily, twice daily, three times daily, or four times daily. In some embodiments, atrasentan is administered to the subject every other day, once every week, or once every three weeks. In some embodiments, atrasentan is administered to the subject once daily. In some embodiments, atrasentan is administered to the subject twice daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.75 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 0.75 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.25 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 0.25 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.35 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 0.35 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 0.5 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 0.5 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 1.0 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 1.0 mg once daily. In some embodiments, atrasentan is administered to the subject at a dose of about 1.75 mg once per day. In some embodiments, atrasentan is administered to the subject at a dose of 1.75 mg once daily.

G. COMBINED THERAPY

[0481] The methods of the present disclosure also contemplate treatments comprising administering atrasentan or a pharmaceutically acceptable salt thereof, as described in any of the embodiments of the disclosure, in combination with one or more additional therapeutic agents (such as an inhibitor of a or more elements of the renin-angiotensin-aldosterone system). Accordingly, atrasentan or a pharmaceutically acceptable salt thereof, as described elsewhere herein, may be administered alone or in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, separate dosage forms may be administered to the subject or a single dosage form comprising both atrasentan or a pharmaceutically acceptable salt thereof and the therapeutic agent(s). ) additional(s) may be administered to the topic(s). If administered as a separate dosage form, the additional therapeutic agent may be administered simultaneously with the atrasentan dosage form of the present disclosure or sequentially (in any order) with the atrasentan dosage form of the present disclosure. The administration of two or more agents in combination may also be referred to herein as “coadministration”.

[0482] Representative additional therapeutic agents include, for example, diuretics, antihypertensive agents, therapeutic agents for diabetes or diabetic complications, and therapeutic agents for hyperlipidemia.

[0483] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more diuretics, such as hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™), bemetanide (such as BUMEX™), torsemide (such as DEMADEX™), metolazone (such as ZAROXOLYN™), chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such as EDECRIN™), chlorthalidone (such as HYGROTON™), furosemide ( such as LASIX™), indapamide (such as LOZOL™) or amiloride (such as MIDAMOR™ or MODURETIC™).

[0484] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof can be co-administered with one or more thiazide diuretics, such as chlorothiazide, chlorthalidone, hydrochlorothiazide, trichlormethiazide, indapamide or metolazone.

[0485] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more loop diuretics, such as bumetanide, ethacrynic acid, furosemide, or torsemide.

[0486] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more potassium-sparing diuretics, such as amiloride, eplerenone, spironolactone, and triamterene.

[0487] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more angiotensin-converting enzyme (ACE) inhibitors, such as quinapril (such as ACCUPRIL™), fosinopril, perindopril (such as ACEON™ ), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™), ENALAPRILAT™, ramipril (such as ALTACE™), cilazapril, delapril, fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (such as LOTENSIN™), lisinopril (such as PRINIVIL™ or ZESTRIL™), spirapril, trandolapril (such as MAVIK™), perindep, pentopril, moexipril (such as UNIVASC™), pivopril, temocapril, omapatrilat, imidapril, rescinamin, benazeprilat, fosinoprilat, ramiprilat, perindoprilat, quinaprilat, trandolaprilat , moexiprilat, quinoline yellow WS or cilazaprilat. In certain embodiments, the ACE inhibitor is selected from: quinapril, fosinopril perindopril, captopril, enalapril, enalapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril , rescinamine and pivopril.

[0488] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more angiotensin II receptor blockers (ARB), such as candesartan (such as ATACAND™), candesartan cilexetil, eprosartan (such as TEVETEN™), irbesartan (as AVEPRO™), losartan (as COZAAR™), olmesartan, olmesartan medoxomil (as BENICAR™), tasosartan, telmisartan (as MICARDIS™), valsartan (as DIOVAN™), zolasartan, azilsartan medoxomil, F1-6828K, RNH- 6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657 or TA-606. In certain embodiments, the ARB is selected from: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0489] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more calcium channel blockers, such as nifedipine (such as ADALAT™, ADALAT CC™ or PROCARDIA™), verapamil (such as GALAN™, COVERA -HS™, ISOPTIN SR™ or VERELAN™), diltiazem (such as CARDIZEM™, CARDIZEM CD™, CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™ or TIAZAC™), isradipine (such as DYNACIRC™ or DYNACIRC CR™) , amlodipine (such as NORVASC™), felodipine (such as PLENDIL™), nisoldipine (such as SULAR™), bepridil (such as VASCOR™), vatanidipine, clevidipine, lercanidipine or dilithiazem.

[0490] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more renin inhibitors, such as aliskiren (such as TEKTURNA™).

[0491] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more aldosterone receptor antagonists, such as eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).

[0492] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more alpha blockers, such as dozazosin (such as CARDURA™), phenoxybenzamine (such as DIBENZYLINE™), terazosin (such as HYTRIN™), CDR1-93 /478 or CR-2991.

[0493] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more beta blockers, such as timolol (such as BLOCARDEN™), carteolol (such as CARTROL™), carvedilol (such as COREG™), nadolol (such as CORGARD™ ), propranolol (such as INNOPRAN .

[0494] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more alpha-beta blockers, such as labetalol (such as NORMODYNE™ or TRANDATE™).

[0495] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more central antiadrenergics, such as methyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ or CATAPRES-TTS™), guanfacine (such as TENEX™ ) or guanabenz (such as WYTENSIN™).

[0496] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more glycosides/inotropic agents, such as digoxin (such as LANOXIN™).

[0497] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more alpha glucosidase inhibitors, such as miglitol (such as GLYSET™) or acarbose (such as PRECOSE™).

[0498] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more biguanides, such as roseiglitazone (such as AVANDAMET™) or metformin (such as GLUCOPHAGE™ or GLUCOPHAGE XR™).

[0499] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more insulins, such as HUMALOG™, HUMALOG 50/50™, HUMALOG 75/25™, HUMULIN 50/50™, HUMALIN 75/25 ™, HUMALIN L™, HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN II LENTE™, ILETIN II NPH™, ILETIN II REGULAR™, LANTUS™, NOVOLIN 70/30™, NOVILIN N™, NOVILIN R™, NOVOLOG™ or VELOSULIN BR™ and EXUBERA™.

[0500] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof can be co-administered with one or more meglithnoids, such as repaglinide (such as PRANDIN™) or nateglinide (such as STARLIX™).

[0501] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more sulfonylureas, such as glimepiride (such as AMARYL™), glyburide (such as DIABETA™, GLYNASE PRESTAB™ or MICRONASE™) or glipizide (such as GLUCOTROL ™ or GLUCOTROL XL™).

[0502] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with one or more thiazolidinediones, such as pioglitazone (such as ACTOS™) or rosiglitazone (such as AVANDIA™).

[0503] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with niacin or one or more nicotinic acid derivatives, such as NIACOR™, NIASPAN™, NICOLAR™ or SLO-NIACIN™.

[0504] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more tissue acid derivatives, such as clofibrate (such as ATROMID-S™), gemfibrozil (such as LOPID™) or fenofibrate (such as TRICOR™ ).

[0505] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more bile acid sequestrants, such as colestipol (such as COLESTID™), cholestyramine (such as LOCHOLEST™, PREVALITE™, QUESTRAN™ or QUESTRAN LIGHT™ ), or colesevelam (such as WELCHOL™).

[0506] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more cholesterol absorption inhibitors, such as ezetimibe (such as ZETIA™).

[0507] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), such as fluvastatin (such as LESCOL™ ), atorvastatin (such as LIPITOR™), lovastatin (such as ALTOCOR™ or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatin (such as CRESTOR™), simvastatin (such as ZOCOR™), or pitavastatin.

[0508] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more additional agents. In some embodiments, the one or more additional agents is an immunosuppressant. In some embodiments, one or more additional agents are selected from aminopterin, azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, rapamycin, sulfasalazine, tacrolimus (FK506) and pharmaceutically acceptable salts thereof. As a non-limiting example, one or more additional agents may be hydroxychloroquine.

[0509] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be co-administered with one or more additional therapeutic agents selected from the group consisting of SGLT-2 inhibitor (such as canagliflozin), GR immunosuppressant (such as budesonide), MASP- 2 antibodies (such as OMS721), dual ET1A/ARB inhibitors (such as sparsentan), B cell modulators (e.g., APRIL modulators such as atacicept, APL-2, and VIS649), SYK inhibitor (such as fosamatinib), complement 3 convertase inhibitor (such as LNP023), NRF2 activator (such as Bardoxolone), and RNAi therapeutics targeting the C5 component of the complement pathway (e.g., cemdisiram).

[0510] In some embodiments, one or more additional agents are SGLT-2 inhibitors. In some embodiments, the one or more additional agents are an SGLT-2 inhibitor selected from dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR-3824), enavogliflozin ( DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3-(4-ethylbenzyl) -1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate, remogliflozin, remogliflozin etabonate and T-1095 etabonate (((2R,3S,4S,5R,6S)-6 -(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl). In some embodiments, the one or more additional agents are an SGLT-2 inhibitor selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, serfliflozin, licofliglozin, sotagliflozin and tofogliflozin. It's bexagliflozin. In some embodiments, one or more additional agents are canagliflozin. In some embodiments, one or more additional agents are dapagliflozin. In some embodiments, one or more additional agents are empagliflozin. In some embodiments, one or more additional agents are ertugliflozin. In some embodiments, one or more additional agents are ipragliflozin. In some embodiments, one or more additional agents are luseogliflozin. In some embodiments, the one or more additional agents is remogliflozin. In some embodiments, one or more additional agents are serfliflozin. In some embodiments, the one or more additional agents is licofliglozin. In some embodiments, one or more additional agents are sotagliflozin. In some embodiments, the one or more additional agents is tofogliflozin. In some embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate. In some embodiments, the SGLT-2 inhibitor is canagliflozin hemihydrate.

[0511] In some embodiments, the amount of the SGLT-2 inhibitor is from about 1 mg to about 350 mg. For example, about 1 mg to about 175 mg, about 175 mg to about 350 mg, or about 90 mg to about 260 mg. In some embodiments, the amount of the SGLT-2 inhibitor is from about 85 mg to about 325 mg. In some embodiments, the amount of the SGLT-2 inhibitor is about 1 mg to about 50 mg, about 20 mg to about 70 mg, about 50 mg to about 100 mg, about 70 mg to about 120 mg, about 90 mg to about 140 mg, about 110 mg to about 160 mg, about 130 mg to about 180 mg, about 150 mg to about 200 mg, about 170 mg to about 220 mg, about 190 mg to about 240 mg, about 210 mg to about 260 mg, about 230 mg to about 280 mg, about 250 mg to about 300 mg, about 270 mg to about from 320 mg or about 290 mg to about 350 mg. For example, about 100 mg or about 300 mg. In some embodiments, the amount of the SGLT-2 inhibitor is from about 1 to about 15 mg. For example, about 1 to about 10 mg or about 5 to about 15 mg. In some embodiments, the amount of the SGLT-2 inhibitor is from 1 mg to about 3 mg, about 2 mg to about 4 mg, about 3 mg to about 5 mg, about 4 mg to about 6 mg. mg, about 5 mg to about 7 mg, about 6 mg to about 8 mg, about 7 mg to about 9 mg, about 8 mg to about 10 mg, about 9 mg to about 11 mg, about 10 mg to about 12 mg, about 11 mg to about 13 mg, about 12 mg to about 14 mg, or about 13 mg to about 15 mg.

[0512] In some embodiments, the SGLT-2 inhibitor is canagliflozin. In some embodiments, 100 mg or 300 mg of canagliflozin is administered. In some embodiments, 100 mg or 300 mg of canagliflozin hemihydrate is administered. In some embodiments, the SGLT-2 inhibitor is dapagliflozin. In some embodiments, the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate. In some embodiments, 5 mg or 10 mg of dapagliflozin is administered. In some embodiments, 5 mg or 10 mg of dapagliflozin propylene glycol hydrate is administered. In some embodiments, the SGLT-2 inhibitor is empagliflozin. In some embodiments, 10 mg or 25 mg of empagliflozin is administered. In some embodiments, the SGLT-2 inhibitor is ertugliflozin. In some embodiments, 5 mg or 15 mg of ertugliflozin is administered. In some embodiments, the SGLT-2 inhibitor is ipragliflozin. In some embodiments, 25 mg or 50 mg of ipragliflozin is administered. In some embodiments, the SGLT-2 inhibitor is bexagliflozin. In some embodiments, 20 mg of bexagliflozin is administered. In some embodiments, the SGLT-2 inhibitor is sotagliflozin. In some embodiments, 200 mg or 400 mg of sotagliflozin is administered. In some embodiments, the SGLT-2 inhibitor is licogliflozin. In some embodiments, 15 mg, 50 mg, 75 mg, or 150 mg of licogliflozin are administered.

[0513] In any of the embodiments described herein, various combinations of atrasentan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor are contemplated, producing an effect. In some embodiments, the effect, e.g., any of the beneficial or desired results as described herein, is greater than the sum of the effect observed when the same amount of atrasentan or a pharmaceutically acceptable salt thereof, when co-administered, and the same amount of SGLT-2 inhibitor when co-administered, are administered as monotherapy. In some embodiments, coadministration of atrasentan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor, produces an effect, for example, a therapeutic effect using a lower dose of one or both compounds as a monotherapy. For example, producing a therapeutic effect using a lower dose of atrasentan or a pharmaceutically acceptable salt thereof, and/or the SGLT-2 inhibitor compared to the amount used in monotherapy. For example, in some embodiments, the dose of atrasentan or a pharmaceutically acceptable salt thereof administered in combination with an SGLT-2 inhibitor may be about 50% to about 90% of the dose of atrasentan or a pharmaceutically acceptable salt thereof. acceptable thereof, administered as a monotherapy to produce the same therapeutic effect, e.g., any of the beneficial or desired results, including those described herein. In some embodiments, the dose of the SGLT-2 inhibitor administered in combination with atrasentan, or a pharmaceutically acceptable salt thereof, may be about 50% to about 90% of the dose of the SGLT-2 inhibitor administered as monotherapy. to produce the same therapeutic effect, for example, any of the beneficial or desired results, including those described herein. For example, treat IgA nephropathy, decrease renal inflammation and/or fibrosis, decrease hematuria, decrease proteinuria, stabilize eGFR, decrease the number of disease flares associated with IgA nephropathy, delay the onset of ESRD, decrease fatigue and reduce the activation of a mesangial cell.

[0514] In some embodiments, the present disclosure relates to the use of atrasentan or a pharmaceutically acceptable salt thereof in combination with a second therapeutic for treating a condition as described in various embodiments of the disclosure.

[0515] In some embodiments, the present disclosure relates to the use of atrasentan or a pharmaceutically acceptable salt thereof, to treat a condition as described in various embodiments of the disclosure, wherein the use comprises one or more additional therapeutic agents.

[0516] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising atrasentan or a pharmaceutically acceptable salt thereof and further comprising one or more additional therapeutic agents.

[0517] In some embodiments, one or more additional therapeutic agents inhibit one or more elements of the renin-angiotensin-aldosterone system. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), calcium channel blockers, renin inhibitors, and aldosterone antagonists. In certain particular embodiments, one or more additional therapeutic agents are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). In certain embodiments, one or more additional therapeutic agents are selected from one or more angiotensin-converting enzyme inhibitors. In certain embodiments, one or more additional therapeutic agents are selected from one or more angiotensin II receptor blockers. In certain embodiments, one or more additional therapeutic agents comprise one or more ACE inhibitors and one or more ARBs. For example, one or more renin-angiotensin system inhibitors may be ACE inhibitors, ARB inhibitors, or a combination thereof. For example, the ACE inhibitor can be selected from: quinapril, fosinopril perindopril, captopril, enalapril, enalapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril , rescinamine and pivopril. For example, the ARB can be selected from: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0518] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof, may be co-administered with an SGLT-2 inhibitor and one or more ACE inhibitors and/or one or more ARBs. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with an SGLT-2 inhibitor and one or more ACE inhibitors. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with an SGLT-2 inhibitor and one or more ARBs. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof may be coadministered with an SGLT-2 inhibitor, an ACE inhibitor, and an ARB.

[0519] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included in the spirit and scope of this application and scope of the appended claims. All publications, patents, patent applications and sequence accession numbers cited herein are incorporated herein by reference in their entirety for all purposes.

[0520] The disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the disclosure. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included in the spirit and scope of this application and scope of the appended claims.

SELECTED MODALITIES

[0521] Modality 1: A method for inhibiting the activation of mesangial cells in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, to the subject;

[0522] wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0523] Modality 2: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0524] wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0525] Modality 3: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0526] wherein the subject does not have one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0527] Modality 4: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0528] in which the subject does not suffer from one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0529] Modality 5: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0530] wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS, prostate cancer or acute renal failure.

[0531] Modality 6: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0532] wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer or acute renal failure.

[0533] Modality 7: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0534] wherein the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV-related nephropathy or acute renal failure.

[0535] Modality 8: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0536] wherein the subject is not being treated for one or more of diabetic nephropathy, HIV-related nephropathy, or acute renal failure.

[0537] Modality 9: A method of treating IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0538] wherein the subject was determined to have controlled serum glucose levels;

[0539] wherein the subject has not been diagnosed with one or more of HIV-related nephropathy or acute renal failure.

[0540] Embodiment 10: A method of decreasing renal inflammation and/or fibrosis in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0541] Modality 11: A method for decreasing the occurrence of hematuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0542] Embodiment 12: A method of stabilizing eGFR in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0543] Embodiment 13: A method for decreasing the number of outbreaks of diseases associated with IgA nephropathy in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof. the same.

[0544] Embodiment 14: A method for delaying the onset of ESRD in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0545] Embodiment 15: A method of decreasing proteinuria in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0546] Modality 16: The method of Modality 1, in which mesangial activation is induced by IgA immune complexes.

[0547] Modality 17: The method of Modality 1, in which mesangial activation is associated with the presence of IgA immune complexes.

[0548] Modality 18: The method of Modality 1, in which the inhibition of mesangial cell activation comprises reducing the expression and/or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0549] Modality 19: The method of Modality 1, in which inhibiting the activation of mesangial cells comprises reducing the inflammation of mesangial cells.

[0550] Modality 20: The method of Modality 19, wherein reducing mesangial cell inflammation comprises reducing the expression and/or activity of one or more of IL6, MCP1 or other biomarkers indicative of mesangial cell inflammation.

[0551] Modality 21: The method of Modality 19 or 20, in which reducing inflammation of mesangial cells comprises reducing IL-6 signaling.

[0552] Modality 22: The method of Modality 1, in which the inhibition of the activation of mesangial cells comprises the reduction of the pro-fibrotic response in the mesangial cells.

[0553] Modality 23: The method of Modality 22, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0554] Modality 24: The method of Modality 22 or 23, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF -α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8 , Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel , Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0555] Modality 25: The method of any of Modalities 22-24, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF , MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF- α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1.

[0556] Modality 26: The method of any of Modalities 22-25, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra , Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1 , Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0557] Modality 27: The method of any of Modalities 22-25, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing NF-KB signaling and/or PDGF signaling.

[0558] Modality 28: The method of any of Modalities 23-27, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells.

[0559] Modality 29: The method of Modality 28, wherein reducing matrix secretion by mesangial cells comprises reducing the expression and/or activity of one or more excess matrix secretion by mesangial cells.

[0560] Modality 30: The method of any of Modalities 1-29, wherein the subject is not currently receiving one or more immunosuppressants.

[0561] Modality 31: The method of any of Modalities 1-30, wherein the subject is also being administered one or more additional agents.

[0562] Modality 32: The method of Modality 31, in which one or more additional agents are selected from alcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B cell inhibitors, cytotoxic agents, mTOR inhibitors and steroids.

[0563] Modality 33: The method of Modality 31 or 32, in which one or more additional agents are immunosuppressive.

[0564] Modality 34: The method of any of Modalities 31-33, wherein one or more additional agents are steroids.

[0565] Modality 35: The method of Modality 34, in which the steroids are selected from the group consisting of prednisone, dexamethasone, hydrocortisone, cyclosporine and combinations of any of the above.

[0566] Modality 36: The method of Modality 31 or 32, in which one or more additional agents are aminoquinolines.

[0567] Modality 37: The method of any of Modalities 31, 32 or 36, wherein the one or more additional agents is hydroxychloroquine.

[0568] Modality 38: The method of any of Modalities 31-37, wherein the dosage of one or more additional agents is decreased after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof .

[0569] Modality 39: The method of any of Modalities 33-38, in which the dosage of one or more additional agents is decreased by about 25% to about 100%.

[0570] Modality 40: The method of any of Modalities 33-39, in which the dosage of one or more additional agents is decreased by about 50% to about 100%.

[0571] Modality 41: The method of any of Modalities 33-40, in which the dosage of one or more additional agents is decreased by about 75% to about 100%.

[0572] Embodiment 42: A method for decreasing fatigue in a subject with IgA nephropathy, comprising administering a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof to a subject in need thereof;

[0573] wherein the subject was determined not to suffer from one or more of diabetic nephropathy, HIV-related nephropathy, prostate cancer, or acute renal failure.

[0574] Modality 43: The method of Modality 42, in which fatigue is reduced by about 10% to about 20%.

[0575] Modality 44: The method of Modality 42 or 43, wherein the decrease in fatigue comprises a decrease in the score on one or more of the Fatigue Severity Scale, the Chalder Fatigue Scale, the FACIT Fatigue Scale, the Inventory of Brief Fatigue, the FACT-F Subscale, Vigor and Global Affect, the May and Kline Adjective Checklist, the Pearson-Byars Feelings of Fatigue Checklist, the Rhoten Fatigue Scale, the Fatigue Schedule and Anergy or the Individual Strength Checklist.

[0576] Modality 45: The method of any of Modalities 1-44, wherein the subject is concomitantly receiving an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an antagonist of aldosterone, fish oil, hydroxychloroquine, or a combination of any of the above.

[0577] Modality 46: The method of any of Modalities 1-45, in which the subject is concomitantly receiving an ACE inhibitor, an ARB, or a combination thereof.

[0578] Modality 47: The method of Modality 45 or 46, in which the statin is selected from: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and pitavastatin.

[0579] Modality 48: The method of any of Modalities 45-47, wherein the diuretic is selected from: hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, quinetazone, metolazone, chlorothiazide, chlorthalidone, indapamide, methylclothiazide bemethanide, torsemide, piretanide, ethacrynic acid, bumetanide, furosemide, triamterene, spironolactone, eplerenone and amiloride.

[0580] Modality 49: The method of any of Modalities 45-48, in which the ACE inhibitor is selected from: quinapril, fosinopril, perindopril, captopril, enalapril, enalapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril , benazepril, lisinopril, spirapril, trandolapril, perindep, pentopril, moexipril, rescinamine and pivopril.

[0581] Modality 50: The method of any of Modalities 45-49, in which the ACE inhibitor is selected from: quinapril, fosinopril, captopril, enalapril and lisinopril.

[0582] Modality 51: The method of any of Modalities 45-50, wherein the ACE inhibitor is quinapril.

[0583] Modality 52: The method of any of Modalities 45-50, wherein the ACE inhibitor is fosinopril.

[0584] Modality 53: The method of any of Modalities 45-50, wherein the ACE inhibitor is captopril.

[0585] Modality 54: The method of any of Modalities 45-50, wherein the ACE inhibitor is enalapril.

[0586] Modality 55: The method of any of Modalities 45-50, wherein the ACE inhibitor is lisinopril.

[0587] Modality 56: The method of any of Modalities 45-55, in which the ARB is selected from: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil and BRA- 657.

[0588] Modality 57: The method of any of Modalities 45-56, in which the ARB is selected from: candesartan, losartan, olmesartan and valsartan.

[0589] Modality 58: The method of any of Modalities 45-57, wherein the ARB is candesartana.

[0590] Modality 59: The method of any of Modalities 45-57, wherein the ARB is losartan.

[0591] Modality 60: The method of any of Modalities 45-57, wherein the ARB is olmesartan.

[0592] Modality 61: The method of any of Modalities 45-57, wherein the ARB is valsartan.

[0593] Modality 62: The method of any of Modalities 45-61, wherein dosing an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a beta blocker, an aldosterone antagonist , fish oil, hydroxychloroquine or a combination of any of the above, is tapered after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0594] Modality 63: The method of any of Modalities 45-62, in which the dosage is decreased by about 25% to about 100%.

[0595] Modality 64: The method of any of Modalities 45-63, in which the dosage is decreased by about 50% to about 100%.

[0596] Modality 65: The method of any of Modalities 45-64, in which the dosage is decreased by about 75% to about 100%.

[0597] Modality 66: The method of any of Modalities 46 or 49-65, in which the dosage of an ACE inhibitor, an ARB and/or a diuretic is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof .

[0598] Modality 67: The method of any of Modalities 46 or 49-66, in which the dosage of an ACE inhibitor, an ARB and/or a diuretic is decreased after about 15 days to about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0599] Modality 68: The method of any of Modalities 46 or 49-67, in which the dosage of an ACE inhibitor, an ARB and/or a diuretic, is decreased by about 25% to about 100% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0600] Modality 69: The method of any of Modalities 46 or 49-68, in which the dosage of an ACE inhibitor, an ARB and/or a diuretic is decreased by about 50% to about 100% after the treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0601] Modality 70: The method of any of Modalities 46 or 49-69, in which the dosage of an ACE inhibitor, an ARB and/or a diuretic, is decreased by about 75% to about 100% after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0602] Modality 71: The method of Modality 66, in which the dosage of an ACE inhibitor is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0603] Modality 72: The method of Modality 66, in which the dosage of an ARB is decreased after treatment with atrasentan, or a pharmaceutically acceptable salt thereof.

[0604] Modality 73: The method of Modality 66, in which the dosage of a diuretic is decreased after treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0605] Modality 74: The method of any of Modalities 1-73, in which atrasentan is administered as a pharmaceutically acceptable salt.

[0606] Modality 75: The method of any of Modalities 1-74, in which atrasentan is administered as atrasentan hydrochloride or atrasentan mandelate.

[0607] Modality 76: The method of any of Modalities 1-75, in which atrasentan is administered as atrasentan hydrochloride.

[0608] Modality 77: The method of any of Modalities 1-76, in which atrasentan is administered as the free base.

[0609] Modality 78: The method of any of Modalities 1-77, in which the subject is at high risk of progression to ESRD.

[0610] Modality 79: The method of any of Modalities 1-78, in which the subject has been diagnosed with IgA nephropathy.

[0611] Modality 80: The method of Modality 79, wherein the diagnosis of IgA nephropathy comprises a renal biopsy, detection of antiglycan antibodies, detection of deposition of IgA immune complexes in the kidney, or a combination of any of the foregoing.

[0612] Modality 81: The method of Modality 79 or 80, in which the diagnosis of IgA nephropathy comprises a renal biopsy.

[0613] Modality 82: The method of any of Modalities 1-81, wherein the subject is excreting an average of about 0.5 grams or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0614] Modality 83: The method of any of Modalities 1-82, wherein the subject is excreting an average of about 0.75 grams or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0615] Modality 84: The method of any of Modalities 1-82, wherein the subject is excreting an average of about 1 gram or more of protein in the urine per day for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0616] Modality 85: The method of any of Modalities 1-84, wherein the subject has an average eGFR of about 20 to about 90 ml/min/1.73 m2 for at least about 3 months prior to first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0617] Modality 86: The method of any of Modalities 1-85, wherein the subject has an average eGFR of about 30 to about 90 ml/min/1.73 m2 for at least about 3 months prior to first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0618] Modality 87: The method of any of Modalities 1-85, wherein the subject has an average eGFR of about 20 to about 60 ml/min/1.73 m2 for at least about 3 months prior to first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0619] Modality 88: The method of any of Modalities 1-87, wherein the subject has an average HbA1c of about 4% to about 6% for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0620] Modality 89: The method of any of Modalities 1-88, wherein the subject has an average fasting blood glucose level of about 125 mg/dl or less for at least about 3 months prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0621] Modality 90: The method of any of Modalities 1-89, in which the subject maintains a potassium level within the normal physiological range.

[0622] Modality 91: The method of any of Modalities 1-90, in which the subject maintains a sodium level within the normal physiological range.

[0623] Modality 92: The method of any of Modalities 1-91, wherein the subject has ALT/AST levels during administration of atrasentan or a pharmaceutically acceptable salt thereof, which are approximately the same as the levels of ALT/AST before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0624] Modality 93: The method of any of Modalities 1-92, wherein the subject has bilirubin levels during administration of atrasentan or a pharmaceutically acceptable salt thereof that are approximately the same as the bilirubin levels before of the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0625] Modality 94: The method of any of Modalities 1-93, wherein fluid retention in the subject is manageable with diuretics.

[0626] Modality 95: The method of any of Modalities 1-94, in which the amount of protein in the subject's urine is reduced by about 20% to about 80% after between about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0627] Modality 96: The method of Modality 95, in which the amount of protein in the subject's urine is reduced by about 35% to about 80%.

[0628] Modality 97: The method of any of Modalities 1-96, in which the amount of protein in the subject's urine is reduced by about 100 mg/dl to about 500 mg/dl after about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0629] Modality 98: The method of any of Modalities 1-97, wherein the amount of protein in the subject's urine is reduced by about 500 mg/dl to about 900 mg/dl after about 15 days and about 30 days of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0630] Modality 99: The method of any of Modalities 1-98, wherein the subject's risk of developing ESRD is reduced by about 20% to about 99% after between about 6 months and about 24 months of treatment with atrasentan or a pharmaceutically acceptable salt thereof.

[0631] Modality 100: The method of any of Modalities 1-99, wherein the subject's risk of developing ESRD is reduced by about 20% to about 99% after between about 12 months and about 24 months of treatment with atrasentan, or a pharmaceutically acceptable salt thereof.

[0632] Modality 101: The method of any of Modalities 1-100, wherein the average rate of decrease in eGFR is from about 0.75 ml/min/year to about 6 ml/min/year for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0633] Modality 102: The method of any of Modalities 1-101, wherein the average rate of decrease in eGFR is from about 3 ml/min/year to about 6 ml/min/year for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0634] Modality 103: The method of any of Modalities 1-102, wherein the average rate of decrease in eGFR is from about 4 ml/min/year to about 5 ml/min/year for at least about 3 months before the first administration of atrasentan or a pharmaceutically acceptable salt thereof.

[0635] Modality 104: The method of any of Modalities 1-103, wherein the average rate of decrease in eGFR is reduced by about 15% to about 30% after between about 6 months and about 24 months of treatment with atrasentan, or a pharmaceutically acceptable salt thereof.

[0636] Modality 105: The method of any of Modalities 1-104, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, is about 0.20 mg to about 1.5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0637] Modality 106: The method of any of Modalities 1-105, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, is about 0.25 mg to about 1.25 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0638] Modality 107: The method of any of Modalities 1-106, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof, is about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0639] Modality 108: The method of any of Modalities 1-107, wherein the therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof is about 0.75 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0640] Modality 109: The method of any of Modalities 1-108, further comprising determining the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM , COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3 , Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1 , Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0641] Modality 110: The method of any of Modalities 1-109, further comprising determining the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN , ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1.

[0642] Modality 111: The method of any of Modalities 1-110, further comprising determining the expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0643] Modality 112: The method of any of Modalities 1-108, further comprising determining the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, NF-kB and IL6 in the subject.

[0644] Modality 113: The method of Modality 109, in which the determination of expression and/or activity is performed prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0645] Modality 114: The method of Modality 109, in which the determination of expression and/or activity is carried out after administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0646] Modality 115: The method of any of Modalities 1-114, further comprising administering a therapeutically effective amount of an SGLT-2 inhibitor.

[0647] Modality 116: The method of Modality 115, in which the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR- 3824), enavogliflozin DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glucoside 18 (3-( 4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate, remogliflozin, remogliflozin etabonate and T-1095 etabonate (((2R,3S,4S,5R, 6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl ).

[0648] Modality 117: The method of Modality 115 or 116, in which the SGLT-2 inhibitor is selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, serfliflozin, licofliglozin, sotagliflozin and ozina.

[0649] Modality 118: The method of any of Modalities 115-117, wherein the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin or ertugliflozin.

[0650] Modality 119: The method of any of Modalities 115-117, wherein the SGLT-2 inhibitor is canagliflozin.

[0651] Modality 120: The method of any of Modalities 115-117, wherein the SGLT-2 inhibitor is dapagliflozin.

[0652] Modality 121: The method of any of Modalities 115-117, wherein the SGLT-2 inhibitor is empagliflozin.

[0653] Modality 122: The method of any of Modalities 115-117, wherein the SGLT-2 inhibitor is ertugliflozin.

[0654] Modality 123: The method of any of Modalities 115-122, wherein the subject receives an SGLT-2 inhibitor and one or more ACE inhibitors and/or one or more ARBs.

[0655] Modality 124: The method of any of Modalities 115-123, wherein the subject receives an SGLT-2 inhibitor and one or more ACE inhibitors.

[0656] Modality 125: The method of any of Modalities 115-123, wherein the subject receives an SGLT-2 inhibitor and one or more ARBs.

[0657] Modality 126: The method of any of Modalities 115-123, wherein the subject receives an SGLT-2 inhibitor and an ACE inhibitor.

[0658] Modality 127: The method of any of Modalities 115-123, wherein the subject receives an SGLT-2 inhibitor and an ARB.

[0659] Modality 128: The method of any of Modalities 115-123, wherein the subject receives an SGLT-2 inhibitor, an ACE inhibitor, and an ARB.

[0660] Embodiment 129: A method for inhibiting the activation of mesangial cells, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0661] Modality 130: The method of Modality 129, in which mesangial activation is induced by IgA immune complexes.

[0662] Modality 131: The method of Modality 129, in which mesangial activation is associated with the presence of IgA immune complexes.

[0663] Modality 132: The method of Modality 129, wherein inhibiting mesangial cell activation comprises reducing the expression and/or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0664] Modality 133: The method of Modality 129, in which inhibiting the activation of mesangial cells comprises reducing the inflammation of mesangial cells.

[0665] Modality 134: The method of Modality 133, wherein reducing mesangial cell inflammation comprises reducing the expression and/or activity of one or more of IL6, MCP1 or other biomarkers indicative of mesangial cell inflammation.

[0666] Modality 135: The method of Modality 134, in which reducing inflammation of mesangial cells comprises reducing IL-6 signaling.

[0667] Modality 136: The method of Modality 129, in which inhibiting the activation of mesangial cells comprises reducing the pro-fibrotic response in mesangial cells.

[0668] Modality 137: The method of Modality 136, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0669] Modality 138: The method of Modality 136 or 137, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF -α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1 , Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5 , Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0670] Modality 139: The method of Modality 136 or 137, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF -α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1.

[0671] Modality 140: The method of Modality 136 or 137, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0672] Modality 141: The method of Modality 136 or 137, in which the reduction of the pro-fibrotic response in mesangial cells comprises the reduction of NF-KB signaling and/or PDGF signaling.

[0673] Modality 142: The method of any of Modalities 136-141, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells.

[0674] Modality 143: The method of Modality 142, wherein reducing matrix secretion by mesangial cells comprises reducing the expression and/or activity of one or more excess matrix secretion by mesangial cells.

[0675] Embodiment 144: A method for reducing the activation of a mesangial cell in contact with an IgA immune complex, comprising contacting a mesangial cell with an effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0676] Modality 145: The method of Modality 144, in which the reductive activation of a mesangial cell comprises the reduction of the expression and/or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0677] Modality 146: The method of Modality 144, in which the reductive activation of a mesangial cell comprises the reduction of inflammation of the mesangial cells.

[0678] Modality 147: The method of Modality 146, wherein reducing mesangial cell inflammation comprises reducing the expression and/or activity of one or more of IL6, MCP1 or other biomarkers indicative of mesangial cell inflammation.

[0679] Modality 148: The method of Modality 144, in which the reductive activation of a mesangial cell comprises the reduction of the pro-fibrotic response in the mesangial cells.

[0680] Modality 149: The method of Modality 148, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0681] Modality 150: The method of Modality 148 or 149, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF -α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1 , Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5 , Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0682] Modality 151: The method of Modality 148 or 149, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1/2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF -α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt/PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1.

[0683] Modality 152: The method of Modality 148 or 149, in which reducing the pro-fibrotic response in mesangial cells comprises reducing the expression and/or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb.

[0684] Modality 153: The method of any of Modalities 148-152, wherein reducing the pro-fibrotic response in mesangial cells comprises reducing matrix secretion by mesangial cells.

[0685] Modality 154: The method of Modality 153, wherein reducing matrix secretion by mesangial cells comprises reducing the expression and/or activity of one or more biomarkers indicative of excess matrix secretion by mesangial cells.

[0686] Modality 155: The method of Modality 144, in which the reductive activation of a mesangial cell comprises the reduction of unwanted migration of mesangial cells.

[0687] Modality 156: The method of any of Modalities 129-155, in which contact occurs in vitro.

[0688] Modality 157: The method of any of Modalities 129-155, in which contact occurs in vivo.

[0689] Modality 158: A method of treating IgA nephropathy in a subject in need thereof, characterized by the fact that it comprises:

[0690] a) determine that the subject has IgA immune complex deposition in the kidney; It is

[0691] b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0692] Modality 159: The method of Modality 158, in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0693] Modality 160: The method of Modality 158, in which the subject has not been previously diagnosed with HIV-related nephropathy.

[0694] Modality 161: The method of any of Modalities 158-160, wherein the subject is not currently diagnosed with cancer.

[0695] Modality 162: The method of any of Modalities 158-160, wherein the subject is not currently being treated for cancer.

[0696] Modality 163: The method of any of Modalities 158-160, wherein the subject has not been previously diagnosed with cancer.

[0697] Modality 164: The method of Modality 163, wherein the cancer is lung cancer or prostate cancer.

[0698] Modality 165: A method of treating IgA nephropathy in a subject in need thereof, characterized by the fact that it comprises:

[0699] a) determine that the subject has high levels of mesangial activation; It is

[0700] b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0701] Modality 166: The method of Modality 165, in which determining high levels of mesangial activation comprises obtaining a sample from the subject and evaluating the level of mesangial activation therein.

[0702] Modality 167: The method of Modality 166, wherein the sample is a kidney biopsy sample.

[0703] Modality 168: The method of Modality 166 or 167, in which the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition, mesangial cell proliferation and endocapillary cell proliferation.

[0704] Modality 169: The method of any of Modalities 166-168, wherein the sample exhibits high levels of IgA immune complex deposition.

[0705] Modality 170: The method of any of Modalities 165-169, in which the subject was determined to have proteinuria of at least 1 g/day in at least two of three consecutive readings over the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0706] Modality 171: The method of any of Modalities 165-170, wherein the subject has received a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a salt pharmaceutically acceptable thereof.

[0707] Modality 172: The method of any of Modalities 165-171, wherein the subject is simultaneously administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof .

[0708] Modality 173: The method of any of Modalities 165-171, wherein the subject was determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0709] Modality 174: The method of Modality 173, in which the hematuria is microhematuria.

[0710] Modality 175: The method of Modality 173, in which the hematuria is gross hematuria.

[0711] Modality 176: The method of any of Modalities 165-175, wherein the subject was determined to have an eGFR of at least 30 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or of a pharmaceutically acceptable salt thereof.

[0712] Modality 177: The method of any of Modalities 165-176, in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0713] Modality 178: The method of any of Modalities 165-177, wherein the subject has not been previously diagnosed with HIV-related nephropathy.

[0714] Modality 179: The method of any of Modalities 165-178, wherein the subject is not currently diagnosed with cancer.

[0715] Modality 180: The method of any of Modalities 165-178, wherein the subject is not currently being treated for cancer.

[0716] Modality 181: The method of any of Modalities 165-178, wherein the subject has not been previously diagnosed with cancer.

[0717] Modality 182: The method of Modality 181, wherein the cancer is lung cancer or prostate cancer.

[0718] Modality 183: The method of any of Modalities 165-182, wherein the assessment of the level of mesangial activation in the sample comprises one or more of serum analysis, urinalysis, light microscopy and immunofluorescence microscopy.

[0719] Modality 184: A method of treating IgA nephropathy in a subject in need thereof that comprises:

[0720] a) determine that the subject has elevated levels of IgA immune complexes in the kidney; It is

[0721] b) administering to the subject a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0722] Modality 185: The method of Modality 184, in which determining elevated levels of IgA immune complexes in the kidney comprises obtaining a renal biopsy sample from the subject and evaluating the level of IgA immune complexes therein.

[0723] Modality 186: The method of Modality 184 or 185, in which the sample exhibits elevated levels of one or more of: matrix secretion by mesangial cells, activation of mesangial cells, proliferation of mesangial cells, and proliferation of endocapillary cells.

[0724] Modality 187: The method of any of Modalities 184-186, wherein the subject was determined to have proteinuria of at least 1 g/day in at least two of three consecutive readings over the year prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0725] Modality 188: The method of any of Modalities 184-187, wherein the subject has received a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0726] Modality 189: The method of any of Modalities 184-188, wherein the subject is simultaneously administered a maximum tolerated stable dose of a RAS inhibitor and a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof .

[0727] Modality 190: The method of any of Modalities 184-189, wherein the subject was determined to have hematuria prior to administration of a therapeutically effective amount of atrasentan or a pharmaceutically acceptable salt thereof.

[0728] Modality 191: The method of Modality 190, in which the hematuria is microhematuria.

[0729] Modality 192: The method of Modality 190, in which the hematuria is gross hematuria.

[0730] Modality 193: The method of any of Modalities 184-192, wherein the subject was determined to have an eGFR of at least 30 ml/min/1.73 m2 prior to administration of a therapeutically effective amount of atrasentan or of a pharmaceutically acceptable salt thereof.

[0731] Modality 194: The method of any of Modalities 184-193, in which the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure.

[0732] Modality 195: The method of any of Modalities 184-194, wherein the subject has not been previously diagnosed with HIV-related nephropathy.

[0733] Modality 196: The method of any of Modalities 184-195, wherein the subject is not currently diagnosed with cancer.

[0734] Modality 197: The method of any of Modalities 184-196, wherein the subject is not currently being treated for cancer.

[0735] Modality 198: The method of any of Modalities 184-197, wherein the subject has not been previously diagnosed with cancer.

[0736] Modality 199: The method of any of Modalities 196-198, wherein the cancer is lung cancer or prostate cancer.

[0737] Modality 200: The method of any of Modalities 185-199, wherein the assessment of the level of IgA immune complexes in the sample comprises one or more of serum analysis, urinalysis, light microscopy and immunofluorescence microscopy.

[0738] Modality 201: The method of any of Modalities 158-200, further comprising administering an SGLT-2 inhibitor.

[0739] Modality 202: The method of Modality 201, in which the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empaglifozin, bexagliflozin, licogliflozin, janagliflozin (XZP-5695), tofogliflozin, ertugliflozin, henagliflozin (SHR- 3824), enavogliflozin DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glucoside 18 (3-( 4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate, remogliflozin, remogliflozin etabonate and T-1095 etabonate (((2R,3S,4S,5R, 6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl ).

[0740] Modality 203: The method of Modality 200 or 201, in which the SGLT-2 inhibitor is selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, serfliflozin, licofliglozin, sotagliflozin and ozina.

[0741] Modality 204: The method of any of Modalities 201-203, wherein the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin or ertugliflozin.

EXAMPLES EXAMPLE 1. IN VITRO STUDY USING A CELLULAR MODEL OF HUMAN IgA NEPHROPATHY

[0742] Primary human mesangial cells in a culture are stimulated with pathogenic dgIgA immune complexes isolated from patients with human IgA nephropathy or generated in vitro. Proliferation as well as pro-inflammatory and pro-fibrotic responses to these disease-causing immune complexes are observed in mesangial cells within 48 hours. The cells are treated with atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) in an appropriate medium. Changes in proliferation, pro-inflammatory responses and/or pro-fibrotic responses are measured. The outcome of this study will indicate the extent to which atrasentan attenuates the underlying disease processes in IgA nephropathy in an in vitro model.

EXAMPLE 2. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFICACY OF ATRASENTAN IN PATIENTS WITH IgA NEPHROPATHY

[0743] This example describes a randomized, double-blind, placebo-controlled efficacy and safety study of atrasentan in patients with IgA nephropathy on renin angiotensin system (RAS) inhibitors with persistent proteinuria and risk of rapid renal progression.

STUDY OVERVIEW

[0744] This protocol covers 2 periods. The first period involves open-label treatment of approximately 20-30 patients with IgA nephropathy to confirm the safety and tolerability of atrasentan 0.75 mg daily for 6 weeks. After all patients have completed at least 6 weeks of treatment, an independent Data Monitoring Committee (DMC) reviews all available safety data, including adverse events, laboratory studies, and vital signs, and makes a recommendation regarding the feasibility of the profile. safety data be consistent with previous clinical experience, and the safety data support continued evaluation in the larger randomized study. If the DMC recommends continuation of the randomized study, initial open-label patients continue to receive open-label treatment for 110 weeks (approximately two years).

[0745] The second period involves a double-blind, placebo-controlled study of approximately 350-400 patients randomized 1:1 to receive atrasentan 0.75 mg per day or a matched placebo for 110 weeks. Patients are monitored regularly with markers of kidney function in blood and urine, as well as safety assessments.

[0746] Both the initial open cohort and the double-blind randomized cohort receive assigned treatment through week 110. All patients subsequently discontinue study drug at week 110 and return for a safety/study completion visit at week 114. Any patients who discontinue treatment before week 114 will have a safety follow-up visit approximately four weeks after the last dose of study drug. After the safety follow-up visit, patients who discontinue treatment prematurely are encouraged to remain in the study for quarterly efficacy assessments to provide data for study endpoints.

GOALS:

[0747] The main objectives of this study are:

[0748] (1) To confirm the short-term safety and tolerability of atrasentan 0.75 mg per day in patients with IgA nephropathy; It is

[0749] (2) Evaluate the effect of atrasentan on proteinuria levels at week 24 compared to placebo.

[0750] The secondary objectives are:

[0751] (3) Evaluate the effect of atrasentan on reducing the estimated glomerular filtration rate (eGFR) between baseline and week 114 (4 weeks after stopping randomized treatment);

[0752] (4) To compare the two-year on-treatment rates of change in eGFR between atrasentan and placebo (eGFR slope week 6 to 110 of randomized treatment); It is

[0753] (5) Compare the percentage of patients who achieved a partial clinical response with reduction in proteinuria to less than 1 g/day at week 24 between atrasentan and placebo.

[0754] The exploratory objectives are:

[0755] (6) Evaluate the percentage of patients who achieved partial and complete responses at each time point between week 6 and 114;

[0756] (7) Evaluate the quality of life (QoL) of patients who received atrasentan compared to placebo; It is

[0757] (8) Evaluate the steady-state pharmacokinetics of atrasentan that supports exploratory exposure-response analyses.

INDIVIDUALS NUMBER

[0758] Approximately 20-30 patients are enrolled in the phase 2 safety period and approximately 350-400 patients are enrolled in the randomized double-blind period.

[0759] Patients who discontinue the initial open-label period for reasons other than safety may be replaced at the sponsor's discretion to ensure adequate review of safety data after at least 6 weeks of treatment.

NUMBER OF STUDY SITES: APPROXIMATELY 120 SITES WORLDWIDE INCLUSION CRITERIA:

[0760] The inclusion criteria follow. Patients must meet ALL of the following inclusion criteria to be enrolled:

[0761] (1) male and female patients aged 18 or over;

[0762] (2) biopsy-proven diagnosis of IgA nephropathy not due to secondary causes;

[0763] (3) receiving a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to screening;

[0764] (4) proteinuria of at least 1 g/day at screening and in at least two of three consecutive readings in the previous year;

[0765] (5) eGFR of at least 30 ml/min/1.73 m2 at screening;

[0766] (6) willing to comply with highly effective forms of contraception as specified in the protocol throughout the study; It is

[0767] (7) willing and able to provide written informed consent and comply with all study visits and procedures.

EXCLUSION CRITERIA

[0768] The following are the exclusion criteria; Patients must meet NONE of the following exclusion criteria to be enrolled:

[0769] (1) concurrent diagnosis of another cause of chronic kidney disease, including diabetic kidney disease, hypertensive kidney disease, or other primary glomerulopathy. A history of well-controlled hypertension is acceptable;

[0770] (2) presence of cellular glomerular crescents in >25% of glomeruli on renal biopsy (if biopsy is available within 6 months of screening) or clinical suspicion of rapidly progressive glomerulonephritis (RPGN);

[0771] (3) history of organ transplantation;

[0772] (4) use of systemic immunosuppressive medications (or investigational agents) for at least 2 weeks in the last 6 months;

[0773] (5) blood pressure >160 systolic or >100 diastolic at screening;

[0774] (6) history of heart failure or previous hospital admissions for conditions related to fluid overload, such as uncontrolled peripheral edema, pleural effusion or ascites;

[0775] (7) history of clinically significant liver disease and transaminase or bilirubin values above twice the upper limit of normal;

[0776] (8) hemoglobin below 9 g/dl at screening or previous history of blood transfusion for anemia within 3 months of screening;

[0777] (9) history of malignancy, unless cancer-free for at least 5 years or non-melanoma skin cancer that does not require ongoing treatment;

[0778] (10) pregnancy, breastfeeding or intention to become pregnant during the study period for women;

[0779] (11) intention to become a father during the study period for males;

[0780] (12) received any experimental or biological agent within 1 month (or 5 half-lives of the agent, whichever is greater) prior to screening;

[0781] (13) concomitant clinically significant, unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic disease that, in the opinion of the Investigator, may confound the results of the study or represent additional risk to the patient for their participation in the study; or

[0782] (14) history of disorder related to alcohol or illicit drugs.

[0783] Note: Screening a previously ineligible patient may be repeated with the approval of the medical monitor.

TEST PRODUCT(S), DOSE AND METHOD OF ADMINISTRATION:

[0784] Patients in the open-label period receive atrasentan 0.75 mg once daily by oral administration. Patients in the randomized double-blind period receive: atrasentan 0.75 mg once daily by oral administration; or matching placebo once daily by oral administration.

[0785] Treatment assignment during the randomized study period is determined by an interactive voice/web response system (IXRS). Patients, investigators, and the sponsor have access to the assigned study treatment. In the event of a medical emergency, the investigator can receive treatment assignment through the IXRS system if necessary to provide optimal patient care. Randomization is stratified by region (North America versus all other regions) and baseline urinary protein levels at screening (>2 g/day versus <2 g/day).

DURATION OF TREATMENT:

[0786] Screening duration: up to 4 weeks

[0787] Duration of treatment: 110 weeks

[0788] Security follow-up: 4 weeks

[0789] Total study duration for an individual patient: Up to 118 weeks (approximately 2.3 years)

EVALUATION CRITERIA: EFFECTIVENESS

[0790] The primary efficacy endpoint is the change in proteinuria (urine protein/creatinine ratio based on 24-hour urine collection) from baseline to week 24 in atrasentan-treated patients compared to placebo-treated patients.

[0791] The primary secondary efficacy endpoint is the rate of change in eGFR measured via a slope calculated from values at baseline to the follow-up/study completion safety visit (week 114) in patients treated with atrasentan compared to placebo-treated patients.

[0792] Additional secondary efficacy endpoints include: rate of change in eGFR over two years of treatment, measured via a chronic slope calculated from week 6 through week 110 values in patients treated with atrasentan compared to patients treated with placebo and the percentage of patients achieving partial and complete clinical responses.

EVALUATION CRITERIA: SAFETY

[0793] Safety endpoints include:

[0794] (1) frequency and severity of adverse events and serious adverse events;

[0795] (2) Frequency and severity of adverse events of special interest, including heart failure events and/or fluid overload; It is

[0796] (3) Clinically significant changes in safety labs, ECGs, or physical examination findings (including vital signs). STOPPING CRITERIA

[0797] An independent data monitoring committee (DMC) is appointed to monitor the study. The DMC meets periodically to review safety data and makes recommendations regarding continuation, modification, suspension, or termination of the study. The DMC also makes a formal recommendation to proceed with the randomized study after completion of at least 6 weeks of treatment for all patients in the open-label period.

[0798] The only study drug discontinuation criteria required is evidence of pregnancy or noncompliance with protocol-specified contraception or pregnancy monitoring. Other study drug discontinuation criteria may be based on investigator and patient discretion, which may include fluid overload syndromes not controlled with diuretics and medical treatment and any suspected study drug-related adverse event that represents unacceptable toxicity.

[0799] All patients who discontinue study medication before week 110 are encouraged to continue quarterly visits through week 114 for efficacy assessments only.

EVALUATION CRITERIA: PHARMACOKINETICS AND PHARMACODYNAMICS

[0800] The pharmacokinetic and pharmacodynamic endpoints are:

[0801] (1) plasma levels of atrasentan; It is

[0802] (2) exploratory biomarkers.

[0803] Note: PK sampling is insufficient to support the development of a population PK.

STATISTICAL METHODS: TREATMENT POPULATION DEFINITIONS:

[0804] • All open-label participants comprise the Open-Label Population for Safety Analyzes and Non-Comparative Descriptive Efficacy Analyzes

[0805] • All randomized participants receiving any amount of study drug comprise the Safety Population for safety and exposure analyzes

[0806] • All randomized participants comprise the intention-to-treat population for efficacy analyzes

[0807] • All randomized participants who receive any amount of study drug and who have at least one post-baseline PK sample comprise the PK Population

SAFETY AND TOLERABILITY:

[0808] Continuous safety data is summarized with descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum, and maximum) by treatment group. Categorical safety data are summarized with frequency counts and percentages by treatment group. Adverse events are coded using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA) available. The number of participants who experienced treatment-emergent adverse events, as well as maximum severity and relationship to study drug are summarized.

[0809] Laboratory assessments, vital sign assessments, and ECG parameters are summarized by treatment group and protocol-specified collection time point. A summary of the change from baseline at each protocol-specified time point by treatment group is also presented. Concomitant medications are listed by participant and coded using the most current World Health Organization medication dictionary. Medical history is listed by individual. Further details on the presentation and analysis of safety data are detailed in the Statistical Analysis Plan (SAP).

PHARMACOKINETICS:

[0810] Individual steady-state atrasentan concentration data are listed and summarized with descriptive statistics (sample size, arithmetic mean, SD, median, minimum, maximum, geometric mean, and geometric coefficient of variation). These data can be fed into a larger population PK model of atrasentan. Correlations between atrasentan drug levels and safety or efficacy responses can be explored. Details on the statistical analyzes of pharmacokinetic data are provided in the SAP.

EFFECTIVENESS REVIEWS:

[0811] Descriptive statistics are used to assess differences in demographic and baseline characteristics. The primary efficacy endpoint is the change from baseline for each post-baseline visit through week 24 in the ratio of urinary protein to creatinine, as determined from 24-hour urine collection samples. The primary analysis is performed using log-transformed data and a repeated measures analysis using all data collected at baseline, week 12, and week 24. Additional sensitivity analyzes are performed on the primary outcome to assess the robustness and impact of the data absent. Subgroup analyzes are performed as specified in SAP. After collection and analysis of primary outcome data at week 24, randomized study patients continue to receive assigned study treatment until study completion at week 114.

EXAMPLE 3. IN VITRO STUDY USING A CELLULAR MODEL OF HUMAN IgA NEPHROPATHY

[0812] Primary human mesangial cells in a culture were stimulated with immune complexes containing pathogenic galactose (Gd)-IgA deficiency isolated from patients with human IgA nephropathy. Proliferation as well as pro-inflammatory and pro-fibrotic responses to these disease-causing immune complexes were observed in mesangial cells within 48-72 hours. Cells were treated with atrasentan and changes in proliferation, pro-inflammatory responses and/or pro-fibrotic responses were measured.

[0813] Specifically, pathogenic IgA-containing immune complexes have been isolated from the serum of patients with IgA nephropathy or from healthy individuals of similar age, sex and ethnicity. Frozen serum was purchased from BioIVT and IgA-containing immune complexes were purified using jacalin affinity chromatography. Briefly, 2 ml of serum was applied to a jacalin-agarose affinity column (ThermoFisher) and IgA was eluted with 0.1 M melibiose (Sigma Aldrich). Purified IgA-containing immune complexes were concentrated using an Amicon 100K filtration unit and the amount of total IgA and galactose-deficient IgA (Gd-IgA) in the immune complexes was measured by ELISA (ThermoFisher and IBL America, respectively). Primary human renal mesangial cells (HRMCs) from a 23-year-old male donor were purchased from ScienCell Research Laboratories. HRMCs were cultured as recommended by the supplier in MCM medium containing 2% FBS and proprietary growth factors. For proliferation and cytokine production experiments, 5000 cells per well were plated in 96-well plates, cultured overnight in complete medium, then switched to MCM medium containing 0.5% FBS in the absence of growth factors. After one day of low serum treatment, the medium was replaced with MCM containing 0.5% FBS in the presence of purified immune complexes with or without atrasentan for up to 72 hours. See, for example, Novak et. al., Kidney International, 67, pages 504-516; 2005; Novak et. al., Nephrol. Dial. Transplant, 26, pages 3451-3457; 2011; Liang et. al., Cell Physiol. Biochem., 36, pages 1793-1808; 2015; Nguyen et. al., Clin. Kidney J., 12 (2), pages 232-238; 2019. Mesangial cell activation was assessed by measuring proliferation with BrdU incorporation (Abcam) and secretion of inflammatory cytokines including IL-6 was measured by ELISA (R&D Systems).

[0814] Compared to IgA-containing serum fractions from healthy controls, HRMCs treated with purified IgA-containing immune complexes from three separate patients with IgA nephropathy showed increased cell proliferation, a hallmark of mesangial cell activation in response to immune complexes. of pathogenic IgA (Figure 1A). Atrasentan had no effect on basal cell proliferation in HRMCs treated with IgA containing serum fractions from healthy controls, however, atrasentan significantly attenuated the hyperproliferation of HRMCs induced by IgA containing purified immune complexes from three separate patients with IgA nephropathy (Figure 1A). . Immune complexes purified from normal and IgAN donors contained an average of 1.9 and 4.4 μg/ml Gd-IgA, respectively (Figure 1B).

EXAMPLE 4. ATRASENTAN INHIBITS ET-1-INDUCED PROLIFERATION AND IL-6 PRODUCTION IN PRIMARY HUMAN MESANGIAL CELLS

[0815] Primary human renal mesangial cells (HRMCs) from a 23-year-old male donor were purchased from ScienCell Research Laboratories. HRMCs were cultured as recommended by the supplier in MCM medium containing 2% FBS and proprietary growth factors (ScienCell). For proliferation and cytokine production experiments, 5000 cells per well were plated in 96-well plates, cultured overnight in complete medium, then switched to MCM medium containing 0.5% FBS in the absence of growth factors. After one day of low serum treatment, the medium was replaced with MCM containing 0.5% FBS in the presence or absence of 10 ng/ml ET-1 and a range of atrasentan concentrations for up to 72 hours. Mesangial cell activation was assessed by measuring proliferation with bromodeoxyuridine (BrdU) incorporation (Abcam) and secretion of inflammatory cytokines including IL-6 was measured by ELISA (R&D Systems). IC50 values were calculated in GraphPad Prism using a four-parameter variable slope setting.

[0816] ET-1 induced HRMC proliferation at 48 (Figure 2A) and 72 hours (Figure 2B). ET-1-induced HRMC proliferation was blocked in a concentration-dependent manner by atrasentan with IC50 values of 4.2 nm and 50.8 nm after 48 (Figure 2A) and 72 hours (Figure 2B) of treatment, respectively. ET-1 also stimulated IL-6 production in HRMCs at 48 (Figure 3A) and 72 hours (Figure 3B), which was inhibited in a concentration-dependent manner by atrasentan with IC50 values of 1.0 nm and 0. 65 nm at 48 and 72 hours, respectively (Figures 3A and 3B).

EXAMPLE 5. A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY AT RISK FOR PROGRESSIVE LOSS OF RENAL FUNCTION (ALIGN STUDY)

[0817] This example describes a phase 3, randomized, double-blind, placebo-controlled study of atrasentan in patients with IgA nephropathy) at risk of progressive loss of renal function despite treatment with a maximum tolerated and stable dose of a RAS inhibitor.

STUDY OVERVIEW

[0818] Approximately 320 patients with IgA nephropathy will be randomized 1:1 to receive atrasentan 0.75 mg once daily (QD) or a matching placebo for 132 weeks. Randomization will be stratified according to region and UPCR screening levels. Subjects will be evaluated for safety as well as changes in proteinuria and eGFR from baseline. The total duration of study participation per subject is expected to be up to 140 weeks, including 4 weeks for screening, 132 weeks of treatment, and 4 weeks of follow-up.

[0819] An independent data monitoring committee (IDMC) will meet periodically to review the overall unblinded safety and emerging efficacy results. Additionally, an interim re-estimate of the sample size supporting the primary secondary outcome could result in an increase in enrollment to up to 450 individuals in total.

[0820] Subjects who complete the study may be eligible to enroll in an extension study to receive open-label treatment with atrasentan under a separate protocol.

GOALS:

[0821] The main objective of this study is:

[0822] (1) Evaluate the effect of atrasentan on proteinuria levels at week 24 compared to placebo.

[0823] The secondary objectives are:

[0824] (2) Evaluate the effect of atrasentan versus placebo on the change from baseline to Week 136 (4 weeks after stopping randomized treatment) in estimated glomerular filtration rate (eGFR);

[0825] (3) To compare on-treatment 2-year rates of change in eGFR between atrasentan and placebo (eGFR slope Week 12 to Week 120 of randomized treatment); It is

[0826] (4) To compare the overall rates of eGFR change in the study between atrasentan and placebo (eGFR slope from baseline to week 136).

[0827] The exploratory objectives are:

[0828] (5) Evaluate the quality of life (QOL) of patients who received atrasentan compared to placebo; It is

[0829] (6) Evaluate the steady-state pharmacokinetics of atrasentan that supports exploratory exposure-response analyses.

INDIVIDUALS NUMBER

[0830] Approximately 320 patients will be enrolled.

NUMBER OF STUDY LOCATIONS: APPROXIMATELY 150 LOCATIONS WORLDWIDE INCLUSION CRITERIA:

[0831] The inclusion criteria follow. Patients must meet all of the following inclusion criteria to be enrolled:

[0832] 1. Male and female individuals aged 18 or over at the time of signing the TCLE before the start of any specific study activity/procedure.

[0833] 2. Biopsy-proven IgAN that, in the opinion of the Investigator, is not due to secondary causes.

[0834] • The biopsy may have occurred at any time prior to the study.

[0835] • A diagnostic report must be available for review by Sponsor or designee.

[0836] 3. Receiving a maximum tolerated and optimized dose of a RAS inhibitor that has been stable for at least 12 weeks prior to screening.

[0837] • Investigator discretion should be used to determine the maximum tolerated and optimized dose.

[0838] • Individuals who are intolerant to RAS inhibitors are eligible, but will not exceed ~5% of the total randomized population.

[0839] 4. UPCR >1 g/g based on a central laboratory assessment of first morning urine collected at screening.

[0840] 5. eGFR of at least 30 ml/min/1.73 m2 at screening based on the CKD-EPI equation.

[0841] 6. Willing to comply with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month thereafter. In WOCBP, the use of hormonal contraceptives

[0842] 7. Willing and able to provide written informed consent and comply with all study visits and procedures.

EXCLUSION CRITERIA

[0843] The following are the exclusion criteria; Patients must not meet any of the following exclusion criteria to be enrolled:

[0844] 1. Concurrent diagnosis of another cause of chronic kidney disease, including diabetic kidney disease or other primary glomerulopathy.

[0845] 2. Clinical suspicion of rapidly progressive glomerulonephritis (RPGN) based on KDIGO guidelines or clinical suspicion of Henoch-Schonlein purpura.

[0846] 3. Diagnosis of nephrotic syndrome with serum albumin <3 g/dl at screening.

[0847] 4. BNP value >200 pg/ml at screening.

[0848] 5. Platelet count <80,000 per μl at screening.

[0849] 6. History of organ transplantation (subjects with a history of corneal transplantation are not excluded).

[0850] 7. Use of systemic immunosuppressive medications, including mycophenolate, azathioprine, cyclosporine, tacrolimus, etc.; use of herbs such as Tripterygium Wilfordii Hook F, Caulis sinomenii and Sinomenium acutum; for >2 weeks in the last 3 months. Use of rituximab in the last 6 months.

[0851] 8. Confirmed blood pressure >150 mmHg systolic or >95 mmHg diastolic based on an average of 3 measurements obtained at screening.

[0852] 9. Known history of heart failure or previous hospital admissions for conditions related to fluid overload, such as pulmonary edema, uncontrolled peripheral edema, pleural effusion, or ascites.

[0853] 10. Known history of clinically significant liver disease or transaminase or bilirubin values greater than twice the upper limit of normal. Individuals with treated hepatitis C may be considered for inclusion in the study upon consultation with the Sponsor's Medical Monitor (or designee).

[0854] 11. Hemoglobin below 9 g/dl at screening or prior history of blood transfusion for anemia within 3 months of screening.

[0855] 12. History of malignancy unless cancer-free for at least 5 years or non-melanoma skin cancer that does not require ongoing treatment. An individual with curatively treated cervical carcinoma in situ is eligible for this study.

[0856] 13. Pregnancy, breastfeeding, or intention to become pregnant during the study period and at least 1 month thereafter for females.

[0857] 14. Intention to father a child or donate sperm during the study period and at least 1 month thereafter for men.

[0858] 15. Have received any investigational agent within 1 month (or 5 half-lives of the agent, whichever is longer) prior to screening. If the investigational agent is a cytotoxic or immunosuppressive agent, this washout period is 6 months.

[0859] 16. Clinically significant concomitant or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematologic, coagulation, immunologic, endocrine/metabolic diseases that, in the opinion of the Investigator or Sponsor's Medical Monitor (or designee) , may confuse the results of the study or pose additional risk to the subject for their participation in the study.

[0860] 17. History of alcohol or illicit drug-related disorder in the last 3 years.

TEST PRODUCT(S), DOSE AND METHOD OF ADMINISTRATION:

[0861] Subjects will receive atrasentan 0.75 mg once daily by oral administration or matching placebo once daily by oral administration.

[0862] Treatment assignment is determined by an interactive voice/web response system (IXRS). Patients, investigators, and the sponsor have access to the assigned study treatment. In the event of a medical emergency, the investigator can receive treatment assignment through the IXRS system if necessary to provide optimal patient care. Randomization is stratified by region (Asia versus all other regions) and UPCR levels at screening (>2 g/day versus <2 g/day).

DURATION OF TREATMENT:

[0863] Screening duration: up to 4 weeks

[0864] Duration of treatment: 132 weeks

[0865] Security follow-up: 4 weeks

[0866] Total study duration for an individual patient: Up to 140 weeks (approximately 2.3 years)

EVALUATION CRITERIA: EFFECTIVENESS

[0867] The primary efficacy endpoint is the change in proteinuria (urine protein/creatinine ratio based on 24-hour urine collection) from baseline to week 24 in atrasentan-treated patients compared to placebo-treated patients.

[0868] The primary secondary endpoint, change from baseline in eGFR for each subject, will be determined by the difference in eGFR at Week 136 from baseline. eGFR change from baseline will be analyzed using an MMRM model.

[0869] Additional secondary efficacy endpoints include:

[0870] • Rate of change in eGFR during 2 years of treatment, measured through a chronic slope calculated from values from Week 12 to Week 120

[0871] • Rate of change in eGFR during the study, measured by a total slope calculated from baseline values through Week 136

[0872] • Percentage of subjects who achieved reduction in proteinuria to <1 g/day at Week 24 and 40% reduction in UPCR from baseline.

[0873] • Percentage of subjects experiencing at least a 30% reduction in eGFR or achieving ESKD during the study.

[0874] • Percentage of subjects experiencing at least a 40% reduction in eGFR or ESKD achievement during the study. Secondary outcomes will be tested in a hierarchical fashion in the final analysis at Week 136 after approximately 320 subjects in the ITT analysis set complete the Week 136 visit or discontinue the study. Secondary analyzes will be tested in a hierarchical fashion (as listed above) based on a two-sided significance level of 0.05.

EVALUATION CRITERIA: SAFETY

[0875] Safety endpoints include:

[0876] (1) frequency and severity of adverse events and serious adverse events;

[0877] (2) Frequency and severity of adverse events of special interest, including heart failure and/or fluid overload events; It is

[0878] (3) Clinically significant changes in safety labs, ECGs, or physical examination findings (including vital signs).

STOPPING CRITERIA

[0879] An independent data monitoring committee (DMC) is appointed to monitor the study. The DMC meets periodically to review safety data and makes recommendations regarding continuation, modification, suspension, or termination of the study.

[0880] Subjects will be required to permanently discontinue study medication for the following reasons:

[0881] • Evidence of pregnancy or noncompliance with protocol-specified contraception or pregnancy monitoring

[0882] • Chronic dialysis or kidney transplant for ESKD

[0883] • Other criteria for discontinuation of study medication may be based on the discretion of the investigator and the subject, which may include fluid overload syndromes uncontrolled with diuretics and medical treatment, and any suspected adverse event related to the study medication that represents unacceptable toxicity.

[0884] All subjects who discontinue study drug before Week 132 will have an EoT visit at the time of study drug discontinuation, followed by a visit 2 weeks after study drug discontinuation and a safety follow-up visit 4 weeks after discontinuation of study drug. Thereafter, subjects should continue quarterly efficacy assessments for visits through Week 136/EoS.

EVALUATION CRITERIA: PHARMACOKINETICS AND PHARMACODYNAMICS

[0885] The pharmacokinetic and pharmacodynamic outcomes are:

[0886] (1) plasma levels of atrasentan; It is

[0887] (2) Proteomic, metabolomic, and transcriptomic analysis of blood and urine for potential biomarkers of IgAN disease activity (such as galactose-deficient IgA (gd-IgA) and gd-IgA autoantibodies) or factors contributing to the IgAN response subject to atrasentan in terms of efficacy, tolerability and safety.

[0888] (3) Pharmacogenetic (PGx) analyzes can be performed on any biosample from individuals who have consented to PGx sampling. The confidentiality of the matter will be maintained. This analysis is optional.

STATISTICAL METHODS: TREATMENT POPULATION DEFINITIONS:

[0889] Registrants: All subjects who sign the Free and Informed Consent Form (TCLE).

[0890] Intention to treat: All individuals randomly assigned to study the drug. Subjects will be analyzed according to the intervention to which they were randomly assigned.

[0891] Safety All subjects randomly assigned to study medication and taking at least 1 dose of study medication. Subjects will be analyzed according to the intervention they actually received

[0892] Pharmacokinetic (PK) Population All randomized subjects who received any amount of study drug and who have at least one post-baseline PK sample will constitute the PK Population. Data will be analyzed based on the treatment received

SAFETY AND TOLERABILITY:

[0893] Continuous safety data is summarized with descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum, and maximum) by treatment group. Categorical safety data are summarized with frequency counts and percentages by treatment group. Adverse events are coded using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA) available. The number of participants who experienced treatment-emergent adverse events, as well as maximum severity and relationship to study drug are summarized.

[0894] Laboratory assessments, vital sign assessments, and ECG parameters are summarized by treatment group and protocol-specified collection time point. A summary of the change from baseline at each protocol-specified time point by treatment group is also presented. Concomitant medications are listed by participant and coded using the most current World Health Organization medication dictionary. Medical history is listed by individual. Further details on the presentation and analysis of safety data are detailed in the Statistical Analysis Plan (SAP).

PHARMACOKINETICS:

[0895] Individual steady-state atrasentan concentration data are listed and summarized with descriptive statistics (sample size, arithmetic mean, SD, median, minimum, maximum, geometric mean, and geometric coefficient of variation). These data can be fed into a larger population PK model of atrasentan. Correlations between atrasentan drug levels and safety or efficacy responses can be explored. Details on the statistical analyzes of pharmacokinetic data are provided in the SAP.

EFFECTIVENESS REVIEWS:

[0896] Descriptive statistics are used to assess differences in demographic and baseline characteristics.

[0897] The primary efficacy endpoint is change in proteinuria (UPCR based on 24-hour urine collection) from baseline to Week 24. The primary analysis will be conducted after approximately 270 subjects in the intent-to-use analysis set treat (ITT) complete the Week 24 visit or discontinue the study. The primary analysis will be tested based on a two-sided significance level of 0.01. Baseline and Week 24 UPCR values will be estimated as the natural log mean of two separate samples collected 14 days apart prior to any study drug value.

[0898] The primary outcome will be analyzed using a mixed effects model repeated measures (MMRM) design. The MMRM model will include the change from baseline in the natural logarithmic UPCR at each post-baseline measurement as outcomes. The model will also include the fixed effects of treatment, visit, and treatment-by-visit interaction, with covariates of baseline natural log UPCR and baseline eGFR as continuous variables and region randomization stratification factors (region: Asia vs. all other regions). The covariance structure is assumed to be unstructured. Missing data will be considered missing at random. UPCR data collected after dialysis, SGLT-2 inhibitor use, or prohibited systemic corticosteroid use will not be included in the analysis. The resulting analysis at 24 weeks will be used to evaluate efficacy.

[0899] Support and sensitivity analyzes of the primary parameter will be performed to assess the robustness of the data and assess the impact of missing data. A supportive analysis will be performed using analysis of covariance (ANCOVA) methodology on the point estimate of change from baseline to Week 24 in natural log UPCR. Missing data will not be imputed and will therefore be considered missing at random. Sensitivity analyzes will be conducted including all treatment and non-treatment data through 24-week outcome analysis with an MMRM model as described in the primary analysis. Additionally, a tipping point analysis will be conducted to assess the impact of missing data on the endpoint. These sensitivity analyzes will be described in more detail in the SAP. Subjects without baseline UPCR will be excluded from efficacy analyses. Subgroup analyzes for clinically relevant demographic and underlying disease characteristics may be performed as specified in the SAP.

EXAMPLE 6. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IgA NEPHROPATHY AT RISK FOR PROGRESSIVE LOSS OF RENAL FUNCTION STUDY OVERVIEW

[0900] This study is a Phase 3, double-blind, placebo-controlled study to compare the efficacy and safety of atrasentan, a selective endothelin-A receptor antagonist, to placebo in patients with IgA nephropathy at risk of loss. progressive renal function. Approximately 320 patients will be randomized 1:1 to receive atrasentan 0.75 mg daily or a matched placebo for 132 weeks while on a maximally tolerated and stable dose of a RAS inhibitor (physician's choice). Patients who are unable to tolerate RAS inhibition (up to 5% of the study population) may be included. Study arms will be stratified according to region and baseline urine protein levels.

[0901] Patients will have a telephone contact for safety assessment at week 1 and then return to the clinic at week 2, 4, 6, 12, and then every 12 weeks until completion of treatment at week 132 for safety and efficacy assessments. Pregnancy testing and patient counseling regarding contraception requirements will occur monthly throughout the study for women of childbearing potential. A negative pregnancy test result will be verified by a healthcare professional before the patient is approved for continued dosing. A positive or indeterminate pregnancy test result will lead to immediate discontinuation of study medication and repeat serum testing at the clinical trial site within 2 days. Any positive serum pregnancy test will lead to permanent discontinuation of treatment. In certain regions, with the approval of the principal investigator and agreement with the sponsor, patients may have the option of monthly urine pregnancy testing at a local care center/laboratory or urine pregnancy testing at home with a virtual visit to the video/audio enabled location.

[0902] Patients who discontinue treatment prematurely before week 132 must remain in the study for quarterly efficacy assessments to provide data for study endpoints. Patients will return to the clinic approximately 4 weeks after the last dose of study medication. An additional blood draw should be collected approximately 2 weeks after the last dose of study medication. The final study visit will occur at approximately Week 136. Patients who complete the study by Week 136 may be eligible to enroll in an extension study to receive open-label treatment with atrasentan under a separate protocol.

GOALS.

[0903] The main objective of this study is:

[0904] (1) Evaluate the effect of atrasentan versus placebo on proteinuria levels at week 24 compared to placebo.

[0905] The secondary objectives are:

[0906] (2) Evaluate the effect of atrasentan versus placebo on the change from baseline to week 136 (4 weeks after stopping randomized treatment) in estimated glomerular filtration rate (eGFR);

[0907] (3) To compare the two-year on-treatment rates of change in eGFR between atrasentan and placebo (eGFR slope week 12 to 120 of randomized treatment); It is

[0908] (4) To compare the overall in-study rates of change in eGFR between atrasentan and placebo (eGFR slope from baseline to week 136).

[0909] The exploratory objectives are:

[0910] (5) Compare the percentage of patients who achieved a reduction in proteinuria of at least 50% from baseline and with a value less than 1 g/day at week 24 between atrasentan and placebo;

[0911] (6) Evaluate the percentage of patients who reached a proteinuria level of less than 0.3 g/day at week 24;

[0912] (7) Evaluate the percentage of patients with at least a 30% reduction in eGFR during the study;

[0913] (8) Evaluate the percentage of patients with at least a 40% reduction in eGFR during the study;

[0914] (9) Evaluate the quality of life (QOL) of patients who received atrasentan compared to placebo; It is

[0915] (10) Evaluate the steady-state pharmacokinetics of atrasentan that supports exploratory exposure-response analyses.

INDIVIDUALS NUMBER

[0916] Approximately 320 patients will be enrolled. Patients who discontinue for reasons other than safety may be replaced at the sponsor's discretion to ensure adequate review of data after at least 6 weeks of treatment.

[0917] Number of study sites: Approximately 120 sites worldwide

INCLUSION CRITERIA:

[0918] The inclusion criteria follow. Patients must meet ALL of the following inclusion criteria to be enrolled:

[0919] (1) male and female patients aged 18 or over;

[0920] (2) biopsy-proven diagnosis of IgA nephropathy not due to secondary causes;

[0921] (3) receiving a maximum tolerated stable dose of a RAS inhibitor for at least 12 weeks prior to screening;

[0922] (4) Urinary protein to creatinine (UPCR) of at least 1 g/g at screening.

[0923] (5) eGFR of at least 30 ml/min/1.73 m2 at screening;

[0924] (6) willing to comply with highly effective forms of contraception as specified in the protocol throughout the study; It is

[0925] (7) willing and able to provide written informed consent and comply with all study visits and procedures.

EXCLUSION CRITERIA

[0926] The following are the exclusion criteria; Patients must meet NONE of the following exclusion criteria to be enrolled:

[0927] (1) concurrent diagnosis of another cause of chronic kidney disease, including diabetic kidney disease, hypertensive kidney disease, or other primary glomerulopathy. A history of well-controlled hypertension is acceptable;

[0928] (2) presence of cellular glomerular crescents in >25% of glomeruli on renal biopsy (if biopsy is available within 6 months of screening) or clinical suspicion of rapidly progressive glomerulonephritis (RPGN);

[0929] (3) history of organ transplantation;

[0930] (4) use of systemic immunosuppressive medications (or investigational agents) for at least 2 weeks in the last 6 months;

[0931] (5) blood pressure >160 systolic or >100 diastolic at screening;

[0932] (6) history of heart failure or previous hospital admissions for conditions related to fluid overload, such as uncontrolled peripheral edema, pleural effusion or ascites;

[0933] (7) history of clinically significant liver disease and transaminase or bilirubin values above twice the upper limit of normal;

[0934] (8) hemoglobin below 9 g/dl at screening or previous history of blood transfusion for anemia within 3 months of screening;

[0935] (9) history of malignancy, unless cancer-free for at least 5 years or non-melanoma skin cancer that does not require ongoing treatment;

[0936] (10) pregnancy, breastfeeding or intention to become pregnant during the study period for women;

[0937] (11) intention to be a father during the study period for males;

[0938] (12) received any experimental or biological agent within 1 month (or 5 half-lives of the agent, whichever is longer) before screening. If the investigational agent is a cytotoxic or immunosuppressive agent, this washout period is 6 months;

[0939] (13) concomitant clinically significant, unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic disease that, in the opinion of the Investigator, may confound the results of the study or represent additional risk to the patient for their participation in the study;

[0940] (14) history of disorder related to alcohol or illicit drugs;

[0941] (15) Ongoing diagnosis of nephrotic syndrome with serum albumin <3 g/dl at screening; or

[0942] (16) Brain natriuretic peptide (BNP) value of >200 pg/ml at screening.

[0943] Note: Screening of a previously ineligible patient may be repeated with the approval of the medical monitor.

TEST PRODUCT(S), DOSE AND METHOD OF ADMINISTRATION:

[0944] Patients receive: atrasentan 0.75 mg once daily by oral administration; or matching placebo once daily by oral administration.

[0945] Atrasentan or placebo tablets will be supplied in a blinded fashion in bottles with a 4-week supply (35 tablets to accommodate the visiting window). Patients will be instructed to take one tablet per day at approximately the same time, preferably in the morning. On days with study visits, patients should maintain dosing until the clinic to allow for pharmacokinetic sampling prior to dose administration, as applicable. The medication can be taken with or without food. No dose reduction of study medication is permitted during the study. The study drug should be temporarily interrupted or permanently discontinued in the case of unacceptable toxicity that cannot be controlled through supportive measures.

[0946] Treatment assignment will be determined by an interactive voice/web response system (IXRS). Patients, investigators and the sponsor will not have access to the assigned study treatment. In the event of a medical emergency, the investigator will be able to receive treatment assignment through the IXRS system if necessary to provide the best patient care. Randomization will be stratified by region (Asia versus all other regions), baseline urinary protein levels at screening (>2 g/day versus <2 g/day), and baseline eGFR (>60 ml/min/1.73 m2 versus <60 ml/min/1.73 m2). All patients will continue to receive a maximally tolerated and stable dose of RAS inhibitor (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) of the physician's choice per standard of care. Every effort should be made to maintain a stable dosage regimen throughout the study.

DURATION OF TREATMENT:

[0947] The duration of the study for an individual patient is approximately 2 years and 7 months (136 weeks) to include up to 4 weeks for screening, 132 weeks of blinded study treatment, and 4 weeks for untreated follow-up. Patients may provide additional consent for pre-screening to occur up to 6 months prior to the anticipated initial visit; however, pre-screening assessments will have to be repeated for screening if performed outside of the 28-day screening window. The total duration of the study is expected to be 4 to 5 years. Enrollment is anticipated to last 2 to 2.5 years, with the last patient completing treatment and safety follow-up approximately 2 years and 7 months later.

EVALUATION CRITERIA: EFFECTIVENESS

[0948] The primary efficacy endpoint is the change in proteinuria (urine protein/creatinine ratio based on 24-hour urine collection) from baseline to week 24 in atrasentan-treated patients compared to placebo-treated patients.

[0949] The key secondary efficacy endpoint is the rate of change in eGFR using the CKD-EPI creatinine equation from baseline to the study completion visit (week 136) in patients treated with atrasentan compared to patients treated with placebo. Additional secondary efficacy endpoints include: rate of change in eGFR over two years on treatment calculated from baseline through week 136 in atrasentan-treated patients compared to placebo-treated patients.

[0950] Exploratory endpoints include percentage of patients who achieved reduction in proteinuria to less than 1 g/day at week 24 and 50% reduction from baseline, percentage of patients who achieved reduction in proteinuria to less than 0.3 g/day at week 24, percentage of patients with at least a 30% reduction in eGFR during the study, and percentage of patients with at least a 40% reduction in eGFR during the study.

EVALUATION CRITERIA: SAFETY

[0951] Safety endpoints include:

[0952] (1) Type, incidence, severity, grade, severity and relationship of adverse events;

[0953] (2) Incidence, severity, severity and relationship of adverse events of special interest, including fluid overload events; It is

[0954] (3) Clinically significant changes in safety labs, ECGs, or physical examination findings (including vital signs).

STOPPING CRITERIA

[0955] An independent data monitoring committee (DMC) will be appointed to monitor the study. The DMC will meet periodically to review safety and will make recommendations regarding continuation, modification, suspension or termination of the study.

[0956] Patients will be required to discontinue study medication for the following reasons:

[0957] (1) Evidence of pregnancy or noncompliance with protocol-specified contraception or pregnancy monitoring;

[0958] (2) Initiation of high-dose steroids or other immunosuppressants or cytotoxic agents for treatment of IgAN; or

[0959] (3) Chronic dialysis for ESRD.

[0960] Other criteria for stopping study medication may be based on investigator and patient discretion, which may include fluid overload syndromes uncontrolled with diuretics and medical treatment, and any suspected adverse event related to the study medication that represents unacceptable toxicity. All patients who discontinue study drug before week 132 will have blood drawn 2 weeks after discontinuation and a safety follow-up visit after 4 weeks. Patients should continue quarterly visits through week 136 for efficacy assessments only.

STATISTICAL METHODS: TREATMENT POPULATION DEFINITIONS:

[0961] Safety Population: All randomized participants receiving any amount of study drug comprise the Safety Population for safety and exposure analyses. The data will be analyzed based on the treatment received.

[0962] Intention to Treat: All randomized participants comprise the intention to treat population for efficacy analyses. Data will be analyzed based on randomized treatment assignment.

[0963] PK Population: All randomized participants who receive any amount of study drug and who have at least one post-baseline PK sample will constitute the PK Population. The data will be analyzed based on the treatment received.

SAFETY AND TOLERABILITY:

[0964] Continuous safety data is summarized with descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum, and maximum) by treatment group. Categorical safety data are summarized with frequency counts and percentages by treatment group. Adverse events are coded using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA) available. The number of participants who experienced treatment-emergent adverse events, as well as maximum severity and relationship to study drug are summarized.

[0965] Laboratory assessments, vital sign assessments, and ECG parameters are summarized by treatment group and protocol-specified collection time point. A summary of the change from baseline at each protocol-specified time point by treatment group is also presented. Concomitant medications are listed by participant and coded using the most current World Health Organization medication dictionary. Medical history is listed by individual. Further details on the presentation and analysis of safety data are detailed in the Statistical Analysis Plan (SAP).

PHARMACOKINETICS:

[0966] Individual steady-state atrasentan concentration data are listed and summarized with descriptive statistics (sample size, arithmetic mean, SD, median, minimum, maximum, geometric mean and geometric coefficient of variation). These data can be fed into a larger population PK model of atrasentan. Correlations between atrasentan drug levels and safety or efficacy responses can be explored.

EFFECTIVENESS REVIEWS:

[0967] The primary and secondary efficacy endpoints of the study will be ordered hierarchically and tested sequentially with control procedures. The primary outcome will be tested first, acting as a gatekeeper, and if the null hypothesis is rejected at the 1% significance level (alpha=0.01), the key secondary outcome will be tested. The study will be considered positive if the null hypothesis of the key secondary outcome is rejected at the 5% significance level (alpha=0.05).

[0968] The primary efficacy endpoint is the change from baseline for each post-baseline visit through week 24 in urinary protein to creatinine ratio (UPCR) as determined from 24-hour urine collection samples . As the primary analysis is considering longitudinal results, the analysis methodology will be a mixed effects model (MMRM) repeated measures analysis of the change from baseline for each post-baseline measurement of log UPCR. The model will include fixed effects of treatment, visit, and treatment-by-visit interaction, with covariates including randomization stratification factors (region: Asia versus all other regions; baseline urinary protein levels at screening: >2 g/day versus <2 g/day and baseline eGFR >60 ml/min/1.73 m2 versus <60 ml/min/1.73 m2). The covariance structure is assumed to be unstructured. The resulting analysis at 24 weeks will be used to evaluate efficacy. A supportive analysis will be conducted using analysis of covariance (ANCOVA) methodology on the point estimate of change from baseline to Week 24 in log UPCR. This analysis will be performed on the primary outcome to assess the robustness of the data. Missing data will not be imputed and will therefore be considered missing at random. Patients without baseline UPCR will be excluded from efficacy analyses. Further sensitivity analyzes can be performed to assess the impact of missing data. Subgroup analyzes for clinically relevant demographic and underlying disease characteristics will be performed as specified in the statistical analysis plan.

[0969] After collection and analysis of primary endpoint data at week 24, patients will continue to receive assigned blinded study treatment through week 132 and will be followed on study drug for an additional 4 weeks until study completion at week 136 to collect additional data on eGFR decline.

[0970] Baseline and final eGFR values will be estimated as the average of two samples at each time point to reduce variability. The baseline reference eGFR value will be determined from the average of the screening and baseline values (before any study medication) and the final eGFR value will be estimated as the average of two separate samples collected between 7 days and 35 days (including the Windows visit) after the last dose of study drug. Estimated GFR will be determined using the Chronic Kidney Disease Epidemiology Collaboration equation. The change from baseline in eGFR for each patient will be determined by the absolute difference in mean values at baseline and Week 136 and then normalized for individual time on study to decrease the risk of bias from any differences between patients. groups in the incidence of early start time and dropouts from the study. The outcome will be analyzed using an ANCOVA with factors such as treatment group and randomization stratification factors included as independent variables.

EXAMPLE 7. A RANDOMIZED PHASE 3 PLACEBO-CONTROLLED STUDY OF ATRASENTAN AND DAPAGLIFLOZIN IN PATIENTS WITH IgA NEPHROPATHY

[0971] This example describes a phase 3, randomized, double-blind, placebo-controlled study of atrasentan in patients with IgA nephropathy) at risk of progressive loss of renal function despite treatment with a maximum tolerated and stable dose of a RAS inhibitor.

STUDY OVERVIEW

[0972] This example describes a randomized placebo-controlled efficacy and safety study of atrasentan, a selective endothelin-A receptor antagonist, in combination with dapagliflozin, a sodium glucose-linked transporter 2 (SGLT-2) inhibitor, in patients with IgA nephropathy. Approximately 36 patients will be randomized 1:1:1 to receive atrasentan 0.75 mg daily, atrasentan 0.75 mg daily and dapagliflozin 10 mg daily, or a matched placebo (for atrasentan and dapagliflozin) for 4 weeks (plus one two-week washout period), in addition to a maximum tolerated dose of a RAS inhibitor.

[0973] Patients will have a telephone contact for safety assessment in week 1 and will return to the clinic in week 3 and at the end of the washout period (week 6) for safety and efficacy assessments.

GOALS.

[0974] The main objective of this study is:

[0975] (1) Evaluate the effect of atrasentan in combination with dapagliflozin versus atrasentan alone on proteinuria levels compared to placebo.

[0976] The secondary objectives are:

[0977] (2) Evaluate the effect on change from baseline in the albumin to creatinine ratio during the active treatment period and washout period;

[0978] (3) Evaluate the effect on change from baseline in body weight during the active treatment period and washout period;

[0979] (4) Evaluate the effect on change from baseline in extracellular fluid (e.g., measured by bioimpedance spectroscopy (Impedimed)) during the active treatment period and washout period;

[0980] (5) Evaluate the effect on change from baseline in brain natriuretic peptide (BNP) levels during the active treatment period and washout period; It is

[0981] (6) Evaluate the effect on change from baseline in systolic blood pressure during the active treatment period and washout period.

[0982] The exploratory objectives are:

[0983] (7) Compare the change in hematocrit from the beginning to the end of active treatment;

[0984] (8) To compare the change in eGFR from baseline to the end of active treatment; It is

[0985] (9) To compare the change in eGFR from baseline to the end of the wash out period (2 weeks after the last dose of study drug).

INDIVIDUALS NUMBER

[0986] Approximately 36 patients will be enrolled. Patients who discontinue for reasons other than safety may be replaced at the sponsor's discretion to ensure adequate review of data after at least 6 weeks of treatment.

[0987] Number of study sites: approximately 6 sites worldwide

INCLUSION CRITERIA:

[0988] The inclusion criteria follow. Patients must meet ALL of the following inclusion criteria to be enrolled:

[0989] (1) male and female patients aged 18 or over;

[0990] (2) biopsy-proven diagnosis of IgA nephropathy not due to secondary causes;

[0991] (3) receiving a maximum tolerated stable dose of a RAS inhibitor for at least 4 weeks prior to screening;

[0992] (4) eGFR of at least 30 ml/min/1.73 m2 at screening;

[0993] (5) willing to comply with highly effective forms of contraception as specified in the protocol throughout the study; It is

[0994] (6) willing and able to provide written informed consent and comply with all study visits and procedures.

EXCLUSION CRITERIA

[0995] The following are the exclusion criteria; Patients must meet NONE of the following exclusion criteria to be enrolled:

[0996] (1) simultaneous diagnosis of another cause of chronic kidney disease, including diabetic kidney disease, hypertensive kidney disease or other primary glomerulopathy. A history of well-controlled hypertension is acceptable;

[0997] (2) concomitant diagnosis of type 1 diabetes or type 2 diabetes;

[0998] (3) brain natriuretic peptide (BNP) value of >200 pg/ml at screening;

[0999] (4) cardiovascular event in the 3 months prior to screening;

[01000] (5) history of heart failure or previous hospital admissions for conditions related to fluid overload, such as uncontrolled peripheral edema, pleural effusion or ascites;

[01001] (6) use of systemic immunosuppressive medications (or investigational agents) for at least 2 weeks in the last 6 months;

[01002] (7) blood pressure >160 systolic or >100 diastolic at screening;

[01003] (8) history of clinically significant liver disease and transaminase or bilirubin values greater than twice the upper limit of normal;

[01004] (9) hemoglobin below 9 g/dl at screening or previous history of blood transfusion for anemia within 3 months of screening;

[01005] (10) history of malignancy, unless cancer-free for at least 5 years or non-melanoma skin cancer that does not require ongoing treatment;

[01006] (11) received any experimental or biological agent within 1 month (or 5 half-lives of the agent, whichever is longer) prior to screening. If the investigational agent is a cytotoxic or immunosuppressive agent, this washout period is 6 months;

[01007] (12) concomitant clinically significant, unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic disease that, in the opinion of the Investigator, may confound the results of the study or represent additional risk to the patient for their participation in the study;

[01008] (13) history of disorder related to alcohol or illicit drugs; or

[01009] (14) Ongoing diagnosis of nephrotic syndrome with serum albumin <3 g/dl at screening.

[01010] Note: Screening a previously ineligible patient may be repeated with the approval of the medical monitor.

TEST PRODUCT(S), DOSE AND METHOD OF ADMINISTRATION:

[01011] Patients receive: atrasentan 0.75 mg once daily by oral administration; or atrasentan 0.75 mg and dapagliflozin 10 mg, each once daily by oral administration; or matching placebo once daily by oral administration.

[01012] Treatment assignment will be determined by an interactive voice/web response system (IXRS). Patients, investigators and the sponsor will not have access to the assigned study treatment. In the event of a medical emergency, the investigator will be able to receive treatment assignment through the IXRS system if necessary to provide the best patient care. Randomization will be stratified by region (Asia versus all other regions), baseline urinary protein levels at screening (>2 g/day versus <2 g/day), and baseline eGFR (>60 ml/min/1.73 m2 versus <60 ml/min/1.73 m2). All patients will continue to receive a maximally tolerated and stable dose of RAS inhibitor (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) of the physician's choice per standard of care. Every effort should be made to maintain a stable dosage regimen throughout the study.

EVALUATION CRITERIA: EFFECTIVENESS

[01013] The primary efficacy endpoint is the change in proteinuria (urine protein/creatinine ratio based on 24-hour urine collection) from baseline to week 4 in patients treated with atrasentan and in patients treated with atrasentan + dapagliflozin compared to placebo-treated patients.

EVALUATION CRITERIA: SAFETY

[01014] Safety endpoints include:

[01015] (1) Type, incidence, severity, grade, severity and relationship of adverse events;

[01016] (2) Incidence, severity, severity and relationship of adverse events of special interest, including fluid overload events; It is

[01017] (3) Clinically significant changes in safety labs, ECGs, or physical examination findings (including vital signs).

STOPPING CRITERIA

[01018] An independent data monitoring committee (DMC) will be appointed to monitor the study. The DMC will meet periodically to review safety and will make recommendations regarding continuation, modification, suspension or termination of the study.

SAFETY AND TOLERABILITY:

[01019] Continuous safety data is summarized with descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum and maximum) by treatment group. Categorical safety data are summarized with frequency counts and percentages by treatment group. Adverse events are coded using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA) available. The number of participants who experienced treatment-emergent adverse events, as well as maximum severity and relationship to study drug are summarized.

[01020] Laboratory assessments, vital sign assessments, and ECG parameters are summarized by treatment group and protocol-specified collection time point. A summary of the change from baseline at each protocol-specified time point by treatment group is also presented. Concomitant medications are listed by participant and coded using the most current World Health Organization medication dictionary. Medical history is listed by individual.

EFFECTIVENESS REVIEWS:

[01021] The primary efficacy endpoint is the change in proteinuria levels from baseline to the end of the study, as determined from 24-hour urine collection samples. After collection and analysis of primary outcome data at week 4, patients will be followed off study medication for an additional 2 weeks (the washout period) to collect additional data on proteinuria levels.

EXAMPLE 8. IN VIVO STUDY USING A MOUSE MODEL OF IgA NEPHROPATHY

[01022] The clustered ddY (g-ddY) mouse is a spontaneous model of early-onset IgA nephropathy characterized by the deposition of IgA immune complexes in the kidney mesangium, leading to significant proteinuria, glomerular hypercellularity, mesangioproliferative glomerular lesions, glomerular sclerosis, and functional reduced renal function, all features of human IgA nephropathy (J Am Soc Nephrol 23:1364-1374, 2012). Consistent with human IgA nephropathy, mesangial IgA deposits in the g-ddY mouse are also accompanied by IgG and complement C3 deposition.

METHODS

[01023] Approximately 6 week old g-ddY mice received varying doses of atrasentan hydrochloride (10, 20 or 30 mg/kg/day, n=3/group) in drinking water for a period of approximately 5 days. A separate group of 6-week-old male g-ddY control mice (n=2) received regular drinking water without atrasentan. Proteinuria was assessed as the urinary albumin to creatinine ratio (UACR), at baseline before atrasentan administration and on the last day of atrasentan administration. The effect of atrasentan on UACR was compared relative to baseline, within an individual mouse, and also to the control group that did not receive atrasentan.

[01024] RNA sequencing (RNA-seq) was used to evaluate changes in gene expression in kidney tissue after administration of atrasentan to g-ddY mice at 0 (control), 10, 20 or 30 mg/kg/day . RNA isolation and sequencing libraries were generated using standard protocols. Sequencing was performed using an Illumina NextSeq500 using the manufacturer's instructions with a read length of 75 bp and a read depth of 30 million. The raw data was assembled into FASTQ files. After QC analysis, high-quality sequencing reads (e.g., reads with Phred quality score >36) were aligned to the mouse reference genome (GRCm38 - mm10) using the default alignment algorithm parameters and tables of Transcript counts from each library were generated using the default parameters of the RSubread package's featureCounts algorithm (Liao Y, Smyth GK, Shi W, 2019). High-quality sequencing reads mapped to 27129 genes. After additional QC of low-count filtering (i.e., transcripts <10 counts in all samples), 16207 genes were identified and used for further analysis. The remaining sequencing read counts of the 16207 included genes were normalized to library size, log-transformed, and quantified as counts per million (CPM). Selected RNA-seq counts were validated using qPCR.

[01025] Sequencing read counts (CPM) were used to identify differential gene expression between specified populations using the quasi-likelihood methodology of the edgeR package. Genes were considered differentially expressed between populations if they had an adjusted p-value (FDR less than 0.05). MA plots were generated using edgeR. Heatmaps and other plots were generated using the gplots and ggplot2 package.

[01026] Gene pathway analysis was performed using Qiagen's Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (Subramanian, et al., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Nat. Acad. Sci. USA, 102(43), 15545-15550 (2005). with the Global Molecular Network in Ingenuity Pathway Knowledge Base (IPKB). in IPA did not include a fold change threshold and the p-value filter was set at <0.001. The resulting enriched genetic pathways were considered significant with Benjamin-Hochberg adjusted p-value <0.001. in a heatmap with activation zs scores representing pathway enrichment in different populations. See Figure 6. For GSEA, the list of differentially expressed genes from edgeR (Robinson et al., A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics, 26(1), 139-140 (2009)) was ordered based on F-statistic without arbitrary logFC or p-value thresholds. GSEA was implemented using the fgsea package (Korotkevich, et al., BioRxiv 2016, Fast gene set enrichment analysis. 1-29. https://doi.org/10.1101/060012) and the Hallmark gene set collection from MSigDB (Liberzon et al., The Molecular Signatures Database Hallmark Gene Set Collection. Cell Systems, 1(6), 417-425 (2015)).

RESULTS

[01027] Healthy Balb/c mice without IgA nephropathy (the appropriate control strain for the g-ddY mouse) have very low and almost undetectable levels of UACR, even up to 2 years of age (Tsaih et al., 2010, Kidney International). At baseline, the pooled g-ddY mice used in this study had substantial proteinuria, with a mean UACR level (± standard error of the mean (SEM)) of 293.1 ± 16 mg/g. Baseline albuminuria was well matched between treatment groups, with no significant differences between groups (Figure 4).

EFFECT OF ATRASENTAN ON UACR: COMPARISON WITH BASELINE

[01028] Treatment with atrasentan for approximately 5 days at 30 mg/kg/day significantly (P = 0.0002, two-sided paired t-test) reduced albuminuria from baseline (Figure 4). Albuminuria was reduced from baseline to a similar extent by treatment with atrasentan at 20 mg/kg/day, however, this effect did not reach statistical significance (P = 0.0593) (Figure 4). Albuminuria was not significantly changed from baseline in control g-ddY mice that did not receive atrasentan, or in the group of mice treated with atrasentan at 10 mg/kg/day; although albuminuria was reduced in 2/3 mice in this 10 mg/kg/day group (Figure 4).

EFFECT OF ATRASENTAN ON UACR: COMPARISON WITH CONTROL

[01029] The change in albuminuria from baseline (percentage (%) change from baseline) after approximately 5 days of treatment with atrasentan or control is shown in Figure 5. Atrasentan reduced UACR from baseline by 28 ± 44%, 62 ± 8% and 63 ± 6% at 10, 20 and 30 mg/kg/day, respectively. The effect of atrasentan to reduce UACR from baseline at 20 mg/kg/day (P = 0.0498, unpaired t-test) and 30 mg/kg/day (P = 0.029) was statistically significant compared with the control group (0 mg/kg/day) (Figure 5). However, the effect of atrasentan at 10 mg/kg/day was not significant, although again proteinuria was reduced in 2/3 mice in this 10 mg/kg/day group (Figure 5).

GENE EXPRESSION ANALYSIS AFTER TREATMENT WITH ATRASENTAN

[01030] Analysis of RNA-seq data provided the top 100 genes differentially expressed in kidney tissue after administration of atrasentan to g-ddY mice at 0 (control), 10, 20 or 30 mg/kg/day grouped accordingly with disease and atrasentan treatment condition, as shown in Figure 6 and Table 5. Paired comparison between 10 mg/kg/day versus control, 20 mg/kg/day versus control, and 30 mg/kg/day versus control showed dose-dependent changes in gene expression (Figures 7A-7C). Figure 7A shows differentially expressed genes for 10 mg/kg/day versus control, where 25 genes are upregulated (log positive modulation) and 15 genes are downregulated (log negative modulation). The upregulated and downregulated genes from Figure 7A are shown in Table 1. Figure 7B shows differentially expressed genes for 20 mg/kg/day versus control, where 214 genes are upregulated (log positive modulation) and 281 genes are downregulated (negative log modulation). The top 25 upregulated and top 25 downregulated genes from Figure 7B are shown in Table 2. Figure 7C shows differentially expressed genes for 30 mg/kg/day versus control, where 910 genes are upregulated (log positive modulation) and 768 genes are downregulated (log negative modulation). The top 25 upregulated and top 25 downregulated genes from Figure 7C are shown in Table 3.

[01031] Comparing gene expression changes in mice treated with atrasentan with a human-specific Atra/ET1 gene signature showed that 53 of the 60 genes overlapped. Specifically, Figures 8A-8C show differential gene expression genes (p-value < 0.05) annotated as being part of the 60 genes associated with an ET1 gene signature and which are differentially expressed in atrasentan-treated mice. Gene expression analysis showed that ET1 (End1) was downregulated at all three doses (Figures 8A-8C). Furthermore, Ednra and Ednrb were downregulated at 30 mg/kg/day. Of the genes that overlapped between mouse and human and were differentially expressed when comparing the 10 mg/kg/day treatment with the untreated control, Ccnd1, Ppara, Agt, Map2k2 and Hoxa9 were upregulated while Grk5, mllt3, Klf2, Pparg , Hgf, Edn1, Fos, Ptgs2, and IL-1b were downregulated (Figure 8A). Looking at the overlapping genes that were differentially expressed when comparing 20 mg/kg/day atrasentan treatment to the untreated control, Figure 8B shows Ccdn1, Cat, Ppara, Map2k2, Hoxa9, Agt, and Egfr were upregulated while Nfatc1, Grk5 , Klf2, Cav1, Pparg, Itga5, Myc, Ednra, Sell, Hgf, Mmp2, Edn1, Syk, Fos and IL-1b were downregulated. Finally, differentially expressed genes that overlapped between species when comparing 30 mg/kg/day atrasentan treatment to untreated controls included upregulated genes Ccnd1, Agt, Cat, Map2k2, Hoxa9, and Ppara and downregulated genes Ednrb, Myc, mllt3, Hdac7, Ednra, Itga5, Grk5, Pparg, Klf2, Hgf, Mmp2, Sell, Sphk1, Fos, Syk, Edn1 and IL-1b (Figure 8C).

[01032] Ingenuity pathway analysis (IPA) and gene set enrichment analysis (GSEA) were applied to systematically identify pathways associated with genes differentially expressed at different dosages of atrasentan. In IPA, significantly enriched canonical pathways that include an adjusted p-value less than 0.001 with no filter in the activation z-score are shown in Table 4. IPA analysis revealed that treatment with atrasentan at 30 mg/kg/day reduced the NF-KB signaling, IL-6 pathway signaling (e.g. STAT3) and PDGF signaling. Tables 9-11 show specific signaling components impacted by atrasentan treatment for each of NF-kB signaling (Table 9), IL-6 signaling (Table 10), and PDGF signaling (Table 11). Furthermore, IPA demonstrated that atrasentan treatment induced changes in gene expression that function synergistically in rescue pathways including, for example, reduction in inflammatory and proliferative pathways. The GSEA positive and negative enriched gene sets after atrasentan treatment are shown in Table 5. As shown in Table 5, GSEA identified concordant negative enrichment (NES < -1.5 and adjusted p-value < 0.05) indicating underexpression of hallmark signaling pathways, including TNFα signaling via NF-kB, epithelial mesenchymal transition, inflammatory response, IL6-JAK -STAT3 signaling and sets of genes associated with cell proliferation (mitotic spindle and G2M checkpoint) following treatment of g-ddY mice with atrasentan at 10, 20 and 30 mg/kg/day.

[01033] Upstream regulator analysis using Ingenuity Pathway identified the predicted activation/inactivation state of potential upstream regulatory molecules in relation to the biological processes and pathways found to be differentially regulated at the 30 mg/kg/day of atrasentan (Tables 6, 7 and 8). Tables 6, 7 and 8 show that the reduction in pro-inflammation, fibrosis and cell proliferation was the result of predicted inhibition of one or more positive regulators of inflammation, fibrosis and cell proliferation and/or predicted activation of one or more negative regulators. inflammation, fibrosis and cell proliferation. The anticipated inhibition and activation of cytokines, growth factors, transcriptional regulators, ligand-dependent nuclear receptors, transmembrane receptors, and G-coupled protein receptors may include, without limitation, EDN1, CCL5, CD40LG, CSF2, CSF3, CXCL2, IFNA2, IFNG, OSM, PF4, PRL, tumor necrosis family (TNF, TNFSF11, TNFSF12), TSLP, WNT3A, the interleukin family of cytokines (IL1A, IL1B, IL2, IL3, IL6, IL10, IL21, IL33), TGFB1, TGFB2, TGFB3, IGF1, HGF, AGT, EGF, NRG1, PDGFB, VEGFA, FGF23, BMP2, GDF2, FGF2, IL6R, EDNRA, Toll-like receptor family (TLR3, TLR4, TLR9), JUNB, YAP1, TEAD1, TEAD2, TEAD3, TEAD4, NFKB1, JUNB, STAT1, STAT3, STAT4, SMAD2, SMAD3 and SMAD4.

[01034] As shown in Tables 4, 5 and 8, treatment with 30 mg/kg/day of atrasentan reduced NF-KB signaling. The components of NF-kB signaling differentially expressed after treatment with 30 mg/kg/day atrasentan can be found in Table 9. Table 9 shows that the reduction in NK-kB signaling was the result of a decrease in one or more positive regulators of NF-kB signaling and/or increase in one or more negative regulators of NF-kB signaling. Table 9 also shows that the reduction in NK-kB signaling was also the result of modulation of one or more core components of NF-kB signaling, such that NF-kB signaling was reduced. Components of the NF-KB signaling pathway may include, without limitation, CHUK, FADD, IKBKB, IKBKG, IL1A, IL1R1, MAP3K1, MAP3K14, MAP3K7, MYD88, NFKB1, NFKBIA, RELA, RIPK1, TAB1, TNF, TNFAIP3, TNFRSF1A, TNFRSF1B, TRADD and TRAF6 (see, for example, NFKB_PATHWAY BIOCARTA).

[01035] As shown in Tables 5 and 10, treatment with 30 mg/kg/day of atrasentan reduced IL-6 signaling. Components of IL-6 signaling differentially expressed after treatment with 30 mg/kg/day atrasentan can be found in Table 10. Table 10 shows that the reduction in IL-6 signaling was the result of a decrease in one or more regulators positive IL-6 signaling and/or increase in one or more negative IL-6 signaling regulators. Table 10 also shows that the reduction in IL-6 signaling was also a result of modulation of one or more core components of IL-6 signaling, such that IL-6 signaling was reduced. Components of the IL-6 signaling pathway may include, without limitation, AGT, AKT1, BAD, BCL2L1, CREBBP, CRP, GAB1, GRB2, GSK3B, HCK, HDAC1, IL6, IL6R, IL6ST, IRF1, JAK1, JAK2, JUNB , MAP2K1, MAP2K2, MAP2K4, MAP3K7, MAPK1, MAPK3, NCOA1, NLK, NR2F6, PIK3R1, PIK3R2, PRDM1, PRKCD, PTPN11, RAC1, RPS6KB1, SHC1, SOCS3, SOS1, STAT1, STAT3, TIMP1, TYK2, VAV1 and VIP (see e.g. IL6_SIGNALING_PATHWAY Wiki Path).

[01036] As shown in Tables 4 and 11, treatment with 30 mg/kg/day of atrasentan reduced PDGF signaling. The components of PDGF signaling differentially expressed following treatment with 30 mg/kg/day atrasentan can be found in Table 11. Table 11 shows that the reduction in PDGF signaling was the result of a decrease in one or more positive regulators of PDGF signaling and/or an increase in one or more negative regulators of PDGF signaling. Table 11 also shows that the reduction in PDGF signaling was also a result of modulation of one or more core components of PDGF signaling, such that PDGF signaling was reduced. Components of the PDGF signaling pathway may include, without limitation, ARFIP2CDC42, CHUK, ELK1, FOS, GRB2, HRAS, JAK1, JUN, MAP2K1, MAP2K4, MAP3K1, MAPK1, MAPK3, MAPK8, MT-CO2, NFKB1, NFKBIA, PAK1 , PDGFA, PDGFB, PDGFRB, PIK3R1, PLA2G4A, PLCG1, PTPN11, RAC1, RAF1, RASA1, RHOA, SHC1, SOS1, SRC, SRF, STAT1, STAT3, TIAM1, VAV1, VAV2 and WASL (see, for example, Wiki Pathway PDGF_PATHWAY). For example, atrasentan may inhibit the expression and/or activity of one or more components of the PDGF signaling pathway selected from the group of ARFIP2CDC42, CHUK, ELK1, FOS, GRB2, HRAS, JAK1, JUN, MAP2K1, MAP2K4, MAP3K1, MAPK1 , MAPK3, MAPK8, MT-CO2, NFKB1, NFKBIA, PAK1, PDGFA, PDGFB, PDGFRA, PDGFRB, PIK3CG, PIK3R1, PLA2G4A, PLCG1, PTPN11, RAC1, RAF1, RASA1, RHOA, SHC1, SOS1, SRC, SRF, STAT1 , STAT3, TIAM1, VAV1, VAV2 and WASL.

[01037] As shown in Tables 5 and 12, treatment with 30 mg/kg/day of atrasentan reduced signaling associated with cell proliferation. The components of cell proliferation-associated signaling (mitotic spindle and G2M checkpoint) differentially expressed after treatment with 30 mg/kg/day atrasentan can be found in Table 12. Table 12 shows that the reduction in proliferation-associated signaling cell (mitotic spindle and G2M checkpoint) was the result of a decrease in one or more positive regulators of signaling associated with cell proliferation (mitotic spindle and G2M checkpoint) and/or an increase in one or more negative regulators of signaling associated with cell proliferation (mitotic spindle and G2M checkpoint). Table 12 also shows that the reduction in cell proliferation-associated signaling (mitotic spindle and G2M checkpoint) was also the result of modulation of one or more core components of cell proliferation-associated signaling (mitotic spindle and G2M checkpoint) , so that signaling associated with cell proliferation (mitotic spindle checkpoint and G2M checkpoint) was reduced. Cell proliferation-associated signaling pathway components (mitotic spindle and G2M checkpoint) may include, without limitation, CCDC88A, SORBS2, RHOT2, EPB41L2, CEP192, BCAR1, PPP4R2, TUBA4A, OPHN1, CNTRL, TIAM1, NIN, MYH10 , FLNA, RAPGEF5, FGD6, MYO1E, VCL, ITSN1, SMC3, MYH9, SLC12A2, DMD, CCND1, ARID4A, KMT5A, ATRX, SLC38A1, SLC7A1, YTHDC1 and MEIS1 (see, for example, MSigDB HALLMARK_G2M_CHECKPOINT and ).

[01038] As shown in Tables 5 and 13, treatment with 30 mg/kg/day of atrasentan reduced the signaling of the inflammatory response. Components of inflammatory response signaling differentially expressed after treatment with 30 mg/kg/day atrasentan can be found in Table 13. Table 13 shows that the reduction in inflammatory response signaling was the result of a decrease in one or more regulators positive indicators of inflammatory response signaling associated with cell proliferation and/or an increase in one or more negative regulators of inflammatory response signaling. Table 13 also shows that the reduction in inflammatory response signaling was also a result of modulation of one or more core components of inflammatory response signaling, such that inflammatory response signaling was reduced. components of the inflammatory response signaling pathway may include, without limitation, RNF144B, ROS1, SLC7A2, F3, NFKBIA, HPN, SLC4A4, CHST2, IL1B, CDKN1A, BTG2, CSF1, SLC11A2, EIF2AK2, EDN1, NFKB1, SERPINE1, SLC7A1 , CCL20, IL1R1, LY6E, and GABBR1 (see, for example, MSigDB HALLMARK_INFLAMMATORY_RESPONSE).

[01039] Cross-validation of the impact of atrasentan treatment on hallmark gene sets in two models (IgAN and ET-1 treated HRMC g-ddY mouse model) is shown in Figure 10. Figure 10 illustrates the concordance in negative enrichment scores indicating underexpression of characteristic gene sets (i.e., TNFα signaling via NF-KB, mitotic spindle, inflammatory response, epithelial mesenchymal transition, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, G2M point verification, E2F targets, complement, apoptosis and allograft rejection) as a result of atrasentan treatment in the g-ddY and HRMC model systems. Gene sets enriched after treatment of HRMC with ET-1 compared to untreated HRMC (control) show positive enrichment scores indicating overexpression of the same characteristic gene sets (i.e., TNFα signaling via NF-kB, mitotic spindle , inflammatory response, mesenchymal transition, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, G2M checkpoint, E2F targets, complement, apoptosis and allograft rejection).

[01040] Analysis of the mesangial cell-associated gene signature is shown in Figure 11A and Figure 11B. Figure 11A shows the overlapping genes between genes differentially expressed after treatment of g-ddY mice with atrasentan at 30 mg/kg/day compared to atrasentan treatment at 0 mg/kg/day (control), genes differentially expressed after treatment of HRMC with atrasentan at 25 nm in the presence of ET-1 and a published human mesangial single-cell signature (Lake et al., 2018). Figure 11B illustrates the increased and/or decreased expression levels of 44 genes associated with the mesangial cell signature in g-ddY mice treated with atrasentan at 0 mg/kg/day (control) and decreased and/or increased expression levels after the treatment of g-ddY mice with atrasentan at 10, 20 and 30 mg/kg/day. The components of the mesangial cell-associated gene signature are shown in Table 14.

[01041] The evaluation of potential biomarkers based on RNA-seq data is shown in Figures 12A-12B. Figure 12A summarizes mouse versus human translatability between selected biomarkers: ALPL, AMN, ASL, CRYL1, DPEP1, GAPDH, IGF1, PDZK1IP1, PEBP1, SELENBP1, SLC19A1, and SLC6A19. Figure 12A shows which of the potential biomarkers were present in plasma/serum and/or urine and whether the potential biomarker was expressed in both mice and humans. As RNA-seq data was generated in mouse, filtering of potential biomarkers based on a set of criteria, as seen in Figure 12A, was used to limit potential future issues with lack of translatability. Changes in gene expression (log2(CPM)) for each potential biomarker were plotted for control and treatment with atrasentan at 10 mg/kg/day, 20 mg/kg/day, and 30 mg/kg/day (Figure 12B). Based on the criteria in Figure 12A and the RNA-seq data in Figure 12B, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19 were identified as potential biomarkers.

[01042] In summary, gene expression analysis following atrasentan treatment showed treatment-induced changes in genes that act synergistically in rescue pathways (e.g., reduction in inflammatory and proliferative pathways). Furthermore, RNA-seq data identified potential biomarkers (e.g., IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19) that can be used together with ET-1 (EDN1), TNF, and FGF-2. Note that the overall dose-dependent changes in gene expression after treatment suggest that biomarkers and functional UACR readout can be used in conjunction. TABLES TABLE 1: TOP 40 DEGS (25 POSITIVELY REGULATED AND 15 NEGATIVELY REGULATED) IN ATRASENTAN 10 mg/KG/DAY VERSUS CONTROL. TABLE 2: TOP 50 DEGS (25 POSITIVELY REGULATED AND 25 NEGATIVELY REGULATED) IN ATRASENTAN 20 mg/KG/DAY VERSUS CONTROL TABLE 3: TOP 50 DEGS (25 POSITIVELY REGULATED AND 25 NEGATIVELY REGULATED) IN ATRASENTAN 30 mg/KG/DAY VERSUS CONTROL TABLE 4: SIGNALING PATHWAYS ENRICHED AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 0 (CONTROL), 10, 20 OR 30 mg/KG/DAY. Z SCORE VALUES INDICATE THE MAGNITUDE OF THE EFFECT OBSERVED AT EACH DOSAGE. TABLE 5: GENE SET ENRICHMENT ANALYSIS SHOWING ENRICHMENT IN CHARACTERISTIC GENE SETS AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 0 (CONTROL), 10, 20 OR 30 mg/KG/DAY. NES IS THE NORMALIZED ENRICHMENT SCORE THAT INDICATES ACCOUNTING FOR GENE PACK SIZE. NES OF <-1.5 OR >1.5 HAS BEEN CONSIDERED BIOLOGICALLY SIGNIFICANT. ADJUSTED P-VALUE IS THE ESTIMATED PROBABILITY THAT THE RESULTS FOR A PARTICULAR SET OF ENRICHED GENES WILL BE A FALSE POSITIVE FINDING. TABLE 6: LIST OF UPWARD REGULATORS GROUPED BY MOLECULAR TYPES OF CYTOKINES AND GROWTH FACTORS. THE OVERLAP P-VALUE INDICATES THE SIGNIFICANCE OF ENRICHMENT BASED ON THE NUMBER OF OVERLAPPING GENES BETWEEN THE DATA SET AND THE GENE TARGETS IN THE IPKB. ACTIVATION Z-SCORE THRESHOLD <-2 OR >2 AND OVERLAP THRESHOLD P-VALUE <0.05 WERE CONSIDERED SIGNIFICANT. TABLE 7: LIST OF UPWARD REGULATORS GROUPED BY TRANSMEMBRANE RECEPTOR, PROTEIN-COUPLED RECEPTOR G, AND MOLECULAR TYPES OF PROTEIN COMPLEXES. THE OVERLAP P-VALUE INDICATES THE SIGNIFICANCE OF ENRICHMENT BASED ON THE NUMBER OF OVERLAPPING GENES BETWEEN THE DATA SET AND THE GENE TARGETS IN THE IPKB. ACTIVATION Z-SCORE THRESHOLD <-2 OR >2 AND OVERLAP THRESHOLD P-VALUE <0.05 WERE CONSIDERED SIGNIFICANT. TABLE 8: LIST OF UPWARD REGULATORS GROUPED BY TRANSCRIPTION REGULATOR AND MOLECULAR TYPES OF LIGAND-DEPENDENT NUCLEAR RECEPTORS. THE OVERLAP P-VALUE INDICATES THE SIGNIFICANCE OF ENRICHMENT BASED ON THE NUMBER OF OVERLAPPING GENES BETWEEN THE DATA SET AND THE GENE TARGETS IN THE IPKB. ACTIVATION Z-SCORE THRESHOLD <-2 OR >2 AND OVERLAP THRESHOLD P-VALUE <0.05 WERE CONSIDERED SIGNIFICANT. TABLE 9: GENE EXPRESSION OF COMPONENTS OF NF-KB SIGNALING PATHWAYS AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN AT 0 mg/KG/DAY (CONTROL). TABLE 10: EXPRESSION OF IL6 SNALIZATION COMPONENTS PATHWAYS AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN AT 0 mg/KG/DAY (CONTROL). TABLE 11: GENE EXPRESSION OF COMPONENTS OF PDGF SIGNALING PATHWAYS AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN AT 0 mg/KG/DAY (CONTROL). TABLE 12: EXPRESSION OF COMPONENTS OF CELL PROLIFERATION SIGNALING PATHWAYS (MITOTIC SPINDLE AND G2M CELL CYCLE CHECKPOINT) AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN A 0 mg/KG/DAY (CONTROL). TABLE 13: EXPRESSION OF COMPONENTS OF INFLAMMATORY RESPONSE SIGNALING PATHWAYS AFTER TREATMENT OF G-DDY MICE WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN AT 0 mg/KG/DAY (CONTROL). TABLE 14: GENE EXPRESSION OF THE 44 GENES ASSOCIATED WITH THE MESANGIAL CELL SIGNATURE AFTER G-DDY TREATMENT WITH ATRASENTAN AT 10, 20 OR 30 mg/KG/DAY COMPARED TO ATRASENTAN AT 0 mg/KG/DAY (CONTROL).

CONCLUSION:

[01043] Thus, in the g-ddY mouse model of spontaneous IgA nephropathy, treatment with atrasentan at 20 and 30 mg/kg/day significantly reduced albuminuria after approximately 5 days of treatment compared to control g-ddY mice not treated with atrasentan. The magnitude of the reduction in albuminuria observed at these doses (>60% reduction from baseline) is considered highly clinically significant, demonstrating that atrasentan reduces albuminuria in a mouse model of IgA nephropathy.

Claims (31)

1. Use of atrasentan or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament to treat IgA nephropathy in a subject, comprising the administration of about 0.20 mg to about 1 .5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof in a subject diagnosed with IgA nephropathy. 2. Use according to claim 1, characterized by the fact that the diagnosis of IgA nephropathy comprises a renal biopsy. 3. Use according to claim 1 or 2, characterized in that the diagnosis of IgA nephropathy comprises the detection of deposition of IgA immune complexes in the subject's serum or urine, or in a renal biopsy sample of the subject. subject. 4. Use according to any one of claims 1 to 3, characterized by the fact that the diagnosis of IgA nephropathy comprises the detection of galactose-deficient IgA or antiglycan autoantibodies in the subject's serum. 5. Use according to any one of claims 1 to 4, characterized by the fact that the subject is diagnosed with IgA nephropathy as a primary glomerular disease. 6. Use according to any one of claims 1 to 5, characterized by the fact that the subject has not been previously diagnosed with one or more of diabetic nephropathy, HIV/AIDS or acute renal failure. 7. Use according to any one of claims 1 to 6, characterized in that it comprises inhibiting the activation of IgA nephropathy mesangial cells. 8. Use according to claim 7, characterized in that the inhibition of the activation of mesangial cells of IgA nephropathy comprises the reduction of inflammation of the mesangial cells and/or the reduction of the pro-fibrotic response in the mesangial cells. 9. Use according to any one of claims 1 to 8, characterized by the fact that the subject has persistent proteinuria. 10. Use according to any one of claims 1 to 9, characterized in that the subject excretes an average of about 0.3 grams to about 2 grams, or from about 0.5 grams to about 1 .5 grams, or from about 1 gram to about 1.5 grams, or from about 1.5 grams to about 2 grams of urine protein per day for at least 3 months before the first administration of atrasentan, or a pharmaceutically acceptable salt thereof. 11. Use according to any one of claims 1 to 9, characterized in that the subject excretes an average of about 0.75 grams or more, or about 1 gram or more of protein in the urine per day during at least about 3 months before the first administration of atrasentan, or a pharmaceutically acceptable salt thereof. 12. Use according to any one of claims 1 to 9, characterized by the fact that the subject excretes at least about 1 gram of protein in the urine per day in at least two of three consecutive measurements one year before the first administration of atrasentan, or a pharmaceutically acceptable salt thereof. 13. Use according to any one of claims 1 to 9, characterized by the fact that the subject has proteinuria of at least about 1 g/day in at least two of three consecutive readings during the year preceding the administration of atrasentan, or a pharmaceutically acceptable salt thereof; or at least about 2 g/day in at least two of three consecutive readings during the year prior to administration of atrasentan, or a pharmaceutically acceptable salt thereof. 14. Use according to any one of claims 1 to 13, characterized by the fact that the amount of proteins in the urine of the subject diagnosed with IgA nephropathy is reduced by at least about 20%, or by at least about 25%. %, or by at least about 30% after treatment with atrasentan or a pharmaceutically acceptable salt thereof. 15. Use according to any one of claims 9 to 14, characterized in that the proteinuria comprises albuminuria. 16. Use according to any one of claims 1 to 15, characterized by the fact that the subject has an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m2 prior to administration of atrasentan or a pharmaceutically acceptable salt thereof. 17. Use according to claim 16, characterized by the fact that the subject has an average eGFR of about 30 mL/min/1.73 m2 to about 90 mL/min/1.73 m2 for at least about 3 months before the first administration of atrasentan, or a pharmaceutically acceptable salt thereof. 18. Use according to any one of claims 1 to 17, characterized in that it comprises attenuating the rate of decline of eGFR by at least 20%, or by at least about 30%, or by at least about 40 % after treatment with atrasentan, or a pharmaceutically acceptable salt thereof. 19. Use, according to any one of claims 1 to 18, characterized by the fact that it comprises the decrease in the occurrence of hematuria in the subject. 20. Use according to claim 19, characterized by the fact that the hematuria is micro-hematuria, gross hematuria, symptomatic hematuria or asymptomatic hematuria. 21. Use according to any one of claims 1 to 20, characterized in that it comprises administering to the subject of about 0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt. acceptable of the same. 22. Use according to any one of claims 1 to 20, characterized in that it comprises administering to the subject about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. 23. Use according to any one of claims 1 to 20, characterized in that it comprises administering to the subject a dose of about 0.75 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof, once a day. 24. Use according to any one of claims 1 to 23, characterized in that it comprises administering to the subject a tablet comprising about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. 25. Use according to any one of claims 1 to 24, characterized in that atrasentan is administered as atrasentan mandelate or atrasentan hydrochloride. 26. Use according to any one of claims 1 to 25, characterized in that atrasentan is administered as atrasentan monohydrochloride. 27. Use according to any one of claims 1 to 26, characterized in that atrasentan, or a pharmaceutically acceptable salt thereof, is administered in one or more polymorphic forms wherein, when measured at about 25 ° C with Cu-Kα radiation, by an X-ray powder diffraction pattern comprising: (i) at least three peaks having respective 2θ values of about 8.3°, 9.7°, 10.0°, 13.0 °, 15.6°, 17.2° or 19.5° and essentially no peaks having values below about 6.2° and/or between about 6.6° and 8.0°; and/or (ii) peaks having respective 2θ values of about 6.7° and 22.05° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18, 0°, 18.5°, 19.8° or 20.6°; and/or (iii) peaks having respective 2θ values of about 6.7° and 21.95° and at least one peak having a respective 2θ value of about 8.4°, 15.6°, 18.0° , 18.5°, 19.8° or 20.6°. 28. Use according to any one of claims 1 to 27, characterized in that it comprises concomitant administration to the subject of an SGLT-2 inhibitor. 29. Use according to any one of claims 1 to 28, characterized in that it comprises concomitant administration to the subject of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB) or an combination thereof. 30. Use according to any one of claims 1 to 29, characterized by the fact that the subject is receiving a maximum tolerated stable dose of a renin-angiotensin system (RAS) inhibitor for at least about 12 weeks prior to the first administration of atrasentan, or a pharmaceutically acceptable salt thereof. 31. Use of atrasentan or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament to treat IgA nephropathy in a subject comprising the administration of about 0.20 mg to about 1, 5 mg of atrasentan, or an equivalent amount of a pharmaceutically acceptable salt thereof in a subject diagnosed with IgA nephropathy, in which the subject has persistent proteinuria and is receiving a maximum tolerated stable dose of a renin-angiotensin system (RAS) inhibitor ) for at least about 12 weeks prior to the first administration of atrasentan, or a pharmaceutically acceptable salt thereof; thus inhibiting the activation of mesangial cells in IgA nephropathy.