RU2824066C1 - Compounds and methods for treating fungal infections - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a method of treating a fungal infection. Method of treating a fungal infection in a subject, comprising administering to a subject with a fungal infection a therapeutically effective amount of compound 1:

,

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the fungal infection in the subject is caused by Candida spp., wherein a therapeutically effective amount of compound 1 provides 24-hour area under the concentration-time curve (AUC_0-24) at a steady state in a subject taking at least 150 mcg×pts./ml of compound 1A:

;

where the subject has contraindications to standard antifungal therapy due to chronic kidney disease (CKD); wherein administering compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a therapeutic regimen consisting of daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least 1–4 weeks; where the therapeutic regimen comprises a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; where the loading dose of compound 1 or its pharmaceutically acceptable salt, solvate or hydrate is 2000 mg; and wherein the maintenance dose comprises a single daily administration of 600 mg to 1500 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

EFFECT: said invention enables treating a fungal infection caused by Candida species in subjects with chronic kidney disease.

37 cl, 3 tbl, 3 ex

Description

OTHER APPLICATIONS RELEVANT TO THIS APPLICATION

[0001] This application claims priority from U.S. Provisional Patent Application No. 63/040,450, filed June 17, 2020, the entire contents of which are incorporated herein by reference.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] Fungal infections in humans are a major cause of human health problems. The present invention generally relates to the treatment of fungal infections in humans.

PREREQUISITES FOR THE CREATION OF THE INVENTION

[0003] Fungi infect humans and are a major cause of human health problems. They also infect plants, causing great damage to agricultural productivity. The present disclosure generally relates to the treatment and/or prevention of fungal infections and diseases.

ESSENCE OF THE INVENTION

[0004] In one aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject with a fungal infection a therapeutically effective amount of compound 1:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein the subject has contraindications to standard antifungal therapy. In some embodiments, incompatibility with standard antifungal therapy is due to renal dysfunction. Standard therapy (amphotericin B and voriconazole) can cause renal toxicity.

[0005] In another aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject with a fungal infection a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein no adjustment of the dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered to the subject is required based on the subject's renal condition. In some embodiments, the fungal infection is an invasive fungal infection. In some embodiments, the fungal infection is candidiasis. In some embodiments, the fungal infection is aspergillosis.

[0006] In another aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject having a fungal infection a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein the subject has a kidney disease. In some embodiments, the kidney disease comprises renal failure. In some embodiments, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject having a fungal infection a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein the subject has a kidney failure and no dosage adjustment of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is required. In some embodiments, no dosage adjustment is required in subjects with mild, moderate, or severe renal failure. In some embodiments, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, provides a stable 2-4 hour area under the concentration-time curve (AUC0-24) of Compound 1A in a subject of at least about 100 μg×hr/mL, at least about 150 μg×hr/mL, at least about 200 μg×hr/mL, or at least about 250 μg×hr/mL:

[0007] In some embodiments, administering Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a subject comprises a treatment regimen comprising administering Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, daily for at least 1-4 weeks. In some embodiments, the treatment regimen comprises administering a loading dose followed by administering daily maintenance doses. In some embodiments, the loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises at least about 2000 mg/day of Compound 1. In some embodiments, the maintenance dose is at least about 600 mg/day, at least about 700 mg/day, at least about 800 mg/day, at least about 900 mg/day, or at least about 1000 mg/day of Compound 1.

[0008] In one aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject having a fungal infection a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp. , Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp. or Emmonsia-like fungi, or a combination thereof; a therapeutically effective amount of compound 1 provides a sustained 24-hour area under the concentration-time curve (AUC0-24) of compound 1A in a subject receiving at least about 150 μg x h/mL of compound 1A; wherein the subject has contraindications to standard antifungal therapy; and wherein administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject comprises a treatment regimen comprising daily administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for at least 1-4 weeks.

[0009] In another aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject with a fungal infection a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; where the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp., spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or a combination thereof; a therapeutically effective amount of compound 1 provides a 24-hour steady-state area under the concentration-time curve (AUC0-24) of compound 1A in a subject receiving at least about 100 μg x h/mL of compound 1, wherein the subject has contraindications to standard treatment antifungal therapy; and wherein administering compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to the subject comprises a treatment regimen comprising daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least 1-4 weeks.

[0010] In another aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to a subject having a fungal infection a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia - similar fungi, or a combination thereof; wherein the subject is contraindicated in standard antifungal therapy; and wherein the administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a treatment regimen comprising daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least 1-4 weeks.

[0011] In some embodiments, incompatibility with standard antifungal therapy is due to decreased renal function.

[0012] In some embodiments, incompatibility with standard antifungal therapy is due to kidney disease in the subject.

[0013] In some embodiments, the kidney disease is chronic kidney disease, metabolic syndrome, vesicoureteral reflux, tubulointerstitial renal fibrosis, IgA nephropathy, diabetic nephropathy, Alport syndrome, HIV-associated nephropathy, glomerular nephritis (GN), focal segmental glomerulosclerosis, membranous glomerulonephritis, mesangiocapillary GN, interstitial fibrosis and tubular atrophy (IFTA), acute renal failure (AKI), acute obstructive nephropathy, or drug-induced fibrosis.

[0014] In some embodiments, the kidney disease is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease (CKD) is CKD stage 1, CKD stage 2, CKD stage 3, CKD stage 4, or CKD stage 5.

[0015] In some embodiments, the subject has high levels of protein in the urine (proteinuria).

[0016] In some embodiments, a therapeutically effective amount of Compound 1 provides a sustained 24-hour area under the concentration-time curve (AUC _0-24 ) at least 50 μg x hr/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a sustained 24-hour area under the concentration-time curve (AUC _0-24 ) at least 100 μg x hr/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a sustained 24-hour area under the concentration-time curve (AUC _0-24 ) at least 150 μg x hr/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a sustained 24-hour area under the concentration-time curve (AUC _0-24 ) of at least 200 μg h/mL of Compound 1A.

[0017] In some embodiments, a contraindication to standard antifungal therapy includes incompatibility with an azole-based antifungal agent, an allylamine-based antifungal agent, an echinocandin-based antifungal agent, or a polyene-based antifungal agent.

[0018] In some embodiments, the contraindication to standard antifungal therapy includes incompatibility with antifungal agents from the list: amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftungifine or terbinafine, anidulafungin, caspofungin, caspofungin or a pharmaceutically acceptable salt of any of the foregoing antifungal agents.

[0019] In some embodiments, the fungal infection is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., or Mucorales fungi, or a combination thereof.

[0020] In some embodiments, the subject is immunocompromised.

[0021] In some embodiments, the subject is infected with HIV/AIDS or has cancer.

[0022] In some embodiments, the cancer is acute myeloid leukemia or acute lymphoid leukemia.

[0023] In some embodiments, the subject has neutropenia.

[0024] In some embodiments, the subject has lymphopenia.

[0025] In some embodiments, the subject is undergoing or has undergone chemotherapeutic treatment for cancer.

[0026] In some embodiments, the subject is undergoing or has undergone treatment with corticosteroids.

[0027] In some embodiments, the subject is undergoing or has been treated with a TNF inhibitor.

[0028] In some embodiments, the subject is an organ transplant recipient.

[0029] In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant.

[0030] In some embodiments, the subject has graft-versus-host disease.

[0031] In some embodiments, the fungal infection is superficial, locally invasive, or disseminated throughout the subject's body.

[0032] In some embodiments, the fungal infection is a skin infection, a lung infection, a sinus infection, a central nervous system infection, a brain infection, an eye infection, a heart infection, a kidney infection, a gastrointestinal tract infection, a stomach infection, a pelvic infection, a blood infection, or a combination thereof.

[0033] In some embodiments, the fungal infection comprises a fungal disease or condition that is candidiasis, aspergillosis, blastomycosis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, pneumocystis pneumonia (PCP), ringworm, sporotrichosis, thalaromycosis, allergic bronchopulmonary aspergillosis, allergic sinusitis, azole-resistant A. fumigatus, aspergilloma, pulmonary aspergillosis, invasive aspergillosis, cutaneous aspergillosis, fusarium, scedosporiosis, rhinocerebral mucormycosis, pulmonary mucormycosis, disseminated mucormycosis, peritoneal mucormycosis, gastric mucormycosis, cutaneous mucormycosis, or a combination thereof.

[0034] In some embodiments, the treatment regimen comprises a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0035] In some embodiments, the treatment regimen comprises a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0036] In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion.

[0037] In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof comprises administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a subject by intravenous (IV) infusion.

[0038] In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject by intravenous (IV) infusion over a period of from about 30 minutes to about 4 hours.

[0039] In some embodiments, each loading dose contains about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0040] In some embodiments, the loading dose comprises administering about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (IV) infusion, followed by a second administration of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (IV) infusion within about 24 hours of the first infusion.

[0041] In some embodiments, the maintenance dose is administered once daily, beginning on the second day of treatment.

[0042] In some embodiments, the maintenance dose comprises a single daily administration of about 600 mg to about 1500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0043] In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of time from about 30 minutes to about 4 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment.

[0044] In some embodiments, a maintenance dose of about 600 mg to about 1200 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered over a period of about 30 minutes to about 4 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment.

[0045] In some embodiments, a maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally to the subject beginning on the second, third, or fourth day of treatment.

[0046] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject orally once a day, beginning on the second, third, or fourth day of treatment.

[0047] In some embodiments, beginning on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered over a period of about 30 minutes to about 3 hours by intravenous infusion; or b) about 700 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally once per day.

[0048] In some embodiments, beginning on the second day of treatment, about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered over a period of about 30 minutes to about 3 hours by intravenous infusion; and beginning on the fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered intravenously over a period of about 30 minutes to about 3 hours by intravenous infusion; or b) about 700 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally once per day.

[0049] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with an additional therapeutic agent.

[0050] In some embodiments, the treatment regimen comprises daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for about 4 weeks to about 6 weeks.

[0051] In some embodiments, the treatment regimen comprises daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for about 4 weeks to about 12 weeks.

[0052] In some embodiments, the treatment regimen comprises a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof and maintenance doses of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises administering two doses of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to the subject by intravenous (IV) infusion on the first day of therapy, each dose containing approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, followed by administration of maintenance doses comprising a single daily administration of approximately 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof by intravenous (IV) infusion for at least two days, followed by either: a single daily administration of approximately 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof by intravenous (IV) infusion; or oral administration once daily of approximately 700 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0053] In some embodiments, the treatment regimen comprises up to 14 days of administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0054] In some embodiments, the fungal infection in the subject is caused by Candida spp.

[0055] In some embodiments, the fungal infection in the subject is caused by Candida spp. and the treatment regimen comprises up to 14 days of administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0056] In some embodiments, the treatment regimen increases the chance of survival of the subject, reduces galactomannan levels in the subject, reduces β-d-glucan levels in the subject, or a combination thereof.

[0057] In some embodiments, no dosage adjustment of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered to a subject is required based on the subject's renal status.

[0058] Articles of manufacture are provided comprising a packaging material, compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof in the packaging material, and a label indicating that compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is used to treat a fungal infection or to prevent or alleviate one or more symptoms of a fungal infection.

[0059] Other objects, features and advantages of the Compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION

[0060] Provided herein are, for example, compositions for treating and/or preventing a fungal infection or disease. Also provided herein are, for example, methods for treating and/or preventing a fungal infection or disease.

[0061] In many patients, antifungal treatment options are limited or non-existent due to documented/suspected resistance, contraindications, intolerance, or lack of clinical response to standard antifungal therapy (SOC). In these settings, Compound 1 (shown below) has advantages over SOC antifungal therapy and thus supports preliminary investigation for the treatment of invasive mold infections (IMI).

[0062] Compound 1, a prodrug that is rapidly converted in vivo by phosphatases to the microbiologically active compound 1A, is a broad-spectrum antifungal agent for the treatment of invasive fungal infections by both intravenous and oral routes of administration. Compound 1 is a prodrug with a labile phosphate moiety. The phosphate moiety improves the solubility of the drug in water at a higher pH range, but also has limited stability.

[0063] Compound 1A inhibits the fungal glycosylphosphatidylinositol (GPI)-anchored protein wall transfer enzyme 1 (GWT1), a highly conserved inositol acylase that catalyzes an early step in the GPI-anchored biosynthetic pathway. This inhibition has a pleiotropic effect on the fungal cell due to inhibition of cell wall mannoprotein localization, which mediates cell wall integrity, biofilm formation, germ tube formation, and fungal growth. Compound 1A does not inhibit phosphatidylinositol glycan anchor protein biosynthesis class W (PIGW), the closest mammalian ortholog of the fungal GWT1 protein, consistent with the possibility of a large target-specific therapeutic window.

[0064] Compound 1A demonstrated broad antifungal activity in vitro against Candida spp., Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium spp., and some Mucorales fungi, including activity against azole- and echinocandin-resistant strains. In 5-fluorouracil-immunosuppressed mice challenged with IMIs (Aspergillus fumigatus, Scedosporium prolificans, and Fusarium solani), Compound 1 or 1A demonstrated statistically significant improvement in survival and reduction in pulmonary fungal colonization. In cyclophosphamide and cortisone acetate immunosuppressed mice challenged with IMI (A. fumigatus, S. apiospermum, F. solani, and Rhizopus spp.), Compound 1 demonstrated statistically significant improvement in survival rates and reduction in fungal burden.

[0065] In addition, compound 1A demonstrated antifungal activity against a wide range of clinical isolates of rare mold infections and rare yeast infections, including activity against a number of species of Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Mucorales fungi, Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia - similar fungi. These rare molds and rare yeasts are usually not a threat to healthy people, but can cause invasive mold infections in people with weakened immune systems.

[0066] In some embodiments, compound 1 or compound 1A is used to treat various fungal infections caused by Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidioides, or a combination thereof.

[0067] In some embodiments, compound 1 or compound 1A is used to treat various mold and rare mold infections. In some embodiments, the mold or rare mold infections are caused by Aspergillus spp., Mucorales, Hyalohyphomycete, Phaeohyphomycete, or a combination thereof.

[0068] Aspergillus spp. include A. flavus, A. niger, A. fumigatus, A. terreus.

[0069] Mucorales fungi include Rhizopus spp., Mucor spp., Lichtheimia spp., Cunninghamella spp.

[0070] Hyalohyphomycete fungi include Acremonium spp., Acremonium spp., Fusarium spp., Paecilomyces spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp..

[0071] Phaeohyphomycete fungi include Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp.

[0072] Scedosporium spp. include S. apiospermum, S. boydii, S. dehoogii.

[0073] Fusarium spp. includes F. solani.

[0074] Rhizopus spp. include Rhizopus oryzae.

[0075] In some embodiments, Compound 1 or Compound 1A is used to treat infections caused by Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., or Mucorales fungi, or a combination thereof; including A. flavus, A. niger, A. fumigatus, A. terreus, S. apiospermum, S. boydii, S. dehoogii, F. solani, P. lilacinus, P. variotii, and Rhizopus oryzae.

[0076] In some embodiments, Compound 1 or Compound 1A is used to treat various yeast and rare yeast infections, including those caused by Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., SporoboIomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., or Wickerhamomyces (Pichia) spp., or a combination thereof; including G. clavatum, T. asahii, T. mucoides, T. mycotoxinivorans, M. furfur, R. mucilaginosa, or S. cerevisiae.

[0077] In some embodiments, compound 1 or compound 1A is used to treat a plurality of additional fungal infections, including dimorphic fungal infections caused by Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or a combination thereof; including T. marneffei.

[0078] Pharmacokinetic-pharmacodynamic (PK-PD) studies in immunocompromised mice with invasive A. fumigatus infections demonstrated that the area under the concentration-time curve (AUC) divided by the minimum effective concentration (MEC) ratio was a driver of efficacy. The dosing regimen used in this study resulted in a steady-state AUC of ≥200 μg×hr/mL of Compound 1 or the active metabolite of Compound 1 (i.e., Compound 1A) that was associated with efficacy (colony counts and improved survival) in immunocompromised mice with invasive pulmonary aspergillosis (IPA). Additionally, formal PK-PD studies demonstrated that the dosing regimen had a favorable probability of target (PTA) for the majority of isolates expected to be detected in this study.

[0079] Phase 1 clinical studies of Compound 1 have investigated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses administered intravenously (IV) and orally (PO). To date, a total of 197 healthy volunteers and 21 patients with acute myeloid leukemia (AML) have received Compound 1 in 5 Phase 1 studies. The duration of the multiple-dose regimens in these studies was 7, 14, and 42 days (6 weeks).

[0080] Compound 1 may have potential advantages over existing SOC for the treatment of invasive infections caused by Candida spp., including candidemia and Aspergillus spp. or rare molds. In addition, Compound 1 has a differentiated safety profile, is available as intravenous and oral formulations, and may have a lower DDI than SOC.

[0081] Patients with azole-resistant mold infections, including azole-resistant Candida spp., A. fumigatus, and certain rare molds (e.g., Fusarium spp., Scedosporium spp., Mucorales species), are commonly treated with intravenous polyenes. Polyenes are associated with a risk of nephrotoxicity, electrolyte imbalances, and infusion reactions that may be limiting in patient care. Compound 1 has broad-spectrum antifungal activity, including against azole-resistant molds, and may potentially be safer and easier to use than polyenes.

[0082] In some embodiments, Compound 1 provides an advantage over polyenes for the treatment of breakthrough infections in patients receiving prophylaxis with mold-active triazoles. Compound 1 has the potential to provide antifungal activity against Candida spp, A. fumigatus, and rare molds without the potential toxicity associated with polyenes. Due to its broad tissue penetration, Compound 1 may be particularly useful in the treatment of patients with invasive fungal infections of the eye and central nervous system.

[0083] In some embodiments, Compound 1 provides benefit to those patients with invasive fungal infections who cannot receive azole antifungal treatment due to intolerance, toxicity, or clinically significant drug interactions. Compound 1 has the potential to provide broad-spectrum antifungal activity without the risk of liver or other azole-associated toxicity and is expected to be less likely to cause clinically significant drug interactions.

[0084] Compound 1 has a novel mechanism of action with broad-spectrum activity against Candida spp. (yeast) and Aspergillus spp. (mold), including activity against polyene and azole-resistant Aspergillus spp. Compound 1 has demonstrated efficacy in a number of animal models of IMI, including Aspergillus spp., Fusarium spp., Scedosporium spp., and species of the order Mucorales. Compound 1 is available in both intravenous and oral formulations with broad tissue distribution, including the eye and central nervous system, and has been shown to be safe and well tolerated with a favorable safety and drug interaction (DDI) profile that is distinct from the antifungal profile of SOC therapies. Compound 1 has the potential to be used as a first-line agent for the treatment of IMI due to its unique mechanism of action. Thus, Compound 1 has the potential to address unmet needs in patients with limited antifungal treatment options due to confirmed/suspected resistance, contraindications, intolerance, or lack of clinical response to standard antifungal therapy (SOC) or no such treatment.

[0085] Nephrotoxicity is one of the most problematic side effects of antifungal therapy. Drug-induced kidney injury is one of the reasons for the failure of compounds in drug development. It is a common side effect of amphotericin B, which is considered the “gold standard” antifungal agent (Kuznar W, Baglin T. (2015). MD Conf. Express 13 (13), 12-13). Therefore, the nephrotoxic effect of existing antifungal agents, especially amphotericin B, has been extensively studied using in vitro and in vivo models (van Etten et al. J Antimicrob Chemother. 1993 Nov; 32 (5): 723-39).

[0086] Patients with significant renal dysfunction during amphotericin B therapy require continuous dialysis after discontinuation of the antifungal agent (Groll et al. Adv Pharmacol 1998; 44: 343-500). A patient's risk of developing severe renal injury during amphotericin B therapy depends on the dose and duration of amphotericin B, the patient's baseline health and fluid status, previous or underlying renal disease, and the use of other potentially nephrotoxic drugs (e.g., aminoglycoside antibiotics, radiocontrast dye, cyclosporine, etc.).

[0087] In some cases, drug-induced kidney injury from antifungal therapy, particularly in patients with invasive fungal infections, leads to an increased risk of death or prolonged hospital stay.

[0088] In some embodiments, standard antifungal therapy (SOC) is contraindicated in patients with kidney disease and/or comorbidities leading to renal dysfunction, such as renal failure or other renal impairment. Examples of such diseases and lesions include chronic kidney disease, metabolic syndrome, vesicoureteral reflux, renal tubulointerstitial fibrosis, IgA nephropathy, diabetes (including diabetic nephropathy), Alport syndrome, HIV-associated nephropathy, resultant glomerular nephritis (GN), including, but not limited to, focal segmental glomerulosclerosis and membranous glomerulonephritis, mesangiocapillary GN, and resultant interstitial fibrosis and tubular atrophy (IFTA), including, but not limited to, recovery from acute kidney injury (AKI), acute obstructive nephropathy, and drug-induced fibrosis and resulting glomerular nephritis (GN), including, but not limited to, focal segmental glomerulosclerosis and membranous glomerulonephritis.

[0089] Glomerulonephritis, which causes inflammation in the glomeruli, is a common cause of end-stage renal disease. Severe and prolonged inflammation can damage the glomeruli and lead to kidney damage. Connective tissue growth factor (CTGF) is a member of the CCN family of four-domain matricellular proteins that regulates signaling of other growth factors and contributes to kidney injury.

[0090] Metabolic syndrome has been recognized as a group of abnormalities that include diabetic features such as insulin resistance, as well as central or visceral obesity and hypertension. In almost all cases, impaired glucose regulation leads to stimulation of cytokine release and increased extracellular matrix deposition. Additional factors that contribute to chronic kidney disease, diabetes, metabolic syndrome, and glomerular nephritis include hyperlipidemia, hypertension, and proteinuria, all of which lead to further kidney injury and further stimulate extracellular matrix deposition. Thus, regardless of the underlying cause, renal injury can lead to renal fibrosis and concomitant loss of renal function. Schena, F. and Gesualdo, L., Pathogenic Mechanisms of Diabetic Nephropathy, J. Am. Soc. Nephrol., 16: S30-33 (2005); Whaley-Connell, A., and Sower, J. R., Chronic Kidney Disease and the Cardiometabolic Syndrome, J. Clin. Hypert., 8 (8): 546-48 (2006 )).

[0091] In some embodiments, Compound 1 therapy is not contraindicated in subjects with already impaired renal function. In some embodiments, Compound 1 therapy is not contraindicated in subjects with kidney disease. In some embodiments, the kidney disease is chronic kidney disease (CKD). In some embodiments, the kidney disease is Alport syndrome.

[0092] In some embodiments, Compound 1 therapy is not contraindicated in subjects with high levels of protein in the urine (proteinuria).

[0093] In some embodiments, described herein is a method of treating a fungal infection in a subject using Compound 1, comprising administering Compound 1, wherein the subject also has a kidney disease, and wherein administering Compound 1 delays, slows, or prevents the progression of the kidney disease to end-stage renal disease (ESRD).

[0094] Chronic kidney disease (CKD) refers to all five stages of kidney damage, from very mild damage in stage 1 to complete kidney failure in stage 5. The stages of kidney disease are classified based on how well the kidneys can filter waste products (waste) and extra fluids from the blood. In the early stages of kidney disease, the kidneys are still able to filter waste from the blood. In later stages, the kidneys have to work harder to rid the blood of waste, and they may stop working altogether.

[0095] The way doctors measure how well the kidneys filter waste from the blood is called the estimated glomerular filtration rate, or eGFR. eGFR is a number based on a blood test for creatinine, a waste product in the blood.

[0096] Kidney disease stages are based on the amount of eGFR.

[0097] Stage 1 CKD: eGFR 90 or greater. Stage 1 CKD indicates mild kidney damage and corresponds to eGFR 90 or greater.

[0098] Stage 2 CKD: eGFR 60 to 89. Stage 2 CKD indicates mild kidney damage and corresponds to an eGFR of 60 to 89.

[0099] Stage 3 CKD: eGFR between 30 and 59. Stage 3 CKD refers to an eGFR between 30 and 59. An eGFR between 30 and 59 means that there is some kidney damage and the kidneys are not working properly. Stage 3 CKD is divided into two stages: stage 3a refers to an eGFR between 45 and 59; stage 3b refers to an eGFR between 30 and 44. Many people with stage 3 kidney disease have no symptoms.

[0100] Stage 4 CKD corresponds to an eGFR of 15 to 29. Stage 4 CKD corresponds to an eGFR of 15 to 29. An eGFR of 15 to 30 means that the kidneys are moderately to severely damaged and not working properly. Stage 4 kidney disease should be taken very seriously - it is the last stage before kidney failure.

[0101] Stage 5 CKD is defined as an eGFR of less than 15. An eGFR of less than 15 means that the kidneys are very close to failure or have completely failed. When the kidneys fail, waste products build up in the blood, making the patient's condition very serious.

[0102] In some embodiments, methods of treating fungal infections in subjects with impaired renal function are provided. In some embodiments, the methods of treatment include treatment regimens comprising administering Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a subject with a fungal infection. In some embodiments, no dosage adjustment of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered to the subject is required based on the renal condition of the subject. In some embodiments, the administered formulations do not contain cyclodextrin (i.e., do not include one or more cyclodextrin excipients).

Fungal diseases

[0103] In some embodiments, the fungal disease is selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and thalaromycosis.

[0104] In some embodiments, the fungal disease is aspergillosis. In some embodiments, the aspergillosis is allergic bronchopulmonary aspergillosis (abpa), allergic aspergillosis sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous aspergillosis. In some embodiments, the subject has an aspergilloma.

[0105] In some embodiments, the fungal disease is blastomycosis.

[0106] In some embodiments, the fungal disease is candidiasis. In some embodiments, the candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia, or invasive candidiasis.

[0107] In some embodiments, the fungal disease is coccidioidomycosis (valley fever). In some embodiments, the coccidioidomycosis is acute coccidioidomycosis (primary pulmonary coccidioidomycosis), chronic coccidioidomycosis, or disseminated coccidioidomycosis, including primary cutaneous coccidioidomycosis.

[0108] In some embodiments, the fungal disease is cryptococcosis. In some embodiments, the cryptococcosis is wound or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis. In some embodiments, the fungal disease is a fungal ocular infection. In some embodiments, the fungal ocular infection is fungal keratitis, fungal exogenous endophthalmitis, or fungal endogenous endophthalmitis.

[0109] In some embodiments, the fungal disease is histoplasmosis. In some embodiments, the histoplasmosis is acute histoplasmosis. In some embodiments, the histoplasmosis is chronic histoplasmosis.

[0110] In some embodiments, the fungal disease is mucormycosis. In some embodiments, the mucormycosis is rhinocerebral (nose and brain) mucormycosis, pulmonary (lung) mucormycosis, gastrointestinal mucormycosis, cutaneous mucormycosis, or disseminated mucormycosis.

[0111] In some embodiments, the fungal disease is Pneumocystis pneumonia (PCP).

[0112] In some embodiments, the fungal disease is ringworm. In some embodiments, the ringworm is tinea pedis, tinea cruris, tinea capitis, tinea barbae, tinea mange, tinea nails, or tinea corporis. In some embodiments, the ringworm is caused by a type of fungus including Trichophyton, Microsporum, or Epidermophyton.

[0113] In some embodiments, the fungal disease is sporotrichosis. In some embodiments, the sporotrichosis is cutaneous sporotrichosis, pulmonary sporotrichosis, or disseminated sporotrichosis.

[0114] In some embodiments, the fungal disease is thalaromycosis.

[0115] In some embodiments, the fungal disease or infection is caused by Cryptococcus, Aspergillus, Candida, Coccidioides, Blastomyces, Ajellomyces, Histoplasma, Rhizopus, Apophysomyces, Absidia, Saksenaea, Rhizomucor pusillus, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias, Fusarium, or Scedosporium fungi/species. In some embodiments, the fungal disease is caused by a fungal species including, but not limited to, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Blastomyces dermatifcidis, Ajellomyces dermatitidis, Candida albicans, Candida auris, Candida glabrata, Candida parapsilosis, Candida rugosa, Candida tropicalis, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias albicans, Fusarium solani, Scedosporium apiospermum, and Rhizomucor pusillus. In some embodiments, the fungal disease is caused by the fungal species Aspergillus fumigatus. In some embodiments, the fungal disease is caused by the fungal species Candida albicans. In some embodiments, the fungal disease is caused by the fungal species Fusarium solani. In some embodiments, the fungal disease is caused by Mucor indicus. In some embodiments, the fungal disease is caused by the fungal species Scedosporium apiospermum. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus neoformans. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus gattii. In some embodiments, the fungal disease is caused by the fungal species Candida auris.

[0116] In some embodiments, the fungal disease or infection is caused by Aspergillus fumigatus, Blastomyces, Ajellomyces, Candida, Coccidioides, Cryptococcus, Histoplasm, Rhizopus Muco, Cunninghamell, Apophysomyces, Absidi, Saksenaea, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis, Talaromyces, Asclepias, Fusarium, Scedosporium, or fungi of the order Mucorales, or any combination thereof.

[0117] In some embodiments, the fungal disease or infection is caused by a Cryptococcus, Aspergillus, Candida, Fusarium, Scedosporium, or Mucorales fungus, or any combination thereof. In some embodiments, the fungal disease or infection is caused by Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajellomyces dermatitidi, Candida albican, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias albicans, Fusarium solani, Scedosporium apiospermum, Rhizomucor pusillus, or any combination thereof.

[0118] In some embodiments, a compound described herein is active against the fungal protein Gwt1. This conserved enzyme catalyzes the post-translational modification of glycosylphosphatidylinositol (GPI), which anchors eukaryotic cell surface proteins to the cell membrane. In yeast, GPI mediates the cross-linking of cell wall mannoproteins to β-1,6-glucan. Inhibition of this enzyme in both Candida albicans and Saccharomyces cerevisiae has been shown to result in inhibition of the maturation and localization of GPI-anchored mannoproteins, which exhibits pleiotropic effects that include inhibition of fungal adhesion to surfaces, inhibition of biofilm formation, inhibition of germ tube formation, severe growth defects, or lethality.

Subjects

[0119] In some embodiments, the subject is a human. In some embodiments, the subject is immunocompromised. In some embodiments, the subject is undergoing therapy with at least one immunosuppressive drug. In some embodiments, the immunosuppressive drug increases the risk of opportunistic infections in the subject.

[0120] Immunosuppressants/drugs that can weaken the immune system include, but are not limited to, corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, everolimus, pomalidomide, omalizumab, azathioprine, lenalidomide, thalidomide, anti-TNF inhibitors, interleukin inhibitors, Janus kinase inhibitors, sphingosine-1-phosphate receptor (S1P) agonists, S1P antagonists, calcineurin inhibitors, mTOR inhibitors, nucleotide synthesis inhibitors, biologics, and monoclonal antibodies.

[0121] Corticosteroids include, but are not limited to, prednisolone, budesonide, prednisolone, methylprednisolone.

[0122] Janus kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, and upadacitinib.

[0123] Sphingosine-1-phosphate receptor antagonists include, but are not limited to, FTY720.

[0124] S1P agonists include, but are not limited to, ozanimod, etrasimod.

[0125] Calcineurin inhibitors include, but are not limited to, cyclosporine and tacrolimus.

mTOR inhibitors include, but are not limited to, sirolimus and everolimus.

[0127] Interleukin inhibitors include, but are not limited to, rilonacept, canakinumab, anakinra, reslizumab, brodalumab, ustekinumab, benralizumab, mepolizumab, tocilizumab, ixekizumab, dupilumab, secukinumab, tildrakizumab, guselkumab, sarilumab, basiliximab, risankizumab, daclizumab, siltclizumab.

[0128] Nucleotide synthesis inhibitors include, but are not limited to, azathioprine, leflunomide, mycophenolate.

[0129] Biologics include, but are not limited to, TNF-alpha inhibitors, integrin inhibitors, IL-12/23 inhibitors. Biologics include, but are not limited to, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, etrolizumab, vedolizumab.

[0130] Monoclonal antibodies include, but are not limited to, basiliximab, daclizumab, alemtuzumab, rituximab, belatacept.

[0131] In some embodiments, the human subject is under 1 year of age. In some embodiments, the human subject is an infant under 1 month of age. In some embodiments, the human subject is over 70 years of age. In some embodiments, the subject is infected with HIV/AIDS. In some embodiments, the subject is undergoing or has undergone chemotherapy treatment for cancer. In some embodiments, the subject is undergoing or has undergone treatment with a corticosteroid. In some embodiments, the subject is undergoing or has been treated with a TNF inhibitor. In some embodiments, the subject is a transplant recipient. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant, a bone marrow transplant, a lung transplant, a liver transplant, a heart transplant, a kidney transplant, a pancreas transplant, or a combination thereof. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant. In some embodiments, the subject is a recipient of a bone marrow transplant. In some embodiments, the subject is a recipient of a lung transplant. In some embodiments, the subject is a liver transplant recipient. In some embodiments, the subject is a heart transplant recipient. In some embodiments, the subject is a kidney transplant recipient. In some embodiments, the subject is a pancreas transplant recipient.

Some terminology

[0132] Unless otherwise indicated, the following terms used in this application have the definitions set forth below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not intended to be limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0133] The term "acceptable" with respect to a composition, formulation or ingredient as used herein means the absence of a persistent adverse effect on the general health of the subject being treated.

[0134] The term "pharmaceutically acceptable salt" when applied to a compound refers to a salt of the compound that does not cause significant irritation to a mammal to which it is administered and does not substantially alter the biological activity and properties of the compound. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. In some embodiments, pharmaceutical salts are typically more soluble and dissolve more rapidly in gastric and intestinal juices than nonionic species, and thus may be used in solid dosage forms. In addition, since their solubility is often a function of pH, selective dissolution in one part of the digestive tract or another is possible, and in some cases this dissolution ability may be controlled as an aspect of delayed and sustained release behavior. Also, since the salt-forming molecule is in equilibrium with the neutral form in some cases, its passage through biological membranes may be controlled in some cases.

[0135] In some embodiments, pharmaceutically acceptable salts are typically prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. The term may be used in relation to any compound of the present invention. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl larsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. In some embodiments, when an acidic substituent such as _-CO2H is present, ammonium, morpholinium, sodium, potassium, barium or calcium salts and the like are formed. In some embodiments, when a basic group such as amino or a basic heteroaryl ring such as pyridyl is present, an acid addition salt is formed such as a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulfate salt, a trifluoroacetate salt, a trichloroacetate salt, an acetate salt, an oxalate salt, a maleate salt, a pyruvate salt, a malonate salt, a succinate salt, a citrate salt, a tartrate salt, a fumarate salt, a mandelate salt, a benzoate salt, a cinnamate salt, a methanesulfonate salt, an ethanesulfonate salt, a picrate salt, and the like. Additional pharmaceutically acceptable salt forms of the therapeutic agents are listed in Berge, et al., Journal of Pharmaceutical Sciences, Vol. 66(1), pp. 1-19 (1977).

[0136] The term "modulate" as used herein means to "interact" with a target, directly or indirectly, to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0137] The terms "administering," "administering," and the like, as used herein, refer to methods that, in some cases, deliver compounds or compositions to a desired site of biological action. These methods include, but are not limited to, oral, intraduodenal, and parenteral routes of administration (including intravenous, intraperitoneal, intravascular, or infusion). Those skilled in the art are familiar with the methods of administration that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. In some embodiments, the compounds and compositions described herein are administered intravenously. In some embodiments, the compounds and compositions described herein are administered by intravenous infusion.

[0138] The terms "co-administration" and the like as used herein are intended to refer to the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0139] The terms "effective amount" or "therapeutically effective amount" as used herein refer to a sufficient amount of an administered agent or compound that will alleviate to some extent one or more symptoms of a disease or condition being treated. The result includes a reduction and/or alleviation of the signs, symptoms, or causes of the disease or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein necessary to provide a clinically significant reduction in the symptoms of the disease. The appropriate "effective" amount in each individual case is not necessarily determined using methods such as a dose escalation study.

[0140] The terms "enhancement" or "enhance" as used herein mean increasing or prolonging a desired effect, either in potency or duration. Thus, with respect to enhancing the action of therapeutic agents, the term "enhancement" refers to the ability to enhance or prolong either the effectiveness or duration of action of other therapeutic agents on a system. The term "enhancing-effective amount" as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0141] As used herein, the terms "fungal infection" or "fungal disease" refer to a disease caused by pathogenic fungi. A fungal infection may be an opportunistic or primary infection and may be caused by yeast and/or mold fungi.

[0142] As used herein, the term "pharmaceutical combination" means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, for example, a compound described herein or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a co-agent, are administered to a patient simultaneously as a single dose or dosage. The term "non-fixed combination" means that the active ingredients, for example, a compound described herein or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a co-agent, are administered to a patient as separate components or simultaneously, concurrently, or sequentially without specific intervening time limitations, wherein such administration provides effective levels of both compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0143] The terms "kit" and "product of manufacture" are used as synonyms.

[0144] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other monkeys and ape species. In one aspect, the mammal is a human.

[0145] The terms "treating," "treating," or "treating" as used herein include alleviating, ameliorating, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, such as arresting the progression of a disease or condition, alleviating a disease or condition, inducing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping symptoms of a disease or condition in a prophylactic and/or therapeutic manner.

[0146] As used herein, the term “about” means “within ±10% of the value.”

Methods of use

[0147] In one embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is used in the preparation of medicaments for the treatment of diseases or conditions caused by fungal infections in mammals. Methods of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprise administering pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an active metabolite of Compound 1 (i.e., Compound 1A) in therapeutically effective amounts to said mammal.

[0148] In some embodiments, compositions comprising the compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially relieve at least one symptom of the disease or condition. Amounts effective for this application depend on the severity and progression of the disease or condition, prior therapy, the patient's health, weight, and response to medications, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and/or dose-ranging clinical testing.

[0149] For prophylactic purposes, compositions comprising Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof are administered to a patient predisposed to or otherwise at risk for a particular disease or condition. Such an amount is defined as a "prophylactically effective amount or dose." In such use, the exact amounts also depend on the patient's health condition, weight, etc. In use, effective amounts for such use will depend on the patient's baseline risk of developing a fungal infection, previous therapy, the patient's health condition and response to drugs, and the discretion of the treating physician. In one aspect, prophylactic treatment involves administering to a mammal to be treated that has previously exhibited at least one symptom of the disease and is currently in remission, a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, to prevent a recurrence of the symptoms of the disease or condition.

[0150] In some embodiments, if the patient's condition does not improve, at the discretion of the physician, administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is carried out chronically, i.e., over an extended period of time, including throughout the patient's life, to improve or limit the symptoms of the disease or condition of the patient or otherwise control.

[0151] After the patient's condition improves, a maintenance dose is administered as needed. Thereafter, in specific embodiments, the dosage or frequency of administration, or both, is reduced depending on the symptoms to a level at which the improved disease or condition is maintained. However, in some embodiments, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0152] In one aspect, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered daily to humans in need of therapy with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered once per day. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice per day.

[0153] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily, such as in the morning and evening.

[0154] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, or more.

[0155] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the human on a continuous dosing schedule. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the human on a continuous daily dosing schedule.

[0156] The term "continuous dosing regimen" refers to the administration of a particular therapeutic agent at regular intervals. In some embodiments, a continuous dosing regimen refers to the administration of a particular therapeutic agent at regular intervals without any breaks in the administration of the particular therapeutic agent. In some other embodiments, a continuous dosing regimen refers to the administration of a particular therapeutic agent in cycles. In some other embodiments, a continuous dosing regimen refers to the administration of a particular therapeutic agent in cycles of drug administration followed by a break in drug administration (e.g., a washout period or other similar period of time when the drug is not administered). For example, in some embodiments, the therapeutic agent is administered once daily, twice daily, daily for a week followed by a week without administration of the therapeutic agent; daily for two weeks followed by one or two weeks without administration of the therapeutic agent; daily for three weeks followed by one, two, or three weeks without administration of the therapeutic agent; daily for four weeks followed by one, two, three or four weeks without administration of the therapeutic agent; weekly administration of the therapeutic agent followed by a week without administration of the therapeutic agent, or biweekly administration of the therapeutic agent followed by a two-week period without administration of the therapeutic agent. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice a day.

[0157] The term "continuous daily dosing regimen" refers to the administration of a particular therapeutic agent at approximately the same time each day. In some embodiments, the daily administration is once per day. In some embodiments, the daily administration is twice per day. In some embodiments, the daily administration is three times per day. In some embodiments, the daily administration is more than three times per day.

[0158] In some embodiments, the determined amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered once per day. In some other embodiments, the determined amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice per day.

[0159] In some embodiments, when no improvement in the symptoms of the disease or condition is observed in the human subject, the daily dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, the frequency of administration is increased to provide constant or more regular exposure to Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the frequency of administration is increased to provide repeated high C _max levels on a more or less regular basis and to provide constant or more regular exposure to Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an active metabolite of Compound 1, (i.e., Compound 1A), such as to provide a higher AUC level. In some embodiments, the frequency of administration is increased to provide constant or more regular exposure to Compound 1A. In some embodiments, the frequency of administration is increased to provide repeated high C _max levels on a more regular basis and to maintain or more regular exposure to compound 1A, such as a higher AUC level.

[0160] In any of the above aspects, further embodiments are provided comprising a single administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, including further embodiments wherein Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered (i) once per day; or (ii) multiple times within one day.

[0161] In any of the above aspects, further embodiments are provided comprising multiple administrations of an effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, including further embodiments wherein (i) Compound 1 is administered continuously or periodically in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) Compound 1 is administered to the mammal every 8 hours; (iv) Compound 1 is administered to the mammal every 12 hours; (v) Compound 1 is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug interruption in which administration of the Compound is temporarily suspended or the dose of the Compound administered is temporarily reduced; at the end of such drug interruption, dosing of the Compound is resumed. In one embodiment, the duration of the interruption ranges from 2 days to 1 year.

[0162] Typically, a suitable dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for administration to a human will be in the range of from about 500 mg/day to about 2000 mg/day; from about 600 mg/day to about 2000 mg/day; from about 800 mg/day to about 2000 mg/day; or from about 1000 mg/day to about 2000 mg/day.

[0163] In some embodiments, administering an effective amount of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises a treatment regimen comprising administering a loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, followed by a maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in a manner different from the maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in the same manner as the maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0164] In some embodiments, the loading dose is administered as a solution by intravenous (IV) infusion.

[0165] In some embodiments, the maintenance doses are administered orally as solid dosage forms. In some embodiments, the solid dosage form is a tablet. In some embodiments, the maintenance doses are administered as a solution by intravenous (IV) infusion.

[0166] In some embodiments, the loading dose comprises about 1500 mg to about 2500 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose comprises about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises administering two doses of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject by intravenous (IV) infusion. In some embodiments, each loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject by intravenous (IV) infusion over about 30 minutes to about 3 hours. In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject by intravenous (IV) infusion over about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 3 hours or more. In some embodiments, each of the two loading doses comprises about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0167] In some embodiments, the loading dose comprises administering about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (IV) infusion, followed by a second administration of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (IV) infusion within about 24 hours of the first infusion. In some embodiments, the second loading dose is administered within about 12 hours after the first loading dose, within about 13 hours after the first loading dose, within about 14 hours after the first loading dose, within about 15 hours after the first loading dose, within about 16 hours after the first loading dose, within about 17 hours after the first loading dose, within about 18 hours after the first loading dose, within about 19 hours after the first loading dose, within about 20 hours after the first loading dose, within about 21 hours after the first loading dose, within about 22 hours after the first loading dose, within about 23 hours after the first loading dose, or within about 24 hours after the first loading dose.

[0168] In some embodiments, administration of maintenance doses is initiated on the second day of treatment. In some embodiments, the maintenance dose is administered once daily, beginning on the second day of treatment.

[0169] In some embodiments, each maintenance dose comprises a single daily administration of about 1000 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a once-daily administration of about 600 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a once-daily administration of about 600 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of about 650 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a once-daily administration of about 700 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises administering about 750 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 800 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 850 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 950 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. In some embodiments, each maintenance dose comprises administering about 1050 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof once daily. In some embodiments, each maintenance dose comprises administering about 1100 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof once daily. In some embodiments, each maintenance dose comprises administering about 1150 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof once daily. In some embodiments, each maintenance dose comprises administering about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof once daily. In some embodiments, each maintenance dose comprises administering more than about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof once daily.

[0170] In some embodiments, each maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by intravenous infusion over a period of about 30 minutes to about 3 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, each maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered over about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or more than about 3 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment.

[0171] In some embodiments, maintenance doses of about 600 mg to about 1500 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered by intravenous infusion over a period of about 30 minutes to about 5 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, maintenance doses of about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered by intravenous infusion over a period of about 30 minutes to about 5 hours, beginning on the second, third, or fourth day of treatment.

[0172] In some embodiments, maintenance doses of about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered over a period of about 30 minutes to about 3 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment. In some embodiments, maintenance doses of about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered over a period of about 30 minutes to about 3 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment.

[0173] In some embodiments, each maintenance dose comprises a single daily administration of greater than about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose is a once-daily administration of about 900 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, maintenance doses of about 900 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered by intravenous infusion over a period of about 30 minutes to about 3 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, maintenance doses of about 900 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered by intravenous infusion over a period of greater than 3 hours, beginning on the second, third, or fourth day of treatment.

[0174] In some embodiments, a maintenance dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally to the subject beginning on the second, third, or fourth day of treatment.

[0175] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally once a day to the subject, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 800 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally to the subject once a day, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally to the subject once a day, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily to a subject beginning on the second, third, or fourth day of treatment.

[0176] In some embodiments, beginning on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; or b) about 800 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally once per day.

[0177] In some embodiments, beginning on the second day of treatment, about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; and beginning on the fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; or b) about 800 mg to about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally once a day.

[0178] In some embodiments, the daily dose or amount of active substance in the dosage form is lower or higher than the ranges set forth herein, taking into account a number of variables with respect to the individual treatment regimen. In various embodiments, the daily and unit doses vary depending on a number of variables, including, but not limited to, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, the personal characteristics (e.g., weight) of the individual, and the specific additional therapeutic agents to be administered (if applicable), as well as the judgment of the practitioner.

[0179] The toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ and ED ₅₀ . The dose ratio between toxic and therapeutic effects is the therapeutic index and is expressed as the ratio between LD ₅₀ and ED ₅₀ . In some embodiments, data obtained from cell culture analysis and animal studies are used to determine a therapeutically effective daily dose range and/or a therapeutically effective unit dose amount for use in mammals, including humans. In some embodiments, the daily dose of Compound 1 is within a range of circulating concentrations that includes the ED ₅₀ with minimal toxicity. In some embodiments, the daily dose range and/or unit dose amount varies within this range depending on the dosage form used and the route of administration used.

[0180] In some embodiments, methods of treating fungal infections in mammals using Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvement of clinical symptoms associated with the infection, improvement of radiographic abnormalities, and resolution of fungemia, if present. In some embodiments, clinical symptoms associated with the infection include, for example, the general appearance, including the appearance of the skin, head, eyes, ears, nose, throat, neck, trunk, or lymph nodes, or the state of the respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, nervous, mental, lymphatic/hematological, and endocrine/metabolic systems of the mammal.

[0181] In some embodiments, the improvement in one or more outcome measures is at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a mammal with a fungal infection or mold infection results in an improvement in one or more baseline measures of at least or about 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or greater than 10-fold. Improvements in some embodiments are compared to a control. In some embodiments, the control is an individual who does not receive compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the control is an individual who does not receive a full dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the control is the individual's baseline level before receiving compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0182] In some embodiments, methods of treating a fungal or mold infection in a subject using Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, result in an improvement in one or more outcome measures. In some embodiments, a baseline assessment is determined, typically prior to administration of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Improvements in outcome measures are assessed using repeated assessments conducted during treatment with Compound 1 and compared to the baseline assessment and/or any previous assessment(s).

[0183] Evaluation of patients for fungal infections and assessment of the effectiveness of treatment with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof includes several diagnostic testing methods, including: radiologic evaluations, including CT scans of the chest, sinuses, and abdomen; fungal culture and microscopy of respiratory tract specimens; fungal antigen testing of blood, serum, or bronchoalveolar fluid; pathogenic DNA testing of blood, serum, or bronchoalveolar fluid; lung biopsy (open, percutaneous, or transbronchial); urine testing for aspergillosis; and other molecular testing of respiratory tract specimens.

[0184] In some embodiments, methods of treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements that are measured by radiological assessment, such as computed tomography (CT). In some embodiments, imaging methods that detect inflammation are used, such as positron emission tomography or indium-labeled leukocyte scintigraphy. In some embodiments, radiological assessment is used to determine the presence of a fungal infection.

[0185] In some embodiments, radiological assessment is used to determine the extent or prevalence of infection. In some embodiments, CT scanning is performed every 7 days or 14 days while the mammal is being treated with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the overall infectious load is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% with a treatment regimen of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0186] In some embodiments, methods of treating fungal infections in mammals using Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements as measured by fungal culture from body fluids such as bronchoalveolar fluid, sputum, bronchial brush, or sinus aspirate. In some embodiments, the fungal load, as determined in a fungal culture, is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% following a treatment regimen with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0187] In some embodiments, the methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements that are measured using a suitable pathogen DNA assay. In some embodiments, pathogen DNA levels are measured in blood samples of the mammal. In some embodiments, pathogen DNA levels are measured in serum samples of the mammal. In some embodiments, pathogen DNA levels are measured in bronchoalveolar lavage fluid samples of the mammal. In some embodiments, pathogen DNA levels are determined using a known pathogen DNA detection assay. In some embodiments, pathogen DNA levels are determined using next generation sequencing and/or polymerase chain reaction (PCR) analysis. In some embodiments, pathogen DNA levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% with a treatment regimen of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0188] In some embodiments, methods of treating fungal infections in a subject using Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in histological improvements in biopsy tissue samples taken from a subject with a fungal or mold infection. In some embodiments, the biopsy tissue is lung tissue.

[0189] In some embodiments, the methods of treating fungal infections in mammals using Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, increase the overall survival of the subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%. In some embodiments, overall survival is measured at 42 days. In some embodiments, overall survival is measured at 84 days.

[0190] In some embodiments, the methods of treating fungal infections in mammals using Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, reduce the all-cause mortality rate of the subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%. In some embodiments, the all-cause mortality rate is measured at 42 days. In some embodiments, the all-cause mortality rate is measured at 84 days.

Pharmaceutical compositions

[0191] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients to facilitate processing of the active Compounds into formulations useful in pharmaceuticals. The proper formulation depends on the route of administration selected. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for this disclosure.

[0192] In some embodiments, the Compounds described herein are administered in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the Compounds and compositions described herein is by any route that delivers the Compounds to the site of action. These methods include, but are not limited to, delivery by the enteral route (including oral, gastric, or duodenal tube) or the parenteral route (injection or infusion), although the most appropriate route in some cases depends on, for example, the condition and disease of the recipient.

[0193] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is included in a pharmaceutical composition. As used herein, the term "pharmaceutical composition" refers to a liquid or solid composition that comprises a pharmaceutically active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof) and at least a carrier, wherein none of the ingredients is typically biologically undesirable in the amounts administered.

[0194] Pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be in any physical form that is pharmaceutically acceptable. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for oral administration. In one embodiment, such pharmaceutical compositions include a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0195] In some embodiments, conventional inert ingredients and a method for preparing pharmaceutical compositions are used. In some embodiments, known methods for preparing pharmaceutical compositions are used. All conventional types of compositions are contemplated, including, but not limited to, tablets, capsules, and solutions. However, the amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is best determined by an effective amount, that is, the amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof that provides the desired dose to a subject in need of treatment.

[0196] In some cases, capsules are prepared by mixing compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof with a suitable diluent and then filling the capsules with the appropriate amount of the mixture. Common diluents include inert powders such as starch of various types, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flour and similar food powders.

[0197] In some cases, tablets are prepared by direct compression, wet granulation or dry granulation. Their formulations typically include diluents, binders, lubricants and disintegrants, as well as Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also conveniently used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. In some cases, polyethylene glycol, ethyl cellulose and waxes are used as binders.

[0198] In some cases, a lubricant in the tablet formulation helps prevent the tablet and punches from sticking to the die. In some cases, the lubricant is selected from such solids as talc, magnesium and calcium stearates, stearic acid, and hydrogenated vegetable oils.

[0199] Tablet disintegrants are substances that swell when wet, breaking up the tablet and releasing the compound. They include starches, clays, celluloses, and gums. Specific tablet disintegrants include corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and sodium lauryl sulfate.

[0200] Enteric-coated formulations are often used to protect the active ingredient from the highly acidic contents of the stomach. Such formulations are created by coating the solid dosage form with a film of a polymer that is insoluble in acidic media and soluble in alkaline media. Examples of films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.

[0201] Tablets are often coated with sugar as a flavoring and sealant. Tablets may also be coated to impart a desired color.

[0202] In some embodiments, pharmaceutical compositions for use in any of the methods provided herein are described in the examples.

Combination treatment

[0203] In some cases, it is advantageous to administer Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof in combination with one or more other therapeutic agents.

[0204] In one embodiment, the therapeutic efficacy of compound 1 or a pharmaceutically acceptable salt thereof is enhanced by administering an adjuvant (i.e., the adjuvant alone has minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic effect is increased and the benefit to the patient is enhanced). Or, in some embodiments, the benefit to the patient is increased by administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another agent (which also includes the use of a therapeutic regimen) that also has a therapeutic effect.

[0205] In one specific embodiment, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is co-administered with a second therapeutic agent, wherein compound 1 or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0206] In any case, regardless of the disease or condition being treated, the overall benefit to the patient is either simply the addition of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0207] In some embodiments, various therapeutically effective doses of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, may be used in formulating a pharmaceutical composition and/or in treatment regimens where Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in combination with one or more additional agents, such as an additional therapeutically effective drug, an adjuvant, or the like. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens are optionally determined by methods similar to those set forth above for the active agents themselves. Furthermore, the prophylactic/therapeutic methods described herein encompass the use of metronomic dosing, i.e., more frequent administration of lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen includes treatment regimens in which the administration of Compound 1 or a pharmaceutically acceptable salt or solvate thereof begins before, during or after treatment with a second agent described herein and continues until any time during the period of treatment with the second agent or after the cessation of treatment with the second agent. It also includes treatment in which Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and the second agent used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes intermittent treatment that begins and stops at different times to facilitate clinical management of the patient.

[0208] It is understood that the dosage regimen for treating, preventing, or alleviating the condition(s) for which relief is sought is modified according to various factors (e.g., the disease or condition being treated; the age, weight, sex, diet, and health status of the subject). Thus, in some cases, the actual dosage regimen used varies and, in some embodiments, differs from the dosage regimens set forth herein.

[0209] For the combination therapy described herein, the dosages of the co-administered Compounds vary depending on the type of co-drug used, the particular drug used, the type of disease or condition being treated, etc. In further embodiments, when co-administered with one or more other therapeutic agents, Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered either simultaneously with one or more other therapeutic agents or sequentially.

[0210] In combination therapy, multiple therapeutic agents (one of which is compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof) are administered in any order or even simultaneously. If the administration is simultaneous, the multiple therapeutic agents are provided, by way of example only, in a single unit form or in multiple forms (e.g., as a single tablet or as two separate pills; or as a solution for intravenous infusion or as two separate infusion solutions for intravenous infusions).

[0211] Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, as well as combination therapeutic agents, are administered before, during or after the onset of a disease or condition, as well as during the administration of a composition comprising Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. Thus, in one embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is used as a prophylactic agent and is continuously administered to subjects susceptible to developing conditions or diseases in order to prevent the onset of the disease or condition. In another embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to a subject at or as soon as possible after the onset of symptoms. In specific embodiments, Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered as soon as possible after the onset of a disease or condition is detected or suspected and for a period of time necessary to treat the disease. In some embodiments, the period of time necessary for treatment is variable and the duration of treatment is adjusted according to the specific needs of each subject. For example, in specific embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, or a formulation comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, or more than 12 weeks.

Examples of agents for use in combination therapy

[0212] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with one or more additional therapeutic agents used to treat fungal and/or mold infections in mammals.

[0213] In some embodiments, at least one additional therapeutic agent is administered concurrently with Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the at least one additional therapeutic agent is administered less frequently than Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the at least one additional therapeutic agent is administered more frequently than Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the at least one additional therapeutic agent is administered prior to Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, at least is administered after Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0214] In some embodiments, at least one additional therapeutic agent is an antifungal agent. In some embodiments, the second additional therapeutic agent is an antifungal agent selected from the group consisting of a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, and an echinocandin antifungal agent.

[0215] In some embodiments, the polyene antifungal agent is amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, or rimocidin.

[0216] In some embodiments, the azole antifungal agent is an imidazole, a triazole, or a thiazole. In some embodiments, the imidazole is bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, or tioconazole. In some embodiments, the triazole is albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, or voriconazole. In some embodiments, the thiazole is abafungin.

[0217] In some embodiments, the allylamine antifungal agent is amorolfine, butenafine, naftifine, or terbinafine.

[0218] In some embodiments, the echinocandin antifungal agent is selected from the group consisting of anidulafungin, caspofungin, micafungin, and rezafungin.

Complementary therapies

[0219] In addition to antifungal treatment, optimal treatment of patients with fungal infections includes surgical debulking of infected tissue and removal of venous catheters in selected patients with confirmed catheter-related fungal infections. In some embodiments, treatment with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof comprises transfusions of granulocytes stimulated with G-CSF or GM-CSF. In some embodiments, treatment with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof comprises gamma interferon.

Kits and products of production

[0220] The present document describes kits for the therapeutic treatment of a fungal infection in a subject, for administering said subject compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0221] Also described herein are kits and articles of manufacture for use in the therapeutic applications described herein. In some embodiments, such kits include a carrier, package, or container divided into compartments to accommodate one or more containers, such as vials, tubes, and the like, wherein each of the containers includes one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and tubes. In some embodiments, the containers are made of different materials, such as glass or plastic.

[0222] The articles of manufacture provided herein comprise packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, vials, tubes, inhalers, pumps, bags, bottles, containers, syringes, vials, and any packaging material suitable for the selected formulation and the intended route of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated, as well as a variety of treatment regimens in which administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof would be beneficial.

[0223] The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierced by a hypodermic needle). Such kits optionally contain a compound with an identifying description or label or instructions regarding its use in the methods described herein.

[0224] The kit typically includes one or more additional containers, each of which contains one or more different materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for using the compound described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels on the carrier, package, container, vial, and/or tube indicating the contents and/or instructions for use, and package inserts with instructions for use. An instruction set is typically also included.

[0225] In some embodiments, the label is on or associated with the container. In some cases, the label is on the container when the letters, numbers, or other symbols that form the label are affixed, molded, or engraved on the container itself; the label is in some cases associated with the container if it is present, for example, as a package insert in a container or carrier that also contains the container. The label is in some cases used to indicate how the contents are to be used for a particular therapeutic use. The label in some cases provides directions for using the contents, for example, in the methods described herein.

[0226] In some embodiments, a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided in a package or dispenser, which in some cases comprises one or more unit dosage forms. The package in some cases, for example, comprises a metal or plastic foil, such as a blister pack. The package or dispenser device in some cases includes instructions for use. The package or dispenser in some cases also includes a notice associated with the container, in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, that reflects the agency's approved forms of the drug for human or veterinary use. Such a notice is, for example, in some cases, labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved package insert. Compositions containing a compound as provided herein, formulated in a compatible pharmaceutical carrier, are in some cases also prepared, placed in an appropriate container, and labeled as suitable for treating the indicated condition.

EXAMPLES

[0227] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

Example 1: Injection of Compound 1

[0228] Compound 1 for injection is prepared as a sterile solution, which is further diluted with 0.9% sodium chloride injection solution prior to administration. Compound 1 for injection is a solution with a concentration of 20 mg/mL. The preparation consists of the drug substance Compound 1, sodium chloride, potassium phosphate (dibasic and monobasic), hydrochloric acid, sodium hydroxide, and water for injection (WFI).

[0229] A 50 mL sterile glass vial is filled with 35 mL of Compound 1 injection to yield 700 mg/vial. Compound 1 injection is further diluted and administered as an intravenous infusion as specified in the clinical protocol. During preparation of the solution containing Compound 1, Compound 1 injection is filtered through a 0.2 µm filter prior to infusion to remove any inherent particulate matter.

[0230] Table 1 describes the composition of compound 1 for injection, 20 mg/mL, for filling a 35 mL vial of 50 mL volume.

[0231] To prepare a formulation of Compound 1 for injection, it is necessary: 1. Add sodium chloride, potassium phosphate (monobasic and dibasic) to a vessel containing water for injection; 2. Adjust the pH to 8.0 using 1 M hydrochloric acid solutions and / or 1 M sodium hydroxide solutions; 3. Slowly add the drug substance - Compound 1 to the solution and mix at a temperature of 15 ° C to 30 ° C; 4. Adjust the pH to 8.0 using hydrochloric acid solutions and / or sodium hydroxide solutions for dissolution; 5. Q.S. with water for injection and continue mixing at a temperature of 15 ° C to 30 ° C; 6. Aseptically filter through 2 x 0.2 μm membrane filters into sterile 50 ml vials with a filling volume of 35 ml, closed with a chlorobutyl stopper. (Note: Upon completion of each manufactured batch, filter integrity is checked using a bubble point test and the result is documented in the batch report); and 7. Inspect vials prior to packaging and labeling.

Example 2: Compound 1 tablets

[0232] Compound 1 tablets are manufactured in 100 mg and 200 mg strengths as film-coated white tablets. Table 2 and Table 3 provide the contents of Compound 1 tablets in 100 mg and 200 mg strengths, respectively.

Example 3: An open-label study to evaluate the efficacy and safety of compound 1 in non-neutropenic patients with candidemia, with or without invasive candidiasis, including patients suspected of being resistant to standard antifungal treatment

[0233] The need for improved treatment of IFD remains high, particularly given the growing number of immunocompromised patients, such as hematopoietic stem cell and solid organ transplant recipients, who are at particular risk for developing these infections and whose treatment can be challenging. Candida and Aspergillus species are considered the two leading causes of fungal infections in these patients, although other emerging fungi, such as C. albicans (e.g., C. glabrata and C. auris), Fusarium spp., Scedosporium spp., and Mucorales, require new and more effective strategies to combat these infections. Existing antifungal agents can be difficult to use, are often poorly tolerated, or are becoming increasingly ineffective due to the rise of drug-resistant fungal strains.

[0234] Compound 1 will be administered at a concentration of 1000 mg intravenously twice daily (IV BID) on Day 1, 600 mg intravenously (IV QD) on Days 2 through 3, and then subsequently 600 mg IV or 700 mg orally (PO) for the entire treatment period under study. This treatment may have advantages over standard of care (SOC) against certain resistant fungal infections where SOC treatment has demonstrated limited or no therapeutic efficacy.

The main goal

[0235] The primary objective of this study is to evaluate the efficacy and safety of Compound 1 for the treatment of non-neutropenic adult patients aged 18 to 80 years (inclusive) with candidemia, which may include patients with suspected or confirmed resistance to antifungal SOC therapy.

Secondary goals

[0236] The secondary objectives of this study are:

• Determine the time to obtain the first negative blood culture.

• To determine the percentage of patients with mycological results at the end of the study drug treatment (EOST), at the end of antifungal treatment (EOT), and 2 and 4 weeks after EOT.

• To determine the percentage of patients with successful treatment at EOT and at 2 and 4 weeks post-EOT.

• To determine overall survival at day 30 of the study.

• To determine safety parameters, including the number of patients with TEAE.

• To evaluate the pharmacokinetic parameters of Compound 1.

Brief description of the study design

[0237] This is a multicenter, open-label, single-arm, single-arm study to evaluate the efficacy and safety of compound 1 for the treatment of candidemia, including suspected or confirmed antifungal-resistant candidemia, in non-neutropenic patients 18 to 80 years of age (inclusive). Suspicion of antifungal-resistant candidemia is sufficient and subsequent documented resistance is not required for study inclusion. The study drug treatment period will be a maximum of 14 days (including the loading dose [study day 1]). Following completion of 14 days of study drug therapy, if further antifungal treatment is indicated to complete treatment of candidemia according to standard practice guidelines, fluconazole (unless susceptibility results require alternative antifungal therapy) may be administered for up to 7 days thereafter. A follow-up period of 4 weeks (+4 days) after EOT is also planned. The total duration of study participation is approximately 7.5 weeks (including the screening period [≤96 hours before treatment initiation (Baseline)].

[0238] Patients with yeast identified by blood culture or a positive rapid diagnostic test result are eligible for consent and screening for participation in the study. Patients must have at least 1 positive blood test result for Candida spp. (or yeast suspected of Candida) for the diagnosis of candidemia to be included in the study. Patients with a positive blood culture showing yeast suspected of Candida must have confirmed identification of Candida spp. from a positive blood culture prior to dosing. Screening and baseline procedures, and initiation of study drug Compound 1, will be initiated within 96 hours of receipt of the SOC blood sample for Candida spp. detection by cell culture or rapid diagnostic test. Patients with equivalent of 2 days (>48 hours) of prior systemic antifungal treatment at approved doses for the treatment of a current episode of candidemia within 96 hours prior to the first dose will be excluded. However, patients with candidal infections proven resistant to the prescribed antifungal agent may have received ≤5 days (≤120 hours) of treatment equivalent to the prior treatment (antibiotic susceptibility testing results are required prior to study entry).

[0239] Patients with >2 days (>48 hours) equivalent of previous systemic antifungal treatment at approved doses for treatment of a current episode of candidemia within 96 hours prior to the first dose will be excluded. However, patients with candidal infections proven resistant to the prescribed antifungal agent may have received ≤5 days (≤120 hours) equivalent of previous treatment (antibiotic susceptibility testing results are required prior to study entry).

[0240] On Study Day 1 (or for the first 24 hours if starting in the evening), a loading dose of 1000 mg Compound 1 will be administered over 3 hours by intravenous infusion (IV BID). On Study Days 2 and 3, a maintenance dose of 600 mg Compound 1 will be administered over 3 hours by intravenous infusion (IV QD). On Study Day 4 and thereafter, the maintenance dose of Compound 1 will be administered as either 600 mg Compound 1 IV (IV QD) over 3 hours or 700 mg orally QD. Patients who have completed at least 3 days of intravenous Compound 1 administration and are clinically stable as determined by the investigator, able to swallow tablets, and showing no further growth of infectious organisms 48 hours after the last blood culture may switch from intravenous to oral administration on Study Day 4 and thereafter. Study drug will be administered for a maximum of 14 days. At the discretion of the investigator, patients requiring longer antifungal therapy will be switched to fluconazole (unless antibiotic susceptibility testing results require alternative antifungal therapy) in accordance with IDSA clinical guidelines for the treatment of candidiasis. Candida spp. bloodstream infection will be monitored by daily blood cultures during study drug treatment until 2 consecutive blood cultures are negative, and at EOST, EOT, and 2 and 4 weeks after EOT or early discontinuation. Concurrent blood samples will be collected for Candida testing by T2 magnetic resonance (T2MR) at baseline, during study drug treatment, and at EOST or early discontinuation. Other cultures, histopathology and imaging tests to assess the site(s) and extent of candidemic infection in other sites will be performed as clinically indicated and the results will be recorded in an electronic case report form (eCRF). The management of intravascular catheters, intravascular devices and, if applicable, any drains will be recorded, including any associated microbiology results. Patient safety will be monitored throughout the study.

[0241] Plasma samples for pharmacokinetic analysis (compound 1 [prodrug] and compound 1A [active moiety]) will be collected at baseline (pre-dose), twice weekly during study drug treatment, at EOST, EOT, 2 weeks after EOT, or early treatment discontinuation. Serum samples for (1,3)-β-D-glucan levels will be collected at baseline (pre-dose) and EOST or early treatment discontinuation (if applicable).

[0242] Treatment outcome assessments will be at EOST, EOT, and 2 and 4 weeks after EOT or early completion of treatment. The end of the study will occur after the last visit of the last patient under the study protocol.

[0243] Indications: Treatment of patients with candidemia without neutropenia, including patients with suspected or confirmed antifungal-resistant candidemia.

Population:

[0244] This study will include male and female patients aged 18 to 80 years (inclusive) with a new diagnosis of candidemia (positive blood test for Candida spp.).

Inclusion criteria:

[0245] Patients must meet all of the following criteria to be eligible to participate in the study:

1. Man or woman from 18 to 80 years old (inclusive)

2. New diagnosis of candidemia based on a blood sample taken within 96 hours of administration:

a. Positive blood culture for Candida spp., including suspected Candida spp. (in the opinion of the Investigator) or documented resistance to at least 1 SOC systemic antifungal agent; or

b. A positive result on a Sponsor-approved rapid blood test for Candida spp. infection (a rapid test may be used for preliminary eligibility assessment; however, a subsequent confirmatory blood culture is required prior to administration of a dose of Compound 1)

3. It is possible to remove and replace previously existing intravascular catheters (if necessary).

Dosing criteria

[0246] Patients must meet the following criteria to initiate dosing:

1. Patients have a confirmed diagnosis of candidemia

2. Patients have received ≤2 days (≤48 hours) of prior systemic antifungal therapy at approved doses for treatment of the current episode of candidemia OR ≤5 days (≤120 hours) of prior treatment for candidemia caused by Candida spp. with documented resistance to a specific previously administered antifungal agent.

Treatment groups

[0247] All patients will receive a loading dose of Compound 1 at 1000 mg twice daily BID, followed by a maintenance dose of Compound 1 at 600 mg QD on Study Day 2 and Study Day 3. Beginning on Study Day 4, the maintenance dose of Compound 1 will be administered as either an intravenous infusion of 600 mg Compound 1 over 3 hours QD, or a possible switch to 700 mg PO QD when/if oral dosing criteria are met.

Dose

[024 8] In PK-PD studies, immunocompromised mice were infected with one of three Candida species (C. albicans, C. glabrata, and C. auris) and groups of animals were administered Compound 1 at different dose fractionations. The AUC/MIC ratio was determined to be the PK-PD variable that best correlated with antifungal efficacy as assessed by fungal load (colony forming units [CFU]) in the kidneys. The probability of target attainment (PTA) was calculated separately for each Candida spp. The PTA was calculated using the AUC without Compound 1A at the stasis endpoint, divided by the MIC required to inhibit the growth of 90% of the organisms ( _MIC90 ) of each Candida spp. AUC levels were estimated using a population pharmacokinetic model derived primarily from phase 1 pharmacokinetic data. The stasis endpoint was defined as the number of Candida spp. in CFU immediately before administration of Compound 1 compared to the CFU at the endpoint of assessment (i.e., 24 hours for C. albicans; 96 hours for C. glabrata and C. auris). MIC data for the Candida strains tested were obtained from recent surveillance data. Using the AUC at the stasis endpoint, as well as the _MIC90 from the surveillance data and the predicted exposure at the dosing regimen to be used in this study, the PTA for the three Candida spp. species tested was approximately 100%. In addition, sensitivity analyses were performed to evaluate the PTA under various scenarios, including increased variability in pharmacokinetic parameters and higher Candida spp. _MIC90 values. For both scenarios, the PTA remained >90%.

[0249] In two Phase 1 studies in healthy volunteers, the IV and PO formulations of Compound 1 were safe and well tolerated. Most TEAEs were mild, transient, and resolved without intervention. No DLTs were observed. Specifically, in the Phase 1 FIH clinical study, a Compound 1 loading dose of 1000 mg IV over 2 hours twice daily on Day 1 followed by a Compound 1 maintenance dose of 600 mg IV over 1 hour infusion QD on Days 2 through 7 was safe and well tolerated. This IV dosing regimen is identical to the IV dosing regimen that will be used in this study. In a second Phase 1 clinical study, a 1000 mg dose of Compound 1 administered orally QD on Days 1 through 14 was safe and well tolerated. This oral dosing regimen is higher than the 700 mg oral dose that will be used in this study.

Schedule/Timetable

[0250] To ensure the safety and tolerability of Compound 1 dosing for 14 days, this study will utilize the Compound 1 dose and infusion duration already studied in Phase 1 for 14 days of therapy, including both intravenous and oral administration in the investigational drug therapy. A loading dose of 1000 mg IV twice daily over a 3-hour infusion followed by 600 mg IV QD over a 3-hour infusion optimizes safety and tolerability for patients throughout the study. On day 4 of the study, provided the patient meets protocol-established criteria for switching to oral dosing, a switch to Compound 1 orally at 700 mg QD will be made for up to 14 days of combined intravenous and oral Compound 1 therapy.

Randomization and blinding

[0251] This is a non-randomized, open-label study.

Supplies of medicines

[0252] The formulation and as-supplied packages of Compound 1 for injection are prepared at a concentration of 20 mg/mL. The formulation consists of Compound 1 drug substance, sodium chloride, potassium phosphate (dibasic and monobasic), hydrochloric acid, sodium hydroxide, and sterile water for injection. A 50 mL sterile vial is filled with 35 mL of Compound 1 for injection. Compound 1 for injection is diluted and administered as an intravenous infusion. Instructions for preparation and dilution will be provided in the Pharmaceutical Manual.

[0253] Compound 1 tablets are prepared in doses of 100 mg and 200 mg as white coated tablets. The dosage form consists of the drug substance compound 1, microcrystalline cellulose, anhydrous dibasic calcium phosphate, colloidal silicon dioxide, pregelatinized starch, povidone, talc, magnesium.

Administration of the investigational drug

[0254] On Day 1 of the study (or for the first 24 hours if initiated in the evening), a loading dose of 1000 mg of Compound 1 will be administered over 3 hours by intravenous infusion twice daily (IV BID). On Days 2 and 3 of the study, a maintenance dose of Compound 1 of 600 mg will be administered over 3 hours by intravenous infusion (IV QD). On Day 4 of the study and thereafter, the maintenance dose of Compound 1 will be administered as either 600 mg of Compound 1 IV (QD) over 3 hours or 700 mg orally (QD). Patients who have received at least 3 days of IV Compound 1, are clinically stable as determined by the investigator, are able to swallow tablets, and have no further growth of the infecting organism for 48 hours after the last blood culture, may switch from IV dosing to oral (PO) dosing on study day 4 and thereafter. Study drug will be administered for a maximum of 14 days (including the loading dose [study day 1]). Tablets should be taken whole orally with water at the same time each day within 30 minutes of removal from the refrigerator. Tablets should not be crushed or divided. If antifungal therapy is indicated for more than 14 days, fluconazole may be initiated at the discretion of the investigator (unless antimicrobial susceptibility testing results warrant alternative antifungal therapy) for up to 7 days in accordance with IDSA clinical guidelines for the treatment of candidiasis.

End of Antifungal Treatment (EOT):

[0255] Following completion of 14 days of study drug therapy, if further antifungal treatment is indicated to complete treatment of candidemia according to standard practice guidelines, fluconazole (unless susceptibility results require alternative antifungal therapy) may be prescribed for an additional 7 days. If applicable, an efficacy assessment will also be performed at the end of this antifungal treatment at EOT. Treatment success is defined as meeting all of the following criteria:

• Two consecutive blood cultures negative for Candida spp.

• Patient alive at EOT

• No additional systemic antifungal therapy (except protocol-approved step therapy [eg, fluconazole]) was administered during EOT

• Treatment failure is defined as any event that does not meet the criteria for treatment success.

[0256] Mycological result:

[0257] Eradication is defined as negative blood culture(s) for Candida spp. in the absence of additional antifungal therapy (except protocol-approved step therapy [eg, fluconazole]) prior to EOT

At follow-up (2 weeks and 4 weeks after completion of antifungal treatment):

[0258] Relapse (mycological) is defined as mycologically confirmed infection based on blood culture with the same baseline Candida spp. within 4 weeks after EOT. Relapse (DRC score) is defined as reappearance of Candida in blood culture during the observation period or the presence of diagnostic parameters suggestive of relapse or late dissemination of Candida infection.

Results obtained

[0259] A total of 21 patients were included in the study: 20 were included in the mlTT. The median duration of Compound 1 therapy was 11 days (range, 5-14). All patients received Compound 1 intravenously; 48% (10/21) received Compound 1 orally. The DRC-assessed success rate for EOST was 80% (16/20). Survival at day 30 was 85% (17/20); mortality was not related to Compound 1. Compound 1 was well tolerated with no serious adverse events or discontinuations due to treatment-related problems. Compound 1 had significant in vitro activity against all Candida spp. in this study, including isolates resistant to other antifungal agents.

Outcomes in patients with renal failure: a subset analysis

[0260] Fourteen of 21 (66%) subjects had some degree of renal impairment: 7 had mild renal impairment (GFR: 60-89), 5 had moderate renal impairment (GFR: 30-59), and 2 had severe renal impairment (GFR: 15-29). The majority (12/14) completed study treatment. The treatment success rate for EOST in patients with renal impairment was 86% (12/14). No patients experienced worsening renal function during EOST. Four patients experienced worsening renal function in the late period. Renal impairment did not increase FMTX exposure. No treatment-related adverse events were observed.

[0261] The examples and embodiments described herein are intended for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of the present application and the scope of the appended claims.

Claims (63)

1. A method of treating a fungal infection in a subject, comprising administering to a subject with a fungal infection a therapeutically effective amount of compound 1: or a pharmaceutically acceptable salt, solvate or hydrate thereof; Where the subject's fungal infection is caused by Candida spp.; wherein a therapeutically effective amount of compound 1 provides a 24-hour area under the concentration-time curve (AUC _0-24 ) at steady state in a subject receiving at least 150 μg×h/mL of compound 1A: where the subject has contraindications to standard antifungal therapy due to chronic kidney disease (CKD); wherein the administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a treatment regimen consisting of daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least 1-4 weeks; wherein the treatment regimen comprises a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is 2000 mg; and wherein the maintenance dose comprises a single daily administration of 600 mg to 1500 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. 2. The method of claim 1, wherein the chronic kidney disease (CKD) is CKD stage 3, CKD stage 4, or CKD stage 5. 3. The method of claim 1, wherein the chronic kidney disease (CKD) is CKD stage 3 or CKD stage 4. 4. The method according to any one of claims 1-3, wherein treatment with compound 1 is not contraindicated in patients with chronic kidney disease. 5. The method according to any one of claims 1-4, wherein the fungal infection is a kidney infection. 6. The method of any one of claims 1-5, wherein the contraindication to standard antifungal therapy comprises intolerance to an azole antifungal agent, an allylamine antifungal agent, an echinocandin antifungal agent, or a polyene antifungal agent. 7. The method according to any one of paragraphs. 1-5, where the contraindication to standard antifungal therapy includes intolerance to the following agents from the list: amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine or anidulafungin, naftifine, or terbinafine, caspofungin, micafungin, rezafungin or a pharmaceutically acceptable salt of any of the foregoing antifungal agents. 8. The method according to any one of paragraphs 1-7, wherein the subject has a weakened immune system. 9. The method according to any one of claims 1-8, wherein the subject is infected with HIV/AIDS or has cancer. 10. The method of claim 9, wherein the cancer is acute myeloid leukemia or acute lymphoid leukemia. 11. The method according to any one of paragraphs 1-10, wherein the subject has neutropenia. 12. The method according to any one of paragraphs. 1-11, wherein the subject has lymphopenia. 13. The method of any one of claims 1-11, wherein the subject is undergoing or has undergone a course of cancer chemotherapy. 14. The method of any one of claims 1-13, wherein the subject is undergoing or has been treated with corticosteroids. 15. The method of any one of claims 1-14, wherein the subject is undergoing or has been treated with a TNF inhibitor. 16. The method according to any one of claims 1-15, wherein the subject is a recipient of an organ transplant. 17. The method according to any one of claims 1-12, wherein the subject is a recipient of a hematopoietic stem cell transplant. 18. The method of any one of paragraphs 1-12, wherein the subject has a graft-versus-host disease. 19. The method according to any one of claims 1-18, wherein the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject by intravenous (I.V.) infusion. 20. The method of claim 19, wherein the loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof comprises administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a subject by intravenous (I.V.) infusion. 21. The method of claim 20, wherein each loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject by intravenous (I.V.) infusion over a period of 30 minutes to 4 hours. 22. The method according to claim 20 or 21, wherein each dose of the loading dose contains 1000 mg of compound 1 or its pharmaceutically acceptable salt, solvate or hydrate. 23. The method of claim 20 or 21, wherein the loading dose comprises administering 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (I.V.) infusion, followed by a second administration of 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (I.V.) infusion within no more than 24 hours of the first infusion. 24. The method according to any one of claims 1-23, wherein the maintenance dose is administered once a day, starting from the second day of treatment. 25. The method according to any one of claims 1-24, wherein the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of time from 30 minutes to 4 hours, starting on the second, third or fourth day of treatment. 26. The method according to any one of claims 1-25, wherein the maintenance dose is from 600 mg to 1200 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and is administered over a period of time from 30 minutes to 4 hours by intravenous (I.V.) infusion, starting on the second, third or fourth day of treatment. 27. The method according to any one of claims 1-25, wherein the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally to the subject starting on the second, third or fourth day of treatment. 28. The method according to any one of claims 1-25, wherein the maintenance dose is from 800 mg to 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and is administered orally once a day to the subject starting on the second, third or fourth day of treatment. 29. The method according to any one of paragraphs 1-25, wherein, starting from the second, third or fourth day of treatment: a) 600 mg to 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous (I.V.) infusion over a period of 30 minutes to 3 hours; or b) 700 mg to 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once a day. 30. The method according to any one of paragraphs 1-25, where: starting on the second day of treatment, 600 mg to 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous (I.V.) infusion over a period of 30 minutes to 3 hours; and starting from the fourth day of treatment: a) 600 mg to 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous (I.V.) infusion over a period of 30 minutes to 3 hours; or b) 700 mg to 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once a day. 31. The method according to any one of paragraphs 1-30, where: compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in combination with an additional therapeutic agent. 32. The method according to any one of paragraphs 1-31, where: the treatment regimen comprises daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for 4 weeks to 6 weeks. 33. The method according to any one of paragraphs 1-31, where: the treatment regimen comprises daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for 4 weeks to 12 weeks. 34. The method according to any one of paragraphs 1-18, where: the treatment regimen includes a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and maintenance doses of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises administering two doses of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (I.V.) infusion on the first day of therapy, each dose containing 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; followed by maintenance doses comprising once daily administration of 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof by intravenous (I.V.); or oral administration once daily of 700 mg of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate. 35. The method according to claim 34, wherein the treatment regimen comprises up to 14 days of administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. 36. The method according to any one of paragraphs 1-35, where: the treatment regimen increases the subject's chances of survival, decreases the subject's galactomannan levels, decreases the subject's β-d-glucan levels, or a combination of these. 37. The method according to any one of paragraphs 1-36, where: No dosage adjustment of compound 1 or its pharmaceutically acceptable salt, solvate or hydrate administered to a subject is required based on the subject's renal status.