WO2025093760A1

WO2025093760A1 - Treating pfic2 with odevixibat

Info

Publication number: WO2025093760A1
Application number: PCT/EP2024/080980
Authority: WO
Inventors: Erik LINDSTRÖM
Original assignee: Albireo AB
Current assignee: Albireo AB
Priority date: 2023-11-03
Filing date: 2024-11-04
Publication date: 2025-05-08
Anticipated expiration: 2026-05-03

Abstract

Provided herein are methods for treating progressive familial intrahepatic cholestasis (PFIC) including, e.g., PFIC type 2 (bile salt export pump (BSEP) deficiency), with an ileal bile acid transport (IBAT) inhibitor such as odevixibat, or a pharmaceutically acceptable salt thereof. Such methods can include identifying or selecting a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and administering an IBAT inhibitor to the identified or selected subject.

Description

Treating PFIC2 with Qdevixibat

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 63/547,260, filed November

3, 2023. The disclosure of the prior application is considered part of the disclosure of this application and is incorporated in its entirety into this application.

TECHNICAL FIELD

Provided herein are methods for treating progressive familial intrahepatic cholestasis (PFIC) including, e.g., PFIC type 2 (bile salt export pump (BSEP) deficiency), with an ileal bile acid transport (IB AT) inhibitor such as odevixibat, or a pharmaceutically acceptable salt thereof. Such methods can include identifying or selecting a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and administering an IB AT inhibitor to the identified or selected subject.

BACKGROUND

The compound l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(7V-{(R)-a-[7V-((S)-l- carb oxy propyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,2,5- benzothiadi azepine (odevixibat; also known as A4250):

is an inhibitor of the ileal bile acid transport (IBAT) mechanism. Specifically, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted into the feces. The overall removal of bile acids from the enterohepatic circulation leads to a decrease in the level of bile acids in serum and the liver. Odevixibat, or a pharmaceutically acceptable salt thereof, is therefore useful in the treatment of liver diseases that are associated with elevated bile acid levels, and particularly in the treatment of rare paediatric cholestatic liver diseases. SUMMARY

Provided herein are methods of treating progressive familial intrahepatic cholestasis type 2 (PFIC2) with an ileal bile acid transport (IB AT) inhibitor (also referred to as an apical sodium-dependent bile acid transport inhibitor or ASBTI). Also provided herein are methods of treating pruritus with an IB AT inhibitor. Such methods can include identifying or selecting a subject having PFIC2 and a higher percentage of an unconjugated serum bile acid as compared to a reference level and administering a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, to the identified or selected subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of treating progressive familial intrahepatic cholestasis type 2 (PFIC2) in a subject, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and administering to the identified subject a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating PFIC2 in a subject, the method comprising administering a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, to a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and selecting for the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising selecting a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, for a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of treating a subject having PFIC2, the method comprising: (a) administering to the subject a therapeutic agent; (b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and (c) administering to the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is an antipruritic agent such as cholestyramine, ursodeoxycholic acid (UDCA), rifampicin, phenobarbital, ondansetron, sertraline, and naltrexone.

In some embodiments, the unconjugated serum bile acid is cholic acid, chenodeoxycholic acid, or a combination thereof.

In some embodiments, the subject is a pediatric subject.

In some embodiments, the subject is administered about 100 to about 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered aboutl20 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject was odevixibat naive prior to the first administration of the pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject exhibits a reduction in pruritus score relative to baseline. In some embodiments, the reduction in pruritus score relative to baseline is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.0. In some embodiments, the reduction in pruritus score relative to baseline is about 1.5 to about 4. In some embodiments, the reduction in pruritus score relative to baseline is about 1.5 to about 2.5. In some embodiments, the reduction in pruritus score relative to baseline is about 2.

In some embodiments, the reduction in pruritus score relative to baseline occurs following administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

In some embodiments, the pruritus score at baseline is about 2.5 to about 4.0. In some embodiments, the pruritus score at baseline is about 2.5 to about 3.5. In some embodiments, the pruritus score at baseline is about 3.0. In some embodiments, the pruritus score at baseline is about 2.8.

In some embodiments, the subject exhibits a reduction in serum bile acid concentration relative to baseline. In some embodiments, the reduction in serum bile acid concentration is at least about 50 pmol/L, at least about 75 pmol/L, at least about 100 pmol/L, at least about 125 pmol/L, at least about 150 pmol/L, or at least about 175 pmol/L relative to baseline. In some embodiments, the reduction in serum bile acid concentration is about 50 pmol/L to about 180 pmol/L relative to baseline. In some embodiments, the reduction in serum bile acid concentration is about 70 pmol/L to about 120 pmol/L relative to baseline. In some embodiments, the reduction in serum bile acid concentration is about 80 pmol/L to about 110 pmol/L relative to baseline. In some embodiments, the reduction in serum bile acid concentration occurs following administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

In some embodiments, the serum bile acid concentration at baseline is about 180 pmol/L to about 600 pmol/L. In some embodiments, the serum bile acid concentration at baseline is about 200 pmol/L to about 280 pmol/L. In some embodiments, the serum bile acid concentration at baseline is about 230 pmol/L to about 250 pmol/L.

As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

As used herein, the terms “subject,” “individual,” or “patient,” used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

The term “pediatric” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al., Rudolph ’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR, Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

As used herein, the term “baseline” refers to information obtained prior to the first administration of the drug or intervention of interest (e.g., at the beginning of a study) or an initial known value that is used for comparison with later data. Baseline values are taken at time “zero” (i.e., before subjects in a study receive the drug or intervention of interest or placebo).

As used herein, the term “normalized” refers to age-specific values that are within a range corresponding to a healthy individual (i.e., normal or normalized values).

As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic and neither biologically nor otherwise undesirable.

As used herein, the term “about” refers to a value or parameter herein that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about 20” includes description of “20.” Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS

FIG. 1 is an overview of the enterohepatic circulation and BSEP deficiency. Primary bile acids are synthesized in the liver from cholesterol and conjugated to glycine or taurine (Mertens KL et al., Front Neurosci, 11 : 1-16 (2017)). Bile salt export pump (BSEP) then actively secretes the conjugated bile acids into canaliculi (Mertens KL et al., Front Neurosci, 11 : 1-16 (2017); Davit Spraul A et al., Orphanet J Rare Dis (2009)). The ileal bile acid transporter (IB AT) actively reabsorbs most bile acids in the ileum facilitating return to the liver resulting in enterohepatic circulation (Mertens KL et al., Front Neurosci, 11 : 1-16 (2017); Gaffner H et al., Aliment Pharmacol Ther. 43:303-310 (2016)). In the intestine, unconjugated and secondary bile acids result from microbial modification (Mertens KL et al., Front Neurosci, 11 : 1-16 (2017)). BA, bile acid; BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G-, glycine conjugated; IBAT, ileal bile acid transporter; LCA, lithocholic acid; T-, taurine conjugated.

FIG. 2 is an overview of the timing of serum bile acid sampling and assessment of the treatment response. ^aPEDFIC 2 also enrolled new patients with PFIC2 (ie, who had not participated in PEDFIC 1); however, these patients are not included in the current analysis. ^bsBA responsiveness was defined as sBAs reduced >70% from baseline or levels <70 pmol/L at week 24. PFIC, progressive familial intrahepatic cholestasis; sBA, serum bile acid.

FIG. 3A- FIG. 3C is a plot showing the receiver operating characteristic curves for serum bile acid level and response to odevixibat in patients with PFIC2. Receiver operating characteristic curve analysis for CA percentage (FIG. 3A), CDCA percentage (FIG. 3B), and absolute concentration of CA+ CDCA (FIG. 3C). AUC, area under the curve; CA, cholic acid; CDCA, chenodeoxycholic acid; PFIC, progressive familial intrahepatic cholestasis.

FIG. 4 is a table showing serum bile acid levels in responding and nonresponding patients with PFIC2. “Calculated using a Mann-Whitney U test. CA, cholic acid; CDCA, chenodeoxycholic acid; PFIC, progressive familial intrahepatic cholestasis; UDCA, ursodeoxycholic acid; sBA, serum bile acid.

FIG. 5 is a contingency table classified by whether patients with PFIC2 met at least 1 of the 3 unconjugated bile acid thresholds before treatment and by subsequent treatment response to odevixibat. Positive Predictive Value=85%; Negative Predictive Value=90.5%. ^aThresholds were unconjugated CA percentage (>0.03409%), unconjugated CDCA percentage (>0.02833%), and unconjugated CA concentration + unconjugated CDCA concentration (>0.1209 pmol/L). BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; PFIC, progressive familial intrahepatic cholestasis; sBA, serum bile acid. FIG. 6 is a table with individual patient data depicting unconjugated bile acid thresholds and serum bile acid responses. Thresholds were unconjugated CA percentage (>0.03409%), unconjugated CDCA percentage (>0.02833%), and unconjugated CA concentration + unconjugated CDCA concentration (>0.1209 pmol/L). CA, cholic acid; CDCA, chenodeoxycholic acid; FN, false negative; FP, false positive; N, no; NR, nonresponder; R, responder; sBA, serum bile acid; TN, true negative; TP, true positive; Y, yes.

FIG. 7 is a plot showing secondary serum bile acids as a median percentage of total serum bile acids for placebo, nonresponders, and responders.

FIG. 8A is plot showing unconjugated serum bile acids as a percentage of total serum bile acids for placebo, nonresponders, and responders.

FIG. 8B is plot showing unconjugated serum bile acids as a median percentage of total serum bile acids for placebo, nonresponders, and responders.

FIG. 9A is plot showing unconjugated cholic acid (CA) as a percentage of total serum bile acids for placebo, nonresponders, and responders.

FIG. 9B is plot showing unconjugated chenodeoxycholic acid (CDCA) as a median percentage of total serum bile acids for placebo, nonresponders, and responders.

FIG. 10A is plot showing median G/T conjugation ratio for placebo, nonresponders, and responders. CA, cholic acid; CDCA, chenodeoxycholic acid; G, glycine; T, taurine.

FIG. 10B is plot showing median CA/CDCA ratio for placebo, nonresponders, and responders. CA, cholic acid; CDCA, chenodeoxycholic acid; G, glycine; T, taurine.

DETAILED DESCRIPTION

Methods of Treating PFIC

Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic disorder that is estimated to affect between one in every 50,000 to 100,000 children bom worldwide and causes progressive, life-threatening liver disease. Four alternative gene defects have been identified that correlate to four separate PFIC subtypes known as types 1, 2, 3, and 6.

• PFIC, type 1, which is sometimes referred to as “Byler disease,” is caused by impaired bile secretion due to mutations in the ATP8B1 gene, which codes for a protein that helps to maintain an appropriate balance of fats known as phospholipids in cell membranes in the bile ducts. An imbalance in these phospholipids is associated with cholestasis and elevated bile acids in the liver. Subjects affected by PFIC, type 1 usually develop cholestasis in the first months of life and, in the absence of surgical treatment, progress to cirrhosis and end-stage liver disease before the end of the first decade of life.

• PFIC, type 2 (BSEP deficiency), which is sometimes referred to as “Byler syndrome,” is caused by impaired bile salt secretion due to mutations in the ABCB11 gene, which codes for a protein known as the bile salt export pump, that moves bile acids out of the liver. Subjects with PFIC, type 2 often develop liver failure within the first few years of life and are at increased risk of developing a type of liver cancer known as hepatocellular carcinoma.

• PFIC, type 3, which typically presents in the first years of childhood with progressive cholestasis, is caused by mutations in the ABCB4 gene, which codes for a transporter that moves phospholipids across cell membranes.

• PFIC, type 6, resulting from mutation of the gene encoding myosin 5B (MY05B).

In addition, TJP2 gene and NR1H4 gene mutations have been proposed to be causes of PFIC. However, some subjects with PFIC do not exhibit a mutation in any of the A TP8 L ABCB11, ABCB4, TJP2, NR1H4 ox MY05B genes. In these cases, the cause of the condition is unknown.

Previously, it was not possible to predict the responsiveness to odevixibat in patients with PFIC2 (BSEP deficiency). The present disclosure is based, at least in part, on the finding that pretreatment unconjugated serum bile acid concentrations are strongly associated with subsequent responsiveness to ileal bile acid transporter (IBAT) inhibitor (also referred to as an apical sodium-dependent bile acid transport inhibitor or ASBTI) treatment by odevixibat in patients with PFIC2. Accordingly, the present disclosure advantageously provides methods of identifying a subject having PFIC2 and a higher percentage of an unconjugated serum bile acid as compared to a reference level as likely being responsive to treatment with an IBAT inhibitor.

Also provided herein are methods of treating PFIC2 in a subject, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying a subject having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and administering to the identified subject a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating PFIC2 in a subject, the method comprising administering a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof, to a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying a subject having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and selecting for the identified subject a treatment comprising a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising selecting a treatment comprising a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof, for a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of treating a subject having PFIC2, the method comprising: (a) administering to the subject a therapeutic agent; (b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying the subject as having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and (c) administering to the identified subject a treatment comprising a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof.

One manifestation of PFIC is pruritus, which often results in a severely diminished quality of life. In some cases, PFIC leads to cirrhosis and liver failure. Current therapies include Partial External Biliary Diversion (PEBD) and liver transplantation, however, these options can carry substantial risk of post-surgical complications, as well as psychological and social issues. In some embodiments, provided herein are methods of treating pruritus in a subject having PFIC2. Such methods can include identifying or selecting a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying or selecting a subject having a higher concentration an unconjugated serum bile acid as compared to a reference level; and administering a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof, to the identified or selected subject. In some embodiments, provided herein are methods of treating pruritus in a subject having PFIC2, the method comprising: (a) administering to the subject a therapeutic agent; (b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying the subject as having a higher concentration an unconjugated serum bile acid as compared to a reference level; and (c) administering to the identified subject a treatment comprising a therapeutically effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt thereof.

The IBAT, also called the apical sodium-dependent bile acid transporter (SLC10A2), is located on the luminal surface of enterocytes in the terminal ileum; this transporter mediates resorption of conjugated bile acids for recirculation back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids similar to surgical interruption of the enterohepatic circulation.

In some embodiments, the IBAT inhibitor is

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SUBSTITUTE SHEET (RULE 26)

, or a pharmaceutically acceptable salt thereof. An IBAT inhibitor as provided herein includes solvates and hydrates thereof. For example, odevixibat can be present as a hydrate (e.g., a sesquihydrate). In some embodiments, the IBAT inhibitor is odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor is maralixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor is volixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor is elobixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor is linerixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor comprises a combination of two or more of odevixibat, maralixibat, volixibat, elobixibat, and linerixibat, or a pharmaceutically acceptable salt thereof.

IBAT inhibitors can be prepared using described methods, for example, U.S. Patent Nos. 5,994,391; 6,020,330; 6,906,058; 7,192,945; 7,132,416; 7,238,684; and International Publication No. WO 96/05188. The IBAT inhibitor can be present in amorphous or crystalline form. See, for example, U.S. Patent No. 9,409,875; 10,183,920; and International Publication No. WO 2019/245448.

Odevixibat is an orally administered, potent, luminally restricted, selective IBAT inhibitor in development to treat cholestatic liver diseases. By inhibiting IBAT with high selectivity and potency, odevixibat can reduce the elevations in systemic bile acids that result from cholestasis and decrease pruritus in patients with BSEP deficiency. The rationale for using odevixibat is to decrease serum bile acid levels, and to reduce the major morbidity of pruritus, improving the health and wellbeing of patients affected with BSEP deficiency. By reducing the elevations in systemic bile acids, odevixibat also can improve liver function and modify the progression of liver damage in patients with BSEP deficiency. Odevixibat, as referred to herein, includes solvates and hydrates thereof. For example, odevixibat can be present as a hydrate (e.g., a sesquihydrate).

Provided herein are methods for treating PFIC2 with odevixibat, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying a subject having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and administering to the identified subject a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating PFIC2 in a subject, the method comprising administering a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, to a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying a subject having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and selecting for the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of selecting a treatment for a subject having PFIC2, the method comprising selecting a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, for a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Also provided herein are methods of treating a subject having PFIC2, the method comprising: (a) administering to the subject a therapeutic agent; (b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying the subject as having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and (c) administering to the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of treating pruritus in a subject having PFIC2. Such methods can include identifying or selecting a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying a subject having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and administering a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, to the identified or selected subject. In some embodiments, provided herein are methods of treating pruritus in a subject having PFIC2, the method comprising: (a) administering to the subject a therapeutic agent; (b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or identifying the subject as having a higher concentration of an unconjugated serum bile acid as compared to a reference level; and (c) administering to the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof.

Also provided herein is a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof, for use in treating PFIC2 in a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or as having a higher concentration of an unconjugated serum bile acid as compared to a reference level. In some embodiments, provided herein is a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof, for use in treating pruritus in a subject having PFIC2 and identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or as having a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Also provided herein is the use of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of PFIC2 and for the treatment of pruritus associated with PFIC2 in a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level and/or having a higher concentration of an unconjugated serum bile acid as compared to a reference level.

Retention of bile acids within the liver is a central component of the etiopathogenesis of cholestasis in PFIC. Secondary spillover of bile acids into the peripheral circulation is easily measured and forms a clinically useful marker of disease severity. Non-limiting examples of bile acid include cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), lithocholic acid (LCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acids (TLCA), tauroursodeoxycholic acid (TUDCA), ursodeoxycholic acid (UDCA), and 12-ketolithocholic acid (12-KLCA). The primary bile acids in humans are cholic acid (CA) and chenodeoxycholic acid (CDCA). Both of these bile acids are produced in the liver through the oxidation of cholesterol. After being secreted into the small intestine, these primary bile acids can be converted to secondary bile acids, such as deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA), by through action of intestinal flora. Primary bile acids can also be conjugated in the liver with the amino acid glycine or taurine through the terminal carboxylic group. Non-limiting examples of an unconjugated serum bile acid include cholic acid (CA) and chenodeoxycholic acid (CDCA).

The concentration of bile acids in a sample from the subject can be determined using any appropriate methods known in the art (e.g., any of the assays described herein). For example, determining the concentration of one or more bile acids in a sample (e.g., a blood sample) from a subject can include assays using, e.g., liquid chromatography -tandem mass spectrometry, reversed phase ultra-high-performance liquid chromatography, QTOF mass spectrometry. See, e.g., Sugita et al. Gastroenterol Res Pract. 2015, 3 ;2015 :717431 ; Ghaffarzadegan et al. Set Rep. 2019, 7;9(l):3800. Such assays can be used to determine the concentration of different bile acids within a sample. For example, such assays can be used to determine the concentration of one or more of CA, CDCA, DCA, GCA, GCDCA, GDCA, GLCA, GUDCA, LCA, TCA, TCDCA, TDCA, TLCA, TUDCA, UDCA, and 12-KLCA. In some embodiments, the concentration of an unconjugated serum bile acid is determined. In some embodiments, the total concentration of serum bile acids is determined.

Determining the percentage of one or more serum bile acids in a sample can include dividing the concentration of the one or more serum bile acids by the total concentration of serum bile acids. In some embodiments, the percentage of an unconjugated serum bile acid includes dividing the concentration of the unconjugated serum bile acid by the total concentration of serum bile acids. In some embodiments, determining the percentage of an unconjugated serum bile acid includes dividing the concentration of the unconjugated serum bile acid by the total concentration of serum bile acids excluding the concentration of UCDA or excluding the concentration of UCDA and its glycine and taurine conjugates. A higher percentage of an unconjugated serum bile acid as compared to a reference level can refer to a higher percentage of one unconjugated serum bile acid compared to a reference level or a higher percentage of two or more unconjugated serum bile acids compared to a reference level. For example, a higher percentage of an unconjugated serum bile acid as compared to a reference level can refer to a higher percentage of cholic acid, chenodeoxy cholic acid, or a combination thereof compared to a reference level.

In some embodiments, a higher percentage of an unconjugated serum bile acid compared to a reference level is an increase in the percentage of an unconjugated serum bile acid of at least 0.008% compared to a reference level (e.g., any of the reference levels described herein). For example, a higher percentage of an unconjugated serum bile acid compared to a reference level can be an increase in the percentage of an unconjugated serum bile acid of at least about 0.01%, at least about 0.012%, at least about 0.014%, at least about 0.016%, at least about 0.018%, about 0.02%, about 0.022%, about 0.024%, about 0.026%, about 0.03%, about 0.032%, about 0.034%, about 0.036%, about 0.04%, about 0.042%, about 0.044%, about 0.046%, or about 0.048% compared to a reference level (e.g., any of the reference levels described herein).

In some embodiments, a higher percentage of an unconjugated serum bile acid compared to a reference level is an increase in the percentage of an unconjugated serum bile acid of about 0.008% to about 0.07% compared to a reference level (e.g., any of the reference levels described herein). For example, the higher percentage of an unconjugated serum bile acid compared to a reference level can be an increase in the percentage of an unconjugated serum bile acid of about 0.008% to about 0.01%, about 0.008% to about 0.015%, about 0.008% to about 0.02%, about 0.008% to about 0.025%, about 0.008% to about 0.03%, about 0.008% to about 0.035%, about 0.008% to about 0.04%, about 0.008% to about 0.045%, about 0.008% to about 0.05%, about 0.01% to about 0.015%, about 0.01% to about 0.02%, about 0.01% to about 0.025%, about 0.01% to about 0.03%, about 0.01% to about 0.035%, about 0.01% to about 0.04%, about 0.01% to about 0.045%, about 0.01% to about 0.05%, about 0.01% to about 0.06%, about 0.01% to about 0.07%, about 0.015% to about 0.02%, about 0.015% to about 0.025%, about 0.015% to about 0.03%, about 0.015% to about 0.035%, about 0.015% to about 0.04%, about 0.015% to about 0.045%, about 0.015% to about 0.05%, about 0.015% to about 0.06%, about 0.015% to about 0.07%, about 0.02% to about 0.025%, about 0.02% to about 0.03%, about 0.02% to about 0.035%, about 0.02% to about 0.04%, about 0.02% to about 0.045%, about 0.02% to about 0.05%, about 0.02% to about 0.06%, about 0.02% to about 0.07%, about 0.025% to about 0.03%, about 0.025% to about 0.035%, about 0.025% to about 0.04%, about 0.025% to about 0.045%, about 0.025% to about 0.05%, about 0.025% to about 0.06%, about 0.025% to about 0.07%, about 0.03% to about 0.035%, about 0.03% to about 0.04%, about 0.03% to about 0.045%, about 0.03% to about 0.05%, about 0.03% to about 0.06%, about 0.03% to about 0.07%, about 0.035% to about 0.04%, about 0.035% to about 0.045%, about 0.035% to about 0.05%, about 0.035% to about 0.06%, about 0.035% to about 0.07%, about 0.04% to about 0.045%, about 0.04% to about 0.05%, about 0.04% to about 0.06%, about 0.04% to about 0.07%, about 0.045% to about 0.05%, about 0.045% to about 0.06%, about 0.045% to about 0.07%, about 0.05% to about 0.06%, about 0.05% to about 0.07%, or about 0.06% to about 0.07% as compared to a reference level (e.g., any of the reference levels described herein). In some embodiments, the higher percentage of an unconjugated serum bile acid compared to a reference level can be an increase in the percentage of an unconjugated serum bile acid of about 0.008%, about 0.01%, about 0.012%, about 0.014%, about 0.016%, about 0.018%, about 0.02%, about 0.022%, about 0.024%, about 0.026%, about 0.03%, about 0.032%, about 0.034%, about 0.036%, about 0.04%, about 0.042%, about 0.044%, about 0.046%, about 0.048%, about 0.05, about 0.055%, about 0.06%, about 0.065%, or about 0.07% as compared to a reference level (e.g., any of the reference levels described herein). In some embodiments, the reference level is the mean of the percentages of cholic acid, chenodeoxycholic acid, or a combination thereof in samples from non-responders.

In some embodiments, a reference level is a mean of percentages of an unconjugated serum bile acid in non-responders. Responders (e.g., serum bile acid responders) include subjects that have PFIC2 and their serum bile acids were reduced >70% from baseline and/or they had a total serum bile acid concentration <70 pmol/L after treatment with odevixibat (e.g., after treatment with odevixibat for about 1 weeks to about 72 weeks). Non-responders are subjects that did not meet the serum bile acid response criteria. Determining the percentage of an unconjugated serum bile acid for a reference level can include dividing the concentration of the unconjugated serum bile acid by the total concentration of serum bile acids in a sample from a responder. In some embodiments, determining the percentage of an unconjugated serum bile acid for a reference level includes dividing the concentration of the unconjugated serum bile acid by the total concentration of serum bile acids in a sample from a responder excluding the concentration of UCDA or excluding the concentration of UCDA and its glycine and taurine conjugates.

In some embodiments, a higher concentration of an unconjugated serum bile acid as compared to a reference level can be an increase in the concentration of an unconjugated serum bile acid of about 0.01 to about 0.3 pmol/L compared to a reference level (e.g., any of the reference levels described herein). For example, a higher concentration of an unconjugated serum bile acid as compared to a reference level can be an increase in the concentration of an unconjugated serum bile acid of about 0.01 to about 0.05 pmol/L, about 0.01 to about 0.1 pmol/L, about 0.01 to about 0.15 pmol/L, about 0.01 to about 0.2 pmol/L, about 0.01 to about 0.25 pmol/L, about 0.05 to about 0.1 pmol/L, about 0.05 to about 0.15 pmol/L, about 0.05 to about 0.2 pmol/L, about 0.05 to about 0.25 pmol/L, about 0.05 to about 0.3 pmol/L, about 0.1 to about 0.15 pmol/L, about 0.1 to about 0.2 pmol/L, about 0.1 to about 0.25 pmol/L, about 0.1 to about 0.3 pmol/L, about 0.15 to about 0.2 pmol/L, about 0.15 to about 0.25 pmol/L, about 0.15 to about 0.3 pmol/L, about 0.2 to about 0.25 pmol/L, about 0.2 to about 0.3 pmol/L, or about 0.25 to about 0.3 pmol/L as compared to a reference level (e.g., any of the reference levels described herein). In some embodiments, the higher concentration of an unconjugated serum bile acid as compared to a reference level can be an increase in the concentration of an unconjugated serum bile acid of about 0.01 pmol/L, about 0.015 pmol/L, about 0.2 pmol/L, about 0.25 pmol/L, or about 0.3 pmol/L as compared to a reference level (e.g., any of the reference levels described herein).

In some embodiments, a reference level is a mean of concentrations of an unconjugated serum bile acid in non-responders. In some embodiments, the reference level is about 0.06 to about 0.2 pmol/L. For example the reference level can be about 0.06 to about 0.08 pmol/L, about 0.06 to about 0.1 pmol/L, about 0.06 to about 0.12 pmol/L, about 0.06 to about 0.14 pmol/L, about 0.06 to about 0.16 pmol/L, about 0.06 to about 0.18 pmol/L, about 0.08 to about 0.1 pmol/L, about 0.08 to about 0.12 pmol/L, about 0.08 to about 0.14 pmol/L, about 0.08 to about 0.16 pmol/L, about 0.08 to about 0.18 pmol/L, about 0.08 to about 0.2 pmol/L, about 0.1 to about 0.12 pmol/L, about 0.1 to about 0.14 pmol/L, about 0.1 to about 0.16 pmol/L, about 0.1 to about 0.18 pmol/L, about 0.1 to about 0.2 pmol/L, about 0.12 to about 0.14 pmol/L, about 0.12 to about 0.16 pmol/L, about 0.12 to about 0.18 pmol/L, about 0.12 to about 0.2 pmol/L, about 0.14 to about 0.16 pmol/L, about 0.14 to about 0.18 pmol/L, about 0.14 to about 0.2 pmol/L, about 0.16 to about 0.18 pmol/L, about 0.16 to about 0.2 pmol/L, or about 0.18 to about 0.2 pmol/L. In some embodiments, the reference level is about 0.06 pmol/L, about 0.08 pmol/L, about 0.1 pmol/L, about 0.12 pmol/L, about 0.14 pmol/L, about 0.16 pmol/L, about 0.18 pmol/L, or about 0.2 pmol/L. In some embodiments, the reference level is the mean of the concentrations of cholic acid, chenodeoxy cholic acid, or a combination thereof in samples from non-responders.

In some embodiments, the methods provided herein further include obtaining a blood sample from the subject. The blood sample may be taken from a human, or from non-human mammals such as, mice, rats, non-human primates, canines, felines, ruminants, swine, or sheep. In some embodiments, blood samples are taken from a subject at multiple time points, for example, before treatment, during treatment, and/or after treatment.

In some embodiments, following administration of odevixibat, or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in bile acid concentration relative to baseline. In some embodiments, the reduction in bile acid concentration is at least 25 pmol/L, at least 50 pmol/L, at least 75 pmol/L, at least 100 pmol/L, at least 125 pmol/L, at least 150 pmol/L, at least 175 pmol/L, at least 200 pmol/L, at least 300 pmol/L, at least 400 pmol/L, at least 500 pmol/L, or at least 600 pmol/L relative to baseline. For example, the reduction in mean bile acid concentration is about 25 pmol/L to about 200 pmol/L relative to baseline (e.g., about 25 pmol/L to about 50 pmol/L; about 25 pmol/L to about 50 pmol/L; about 25 pmol/L to about 75 pmol/L; about 25 pmol/L to about 100 pmol/L; about 25 pmol/L to about 125 pmol/L; about 25 pmol/L to about 150 pmol/L; about 25 pmol/L to about 175 pmol/L; about 25 pmol/L to about 75 pmol/L). In some embodiments, the reduction in bile acid concentration is about 50 pmol/L to about 180 pmol/L relative to baseline (e.g., about 50 pmol/L to about 100 pmol/L; about 50 pmol/L to about 120 pmol/L; about 50 pmol/L to about 150 pmol/L; about 65 pmol/L to about 120 pmol/L; about 50 pmol/L to about 90 pmol/L; about 65 pmol/L to about 85 pmol/L; about 100 pmol/L to about 130 pmol/L; about 100 pmol/L to about 180 pmol/L; or about 150 pmol/L to about 180 pmol/L). In some embodiments, the reduction in bile acid concentration is about 50 pmol/L to about 600 pmol/L, about 100 pmol/L to about 600 pmol/L, about 150 pmol/L to about 600 pmol/L, about 200 pmol/L to about 600 pmol/L, about 250 pmol/L to about 600 pmol/L, about 300 pmol/L to about 600 pmol/L, about 350 pmol/L to about 600 pmol/L, about 400 pmol/L to about 600 pmol/L, about 450 pmol/L to about 600 pmol/L, about 500 pmol/L to about 600 pmol/L, about 550 pmol/L to about 600 pmol/L, about 50 pmol/L to about 500 pmol/L, about 100 pmol/L to about 500 pmol/L, about 150 pmol/L to about 500 pmol/L, about 200 pmol/L to about 500 pmol/L, about 250 pmol/L to about 500 pmol/L, about 300 pmol/L to about 500 pmol/L, about 350 pmol/L to about 500 pmol/L, about 400 pmol/L to about 500 pmol/L, about 450 pmol/L to about 500 pmol/L, about 50 pmol/L to about 400 pmol/L, about 100 pmol/L to about 400 pmol/L, about 150 pmol/L to about 400 pmol/L, about 200 pmol/L to about 400 pmol/L, about 250 pmol/L to about 400 pmol/L, about 300 pmol/L to about 400 pmol/L, about 350 pmol/L to about 400 pmol/L, about 50 pmol/L to about 300 pmol/L, about 100 pmol/L to about 300 pmol/L, about 150 pmol/L to about 300 pmol/L, about 200 pmol/L to about 300 pmol/L, about 250 pmol/L to about 300 pmol/L, about 50 pmol/L to about 300 pmol/L, about 100 pmol/L to about 300 pmol/L, about 150 pmol/L to about 300 pmol/L, about 200 pmol/L to about 300 pmol/L, about 250 pmol/L to about 300 pmol/L, about 50 pmol/L to about 200 pmol/L, about 100 pmol/L to about 200 pmol/L, or about 150 pmol/L to about 200 pmol/L relative to baseline. In some embodiments, the reduction in bile acid concentration of about 70 pmol/L to about 120 pmol/L relative to baseline. In some embodiments, the reduction in bile acid concentration is about 150 pmol/L to about 180 pmol/L. In some embodiments, the bile acid concentration is the serum bile acid concentration. In some embodiments, the reduction in bile acid concentration occurs after about 1 weeks to about 72 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof. For example, about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 12 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 20 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 36 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 48 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 60 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 12 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 20 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 28 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 40 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 52 weeks, about 8 weeks to about 60 weeks, about 8 weeks to about 72 weeks, about 12 weeks to about 16 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 24 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 36 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 48 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 60 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 20 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 28 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 40 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 52 weeks, about 16 weeks to about 60 weeks, about 16 weeks to about 72 weeks, about 20 weeks to about 24 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 36 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 48 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 60 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 28 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 40 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 52 weeks, about 24 weeks to about 60 weeks, about 24 weeks to about 72 weeks, about 28 weeks to about 36 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 48 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 60 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 40 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 52 weeks, about 36 weeks to about 60 weeks, about 36 weeks to about 72 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 48 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in bile acid concentration occurs after about 5 weeks to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, following administration of the IBAT inhibitor for at least 48 weeks, the subject exhibits a serum bile acid concentration below the threshold for PFIC2 disease modification. See, e.g., van Wessel DBE, et al. J Hepatol. 2020; 73:84-93.

In some embodiments, following administration of odevixibat, or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in pruritus score relative to baseline. The pruritus score (also referred to herein as a “scratching score”) disclosed herein can be measured according to the PRECISION™ patient-reported outcome (PRO) and observer- reported outcome (ObsRO) instruments to estimate a threshold for clinically meaningful change in pruritus score. These instruments can be used to demonstrate the change from baseline in pruritus score and calculate the percentage of patients who achieve a clinically meaningful response. For a description of PRECISION™ instruments see, e.g., Gwaltney et al., Adv. Ther. (2022), 39:5105-5125, which is incorporated by reference herein in its entirety.

In some embodiments, the reduction in pruritus score (i.e., scratching score) relative to baseline is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in pruritus score relative to baseline is about 0.3 to about 4.0. For example, about 0.3 to about 3.5, about 0.3 to about 3.0, about 0.3 to about 2.5, about 0.3 to about 2.0, about 0.3 to about 1.5, about 0.3 to about 1.0, about 0.3 to about 0.5, about 0.5 to about 3.5, about 0.5 to about 3.0, about 0.5 to about 2.5, about 0.5 to about 2.0, about 0.5 to about 1.5, about 0.5 to about 1.0, about 1.0 to about 4.0 about 1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.5 to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.5 to about 2.5, about 1.5 to about 2.0, about 2.0 to about 1.0, about 2.0 to about 3.5, about 2.0 to about 3.0, about 2.0 to about 2.5, about 2.5 to about 4.0 about 2.5 to about 3.5, about 2.5 to about 3.0, about 3.0 to about 4.0, about 3.0 to about 3.5, or about 3.5 to about 4.0. In some embodiments, the reduction in pruritus score relative to baseline is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the reduction in pruritus score relative to baseline is about 2.0. In some embodiments, the reduction in pruritus score relative to baseline is about 1.6.

In some embodiments, the subject exhibits a scratching score of 2.5 or more prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof. For example, the subject can exhibit a scratching score of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject exhibits an average scratching score of about 2.5 to about 4.0 prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof. For example, the subject can exhibit an average scratching score of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits an average scratching score of about 2.8 prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, a subject has a decrease in scratching score of 1 or more points after administration of odevixibat, or a pharmaceutically acceptable salt thereof, relative to baseline.

In some embodiments, the reduction in pruritus score relative to baseline occurs after about 1 week to about 72 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof. For example, about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 12 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 20 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 36 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 48 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 60 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 12 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 20 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 28 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 40 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 52 weeks, about 8 weeks to about 60 weeks, about 8 weeks to about 72 weeks, about 12 weeks to about 16 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 24 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 36 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 48 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 60 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 20 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 28 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 40 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 52 weeks, about 16 weeks to about 60 weeks, about 16 weeks to about 72 weeks, about 20 weeks to about 24 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 36 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 48 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 60 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 28 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 40 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 52 weeks, about 24 weeks to about 60 weeks, about 24 weeks to about 72 weeks, about 28 weeks to about 36 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 48 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 60 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 40 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 52 weeks, about 36 weeks to about 60 weeks, about 36 weeks to about 72 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 48 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in pruritus score relative to baseline occurs after about 5 weeks to about 8 weeks, about 9 to about 12 weeks, about 13 to about 16 weeks, about 17 to about 20 weeks, about 21 to about 24 weeks of administration of odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is a pruritus responder. For example, the subject has a decrease or one or more points in scratching score after administration of odevixibat, or a pharmaceutically acceptable salt thereof, relative to baseline. In some embodiments, a pruritus responder has a decrease in scratching score of 1 or more points after administration of odevixibat, or a pharmaceutically acceptable salt thereof, for 21 to 24 weeks (e.g., 21, 22, 23, and/or 24 weeks) relative to baseline. In some embodiments, a pruritus responder has a scratching score averaged at weeks 20-24 of odevixibat administration that is one or more points decreased relative to baseline. In some embodiments, the scratching score as measured using the PRUCISION™ ObsRO instrument.

In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is not a pediatric subject. In some embodiments, the subject is an adult subject.

Dosages and Administration

In some embodiments, the subject is administered about 20 to about 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof. For example, about 20 to about 600, about 20 to about 400, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about 20 to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 800, about 40 to about 600, about 40 to about 400, about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 800, about 60 to about 600, about 60 to about 400, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 80, about 80 to about 800, about 80 to about 600, about 80 to about 400, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 to about 120, about 80 to about 100, about 100 to about 800, about 100 to about 600, about 100 to about 400, about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 120 to about 800, about 120 to about 600, about 120 to about 400, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 140 to about 800, about 140 to about 600, about 140 to about 400, about 140 to about 200, about 140 to about 180, about 140 to about 160, about 160 to about 800, about 160 to about 600, about 160 to about 400, about 160 to about 200, about 160 to about 180, about 180 to about 800, about 180 to about 600, about 180 to about 400, about 180 to about 200, about 200 to about 800, about 200 to about 600, about 200 to about 400, about 400 to about 800, about 400 to about 600, or about 600 to about 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 400, about 600, or about 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered 120 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is administered odevixibat, or a pharmaceutically acceptable salt thereof, in an amount that does not exceed 6 mg per day.

In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose ranging from about 1 pg to about 100 mg, such as from about 10 pg to about 10 mg, such as from about 100 pg to about 2000 pg, or such as from about 200 pg to about 1500 pg. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose ranging from about 10 pg to about 9 mg, about 10 pg to about 8 mg, about 10 pg to about 7 mg, about 10 pg to about 6 mg, about 10 pg to about 5 mg, about 10 pg to about 4 mg, about 10 pg to about 3 mg, about 10 pg to about 2 mg, about 10 pg to about 1 mg, about 10 pg to about 800 pg, about 10 pg to about 600 pg, about 10 pg to about 400 pg, about 10 pg to about 200 pg, about 10 pg to about 100 pg, about 10 pg to about 50 pg, about 50 pg to about 10 mg, about 50 pg to about 9 mg, about 50 pg to about 8 mg, about 50 pg to about 7 mg, about 50 pg to about 6 mg, about 50 pg to about 5 mg, about 50 pg to about 4 mg, about 50 pg to about 3mg, about 50 pg to about 2 mg, about 50 pg to about 1 mg, about 50 pg to about 800 pg, about 50 pg to about 600 pg, about 50 pg to about 400 pg, about 50 pg to about 200 pg, about 50 pg to about 100 pg, about 100 pg to about 10 mg, about 100 pg to about 9 mg, about 100 pg to about 8 mg, about 100 pg to about 7 mg, about 100 pg to about 6 mg, about 100 pg to about 5 mg, about 100 pg to about 4 mg, about 100 pg to about 3 mg, about 100 pg to about 2 mg, about 100 pg to about 1 mg, about 100 pg to about 800 pg, about 100 pg to about 600 pg, about 100 pg to about 400 pg, about 100 pg to about 200 pg, about 200 pg to about 10 mg, about 200 pg to about 9 mg, about 200 pg to about 8 mg, about 200 pg to about 7 mg, about 200 pg to about 6 mg, about 200 pg to about 5 mg, about 200 pg to about 4 mg, about 200 pg to about 3 mg, about 200 pg to about 2 mg, about 200 pg to about 1 mg, about 200 pg to about 800 pg, about 200 pg to about 600 pg, about 200 pg to about 400 pg, about 200 pg to about 10 mg, about 200 pg to about 9 mg, about 400 pg to about 8mg, about 400 pg to about 7 mg, about 400 pg to about 6 mg, about 400 pg to about 5 mg, about 400 pg to about 4 mg, about 400 pg to about 3 mg, about 400 pg to about 2 mg, about 400 pg to about 1 mg, about 400 pg to about 800 pg, about 400 pg to about 600 pg, about 600 pg to about 10 mg, about 600 pg to about 9 mg, about 600 pg to about 8 mg, about 600 pg to about 7 mg, about 600 pg to about 6 mg, about 600 pg to about 5 mg, about 600 pg to about 4 mg, about 600 pg to about 3 mg, about 600 pg to about 2 mg, about 600 pg to about 1 mg, about 600 pg to about 800 pg, about 800 pg to about 10 mg, about 800 pg to about 9 mg, about 800 pg to about 8 mg, about 800 pg to about 7 mg, about 800 pg to about 6 mg, about 800 pg to about 5 mg, about 800 pg to about 4 mg, about 800 pg to about 3 mg, about 800 pg to about 2 mg, about 800 pg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about

5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about

7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about

8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about

8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about

6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 10 mg, about 7 mg to about

9 mg, about 7 mg to about 8 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg, In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 100 pg, about 200 pg, about 300 pg, about 400 pg, about 500 pg, about 600 pg, about 700 pg, about 800 pg, about 900 pg, about 1000 pg, about 1100 pg, about 1200 pg, about 1300 pg, about 1400 pg, about 1500 pg, about 1600 pg, about 1700 pg, about 1800 pg, about 1900 pg, or about 2000 pg.

In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 200 pg. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 400 pg. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 600 pg. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 1200 pg.

The frequency of administration can vary from once or twice a week to once or more times a day, such as two or three times daily. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered once daily. The frequency of administration can furthermore remain constant or be variable during the duration of the treatment. Several factors can influence the frequency of administration and the effective amount of the formulation that should be used for a particular treatment, such as the severity of the condition being treated, the duration of the treatment, as well as the age, weight, sex, diet and general medical condition of the patient being treated.

In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 200 pg per day. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 400 pg per day. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 600 pg per day. In some embodiments, odevixibat, or a pharmaceutically acceptable salt thereof, is administered as a unit dose of about 1200 pg per day.

In some embodiments, the subject was administered one or more antiprurituc agents prior to the first administration of a pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof. Non-limiting examples of an antiprurituc agent include cholestyramine, ursodeoxycholic acid (UDCA), rifampicin, phenobarbital, ondansetron, sertraline, and naltrexone.

Formulations

IB AT inhibitors as provided herein can be formulated as previously described. See, for example, International Publication Nos. WO 2019/245449; WO 2020/0167981; WO 2020/0167985; WO 2020/0167964; U.S. Patent No. 10,709,755; and U.S. Application No. US 2017/0143738. Odevixibat, for example, exhibits high potency and can be administered in low doses, such as ranging from about 40 pg/kg/day to about 120 pg/kg/day. This can correspond to doses such as 200 pg to 7200 pg in the treatment of paediatric patients that weigh about 4 kg to > 55.5 kg. In some embodiments, this can correspond to doses as low as 200 pg to 800 pg in the treatment of paediatric patients that weigh about 4 kg to about 20 kg (e.g., infants and toddlers). It is desirable that a formulation of odevixibat can be administered to young patients in a dosage form having a small size. It is further desirable that such a formulation has good palatability, is not perceived as gritty, and is well-tolerated by infants and small children.

Multiparticulates can be administered to infants from birth if they are administered with a liquid. For children aged approximately 6 months and older (i.e., after weaning), the multiparticulates can be administered in their solid form either directly into the mouth or mixed with semi-solid food. Particle size, shape, texture, hardness, taste and dose volume (i.e., the number of particles) have been reported to be important for acceptability of multiparticulates by infants and children (Kozarewicz, Int. J. Pharm. 2014, vol. 469, pp 245-248). Various literature reviews have been conducted on the acceptability of different oral dosage forms in paediatric and older adult patients (see e.g. Liu, et al., Drugs 2014, vol. 74, pp. 1871-1889; Drumond et al., Int. J. Pharm. 2017, vol. 521, pp. 294-305; Mistry et al., J. Pharm. Pharmacol. 2017, vol. 69, pp. 361-376; Walsh et al., Int. J. Pharm. 2017, vol. 536, pp. 547-562), but the size and/or dose volume (amount) of multiparticulates investigated have not always been reported in these reviews.

Perception of grittiness can be influenced by a range of factors including particle size, quantity, and dosing vehicle (see Mishra et al., Yakugaku Zasshi 2009, vol. 129, pp. 1537-1544; Lopez et al., Eur. J. Pharm. Set. 2016, vol. 92, pp. 156-162), as well as the hardness and shape of the particles (Tyle, Acta Psychologica 1993, vol. 84, pp. 111-118), with irregular particles being perceived as larger than round (spherical) particles of the same size (Engelen et al., J. Text. Studies 2005, vol. 36, pp. 373-386). Grittiness perception studies have shown that grittiness scores may increase with increasing size and dose of the multiparticulates, whereas grittiness scores may decrease with increasing vehicle viscosity (Lopez et al., Eur. J. Pharm. Sci. 2016, vol. 92, pp. 156-162).

Capsules can be acceptable for children from approximately 6 years of age. The swallowability of the capsules can depend upon the dosage form dimensions (i.e. the size) and the ability of the child. The size, shape, taste and after taste are important capsule attributes that can influence patient acceptability (Kozarewicz, Int. J. Pharm. 2014, vol. 469, pp 245- 248). In some embodiments, the size of the capsules is kept as small as possible, and the number of capsules required per dose is kept to a minimum, e.g. not more than 1-3 capsules.

Provided herein is a multiparticulate formulation containing low doses of odevixibat. In some embodiments, the formulation is a paediatric formulation. In some embodiments, the formulation enables weight-based dosing and can be sprinkled onto food. The formulation can be designed to have a good palatability, with an optimal balance between particle size and dose volume.

Provided herein is a pharmaceutical formulation of odevixibat, comprising a plurality of particles, wherein each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.1% w/w to about 5.0% w/w based on the total weight of the particle.

Because of the low doses in which odevixibat can be administered, and further because of the multiparticulate form of the application, each particle of the formulation contains only a very low amount of the active ingredient. For example, the amount of odevixibat, or a pharmaceutically acceptable salt thereof, in each particle can be from about 0.2% w/w to about 3.5% w/w, for example, from about 0.3% w/w to about 3.0% w/w, from about 0.4% w/w to about 2.5% w/w, or from about 0.5% w/w to about 2.0% w/w based on the total weight of the particle. In some embodiments, each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w/w based on the total weight of the particle. In another embodiment, each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of about 1.0% w/w based on the total weight of the particle. In yet another embodiment, each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of about 1.5% w/w based on the total weight of the particle.

As used herein, the term “particles” refers to small particles ranging in size from about 0.1 to about 1.5 mm. Such particles are essentially spherical, although elongated or oblong particles also might be used. The particles may e.g. be pellets, beads, microparticles, microspheres, granules or minitablets, and may optionally be coated with one or more coating layers surrounding every such pellet, bead, microparticle, microsphere, granule or minitablet.

In some embodiments, the particles of the formulation are small enough, that they can be sprinkled onto food and easily swallowed. In some embodiments, the particles can be swallowed without causing a perception of grittiness. In some embodiments, the particles do not give the patient an urge to chew the particles. The particles are, therefore, between about 0.1 and about 1.5 mm in size, for example, between about 0.1 and about 1.0 mm, or between about 0.1 and 0.8 mm, such as about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, or about 0.7 mm. In some embodiments, the particles are between about 0.4 and about 0.8 mm, such as about 0.5 mm, or such as about 0.6 mm, or such as about 0.7 mm. In some embodiments, the particles are about 0.7 mm.

In some embodiments, provided herein is a formulation of odevixibat, wherein each particle comprises a core and a coating layer surrounding the core. The core of each particle may be a pellet, a granule, a minitablet, a bead, a microparticle or a microsphere.

In some embodiments, the core of each particle comprises the active pharmaceutical ingredient (odevixibat), while the coating layer of each particle does not comprise the active pharmaceutical ingredient. In some embodiments, the core of each particle comprises from about 0.1% to about 5% w/w of the active pharmaceutical ingredient, based on the total weight of the particle, such as from about 0.1% to about 2% w/w, such as from about 0.1% to about 1% w/w, or such as from about 0.1% to about 0.5% w/w of the active pharmaceutical ingredient, based on the total weight of the particle.

In some embodiments, the coating layer of each particle contains the active pharmaceutical ingredient (odevixibat), while the core of each particle does not comprise the active pharmaceutical ingredient. In some embodiments, the coating layer of each particle contains from about 0.1% to about 5% w/w of the active pharmaceutical ingredient, based on the total weight of the particle, such as from about 0.1% to about 2% w/w, such as from about 0.1% to about 1% w/w, or such as from about 0.1% to about 0.5% w/w of the active pharmaceutical ingredient, based on the total weight of the particle.

The cores can be orally dispersible and contain soluble ingredients such as a sugar (e.g., sucrose) or a soluble polymer (e.g. hydroxypropyl methylcellulose) or may be non-orally dispersible and contain non-soluble ingredients such as a non-soluble polymer (e.g., microcrystalline cellulose). In some embodiments, the cores contain microcrystalline cellulose. In some embodiments, the cores are microcrystalline cellulose spheres.

The coating layer can further contain a film-forming polymer, such as a cellulose-based polymer, a polysaccharide-based polymer, an 7V-vinylpyrrolidone-based polymer, an acrylate, an acrylamide, or copolymers thereof. Examples of suitable film-forming polymers include polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymers, starch, hydroxypropyl starch, chitosan, shellac, methyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), as well as combinations thereof, such as a mixture of methyl cellulose and hydroxypropyl methylcellulose (metolose). In some embodiments, the coating layer comprises a film-forming polymer selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), starch, hydroxypropyl starch and hydroxypropyl cellulose (HPC). For example, the coating layer can contain hydroxypropyl methylcellulose as the film-forming polymer.

The coating layer can optionally comprise one or more additional ingredients, such as a plasticizer (e.g. polyethylene glycol, triacetin or triethyl citrate), an anti-tack agent (e.g. talc or magnesium stearate), or a colouring agent (e.g. titanium dioxide, iron oxides, riboflavin or turmeric).

In some embodiments, the formulation comprises odevixibat in crystalline form. In some embodiments, the formulation comprises a crystalline hydrate of odevixibat. In some embodiments, the formulation comprises crystal modification 1 of odevixibat. This stable crystal modification can be obtained from a slurry of odevixibat in a mixture of water and an organic solvent such as ethanol. See, e.g., International Publication No. WO2019/245448A1.

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

EXAMPLES

EXAMPLE 1. Pretreatment Serum Bile Acid Composition in Patients With Bile Salt Export Pump Deficiency Is Strongly Associated With Treatment Response to IBAT Inhibition By Odevixibat.

Bile salt export pump (BSEP) deficiency (i.e., progressive familial intrahepatic cholestasis [PFIC] type 2 [PFIC2]) is a rare genetic liver disease characterized by defective secretion of bile acids (Baker Aet al., Clin Res Hepatol Gastroenterol, 43:20-36 (2019); Henkel SA et al., World J Hepatol, 11 :450-63 (2019)). (FIG. 1). Odevixibat, an inhibitor of the ileal bile acid transporter (IBAT), blocks the reabsorption of conjugated bile acids and effectively reduced the total concentration of serum bile acids in a proportion of patients with PFIC2. Reduction of the total concentration of serum bile acids by interruption of the enterohepatic circulation has been associated with longer survival with native liver. However, it has so far not been possible to predict the responsiveness to odevixibat in patients with PFIC2.

Methods

Patients eligible for PEDFIC 1 (NCT03566238) and PEDFIC 2 (NCT03659916) had elevated serum bile acids and significant pruritus at screening (Thompson RJ et al., Lancet Gastroenterol Hepatol, 7:830-42 (2022); Thompson RJ et al., JHEP Rep, 5:100782 (2023)). In PEDFIC 1, children with PFIC1 and PFIC2 were randomized to either placebo (n=15) or odevixibat (n=30) in a 24-week, double-blinded study (Thompson RJ et al., Lancet Gastroenterol Hepatol, 7:830-42 (2022)). At week 24, serum bile acid composition was measured by LC-MS/MS.

Following PEDFIC 1, patients could enroll in PEDFIC 2, an ongoing, 72-week, open label extension study in which all patients received odevixibat (Thompson RJ et al., JHEP Rep, 5: 100782 (2023)).

Pretreatment serum bile acid composition was evaluated in 2 groups of patients with PFIC2: i) those who were treated with odevixibat for 24 weeks in PEDFIC 1, and ii) those who initially received placebo in PEDFIC 1 and then went on to be treated with odevixibat for 24 weeks in PEDFIC 2 (FIG. 2). Concentrations of individual serum bile acids were measured by liquid chromatography-tandem mass spectrometry. Relative contributions per serum bile acid were calculated by dividing the individual bile acid concentration by the total concentration of serum bile acids from which the concentration of ursodeoxycholic acid (UDCA) and its glycine and taurine conjugates were subtracted.

Serum bile acid responsiveness was assessed after 24 weeks of odevixibat treatment. Patients were classified as serum bile acid responders if their serum bile acids were reduced >70% from baseline. Patients were classified as nonresponders if their serum bile acids were <70 pmol/L.

Results

Patients

Overall, 41 patients with PFIC2 who participated in PEDFIC 1 and were treated with odevixibat in PEDFIC 1 (n=29) or PEDFIC 2 (n=12) were included. The mean age of the patients was 4.5 years, and 22 of 41 were female. Serum bile acid levels in responders and nonresponders

In pretreatment serum samples, total serum bile acid and UDCA concentrations were similar between responders and nonresponders (FIG. 4). However, responders had higher percentages of unconjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) compared with nonresponders. The absolute concentration of CA + CDCA was higher in responders compared with nonresponders (FIG. 4).

Receiver operating characteristic curve analysis for CA percentage, CDCA percentage, and absolute concentration of CA + CDCA revealed respective areas under the curve of 0.70, 0.73, and 0.76 (FIG. 3). Based on whether a patient met at least 1 of the 3 optimal thresholds, 36 of 41 patients with PFIC2 (87.8%) were correctly classified as responders or nonresponders, respectively (sensitivity: 89.5%; specificity: 86.4%) (FIG. 5). Individual patient data are presented in FIG. 6.

EXAMPLE 2. Odevixibat Treatment in Responsive Patients With Bile Salt Export Pump Deficiency Restores Biliary Bile Acid Secretion, as Indicated by Serum Bile Acid Composition.

Of 45 patients with PFIC2 enrolled in PEDFIC 1, 15 were randomized to placebo and 30 were randomized to odevixibat. Among odevixibat treated patients, 15 were serum bile acid responders based on thresholds defined in PEDFIC 1, i.e., levels reduced >70% from baseline to the end of treatment or reaching levels <70 pmol/L).

Serum bile acid composition was measured by LC MS/MS at week 24. Primary and secondary bile acids as well as glycine or taurine conjugated and unconjugated bile acids were measured. Bile acid composition was expressed as a percentage of total serum bile acids.

No significant difference in secondary serum bile acids (DCA and LCA) at end of treatment (FIG. 7). Responders had ~70-fold increase in unconjugated serum bile acids (FIGS. 8A and 8B). Both CA and CDCA contributed to the unconjugated bile acid effect in responders (FIGS. 9A and 9B). Responders had increase in G/T conjugation ratio and decrease in CA/CDCA ratio toward normal (FIGS. 10A and 10B).

Claims

WHAT IS CLAIMED IS:

1. A method of treating progressive familial intrahepatic cholestasis type 2 (PFIC2) in a subject, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and administering to the identified subject a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof.

2. A method of treating PFIC2 in a subject, the method comprising administering a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, to a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level.

3. A method of selecting a treatment for a subject having PFIC2, the method comprising: identifying a subject having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and selecting for the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof.

4. A method of selecting a treatment for a subject having PFIC2, the method comprising selecting a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof, for a subject identified as having a higher percentage of an unconjugated serum bile acid as compared to a reference level.

5. A method of treating a subject having PFIC2, the method comprising:

(a) administering to the subject a therapeutic agent;

(b) after (a), identifying the subject as having a higher percentage of an unconjugated serum bile acid as compared to a reference level; and

(c) administering to the identified subject a treatment comprising a therapeutically effective amount of odevixibat, or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein the therapeutic agent is an antipruritic agent such as cholestyramine, ursodeoxycholic acid (UDCA), rifampicin, phenobarbital, ondansetron, sertraline, and naltrexone.

7. The method of any one of claims 1-6, wherein the unconjugated serum bile acid is cholic acid, chenodeoxycholic acid, or a combination thereof.

8. The method of any one of claims 1-7, wherein the subject is a pediatric subject.

9. The method of any one of claims 1-8, wherein the subject is administered about 100 to about 800 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the subject is administered 120 pg/kg/day of odevixibat, or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-10, wherein the subject was odevixibat naive prior to the first administration of the pharmaceutical formulation comprising odevixibat, or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1-11, wherein the subject exhibits a reduction in pruritus score relative to baseline.

13. The method of claim 12, wherein the reduction in pruritus score relative to baseline is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.0.

14. The method of any one of claims 12-13, wherein the reduction in pruritus score relative to baseline is about 1.5 to about 4.

15. The method of any one of claims 12-13, wherein the reduction in pruritus score relative to baseline is about 1.5 to about 2.5.

16. The method of any one of claims 12-13, wherein the reduction in pruritus score relative to baseline is about 2.

17. The method of any one of claims 12-16, wherein the reduction in pruritus score relative to baseline occurs following administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

18. The method of any one of claims 1-17, wherein the pruritus score at baseline is about 2.5 to about 4.0.

19. The method of any one of claims 1-18, wherein the pruritus score at baseline is about 2.5 to about 3.5.

20. The method of any one of claims 1-19, wherein the pruritus score at baseline is about 3.0.

21. The method of any one of claims 1-20, wherein the pruritus score at baseline is about 2.8.

22. The method of any one of claims 1-21, wherein the subject exhibits a reduction in serum bile acid concentration relative to baseline.

23. The method of claim 22, wherein the reduction in serum bile acid concentration is at least 50 pmol/L, at least 75 pmol/L, at least 100 pmol/L, at least 125 pmol/L, at least 150 pmol/L, or at least 175 pmol/L relative to baseline.

24. The method of any one of claims 22-23, wherein the reduction in serum bile acid concentration is about 50 pmol/L to about 180 pmol/L relative to baseline.

25. The method of any one of claims 22-24, wherein the reduction in serum bile acid concentration is about 70 pmol/L to about 120 pmol/L relative to baseline.

26. The method of any one of claims 22-25, wherein the reduction in serum bile acid concentration is about 80 pmol/L to about 110 pmol/L relative to baseline.

27. The method of any one of claims 22-26, wherein the reduction in serum bile acid concentration occurs following administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

28. The method of any one of claims 1-27, wherein the serum bile acid concentration at baseline is about 180 pmol/L to about 600 pmol/L.

29. The method of any one of claims 1-28, wherein the serum bile acid concentration at baseline is about 200 pmol/L to about 280 pmol/L.

30. The method of any one of claims 1-29, wherein the serum bile acid concentration at baseline is about 230 pmol/L to about 250 pmol/L.