Treatment of alagger syndrome (ALGS)

Abstract

Provided herein are methods of treating Alager's Syndrome (ALGS) using an ileum bile acid transport (IBAT) inhibitor (e.g., Ovixabet or a pharmaceutically acceptable salt thereof). These methods may include reducing itch score, serum bile acid concentration, increasing height, normalizing weight, improving sleep, and improving liver parameters.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 422,235, filed on November 3, 2022; U.S. Provisional Application No. 63 / 439,945, filed on January 19, 2023; U.S. Provisional Application No. 63 / 454,410, filed on March 24, 2023; and U.S. Provisional Application No. 63 / 544,079, filed on October 13, 2023, the disclosures of which are hereby incorporated by reference in their entireties. Technical field

[0003] Provided herein are methods of treating Alagille syndrome (ALGS) using an ileal bile acid transporter (IBAT) inhibitor (e.g., odevixibat or a pharmaceutically acceptable salt thereof). These methods can include reducing the itch score, bile acid (BA) concentration, increasing height, normalizing body weight, improving sleep parameters, enhancing quality of life, improving itch / scratch symptoms and sleep, and improving liver biochemical parameters and xanthomas. Background art

[0004] Compound 1,1 - dioxo - 3,3 - dibutyl - 5 - phenyl - 7 - (methylthio) - 8 - ({N - [(R)-α - {N - [(S)-1 - carboxypropyl]carbamoyl}-4 - hydroxybenzyl]carbamoyl}methoxy) - 2,3,4,5 - tetrahydro - 1,2,5 - benzothiadiazepine (odevixibat; also known as A4250):

[0005]

[0006] Is an inhibitor of the ileal bile acid transporter (IBAT) mechanism. Specifically, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatoportal circulation. Bile acids that are not reabsorbed by the ileum are instead excreted into the feces. Complete clearance of bile acids from the enterohepatic circulation results in a decrease in bile acid levels in the serum and liver. Thus, odevixibat or a pharmaceutically acceptable salt thereof can be used to treat liver diseases associated with elevated bile acid levels, particularly for the treatment of rare pediatric cholestatic liver diseases, including Alagille syndrome (ALGS). Summary of the invention

[0007] The present invention provides methods for treating Alagille syndrome (ALGS) in subjects in need thereof, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administration of the pharmaceutical formulation, the subject exhibits a reduction in the scratching score relative to baseline. The present invention also provides methods for treating pruritus associated with ALGS in subjects in need thereof, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administration of the pharmaceutical formulation, the subject exhibits a reduction in the scratching score relative to baseline.

[0008] The present invention further provides methods for reducing the monthly scratching score of a subject with ALGS, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the subject exhibits a reduction in one or more of the average morning scratching score, the average afternoon scratching score, and the average morning and afternoon scratching score relative to baseline.

[0010] In some embodiments, the present invention provides methods for treating ALGS in subjects in need thereof, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administration of the pharmaceutical formulation, the subject exhibits a reduction in serum bile acid concentration.

[0011] The present invention also provides methods for treating pruritus associated with ALGS in subjects in need thereof, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administration of the pharmaceutical formulation, the subject exhibits a reduction in serum bile acid concentration.

[0012] The present invention further provides methods for reducing the serum bile acid concentration of a subject with ALGS, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

[0013] The present invention provides methods for treating ALGS in subjects in need thereof, which methods comprise orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administration of the pharmaceutical formulation for at least 4 weeks, the subject exhibits a change in serum bile acid concentration relative to baseline.

[0014] The present invention also provides a method for treating ALGS-related pruritus in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administering the pharmaceutical preparation for at least 4 weeks, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

[0015] The present invention further provides a method for treating ALGS in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administering the pharmaceutical preparation for at least 24 weeks, the subject exhibits a decrease in serum bile acid concentration relative to baseline.

[0016] In some embodiments, the present invention provides a method for treating ALGS in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein, after administering the pharmaceutical preparation for at least 24 weeks, the subject exhibits a decrease in bile acid concentration of at least 50% relative to baseline.

[0017] The present invention also provides a method for decreasing serum bile acid concentration relative to baseline in a subject suffering from ALGS, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for about 4 to about 24 weeks. For example, about 4 to about 8 weeks, about 8 to about 12 weeks, about 12 to about 16 weeks, about 16 to about 20 weeks, or about 20 to about 24 weeks.

[0018] Details of one or more embodiments of the present invention are set forth in the accompanying drawings and the following description. Other features, objects, and advantages of the present invention will be apparent from the description, the drawings, and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 A schematic diagram of the study design and key inclusion criteria of the ALGS ASSERT placebo-controlled trial is provided.

[0020] Figure 2 The distribution of patients in the double-blind, randomized, placebo-controlled ALGS ASSERT study is shown. A total of 52 patients participated in the study: 17 patients received placebo treatment and 35 patients received obeticholic acid treatment. All 52 patients (100%) completed the study, and 50 patients elected to participate in the open-label extension study.

[0021] Figure 3 The baseline demographics and disease characteristics of patients in the placebo-controlled ALGS ASSERT trial are provided.

[0022] Figure 4 It is a bar graph showing the least-squares (LS) mean change in scratch scores from baseline to weeks 21 - 24 of treatment with obeticholic acid relative to placebo.

[0023] Figure 5 It is a line graph showing the change in the least-squares (LS) mean (95% confidence interval (CI)) of scratch scores from baseline to weeks 21 - 24 of treatment with obeticholic acid relative to placebo.

[0024] Figure 6 It is a bar graph showing the least-squares (LS) mean change in the mean of bile acids (µmol / L) from baseline to weeks 20 and 24 of treatment with obeticholic acid relative to placebo.

[0025] Figure 7 It is a line graph showing the change in the least-squares (LS) mean (95% confidence interval (CI)) of the mean of bile acids (µmol / L) over time from baseline to weeks 20 and 24 of treatment with obeticholic acid relative to placebo.

[0026] Figure 8A It is a bar graph showing the percentage of patients with a pruritus response (pruritus response defined as a reduction in scratch score of ≥1 point per month relative to baseline) at weeks 9 - 12 and 21 - 24 of treatment with obeticholic acid compared to placebo.

[0027] Figure 8B It is a table showing the number of patients with a pruritus response (pruritus response defined as a reduction in scratch score of ≥1.5 points per month relative to baseline) at weeks 9 - 12 and 21 - 24 of treatment with obeticholic acid compared to placebo.

[0028] Figure 8C It is a bar graph showing the percentage of patients with a pruritus response (pruritus response defined as a reduction in scratch score of ≥1.5 points per month relative to baseline) at weeks 9 - 12 and 21 - 24 of treatment with obeticholic acid compared to placebo.

[0029] Figure 9 It is a line graph showing the change in the least-squares (LS) mean (95% confidence interval (CI)) of the percentage of days that patients slept with a caregiver from baseline to weeks 21 - 24 of treatment with obeticholic acid relative to placebo.

[0030] Figure 10 It provides the least-squares (LS) mean change in all sleep parameters measured by ObsRO from baseline to weeks 21 - 24 of treatment with obeticholic acid relative to placebo.

[0031] Figure 11A It is a bar graph showing the overall impression of change in scratching (GIC) expressed as the percentage of clinician responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0032] Figure 11B It is a bar graph showing the overall impression of change in sleep (GIC) expressed as the percentage of clinician responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0033] Figure 11C It is a bar graph showing the overall impression of change in scratching (GIC) expressed as the percentage of caregiver responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0034] Figure 11D It is a bar graph showing the overall impression of change in sleep (GIC) expressed as the percentage of caregiver responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0035] Figure 11E It is two bar graphs showing the overall impression of change in itching (GIC) expressed as the percentage of patient responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0036] Figure 11F It is a bar graph showing the overall impression of change in sleep (GIC) expressed as the percentage of patient responses after 24 weeks of treatment with obeticholic acid relative to placebo.

[0037] Figure 12A It is a bar graph showing the mean (SD) change in scratching score from baseline to weeks 21 - 24 in patients with JAG1 and NOTCH2 mutations (after treatment with obeticholic acid relative to placebo).

[0038] Figure 12B It is a bar graph showing the change (right) in mean bile acids (µmol / L) from baseline to weeks 20 and 24 in patients with JAG1 and NOTCH2 mutations (after treatment with obeticholic acid relative to placebo).

[0039] Figure 13 It provides a summary of the safety of all patients during treatment with obeticholic acid relative to placebo. No patients discontinued the ASSERT placebo - controlled study, and no discontinuations due to death or treatment - emergent adverse events (TEAEs) were reported.

[0040] Figure 14 It is a modified eDISH graph showing peak total bilirubin (x baseline) and peak alanine aminotransferase (ALT) (x baseline) for each patient from after baseline to weeks 21 - 24 of treatment with obeticholic acid relative to placebo.

[0041] Figure 15 Patient baseline ALT and total bilirubin data are provided, as well as the changes in ALT and total bilirubin from baseline to week 24 in patients treated with obeticholic acid relative to placebo.

[0042] Figure 16A A bar graph showing the mean change in the clinician xanthoma score from baseline to weeks 12 and 24 in patients treated with obeticholic acid relative to placebo.

[0043] Figure 16B A line graph showing the mean change over time in the serum cholesterol level (mmol / L) in patients from baseline to week 24 treated with obeticholic acid relative to placebo.

[0044] Figure 17 A table summarizing the exposure of ALGS patients treated with obeticholic acid through week 9 - 12 (itching and sleep) and week 12 (bile acids) in ASSERT and ASSERT - EXT, as well as pooling baseline and post - treatment results.

[0045] Figure 18A A graph showing the change over time in the mean (SD) scratch score in the pooled population of ALGS patients treated with obeticholic acid.

[0046] Figure 18B A graph showing the change over time in the mean (SD) bile acid level in the pooled population of ALGS patients treated with obeticholic acid.

[0047] Figure 18C A graph showing the change over time in the mean (SD) autotaxin level in the pooled population of ALGS patients treated with obeticholic acid.

[0048] Figure 18D A graph showing the change over time in the mean (SD) C4 level in the pooled population of ALGS patients treated with obeticholic acid.

[0049] Figure 19A A graph showing the serum bile acid levels in patients found to have Alagille syndrome before and after treatment with obeticholic acid. Vertical short dashes indicate the start of obeticholic acid treatment, and shading indicates the different doses of obeticholic acid administered.

[0050] Figure 19B A graph showing the total bilirubin levels in patients found to have Alagille syndrome before and after treatment with obeticholic acid. Vertical short dashes indicate the start of obeticholic acid treatment, and shading indicates the different doses of obeticholic acid administered.

[0051] Figure 20Flowchart of key disease features throughout the lives of patients with Alagille syndrome and the impact of obeticholic acid treatment. ALT, alanine transaminase; AST, aspartate transaminase; GGT, γ-glutamyl transferase; UDCA, ursodeoxycholic acid.

[0052] Figure 21 Table showing blinded sample size re-estimation.

[0053] Figure 22 Line graph showing the mean (SE) scratch scores over time from ASSERT baseline to Weeks 9–12 of ASSERT-EXT with placebo–obeticholic acid versus obeticholic acid–obeticholic acid treatment. Values shown at ASSERT time points represent all patients randomized in ASSERT (placebo group, n = 17; obeticholic acid group, n = 35); values shown at ASSERT-EXT time points represent only those patients who were transferred to ASSERT-EXT and received obeticholic acid treatment before the data cutoff date (placebo–obeticholic acid group, n = 17; obeticholic acid–obeticholic acid group, n = 32). Scratch scores range from 0–4, with higher scores indicating more severe symptoms. At Weeks 9–12 of ASSERT-EXT, 70% of patients in the placebo–obeticholic acid group had a ≥1-point reduction in pruritus severity from baseline.

[0054] Figure 23 Line graph showing the mean (SE) bile acid levels (µmol / L) over time from ASSERT baseline to Weeks 9–12 of ASSERT-EXT with placebo–obeticholic acid versus obeticholic acid–obeticholic acid treatment. Values shown at ASSERT-EXT time points represent all patients enrolled in ASSERT (placebo group, n = 17; obeticholic acid group, n = 35); values shown at ASSERT-EXT time points represent only those patients who were transferred to ASSERT-EXT and received obeticholic acid treatment before the data cutoff date (placebo–obeticholic acid group, n = 17; obeticholic acid–obeticholic acid group, n = 32).

[0055] Figure 24AIt is a line graph showing the mean (SE) fatigue scores over time from the ASSERT baseline to weeks 9 - 12 of ASSERT-EXT in the treatment with placebo-obeticholic acid versus obeticholic acid-obeticholic acid. The values shown at the ASSERT time points represent all patients participating in ASSERT (placebo group, n = 17; obeticholic acid group, n = 35); the values shown at the ASSERT-EXT time points represent only those patients who were transferred to ASSERT-EXT and received obeticholic acid treatment before the data cut-off date (placebo-obeticholic acid group, n = 17; obeticholic acid-obeticholic acid group, n = 32). The fatigue scores range from 0 - 4, with higher scores indicating more severe symptoms.

[0056] Figure 24B It is a table showing all sleep parameters.

[0057] Figure 25 It is a table showing a summary of adverse events occurring during treatment.

[0058] Figure 26 It is an example of an observer-reported item of the PRUCISION TM instrument.

[0059] Figure 27 It is a table showing the Global Impression of Change (GIC) over time. The GIC items are evaluated using a 7-point scale: 1 = very marked improvement; 2 = marked / moderate improvement; 3 = slight improvement; 4 = no change; 5 = slight worsening; 6 = marked / moderate worsening; 7 = very marked worsening. The change based on GIC is analyzed using a proportional odds model with treatment and baseline GIS scores as covariates, considering three categories (improvement, no change, worsening). "Improvement" includes "very marked improvement", "marked improvement", and "slight improvement", and "worsening" includes "slight worsening", "marked worsening", and "very marked worsening". CaGIC = Caregiver's Global Impression of Change. CGIC = Clinician's Global Impression of Change. PGIC = Patient's Global Impression of Change.

[0060] Figure 28 It is a table showing the Global Impression of Symptoms (GIS) over time. CaGIS = Caregiver's Global Impression of Symptoms. CGIS = Clinician's Global Impression of Symptoms. PGIS = Patient's Global Impression of Symptoms.

[0061] Figure 29A and 29B It is a table showing the scratching score ( Figure 29A ) and bile acids ( Figure 29BLine graph showing changes relative to the baseline.

[0062] Figure 30 It is a graph showing the serum bile acid levels of individual patients with ALGS who received obeticholic acid treatment in ASSERT and / or ASSERT-EXT.

[0063] Figure 31 It is a graph showing the scratch scores of individual patients with ALGS who received obeticholic acid treatment in ASSERT and / or ASSERT-EXT.

[0064] Figure 32A It is a graph showing the average baseline change in ALT after obeticholic acid treatment in the combined patients in the ASSERT and ASSERT-EXT studies.

[0065] Figure 32B It is a graph showing the average baseline change in AST after obeticholic acid treatment in the combined patients in the ASSERT and ASSERT-EXT studies.

[0066] Figure 32C It is a graph showing the average baseline change in GGT after obeticholic acid treatment in the combined patients in the ASSERT and ASSERT-EXT studies.

[0067] Figure 32D It is a graph showing the average baseline change in total bilirubin after obeticholic acid treatment in the combined patients in the ASSERT and ASSERT-EXT studies.

[0068] Figure 33A and 33B are bar graphs showing the percentage of patients with FSV deficiency at baseline and week 24 in ASSERT in patients who received obeticholic acid ( Figure 33A ) and placebo ( Figure 33B ). The total population was evaluated for vitamin D deficiency and any vitamin deficiencies a n = 32. Vitamin deficiency was defined as low vitamin levels based on the lower limit of the normal reference range for vitamin A (0.2 mg / L), vitamin D (25-hydroxyvitamin D; 20 ng / L), and vitamin E (α-tocopherol; 2.0 mg / L) and the upper limit of the normal reference range for vitamin K (INR; 1.1) in the corresponding age groups. FSV, fat-soluble vitamin; INR, international normalized ratio.

[0069] Figure 34A and 34B are, respectively, a graph showing the change in scratch score relative to the baseline in pruritus responders who received obeticholic acid treatment during ASSERT ( Figure 34A ) and a violin plot ( Figure 34B)。The violin plot depicts the numerical distribution and relative density within the range of possible scratching score values; the dotted lines represent the quartiles (quartile 1, quartile 3), and the dash represents the median.

[0070] Figure 35A and 35B are graphs ([[]] Figure 35A Figure 35A ) and violin plots ([[]] Figure 35B Figure 35B ) showing the change in bile acids relative to baseline in pruritus responders who received obeticholic acid during ASSERT. The violin plot depicts the data distribution and relative density within the observed range of bile acid values; the dotted lines represent the quartiles (quartile 1, quartile 3), and the dash represents the median. a The mean values at week 20 and week 24.

[0071] Figure 36 is a box plot showing the change in sleep parameters relative to baseline in pruritus responders who received obeticholic acid during ASSERT. In a box plot, the maximum and minimum values are represented by whiskers, the quartiles (first quartile, third quartile) are represented by the ends of the box, the median is represented by the horizontal line in the box, and the mean is represented by the "+" symbol. This graph depicts the data for each parameter of n = 27 patients.

[0072] Figure 37 is a box plot showing the change in the total PedsQL score and domain scores relative to baseline in pruritus responders who received obeticholic acid. The total PedsQL score and domain scores range from 0 to 100, with higher scores indicating better function. In a box plot, the maximum and minimum values are represented by whiskers, the quartiles (first quartile, third quartile) are represented by the ends of the box, the median is represented by the horizontal line in the box, and the mean is represented by the "+" symbol. This graph depicts the data for each score of n = 23 patients. PedsQL, Pediatric Quality of Life Inventory; QoL, quality of life. DETAILED DESCRIPTION OF THE INVENTION

[0074] Definition

[0075] 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 for this invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not 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) shall prevail.

[0076] As used herein, the terms “treat” or “treatment” 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 appeared. In other embodiments, treatment may be administered in the absence of any symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to prevent or delay their recurrence.

[0077] As used herein, the terms “subject,” “individual,” or “patient,” which are used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0078] As used herein, the term “pediatric subject” refers to a subject who is less than 21 years of age at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age (up to but not including the 22nd birthday)) See, e.g., 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, the pediatric subject is from birth to the first 28 days of life, from 29 days to less than two years of age, from two years to less than 12 years of age, or 12 years to 21 years of age (up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days to less than one year of age, from one month to less than four months of age, from three months to less than seven months of age, from six months to less than one year of age, from one year to less than two years of age, from two years to less than three years of age, from two years to less than seven years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[0079] As used herein, the term "baseline" refers to information obtained before the first administration of a drug or an intervention of interest (e.g., at the start of a study) or an initial known value used for comparison with later data. Baseline values are obtained at "zero" time (i.e., before a subject in a study receives the drug or intervention or placebo of interest).

[0080] As used herein, the term "normalized" refers to specific age values within the range corresponding to healthy individuals (i.e., normal values or normalized values).

[0081] As used herein, the term "pharmaceutically acceptable" refers to those compounds, substances, compositions, and / or dosage forms that are suitable for human pharmaceutical use and are generally safe, non-toxic, and biologically or otherwise not undesirable.

[0082] As used herein, the term "about" refers to embodiments that include (and describe) the value or parameter itself for the value or parameter in question herein. For example, a description involving "about 20" includes a description of "20". A numerical range includes the numerical values that define the range itself. Generally, the term "about" refers to the specified value of a variable and all values of the variable within the experimental error of the specified value (e.g., within the 95% confidence interval of the mean) or within 10% of the specified value, whichever is greater.

[0083] The term "crystal modification" refers to the crystalline solid phase of an organic compound. Crystal modifications can be solvates or non-solvates.

[0084] The term "solvate" refers to the crystalline solid phase of an organic compound that has a solvent (e.g., a solvent molecule) incorporated into its crystal structure. A "hydrate" is a solvate in which the solvent is water.

[0085] The term "sesquihydrate" refers to a hydrate in which each mole of the organic compound contains about 1.5 moles of water associated with the crystal (i.e., 1.5 hydrate). As used herein, sesquihydrates contain about 1.2 to about 1.8, for example, about 1.3 to about 1.7, about 1.4 to about 1.6, or about 1.45 to about 1.55 moles of water associated with each mole of obeticholic acid in the crystal. The amount of water calculated herein does not include water adsorbed to the crystal surface.

[0086] The term "mixed solvate" refers to the crystalline solid phase of an organic compound in which two or more different solvent molecules are incorporated into the crystal structure. At least one of the two or more solvent molecules can be water.

[0087] The term "slurry" refers to a saturated solution to which an excess of solid is added, thereby forming a mixture of the solid and the saturated solution.

[0088] As used herein, the term "void volume" refers to channels, layers or other more or less isolated voids in a crystalline structure.

[0089] The crystallinity of a crystalline sample of obeticholic acid can be measured, for example, via X-ray powder diffraction (XRPD) method or via differential scanning calorimetry (DSC) method, such as the methods disclosed in the experimental section. When referring to a crystalline compound herein, the crystallinity measured via DSC method is greater than about 70%, such as greater than about 80%, specifically greater than about 90%, more specifically greater than about 95%. In some embodiments, the crystallinity measured via DSC method is greater than about 98%. In some embodiments, the crystallinity measured via DSC method is greater than about 99%. % crystallinity refers to the weight percentage of the total sample material that is crystalline.

[0090] Method for treating ALGS

[0091] Alagille syndrome (ALGS) is a rare multisystem disorder with diverse clinical manifestations that can affect the liver, heart, bones, eyes, central nervous system, kidneys and facial features. The disease is an autosomal dominant genetic disorder caused by defects in components of the NOTCH signaling pathway, and the most common cause in about 90% of patients is a mutation in the JAG1 gene. A small number of ALGS patients have mutations in the NOTCH2 receptor gene. Approximately 60% of cases are de novo mutations. Most patients present with jaundice or cardiac symptoms early (usually within 3 months after birth).

[0092] One manifestation of ALGS is pruritus, which occurs in up to 88% of patients and severe pruritus in up to 45% of patients, which usually leads to a significant decline in quality of life. In some cases, ALGS can lead to cirrhosis and liver failure. Current treatment options include partial external biliary diversion (PEBD) and liver transplantation. However, these options may carry a significant risk of postoperative complications as well as psychological and social problems.

[0093] IBAT, also known as apical sodium-dependent bile acid transporter (SLC10A2), is located on the luminal surface of enterocytes in the terminal ileum; this transporter mediates the reabsorption of conjugated bile acids and recirculation back to the liver. Inhibiting IBAT disrupts the enterohepatic circulation, resulting in the excretion of bile acids via feces, similar to surgically interrupting the enterohepatic circulation.

[0094] Odevixibat is an oral, potent, lumen-restricted, selective IBAT inhibitor being developed for the treatment of cholestatic liver diseases. By highly selectively and potently inhibiting IBAT, odevixibat can reduce the systemic bile acid elevation caused by cholestasis and relieve the pruritus symptoms in patients with ALGS. The purpose of using odevixibat is to reduce serum bile acid levels, reduce the major morbidity of pruritus, and improve the health and well-being of patients with ALGS. By reducing the systemic bile acid elevation, odevixibat can also improve the liver function of patients with ALGS and delay the progression of liver injury.

[0095] This article provides methods for treating ALGS in subjects in need thereof, which include orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof. This article also provides methods for treating pruritus associated with ALGS in subjects in need thereof, which include orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, this article provides methods for treating cholestasis associated with ALGS in subjects in need thereof, which include orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof.

[0096] This article also provides a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof for the treatment of ALGS and for the treatment of pruritus associated with ALGS. In some embodiments, this article also provides a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof for the treatment of ALGS and for the treatment of cholestasis associated with ALGS.

[0097] This article also provides the use of a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of ALGS and for the treatment of pruritus associated with ALGS. In some embodiments, this article provides the use of a pharmaceutical preparation comprising odevixibat or a pharmaceutically acceptable salt thereof in the treatment of cholestasis associated with ALGS.

[0098] The odevixibat referred to in this article includes its solvates and hydrates. For example, odevixibat can exist as a hydrate (e.g., sesquihydrate).

[0099] In some embodiments, for patients with ALGS, relieving pruritus is an important treatment goal. However, currently, few instruments can adequately measure the degree of pruritus in patients (such as pediatric patients with ALGS). The pruritus score disclosed in this article (also referred to herein as the "scratch score") can be based on PRUCISION TMPatient-reported outcomes (PRO) and observer-reported outcomes (ObsRO) instruments are used to estimate the threshold for a clinically meaningful change in the pruritus score. These instruments can be used to show the change in the pruritus score relative to baseline and to calculate the percentage of patients who achieve a clinically meaningful response. For a description of the PRUCISION TM instrument, see, for example, Gwaltney et al., Adv. Ther. (2022), 39:5105-5125, which is incorporated herein by reference in its entirety.

[0100] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in the mean monthly pruritus score.

[0101] In some embodiments, the average monthly pruritus score (i.e., scratching score) is reduced by 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 average monthly pruritus score is reduced by 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 average monthly pruritus score is reduced by 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 average monthly pruritus score is reduced by about 2.0. In some embodiments, the average monthly pruritus score is reduced by about 1.6.

[0102] In some embodiments, a reduction in the average monthly pruritus score occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, a reduction in the average monthly pruritus score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, a reduction in the average monthly pruritus score occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, a reduction in the average monthly pruritus score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, a reduction in the average monthly pruritus score occurs 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a reduction in the average monthly pruritus score occurs 4 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 24 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 48 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 72 weeks after administration.

[0105] In some embodiments, about 0.3 to about 2.0 reduction in the average monthly pruritus score occurs 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, about 0.5 to about 1.5 reduction in the average monthly pruritus score occurs 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 0.9 to about 1.3 reduction in the average monthly pruritus score occurs 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, about 1.1 reduction in the average monthly pruritus score occurs 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, about 1.2 to about 2.0 reduction in the average monthly pruritus score occurs 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 1.4 to about 1.8 reduction in the average monthly pruritus score occurs 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, about 1.6 reduction in the average monthly pruritus score occurs 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the average monthly pruritus score normalizes after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the average monthly pruritus score normalizes 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in the pruritus score relative to baseline. In some embodiments, the pruritus score (i.e., the scratching score) decreases by 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 relative to baseline. In some embodiments, the pruritus score decreases by about 0.3 to about 4.0 relative to baseline. 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 pruritus score decreases by about 0.5 to about 2.0 relative to baseline (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 pruritus score decreases by about 2.0 relative to baseline. In some embodiments, the pruritus score decreases by about 1.6 relative to baseline.

[0109] In some embodiments, the subject exhibits a scratching score of 2.5 or higher prior to the first administration of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the subject may 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 obeticholic acid or a pharmaceutically acceptable salt thereof.

[0110] 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 obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the subject may 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 obeticholic acid 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 obeticholic acid or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, a reduction in the itch score relative to baseline occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, a decrease in the pruritus score relative to baseline occurs about 5 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, a decrease in the pruritus score relative to baseline occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, a decrease in the pruritus score relative to baseline occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, a decrease in the pruritus score relative to baseline occurs 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a decrease in the pruritus score relative to baseline occurs 1 week after administration. In some embodiments, a decrease in the pruritus score relative to baseline occurs 4 weeks after administration. In some embodiments, a decrease in the pruritus score relative to baseline occurs 24 weeks after administration. In some embodiments, a decrease in the pruritus score relative to baseline occurs 48 weeks after administration. In some embodiments, a decrease in the pruritus score relative to baseline occurs 72 weeks after administration.

[0114] In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the pruritus score decreases by about 0.3 to about 2.0 relative to baseline. In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the pruritus score decreases by about 0.5 to about 1.5 relative to baseline. For example, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the pruritus score decreases by about 0.9 to about 1.3 relative to baseline. In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the pruritus score decreases by about 1.1 relative to baseline. In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the pruritus score decreases by about 2.0 relative to baseline.

[0115] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the itching score is reduced by about 1.2 to about 2.0 relative to the baseline. For example, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the itching score is reduced by about 1.4 to about 1.8 relative to the baseline. In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the itching score is reduced by about 1.6 relative to the baseline.

[0116] In some embodiments, the reduction in the itching score (i.e., scratching score) relative to the baseline refers to a reduction in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching scores. In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the average morning and afternoon scratching scores relative to the baseline. In some embodiments, the average morning and afternoon scratching scores are the worst scratching scores measured by the ObsRO instrument. In some embodiments, the average morning and afternoon scratching scores are the worst scratching scores measured by the ObsRO morning and afternoon caregiver-reported instrument.

[0117] In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by 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 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 0.3 to about 4.0 relative to the baseline. 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 average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by 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 average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 1.1 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 1.6 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 2.0 relative to the baseline.

[0118] In some embodiments, a reduction in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 1 week to about 72 weeks after administration of obeticholic acid 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 1 week to about 72 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs at least 1 week, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs at least 1 week, 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits a decrease in the average serum bile acid concentration.

[0121] In some embodiments, the reduction in average serum bile acid concentration from baseline is at least 25 μmol / L, at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L, at least 175 μmol / L, at least 200 μmol / L, at least 300 μmol / L, at least 400 μmol / L, at least 500 μmol / L, or at least 600 μmol / L relative to baseline. For example, the average serum bile acid concentration is reduced by about 25 μmol / L to about 200 μmol / L relative to baseline (e.g., about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 75 μmol / L; about 25 μmol / L to about 100 μmol / L; about 25 μmol / L to about 125 μmol / L; about 25 μmol / L to about 150 μmol / L; about 25 μmol / L to about 175 μmol / L; about 25 μmol / L to about 75 μmol / L). In some embodiments, the average serum bile acid concentration is reduced by about 50 μmol / L to about 180 μmol / L relative to baseline (e.g., about 50 μmol / L to about 100 μmol / L; about 50 μmol / L to about 120 μmol / L; about 50 μmol / L to about 150 μmol / L; about 65 μmol / L to about 120 μmol / L; about 50 μmol / L to about 90 μmol / L; about 65 μmol / L to about 85 μmol / L; about 100 μmol / L to about 130 μmol / L; about 100 μmol / L to about 180 μmol / L; or about 150 μmol / L to about 180 μmol / L).In some embodiments, the average serum bile acid concentration is reduced by about 50 μmol / L to about 600 μmol / L, about 100 μmol / L to about 600 μmol / L, about 150 μmol / L to about 600 μmol / L, about 200 μmol / L to about 600 μmol / L, about 250 μmol / L to about 600 μmol / L, about 300 μmol / L to about 600 μmol / L, about 350 μmol / L to about 600 μmol / L, about 400 μmol / L to about 600 μmol / L, about 450 μmol / L to about 600 μmol / L, about 500 μmol / L to about 600 μmol / L, about 550 μmol / L to about 600 μmol / L, about 50 μmol / L to about 500 μmol / L, about 100 μmol / L to about 500 μmol / L, about 150 μmol / L to about 500 μmol / L, about 200 μmol / L to about 500 μmol / L, about 250 μmol / L to about 500 μmol / L, about 300 μmol / L to about 500 μmol / L, about 350 μmol / L to about 500 μmol / L, about 400 μmol / L to about 500 μmol / L, about 450 μmol / L to about 500 μmol / L, about 50 μmol / L to about 400 μmol / L, about 100 μmol / L to about 400 μmol / L, about 150 μmol / L to about 400 μmol / L, about 200 μmol / L to about 400 μmol / L, about 250 μmol / L to about 400 μmol / L, about 300 μmol / L to about 400 μmol / L, about 350 μmol / L to about 400 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 200 μmol / L, about 100 μmol / L to about 200 μmol / L, or about 150 μmol / L to about 200 μmol / L relative to the baseline.In some embodiments, the average serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline. In some embodiments, the average serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L.

[0122] In some embodiments, a decrease in the average serum bile acid concentration occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, a decrease in the average serum bile acid concentration occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, a decrease in the average serum bile acid concentration occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, a decrease in the average serum bile acid concentration occurs at least 1 week, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 96 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a decrease in the average serum bile acid concentration occurs 4 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 12 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 24 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 48 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 72 weeks after administration.

[0125] In some embodiments, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 50 μmol / L to about 90 μmol / L. For example, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 65 μmol / L to about 85 μmol / L. In some embodiments, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 70 μmol / L (e.g., about 73 μmol / L).

[0126] In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 100 μmol / L to about 130 μmol / L. For example, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 110 μmol / L to about 120 μmol / L. In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average serum bile acid concentration decreases by about 115 μmol / L.

[0127] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the average serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the average serum bile acid concentration is reduced by about 155 μmol / L to about 170 μmol / L. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the average serum bile acid concentration is reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0128] In some embodiments, the subject exhibits a decrease in bile acid concentration relative to baseline. In some embodiments, the bile acid concentration is decreased by at least 25 μmol / L, at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L, at least 175 μmol / L, at least 200 μmol / L, at least 300 μmol / L, at least 400 μmol / L, at least 500 μmol / L, or at least 600 μmol / L relative to baseline. For example, the average bile acid concentration is decreased by about 25 μmol / L to about 200 μmol / L relative to baseline (e.g., about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 75 μmol / L; about 25 μmol / L to about 100 μmol / L; about 25 μmol / L to about 125 μmol / L; about 25 μmol / L to about 150 μmol / L; about 25 μmol / L to about 175 μmol / L; about 25 μmol / L to about 75 μmol / L). In some embodiments, the bile acid concentration is decreased by about 50 μmol / L to about 180 μmol / L relative to baseline (e.g., about 50 μmol / L to about 100 μmol / L; about 50 μmol / L to about 120 μmol / L; about 50 μmol / L to about 150 μmol / L; about 65 μmol / L to about 120 μmol / L; about 50 μmol / L to about 90 μmol / L; about 65 μmol / L to about 85 μmol / L; about 100 μmol / L to about 130 μmol / L; about 100 μmol / L to about 180 μmol / L; or about 150 μmol / L to about 180 μmol / L).In some embodiments, the bile acid concentration is reduced by about 50 μmol / L to about 600 μmol / L, about 100 μmol / L to about 600 μmol / L, about 150 μmol / L to about 600 μmol / L, about 200 μmol / L to about 600 μmol / L, about 250 μmol / L to about 600 μmol / L, about 300 μmol / L to about 600 μmol / L, about 350 μmol / L to about 600 μmol / L, about 400 μmol / L to about 600 μmol / L, about 450 μmol / L to about 600 μmol / L, about 500 μmol / L to about 600 μmol / L, about 550 μmol / L to about 600 μmol / L, about 50 μmol / L to about 500 μmol / L, about 100 μmol / L to about 500 μmol / L, about 150 μmol / L to about 500 μmol / L, about 200 μmol / L to about 500 μmol / L, about 250 μmol / L to about 500 μmol / L, about 300 μmol / L to about 500 μmol / L, about 350 μmol / L to about 500 μmol / L, about 400 μmol / L to about 500 μmol / L, about 450 μmol / L to about 500 μmol / L, about 50 μmol / L to about 400 μmol / L, about 100 μmol / L to about 400 μmol / L, about 150 μmol / L to about 400 μmol / L, about 200 μmol / L to about 400 μmol / L, about 250 μmol / L to about 400 μmol / L, about 300 μmol / L to about 400 μmol / L, about 350 μmol / L to about 400 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 200 μmol / L, about 100 μmol / L to about 200 μmol / L, or about 150 μmol / L to about 200 μmol / L relative to the baseline.In some embodiments, the bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline. In some embodiments, the bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L.

[0129] In some embodiments, the reduction in bile acid concentration occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, the reduction in bile acid concentration occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the subject exhibits a decrease in serum bile acid concentration relative to baseline. For example, the serum bile acid concentration decreases by at least 25 μmol / L, at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L, at least 175 μmol / L, at least 200 μmol / L, at least 300 μmol / L, at least 400 μmol / L, at least 500 μmol / L, or at least 600 μmol / L relative to baseline. For example, the average serum bile acid concentration decreases by about 25 μmol / L to about 200 μmol / L relative to baseline (e.g., about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 75 μmol / L; about 25 μmol / L to about 100 μmol / L; about 25 μmol / L to about 125 μmol / L; about 25 μmol / L to about 150 μmol / L; about 25 μmol / L to about 175 μmol / L; about 25 μmol / L to about 75 μmol / L). In some embodiments, the serum bile acid concentration decreases by about 50 μmol / L to about 180 μmol / L relative to baseline (e.g., about 50 μmol / L to about 100 μmol / L; about 50 μmol / L to about 120 μmol / L; about 50 μmol / L to about 150 μmol / L; about 65 μmol / L to about 120 μmol / L; about 50 μmol / L to about 90 μmol / L; about 65 μmol / L to about 85 μmol / L; about 100 μmol / L to about 130 μmol / L; about 100 μmol / L to about 180 μmol / L; or about 150 μmol / L to about 180 μmol / L).In some embodiments, the serum bile acid concentration is reduced by about 50 μmol / L to about 600 μmol / L, about 100 μmol / L to about 600 μmol / L, about 150 μmol / L to about 600 μmol / L, about 200 μmol / L to about 600 μmol / L, about 250 μmol / L to about 600 μmol / L, about 300 μmol / L to about 600 μmol / L, about 350 μmol / L to about 600 μmol / L, about 400 μmol / L to about 600 μmol / L, about 450 μmol / L to about 600 μmol / L, about 500 μmol / L to about 600 μmol / L, about 550 μmol / L to about 600 μmol / L, about 50 μmol / L to about 500 μmol / L, about 100 μmol / L to about 500 μmol / L, about 150 μmol / L to about 500 μmol / L, about 200 μmol / L to about 500 μmol / L, about 250 μmol / L to about 500 μmol / L, about 300 μmol / L to about 500 μmol / L, about 350 μmol / L to about 500 μmol / L, about 400 μmol / L to about 500 μmol / L, about 450 μmol / L to about 500 μmol / L, about 50 μmol / L to about 400 μmol / L, about 100 μmol / L to about 400 μmol / L, about 150 μmol / L to about 400 μmol / L, about 200 μmol / L to about 400 μmol / L, about 250 μmol / L to about 400 μmol / L, about 300 μmol / L to about 400 μmol / L, about 350 μmol / L to about 400 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 200 μmol / L, about 100 μmol / L to about 200 μmol / L, or about 150 μmol / L to about 200 μmol / L.In some embodiments, the serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline. In some embodiments, the serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L.

[0131] In some embodiments, a decrease in serum bile acid concentration occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, a reduction in serum bile acid concentration occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, a reduction in serum bile acid concentration occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, a reduction in serum bile acid concentration occurs at least 1 week, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 54 weeks, at least 60 weeks, at least 66 weeks, at least 72 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a reduction in serum bile acid concentration occurs 4 weeks after administration. In some embodiments, a reduction in serum bile acid concentration occurs 12 weeks after administration. In some embodiments, a reduction in serum bile acid concentration occurs 24 weeks after administration. In some embodiments, a reduction in serum bile acid concentration occurs 48 weeks after administration. In some embodiments, a reduction in serum bile acid concentration occurs 72 weeks after administration.

[0134] In some embodiments, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 50 μmol / L to about 90 μmol / L. For example, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 65 μmol / L to about 85 μmol / L. In some embodiments, about 12 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 70 μmol / L (e.g., about 73 μmol / L).

[0135] In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 100 μmol / L to about 130 μmol / L. For example, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 110 μmol / L to about 120 μmol / L. In some embodiments, about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration decreases by about 115 μmol / L.

[0136] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the serum bile acid concentration decreases by about 150 μmol / L to about 180 μmol / L. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the serum bile acid concentration decreases by about 155 μmol / L to about 170 μmol / L. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the serum bile acid concentration decreases by about 165 μmol / L (e.g., about 166 μmol / L).

[0137] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks, the subject exhibits a serum bile acid concentration below 70 μmol / L (e.g., below 60 μmol / L; below 50 μmol / L, etc.).

[0138] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks, the subject exhibits a decrease in serum bile acid concentration of at least 50% relative to baseline (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; at least 95%). In some embodiments, the subject exhibits a decrease in serum bile acid concentration of at least 60%, at least 70% or at least 80% relative to baseline.

[0139] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum bile acid concentration returns to normal. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the serum bile acid concentration returns to normal.

[0140] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, growth is improved relative to placebo. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in mean height Z-score relative to baseline.

[0141] In some embodiments, the mean height Z-score increases by at least 0.1, at least 0.2, at least 0.5, at least 0.75, at least 1, at least 1.25 or at least 1.5 relative to baseline. For example, the mean height Z-score increases by about 0.5 to about 2.0 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the mean height Z-score increases by about 1.1.

[0142] In some embodiments, an increase in mean height Z-score occurs about 20 to about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 20 to about 24 weeks, about 20 to about 28 weeks, about 20 to about 36 weeks, about 20 to about 40 weeks, about 20 to about 48 weeks, about 20 to about 52 weeks, about 20 to about 60 weeks, about 20 to about 72 weeks, about 24 to about 28 weeks, about 24 to about 36 weeks, about 24 to about 40 weeks, about 24 to about 48 weeks, about 24 to about 52 weeks, about 24 to about 60 weeks, about 24 to about 72 weeks, about 28 to about 36 weeks, about 28 to about 40 weeks, about 28 to about 48 weeks, about 28 to about 52 weeks, about 28 to about 60 weeks, about 28 to about 72 weeks, about 36 to about 40 weeks, about 36 to about 48 weeks, about 36 to about 52 weeks, about 36 to about 60 weeks, about 36 to about 72 weeks, about 40 to about 44 weeks, about 40 to about 48 weeks, about 40 to about 52 weeks, about 40 to about 60 weeks, about 40 to about 72 weeks, about 44 to about 48 weeks, about 44 to about 52 weeks, about 44 to about 60 weeks, about 44 to about 72 weeks, about 48 to about 52 weeks, about 48 to about 60 weeks, about 48 to about 72 weeks, about 52 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in mean height Z-score occurs about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, an increase in mean height Z-score occurs about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, an increase in mean height Z-score occurs at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48, etc. weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in mean height Z-score occurs 24 weeks after administration. In some embodiments, an increase in mean height Z-score occurs 48 weeks after administration. In some embodiments, an increase in mean height Z-score occurs 72 weeks after administration.

[0145] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the mean height Z-score increases by about 0.9 to about 1.3. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the mean height Z-score increases by about 1.0 to about 1.2. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the mean height Z-score increases by about 1.1.

[0146] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in mean weight Z-score.

[0147] In some embodiments, the mean weight Z-score increases by at least 0.2, at least 0.4, at least 0.6, at least 0.8, at least 1, at least 1.2, or at least 1.4. For example, the mean weight Z-score increases by about 0.2 to about 1.5 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the mean weight Z-score increases by about 1.1.

[0148] In some embodiments, an increase in mean weight Z-score occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, an increase in the average weight Z-score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, an increase in the average weight Z-score occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, an increase in the average weight Z-score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, an increase in the average weight Z-score occurs 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in the average weight Z-score occurs 12 weeks after administration. In some embodiments, an increase in the average weight Z-score occurs 24 weeks after administration. In some embodiments, an increase in the average weight Z-score occurs 48 weeks after administration. In some embodiments, an increase in the average weight Z-score occurs 72 weeks after administration.

[0151] In some embodiments, about 0.9 to about 1.3 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average weight Z-score increases. In some embodiments, about 1.0 to about 1.2 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average weight Z-score increases. In some embodiments, about 1.1 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the average weight Z-score increases.

[0152] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in the height Z-score relative to baseline. In some embodiments, the height Z-score increases by at least 0.1, at least 0.2, at least 0.5, at least 0.75, at least 1, at least 1.25, or at least 1.5 relative to baseline. For example, the height Z-score increases by about 0.5 to about 2.0 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the height Z-score increases by about 1.1.

[0153] In some embodiments, an increase in height Z-score occurs about 20 to about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 20 to about 24 weeks, about 20 to about 28 weeks, about 20 to about 36 weeks, about 20 to about 40 weeks, about 20 to about 48 weeks, about 20 to about 52 weeks, about 20 to about 60 weeks, about 20 to about 72 weeks, about 24 to about 28 weeks, about 24 to about 36 weeks, about 24 to about 40 weeks, about 24 to about 48 weeks, about 24 to about 52 weeks, about 24 to about 60 weeks, about 24 to about 72 weeks, about 28 to about 36 weeks, about 28 to about 40 weeks, about 28 to about 48 weeks, about 28 to about 52 weeks, about 28 to about 60 weeks, about 28 to about 72 weeks, about 36 to about 40 weeks, about 36 to about 48 weeks, about 36 to about 52 weeks, about 36 to about 60 weeks, about 36 to about 72 weeks, about 40 to about 44 weeks, about 40 to about 48 weeks, about 40 to about 52 weeks, about 40 to about 60 weeks, about 40 to about 72 weeks, about 44 to about 48 weeks, about 44 to about 52 weeks, about 44 to about 60 weeks, about 44 to about 72 weeks, about 48 to about 52 weeks, about 48 to about 60 weeks, about 48 to about 72 weeks, about 52 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in height Z-score occurs about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, an increase in height Z-score occurs about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, an increase in height Z-score occurs at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48, etc. weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in height Z-score occurs 24 weeks after administration. In some embodiments, an increase in height Z-score occurs 48 weeks after administration. In some embodiments, an increase in height Z-score occurs 72 weeks after administration.

[0156] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the height Z-score increases by about 0.9 to about 1.3. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the height Z-score increases by about 1.0 to about 1.2. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the height Z-score increases by about 1.1.

[0157] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in weight Z-score.

[0158] In some embodiments, the weight Z-score increases by at least 0.2, at least 0.4, at least 0.6, at least 0.8, at least 1, at least 1.2, or at least 1.4. For example, the weight Z-score increases by about 0.2 to about 1.5 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the weight Z-score increases by about 1.1.

[0159] In some embodiments, an increase in weight Z-score occurs about 1 week to about 72 weeks after administration of obeticholic acid 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.In some embodiments, an increase in weight Z-score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, an increase in weight Z-score occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, an increase in weight Z-score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, an increase in weight Z-score occurs 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an increase in weight Z-score occurs 12 weeks after administration. In some embodiments, an increase in weight Z-score occurs 24 weeks after administration. In some embodiments, an increase in weight Z-score occurs 48 weeks after administration. In some embodiments, an increase in weight Z-score occurs 72 weeks after administration.

[0162] In some embodiments, about 0.9 to about 1.3 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the weight Z-score increases. In some embodiments, about 1.0 to about 1.2 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the weight Z-score increases. In some embodiments, about 1.1 weeks after 48 weeks of administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the weight Z-score increases.

[0163] In some embodiments, the subject shows improvement in sleep parameters after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. Improvement in sleep parameters can include: for example, a decrease in the degree of fatigue, a decrease in the percentage of days with bleeding-related scratching, need for help falling asleep, need for soothing, sleeping with the caregiver or taking hypnotic drugs reported by the caregiver, a decrease in the percentage of days with daytime fatigue reported by the caregiver, and a decrease in the number of awakenings per night reported by the caregiver. As described in the examples, at week 24, most sleep parameters of the patient have been significantly improved since starting to take obeticholic acid.

[0164] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days of bleeding-related scratching reported by caregivers is on average reduced by about 14% to about 45% (e.g., on average reduced by about 15%, about 20%, about 25%, about 30%, about 35%, or about 45%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days of bleeding-related scratching reported by caregivers is on average reduced by about 14% to about 45%.

[0165] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days of needing help to fall asleep reported by caregivers is on average reduced by about 20% to about 75% (e.g., on average reduced by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days of needing help to fall asleep reported by caregivers is on average reduced by about 20% to about 75%.

[0166] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days of needing to be soothed reported by caregivers is on average reduced by about 20% to about 75% (e.g., on average reduced by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days of needing to be soothed reported by caregivers is on average reduced by about 20% to about 75%.

[0167] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days that the caregiver reports needing to sleep with the caregiver decreases on average by about 20% to about 75% (e.g., on average by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports needing to sleep with the caregiver decreases on average by about 20% to about 75%.

[0168] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days that the caregiver reports taking hypnotic drugs decreases on average by about 0.5% to about 10% (e.g., on average by about 1%, about 2%, about 2.5%, about 3%, about 5%, or about 7.5%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases on average by about 0.5% to about 10%. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases on average by about 1% to about 5%.

[0169] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the average number of days of daytime fatigue reported by the caregiver decreases by about 0.1 to about 5 (e.g., on average by about 0.1, about 0.5, about 1, about 1.5, about 2, or about 3.5). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases on average by about 0.1 to about 5. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases on average by about 0.5 to about 1.5.

[0170] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the average number of awakenings per night reported by the caregiver is reduced by about 0.1 to about 7.5 (e.g., an average reduction of about 0.5, about 1, about 2, about 2.5, about 3, or about 5). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days on which a hypnotic drug is taken, as reported by the caregiver, is reduced by about 0.1 to about 7.5. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days on which a hypnotic drug is taken, as reported by the caregiver, is reduced by about 1 to about 5.

[0171] In some embodiments, the degree of fatigue is reduced by 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 relative to the baseline. In some embodiments, the degree of fatigue is reduced by about 0.3 to about 4.0 relative to the baseline. 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 the degree of fatigue is measured according to a PRO instrument and / or an ObsRO instrument.

[0172] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days with bleeding-related scratching reported by the caregiver decreases by about 14% to about 45% (e.g., by about 15%, about 20%, about 25%, about 30%, about 35%, or about 45%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days with bleeding-related scratching reported by the caregiver decreases by about 14% to about 45%.

[0173] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days with difficulty falling asleep reported by the caregiver decreases by about 20% to about 75% (e.g., by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days with difficulty falling asleep reported by the caregiver decreases by about 20% to about 75%.

[0174] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days with need for soothing reported by the caregiver decreases by about 20% to about 75% (e.g., by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days with need for soothing reported by the caregiver decreases by about 20% to about 75%.

[0175] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days that the caregiver reports the need to sleep with the caregiver decreases by about 20% to about 75% (e.g., decreases by about 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports the need to sleep with the caregiver decreases by about 20% to about 75%.

[0176] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the percentage of days that the caregiver reports taking hypnotic drugs decreases by about 0.5% to about 10% (e.g., decreases by about 1%, about 2%, about 2.5%, about 3%, about 5%, or about 7.5%). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases by about 0.5% to about 10%. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases by about 1% to about 5%.

[0177] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the daytime fatigue score reported by the caregiver decreases by about 0.1 to about 5 (e.g., decreases by about 0.1, about 0.5, about 1, about 1.5, about 2, or about 3.5).

[0178] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases by about 0.1 to about 5. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days that the caregiver reports taking hypnotic drugs decreases by about 0.5 to about 1.5.

[0179] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the number of awakenings per night reported by the caregiver is reduced by about 0.1 to about 7.5 (e.g., reduced by about 0.5, about 1, about 2, about 2.5, about 3, or about 5). In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days on which the caregiver reports taking hypnotic medications is reduced by about 0.1 to about 7.5. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the percentage of days on which the caregiver reports taking hypnotic medications is reduced by about 1 to about 5.

[0180] In some embodiments, the subject shows improvement in liver parameters or liver biomarkers after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. Non-limiting examples of biomarkers indicative of one or more of liver injury, liver inflammation, liver fibrosis, and / or cirrhosis include alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, alkaline phosphatase (ALP) level, gamma-glutamyl transferase (GGT) level, total and direct bilirubin levels, autotaxin level, prothrombin time (PT), international normalized ratio (INR), and total protein and albumin (see, e.g., Lala et al., “Liver Function Tests.” StatPearls, StatPearls Publishing, October 5, 2022 (PMID: 29494096).

[0181] For example, in some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the levels of autotaxin and / or plasma 7α-hydroxy-4-cholesten-3-one (p-C4) (a marker of bile acid synthesis), which are related to the intensity of cholestatic pruritus, are improved.

[0182] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the autocrine motility factor level is decreased. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the autocrine motility factor level may be decreased by about 10 to about 1000 ng / mL relative to baseline.For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the autocrine motility factor level may decrease by about 10 to about 100 ng / mL, about 10 to about 200 ng / mL, about 10 to about 300 ng / mL, about 10 to about 400 ng / mL, about 10 to about 500 ng / mL, about 10 to about 600 ng / mL, about 10 to about 700 ng / mL, about 10 to about 800 ng / mL, about 10 to about 900 ng / mL, about 100 to about 200 ng / mL, about 100 to about 300 ng / mL, about 100 to about 400 ng / mL, about 100 to about 500 ng / mL, about 100 to about 600 ng / mL, about 100 to about 700 ng / mL, about 100 to about 800 ng / mL, about 100 to about 900 ng / mL, about 100 to about 1000 ng / mL, about 200 to about 300 ng / mL, about 200 to about 400 ng / mL, about 200 to about 500 ng / mL, about 200 to about 600 ng / mL, about 200 to about 700 ng / mL, about 200 to about 800 ng / mL, about 200 to about 900 ng / mL, about 200 to about 1000 ng / mL, about 300 to about 400 ng / mL, about 300 to about 500 ng / mL, about 300 to about 600 ng / mL, about 300 to about 700 ng / mL, about 300 to about 800 ng / mL, about 300 to about 900 ng / mL, about 300 to about 1000 ng / mL, about 400 to about 500 ng / mL, about 400 to about 600 ng / mL, about 400 to about 700 ng / mL, about 400 to about 800 ng / mL, about 400 to about 900 ng / mL, about 400 to about 1000 ng / mL, about 500 to about 600 ng / mL, about 500 to about 700 ng / mL, about 500 to about 800 ng / mL, about 500 to about 900 ng / mL, about 500 to about 1000 ng / mL, about 600 to about 700 ng / mL, about 600 to about 800 ng / mL, about 600 to about 900 ng / mL, about 600 to about 1000 ng / mL, about 700 to about 800 ng / mL, about 700 to about 900 ng / mL, about 700 to about 1000 ng / mL, about 800 to about 900 ng / mL, about 800 to about 1000 ng / mL, or about 900 to about 1000 ng / mL relative to the baseline.

[0183] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the autocrine motility factor level can be reduced by about 500 to about 1000 ng / mL, about 750 to about 1500 ng / mL, about 1000 to about 2000 ng / mL, or about 1500 to about 2500 ng / mL relative to the baseline. For example, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks, the autocrine motility factor level can be reduced by about 50%.

[0184] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof, the plasma C4 level increases. In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof, the plasma C4 level (ng / mL) can increase by about 1 to about 30 ng / mL relative to the baseline. For example, after administering obeticholic acid or a pharmaceutically acceptable salt thereof, it increases by about 1 to about 5 ng / mL, about 1 to about 10 ng / mL, about 1 to about 15 ng / mL, about 1 to about 20 ng / mL, about 1 to about 25 ng / mL, about 5 to about 10 ng / mL, about 5 to about 15 ng / mL, about 5 to about 20 ng / mL, about 5 to about 25 ng / mL, about 5 to about 30 ng / mL, about 10 to about 15 ng / mL, about 10 to about 20 ng / mL, about 10 to about 25 ng / mL, about 10 to about 30 ng / mL, about 15 to about 20 ng / mL, about 15 to about 25 ng / mL, about 15 to about 30 ng / mL, about 20 to about 25 ng / mL, about 20 to about 30 ng / mL, or about 25 to about 30 ng / mL relative to the baseline.

[0185] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the plasma C4 level (ng / mL) can increase by 7.5 to 15 ng / mL, 10 to 20 ng / mL, 15 to 25 ng / mL, 20 to 30 ng / mL, or 25 to 35 ng / mL relative to the baseline.

[0186] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum alanine aminotransferase (ALT) level is improved. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the ALT level is decreased. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the ALT level is decreased by about 10 U / L to about 125 U / L relative to the baseline. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the ALT level is decreased by about 10 U / L to about 25 U / L, about 10 U / L to about 50 U / L, about 10 U / L to about 75 U / L, about 25 U / L to about 50 U / L, about 25 U / L to about 75 U / L, about 25 U / L to about 100 U / L, about 50 U / L to about 75 U / L, about 50 U / L to about 100 U / L, or about 75 U / L to about 100 U / L relative to the baseline.

[0187] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the ALT level is decreased by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L or about 100 U / L to about 150 U / L relative to the baseline. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 21 - 24 weeks, the ALT level can be decreased by about 70%.

[0188] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the total bilirubin level is reduced. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the total bilirubin level is reduced by about 0.5 mg / dL to about 5.5 mg / dL, about 1 mg / dL to about 5.5 mg / dL, about 1.5 mg / dL to about 5.5 mg / dL, about 2 mg / dL to about 5.5 mg / dL, about 2.5 mg / dL to about 5.5 mg / dL, about 3 mg / dL to about 5.5 mg / dL, about 3.5 mg / dL to about 5.5 mg / dL, about 4 mg / dL to about 5.5 mg / dL, about 4.5 mg / dL to about 5.5 mg / dL, about 5 mg / dL to about 5.5 mg / dL, about 1 mg / dL to about 5 mg / dL, about 1.5 mg / dL to about 5 mg / dL, about 2 mg / dL to about 5 mg / dL, about 2.5 mg / dL to about 5 mg / dL, about 3 mg / dL to about 5 mg / dL, about 3.5 mg / dL to about 5 mg / dL, about 4 mg / dL to about 5 mg / dL, about 4.5 mg / dL to about 5 mg / dL, about 1 mg / dL to about 4.5 mg / dL, about 1.5 mg / dL to about 4.5 mg / dL, about 2 mg / dL to about 4.5 mg / dL, about 2.5 mg / dL to about 4.5 mg / dL, about 3 mg / dL to about 4.5 mg / dL, about 3.5 mg / dL to about 4.5 mg / dL, about 4 mg / dL to about 4.5 mg / dL, about 1 mg / dL to about 4 mg / dL, about 1.5 mg / dL to about 4 mg / dL, about 2 mg / dL to about 4 mg / dL, about 2.5 mg / dL to about 4 mg / dL, about 3 mg / dL to about 4 mg / dL, about 3.5 mg / dL to about 4 mg / dL, about 1 mg / dL to about 3.5 mg / dL, about 1.5 mg / dL to about 3.5 mg / dL, about 2 mg / dL to about 3.5 mg / dL, about 2.5 mg / dL to about 3.5 mg / dL, about 3 mg / dL to about 3.5 mg / dL, about 1 mg / dL to about 3 mg / dL, about 1.5 mg / dL to about 3 mg / dL, about 2 mg / dL to about 3 mg / dL, about 2.5 mg / dL to about 3 mg / dL, about 1 mg / dL to about 2.5 mg / dL, about 1.5 mg / dL to about 2.5 mg / dL, from about 2 mg / dL to about 2.5 mg / dL, from about 1 mg / dL to about 2 mg / dL, from about 1.5 mg / dL to about 2 mg / dL, or from about 1 mg / dL to about 1.5 mg / dL. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks, total bilirubin can be reduced by at least 70% (e.g., about 99%).

[0189] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc., the total bilirubin level is reduced by about 0.5 mg / dL to about 3.5 mg / dL, about 1 mg / dL to about 3.5 mg / dL, about 1 mg / dL to about 3 mg / dL, or about 1.5 mg / dL to about 3.1 mg / dL relative to the baseline. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks, total bilirubin can be reduced by at least 70% (e.g., about 99%).

[0190] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the serum aspartate aminotransferase (AST) level is improved.

[0191] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the clinician xanthoma score. The clinician xanthoma score ranges from 0 to 4, with a higher score (e.g., 4 or 3) indicating more lesions and greater interference with activities, and a lower score indicating no lesions or fewer lesions and no or less interference with activities.

[0192] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the clinician xanthoma score is reduced by at least 0.2, 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 2.2, at least 2.4, at least 2.6, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or at least 4.0 relative to baseline. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the clinician xanthoma score is reduced by about 0.3 to about 4.0 relative to baseline. For example, the reduction is about 0.3 to about 1.0, about 0.3 to about 2.0, about 0.3 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 3.0, about 1.0 to about 4.0, about 2.0 to about 3.0, about 2.0 to about 4.0, or about 3.0 to about 4.0 relative to baseline. In some embodiments, the clinician xanthoma score is reduced by about 0.3 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.5 to about 1; or about 0.5 to about 0.8). In some embodiments, the clinician xanthoma score is reduced by about 0.5. In some embodiments, the clinician xanthoma score is reduced by about 0.6.

[0193] In some embodiments, the reduction in the clinician xanthoma score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the reduction in the clinician xanthoma score can occur 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in the clinician xanthoma score occurs 4 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score occurs 24 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score occurs 48 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score occurs 72 weeks after administration.

[0194] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.4 to about 1. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.5 to about 0.8. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.6.

[0195] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the clinician xanthoma score is reduced by about 0.5 to about 2.0. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the clinician xanthoma score is reduced by about 0.8 to about 1.5.

[0196] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the clinician xanthoma score relative to baseline. In some embodiments, the clinician xanthoma score is reduced by at least 0.2, 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, or at least 2.0 relative to baseline. For example, the clinician xanthoma score is reduced by about 0.3 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.5 to about 1; or about 0.5 to about 0.8) relative to baseline. In some embodiments, the clinician xanthoma score is reduced by about 0.5 relative to baseline. In some embodiments, the clinician xanthoma score is reduced by about 0.6.

[0197] In some embodiments, the reduction in the clinician xanthoma score relative to baseline occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 72 weeks, at least 96 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the reduction in the clinician xanthoma score relative to baseline can occur 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in the clinician xanthoma score relative to baseline occurs 4 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score relative to baseline occurs 24 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score relative to baseline occurs 48 weeks after administration. In some embodiments, the reduction in the clinician xanthoma score relative to baseline occurs 72 weeks after administration.

[0198] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.4 to about 1 relative to baseline. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.5 to about 0.8 relative to baseline. In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 24 weeks, the clinician xanthoma score is reduced by about 0.6 relative to baseline.

[0199] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the clinician xanthoma score is reduced by about 0.5 to about 2.0 relative to baseline. For example, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the clinician xanthoma score is reduced by about 0.8 to about 1.5 relative to baseline.

[0200] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in serum cholesterol level (mmol / L).

[0201] In some embodiments, the cholesterol level is reduced by at least 0.2, 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 or at least 2.2 mmol / L. For example, the cholesterol level is reduced by about 0.2 to about 2.5 mmol / L (e.g., about 0.2 to about 2.0; about 0.2 to about 1.5; about 0.2 to about 1.2; about 0.2 to about 1.0; about 0.2 to about 0.8; about 0.2 to about 0.5; 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 1.2; about 0.5 to about 1.0; about 0.5 to about 0.8; about 1.0 to about 2.5; about 1.0 to about 2.0; about 1.0 to about 1.5; about 1.0 to about 1.2; about 1.2 to about 2.5; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.5 to about 2.5; about 1.5 to about 2.0; or about 2.0 to about 2.5 mmol / L). In some embodiments, the cholesterol level is reduced by about 0.5 mmol / L. In some embodiments, the cholesterol level is reduced by about 0.6 mmol / L.

[0202] In some embodiments, a reduction in cholesterol levels occurs about 1 week to about 72 weeks after administration of obeticholic acid 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 after administration.In some embodiments, the reduction in cholesterol level occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the reduction in cholesterol level occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the reduction in cholesterol level occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the reduction in cholesterol level can occur 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in cholesterol level occurs 4 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 24 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 48 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 72 weeks after administration.

[0205] In some embodiments, about 0.4 to about 1 mmol / L of cholesterol level is reduced 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 0.5 to about 0.8 mmol / L of cholesterol level is reduced 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, about 0.6 mmol / L of cholesterol level is reduced 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, about 0.5 to about 2.0 mmol / L of cholesterol level is reduced 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, about 0.8 to about 1.5 mmol / L of cholesterol level is reduced 48 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in cholesterol level relative to baseline. In some embodiments, the cholesterol level is decreased by at least 0.2, 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, or at least 2.0 mmol / L relative to baseline. For example, the cholesterol level is decreased by about 0.3 to about 2.0 mmol / L (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.5 to about 1; or about 0.5 to about 0.8 mmol / L) relative to baseline. In some embodiments, the cholesterol level is decreased by about 0.5 mmol / L relative to baseline. In some embodiments, the cholesterol level is decreased by about 0.6 mmol / L.

[0208] In some embodiments, the decrease in cholesterol level relative to baseline occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. For example, the decrease in cholesterol level relative to baseline can occur 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 after administration of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in cholesterol level relative to baseline occurs 4 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 24 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 48 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 72 weeks after administration.

[0209] In some embodiments, 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the cholesterol level is decreased by about 0.4 mmol / L to about 1 mmol / L relative to baseline. For example, 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the cholesterol level is decreased by about 0.5 mmol / L to about 0.8 mmol / L relative to baseline. In some embodiments, 24 weeks after administration of obeticholic acid or a pharmaceutically acceptable salt thereof, the cholesterol level is decreased by about 0.6 mmol / L relative to baseline.

[0210] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the cholesterol level is reduced by about 0.5 to about 2.0 mmol / L relative to the baseline. For example, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 48 weeks, the cholesterol level is reduced by about 0.8 to about 1.5 mmol / L relative to the baseline.

[0211] 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.

[0212] In some embodiments, after administering obeticholic acid or a pharmaceutically acceptable salt thereof to the subject, the scratching score is reduced by one or more points relative to the baseline.

[0213] In some embodiments, the subject is a pruritus responder. For example, after administering obeticholic acid or a pharmaceutically acceptable salt thereof to the subject, the scratching score is reduced by one or more points relative to the baseline. In some embodiments, in pruritus responders, after administering obeticholic acid or a pharmaceutically acceptable salt thereof for 21 to 24 weeks (e.g., 21, 22, 23, and / or 24 weeks), the scratching score is reduced by one or more points relative to the baseline. In some embodiments, in pruritus responders, the average scratching score at 20 - 24 weeks after administering obeticholic acid is reduced by one or more points relative to the baseline. In some embodiments, the scratching score is measured using PRUCISION TMObsRO instrument measurement. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject at a daily dose of about 20 to about 800 μg / kg. 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 μg / kg / day of obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 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 μg / kg / day. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 120 μg / kg / day.In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject at 800 μg / kg / day.

[0214] In some embodiments, the amount of obeticholic acid or a pharmaceutically acceptable salt thereof administered to the subject does not exceed 6 mg per day.

[0215] In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in unit doses in the range of from about 1 μg to about 100 mg, such as from about 10 μg to about 10 mg, such as from about 100 μg to about 2000 μg, or such as from about 200 μg to about 1500 μg. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in unit doses in the following ranges: from about 10 µg to about 9 mg, from about 10 µg to about 8 mg, from about 10 µg to about 7 mg, from about 10 µg to about 6 mg, from about 10 µg to about 5 mg, from about 10 µg to about 4 mg, from about 10 µg to about 3 mg, from about 10 µg to about 2 mg, from about 10 µg to about 1 mg, from about 10 µg to about 800 µg, from about 10 µg to about 600 µg, from about 10 µg to about 400 µg, from about 10 µg to about 200 µg, from about 10 µg to about 100 µg, from about 10 µg to about 50 µg, from about 50 µg to about 10 mg, from about 50 µg to about 9 mg, from about 50 µg to about 8 mg, from about 50 µg to about 7 mg, from about 50 µg to about 6 mg, from about 50 µg to about 5 mg, from about 50 µg to about 4 mg, from about 50 µg to about 3 mg, from about 50 µg to about 2 mg, from about 50 µg to about 1 mg, from about 50 µg to about 800 µg, from about 50 µg to about 600 µg, from about 50 µg to about 400 µg, from about 50 µg to about 200 µg, from about 50 µg to about 100 µg, from about 100 µg to about 10 mg, from about 100 µg to about 9 mg, from about 100 µg to about 8 mg, from about 100 µg to about 7 mg, from about 100 µg to about 6 mg, from about 100 µg to about 5 mg, from about 100 µg to about 4 mg, from about 100 µg to about 3 mg, from about 100 µg to about 2 mg, from about 100 µg to about 1 mg, from about 100 µg to about 800 µg, from about 100 µg to about 600 µg, from about 100 µg to about 400 µg, from about 100 µg to about 200 µg, from about 200 µg to about 10 mg, from about 200 µg to about 9 mg, from about 200 µg to about 8 mg, from about 200 µg to about 7 mg, from about 200 µg to about 6 mg, from about 200 µg to about 5 mg, from about 200 µg to about 4 mg, from about 200 µg to about 3 mg, from about 200 µg to about 2 mg, from about 200 µg to about 1 mg, from about 200 µg to about 800 µg, from about 200 µg to about 600 µg, from about 200 µg to about 400 µg, from about 200 µg to about 10 mg, from about 200 µg to about 9 mg, from about 400 µg to about 8 mg, from about 400 µg to about 7 mg, from about 400from μg to about 6 mg, from about 400 μg to about 5 mg, from about 400 μg to about 4 mg, from about 400 μg to about 3 mg, from about 400 μg to about 2 mg, from about 400 μg to about 1 mg, from about 400 μg to about 800 μg, from about 400 μg to about 600 μg, from about 600 μg to about 10 mg, from about 600 μg to about 9 mg, from about 600 μg to about 8 mg, from about 600 μg to about 7 mg, from about 600 μg to about 6 mg, from about 600 μg to about 5 mg, from about 600 μg to about 4 mg, from about 600 μg to about 3 mg, from about 600 μg to about 2 mg, from about 600 μg to about 1 mg, from about 600 μg to about 800 μg, from about 800 μg to about 10 mg, from about 800 μg to about 9 mg, from about 800 μg to about 8 mg, from about 800 μg to about 7 mg, from about 800 μg to about 6 mg, from about 800 μg to about 5 mg, from about 800 μg to about 4 mg, from about 800 μg to about 3 mg, from about 800 μg to about 2 mg, from about 800 μg to about 1 mg, from about 1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 1 mg to about 8 mg, from about 1 mg to about 7 mg, from about 1 mg to about 6 mg, from about 1 mg to about 5 mg, from about 1 mg to about 4 mg, from about 1 mg to about 3 mg, from about 1 mg to about 2 mg, from about 2 mg to about 10 mg, from about 2 mg to about 9 mg, from about 2 mg to about 8 mg, from about 2 mg to about 7 mg, from about 2 mg to about 6 mg, from about 2 mg to about 5 mg, from about 2 mg to about 4 mg, from about 2 mg to about 3 mg, from about 3 mg to about 10 mg, from about 3 mg to about 9 mg, from about 3 mg to about 8 mg, from about 3 mg to about 7 mg, from about 3 mg to about 6 mg, from about 3 mg to about 5 mg, from about 3 mg to about 4 mg, from about 4 mg to about 10 mg, from about 4 mg to about 9 mg, from about 4 mg to about 8 mg, from about 4 mg to about 7 mg, from about 4 mg to about 6 mg, from about 4 mg to about 5 mg, from about 5 mg to about 10 mg, from about 5 mg to about 9 mg, from about 5 mg to about 8 mg, from about 5 mg to about 7 mg, from about 5 mg to about 6 mg, from about 6 mg to about 10 mg, from about 6 mg to about 9 mg, from about 6 mg to about 8 mg, from about 6 mg to about 7 mg, from about 7 mg to about 10 mg, from about 7 mg to about 9 mg, from about 7 mg to about 8 mg, from about 8 mg to about 10 mg, from about 8 mg to about 9 mg, or from about 9 mg to about 10mg. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in unit doses of about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1000 μg, about 1100 μg, about 1200 μg, about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, about 1800 μg, about 1900 μg or about 2000 μg.

[0216] In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 200 μg. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 400 μg. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 600 μg. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 1200 μg.

[0217] The dosing frequency can vary from once or twice a week to once or more times a day, such as twice or three times a day. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered once a day. Additionally, the dosing frequency can remain constant or vary during the course of treatment. A variety of factors can influence the dosing frequency and the effective amount of the formulation for a particular treatment, such as the severity of the disease being treated, the duration of treatment, and the age, weight, sex, diet, and general health of the patient being treated.

[0218] In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 200 μg / day. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 400 μg / day. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 600 μg / day. In some embodiments, obeticholic acid or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 1200 μg / day.

[0219] In some embodiments, the subject has not previously used obeticholic acid prior to the first administration of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, one or more antipruritics have been administered to the subject prior to the first administration of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof. Non-limiting examples of antipruritics include cholestyramine, ursodeoxycholic acid (UDCA), rifampicin, phenobarbital, ondansetron, sertraline, and naltrexone.

[0221] In some embodiments, prior to the first administration of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, the scratching score of the subject is ____.

[0222] IBAT inhibitor

[0223] Provided herein are methods of treating ALGS using an ileal bile acid transporter (IBAT) inhibitor (also known as an apical sodium-dependent bile acid transporter inhibitor, ASBTI). In some embodiments, the IBAT inhibitor is

[0224] (obeticholic acid)

[0225] (elobixibat)

[0226] (maralixibat)

[0227] (volixibat)

[0228] (linerixibat)

[0229] or a pharmaceutically acceptable salt thereof. The IBAT inhibitors provided herein include solvates and hydrates thereof. For example, obeticholic acid can exist in the form of a hydrate (e.g., sesquihydrate). In some embodiments, the IBAT inhibitor is obeticholic acid 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 obeticholic acid, maralixibat, volixibat, elobixibat, and linerixibat or a pharmaceutically acceptable salt thereof.

[0230] IBAT inhibitors can be prepared using methods described previously (e.g., 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). IBAT inhibitors can exist in amorphous or crystalline form. See, e.g., U.S. Patent Nos. 9,409,875; 10,183,920 and International Publication No. WO 2019 / 245448.

[0231] Provided herein are methods of treating Alagille syndrome (ALGS) in a subject in need thereof, the method comprising administering (e.g., orally) to the subject a therapeutically effective amount of a pharmaceutical formulation comprising an IBAT inhibitor or a pharmaceutically acceptable salt thereof. Also provided herein are methods of treating pruritus associated with Alagille syndrome (ALGS) in a subject in need thereof, the method comprising administering (e.g., orally) to the subject a therapeutically effective amount of a pharmaceutical formulation comprising an IBAT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating cholestasis associated with ALGS in a subject in need thereof, the method comprising administering (e.g., orally) to the subject a therapeutically effective amount of a pharmaceutical formulation comprising an IBAT inhibitor or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits a decrease in the mean monthly pruritus score.

[0233] In some embodiments, the average monthly pruritus score (i.e., scratching score) is reduced by 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 average monthly pruritus score is reduced by 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 average monthly pruritus score is reduced by 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 average monthly pruritus score is reduced by about 2.0. In some embodiments, the average monthly pruritus score is reduced by about 1.6.

[0234] In some embodiments, a reduction in the average monthly itch score occurs about 1 week to about 72 weeks after administration of the IBAT inhibitor. For example, administration of the IBAT inhibitor for 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.In some embodiments, a reduction in the average monthly pruritus score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0235] In some embodiments, a reduction in the average monthly pruritus score occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of the IBAT inhibitor.

[0236] In some embodiments, a reduction in the average monthly pruritus score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, a reduction in the average monthly pruritus score occurs 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 after administration of the IBAT inhibitor. In some embodiments, a reduction in the average monthly pruritus score occurs 4 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 24 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 48 weeks after administration. In some embodiments, a reduction in the average monthly pruritus score occurs 72 weeks after administration.

[0237] In some embodiments, about 0.3 to about 2.0 reduction in the average monthly pruritus score occurs 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 0.5 to about 1.5 reduction in the average monthly pruritus score occurs 24 weeks after administration of the IBAT inhibitor. For example, about 0.9 to about 1.3 reduction in the average monthly pruritus score occurs 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 1.1 reduction in the average monthly pruritus score occurs 24 weeks after administration of the IBAT inhibitor.

[0238] In some embodiments, about 1.2 to about 2.0 reduction in the average monthly pruritus score occurs 48 weeks after administration of the IBAT inhibitor. For example, about 1.4 to about 1.8 reduction in the average monthly pruritus score occurs 48 weeks after administration of the IBAT inhibitor. In some embodiments, about 1.6 reduction in the average monthly pruritus score occurs 48 weeks after administration of the IBAT inhibitor.

[0239] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a decrease in the itch score relative to baseline. In some embodiments, the itch score (i.e., scratch score) decreases relative to baseline by 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 itch score decreases relative to baseline by 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 itch score decreases relative to baseline by 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 itch score decreases relative to baseline by about 2.0. In some embodiments, the itch score decreases relative to baseline by about 1.6.

[0240] In some embodiments, a reduction in the itch score relative to baseline occurs about 1 week to about 72 weeks after administration of the IBAT inhibitor. For example, administration of the IBAT inhibitor for 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.In some embodiments, a reduction in the itch score relative to baseline occurs about 5 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 after administration of the IBAT inhibitor.

[0241] In some embodiments, a reduction in the itch score relative to baseline occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of the IBAT inhibitor.

[0242] In some embodiments, a reduction in the itch score relative to baseline occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, a reduction in the itch score relative to baseline occurs 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 after administration of the IBAT inhibitor. In some embodiments, a reduction in the itch score relative to baseline occurs 1 week after administration. In some embodiments, a reduction in the itch score relative to baseline occurs 4 weeks after administration. In some embodiments, a reduction in the itch score relative to baseline occurs 24 weeks after administration. In some embodiments, a reduction in the itch score relative to baseline occurs 48 weeks after administration. In some embodiments, a reduction in the itch score relative to baseline occurs 72 weeks after administration.

[0243] In some embodiments, about 0.3 to about 2.0 reduction in the itch score relative to baseline occurs 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 0.5 to about 1.5 reduction in the itch score relative to baseline occurs 24 weeks after administration of the IBAT inhibitor. For example, about 0.9 to about 1.3 reduction in the itch score relative to baseline occurs 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 1.1 reduction in the itch score relative to baseline occurs 24 weeks after administration of the IBAT inhibitor.

[0244] In some embodiments, about 1.2 to about 2.0 reduction in the itch score relative to baseline occurs 48 weeks after administration of the IBAT inhibitor. For example, about 1.4 to about 1.8 reduction in the itch score relative to baseline occurs 48 weeks after administration of the IBAT inhibitor. In some embodiments, about 1.6 reduction in the itch score relative to baseline occurs 48 weeks after administration of the IBAT inhibitor.

[0245] In some embodiments, a decrease in the itch score (i.e., scratch score) relative to baseline refers to a decrease in the average morning scratch score, the average afternoon scratch score, or the average morning and afternoon scratch scores. In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a decrease in the average morning and afternoon scratch scores relative to baseline. In some embodiments, the average morning and afternoon scratch scores are the worst scratch scores measured by the ObsRO instrument. In some embodiments, the average morning and afternoon scratch scores are the worst scratch scores measured by the ObsRO instrument reported by morning and afternoon caregivers.

[0246] In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by 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 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 0.3 to about 4.0 relative to the baseline. 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 average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by 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 average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 1.1 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 1.6 relative to the baseline. In some embodiments, the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score is reduced by about 2.0 relative to the baseline.

[0247] In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 1 week to about 72 weeks after administration of the IBAT inhibitor. 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 1 week to about 72 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.In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0248] In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of the IBAT inhibitor.

[0249] In some embodiments, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs at least 1 week, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, a decrease in the average morning scratching score, the average afternoon scratching score, or the average morning and afternoon scratching score relative to baseline occurs at least 1 week, 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 after administration of the IBAT inhibitor.

[0250] In some embodiments, the subject exhibits a decrease in the average serum bile acid concentration.

[0251] In some embodiments, the average serum bile acid concentration is reduced by at least 25 μmol / L, at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L, at least 175 μmol / L, at least 200 μmol / L, at least 300 μmol / L, at least 400 μmol / L, at least 500 μmol / L, or at least 600 μmol / L relative to the baseline. For example, the average serum bile acid concentration is reduced by about 25 μmol / L to about 200 μmol / L relative to the baseline (e.g., about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 75 μmol / L; about 25 μmol / L to about 100 μmol / L; about 25 μmol / L to about 125 μmol / L; about 25 μmol / L to about 150 μmol / L; about 25 μmol / L to about 175 μmol / L; about 25 μmol / L to about 75 μmol / L). In some embodiments, the average serum bile acid concentration is reduced by about 50 μmol / L to about 180 μmol / L relative to the baseline (e.g., about 50 μmol / L to about 100 μmol / L; about 50 μmol / L to about 120 μmol / L; about 50 μmol / L to about 150 μmol / L; about 65 μmol / L to about 120 μmol / L; about 50 μmol / L to about 90 μmol / L; about 65 μmol / L to about 85 μmol / L; about 100 μmol / L to about 130 μmol / L; about 100 μmol / L to about 180 μmol / L; or about 150 μmol / L to about 180 μmol / L).In some embodiments, the average serum bile acid concentration is reduced by about 50 μmol / L to about 600 μmol / L, about 100 μmol / L to about 600 μmol / L, about 150 μmol / L to about 600 μmol / L, about 200 μmol / L to about 600 μmol / L, about 250 μmol / L to about 600 μmol / L, about 300 μmol / L to about 600 μmol / L, about 350 μmol / L to about 600 μmol / L, about 400 μmol / L to about 600 μmol / L, about 450 μmol / L to about 600 μmol / L, about 500 μmol / L to about 600 μmol / L, about 550 μmol / L to about 600 μmol / L, about 50 μmol / L to about 500 μmol / L, about 100 μmol / L to about 500 μmol / L, about 150 μmol / L to about 500 μmol / L, about 200 μmol / L to about 500 μmol / L, about 250 μmol / L to about 500 μmol / L, about 300 μmol / L to about 500 μmol / L, about 350 μmol / L to about 500 μmol / L, about 400 μmol / L to about 500 μmol / L, about 450 μmol / L to about 500 μmol / L, about 50 μmol / L to about 400 μmol / L, about 100 μmol / L to about 400 μmol / L, about 150 μmol / L to about 400 μmol / L, about 200 μmol / L to about 400 μmol / L, about 250 μmol / L to about 400 μmol / L, about 300 μmol / L to about 400 μmol / L, about 350 μmol / L to about 400 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 200 μmol / L, about 100 μmol / L to about 200 μmol / L, or about 150 μmol / L to about 200 μmol / L.In some embodiments, the average serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline. In some embodiments, the average serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L.

[0252] In some embodiments, a decrease in average serum bile acid concentration occurs about 1 week to about 72 weeks after administration of an IBAT inhibitor. 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.In some embodiments, a decrease in the average serum bile acid concentration occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of an IBAT inhibitor.

[0253] In some embodiments, a decrease in the average serum bile acid concentration occurs about 1, about 4, about 8, about 12, about 16, about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of an IBAT inhibitor.

[0254] In some embodiments, a decrease in the average serum bile acid concentration occurs at least 1, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48, at least 60, at least 72, at least 96 weeks, etc. after administration of an IBAT inhibitor. In some embodiments, a decrease in the average serum bile acid concentration occurs 4 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 12 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 24 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 48 weeks after administration. In some embodiments, a decrease in the average serum bile acid concentration occurs 72 weeks after administration.

[0255] In some embodiments, about 50 μmol / L to about 90 μmol / L decrease in the average serum bile acid concentration 12 weeks after administration of an IBAT inhibitor. For example, about 65 μmol / L to about 85 μmol / L decrease in the average serum bile acid concentration 12 weeks after administration of an IBAT inhibitor. In some embodiments, about 70 μmol / L (e.g., about 73 μmol / L) decrease in the average serum bile acid concentration 12 weeks after administration of an IBAT inhibitor.

[0256] In some embodiments, about 100 μmol / L to about 130 μmol / L decrease in the average serum bile acid concentration 24 weeks after administration of an IBAT inhibitor. For example, about 110 μmol / L to about 120 μmol / L decrease in the average serum bile acid concentration 24 weeks after administration of an IBAT inhibitor. In some embodiments, about 115 μmol / L decrease in the average serum bile acid concentration 24 weeks after administration of an IBAT inhibitor.

[0257] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the average serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L. For example, after 48 weeks of administration of an IBAT inhibitor, the average serum bile acid concentration is reduced by about 155 μmol / L to about 170 μmol / L. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the average serum bile acid concentration is reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0258] In some embodiments, the subject exhibits a decrease in serum bile acid concentration relative to baseline. In some embodiments, the serum bile acid concentration is decreased by at least 25 μmol / L, at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L, at least 175 μmol / L, at least 200 μmol / L, at least 300 μmol / L, at least 400 μmol / L, at least 500 μmol / L, or at least 600 μmol / L relative to baseline. For example, the average serum bile acid concentration is decreased by about 25 μmol / L to about 200 μmol / L relative to baseline (e.g., about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 50 μmol / L; about 25 μmol / L to about 75 μmol / L; about 25 μmol / L to about 100 μmol / L; about 25 μmol / L to about 125 μmol / L; about 25 μmol / L to about 150 μmol / L; about 25 μmol / L to about 175 μmol / L; about 25 μmol / L to about 75 μmol / L). In some embodiments, the serum bile acid concentration is decreased by about 50 μmol / L to about 180 μmol / L relative to baseline (e.g., about 50 μmol / L to about 100 μmol / L; about 50 μmol / L to about 120 μmol / L; about 50 μmol / L to about 150 μmol / L; about 65 μmol / L to about 120 μmol / L; about 50 μmol / L to about 90 μmol / L; about 65 μmol / L to about 85 μmol / L; about 100 μmol / L to about 130 μmol / L; about 100 μmol / L to about 180 μmol / L; or about 150 μmol / L to about 180 μmol / L).In some embodiments, the serum bile acid concentration is reduced by about 50 μmol / L to about 600 μmol / L, about 100 μmol / L to about 600 μmol / L, about 150 μmol / L to about 600 μmol / L, about 200 μmol / L to about 600 μmol / L, about 250 μmol / L to about 600 μmol / L, about 300 μmol / L to about 600 μmol / L, about 350 μmol / L to about 600 μmol / L, about 400 μmol / L to about 600 μmol / L, about 450 μmol / L to about 600 μmol / L, about 500 μmol / L to about 600 μmol / L, about 550 μmol / L to about 600 μmol / L, about 50 μmol / L to about 500 μmol / L, about 100 μmol / L to about 500 μmol / L, about 150 μmol / L to about 500 μmol / L, about 200 μmol / L to about 500 μmol / L, about 250 μmol / L to about 500 μmol / L, about 300 μmol / L to about 500 μmol / L, about 350 μmol / L to about 500 μmol / L, about 400 μmol / L to about 500 μmol / L, about 450 μmol / L to about 500 μmol / L, about 50 μmol / L to about 400 μmol / L, about 100 μmol / L to about 400 μmol / L, about 150 μmol / L to about 400 μmol / L, about 200 μmol / L to about 400 μmol / L, about 250 μmol / L to about 400 μmol / L, about 300 μmol / L to about 400 μmol / L, about 350 μmol / L to about 400 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 300 μmol / L, about 100 μmol / L to about 300 μmol / L, about 150 μmol / L to about 300 μmol / L, about 200 μmol / L to about 300 μmol / L, about 250 μmol / L to about 300 μmol / L, about 50 μmol / L to about 200 μmol / L, about 100 μmol / L to about 200 μmol / L, or about 150 μmol / L to about 200 μmol / L relative to the baseline.In some embodiments, the serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline. In some embodiments, the serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L.

[0259] In some embodiments, a decrease in serum bile acid concentration occurs about 1 week to about 72 weeks after administration of an IBAT inhibitor. For example, administration of the IBAT inhibitor for 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.In some embodiments, the reduction in serum bile acid concentration occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0260] In some embodiments, the reduction in serum bile acid concentration occurs about 1, about 4, about 8, about 12, about 16, about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of the IBAT inhibitor.

[0261] In some embodiments, the reduction in serum bile acid concentration occurs at least 1, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48, at least 54, at least 60, at least 66, at least 72 weeks, etc. after administration of the IBAT inhibitor. In some embodiments, the reduction in serum bile acid concentration occurs 4 weeks after administration. In some embodiments, the reduction in serum bile acid concentration occurs 12 weeks after administration. In some embodiments, the reduction in serum bile acid concentration occurs 24 weeks after administration. In some embodiments, the reduction in serum bile acid concentration occurs 48 weeks after administration. In some embodiments, the reduction in serum bile acid concentration occurs 72 weeks after administration.

[0262] In some embodiments, about 50 μmol / L to about 90 μmol / L reduction in serum bile acid concentration occurs 12 weeks after administration of the IBAT inhibitor. For example, about 65 μmol / L to about 85 μmol / L reduction in serum bile acid concentration occurs 12 weeks after administration of the IBAT inhibitor. In some embodiments, about 70 μmol / L (e.g., about 73 μmol / L) reduction in serum bile acid concentration occurs 12 weeks after administration of the IBAT inhibitor.

[0263] In some embodiments, about 100 μmol / L to about 130 μmol / L reduction in serum bile acid concentration occurs 24 weeks after administration of the IBAT inhibitor. For example, about 110 μmol / L to about 120 μmol / L reduction in serum bile acid concentration occurs 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 115 μmol / L reduction in serum bile acid concentration occurs 24 weeks after administration of the IBAT inhibitor.

[0264] In some embodiments, after administering the IBAT inhibitor for 48 weeks, the serum bile acid concentration decreases by about 150 μmol / L to about 180 μmol / L. For example, after administering the IBAT inhibitor for 48 weeks, the serum bile acid concentration decreases by about 155 μmol / L to about 170 μmol / L. In some embodiments, after administering the IBAT inhibitor for 48 weeks, the serum bile acid concentration decreases by about 165 μmol / L (e.g., about 166 μmol / L).

[0265] In some embodiments, after administering the IBAT inhibitor for at least 24 weeks, the subject exhibits a serum bile acid concentration below 70 μmol / L (e.g., below 60 μmol / L; below 50 μmol / L, etc.).

[0266] In some embodiments, after administering the IBAT inhibitor for at least 24 weeks, the subject exhibits a serum bile acid concentration that is reduced by at least 50% relative to baseline (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; at least 95%). In some embodiments, the subject exhibits a serum bile acid concentration that is reduced by at least 60%, at least 70%, or at least 80% relative to baseline.

[0267] In some embodiments, after administering the IBAT inhibitor, the subject exhibits an increase in the average height Z-score relative to baseline.

[0268] In some embodiments, after administering the IBAT inhibitor, the growth of the subject is improved relative to placebo. In some embodiments, after administering the IBAT inhibitor, the subject exhibits an increase in the average height Z-score relative to baseline.

[0269] In some embodiments, the average height Z-score increases by at least 0.1, at least 0.2, at least 0.5, at least 0.75, at least 1, at least 1.25, or at least 1.5 relative to baseline. For example, the average height Z-score increases by about 0.5 to about 2.0 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the average height Z-score increases by about 1.1.

[0270] In some embodiments, an increase in mean height Z-score occurs about 20 to about 72 weeks after administration of an IBAT inhibitor. For example, administration of the IBAT inhibitor for about 20 to about 24 weeks, about 20 to about 28 weeks, about 20 to about 36 weeks, about 20 to about 40 weeks, about 20 to about 48 weeks, about 20 to about 52 weeks, about 20 to about 60 weeks, about 20 to about 72 weeks, about 24 to about 28 weeks, about 24 to about 36 weeks, about 24 to about 40 weeks, about 24 to about 48 weeks, about 24 to about 52 weeks, about 24 to about 60 weeks, about 24 to about 72 weeks, about 28 to about 36 weeks, about 28 to about 40 weeks, about 28 to about 48 weeks, about 28 to about 52 weeks, about 28 to about 60 weeks, about 28 to about 72 weeks, about 36 to about 40 weeks, about 36 to about 48 weeks, about 36 to about 52 weeks, about 36 to about 60 weeks, about 36 to about 72 weeks, about 40 to about 44 weeks, about 40 to about 48 weeks, about 40 to about 52 weeks, about 40 to about 60 weeks, about 40 to about 72 weeks, about 44 to about 48 weeks, about 44 to about 52 weeks, about 44 to about 60 weeks, about 44 to about 72 weeks, about 48 to about 52 weeks, about 48 to about 60 weeks, about 48 to about 72 weeks, about 52 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks. In some embodiments, an increase in mean height Z-score occurs about 21 to about 24 weeks after administration of an IBAT inhibitor.

[0271] In some embodiments, an increase in mean height Z-score occurs about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of an IBAT inhibitor.

[0272] In some embodiments, an increase in mean height Z-score occurs at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48, etc. weeks after administration of an IBAT inhibitor. In some embodiments, an increase in mean height Z-score occurs 24 weeks after administration. In some embodiments, an increase in mean height Z-score occurs 48 weeks after administration. In some embodiments, an increase in mean height Z-score occurs 72 weeks after administration.

[0273] In some embodiments, about 0.9 to about 1.3 increase in mean height Z-score occurs 48 weeks after administration of an IBAT inhibitor. In some embodiments, about 1.0 to about 1.2 increase in mean height Z-score occurs 48 weeks after administration of an IBAT inhibitor. In some embodiments, about 1.1 increase in mean height Z-score occurs 48 weeks after administration of an IBAT inhibitor.

[0274] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits an increase in mean body weight Z-score.

[0275] In some embodiments, the mean body weight Z-score increases by at least 0.2, at least 0.4, at least 0.6, at least 0.8, at least 1, at least 1.2, or at least 1.4. For example, the mean body weight Z-score increases by about 0.2 to about 1.5 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the mean body weight Z-score increases by about 1.1.

[0276] In some embodiments, an increase in mean body weight Z-score occurs about 1 week to about 72 weeks after administration of an IBAT inhibitor. 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.In some embodiments, an increase in the average body weight Z-score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0277] In some embodiments, an increase in the average body weight Z-score occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks after administration of the IBAT inhibitor.

[0278] In some embodiments, an increase in the average body weight Z-score occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, an increase in the average body weight Z-score occurs 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 after administration of the IBAT inhibitor. In some embodiments, an increase in the average body weight Z-score occurs 12 weeks after administration. In some embodiments, an increase in the average body weight Z-score occurs 24 weeks after administration. In some embodiments, an increase in the average body weight Z-score occurs 48 weeks after administration. In some embodiments, an increase in the average body weight Z-score occurs 72 weeks after administration.

[0279] In some embodiments, about 0.9 to about 1.3 weeks after administration of the IBAT inhibitor for 48 weeks, the average body weight Z-score increases. In some embodiments, about 1.0 to about 1.2 weeks after administration of the IBAT inhibitor for 48 weeks, the average body weight Z-score increases. In some embodiments, about 1.1 weeks after administration of the IBAT inhibitor for 48 weeks, the average body weight Z-score increases.

[0280] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits an increase in the height Z-score relative to the baseline. In some embodiments, the height Z-score increases relative to the baseline by at least 0.1, at least 0.2, at least 0.5, at least 0.75, at least 1, at least 1.25, or at least 1.5. For example, the height Z-score increases by about 0.5 to about 2.0 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the height Z-score increases by about 1.1.

[0281] In some embodiments, an increase in height Z-score occurs about 20 to about 72 weeks after administration of an IBAT inhibitor. For example, about 20 to about 24 weeks, about 20 to about 28 weeks, about 20 to about 36 weeks, about 20 to about 40 weeks, about 20 to about 48 weeks, about 20 to about 52 weeks, about 20 to about 60 weeks, about 20 to about 72 weeks, about 24 to about 28 weeks, about 24 to about 36 weeks, about 24 to about 40 weeks, about 24 to about 48 weeks, about 24 to about 52 weeks, about 24 to about 60 weeks, about 24 to about 72 weeks, about 28 to about 36 weeks, about 28 to about 40 weeks, about 28 to about 48 weeks, about 28 to about 52 weeks, about 28 to about 60 weeks, about 28 to about 72 weeks, about 36 to about 40 weeks, about 36 to about 48 weeks, about 36 to about 52 weeks, about 36 to about 60 weeks, about 36 to about 72 weeks, about 40 to about 44 weeks, about 40 to about 48 weeks, about 40 to about 52 weeks, about 40 to about 60 weeks, about 40 to about 72 weeks, about 44 to about 48 weeks, about 44 to about 52 weeks, about 44 to about 60 weeks, about 44 to about 72 weeks, about 48 to about 52 weeks, about 48 to about 60 weeks, about 48 to about 72 weeks, about 52 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks after administration of the IBAT inhibitor. In some embodiments, an increase in height Z-score occurs about 21 to about 24 weeks after administration of an IBAT inhibitor.

[0282] In some embodiments, an increase in height Z-score occurs about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of an IBAT inhibitor.

[0283] In some embodiments, an increase in height Z-score occurs at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48 weeks, etc. after administration of an IBAT inhibitor. In some embodiments, an increase in height Z-score occurs 24 weeks after administration. In some embodiments, an increase in height Z-score occurs 48 weeks after administration. In some embodiments, an increase in height Z-score occurs 72 weeks after administration.

[0284] In some embodiments, about 0.9 to about 1.3 increase in height Z-score occurs 48 weeks after administration of an IBAT inhibitor. In some embodiments, about 1.0 to about 1.2 increase in height Z-score occurs 48 weeks after administration of an IBAT inhibitor. In some embodiments, about 1.1 increase in height Z-score occurs 48 weeks after administration of an IBAT inhibitor.

[0285] In some embodiments, after administration of an IBAT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in weight Z-score.

[0286] In some embodiments, the weight Z-score increases by at least 0.2, at least 0.4, at least 0.6, at least 0.8, at least 1, at least 1.2, or at least 1.4. For example, the weight Z-score increases by about 0.2 to about 1.5 (e.g., about 0.5 to about 0.8; about 0.5 to about 1.2; about 0.5 to about 1.5; about 0.7 to about 1.5; about 0.8 to about 1.4; about 0.9 to about 1.3; or about 1.0 to about 1.2). In some embodiments, the weight Z-score increases by about 1.1.

[0287] In some embodiments, an increase in the weight Z-score occurs about 1 week to about 72 weeks after administration of the IBAT inhibitor. For example, administration of the IBAT inhibitor for 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.In some embodiments, an increase in the weight Z-score occurs about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0288] In some embodiments, an increase in the weight Z-score occurs about 1, about 4, about 8, about 12, about 16, about 20, about 24, about 28, about 32, about 36, about 40, about 44, about 48, about 52, about 56, about 60, about 64, about 68, or about 72 weeks after administration of the IBAT inhibitor.

[0289] In some embodiments, an increase in the weight Z-score occurs at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, an increase in the weight Z-score occurs at least 4, at least 8, at least 12, at least 16, at least 20, or at least 24 weeks after administration of the IBAT inhibitor. In some embodiments, an increase in the weight Z-score occurs 12 weeks after administration. In some embodiments, an increase in the weight Z-score occurs 24 weeks after administration. In some embodiments, an increase in the weight Z-score occurs 48 weeks after administration. In some embodiments, an increase in the weight Z-score occurs 72 weeks after administration.

[0290] In some embodiments, about 0.9 to about 1.3 weeks after 48 weeks of administration of the IBAT inhibitor, the weight Z-score increases. In some embodiments, about 1.0 to about 1.2 weeks after 48 weeks of administration of the IBAT inhibitor, the weight Z-score increases. In some embodiments, about 1.1 weeks after 48 weeks of administration of the IBAT inhibitor, the weight Z-score increases.

[0291] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits an improvement in sleep parameters. The improvement in sleep parameters can include, for example, an average decrease in the percentage of days of scratching related to bleeding, difficulty falling asleep, need for soothing, co-sleeping with the caregiver, or taking hypnotic drugs reported by the caregiver, and an average decrease in the percentage of days of daytime fatigue reported by the caregiver and the average number of awakenings per night reported by the caregiver. As described in the examples, at week 24, most of the patient's sleep parameters have been significantly improved since the start of administration of the IBAT inhibitor.

[0292] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits an improvement in liver parameters or liver biomarkers. For example, in some embodiments, after administration of an IBAT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the level of autotaxin and / or the plasma level of the bile acid synthesis marker 7α-hydroxy-4-cholesten-3-one (p-C4) related to the intensity of cholestatic pruritus is improved.

[0293] In some embodiments, after administration of an IBAT inhibitor or a pharmaceutically acceptable salt thereof, the serum ALT level is improved. In some embodiments, after administration of an IBAT inhibitor or a pharmaceutically acceptable salt thereof, the serum total bilirubin level is decreased. In some embodiments, after administration of an IBAT inhibitor or a pharmaceutically acceptable salt thereof, the serum AST level is improved.

[0294] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a decrease in serum cholesterol level (mmol / L).

[0295] In some embodiments, the cholesterol level is decreased by at least 0.2, 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 or at least 2.2 mmol / L. For example, the cholesterol level is decreased by about 0.2 to about 2.5 mmol / L (e.g., about 0.2 to about 2.0; about 0.2 to about 1.5; about 0.2 to about 1.2; about 0.2 to about 1.0; about 0.2 to about 0.8; about 0.2 to about 0.5; 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 1.2; about 0.5 to about 1.0; about 0.5 to about 0.8; about 1.0 to about 2.5; about 1.0 to about 2.0; about 1.0 to about 1.5; about 1.0 to about 1.2; about 1.2 to about 2.5; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.5 to about 2.5; about 1.5 to about 2.0; or about 2.0 to about 2.5 mmol / L). In some embodiments, the cholesterol level is decreased by about 0.5 mmol / L. In some embodiments, the cholesterol level is decreased by about 0.6 mmol / L.

[0296] In some embodiments, a reduction in cholesterol levels occurs about 1 week to about 72 weeks after administration of an IBAT inhibitor. For example, administration of the IBAT inhibitor for 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.In some embodiments, the reduction in cholesterol level occurs about 5 to about 8 weeks, about 9 to about 12 weeks, about 21 to about 24 weeks after administration of the IBAT inhibitor.

[0297] In some embodiments, the reduction in cholesterol level occurs about 1 week, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks or about 72 weeks after administration of the IBAT inhibitor.

[0298] In some embodiments, the reduction in cholesterol level occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, the reduction in cholesterol level can occur 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 after administration of the IBAT inhibitor. In some embodiments, the reduction in cholesterol level occurs 4 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 24 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 48 weeks after administration. In some embodiments, the reduction in cholesterol level occurs 72 weeks after administration.

[0299] In some embodiments, about 0.4 to about 1 mmol / L of cholesterol level is reduced 24 weeks after administration of the IBAT inhibitor. For example, about 0.5 to about 0.8 mmol / L of cholesterol level is reduced 24 weeks after administration of the IBAT inhibitor. In some embodiments, about 0.6 mmol / L of cholesterol level is reduced 24 weeks after administration of the IBAT inhibitor.

[0300] In some embodiments, about 0.5 to about 2.0 mmol / L of cholesterol level is reduced 48 weeks after administration of the IBAT inhibitor. For example, about 0.8 to about 1.5 mmol / L of cholesterol level is reduced 48 weeks after administration of the IBAT inhibitor.

[0301] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a decrease in cholesterol level relative to baseline. In some embodiments, the cholesterol level decreases relative to baseline by at least 0.2, 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, or at least 2.0 mmol / L. For example, the cholesterol level decreases relative to baseline by about 0.3 to about 2.0 mmol / L (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.5 to about 1; or about 0.5 to about 0.8 mmol / L). In some embodiments, the cholesterol level decreases relative to baseline by about 0.5 mmol / L. In some embodiments, the cholesterol level decreases by about 0.6 mmol / L.

[0302] In some embodiments, the decrease in cholesterol level relative to baseline occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. after administration of the IBAT inhibitor. For example, the decrease in cholesterol level relative to baseline can occur 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 after administration of the IBAT inhibitor. In some embodiments, the decrease in cholesterol level relative to baseline occurs 4 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 24 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 48 weeks after administration. In some embodiments, the decrease in cholesterol level relative to baseline occurs 72 weeks after administration.

[0303] In some embodiments, 24 weeks after administration of the IBAT inhibitor, the cholesterol level decreases relative to baseline by about 0.4 to about 1 mmol / L. For example, 24 weeks after administration of the IBAT inhibitor, the cholesterol level decreases relative to baseline by about 0.5 to about 0.8 mmol / L. In some embodiments, 24 weeks after administration of the IBAT inhibitor, the cholesterol level decreases relative to baseline by about 0.6 mmol / L.

[0304] In some embodiments, 48 weeks after administration of the IBAT inhibitor, the cholesterol level decreases relative to baseline by about 0.5 to about 2.0 mmol / L. For example, 48 weeks after administration of the IBAT inhibitor, the cholesterol level decreases relative to baseline by about 0.8 to about 1.5 mmol / L.

[0305] In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is not a pediatric subject.

[0306] In some embodiments, an IBAT inhibitor is administered to the subject at about 20 to about 800 μg / kg / day. 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 μg / kg / day of the IBAT inhibitor. In some embodiments, an IBAT inhibitor is administered to the subject at 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 μg / kg / day. In some embodiments, an IBAT inhibitor is administered to the subject at 120 μg / kg / day. In some embodiments, an IBAT inhibitor is administered to the subject at 800 μg / kg / day.

[0307] In some embodiments, the amount of the IBAT inhibitor administered to the subject does not exceed 6 mg per day.

[0308] In some embodiments, the IBAT inhibitor is administered in unit doses of from about 1 µg to about 100 mg, such as from about 10 µg to about 10 mg, such as from about 100 µg to about 2000 µg, or such as from about 200 µg to about 1500 µg. In some embodiments, the IBAT inhibitor is administered in amounts of from about 10 µg to about 9 mg, from about 10 µg to about 8 mg, from about 10 µg to about 7 mg, from about 10 µg to about 6 mg, from about 10 µg to about 5 mg, from about 10 µg to about 4 mg, from about 10 µg to about 3 mg, from about 10 µg to about 2 mg, from about 10 µg to about 1 mg, from about 10 µg to about 800 µg, from about 10 µg to about 600 µg, from about 10 µg to about 400 µg, from about 10 µg to about 200 µg, from about 10 µg to about 100 µg, from about 10 µg to about 50 µg, from about 50 µg to about 10 mg, from about 50 µg to about 9 mg, from about 50 µg to about 8 mg, from about 50 µg to about 7 mg, from about 50 µg to about 6 mg, from about 50 µg to about 5 mg, from about 50 µg to about 4 mg, from about 50 µg to about 3 mg, from about 50 µg to about 2 mg, from about 50 µg to about 1 mg, from about 50 µg to about 800 µg, from about 50 µg to about 600 µg, from about 50 µg to about 400 µg, from about 50 µg to about 200 µg, from about 50 µg to about 100 µg, from about 100 µg to about 10 mg, from about 100 µg to about 9 mg, from about 100 µg to about 8 mg, from about 100 µg to about 7 mg, from about 100 µg to about 6 mg, from about 100 µg to about 5 mg, from about 100 µg to about 4 mg, from about 100 µg to about 3 mg, from about 100 µg to about 2 mg, from about 100 µg to about 1 mg, from about 100 µg to about 800 µg, from about 100 µg to about 600 µg, from about 100 µg to about 400 µg, from about 100 µg to about 200 µg, from about 200 µg to about 10 mg, from about 200 µg to about 9 mg, from about 200 µg to about 8 mg, from about 200 µg to about 7 mg, from about 200 µg to about 6 mg, from about 200 µg to about 5 mg, from about 200 µg to about 4 mg, from about 200 µg to about 3 mg, from about 200 µg to about 2 mg, from about 200 µg to about 1 mg, from about 200 µg to about 800 µg, from about 200 µg to about 600 µg, from about 200 µg to about 400 µg, from about 200 µg to about 10 mg, from about 200 µg to about 9 mg, from about 400 µg to about 8 mg, from about 400 µg to about 7 mg, from about 400 µg to about 6 mg, from about 400 µg to about 5administered in unit doses of from about 100 µg, about 200 µg, about 300 µg, about 400 µg, about 500 µg, about 600 µg, about 800 µg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; from about 400 µg to about 4 mg, from about 400 µg to about 3 mg, from about 400 µg to about 2 mg, from about 400 µg to about 1 mg, from about 400 µg to about 800 µg, from about 400 µg to about 600 µg, from about 600 µg to about 10 mg, from about 600 µg to about 9 mg, from about 600 µg to about 8 mg, from about 600 µg to about 7 mg, from about 600 µg to about 6 mg, from about 600 µg to about 5 mg, from about 600 µg to about 4 mg, from about 600 µg to about 3 mg, from about 600 µg to about 2 mg, from about 600 µg to about 1 mg, from about 600 µg to about 800 µg, from about 800 µg to about 10 mg, from about 800 µg to about 9 mg, from about 800 µg to about 8 mg, from about 800 µg to about 7 mg, from about 800 µg to about 6 mg, from about 800 µg to about 5 mg, from about 800 µg to about 4 mg, from about 800 µg to about 3 mg, from about 800 µg to about 2 mg, from about 800 µg to about 1 mg, from about 1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 1 mg to about 8 mg, from about 1 mg to about 7 mg, from about 1 mg to about 6 mg, from about 1 mg to about 5 mg, from about 1 mg to about 4 mg, from about 1 mg to about 3 mg, from about 1 mg to about 2 mg, from about 2 mg to about 10 mg, from about 2 mg to about 9 mg, from about 2 mg to about 8 mg, from about 2 mg to about 7 mg, from about 2 mg to about 6 mg, from about 2 mg to about 5 mg, from about 2 mg to about 4 mg, from about 2 mg to about 3 mg, from about 3 mg to about 10 mg, from about 3 mg to about 9 mg, from about 3 mg to about 8 mg, from about 3 mg to about 7 mg, from about 3 mg to about 6 mg, from about 3 mg to about 5 mg, from about 3 mg to about 4 mg, from about 4 mg to about 10 mg, from about 4 mg to about 9 mg, from about 4 mg to about 8 mg, from about 4 mg to about 7 mg, from about 4 mg to about 6 mg, from about 4 mg to about 5 mg, from about 5 mg to about 10 mg, from about 5 mg to about 9 mg, from about 5 mg to about 8 mg, from about 5 mg to about 7 mg, from about 5 mg to about 6 mg, from about 6 mg to about 10 mg, from about 6 mg to about 9 mg, from about 6 mg to about 8 mg, from about 6 mg to about 7 mg, from about 7 mg to about 10 mg, from about 7 mg to about 9 mg, from about 7 mg to about 8 mg, from about 8 mg to about 10 mg, from about 8 mg to about 9 mg, or from about 9 mg to about 10 mg. In some embodiments, the IBAT inhibitor is in an amount of about 100 µg, about 200 µg, about 300 µg, about 400 µg, about 500administered in unit doses of about 100 µg, about 200 µg, about 300 µg, about 400 µg, about 500 µg, about 600 µg, about 700 µg, about 800 µg, about 900 µg, about 1000 µg, about 1100 µg, about 1200 µg, about 1300 µg, about 1400 µg, about 1500 µg, about 1600 µg, about 1700 µg, about 1800 µg, about 1900 µg, or about 2000 µg.

[0309] In some embodiments, the IBAT inhibitor is administered in a unit dose of about 200 μg. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 400 μg. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 600 μg. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 1200 μg.

[0310] The dosing frequency can vary from once or twice a week to once or more times a day, such as twice or three times a day. In some embodiments, the IBAT inhibitor is administered once daily. Additionally, the dosing frequency can remain constant or vary during the course of treatment. A variety of factors can affect the dosing frequency and the effective amount of the formulation for a particular treatment, such as the severity of the disease being treated, the duration of treatment, and the age, weight, sex, diet, and general health of the patient being treated.

[0311] In some embodiments, the IBAT inhibitor is administered in a unit dose of about 200 µg per day. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 400 µg per day. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 600 µg per day. In some embodiments, the IBAT inhibitor is administered in a unit dose of about 1200 µg per day.

[0312] In some embodiments, the unit dose of the IBAT inhibitor does not exceed 6 mg per day.

[0313] In some embodiments, the subject has not previously used an IBAT inhibitor prior to the first administration of a pharmaceutical formulation comprising an IBAT inhibitor.

[0314] Preparation

[0315] The IBAT inhibitors provided herein can be formulated as described above. 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.

[0316] For example, obeticholic acid exhibits high potency and should be administered at low doses, such as from about 40 μg / kg / day to about 120 μg / kg / day. This can correspond to doses of from 200 μg to 7200 μg in pediatric patients having a body weight of from about 4 kg to ≥ 55.5 kg. In some embodiments, this can correspond to doses as low as 200 μg to 800 μg in pediatric patients having a body weight of from about 4 kg to about 20 kg (such as infants and toddlers). It is desirable to formulate obeticholic acid for administration to young patients in small-sized dosage forms. It is also desirable that such formulations have good palatability, are not gritty to the feel, and are well tolerated by infants and young children.

[0317] If a neonate is administered a liquid, multiparticulates can be administered to it. For children who are close to 6 months of age or older (such as after weaning), the multiparticulates can be administered directly into the mouth in their solid form or mixed with a semi-solid food. It has been reported that particle size, shape, texture, hardness, taste, and dose volume (i.e., the number of particles) are important for the acceptability of multiparticulates by infants and children (Kozarewicz, Int. J. Pharm. 2014, Vol. 469, pp. 245-248). There have been numerous literature reviews on the acceptability of different oral dosage forms in pediatric and geriatric patients (see, for example, 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 these reviews rarely report on the size and / or dose volume (quantity) of the multiparticulates studied.

[0318] The perception of grittiness can be affected by a number of factors, including particle size, amount, and dosing vehicle (see Mishra et al., Yakugaku Zasshi 2009, Vol. 129, pp. 1537-1544; Lopez et al., Eur. J. Pharm. Sci. 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), where irregular particles are perceived as larger than circular (spherical) particles of the same size (Engelen et al., J. Text. Studies 2005, Vol. 36, pp. 373-386). Grittiness studies have shown that as the size and dose of the multiparticulates increase, the grittiness score increases, while as the viscosity of the vehicle increases, the grittiness score decreases (Lopez et al., Eur. J. Pharm. Sci. 2016, Vol. 92, pp. 156-162).

[0319] The capsule can be acceptable to children close to 6 years of age. The swallowability of the capsule depends on the dosage form size (i.e., dimensions) and the ability of the child. Size, shape, taste, and aftertaste are important capsule attributes that can affect patient acceptability (Kozarewicz, Int. J. Pharm. 2014, Vol. 469, pp. 245-248). In some embodiments, the size of the capsule is kept small enough so that the number of capsules required per dose is kept to a minimum, e.g., not more than 1-3 capsules.

[0320] The present invention provides a multiparticulate formulation comprising a low dose of obeticholic acid. In some embodiments, the formulation is a pediatric formulation. In some embodiments, the formulation enables weight-based dosing and can be sprinkled on food. The formulation can be designed to have good palatability and an optimal balance between particle size and dose volume.

[0321] The present invention provides a pharmaceutical formulation of obeticholic acid comprising a plurality of particles, wherein each particle comprises an amount of obeticholic acid or a pharmaceutically acceptable salt thereof of from about 0.1% w / w to about 5.0% w / w based on the total weight of the particle.

[0322] Since the administered obeticholic acid is in a low dose and due to the multi-particle form of the present application, each particle of the formulation contains only a very small amount of the active ingredient. For example, based on the total weight of the particle, the amount of obeticholic acid or a pharmaceutically acceptable salt thereof in each particle can range from about 0.2% w / w to about 3.5% w / w, such as from about 0.3% w / w to about 3.0% w / w, from about 0.4% w / w to about 2.5% w / w, from about 0.5% w / w to about 2.0% w / w. In some embodiments, each particle contains an amount of obeticholic acid or a pharmaceutically acceptable salt thereof of about 0.5% w / w based on the total weight of the particle. In another embodiment, each particle contains an amount of obeticholic acid or a pharmaceutically acceptable salt thereof of about 1.0% w / w based on the total weight of the particle. In yet another embodiment, each particle contains an amount of obeticholic acid or a pharmaceutically acceptable salt thereof of about 1.5% w / w based on the total weight of the particle.

[0323] As used herein, the term "particle" refers to a small particle size ranging from about 0.1 to about 1.5 mm. Such particles are substantially spherical, but elongated or oblong particles can also be used. The particles can be, for example, agglomerates, beads, microparticles, microspheres, granules or mini-tablets, and the particles can preferably be coated with one or more coating layers surrounding each such agglomerate, bead, microparticle, microsphere, granule or mini-tablet.

[0324] In some embodiments, the particles of the formulation are small enough to sprinkle them on food or are easy to swallow. In some embodiments, the microparticles can be swallowed without causing a gritty sensation. In some embodiments, the particles do not give the patient an urge to chew the particles. Thus, the particle size is between about 0.1 and about 1.5 mm, such as between about 0.1 and about 1.0 mm, or between about 0.1 and about 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.

[0325] In some embodiments, the present invention provides a formulation of obeticholic acid, wherein each particle contains a core and a coating layer surrounding the core. The core of each particle can be an agglomerate, granule, mini-tablet, bead, microparticle or microsphere.

[0326] In some embodiments, the core of each particle contains the active pharmaceutical ingredient (odevixibat), while the coating layer of each particle does not contain the active pharmaceutical ingredient. In some embodiments, the core 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 based on the total weight of the particle, 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.

[0327] In some embodiments, the coating layer of each particle contains the active pharmaceutical ingredient (odevixibat), while the core of each particle does not contain 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 based on the total weight of the particle, 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.

[0328] The core can be orally dispersible and contain soluble components, such as sugars (e.g., sucrose) or soluble polymers (e.g., hydroxypropyl methylcellulose), or can be non - orally dispersible and contain insoluble components, such as insoluble polymers (e.g., microcrystalline cellulose). In some embodiments, the core contains microcrystalline cellulose. In some embodiments, the core is a microcrystalline cellulose sphere.

[0329] The coating layer can further contain film - forming polymers, such as cellulose - based polymers, polysaccharide - based polymers, N - vinylpyrrolidone - based polymers, acrylates, acrylamides, 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, methylcellulose, 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), and combinations thereof, such as a mixture of methylcellulose and hydroxypropyl methylcellulose (metolose). In some embodiments, the coating layer contains a film - forming polymer selected from: 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.

[0330] The coating layer may optionally contain one or more additional ingredients such as plasticizers (e.g., polyethylene glycol, triacetin or triethyl citrate), anti-adhesion agents (e.g., talc or magnesium stearate) or colorants (e.g., titanium dioxide, iron oxide, riboflavin or turmeric).

[0331] In some embodiments, the formulation comprises obeticholic acid in crystalline form. In some embodiments, the formulation comprises an obeticholic acid crystalline hydrate. In some embodiments, the formulation comprises crystal form 1 of obeticholic acid. This stable crystal form can be obtained from a slurry of obeticholic acid in a mixture of water and an organic solvent (e.g., ethanol). Under these conditions, a mixed solvate is initially formed that contains about 2 moles of water and about 1 to about 3 moles, such as about 2 to about 3 moles of ethanol, per mole of obeticholic acid (e.g., dihydrate - diethanolate or dihydrate - triethanolate). Herein, this mixed solvate is referred to as crystal form 2. When crystal form 2 is dried (e.g., under vacuum (e.g., below 5 mbar) or in a nitrogen stream), it loses its organic solvent molecules and becomes crystal form 1. In some embodiments, the conversion of crystal form 2 to crystal form 1 proceeds via a crystallization intermediate. It is believed that this crystallization intermediate is a dehydrated form that rapidly absorbs water from the air. While not wishing to be bound by theory, it is believed that solvent molecules can be removed without dissolving and recrystallizing the crystals.

[0332] Crystal form 1 of obeticholic acid can be obtained not only from the above-described mixture of water and ethanol, but also from a slurry of obeticholic acid in water and an organic solvent selected from methanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, DMF and DMSO. After drying the different mixed solvates (crystal form 2) obtained under these conditions, the same obeticholic acid crystalline hydrate, i.e., crystal form 1, can be obtained.

[0333] Crystal form 1 contains a void volume that can contain up to about 2 moles of water associated with the crystal per mole of obeticholic acid, depending on the relative humidity. This form is thus formally a channel hydrate. However, at about 30% relative humidity, crystal form 1 contains substantially stoichiometric amounts of about 1.5 moles of water per mole of the organic compound and is thus a sesquihydrate. Substantially stoichiometric amounts of water are considered advantageous because the water content of the crystals remains substantially constant even in the presence of humidity changes within the normal relative humidity range of about 30% to about 70% RH. In fact, at normal humidities, for example, between about 30% and about 70% RH, crystal form 1 exhibits relatively low hygroscopicity.

[0334] In one embodiment, the formulation comprises crystalline variant 1 of obeticholic acid, which has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1-radiation and has specific peaks at least at the following °2θ positions: 5.6±0.2, 6.7±0.2, and / or 12.1±0.2.

[0335] In a specific embodiment, the formulation comprises crystalline variant 1, which has an XRPD pattern obtained with CuKα1-radiation and has specific peaks at the following °2θ positions: 5.6±0.2, 6.7±0.2, and 12.1±0.2, and has one or more characteristic peaks at the following positions: 4.1±0.2, 4.6±0.2, 9.3±0.2, 9.4±0.2, and 10.7±0.2.

[0336] In a more specific embodiment, the formulation comprises crystalline variant 1, which has an XRPD pattern obtained with CuKα1-radiation and has specific peaks at the following °2θ positions: 4.6±0.2, 5.6±0.2, 6.7±0.2, 9.3±0.2, 9.4±0.2, and 12.1±0.2.

[0337] In yet a more specific embodiment, the formulation comprises crystalline variant 1, which has an XRPD pattern obtained with CuKα1-radiation and has characteristic peaks at the following °2θ positions: 4.1±0.2, 4.6±0.2, 5.6±0.2, 6.7±0.2, 9.3±0.2, 9.4±0.2, 10.7±0.2, and 12.1±0.2, and has characteristic peaks at one or more of the following positions: 8.1±0.2, 8.6±0.2, 13.4±0.2, 13.8±0.2, 13.9±0.2, 16.6±0.2, 17.3±0.2, 17.7±0.2, 18.3±0.2, 18.9±0.2, 19.4±0.2, 19.7±0.2, 20.5±0.2, 20.8±0.2, 21.6±0.2, 23.2±0.2, 24.3±0.2, 29.8±0.2, and 30.6±0.2.

[0338] In an even more specific embodiment, the formulation comprises crystalline variant 1, which has an XRPD pattern obtained with CuKα1-radiation and has characteristic peaks at the following °2θ positions: 4.1 ± 0.2, 4.6 ± 0.2, 5.6 ± 0.2, 6.7 ± 0.2, 8.1 ± 0.2, 8.6 ± 0.2, 9.3 ± 0.2, 9.4 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 13.4 ± 0.2, 13.8 ± 0.2, 13.9 ± 0.2, 16.6 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.6 ± 0.2, 23.2 ± 0.2, 24.3 ± 0.2, 29.8 ± 0.2 and 30.6 ± 0.2.

[0339] In another embodiment, the formulation comprises crystalline variant 1, which has an XRPD pattern obtained with CuKα1-radiation and is substantially as Figure 1 shown.

[0340] Although crystalline variant 1 is a sesquihydrate containing about 3.5% (w / w) water (based on the total weight of the crystal) at about 30% relative humidity, it has been observed that the crystal can absorb an additional 1.5% (w / w) water when the humidity is increased up to 95% RH. The absorption and desorption of this additional water are completely reversible. The additional water can be absorbed onto the surface or can further fill the channels of the structure. In some embodiments, the term "overhydrated" means that crystalline variant 1 contains about 1.5 to about 4 moles of water per mole of obeticholic acid, such as about 1.5 to about 3.5, or such as about 1.5 to 3, or such as about 1.5 to about 2.5, or such as about 1.5 to about 2 moles of water per mole of obeticholic acid. In some embodiments, the term "overhydrated" means that crystalline variant 1 contains about 2 to about 4 moles of water per mole of obeticholic acid, such as about 2 to about 3.5, or such as about 2 to about 3, or such as about 2 to 2.5 moles of water.

[0341] It has been observed that the XRPD pattern of overhydrated crystalline variant 1 changes slightly when dried, for example, in vacuo at 50 °C. As Figure 3 and Figure 4 show respectively, small displacements of the peaks are very clearly observed in the 5 - 13° and 18 - 25° 2θ ranges. Exposing the dried variant to elevated relative humidity, such as up to 95% RH, causes the XRPD pattern of the overhydrated variant to reappear. The peak displacement is the result of a change in the unit cell volume, which occurs due to water molecules entering and leaving the crystal structure.

[0342] Thus, in another embodiment, the formulation comprises an overhydrated crystalline variant 1 having an X-ray powder diffraction (XRPD) pattern obtained with CuKα1-radiation, which has specific peaks at least at the following °2θ positions: 5.7 ± 0.2, 6.7 ± 0.2, and / or 12.0 ± 0.2.

[0343] In a specific embodiment, the formulation comprises an overhydrated crystalline variant 1 having an XRPD pattern obtained with CuKα1-radiation, which has specific peaks at the following °2θ positions: 5.7 ± 0.2, 6.7 ± 0.2, and 12.0 ± 0.2, and one or more characteristic peaks at the following positions: 4.0 ± 0.2, 9.4 ± 0.2, 9.6 ± 0.2, and 10.8 ± 0.2.

[0344] In a more specific embodiment, the formulation comprises an overhydrated crystalline variant 1 having an XRPD pattern obtained with CuKα1-radiation, which has specific peaks at the following °2θ positions: 4.0 ± 0.2, 5.7 ± 0.2, 6.7 ± 0.2, 9.4 ± 0.2, 9.6 ± 0.2, 10.8 ± 0.2, and 12.1 ± 0.2.

[0345] In an even more specific embodiment, the formulation comprises an overhydrated crystalline variant 1 having an XRPD pattern obtained with CuKα1-radiation, which has characteristic peaks at the following °2θ positions: 4.0 ± 0.2, 5.7 ± 0.2, 6.7 ± 0.2, 9.4 ± 0.2, 9.6 ± 0.2, 10.8 ± 0.2, and 12.1 ± 0.2, and characteristic peaks at one or more of the following positions: 4.7 ± 0.2, 8.0 ± 0.2, 8.6 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.3 ± 0.2, 16.5 ± 0.2, 17.3 ± 0.2, 19.3 ± 0.2, 19.7 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 20.8 ± 0.2, 21.7 ± 0.2, 23.6 ± 0.2, 26.2 ± 0.2, 26.5 ± 0.2, 28.3 ± 0.2, and 30.9 ± 0.2.

[0346] In an even more specific embodiment, the formulation comprises an overhydrated crystalline variant 1 having an XRPD pattern obtained with CuKα1-radiation, which has characteristic peaks at the following °2θ positions: 4.0 ± 0.2, 4.7 ± 0.2, 5.7 ± 0.2, 6.7 ± 0.2, 8.0 ± 0.2, 8.6 ± 0.2, 9.4 ± 0.2, 9.6 ± 0.2, 10.8 ± 0.2, 12.1 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.3 ± 0.2, 16.5 ± 0.2, 17.3 ± 0.2, 19.3 ± 0.2, 19.7 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 20.8 ± 0.2, 21.7 ± 0.2, 23.6 ± 0.2, 26.2 ± 0.2, 26.5 ± 0.2, 28.3 ± 0.2 and 30.9 ± 0.2.

[0347] In yet another embodiment, the formulation comprises an overhydrated crystalline variant 1 of obeticholic acid having an XRPD pattern obtained with CuKα1-radiation, which is substantially as Figure 2 shown.

[0348] It is desirable to avoid the use of organic solvents in the preparation of the formulation. In some embodiments, water is used as the solvent for preparing the formulation. Obeticholic acid has very poor solubility in water and its solubility at pH 7 and 37 °C has been determined to be as low as about 30 μg / mL. Due to the low solubility in water, an aqueous suspension of obeticholic acid can contain larger obeticholic acid aggregates, which can lead to non-uniform distribution of the active pharmaceutical ingredient on the nuclei (i.e., the nuclei can contain different amounts of obeticholic acid, which in turn affects the uniformity of the dose). Therefore, in some embodiments, the aqueous suspension of obeticholic acid is uniform. In some embodiments, a uniform aqueous suspension of obeticholic acid is sprayed onto the nuclei.

[0349] Obeticholic acid exhibits high potency and it should be administered at a low dose, especially when treating pediatric patients weighing about 4 to ≥55.5 kg. In order to achieve a high dose uniformity of the multi-particle formulation described herein, it is very important that each particle of the formulation substantially contains the same amount of obeticholic acid, i.e., the deviation in the obeticholic acid content in the particles of the formulation should be as small as possible.

[0350] As used herein, the term "uniform" refers to a suspension that does not contain obeticholic acid aggregates greater than about 200 µm, such as aggregates greater than about 100 µm, or aggregates greater than about 50 µm. The size of obeticholic acid aggregates in the coating suspension can be determined by optical microscopy, using the method based on European Pharmacopoeia 9.0, monograph 2.9.37 and as described in the experimental section herein. Alternatively, the size of obeticholic acid aggregates in the coating suspension can be determined by light scattering techniques, such as low angle laser light scattering (LALLS). In some embodiments, the d 90 value is less than 15 µm, such as less than 14 µm, such as less than 13 µm, such as less than 12 µm, such as less than 11 µm, or such as less than 10 µm.

[0351] In some embodiments, a uniform suspension of obeticholic acid can be obtained by wet milling the compound in water. Wet milling is a method that disperses solid substances in a liquid by shear, crushing, and grinding. Examples of wet milling devices include colloid mills, conical mills, ball mills, disk mills, and high shear dispersers. A specific example of a wet milling device for the formulations provided by the present invention is a colloid mill.

[0352] In some embodiments, the crystallinity of obeticholic acid increases during wet milling.

[0353] In some embodiments, obeticholic acid is first wetted in a small amount of water using a homogenizer and then dispersed in water using a colloid mill. The homogenized dispersion is sprayed onto the core to evenly distribute the active pharmaceutical ingredient.

[0354] Desirably, the formulation does not contain any ingredients that are not absolutely necessary for the formulation, such as surfactants. Thus, in some embodiments, the coating suspension does not contain surfactants. Similarly, in some embodiments, the coating layer of the formulation does not contain surfactants.

[0355] In one embodiment, the granules are contained in a sachet. In another embodiment, the granules are contained in a capsule. Such capsules can be made of gelatin, of cellulose-based polymers (e.g., hydroxypropyl methylcellulose (hypromellose)), or of polysaccharide-based polymers (e.g., pullulan). The capsule can be swallowed whole or can be designed to open so that, for example, the contents (i.e., the granules) can be sprinkled on a food carrier for administration. In the latter case, the number of granules in one capsule should be suitable to be placed on one teaspoon of food. In some embodiments, the capsule contains from about 20 to about 100 mg of granules, such as about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, or about 90 mg.

[0356] For younger pediatric patients, such as infants, toddlers, and children up to about 6 years of age, the granules can be sprinkled on foods that are easy to swallow and do not require chewing, such as yogurt, applesauce, pureed fruit, or oatmeal. For older pediatric patients, such as children older than about 6 years of age, adolescents, young adults, the capsule containing the granules can be swallowed whole, for example, without opening the capsule. For neonatal patients up to 6 months of age who are not yet weaned or unable to eat semi-solid foods, the dosage formulation can be administered by dispersing the granules in a suitable liquid carrier, such as breast milk, infant formula, or water. When the granules have been dispersed in the liquid vehicle, they can be administered to the patient within 30 minutes after dispersion without signs of loss or degradation of the active ingredient. In some embodiments, the volume of the liquid carrier (including rinsing) used for administering obeticholic acid granules can be less than about 20 mL, such as less than about 15 mL, such as less than about 10 mL, such as less than about 5 mL. In some embodiments, an oral syringe is used to directly administer the dispersed granules into the mouth.

[0357] Multiple embodiments of the invention have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the appended claims. Examples

[0358] Example 1. Phase 3 double-blind, randomized, placebo-controlled study (ASSERT) of the safety and efficacy of obeticholic acid in patients with Alagille syndrome.

[0359] Alagille syndrome (ALGS) is a rare multisystem disorder with diverse clinical manifestations affecting the liver, heart, bones, eyes, central nervous system, kidneys, and facial features. The disease is an autosomal dominant genetic disorder caused by defects in components of the NOTCH signaling pathway, with mutations in the JAG1 gene being the most common cause in about 90% of patients. A minority of ALGS patients have mutations in the gene for the NOTCH2 receptor. About 60% of cases are de novo mutations. Most patients present with jaundice or cardiac symptoms early (usually within 3 months of age).

[0360] The diagnosis of ALGS has historically been difficult because of the variety of clinical presentations; even histologic examination of liver biopsy material may not always be definitive. With the advent of genetic testing, the diagnosis of ALGS has been confirmed clinically or by identification of mutations in JAG1 or NOTCH2 sequence analysis.

[0361] Most patients with ALGS present with severe, intractable pruritus, which can be disabling. Attempts to manage pruritus include incorporating medications such as ursodeoxycholic acid, cholestyramine, rifampin, ondansetron, or naltrexone into the patient’s regimen; these medications are only partially effective at best. Biliary diversion surgery is sometimes used to treat intractable pruritus with some success. Treatment of persistent cholestasis and progressive cirrhosis is supportive and often includes choleretics. Kasai hepaticoportoenterostomy (HPE) has been attempted to increase bile flow from the liver to the intestine, but unlike patients with biliary atresia, patients with ALGS who undergo this procedure have poor outcomes. Approximately 15% to 25% of patients with ALGS require liver transplantation during childhood. Patients with ALGS respond well to transplantation, with approximately 90% experiencing improvement in liver parameters and some catch-up growth. The 5-year survival rate after transplantation in this population is approximately 80%.

[0362] In addition to cholestasis and pruritus, other features of ALGS include jaundice, elevated bile acids and liver biochemical parameters, cardiovascular abnormalities, xanthomas, and fat-soluble vitamin deficiencies.

[0363] IBAT, also known as apical sodium-dependent bile acid transporter (SLC10A2), is located on the luminal surface of enterocytes in the terminal ileum; this transporter mediates the reabsorption of conjugated bile acids and their recycling back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation, resulting in the excretion of bile acids in the feces, similar to surgical interruption of the enterohepatic circulation.

[0364] method

[0365] Study Design and Treatment

[0366] Odevixibat is an orally potent, enterohepatic-restricted, selective IBAT inhibitor that is currently being developed for the treatment of cholestatic liver diseases. The efficacy and safety of odevixibat were evaluated relative to placebo in patients with Alagille syndrome (ALGS) in this Phase 3, double-blind, randomized, 24-week trial (ASSERT). The efficacy of odevixibat in patients with ALGS was evaluated in a 24-week randomized, double-blind, placebo-controlled trial (NCT04674761; ASSERT) conducted in 52 patients diagnosed with ALGS. Patients were randomized 2:1 to receive odevixibat 120 µg / kg / day or placebo. The objectives of this study were to demonstrate the efficacy of the once-daily repeated dose of 120 μg / kg / day odevixibat in relieving pruritus in patients with ALGS, to evaluate the effect of odevixibat on serum bile acid levels in patients with ALGS, and to evaluate the safety and tolerability of odevixibat in patients with ALGS.

[0367] The study included a screening period and a parallel-design treatment period. There were two screening visits: the first was conducted between -56 and -21 days prior to the first administration of study drug, and the second was conducted between -49 and -14 days. On Day 0, all eligible patients were randomized 2:1 to receive oral odevixibat 120 µg / kg / day or placebo once daily. Eligibility for randomization was determined by reports of pruritus or scratching from observer-reported outcomes (ObsRO) / patient-reported outcomes (PRO) data to assess pruritus (PRO), scratching (ObsRO), and sleep disturbance (PRO and ObsRO) in the 14 days prior to Day 1 of the study, clinical genetic diagnosis confirmation, and liver biochemical assessment from previous screening visits. After obtaining written informed consent, patients were assigned to treatment using an interactive web response system (IWRS). The randomization codes were computer-generated by Albireo or a qualified randomization vendor.

[0368] Both odevixibat and placebo were provided in capsule form for oral administration. White opaque capsules containing granules of odevixibat or placebo were provided. There were two different capsule sizes available: Size 0 capsules could be opened, and Size 3 capsules could be swallowed whole. Size 3 capsules were only opened in special circumstances (e.g., the patient was unable to swallow the capsule whole). To ensure the blindness of treatment assignment, the study drug and the matching placebo had the same shape and size, and the labels on the study drug containers did not indicate the randomized treatment assignment. The distribution of the study drug was coordinated by the IWRS.

[0369] Treatment was assigned during the on-site clinic visit, and patients or caregivers were instructed to take or administer the study drug at home every morning, either as intact capsules (swallowed with a glass of water and food) or the capsules could be opened and the contents sprinkled into a small amount of soft food at room temperature (e.g., applesauce) and then mixed with water. The double-blind ASSERT treatment period lasted 24 weeks.

[0370] Patients who completed the treatment period either participated in a follow-up visit 28 days (±7 days) after taking the last dose of the study drug or they could continue to participate in an optional open-label extension study (ASSERT-EXT; ClinicalTrials.gov identifier: NCT05035030), in which all patients received obeticholic acid treatment. Up to 10 clinic visits were planned, including visits for screening, treatment, and follow-up, and a phone call was made between the 2-week and 4-week follow-up visits after randomization.

[0371] Patient - Key Eligibility Criteria

[0372] Patients (of any age) genetically diagnosed with ALGS were eligible for inclusion. Patients must have a history of severe pruritus, elevated baseline serum bile acid levels, an observed mean scratch score reported by the caregiver or a pruritus score reported by the patient ≥2 (on a 0 - 4 scale), which was measured using the ObsRO instrument (for patients <18 years old) or the PRO instrument (for > patients 18 years old) within 14 days before randomization. In addition, the caregiver or age-appropriate patient (≥8 years old) agreed to use an electronic diary (eDiary) device to record symptoms.

[0373] Exclusion criteria included the following: history or presence of other types of liver disease (e.g., any type of biliary atresia, progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis, liver cancer, or liver metastases detected by imaging); diseases or conditions known to interfere with drug absorption, distribution, metabolism (especially bile acid metabolism), or excretion in the gut (e.g., inflammatory bowel disease); chronic (i.e., >3 months) diarrhea; active, clinically significant acute or chronic infections or infections requiring hospitalization or parenteral anti-infective treatment within 4 weeks after treatment initiation; cancer (except basal cell carcinoma) within the past 5 years; cancer >5 years before screening (except non-hepatic cancer without signs of recurrence); or chronic kidney disease. Patients were excluded if they had undergone biliary diversion surgery within 6 months before the start of the screening period; had a liver transplant or were scheduled for a liver transplant within 6 months after randomization; had symptoms of decompensated liver disease (e.g., ascites); or had pruritus caused by any condition other than ALGS (e.g., refractory atopic dermatitis, other primary pruritic skin diseases). The use of resins or drugs that slow gastrointestinal motility was not permitted. Patients with laboratory parameters above the following thresholds were excluded: international normalized ratio (INR) >1.4, serum alanine aminotransferase (ALT) >10 times the upper limit of normal (ULN) at screening, serum ALT >15 times the ULN within the past 6 months, and total bilirubin >15 times the ULN at screening. Other exclusion criteria included any pregnant or lactating patients or patients planning to become pregnant within 24 weeks after randomization; patients with a history of alcohol or drug abuse; and patients who had investigational exposure to drugs, biologics, or medical devices within 30 days before screening or within 5 half-lives (whichever was longer) of the study drug.

[0374] Assessment

[0375] A single primary endpoint was evaluated. The primary endpoint of this study was the change in scratching measured by the Observer Reported Outcome (ObsRO) instrument from baseline to month 6 (weeks 21 to 24).

[0376] The study also investigated a second primary endpoint, which was the change in serum bile acid levels from baseline to the mean at weeks 20 and 24. Other secondary efficacy endpoints were as follows:

[0377] The change in pruritus measured by the Albireo PRO instrument from baseline to month 6 (weeks 21 to 24).

[0378] The percentage of patients who achieved a clinically significant reduction in pruritus (pruritus responders) measured by the ObsRO / PRO instrument.

[0379] Changes in patient-reported itch and scratch severity scores from baseline to week 24, and observer-reported itch and scratch severity scores from baseline to week 24, were for morning and evening assessments, respectively; sleep parameters (such as degree of fatigue and number of awakenings) measured using the Albireo ObsRO / PRO instrument; and PedsQL subdomain scores.

[0380] Assessment of overall symptom relief from baseline to weeks 4, 12, and 24, measured by the patient, caregiver, and clinician global impression of symptoms GIS (PGIS, CaGIS, CGIS) items.

[0381] Changes in xanthomatosis from baseline to week 24, assessed by the clinician xanthoma scale; serum bile acid levels; serum ALT concentration; serum AST concentration; gamma-glutamyl transferase concentration; total bilirubin concentration.

[0382] Biochemical markers and measurements of bile acid synthesis (autotaxin, p-C4, only for patients with body weight > 10 kg); and change in total cholesterol concentration relative to baseline.

[0383] Itch, scratch, and sleep parameters. Itch, observed scratch, and sleep disturbances were recorded twice daily via an electronic diary. Throughout the study, patients and / or caregivers were instructed to complete the electronic diary every morning after the patient woke up and every evening before the patient went to bed. The electronic diary included ObsRO and PRO items. The PRO items evaluated the severity of itch, aspects of sleep disturbance (only in the morning diary), and degree of fatigue. The ObsRO items evaluated the severity of observed scratch, aspects of observed sleep disturbance (only in the morning diary), and signs of fatigue (only in the evening diary). See Figure 26 The ObsRO and PRO scratch and itch severity items used a 0 to 4 response scale.

[0384] Serum bile acids. Blood samples were drawn at all outpatient visits for analysis of fasting serum total bile acids. All post-baseline serum bile acids were blinded. Samples were processed according to the instructions in the laboratory manual and sent to the central laboratory.

[0385] Biomarkers and PK Samples. Blood samples were taken at Screening Visits 1 and 2, randomization (Study Day 1), Weeks 4 to 24 / EOT, and Safety Follow-up Visits for clinical chemistry analysis. As shown in Table 1, total bilirubin, AST, ALT, and gamma-glutamyl transferase assessments were included as part of the routine laboratory parameters. At randomization (Study Day 1), Week 12, and Week 24 / EOT, blood samples were taken only from children weighing >10 kg to measure autocrine motility factor and p-C4. At Week 4, Week 20, and EOT (only for children weighing >10 kg), blood was taken for obeticholic acid PK assessment. Samples were processed according to the instructions in the laboratory manual and shipped to the laboratory.

[0386] Table 1. Routine Laboratory Parameters

[0387]

[0388] ALT = alanine aminotransferase; AST = aspartate aminotransferase.

[0389] Global Impression of Change and Global Impression of Symptoms Measurement. Patients (≥8 years old), caregivers, and clinicians completed the Global Impression of Change (GIC) measurement (Patient Global Impression of Change (PGIC), Caregiver Global Impression of Change (CaGIC), and Clinician Global Impression of Change (CGIC)) and the Global Impression of Symptoms (GIS) measurement (Patient Global Impression of Symptoms (PGIS), Caregiver Global Impression of Symptoms (CaGIS), Clinician Global Impression of Symptoms (CGIS)) at randomization (Study Day 1; only PGIS), Weeks 4, 12, and 24 / EOT.

[0390] The GIC items evaluated changes in itching (patient version), scratching (caregiver and clinician versions), and sleep (all versions) since starting the study drug. The GIS items evaluated itching (patient version), scratching (caregiver and clinician versions), and sleep (all versions) in the past week. Caregivers and clinicians completed the GIC and GIS for all patients; those patients ≥8 years old completed the patient versions.

[0391] Clinical assessment of xanthomas. The xanthoma changes in the subjects were evaluated using the Clinician Xanthoma Scale at randomization (Day 1 of the study), Week 12, and Week 24 / EOT visit. The clinician's assessment of the participants' xanthomatosis focused on the number of existing lesions and the extent to which the participants' lesions interfered with or restricted activities. The Clinician Xanthoma Scale used a 5-point scale, where 0 indicated no evidence of xanthomatosis, 1 indicated fewer than 20 scattered individual lesions, 2 indicated more than 20 lesions but without interference or restriction of activities, 3 indicated a large number of lesions, and their number or size caused deformation of the face or limbs, and 4 indicated xanthomas that interfered with function (such as hand use or walking ability) due to excessive size or number.

[0392] Safety. The primary safety analyses of this study included the incidence of adverse events (AEs) occurring during the total treatment and the incidence of treatment-emergent adverse events (TEAEs), which were classified by the investigator based on the exposure to the study drug and placebo, and evaluated according to causality, severity, and seriousness. Other safety assessments included physical examinations, concomitant medications, vital signs, laboratory tests, and liver ultrasound and elastography.

[0393] Statistical analysis. The planned sample size was forty-five (45) patients under 18 years of age, randomly assigned in a 2:1 experimental to control allocation ratio to obtain approximately 36 completers, assuming a dropout rate of approximately 20%. Subjects under 18 years of age were randomly assigned according to one age stratification factor, i.e., <10 years and 10 to <18 years. This stratification factor was based on the increased prevalence and severity of pruritus in children under 10 years of age. At a one-sided significance level of α = 0.025, assuming a pooled standard deviation (SD) of 1.0 and a difference in pruritus change between treatment groups of 1.2 in favor of the response, using the exact method (ProcPower, SAS v.9.4, Cary, NC), the power of this study was 0.909. The key secondary endpoints were also confirmed with a standardized treatment effect (treatment effect / SD) of 1.2. After at least 18 patients completed the Week 16 visit, an independent statistician calculated the pooled SD of the changes from baseline to Month 4 (assessed at Weeks 13 - 16) and the available change in the mean monthly scratching score from baseline to Month 6 (assessed at Weeks 21 - 24) to evaluate whether a sample size re-estimation was needed. The sample size re-estimation was based on non-comparative blinded data without α adjustment. If the pooled SD was underestimated in this sample size calculation, an adjustment would be made to maintain the study power, assuming a treatment effect of 1.2. It was assumed that the SDs at Week 16 and Week 24 were equal; however, a multiplicative factor (1.07) could be used for the calculated SD based on the current understanding of the instrument at the time of sample size re-estimation. If the standard deviation (SD) was overestimated in the initial sample size calculation, the sample size would not be reduced. Based on Figure 21A planned sample size re - estimation was conducted; the sample size was increased to the target of 48 completers (i.e., based on a 2:1 randomization, approximately 32 and 16 in the obeticholic acid group and the placebo group, respectively). Given the low actual dropout rate at that time, 7 patients were added to the study. A total of 52 patients were included.

[0394] Results

[0395] Patients

[0396] Patient disposition. Study disposition and baseline characteristics are as Figures 1-3 shown. A total of 52 patients were randomized, 17 of whom received placebo treatment and 35 received obeticholic acid 120 μg / kg / day treatment. Overall, all 52 (100%) patients completed the 24 - week treatment period ( Figure 2 ).

[0397] Summary of patient demographics and baseline characteristics is presented in Figure 3 . The mean patient age was 6.3 years; 27 (52%) were male. 92% of the patients carried the JAG1 mutation and 8% carried the NOTCH2 mutation. At baseline (at the start of the study), 89% of the patients were receiving ursodeoxycholic acid (UDCA) treatment and 98% were receiving antipruritic medications. The mean (SD) pruritus score at baseline (range: 0 - 4) was 2.9 (0.6). The mean (SD) bile acid level at baseline was 240 (116) μmol / L. The mean (SD) ALT, AST, and bilirubin levels at baseline were 174 (84) U / L, 167 (83) U / L, and 3.2 (2.8) mg / dL, respectively. See Figure 3 .

[0398] Efficacy

[0399] Primary and secondary endpoints

[0400] The study met the primary endpoint. The primary endpoint was the change in the scratch score measured by the Albireo ObsRO caregiver instrument from baseline to month 6 (weeks 21 - 24). Compared with placebo, the improvement in pruritus symptoms in the obeticholic acid group was significant ( Figure 4 and 5 ). According to the ObsRO instrument, from baseline to weeks 21 - 24 of the treatment period, compared with the placebo group, the overall treatment with obeticholic acid 120 μg / kg / day statistically significantly improved pruritus symptoms: the least - squares (LS) mean change in the scratch score from baseline to weeks 21 - 24 was - 1.69 points (P = 0.0024; 34 patients in obeticholic acid 120 μg / kg / day) compared with 16 patients receiving placebo (a decrease of - 0.8 points in weeks 21 - 24)( Figure 4 and 5)。The pruritus symptoms of patients with JAG1 and NOTCH2 mutations treated with obeticholic acid improved at weeks 21 - 24 compared to those treated with placebo ( Figure 12A )。

[0401] The reduction in serum bile acids in the obeticholic acid group was also significantly greater compared to the mean levels in the placebo group at weeks 20 and 24 (P = 0.0012; Figure 6 )。The serum bile acid levels in patients treated with obeticholic acid decreased by an average of 90 µmol / L, while thos...

Claims

1. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for the treatment of Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a decrease in the itch score relative to the baseline.

2. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for the treatment of pruritus associated with Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a decrease in the itch score relative to the baseline.

3. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for reducing the itch score of a subject with Alagille syndrome (ALGS) relative to the baseline.

4. The preparation for use according to any one of claims 1-3, wherein the itch score is reduced by 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.

5. The preparation for use according to any one of claims 1-4, wherein the itch score is reduced by about 1.2 to about 2.0 relative to the baseline.

6. The preparation for use according to any one of claims 1-5, wherein the itch score is reduced by about 1.6 relative to the baseline.

7. The preparation for use according to any one of claims 1-6, wherein the decrease in the itch score relative to the baseline occurs 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 after administration of the pharmaceutical preparation.

8. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for the treatment of Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a decrease in the serum bile acid concentration.

9. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for the treatment of pruritus associated with Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a decrease in the serum bile acid concentration.

10. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for reducing the serum bile acid concentration of a subject with Alagille syndrome (ALGS).

11. The preparation for use according to any one of claims 8-10, wherein the serum bile acid concentration is reduced by at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L or at least 175 μmol / L relative to the baseline.

12. The preparation for use according to any one of claims 8-10, wherein the serum bile acid concentration is reduced by about 50 μmol / L to about 180 μmol / L relative to the baseline.

13. The preparation for use according to any one of claims 8-10, wherein the serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline.

14. The preparation for use according to any one of claims 8 - 13, wherein the reduction in serum bile acid concentration occurs 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 after administration of the pharmaceutical preparation.

15. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used for the treatment of Alagille syndrome (ALGS), wherein at least 24 weeks after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

16. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used for the treatment of pruritus associated with Alagille syndrome (ALGS), wherein at least 24 weeks after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

17. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used for the treatment of Alagille syndrome (ALGS), wherein at least 24 weeks after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a reduction in serum bile acid concentration of at least 50% relative to the baseline.

18. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used for the treatment of pruritus associated with Alagille syndrome (ALGS), wherein at least 24 weeks after oral administration of the pharmaceutical preparation to a subject, the subject exhibits a reduction in serum bile acid concentration of at least 50% relative to the baseline.

19. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used to reduce the serum bile acid concentration by at least 50% relative to the baseline by orally administering the pharmaceutical preparation to a subject with Alagille syndrome (ALGS) for at least 24 weeks.

20. The preparation for use according to any one of claims 17 - 19, wherein the subject exhibits a reduction in serum bile acid concentration of at least 60%, at least 70%, or at least 80% relative to the baseline.

21. Its pharmaceutically acceptable salt, which is used to improve the sleep parameters of a subject with ALGS.

22. The preparation for use according to claim 21, wherein the sleep parameters are selected from: the percentage of days with scratching related to bleeding, the percentage of days requiring help to fall asleep, the percentage of days requiring soothing, the degree of fatigue, and the percentage of days requiring co - sleeping with a caregiver.

23. The preparation for use according to claim 21 or claim 22, wherein the improvement in sleep parameters occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks after administration of the pharmaceutical preparation.

24. A pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, which is used to improve the liver parameters or biomarkers of a subject with ALGS.

25. The preparation for use according to claim 24, wherein the liver parameter or biomarker is selected from: autocrine motility factor level, plasma C4 level, total bilirubin level, serum alanine aminotransferase (ALT) level, serum γ-glutamyl transferase (GGT), and serum aspartate aminotransferase (AST) level.

26. The preparation for use according to claim 24 or claim 25, wherein the improvement of the liver parameter occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks after administration of the pharmaceutical preparation.

27. The preparation for use according to any one of claims 1-26, wherein the subject is a pediatric subject.

28. The preparation for use according to any one of claims 1-27, wherein obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 120 μg / kg / day.

29. The preparation for use according to any one of claims 1-28, wherein the subject has not used obeticholic acid before the first administration of the pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

30. The preparation for use according to any one of claims 1-29, wherein the pharmaceutical preparation of obeticholic acid or a pharmaceutically acceptable salt thereof comprises a plurality of particles, wherein the size of each particle is between about 0.1 and about 1.5 mm, and comprises from about 0.1% w / w to about 5.0% w / w of obeticholic acid or a pharmaceutically acceptable salt thereof based on the total weight of the particles.

31. The preparation for use according to claim 30, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w to about 2.0% w / w based on the total weight of the particles.

32. The preparation for use according to claim 30 or 31, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w based on the total weight of the particles.

33. The preparation for use according to any one of claims 30-32, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of about 1.5% w / w based on the total weight of the particles.

34. The preparation for use according to any one of claims 30-33, wherein each particle comprises a core and a coating layer surrounding the core.

35. The preparation for use according to any one of claims 30-34, wherein the core does not contain obeticholic acid or a pharmaceutically acceptable salt thereof.

36. The preparation for use according to any one of claims 30-35, wherein the core comprises microcrystalline cellulose.

37. The preparation for use according to any one of claims 34-36, wherein the coating layer comprises obeticholic acid or a pharmaceutically acceptable salt thereof.

38. The preparation for use according to any one of claims 34-37, wherein the coating layer comprises a film-forming polymer.

39. The preparation for use according to any one of claims 34-38, wherein the coating layer is sprayed onto the particles as a homogeneous suspension of obeticholic acid in water.

40. The preparation for use according to claim 39, wherein the homogeneous suspension is prepared by wet milling obeticholic acid or a pharmaceutically acceptable salt thereof in water.

41. The preparation for use according to claim 39 or 40, wherein the homogeneous suspension does not contain obeticholic acid aggregates larger than 200 µm.

42. The preparation for use according to any one of claims 34 - 41, wherein the coating layer does not contain a surfactant.

43. The preparation for use according to any one of claims 30 - 42, wherein the size of the particles is between about 0.1 and about 1.0 mm.

44. The preparation for use according to any one of claims 30 - 43, wherein obeticholic acid is present as the crystalline hydrate of obeticholic acid.

45. The preparation for use according to any one of claims 30 - 44, wherein obeticholic acid is present as crystal form 1 of obeticholic acid.

46. The preparation for use according to claim 45, wherein crystal form 1 of obeticholic acid has an X - ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, which has specific peaks at least at the following °2θ positions: 5.6 ± 0.2, 6.7 ± 0.2, and / or 12.1 ± 0.

2.

47. The preparation for use according to any one of claims 30 - 46, wherein the particles are contained in a sachet or capsule.

48. The preparation for use according to any one of claims 1 - 29, wherein obeticholic acid is present as the hydrate of obeticholic acid.

49. The preparation for use according to claim 48, wherein obeticholic acid is present as the sesquihydrate.

50. The preparation for use according to any one of claims 1 - 29 and 48 - 49, wherein obeticholic acid is present as the crystalline hydrate of obeticholic acid.

51. The preparation for use according to claim 50, wherein obeticholic acid is present as crystal form 1 of obeticholic acid.

52. The preparation for use according to claim 51, wherein crystal form 1 of obeticholic acid has an X - ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, which has specific peaks at least at the following °2θ positions: 5.6 ± 0.2, 6.7 ± 0.2, and / or 12.1 ± 0.

2.

53. A method for treating Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical preparation, the subject exhibits a decrease in the itch score relative to baseline.

54. A method for treating pruritus associated with Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical preparation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical preparation, the subject exhibits a decrease in the itch score relative to baseline.

55. A method of reducing the itch score relative to baseline in a subject with Alagille syndrome (ALGS), the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

56. The method according to any one of claims 53-55, wherein the itch score is reduced by 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 relative to baseline.

57. The method according to any one of claims 53-56, wherein the itch score is reduced by about 1.2 to about 2.0 relative to baseline.

58. The method according to any one of claims 53-57, wherein the itch score is reduced by about 1.6 relative to baseline.

59. The method according to any one of claims 53-58, wherein the reduction in the itch score relative to baseline occurs 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 after administration of the pharmaceutical formulation.

60. A method of treating Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a reduction in serum bile acid concentration.

61. A method of treating pruritus associated with Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a reduction in serum bile acid concentration.

62. A method of reducing serum bile acid concentration in a subject with Alagille syndrome (ALGS), the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

63. The method according to any one of claims 60-62, wherein the serum bile acid concentration is reduced by at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L or at least 175 μmol / L relative to baseline.

64. The method according to any one of claims 60-62, wherein the serum bile acid concentration is reduced by about 50 μmol / L to about 180 μmol / L relative to baseline.

65. The method according to any one of claims 60-62, wherein the serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to baseline.

66. The method according to any one of claims 60-65, wherein the reduction in serum bile acid concentration occurs 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 after administration of the pharmaceutical formulation.

67. A method for treating Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical formulation for at least 24 weeks, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

68. A method for treating pruritus associated with Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical formulation for at least 24 weeks, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

69. A method for treating Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical formulation for at least 24 weeks, the subject exhibits a serum bile acid concentration that is at least 50% lower relative to baseline.

70. A method for treating pruritus associated with Alagille syndrome (ALGS) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof, wherein after administering the pharmaceutical formulation for at least 24 weeks, the subject exhibits a serum bile acid concentration that is at least 50% lower relative to baseline.

71. A method for reducing the serum bile acid concentration in a subject with Alagille syndrome (ALGS) by at least 50% relative to baseline, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof for at least 24 weeks.

72. The method according to any one of claims 69 - 71, wherein the subject exhibits a serum bile acid concentration that is at least 60%, at least 70% or at least 80% lower relative to baseline.

73. A method for improving the sleep parameters of a subject with ALGS, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

74. The method according to claim 73, wherein the sleep parameters are selected from: the percentage of days with scratching related to bleeding, the percentage of days requiring help to fall asleep, the percentage of days requiring soothing, the degree of fatigue, and the percentage of days requiring co - sleeping with a caregiver.

75. The method according to claim 73 or claim 74, wherein the improvement in the sleep parameters occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks or at least 48 weeks after administering the pharmaceutical formulation.

76. A method of improving liver parameters or biomarkers in a subject with ALGS, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

77. The method according to claim 76, wherein the liver parameter or biomarker is selected from: autotaxin level, plasma C4 level, total bilirubin level, serum alanine aminotransferase (ALT) level, serum gamma-glutamyl transferase (GGT), and serum aspartate aminotransferase (AST) level.

78. The method according to claim 76 or claim 77, wherein the improvement in the liver parameter occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks after administering the pharmaceutical formulation.

79. The method according to any one of claims 53-78, wherein the subject is a pediatric subject.

80. The method according to any one of claims 53-79, wherein 120 μg / kg / day of obeticholic acid or a pharmaceutically acceptable salt thereof is administered to the subject.

81. The method according to any one of claims 53-80, wherein the subject has not used obeticholic acid prior to the first administration of the pharmaceutical formulation comprising obeticholic acid or a pharmaceutically acceptable salt thereof.

82. The method according to any one of claims 53-81, wherein the pharmaceutical formulation of obeticholic acid or a pharmaceutically acceptable salt thereof comprises a plurality of particles, wherein the size of each particle is between about 0.1 and about 1.5 mm, and comprises from about 0.1% w / w to about 5.0% w / w of obeticholic acid or a pharmaceutically acceptable salt thereof based on the total weight of the particles.

83. The method according to claim 82, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of from about 0.5% w / w to about 2.0% w / w based on the total weight of the particles.

84. The method according to claim 82 or 83, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w based on the total weight of the particles.

85. The method according to any one of claims 82-84, wherein each particle comprises obeticholic acid or a pharmaceutically acceptable salt thereof in an amount of about 1.5% w / w based on the total weight of the particles.

86. The method according to any one of claims 82-85, wherein each particle comprises a core and a coating layer surrounding the core.

87. The method according to any one of claims 82-86, wherein the core does not contain obeticholic acid or a pharmaceutically acceptable salt thereof.

88. The method according to any one of claims 82-87, wherein the core comprises microcrystalline cellulose.

89. The method according to any one of claims 82-88, wherein the coating layer comprises obeticholic acid or a pharmaceutically acceptable salt thereof.

90. The method according to any one of claims 82-89, wherein the coating layer comprises a film-forming polymer.

91. A method according to any one of claims 86 - 90, wherein the coating layer is sprayed onto the particles as a homogeneous suspension of obeticholic acid in water.

92. A method according to claim 91, wherein the homogeneous suspension is prepared by wet - milling obeticholic acid or a pharmaceutically acceptable salt thereof in water.

93. A method according to claim 91 or 92, wherein the homogeneous suspension does not contain obeticholic acid aggregates greater than 200 µm.

94. A method according to any one of claims 86 - 93, wherein the coating layer does not contain a surfactant.

95. A method according to any one of claims 82 - 94, wherein the particles have a size between about 0.1 and about 1.0 mm.

96. A method according to any one of claims 82 - 95, wherein obeticholic acid is present as an obeticholic acid crystalline hydrate.

97. A method according to any one of claims 82 - 96, wherein obeticholic acid is present as crystal form 1 of obeticholic acid.

98. A method according to claim 97, wherein crystal form 1 of obeticholic acid has an X - ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, having specific peaks at least at the following °2θ positions: 5.6 ± 0.2, 6.7 ± 0.2, and / or 12.1 ± 0.

2.

99. A method according to any one of claims 82 - 98, wherein the particles are contained within a sachet or capsule.

100. A method according to any one of claims 53 - 81, wherein obeticholic acid is present as an obeticholic acid hydrate.

101. A method according to claim 132, wherein obeticholic acid is present as the sesquihydrate.

102. A method according to any one of claims 53 - 81 and 100 - 101, wherein obeticholic acid is present as an obeticholic acid crystalline hydrate.

103. A method according to claim 102, wherein obeticholic acid is present as crystal form 1 of obeticholic acid.

104. A method according to claim 103, wherein crystal form 1 of obeticholic acid has an X - ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, having specific peaks at least at the following °2θ positions: 5.6 ± 0.2, 6.7 ± 0.2, and / or 12.1 ± 0.

2.

105. A method according to any one of claims 60 - 104, wherein the subject exhibits a reduction in the itch score relative to baseline.

106. A method according to claim 105, wherein the itch score is reduced by 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 relative to baseline.

107. A method according to any one of claims 53 - 59 and 105 - 106, wherein the itch score is reduced by about 1.5 to about 4 relative to baseline.

108. A method according to any one of claims 53 - 59 and 105 - 107, wherein the pruritus score is reduced by about 1.5 to about 2.5 relative to the baseline.

109. A method according to any one of claims 53 - 59 and 105 - 108, wherein the pruritus score is reduced by about 2 relative to the baseline.

110. A method according to any one of claims 105 - 109, wherein the reduction of the pruritus score relative to the baseline occurs 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 after administration of the pharmaceutical formulation.

111. A method according to any one of claims 53 - 59 and 105 - 110, wherein the pruritus score at baseline is about 2.5 to about 4.

0.

112. A method according to any one of claims 53 - 59 and 105 - 111, wherein the pruritus score at baseline is about 2.5 to about 3.

5.

113. A method according to any one of claims 53 - 59 and 105 - 112, wherein the pruritus score at baseline is about 3.

0.

114. A method according to any one of claims 53 - 59 and 105 - 112, wherein the pruritus score at baseline is about 2.

8.

115. A method according to any one of claims 53 - 59 and 73 - 114, wherein the subject exhibits a reduction in serum bile acid concentration relative to the baseline.

116. The method according to claim 115, wherein the serum bile acid concentration is reduced by at least 50 μmol / L, at least 75 μmol / L, at least 100 μmol / L, at least 125 μmol / L, at least 150 μmol / L or at least 175 μmol / L relative to the baseline.

117. The method according to any one of claims 115 - 116, wherein the serum bile acid concentration is reduced by about 50 μmol / L to about 180 μmol / L relative to the baseline.

118. The method according to any one of claims 115 - 117, wherein the serum bile acid concentration is reduced by about 70 μmol / L to about 120 μmol / L relative to the baseline.

119. The method according to any one of claims 60 - 72 and 115 - 118, wherein the serum bile acid concentration is reduced by about 80 μmol / L to about 110 μmol / L relative to the baseline.

120. The method according to any one of claims 115 - 119, wherein the reduction of the serum bile acid concentration occurs 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 after administration of the pharmaceutical formulation.

121. The method according to any one of claims 60 - 72 and 115 - 120, wherein the serum bile acid concentration at baseline is about 180 μmol / L to about 600 μmol / L.

122. The method according to any one of claims 60 - 72 and 115 - 121, wherein the serum bile acid concentration at baseline is about 200 μmol / L to about 280 μmol / L. The method according to any one of claims 60 - 72 and 115 - 121, wherein the serum bile acid concentration at baseline is from about 230 μmol / L to about 250 μmol / L.

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