Treatment of Alagille Syndrome (ALGS)

Abstract

Provided herein are methods for treating Alagille syndrome (ALGS) with an ileal bile acid transport (IBAT) inhibitor, such as odevixibat or a pharmaceutically acceptable salt thereof. These methods can include reducing pruritus scores, reducing serum bile acid concentrations, increasing height, normalizing weight, improving sleep, and improving liver parameters.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 422,235, filed November 3, 2022, U.S. Provisional Application No. 63 / 439,945, filed January 19, 2023, U.S. Provisional Application No. 63 / 454,410, filed March 24, 2023, and U.S. Provisional Application No. 63 / 544,079, filed October 13, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] Provided herein are methods for treating Alagille syndrome (ALGS) with an ileal bile acid transporter (IBAT) inhibitor, such as odevixibat or a pharmaceutically acceptable salt thereof. These methods may include reducing pruritus scores, reducing bile acid (BA) concentrations, increasing height, normalizing body weight, improving sleep parameters, improving quality of life, improving itch / scratching symptoms and sleep, and improving liver biochemistry parameters and xanthomas. [Background technology]

[0003] The compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat; also known as A4250):

[0004] [ka]

[0005] Odevixibat is an inhibitor of the ileal bile acid transport (IBAT) mechanism. Specifically, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted in the feces. Total removal of bile acids from the enterohepatic circulation reduces serum and hepatic bile acid levels. Therefore, odevixibat or its pharmaceutically acceptable salts are useful in treating liver diseases associated with elevated bile acid levels, particularly in the treatment of rare pediatric cholestatic liver diseases, including Alagille syndrome (ALGS). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 5,994,391 [Patent Document 2] U.S. Patent No. 6,020,330 [Patent Document 3] U.S. Patent No. 6,906,058 [Patent Document 4] U.S. Patent No. 7,192,945 [Patent Document 5] U.S. Patent No. 7,132,416 [Patent Document 6] U.S. Patent No. 7,238,684 [Patent Document 7] WO96 / 05188 [Patent Document 8] U.S. Patent No. 9,409,875 [Patent Document 9] U.S. Patent No. 10,183,920 [Patent Document 10] WO2019 / 245448 [Patent Document 11] WO2019 / 245449 [Patent Document 12] WO2020 / 0167981 [Patent Document 13] WO2020 / 0167985 [Patent Document 14] WO2020 / 0167964 [License 15] U.S. Patent No. 10,709,755 [License 16] US Chartered Petitions Publication US2017 / 0143738 [Non-licensed literature]

[0007] [Non-licensed Document 1] Berhman RE, Kliegman R, Arvin AM, Nelson WE, Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996 [Non-licensed Document 2] Rudolph AM, Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002 [Non-licensed Document 3] Avery MD, First LR, Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994 [Non-licensed Document 4] Gwaltney, Adv. Ther. (2022), 39:5105-5125 [Non-licensed Document 5] Lalaら, "Liver Function Tests." StatPearls, StatPearls Publishing, October 5, 2022 (PMID: 29494096) [Non-licensed Document 6] Kozarewicz, Int. J. Pharm. 2014, vol. 469, pp 245-248 [Non-licensed Document 7] Liuら, Drugs 2014, vol. 74, pp. 1871-1889 [Non-licensed Document 8] Drumondら, Int. J. Pharm. 2017, vol. 521, pp. 294-305

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[0008] Provided herein is a method for treating Alagille Syndrome (ALGS) in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in scratching behavior score from baseline. Also provided herein is a method for treating pruritus associated with ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in scratching behavior score from baseline.

[0009] Further provided herein is a method for reducing monthly scratching behavior scores in a subject with ALGS, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the subject exhibits a decrease from baseline in one or more of the mean AM scratching score, the mean PM scratching score, and the mean AM and PM scratching scores.

[0011] In some embodiments, provided herein are methods for treating ALGS in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in serum bile acid levels.

[0012] Also provided herein is a method for treating pruritus associated with ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in serum bile acid concentrations.

[0013] Further provided herein is a method for reducing serum bile acid concentrations in a subject with ALGS, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

[0014] Provided herein are methods for treating ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after at least four weeks of administration of the pharmaceutical formulation, the subject exhibits a change from baseline in serum bile acid concentrations.

[0015] Also provided herein is a method for treating pruritus associated with ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after at least four weeks of administration of the pharmaceutical formulation, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

[0016] Further provided herein is a method for treating ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after at least 24 weeks of administration of the pharmaceutical formulation, the subject exhibits a decrease from baseline in serum bile acid concentrations.

[0017] In some embodiments, provided herein are methods for treating ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after at least 24 weeks of administration of the pharmaceutical formulation, the subject exhibits at least a 50% decrease in serum bile acid concentration compared to baseline.

[0018] Also provided herein is a method for reducing serum bile acid concentrations relative to baseline in a subject with ALGS, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation containing odevixibat or a pharmaceutically acceptable salt thereof for about 4 to about 24 weeks, e.g., 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.

[0019] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0020] [Figure 1] A schematic diagram of the study design and key inclusion criteria for the ALGS ASSERT placebo-controlled trial is shown. [Figure 2] Patient disposition in the double-blind, randomized, placebo-controlled ALGS ASSERT trial is shown. Fifty-two patients were enrolled in the trial: 17 received placebo and 35 received odevixibat. All 52 patients (100%) completed the study, and 50 patients were selectively enrolled in an open-label extension study. [Figure 3] 1 shows baseline demographic and disease characteristics of patients in the placebo-controlled ALGS ASSERT trial. [Figure 4] 1 is a bar graph showing the least squares (LS) mean change in scratching behavior score from baseline to weeks 21-24 of treatment with odevixibat compared to placebo. [Figure 5] 1 is a line graph showing the least squares (LS) mean (95% confidence interval (CI)) change in scratching behavior score from baseline to weeks 21 to 24 of treatment with odevixibat compared to placebo. [Figure 6] 1 is a bar graph showing the least squares (LS) mean change in bile acids (μmol / L) from baseline to the mean of 20 and 24 weeks of treatment with odevixibat compared to placebo. [Figure 7] FIG. 1 is a line graph showing the least squares (LS) mean (95% confidence interval (CI)) change over time in bile acids (μmol / L) from baseline to the mean of 20 and 24 weeks of treatment with odevixibat compared to placebo. [Figure 8A] 1 is a bar graph showing the percentage of patients experiencing a pruritic response (defined as a 1 or more point decrease from baseline in monthly scratching scores) at weeks 9-12 and 21-24 of treatment with odevixibat compared to placebo. [Figure 8B] 1 is a table showing the number of patients with a pruritic response (defined as a 1.5-point or greater decrease from baseline in monthly scratching scores) at weeks 9-12 and 21-24 of treatment with odevixibat compared to placebo. [Figure 8C] 1 is a bar graph showing the percentage of patients experiencing a pruritic response (defined as a 1.5-point or greater decrease from baseline in monthly scratching scores) at weeks 9-12 and 21-24 of treatment with odevixibat compared to placebo. [Figure 9] FIG. 1 is a line graph showing the least squares (LS) mean (95% confidence interval (CI)) change from baseline to weeks 21 to 24 of treatment with odevixibat compared to placebo in the percentage of days patients slept with a caregiver. [Figure 10] Least squares (LS) mean changes from baseline to 21-24 weeks of treatment with odevixibat compared to placebo for all sleep parameters measured by ObsRO are shown. [Figure 11A] FIG. 1 is a bar graph showing Global Impression of Change (GIC) for scratching behavior using clinician response percentages at 24 weeks of treatment with odevixibat compared to placebo. [Figure 11B] FIG. 1 is a bar graph showing Global Impression of Change (GIC) for sleep using clinician response percentages at 24 weeks of treatment with odevixibat compared to placebo. [Figure 11C] FIG. 1 is a bar graph showing Global Impression of Change (GIC) for scratching behavior using percent caregiver responses at 24 weeks of treatment with odevixibat compared to placebo. [Figure 11D] FIG. 1 is a bar graph showing Global Impression of Change (GIC) for sleep using caregiver response percentages at 24 weeks of treatment with odevixibat compared to placebo. [Figure 11E] FIG. 1 is a two-bar graph showing Global Impression of Change (GIC) for itch using patient response percentages at 24 weeks of treatment with odevixibat compared to placebo. [Figure 11F] FIG. 1 is a bar graph showing Global Impression of Change (GIC) for sleep using patient response percentages at 24 weeks of treatment with odevixibat compared to placebo. [Figure 12A] 1 is a bar graph showing the mean (SD) change from baseline to weeks 21 to 24 in scratching behavior scores for patients with JAG1 mutations and patients with NOTCH2 mutations (following treatment with odevixibat) (compared to placebo). [Figure 12B] 1 is a bar graph showing the change from baseline to the mean of 20 and 24 weeks (compared to placebo) in bile acids (μmol / L) (right side) in patients with JAG1 mutations and patients with NOTCH2 mutations (after treatment with odevixibat). [Figure 13]A summary of safety for all patients treated with odevixibat compared to placebo is provided. No patients discontinued from the ASSERT placebo-controlled trial, and no deaths or treatment-emergent adverse events (TEAEs) leading to treatment discontinuation were reported. [Figure 14] Modified eDISH plots showing peak total bilirubin (× baseline) and peak alanine aminotransferase (ALT) (× baseline) for each patient from baseline to weeks 21 to 24 of treatment with odevixibat compared to placebo. [Figure 15] Patient baseline ALT and total bilirubin data are presented, as well as the change from baseline to week 24 in ALT and total bilirubin in patients following treatment with odevixibat compared to placebo. [Figure 16A] 1 is a bar graph showing the mean change in patient Clinician Xanthomas Score from baseline to 12 and 24 weeks of treatment with odevixibat compared to placebo. [Figure 16B] 1 is a line graph showing the change over time in patients' mean serum cholesterol levels (mmol / L) from baseline to 24 weeks of treatment with odevixibat compared to placebo. [Figure 17] Table showing an overview of exposure and pooled baseline and post-treatment outcomes from weeks 9 to 12 (pruritus and sleep) and week 12 (bile acids) in patients with ALGS treated with odevixibat in ASSERT and ASSERT-EXT. [Figure 18A] 1 is a plot showing the mean (SD) scratching behavior score over time in a pooled population of patients with ALGS treated with odevixibat. [Figure 18B] 1 is a plot showing mean (SD) bile acid levels over time in a pooled population of patients with ALGS treated with odevixibat. [Figure 18C] 1 is a plot showing mean (SD) autotaxin values ​​over time in a pooled population of patients with ALGS treated with odevixibat. [Figure 18D] 1 is a plot showing mean (SD) C4 values ​​over time in a pooled population of patients with ALGS treated with odevixibat. [Figure 19A] 1 is a plot showing serum bile acid levels before and after odebixibat treatment in patients found to have Alagille syndrome. The vertical dashed line indicates odebixibat initiation, and shading indicates differences in the dose of odebixibat administered. [Figure 19B] 1 is a plot showing total bilirubin levels before and after odebixibat treatment in patients found to have Alagille syndrome. The vertical dashed line indicates odebixibat initiation, and shading indicates differences in the dose of odebixibat administered. [Figure 20] Flow diagram of major disease features over the lifespan of patients found to have Alagille syndrome and the impact of odevixibat treatment. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; UDCA, ursodeoxycholic acid. [Figure 21] 1 is a table showing blinded sample size re-estimation. [Figure 22] This line graph shows the mean (SE) scratching scores over time from ASSERT baseline to weeks 9-12 of ASSERT-EXT where placebo-odebixibat treatment was administered compared to odebixibat-odebixibat. Values ​​shown for the ASSERT time point represent all patients randomized in ASSERT (placebo, n=17; odebixibat, n=35), while values ​​shown for the ASSERT-EXT time point represent only patients who rolled over to ASSERT-EXT and received odebixibat before the data cutoff date (placebo-odebixibat, n=17; odebixibat-odebixibat, n=32). Scratching scores range from 0 to 4, with higher scores indicating more severe symptoms. Seventy percent of patients in the placebo-odebixibat group achieved a 1-point or greater reduction in pruritus from baseline at weeks 9-12 of ASSERT-EXT. [Figure 23] 1 is a line graph showing mean (SE) bile acid levels (μmol / L) over time from ASSERT baseline to weeks 9-12 of ASSERT-EXT treated with placebo-odebixibat compared to odebixibat-odebixibat. Values ​​shown for the ASSERT time point represent all patients enrolled in ASSERT (placebo, n=17; odebixibat, n=35), while values ​​shown for the ASSERT-EXT time point represent only patients who rolled over to ASSERT-EXT and were receiving odebixibat before the data cutoff date (placebo-odebixibat, n=17; odebixibat-odebixibat, n=32). [Figure 24A] This is a line graph showing mean (SE) fatigue scores over time from ASSERT baseline to weeks 9-12 of ASSERT-EXT where treatment with placebo-odebixibat was compared with odebixibat-odebixibat. Values ​​shown for the ASSERT time point represent all patients enrolled in ASSERT (placebo, n=17; odebixibat, n=35), while values ​​shown for the ASSERT-EXT time point represent only patients who rolled over to ASSERT-EXT and were receiving odebixibat prior to the data cutoff date (placebo-odebixibat, n=17; odebixibat-odebixibat, n=32). Fatigue scores range from 0 to 4, with higher scores indicating more severe symptoms. [Figure 24B] 1 is a table showing all sleep parameters. [Figure 25] 1 is a table summarizing treatment-emergent adverse events. [Figure 26] An example of observer-reported items for the PRUCISION™ device. [Figure 27]1 is a table showing the Global Impression of Change (GIC) over time. GIC items are rated on a 7-point scale: 1 = very significant improvement; 2 = significant / moderate improvement; 3 = mild improvement; 4 = no change; 5 = mild worsening; 6 = significant / moderate worsening; 7 = very significant worsening. Changes based on the GIC were analyzed using a proportional odds model with treatment and baseline GIS score as covariates, considering three categories (improvement, no change, worsening). Improvement included "very significant improvement," "significant improvement," and "mild improvement," while worsening included "mild worsening," "significant worsening," and "very significant worsening." CaGIC = Caregiver Global Impression of Change. CGIC = Clinician Global Impression of Change. PGIC = Patient Global Impression of Change. [Figure 28] Table showing Global Impression of Symptoms (GIS) over time. CaGIS = Caregiver Global Impression of Symptoms. CGIS = Clinician Global Impression of Symptoms. PGIS = Patient Global Impression of Symptoms. [Figure 29A] and [Figure 29B] 29A and 29B are line graphs showing the change from baseline in scratching scores (FIG. 29A) and bile acids (FIG. 29B) with odevixibat treatment in pooled patients from the ASSERT and ASSERT-EXT studies. [Figure 30] 1 is a plot showing serum bile acid levels of individual patients with ALGS who received odevixibat in ASSERT and / or ASSERT-EXT. [Figure 31] 1 is a plot showing the scratching behavior scores of individual patients with ALGS who received odevixibat in ASSERT and / or ASSERT-EXT. [Figure 32A] 1 is a plot showing the mean change from baseline in ALT with odevixibat treatment in patients pooled in the ASSERT and ASSERT-EXT trials. [Figure 32B] 1 is a plot showing the mean change from baseline in AST with odevixibat treatment in patients pooled in the ASSERT and ASSERT-EXT trials. [Figure 32C] 1 is a plot showing the mean change from baseline in GGT with odevixibat treatment in patients pooled in the ASSERT and ASSERT-EXT trials. [Figure 32D] 1 is a plot showing the mean change from baseline in total bilirubin with odevixibat treatment in patients pooled in the ASSERT and ASSERT-EXT trials. [Figure 33A] and [Figure 33B] Figure 33A shows bar graphs depicting the percentage of patients with FSV deficiency at baseline and 24 weeks in ASSERT for patients receiving odevixibat (Figure 33A) and placebo (Figure 33B). a) n=32 for the total population evaluated for vitamin D deficiency and any vitamin deficiency. Vitamin deficiency was defined as low vitamin values ​​relative to 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) for the relevant age group, and the upper limit of the normal reference range for vitamin K (INR; 1.1). FSV, fat-soluble vitamins; INR, international normalized ratio. [Figure 34A] and [Figure 34B] 34A and 34B are plots (FIG. 34A) and violin plots (FIG. 34B) showing the change from baseline in scratching scores in odevixibat-treated pruritus responders during ASSERT. The violin plot shows the distribution and relative density of data across the range of possible scratching score values, with dotted lines indicating quartiles (1st quartile, 3rd quartile) and dashed lines indicating the median. [Figure 35A] and [Figure 35B]35A and 35B are plots (FIG. 35A) and violin plots (FIG. 35B) showing the change from baseline in bile acids in odevixibat-treated pruritus responders during ASSERT. The violin plot shows the distribution and relative density of data across the range of observed bile acid values, with dotted lines indicating quartiles (1st quartile, 3rd quartile) and dashed lines indicating the median. a Mean at 20 and 24 weeks. [Figure 36] 1 is a box-and-whisker plot showing the change from baseline in sleep parameters in odevixibat-treated pruritus responders during ASSERT. In the box-and-whisker plot, maximum and minimum values ​​are indicated by the whiskers, quartiles (1st quartile, 3rd quartile) are indicated by the ends of the box, the median is indicated by the horizontal line of the box, and the mean is indicated by the "+" symbol. The plot shows data from 27 patients for each parameter. [Figure 37] Box and whisker plots showing change from baseline in PedsQL total and domain scores in odevixibat-treated pruritus responders. PedsQL total and domain scores range from 0 to 100, with higher scores indicating better function. In the box and whisker plots, maximum and minimum values ​​are indicated by the whiskers, quartiles (1st quartile, 3rd quartile) are indicated by the ends of the box, the median is indicated by the horizontal line of the box, and the mean is indicated by the "+" symbol. The graphs show data from 23 patients for each score. PedsQL, Pediatric Quality of Life Inventory; QoL, quality of life. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition 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 use in the present invention are described herein; however, other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0022] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be performed after one or more symptoms have developed. In other embodiments, treatment may be performed in the absence of symptoms. For example, treatment may be performed in a susceptible individual prior to the onset of symptoms (e.g., taking into account symptom history and / or genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0023] The terms "subject," "individual," or "patient," as used interchangeably herein, 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.

[0024] The term "child" as used herein refers to a subject under 21 years of age at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including neonates (from birth to 1 month); infants (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years (before their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Textbook of Pediatrics, 15th Ed. Philadelphia: WB 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 28 days old, from 29 days old to less than 2 years old, from 2 years old to less than 12 years old, or from 12 years old to 21 years old (less than their 22nd birthday). In some embodiments, the pediatric subject is from birth to 28 days old, from 29 days old to less than 1 year old, from 1 month old to less than 4 months old, from 3 months old to less than 7 months old, from 6 months old to less than 1 year old, from 1 year old to less than 2 years old, from 2 years old to less than 3 years old, from 2 years old to less than 7 years old, from 3 years old to less than 5 years old, from 5 years old to less than 10 years old, from 6 years old to less than 13 years old, from 10 years old to less than 15 years old, or from 15 years old to less than 22 years old.

[0025] As used herein, the term "baseline" refers to information obtained before the first administration of a drug or intervention of interest (e.g., at the beginning of a study), or a known initial value used for comparison with subsequent data. A baseline value is obtained at time "zero" (i.e., before subjects in the study receive the drug or intervention of interest, or a placebo).

[0026] As used herein, the term "normalized" means that the age-specific value is within a range corresponding to healthy individuals (ie, a normal value or normalized value).

[0027] As used herein, the term "pharmaceutically acceptable" means that the compound, material, composition, and / or dosage form is suitable for pharmaceutical use in humans and is generally safe, non-toxic, and not biologically or otherwise undesirable.

[0028] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments relating to the value or parameter itself. For example, a statement about "about 20" includes a statement about "20." Numerical ranges include the numbers defining the range. Generally speaking, the term "about" refers to the indicated value for a variable, and all values ​​for a variable that are within experimental error of the indicated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the indicated value, whichever is greater.

[0029] The term "crystalline modification" refers to a crystalline solid phase of an organic compound. Crystalline modifications can be solvated or non-solvated.

[0030] The term "solvate" refers to a crystalline solid phase of an organic compound in which a solvent (i.e., solvent molecules) is incorporated into the crystal structure. A "hydrate" is a solvate in which the solvent is water.

[0031] The term "sesquihydrate" refers to a hydrate containing about 1.5 moles of water associated with the crystals per mole of organic compound (i.e., a sesquihydrate). As used herein, a sesquihydrate contains about 1.2 to about 1.8 moles, e.g., about 1.3 to about 1.7 moles, about 1.4 to about 1.6 moles, or about 1.45 to about 1.55 moles of water associated with each mole of odevixibat in the crystals. The amount of water calculated here excludes water adsorbed on the surface of the crystals.

[0032] The term "mixed solvate" refers to a crystalline solid phase of an organic compound, wherein two or more different solvent molecules are incorporated into its crystal structure, where one of the at least two solvent molecules may be water.

[0033] The term "slurry" means a saturated solution to which an excess of solids is added to form a mixture of solids and saturated solution.

[0034] As used herein, the term "void volume" refers to channels, layers, or other more or less isolated voids in a crystal structure.

[0035] The crystallinity of a crystalline sample of odevixibat can be measured, for example, by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC), such as those disclosed in the Experimental Section. When referring to crystalline compounds herein, the crystallinity measured by DSC is greater than about 70%, e.g., greater than about 80%, particularly greater than about 90%, and more particularly greater than about 95%. In some embodiments, the crystallinity measured by DSC is greater than about 98%. In some embodiments, the crystallinity measured by DSC is greater than about 99%. Percent crystallinity refers to the mass percent of the total sample mass that is crystalline.

[0036] How to Treat ALGS Alagille syndrome (ALGS) is a rare multisystem disorder with a wide variety of clinical manifestations affecting the liver, heart, skeleton, eyes, central nervous system, kidneys, and facial features. It is an autosomal dominant disorder caused in approximately 90% of patients by deficiencies in components of the NOTCH signaling pathway, most commonly due to mutations in JAG1. A minority of patients with ALGS have mutations in the gene for the NOTCH2 receptor. Approximately 60% of cases exhibit de novo mutations. The majority of patients present early, often within the first three months of life, with jaundice or cardiac symptoms.

[0037] One symptom of ALGS is pruritus, with up to 88% of patients experiencing itching, and up to 45% experiencing severe pruritus, which often significantly reduces quality of life. In some cases, ALGS leads to cirrhosis and liver failure. Current treatments include partial external bile duct drainage (PEBD) and liver transplantation, but these options can be associated with substantial risks of postoperative complications, as well as psychological and social problems.

[0038] IBAT, also known as the apical sodium-dependent bile acid transporter (SLC10A2), is located on the luminal side of enterocytes in the terminal ileum and mediates the reabsorption of conjugated bile acids for recirculation to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and results in fecal excretion of bile acids similar to surgical interruption of the enterohepatic circulation.

[0039] Odevixibat is an investigational, orally administered, potent, luminal-restricted, selective IBAT inhibitor for the treatment of cholestatic liver disease. By inhibiting IBAT with high selectivity and potency, odevixibat can reduce the elevated systemic bile acids caused by cholestasis and reduce pruritus in patients with ALGS. The rationale for using odevixibat is to improve the health and well-being of patients with ALGS by reducing serum bile acid levels and the primary morbidity of pruritus. Furthermore, by reducing elevated systemic bile acids, odevixibat can improve liver function and limit the progression of liver damage in patients with ALGS.

[0040] Provided herein are methods for treating ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof. Also provided herein are methods for treating pruritus associated with ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating cholestasis associated with ALGS in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

[0041] Also provided herein are pharmaceutical formulations comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating ALGS and for use in treating pruritus associated with ALGS. Also provided herein, in some embodiments, are pharmaceutical formulations comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating ALGS and for use in treating cholestasis associated with ALGS.

[0042] Also provided herein is the use of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of ALGS and for the treatment of pruritus associated with ALGS. In some embodiments, provided herein is the use of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof in the treatment of cholestasis associated with ALGS.

[0043] Odevixibat referred to herein includes solvates and hydrates thereof. For example, odevixibat may exist as a hydrate (e.g., sesquihydrate).

[0044] In some embodiments, reducing pruritus is an important treatment goal for patients with ALGS. However, devices that adequately measure pruritus in patients, such as pediatric patients with ALGS, are largely unavailable. The pruritus scores (also referred to herein as "scratching behavior scores") disclosed herein can be measured according to the PRUCISION™ Patient-Reported Outcomes (PRO) and Observer-Reported Outcomes (ObsRO) instruments to estimate thresholds for clinically significant changes in pruritus scores. Using these instruments, the percentage of patients who demonstrate a change from baseline in pruritus scores and achieve a clinically significant response can be calculated. For a description of the PRUCISION™ instrument, see, e.g., Gwaltney et al., Adv. Ther. (2022), 39:5105-5125, incorporated herein by reference in its entirety.

[0045] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in the mean monthly pruritus score.

[0046] In some embodiments, the reduction in mean monthly pruritus score (i.e., scratching behavior score) is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in mean monthly pruritus score is from about 0.3 to about 4.0. For example, about 0.3 to about 3.5, about 0.3 to about 3.0, about 0.3 to about 2.5, about 0.3 to about 2.0, about 0.3 to about 1.5, about 0.3 to about 1.0, about 0.3 to about 0.5, about 0.5 to about 3.5, about 0.5 to about 3.0, about 0.5 to about 2.5, about 0.5 to about 2.0, about 0.5 to about 1.5, about 0.5 to about 1.0, about 1.0 to about 4.0 about 1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.5 to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.5 to about 2.5, about 1.5 to about 2.0, about 2.0 to about 1.0, about 2.0 to about 3.5, about 2.0 to about 3.0, about 2.0 to about 2.5, about 2.5 to about 4.0, about 2.5 to about 3.5, about 2.5 to about 3.0, about 3.0 to about 4.0, about 3.0 to about 3.5, or about 3.5 to about 4.0. In some embodiments, the reduction in the mean monthly pruritus score is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the reduction in the mean monthly pruritus score is about 2.0. In some embodiments, the reduction in the mean monthly pruritus score is about 1.6.

[0047] In some embodiments, the reduction in mean monthly pruritus score occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The reduction in mean monthly pruritus score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in mean monthly pruritus score occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the reduction in mean monthly pruritus score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the reduction in mean monthly pruritus score occurs after administration of odevixibat 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. For example, the reduction in mean monthly pruritus score occurs after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in mean monthly pruritus score occurs after 4 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 24 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 48 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 72 weeks of administration.

[0050] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 0.3 to about 2.0. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 0.5 to about 1.5. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 0.9 to about 1.3. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 1.1.

[0051] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 1.2 to about 2.0. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 1.4 to about 1.8. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean monthly pruritus score is reduced by about 1.6.

[0052] In some embodiments, the mean monthly pruritus score is normalized after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the mean monthly pruritus score is normalized after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in pruritus score from baseline. In some embodiments, the reduction in pruritus score (i.e., scratching behavior score) from baseline is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in pruritus score relative to baseline is about 0.3 to about 4.0, e.g., 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, or 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 itch score relative to baseline is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the reduction in the itch score relative to baseline is about 2.0. In some embodiments, the reduction in the itch score relative to baseline is about 1.6.

[0054] In some embodiments, prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a scratching behavior score of 2.5 or greater. For example, prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject may exhibit a scratching behavior 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.

[0055] In some embodiments, prior to the first administration of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a mean scratching behavior score of about 2.5 to about 4.0. For example, prior to the first administration of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject may exhibit a mean scratching behavior 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. In some embodiments, prior to the first administration of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a mean scratching behavior score of about 2.8.

[0056] In some embodiments, the reduction in pruritus score relative to baseline occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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. 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 Between about 12 weeks and about 60 weeks, between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and 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,The reduction in pruritus score relative to baseline occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in pruritus score relative to baseline occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, about 13 to about 16 weeks, about 17 to about 20 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the reduction in pruritus score compared to baseline occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the reduction in itch score from baseline occurs after administration of odevixibat 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. For example, the reduction in itch score from baseline occurs after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in itch score from baseline occurs after 1 week of administration. In some embodiments, the reduction in itch score from baseline occurs after 4 weeks of administration. In some embodiments, the reduction in itch score from baseline occurs after 24 weeks of administration. In some embodiments, the reduction in itch score from baseline occurs after 48 weeks of administration. In some embodiments, the reduction in pruritus score compared to baseline occurs after 72 weeks of administration.

[0059] In some embodiments, after 24 weeks of administration of odebixibat or a pharmaceutically acceptable salt thereof, the reduction in the itch score from baseline is about 0.3 to about 2.0. In some embodiments, after 24 weeks of administration of odebixibat or a pharmaceutically acceptable salt thereof, the reduction in the itch score from baseline is about 0.5 to about 1.5. For example, after 24 weeks of administration of odebixibat or a pharmaceutically acceptable salt thereof, the reduction in the itch score from baseline is about 0.9 to about 1.3. In some embodiments, after 24 weeks of administration of odebixibat or a pharmaceutically acceptable salt thereof, the reduction in the itch score from baseline is about 1.1. In some embodiments, after about 24 weeks of administration of odebixibat or a pharmaceutically acceptable salt thereof, the reduction in the itch score from baseline is about 2.0.

[0060] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the pruritus score from baseline is about 1.2 to about 2.0. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the pruritus score from baseline is about 1.4 to about 1.8. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the pruritus score from baseline is about 1.6.

[0061] In some embodiments, the reduction in pruritus scores (i.e., scratching scores) from baseline is a reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores. In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the mean AM and PM scratching scores from baseline. In some embodiments, the mean AM and PM scratching scores are the worst scratching scores measured by the ObsRO instrument. In some embodiments, the mean AM and PM scratching scores are the worst scratching scores measured by the ObsRO AM and PM caregiver-report instrument.

[0062] In some embodiments, the reduction from baseline in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline is about 0.3 to about 4.0, e.g., 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, or 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 baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 1.1. In some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 1.6, hi some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 2.0.

[0063] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or about 4 weeks to about 48 weeks. Between about 4 weeks and about 52 weeks, between about 4 weeks and about 60 weeks, between about 4 weeks and about 72 weeks, between about 8 weeks and about 12 weeks, between about 8 weeks and about 16 weeks, between about 8 weeks and about 20 weeks, between about 8 weeks and about 24 weeks, between about 8 weeks and about 28 weeks, between about 8 weeks and about 36 weeks, between about 8 weeks and about 40 weeks, between about 8 weeks and about 48 weeks, between about 8 weeks and about 52 weeks, between about 8 weeks and about 60 weeks, between about 8 weeks and about 72 weeks, between about 12 weeks and about 16 weeks, between about 12 weeks and about 20 weeks, between about 12 weeks and about 24 weeks, between about 12 weeks and about 28 weeks, between about 12 weeks and about 36 weeks, between about 12 weeks about 16 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 4 8 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,This is after administration of odevixibat or a pharmaceutically acceptable salt thereof for 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 the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after about 5 weeks to about 8 weeks, about 9 weeks to about 12 weeks, or about 21 weeks to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after administration of odevixibat or a pharmaceutically acceptable salt thereof for 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. For example, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after administration of odevixibat or a pharmaceutically acceptable salt thereof for 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. In some embodiments, the subject exhibits a decrease in mean serum bile acid concentration.

[0066] In some embodiments, the decrease from baseline in mean serum bile acid concentration 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 decrease in mean serum bile acid concentration is from about 25 μmol / L to about 200 μmol / L (e.g., from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 75 μmol / L; from about 25 μmol / L to about 100 μmol / L; from about 25 μmol / L to about 125 μmol / L; from about 25 μmol / L to about 150 μmol / L; from about 25 μmol / L to about 175 μmol / L; from about 25 μmol / L to about 75 μmol / L) relative to baseline. In some embodiments, the decrease in mean serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L (e.g., from about 50 μmol / L to about 100 μmol / L; from about 50 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 150 μmol / L; from about 65 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 90 μmol / L; from about 65 μmol / L to about 85 μmol / L; from about 100 μmol / L to about 130 μmol / L; from about 100 μmol / L to about 180 μmol / L; or from about 150 μmol / L to about 180 μmol / L) relative to baseline.In some embodiments, the decrease in mean serum bile acid concentration from baseline is 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 / 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 2 00 μmol / L ~ Approx. 500 μmol / L, Approx. 250 μmol / L ~ Approx. 500 μmol / L, Approx. 300 μmol / L ~ Approx. 500 μmol / L, Approx. 350 μmol / L ~ Approx. 500 μmol / L, Approx. 400 μmol / L ~ Approx. 500 μmol / L, Approx. 450 μm ol / L~about 500μmol / L, about 50μmol / L~about 400μmol / L, about 100μmol / L~about 400μmol / L, about 150μmol / L~about 400μmol / L, about 200μmol / L~about 400μmol / L, about 250μmol / L~ Approximately 400μmol / L, approximately 300μmol / L to approximately 400μmol / L, approximately 350μmol / L to approximately 400μmol / L, approximately 50μmol / L to approximately 300μmol / L, approximately 100μmol / L to approximately 300μmol / L, approximately 150μmol / L to approximately 300μ mol / 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 decrease in mean serum bile acid concentration is about 70 μmol / L to about 120 μmol / L relative to baseline.In some embodiments, the decrease in mean serum bile acid concentration is from about 150 μmol / L to about 180 μmol / L.

[0067] In some embodiments, the decrease in mean serum bile acid concentration occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The decrease in mean serum bile acid concentration occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in mean serum bile acid concentration occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the decrease in mean serum bile acid concentration occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the decrease in mean serum bile acid concentration occurs after 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., of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in mean serum bile acid concentration occurs after 4 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 12 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 24 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 48 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 72 weeks of administration.

[0070] In some embodiments, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 50 μmol / L to about 90 μmol / L. For example, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 65 μmol / L to about 85 μmol / L. In some embodiments, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 70 μmol / L (e.g., about 73 μmol / L).

[0071] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 100 μmol / L to about 130 μmol / L. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 110 μmol / L to about 120 μmol / L. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 115 μmol / L.

[0072] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean 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 odevixibat or a pharmaceutically acceptable salt thereof, the mean serum bile acid concentration is reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0073] In some embodiments, the subject exhibits a decrease in bile acid concentration from baseline, ie, the decrease in 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. For example, the decrease in mean bile acid concentration is from about 25 μmol / L to about 200 μmol / L (e.g., from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 75 μmol / L; from about 25 μmol / L to about 100 μmol / L; from about 25 μmol / L to about 125 μmol / L; from about 25 μmol / L to about 150 μmol / L; from about 25 μmol / L to about 175 μmol / L; from about 25 μmol / L to about 75 μmol / L) relative to baseline. In some embodiments, the decrease in bile acid concentration is from about 50 μmol / L to about 180 μmol / L relative to baseline (e.g., from about 50 μmol / L to about 100 μmol / L; from about 50 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 150 μmol / L; from about 65 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 90 μmol / L; from about 65 μmol / L to about 85 μmol / L; from about 100 μmol / L to about 130 μmol / L; from about 100 μmol / L to about 180 μmol / L; or from about 150 μmol / L to about 180 μmol / L).In some embodiments, the decrease in bile acid concentration compared to baseline is 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, Approx. 500 μmol / L ~ Approx. 600 μmol / L, Approx. 550 μmol / L ~ Approx. 600 μmol / L, Approx. 50 μmol / L ~ Approx. 500 μmol / L, Approx. 100 μmol / L ~ Approx. 500 μmol / L, Approx. 150 μmol / L ~ Approx. 500 μmol / L, Approx. 200 μmol / L ~ approx. 500 μmol / L, approx. 250 μmol / L ~ approx. 500 μmol / L, approx. 300 μmol / L ~ approx. 500 μmol / L, approx. 350 μmol / L ~ approx. 500 μmol / L, approx. 400 μmol / L ~ approx. 500 μmol / L, approx. 450 μmol / L~about 500μmol / L, about 50μmol / L~about 400μmol / L, about 100μmol / L~about 400μmol / L, about 150μmol / L~about 400μmol / L, about 200μmol / L~about 400μmol / L, about 250μmol / L~about 400μmol / L, about 300μmol / L to about 400μmol / L, about 350μmol / L to about 400μmol / L, about 50μmol / L to about 300μmol / L, about 100μmol / L to about 300μmol / L, about 150μmol / L to about 300μm mol / 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 decrease in bile acid concentration is about 70 μmol / L to about 120 μmol / L relative to baseline.In some embodiments, the decrease in bile acid concentration is from about 150 μmol / L to about 180 μmol / L.

[0074] In some embodiments, the decrease in bile acid concentration occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The decrease in bile acid concentration occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in bile acid concentration occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the subject exhibits a decrease in serum bile acid concentration from baseline, for example, the decrease in 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. For example, the decrease in mean serum bile acid concentration is from about 25 μmol / L to about 200 μmol / L (e.g., from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 75 μmol / L; from about 25 μmol / L to about 100 μmol / L; from about 25 μmol / L to about 125 μmol / L; from about 25 μmol / L to about 150 μmol / L; from about 25 μmol / L to about 175 μmol / L; from about 25 μmol / L to about 75 μmol / L) relative to baseline. In some embodiments, the decrease in serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L (e.g., from about 50 μmol / L to about 100 μmol / L; from about 50 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 150 μmol / L; from about 65 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 90 μmol / L; from about 65 μmol / L to about 85 μmol / L; from about 100 μmol / L to about 130 μmol / L; from about 100 μmol / L to about 180 μmol / L; or from about 150 μmol / L to about 180 μmol / L) relative to baseline.In some embodiments, the decrease in serum bile acid concentration is from 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 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 20 0 μmol / L ~ approx. 500 μmol / L, approx. 250 μmol / L ~ approx. 500 μmol / L, approx. 300 μmol / L ~ approx. 500 μmol / L, approx. 350 μmol / L ~ approx. 500 μmol / L, approx. 400 μmol / L ~ approx. 500 μmol / L, approx. 450 μmol / L l / L~about 500μmol / L, about 50μmol / L~about 400μmol / L, about 100μmol / L~about 400μmol / L, about 150μmol / L~about 400μmol / L, about 200μmol / L~about 400μmol / L, about 250μmol / L~about 400μmol / L, about 300μmol / L to about 400μmol / L, about 350μmol / L to about 400μmol / L, about 50μmol / L to about 300μmol / L, about 100μmol / L to about 300μmol / L, about 150μmol / L to about 300μm mol / 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 decrease in serum bile acid concentration is about 70 μmol / L to about 120 μmol / L relative to baseline.In some embodiments, the decrease in serum bile acid concentration is from about 150 μmol / L to about 180 μmol / L.

[0076] In some embodiments, the decrease in serum bile acid concentration occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The decrease in serum bile acid concentration occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in serum bile acid concentration occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the decrease in serum bile acid concentration occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the decrease in serum bile acid concentration occurs after 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., of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the decrease in serum bile acid concentration occurs after 4 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 12 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 24 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 48 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 72 weeks of administration.

[0079] In some embodiments, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 50 μmol / L to about 90 μmol / L. For example, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 65 μmol / L to about 85 μmol / L. In some embodiments, after 12 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 70 μmol / L (e.g., about 73 μmol / L).

[0080] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 100 μmol / L to about 130 μmol / L. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 110 μmol / L to about 120 μmol / L. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 115 μmol / L.

[0081] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 150 μmol / L to about 180 μmol / L. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 155 μmol / L to about 170 μmol / L. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, serum bile acid concentrations are reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0082] In some embodiments, after at least 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a serum bile acid concentration of less than 70 μmol / L (e.g., less than 60 μmol / L; less than 50 μmol / L, etc.).

[0083] In some embodiments, after at least 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits at least a 50% (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%) decrease in serum bile acid concentration compared to baseline. In some embodiments, the subject exhibits at least a 60%, at least a 70%, or at least an 80% decrease in serum bile acid concentration compared to baseline.

[0084] In some embodiments, serum bile acid concentrations are normalized after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, serum bile acid concentrations are normalized after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, growth is improved relative to placebo after administration of odevixibat or a pharmaceutically acceptable salt thereof, hi some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, subjects exhibit an increase in mean height Z-score relative to baseline.

[0086] In some embodiments, the increase in mean height Z-score relative to baseline is 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 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.

[0087] In some embodiments, the increase in mean height Z-score occurs after about 20 weeks to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof. For example, 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 4 The period is 0 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 odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in mean height Z-score occurs after about 21 weeks to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the increase in mean height Z-score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the increase in mean height Z-score occurs after 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., of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in mean height Z-score occurs after 24 weeks of administration. In some embodiments, the increase in mean height Z-score occurs after 48 weeks of administration. In some embodiments, the increase in mean height Z-score occurs after 72 weeks of administration.

[0090] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean height Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean height Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean height Z-score increases by about 1.1.

[0091] In some embodiments, the subject exhibits an increase in mean body weight Z-score after administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the increase in the mean body weight Z-score is 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 increased 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 increased by about 1.1.

[0093] In some embodiments, the increase in mean body weight Z-score occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The increase in mean body weight Z-score occurs after about 40 weeks to about 52 weeks, about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in mean body weight Z-score occurs after about 5 weeks to about 8 weeks, about 9 weeks to about 12 weeks, or about 21 weeks to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the increase in mean body weight Z-score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the increase in mean weight Z-score occurs after administration of odevixibat 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. For example, the increase in mean weight Z-score occurs after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the increase in mean weight Z-score occurs after 12 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 24 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 48 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 72 weeks of administration.

[0096] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean body weight Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean body weight Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean body weight Z-score increases by about 1.1.

[0097] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in height Z-score relative to baseline. In some embodiments, the increase in height Z-score relative to baseline is 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.

[0098] In some embodiments, the increase in height Z-score occurs after about 20 weeks to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof. For example, 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 4 The period is 0 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 odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in height Z-score occurs after about 21 weeks to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the increase in height Z-score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the increase in height Z-score occurs after 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., of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in height Z-score occurs after 24 weeks of administration. In some embodiments, the increase in height Z-score occurs after 48 weeks of administration. In some embodiments, the increase in height Z-score occurs after 72 weeks of administration.

[0101] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the height Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the height Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the height Z-score increases by about 1.1.

[0102] In some embodiments, the subject exhibits an increase in body weight Z-score after administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the increase in weight Z-score is 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.

[0104] In some embodiments, the increase in body weight Z-score occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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, or 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 about 16 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 2 8 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,The increase in body weight Z-score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the increase in body weight Z-score occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the increase in weight Z-score occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the increase in weight Z-score occurs after administration of odevixibat 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. For example, the increase in weight Z-score occurs after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the increase in weight Z-score occurs after 12 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 24 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 48 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 72 weeks of administration.

[0107] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the body weight Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the body weight Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the body weight Z-score increases by about 1.1.

[0108] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, subjects show improvements in sleep parameters. Improvements in sleep parameters can include, for example, a reduction in the caregiver-reported percentage of days with fatigue, scratching accompanied by bleeding, days requiring sleep assistance, days requiring sedation, days sleeping with a caregiver, or days taking medication to induce sleep, as well as the caregiver-reported percentage of days with daytime fatigue, and the caregiver-reported number of awakenings per night. As described in the Examples, at 24 weeks after starting odevixibat, the majority of patients' sleep parameters were significantly improved.

[0109] In some embodiments, the mean reduction in caregiver-reported percent of days with bleeding is about 14% to about 45% (e.g., about a 15%, about 20%, about 25%, about 30%, about 35%, or about a 45% mean reduction) after administration of odevixibat 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. In some embodiments, the mean reduction in caregiver-reported percent of days with bleeding is about 14% to about 45% after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the mean reduction in caregiver-reported percent of days requiring assistance with falling asleep is about 20% to about 75% (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about a 75% mean reduction) after 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. In some embodiments, the mean reduction in caregiver-reported percent of days requiring assistance with falling asleep is about 20% to about 75% after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the mean reduction in caregiver-reported percent of days requiring sedation is about 20% to about 75% (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about a 75% mean reduction) after administration of odevixibat 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. In some embodiments, the mean reduction in caregiver-reported percent of days requiring sedation is about 20% to about 75% after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the mean reduction in caregiver-reported percent of days requiring sleep with a caregiver is about 20% to about 75% (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about a 75% mean reduction) after administration of odevixibat 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. In some embodiments, the mean reduction in caregiver-reported percent of days requiring sleep with a caregiver is about 20% to about 75% after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, after administration of odevixibat 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., there is about a 0.5% to about 10% reduction in the mean caregiver-reported percentage of days on which medication is taken to induce sleep (e.g., a mean reduction of about 1%, about 2%, about 2.5%, about 3%, about 5%, or about 7.5%). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, there is about a 0.5% to about 10% reduction in the mean caregiver-reported percentage of days on which medication is taken to induce sleep. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean reduction in caregiver-reported percentage of days on which the drug is taken to induce sleep is about 1% to about 5%.

[0114] In some embodiments, after 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., administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean reduction in the number of caregiver-reported days with daytime fatigue is about 0.1 to about 5 (e.g., a mean reduction of about 0.1, about 0.5, about 1, about 1.5, about 2, or about 3.5). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean reduction in the caregiver-reported percentage of days on which medication is taken to induce sleep is about 0.1 to about 5. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the mean reduction in the caregiver-reported percentage of days on which medication is taken to induce sleep is about 0.5 to about 1.5.

[0115] In some embodiments, after 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 reduction in the caregiver-reported number of awakenings per night is about 0.1 to about 7.5 (e.g., a mean reduction of about 0.5, about 1, about 2, about 2.5, about 3, or about 5). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the mean caregiver-reported percentage of days on which medication is taken to induce sleep is about 0.1 to about 7.5. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the mean caregiver-reported percentage of days on which medication is taken to induce sleep is about 1 to about 5.

[0116] In some embodiments, the reduction in fatigue from baseline is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in fatigue from baseline is from about 0.3 to about 4.0. For example, about 0.3 to about 3.5, about 0.3 to about 3.0, about 0.3 to about 2.5, about 0.3 to about 2.0, about 0.3 to about 1.5, about 0.3 to about 1.0, about 0.3 to about 0.5, about 0.5 to about 3.5, about 0.5 to about 3.0, about 0.5 to about 2.5, about 0.5 to about 2.0, about 0.5 to about 1.5, about 0.5 to about 1.0, about 1.0 to about 4.0 about 1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.5 to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.5 to about 2.5, about 1.5 to about 2.0, about 2.0 to about 1.0, about 2.0 to about 3.5, about 2.0 to about 3.0, about 2.0 to about 2.5, about 2.5 to about 4.0, about 2.5 to about 3.5, about 2.5 to about 3.0, about 3.0 to about 4.0, about 3.0 to about 3.5, or about 3.5 to about 4.0. In some embodiments, the reduction in fatigue is measured according to a PRO device and / or an ObsRO device.

[0117] In some embodiments, after administration of odevixibat 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., there is about a 14% to about 45% reduction in caregiver-reported percent of days with bleeding scratching (e.g., about a 15%, about 20%, about 25%, about 30%, about 35%, or about a 45% reduction). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, there is about a 14% to about 45% reduction in caregiver-reported percent of days with bleeding scratching (e.g., about a 15%, about 20%, about 25%, about 30%, about 35%, or about a 45% reduction).

[0118] In some embodiments, after administration of odevixibat 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., there is about a 20% to about 75% reduction in the caregiver-reported percent of days requiring assistance with falling asleep (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about a 75% reduction). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, there is about a 20% to about 75% reduction in the caregiver-reported percent of days requiring assistance with falling asleep.

[0119] In some embodiments, the caregiver-reported percent reduction in days requiring sedation is about 20% to about 75% (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% reduction) after administration of odevixibat 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. In some embodiments, the caregiver-reported percent reduction in days requiring sedation is about 20% to about 75% after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, after administration of odevixibat 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., there is about a 20% to about 75% reduction in the caregiver-reported percent number of days requiring sleep with a caregiver (e.g., about a 22%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about a 75% reduction). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, there is about a 20% to about 75% reduction in the caregiver-reported percent number of days requiring sleep with a caregiver.

[0121] In some embodiments, after administration of odevixibat 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., there is about a 0.5% to about 10% reduction in the caregiver-reported percent of days on which medication is taken to induce sleep (e.g., about a 1%, about 2%, about 2.5%, about 3%, about 5%, or about 7.5% reduction). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, there is about a 0.5% to about 10% reduction in the caregiver-reported percent of days on which medication is taken to induce sleep. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the caregiver-reported percent reduction in the number of days the drug is taken to induce sleep is about 1% to about 5%.

[0122] In some embodiments, after administration of odevixibat 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 reduction in caregiver-reported daytime fatigue score is about 0.1 to about 5 (e.g., a reduction of about 0.1, about 0.5, about 1, about 1.5, about 2, or about 3.5).

[0123] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the caregiver-reported percent reduction in the number of days medication is taken to induce sleep is about 0.1 to about 5. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the caregiver-reported percent reduction in the number of days medication is taken to induce sleep is about 0.5 to about 1.5.

[0124] In some embodiments, after administration of odevixibat 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 caregiver-reported number of awakenings per night is reduced by about 0.1 to about 7.5 (e.g., a reduction of about 0.5, about 1, about 2, about 2.5, about 3, or about 5). In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the caregiver-reported percent reduction in the number of days on which medication is taken to induce sleep is reduced by about 0.1 to about 7.5. In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the caregiver-reported percent reduction in the number of days on which medication is taken to induce sleep is reduced by about 1 to about 5.

[0125] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits improvement in liver parameters or liver biomarkers. Non-limiting examples of biomarkers indicative of one or more of liver injury, liver inflammation, liver fibrosis, and / or liver cirrhosis include alanine transaminase (ALT) levels, aspartate transaminase (AST) levels, alkaline phosphatase (ALP) levels, gamma-glutamyltransferase (GGT) levels, total and direct bilirubin levels, autotaxin levels, 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)).

[0126] For example, in some embodiments, levels of autotaxin, which are associated with the intensity of cholestatic pruritus, and / or levels of plasma 7α-hydroxy-4-cholesten-3-one (p-C4), a marker of bile acid synthesis, are improved after administration of odevixibat 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.

[0127] In some embodiments, autotaxin levels decrease after administration of odebixibat or a pharmaceutically acceptable salt thereof. In some embodiments, after administration of odebixibat or a pharmaceutically acceptable salt thereof, autotaxin levels may decrease from baseline by about 10 to about 1,000 ng / mL. For example, after administration of odebixibat or a pharmaceutically acceptable salt thereof, autotaxin levels may decrease from baseline 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, or about 100 to about 400 ng / mL. / mL, about 100 to about 500ng / mL, about 100 to about 600ng / mL, about 100 to about 700ng / mL, about 100 to about 800ng / mL, about 100 to about 900ng / mL, about 100 to about 1000ng / mL, about 200 to about 300ng / m L, about 200 to about 400ng / mL, about 200 to about 500ng / mL, about 200 to about 600ng / mL, about 200 to about 700ng / mL, about 200 to about 800ng / mL, about 200 to about 900ng / mL, about 200 to about 1000ng / mL, about 300 to about 400ng / mL, about 300 to about 500ng / mL, about 300 to about 600ng / mL, about 300 to about 700ng / mL, about 300 to about 800ng / mL, about 300 to about 900ng / mL, about 300 to about 1000ng / mL, about 40 0 to about 500ng / mL, about 400 to about 600ng / mL, about 400 to about 700ng / mL, about 400 to about 800ng / mL, about 400 to about 900ng / mL, about 400 to about 1000ng / mL, about 500 to about 600ng / mL, about 500 to about The decrease may be about 700ng / mL, about 500 to about 800ng / mL, about 500 to about 900ng / mL, about 500 to about 1000ng / mL, about 600 to about 700ng / mL, about 600 to about 800ng / mL, about 600 to about 900ng / mL, about 600 to about 1000ng / mL, about 700 to about 800ng / mL, about 700 to about 900ng / mL, about 700 to about 1000ng / mL, about 800 to about 900ng / mL, about 800 to about 1000ng / mL, or about 900 to about 1000ng / mL.

[0128] In some embodiments, after administration of odevixibat 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., autotaxin levels may decrease from baseline 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. For example, after administration of odevixibat or a pharmaceutically acceptable salt thereof for at least 24 weeks, autotaxin levels may decrease by about 50%.

[0129] In some embodiments, plasma C4 levels are increased after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, plasma C4 levels (ng / mL) can increase from baseline by about 1 to about 30 ng / mL after administration of odevixibat or a pharmaceutically acceptable salt thereof. For example, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the change from baseline is 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.

[0130] In some embodiments, after administration of odevixibat 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., plasma C4 levels (ng / mL) may increase from baseline 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.

[0131] In some embodiments, serum alanine aminotransferase (ALT) levels are improved after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, ALT levels are reduced after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, ALT levels are reduced from baseline by about 10 U / L to about 125 U / L after administration of odevixibat or a pharmaceutically acceptable salt thereof. For example, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the change from baseline is 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.

[0132] In some embodiments, ALT levels are reduced from baseline 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 after administration of odevixibat 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. For example, ALT levels may be reduced by about 70% after administration of odevixibat or a pharmaceutically acceptable salt thereof for at least 21 to 24 weeks.

[0133] In some embodiments, total bilirubin levels decrease after administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, total bilirubin levels decrease from baseline 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, or about 3 mg / dL after administration of odevixibat 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. g / dL~about 5.5mg / dL, about 2.5mg / dL~about 5.5mg / dL, about 3mg / dL~about 5.5mg / dL, about 3.5mg / dL~about 5.5mg / dL, about 4mg / dL~about 5.5mg / dL, about 4.5mg / dL~about 5.5mg / dL, about 5mg / dL ~5.5mg / dL, 1mg / dL~5mg / dL, 1.5mg / dL~5mg / dL, 2mg / dL~5mg / dL, 2.5mg / dL~5mg / dL, 3mg / dL~5mg / dL, 3.5mg / dL~5mg / dL, 4mg / d L~about 5mg / dL, about 4.5mg / dL~about 5mg / dL, about 1mg / dL~about 4.5mg / dL, about 1.5mg / dL~about 4.5mg / dL, about 2mg / dL~about 4.5mg / dL, about 2.5mg / dL~about 4.5mg / dL, about 3mg / dL~about 4.5mg / dL, about 3.5mg / dL to about 4.5mg / dL, about 4mg / dL to about 4.5mg / dL, about 1mg / dL to about 4mg / dL, about 1.5mg / dL to about 4mg / dL, about 2mg / dL to about 4mg / dL, about 2.5mg / dL to about 4mg / dL, about 3mg / dL to Approximately 4 mg / dL, approximately 3.5 mg / dL to approximately 4 mg / dL, approximately 1 mg / dL to approximately 3.5 mg / dL, approximately 1.5 mg / dL to approximately 3.5 mg / dL, approximately 2 mg / dL to approximately 3.5 mg / dL, approximately 2.5 mg / dL to approximately 3.5 mg / dL, approximately 3 mg / dL to approximately 3.5 mg / d L, 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, about 2 mg / dL to about 2.The total bilirubin may be reduced by at least 5 mg / dL, about 1 mg / dL to about 2 mg / dL, about 1.5 mg / dL to about 2 mg / dL, or about 1 mg / dL to about 1.5 mg / dL. For example, after at least 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the total bilirubin may be reduced by at least 70% (e.g., about 99%).

[0134] In some embodiments, total bilirubin levels are reduced from baseline 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 after administration of odevixibat 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. For example, total bilirubin may be reduced by at least 70% (e.g., about 99%) after administration of odevixibat or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0135] In some embodiments, serum aspartate aminotransferase (AST) levels are improved following administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in Clinician Xanthomas Score, which ranges from 0 to 4, with higher scores (e.g., 4 or 3) indicating more lesions and greater interference with activity, and lower scores indicating no / less lesions and no / less interference with activity.

[0137] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in Clinician Xanthomas Score from baseline is 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. In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced from baseline by about 0.3 to about 4.0, e.g., 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. In some embodiments, the Clinician Xanthomas 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 Xanthomas Score is reduced by about 0.5. In some embodiments, the Clinician Xanthomas Score is reduced by about 0.6.

[0138] In some embodiments, the reduction in Clinician Xanthomas Score occurs after administration of odevixibat 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. For example, the reduction in Clinician Xanthomas Score may occur after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in Clinician Xanthomas Score occurs after 4 weeks of administration. In some embodiments, the reduction in Clinician Xanthomas Score occurs after 24 weeks of administration. In some embodiments, the reduction in Clinician Xanthomas Score occurs after 48 weeks of administration. In some embodiments, the reduction in Clinician Xanthomas Score occurs after 72 weeks of administration.

[0139] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced by about 0.4 to about 1. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced by about 0.5 to about 0.8. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced by about 0.6.

[0140] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced by about 0.5 to about 2.0. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the Clinician Xanthomas Score is reduced by about 0.8 to about 1.5.

[0141] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the Clinician Xanthomas Score from baseline. In some embodiments, the reduction in the Clinician Xanthomas Score from baseline is 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. For example, the reduction in the Clinician Xanthomas Score from baseline is 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 reduction in the Clinician Xanthomas Score from baseline is about 0.5. In some embodiments, the reduction in the Clinician Xanthomas Score from baseline is about 0.6.

[0142] In some embodiments, the reduction in the Clinician Xanthomas Score from baseline occurs after administration of odevixibat 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. For example, the reduction in the Clinician Xanthomas Score from baseline may occur after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in the Clinician Xanthomas Score from baseline occurs after 4 weeks of administration. In some embodiments, the reduction in the Clinician Xanthomas Score from baseline occurs after 24 weeks of administration. In some embodiments, the reduction in the Clinician Xanthomas Score from baseline occurs after 48 weeks of administration. In some embodiments, the reduction in Clinician Xanthomas Score from baseline occurs after 72 weeks of administration.

[0143] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the Clinician Xanthomas Score from baseline is about 0.4 to about 1. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the Clinician Xanthomas Score from baseline is about 0.5 to about 0.8. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the Clinician Xanthomas Score from baseline is about 0.6.

[0144] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the Clinician Xanthomas Score from baseline is about 0.5 to about 2.0. For example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, the reduction in the Clinician Xanthomas Score from baseline is about 0.8 to about 1.5.

[0145] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in serum cholesterol levels (mmol / L).

[0146] In some embodiments, the reduction in cholesterol levels is 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 reduction in cholesterol levels is from about 0.2 to about 2.5 mmol / L (e.g., from about 0.2 to about 2.0; from about 0.2 to about 1.5; from about 0.2 to about 1.2; from about 0.2 to about 1.0; from about 0.2 to about 0.8; from about 0.2 to about 0.5; from about 0.5 to about 2.5; from about 0.5 to about 2.0; from about 0.5 to about 1.5; from 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 reduction in cholesterol levels is about 0.5 mmol / L. In some embodiments, the reduction in cholesterol levels is about 0.6 mmol / L.

[0147] In some embodiments, the reduction in cholesterol levels occurs after about 1 week to about 72 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, e.g., 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 about 16 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 2 8 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,The reduction in cholesterol levels occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in cholesterol levels occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the reduction in cholesterol levels occurs after 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 of administration of odevixibat or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the reduction in cholesterol levels occurs after administration of odevixibat 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. For example, the reduction in cholesterol levels may occur after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in cholesterol levels occurs after 4 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 24 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 48 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 72 weeks of administration.

[0150] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced by about 0.4 to about 1 mmol / L. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced by about 0.5 to about 0.8 mmol / L. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced by about 0.6 mmol / L.

[0151] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced by about 0.5 to about 2.0 mmol / L, for example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced by about 0.8 to about 1.5 mmol / L.

[0152] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in cholesterol levels relative to baseline. In some embodiments, the decrease in cholesterol levels relative to baseline is 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 decrease in cholesterol levels relative to baseline is 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 decrease in cholesterol levels relative to baseline is about 0.5 mmol / L. In some embodiments, the decrease in cholesterol levels is about 0.6 mmol / L.

[0153] In some embodiments, the reduction in cholesterol levels relative to baseline occurs after administration of odevixibat 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. For example, the reduction in cholesterol levels relative to baseline may occur after administration of odevixibat 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, or at least 24 weeks. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 4 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 24 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 48 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 72 weeks of administration.

[0154] In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced from baseline by about 0.4 to about 1 mmol / L. For example, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced from baseline by about 0.5 to about 0.8 mmol / L. In some embodiments, after 24 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced from baseline by about 0.6 mmol / L.

[0155] In some embodiments, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced from baseline by about 0.5 to about 2.0 mmol / L, for example, after 48 weeks of administration of odevixibat or a pharmaceutically acceptable salt thereof, cholesterol levels are reduced from baseline by about 0.8 to about 1.5 mmol / L.

[0156] 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.

[0157] In some embodiments, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in scratching behavior score of 1 point or more compared to baseline.

[0158] In some embodiments, the subject is an itch responder. For example, after administration of odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in scratching score of 1 or more points compared to baseline. In some embodiments, after 21 to 24 weeks (e.g., 21, 22, 23, and / or 24 weeks) of administration of odevixibat or a pharmaceutically acceptable salt thereof, the itch responder exhibits a decrease in scratching score of 1 or more points compared to baseline. In some embodiments, the itch responder exhibits a mean scratching score after 20 to 24 weeks of odevixibat administration that is decreased by 1 or more points compared to baseline. In some embodiments, the scratching score is measured using a PRUCISION™ ObsRO device. In some embodiments, the subject is administered about 20 to about 800 μg / kg / day of odevixibat or a pharmaceutically acceptable salt thereof.For example, about 20 to about 600, about 20 to about 400, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about 20 to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 800, about 40 to about 600, about 40 to about 400, about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 800, about 60 to about 600, about 60 to about 400, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 80, about 80 to about 800, about 80 to about 600, about 80 to about 400, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 to about 120, about 80 to about 100, about 100 to about 800, about 100 to about 600, about 100 to about 400, about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 120 to about 800, about 120 to about 600, about 120 to about 400, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 140 to about 800, about 140 to about 600, about 140 to about 400, about 140 to about 200, about 140 to about 180, about 140 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 odevixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 400, about 600, or about 800 μg / kg / day of odevixibat or a pharmaceutically acceptable salt thereof, hi some embodiments, the subject is administered 120 μg / kg / day of odevixibat or a pharmaceutically acceptable salt thereof.In some embodiments, the subject is administered 800 μg / kg / day of odevixibat or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the subject is administered odevixibat or a pharmaceutically acceptable salt thereof in an amount not exceeding 6 mg per day.

[0160] In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered as a unit dose ranging from about 1 μg to about 100 mg, e.g., from about 10 μg to about 10 mg, e.g., from about 100 μg to about 2000 μg, or e.g., from about 200 μg to about 1500 μg. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 μg to about 9 mg, about 10 μg to about 8 mg, about 10 μg to about 7 mg, about 10 μg to about 6 mg, about 10 μg to about 5 mg, about 10 μg to about 4 mg, about 10 μg to about 3 mg, about 10 μg to about 2 mg, about 10 μg to about 1 mg, about 10 μg to about 800 μg, about 10 μg to about 600 μg, about 10 μg to about 400 μg, about 10 μg to about 200 μg, about 10 μg to about 100 μg, about 10 μg to about 50 μg, or about 50 μg to about 1 mg. 0mg, about 50μg to about 9mg, about 50μg to about 8mg, about 50μg to about 7mg, about 50μg to about 6mg, about 50μg to about 5mg, about 50μg to about 4mg, about 50μg to about 3mg, about 50μg to about 2mg, about 50μg to about 1mg, about 50μg Approximately 800μg, approximately 50μg to approximately 600μg, approximately 50μg to approximately 400μg, approximately 50μg to approximately 200μg, approximately 50μg to approximately 100μg, approximately 100μg to approximately 10mg, approximately 100μg to approximately 9mg, approximately 100μg to approximately 8mg, approximately 100μg to approximately 7mg, approximately 1 00μg to about 6mg, about 100μg to about 5mg, about 100μg to about 4mg, about 100μg to about 3mg, about 100μg to about 2mg, about 100μg to about 1mg, about 100μg to about 800μg, about 100μg to about 600μg, about 100μg to about 400 μg, approximately 100 μg to approximately 200 μg, approximately 200 μg to approximately 10 mg, approximately 200 μg to approximately 9 mg, approximately 200 μg to approximately 8 mg, approximately 200 μg to approximately 7 mg, approximately 200 μg to approximately 6 mg, approximately 200 μg to approximately 5 mg, approximately 200 μg to approximately 4 mg, approximately 200 μg to approximately 3mg, about 200μg to about 2mg, about 200μg to about 1mg, about 200μg to about 800μg, about 200μg to about 600μg, about 200μg to about 400μg, about 200μg to about 10mg, about 200μg to about 9mg, about 400μg to about 8mg, about 4 00μg to about 7mg, about 400μg to about 6mg, about 400μg to about 5mg, about 400μg to about 4mg, about 400μg to about 3mg, about 400μg to about 2mg, about 400μg to about 1mg, about 400μg to about 800μg, about 400μg to about 600μg,Approximately 600μg to approximately 10mg, approximately 600μg to approximately 9mg, approximately 600μg to approximately 8mg, approximately 600μg to approximately 7mg, approximately 600μg to approximately 6mg, approximately 600μg to approximately 5mg, approximately 600μg to approximately 4mg, approximately 600μg ~3mg, about 600μg~about 2mg, about 600μg~about 1mg, about 600μg~about 800μg, about 800μg~about 10mg, about 800μg~about 9mg, about 800μg~about 8mg, about 800μg~about 7mg , about 800μg to about 6mg, about 800μg to about 5mg, about 800μg to about 4mg, about 800μg to about 3mg, about 800μg to about 2mg, about 800μg to about 1mg, about 1mg to about 10mg, about 1mg to about 9 mg, about 1mg to about 8mg, about 1mg to about 7mg, about 1mg to about 6mg, about 1mg to about 5mg, about 1mg to about 4mg, about 1mg to about 3mg, about 1mg to about 2mg, about 2mg to about 10mg, about 2mg to about 9m g, about 2mg to about 8mg, about 2mg to about 7mg, about 2mg to about 6mg, about 2mg to about 5mg, about 2mg to about 4mg, about 2mg to about 3mg, about 3mg to about 10mg, about 3mg to about 9mg, about 3mg to about 8m g, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg , about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered as a unit dose of about 100 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.

[0161] In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 200 μg. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 400 μg. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 600 μg. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 1200 μg.

[0162] The dosing frequency can vary from once or twice a week to once or more daily, for example, twice or three times daily. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered once daily. Furthermore, the dosing frequency can remain constant or can vary over the course of treatment. Several factors, such as the severity of the condition being treated, the duration of treatment, and the age, weight, sex, diet, and general health of the patient being treated, can affect the dosing frequency and effective amount of the formulation to be used for a particular treatment.

[0163] In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 200 μg per day. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 400 μg per day. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 600 μg per day. In some embodiments, odevixibat or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 1200 μg per day.

[0164] In some embodiments, the subject was odevixibat naive prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject has been administered one or more antipruritic agents, non-limiting examples of which include cholestyramine, ursodeoxycholic acid (UDCA), rifampicin, phenobarbital, ondansetron, sertraline, and naltrexone.

[0166] In some embodiments, prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, the subject exhibits a scratching behavior score of ____.

[0167] IBAT inhibitors Provided herein are methods for treating ALGS with an ileal bile acid transport (IBAT) inhibitor (also referred to as apical sodium-dependent bile acid transport inhibitor, ASBTI). In some embodiments, the IBAT inhibitor

[0168] [ka]

[0169] [ka]

[0170] or a pharmaceutically acceptable salt thereof. The IBAT inhibitors provided herein include solvates and hydrates thereof. For example, odebixibat can exist as a hydrate (e.g., a sesquihydrate). In some embodiments, the IBAT inhibitor is odebixibat 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 vorixibat 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 linelixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the IBAT inhibitor comprises a combination of two or more of odebixibat, maralixibat, vorixibat, elobixibat, and linelixibat, or pharmaceutically acceptable salts thereof.

[0171] IBAT inhibitors can be prepared using methods described, for example, in 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 WO96 / 05188. IBAT inhibitors can exist in amorphous or crystalline form. See, for example, U.S. Patent Nos. 9,409,875; 10,183,920; and International Publication WO2019 / 245448.

[0172] Provided herein are methods for treating Alagille Syndrome (ALGS) in a subject in need thereof, 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 for treating pruritus associated with Alagille Syndrome (ALGS) in a subject in need thereof, 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 for treating cholestasis associated with ALGS in a subject in need thereof, 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.

[0173] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits a decrease in the mean monthly pruritus score.

[0174] In some embodiments, the reduction in mean monthly pruritus score (i.e., scratching behavior score) is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in mean monthly pruritus score is from about 0.3 to about 4.0. For example, about 0.3 to about 3.5, about 0.3 to about 3.0, about 0.3 to about 2.5, about 0.3 to about 2.0, about 0.3 to about 1.5, about 0.3 to about 1.0, about 0.3 to about 0.5, about 0.5 to about 3.5, about 0.5 to about 3.0, about 0.5 to about 2.5, about 0.5 to about 2.0, about 0.5 to about 1.5, about 0.5 to about 1.0, about 1.0 to about 4.0 about 1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.5 to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.5 to about 2.5, about 1.5 to about 2.0, about 2.0 to about 1.0, about 2.0 to about 3.5, about 2.0 to about 3.0, about 2.0 to about 2.5, about 2.5 to about 4.0, about 2.5 to about 3.5, about 2.5 to about 3.0, about 3.0 to about 4.0, about 3.0 to about 3.5, or about 3.5 to about 4.0. In some embodiments, the reduction in the mean monthly pruritus score is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the reduction in the mean monthly pruritus score is about 2.0. In some embodiments, the reduction in the mean monthly pruritus score is about 1.6.

[0175] In some embodiments, the reduction in mean monthly pruritus score occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 ... 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,after 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 of administration of the IBAT inhibitor. In some embodiments, the reduction in mean monthly pruritus score occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0176] In some embodiments, the reduction in mean monthly pruritus score occurs after 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 of administration of the IBAT inhibitor.

[0177] In some embodiments, the reduction in mean monthly pruritus score occurs after 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. of administration of the IBAT inhibitor. For example, the reduction in mean monthly pruritus score occurs after 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 of administration of the IBAT inhibitor. In some embodiments, the reduction in mean monthly pruritus score occurs after 4 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 24 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 48 weeks of administration. In some embodiments, the reduction in mean monthly pruritus score occurs after 72 weeks of administration.

[0178] In some embodiments, after 24 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 0.3 to about 2.0. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 0.5 to about 1.5. For example, after 24 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 0.9 to about 1.3. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 1.1.

[0179] In some embodiments, after 48 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 1.2 to about 2.0. For example, after 48 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 1.4 to about 1.8. In some embodiments, after 48 weeks of administration of the IBAT inhibitor, the reduction in the mean monthly pruritus score is about 1.6.

[0180] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a reduction in itch score from baseline. In some embodiments, the reduction in itch score (i.e., scratching behavior score) from baseline is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in pruritus score relative to baseline is about 0.3 to about 4.0, e.g., 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, or about 1.0 to about 4.0. about 1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.5 to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.5 to about 2.5, about 1.5 to about 2.0, about 2.0 to about 1.0, about 2.0 to about 3.5, about 2.0 to about 3.0, about 2.0 to about 2.5, about 2.5 to about 4.0, about 2.5 to about 3.5, about 2.5 to about 3.0, about 3.0 to about 4.0, about 3.0 to about 3.5, or about 3.5 to about 4.0. In some embodiments, the reduction in pruritus score relative to baseline is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8).In some embodiments, the reduction in itch score from baseline is about 2.0, hi some embodiments, the reduction in itch score from baseline is about 1.6.

[0181] In some embodiments, the reduction in pruritus score relative to baseline occurs after about 1 week to about 72 weeks of 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 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 ... 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,This is after about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of the IBAT inhibitor. In some embodiments, the reduction in pruritus score compared to baseline occurs after about 5 weeks to about 8 weeks, about 9 weeks to about 12 weeks, about 13 weeks to about 16 weeks, about 17 weeks to about 20 weeks, or about 21 weeks to about 24 weeks of administration of the IBAT inhibitor.

[0182] In some embodiments, the reduction in pruritus score compared to baseline occurs after 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 of administration of the IBAT inhibitor.

[0183] In some embodiments, the reduction in the itch score relative to baseline occurs after administration of the 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. For example, the reduction in the itch score relative to baseline occurs after administration of the IBAT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks. In some embodiments, the reduction in the itch score relative to baseline occurs after 1 week of administration. In some embodiments, the reduction in the itch score relative to baseline occurs after 4 weeks of administration. In some embodiments, the reduction in the itch score relative to baseline occurs after 24 weeks of administration. In some embodiments, the reduction in the itch score relative to baseline occurs after 48 weeks of administration. In some embodiments, the reduction in the itch score relative to baseline occurs after 72 weeks of administration.

[0184] In some embodiments, after 24 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score relative to baseline is about 0.3 to about 2.0. In some embodiments, after 24 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score relative to baseline is about 0.5 to about 1.5. For example, after 24 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score relative to baseline is about 0.9 to about 1.3. In some embodiments, after 24 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score relative to baseline is about 1.1.

[0185] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score from baseline is about 1.2 to about 2.0. For example, after 48 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score from baseline is about 1.4 to about 1.8. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the reduction in the pruritus score from baseline is about 1.6.

[0186] In some embodiments, the reduction in pruritus scores (i.e., scratching scores) from baseline is a reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores. In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a reduction in the mean AM and PM scratching scores from baseline. In some embodiments, the mean AM and PM scratching scores are the worst scratching scores measured by the ObsRO instrument. In some embodiments, the mean AM and PM scratching scores are the worst scratching scores measured by the ObsRO AM and PM caregiver-report instrument.

[0187] In some embodiments, the reduction from baseline in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, or at least 3.9. In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline is about 0.3 to about 4.0, e.g., 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, or 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 baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 0.5 to about 2.0 (e.g., about 0.5 to about 1.5; about 0.5 to about 1.2; about 0.8 to about 1.4; about 0.9 to about 1.2; about 1.2 to about 2.0; about 1.2 to about 1.5; about 1.2 to about 1.8; about 1.4 to about 2.0; about 1.6 to about 2.0; about 1.5 to about 2.0; about 1.3 to about 1.6; or about 1.4 to about 1.8). In some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 1.1. In some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 1.6, hi some embodiments, the baseline reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores is about 2.0.

[0188] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 Between about 12 weeks and about 48 weeks, between about 12 weeks and about 52 weeks, between about 12 weeks and about 60 weeks, between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks ~ 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,This is after administration of an IBAT inhibitor for 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 the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after about 5 weeks to about 8 weeks, about 9 weeks to about 12 weeks, or about 21 weeks to about 24 weeks of administration of the IBAT inhibitor.

[0189] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after 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 of administration of the IBAT inhibitor.

[0190] In some embodiments, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after administration of the IBAT inhibitor for 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. For example, the reduction in the mean AM scratching score, the mean PM scratching score, or the mean AM and PM scratching scores relative to baseline occurs after administration of the IBAT inhibitor for 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.

[0191] In some embodiments, the subject exhibits a decreased mean serum bile acid concentration.

[0192] In some embodiments, the decrease from baseline in mean serum bile acid concentration 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 decrease in mean serum bile acid concentration is from about 25 μmol / L to about 200 μmol / L (e.g., from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 75 μmol / L; from about 25 μmol / L to about 100 μmol / L; from about 25 μmol / L to about 125 μmol / L; from about 25 μmol / L to about 150 μmol / L; from about 25 μmol / L to about 175 μmol / L; from about 25 μmol / L to about 75 μmol / L) relative to baseline. In some embodiments, the decrease in mean serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L (e.g., from about 50 μmol / L to about 100 μmol / L; from about 50 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 150 μmol / L; from about 65 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 90 μmol / L; from about 65 μmol / L to about 85 μmol / L; from about 100 μmol / L to about 130 μmol / L; from about 100 μmol / L to about 180 μmol / L; or from about 150 μmol / L to about 180 μmol / L) relative to baseline.In some embodiments, the decrease in mean serum bile acid concentration from baseline is 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 / 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 2 00 μmol / L ~ Approx. 500 μmol / L, Approx. 250 μmol / L ~ Approx. 500 μmol / L, Approx. 300 μmol / L ~ Approx. 500 μmol / L, Approx. 350 μmol / L ~ Approx. 500 μmol / L, Approx. 400 μmol / L ~ Approx. 500 μmol / L, Approx. 450 μm ol / L~about 500μmol / L, about 50μmol / L~about 400μmol / L, about 100μmol / L~about 400μmol / L, about 150μmol / L~about 400μmol / L, about 200μmol / L~about 400μmol / L, about 250μmol / L~ Approximately 400μmol / L, approximately 300μmol / L to approximately 400μmol / L, approximately 350μmol / L to approximately 400μmol / L, approximately 50μmol / L to approximately 300μmol / L, approximately 100μmol / L to approximately 300μmol / L, approximately 150μmol / L to approximately 300μ mol / 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 decrease in mean serum bile acid concentration is about 70 μmol / L to about 120 μmol / L relative to baseline.In some embodiments, the decrease in mean serum bile acid concentration is from about 150 μmol / L to about 180 μmol / L.

[0193] In some embodiments, the decrease in mean serum bile acid concentration occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 ... 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,after 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 of administration of the IBAT inhibitor. In some embodiments, the decrease in mean serum bile acid concentration occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0194] In some embodiments, the decrease in mean serum bile acid concentration occurs after 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 of administration of the IBAT inhibitor.

[0195] In some embodiments, the decrease in mean serum bile acid concentration occurs after 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., of administration of the IBAT inhibitor. In some embodiments, the decrease in mean serum bile acid concentration occurs after 4 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 12 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 24 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 48 weeks of administration. In some embodiments, the decrease in mean serum bile acid concentration occurs after 72 weeks of administration.

[0196] In some embodiments, after 12 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 50 μmol / L to about 90 μmol / L. For example, after 12 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 65 μmol / L to about 85 μmol / L. In some embodiments, after 12 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 70 μmol / L (e.g., about 73 μmol / L).

[0197] In some embodiments, after 24 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 100 μmol / L to about 130 μmol / L. For example, after 24 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 110 μmol / L to about 120 μmol / L. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 115 μmol / L.

[0198] In some embodiments, after 48 weeks of administration of the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L. For example, after 48 weeks of administration of the IBAT inhibitor, the mean 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 the IBAT inhibitor, the mean serum bile acid concentration is reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0199] In some embodiments, the subject exhibits a decrease in serum bile acid concentration from baseline, ie, the decrease in 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. For example, the decrease in mean serum bile acid concentration is from about 25 μmol / L to about 200 μmol / L (e.g., from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 50 μmol / L; from about 25 μmol / L to about 75 μmol / L; from about 25 μmol / L to about 100 μmol / L; from about 25 μmol / L to about 125 μmol / L; from about 25 μmol / L to about 150 μmol / L; from about 25 μmol / L to about 175 μmol / L; from about 25 μmol / L to about 75 μmol / L) relative to baseline. In some embodiments, the decrease in serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L (e.g., from about 50 μmol / L to about 100 μmol / L; from about 50 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 150 μmol / L; from about 65 μmol / L to about 120 μmol / L; from about 50 μmol / L to about 90 μmol / L; from about 65 μmol / L to about 85 μmol / L; from about 100 μmol / L to about 130 μmol / L; from about 100 μmol / L to about 180 μmol / L; or from about 150 μmol / L to about 180 μmol / L) relative to baseline.In some embodiments, the decrease in serum bile acid concentration is from 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 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 20 0 μmol / L ~ approx. 500 μmol / L, approx. 250 μmol / L ~ approx. 500 μmol / L, approx. 300 μmol / L ~ approx. 500 μmol / L, approx. 350 μmol / L ~ approx. 500 μmol / L, approx. 400 μmol / L ~ approx. 500 μmol / L, approx. 450 μmol / L l / L~about 500μmol / L, about 50μmol / L~about 400μmol / L, about 100μmol / L~about 400μmol / L, about 150μmol / L~about 400μmol / L, about 200μmol / L~about 400μmol / L, about 250μmol / L~about 400μmol / L, about 300μmol / L to about 400μmol / L, about 350μmol / L to about 400μmol / L, about 50μmol / L to about 300μmol / L, about 100μmol / L to about 300μmol / L, about 150μmol / L to about 300μm mol / 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 decrease in serum bile acid concentration is about 70 μmol / L to about 120 μmol / L relative to baseline.In some embodiments, the decrease in serum bile acid concentration is from about 150 μmol / L to about 180 μmol / L.

[0200] In some embodiments, the decrease in serum bile acid concentration occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,This occurs after 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 of administration of the IBAT inhibitor. In some embodiments, the decrease in serum bile acid concentration occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0201] In some embodiments, the decrease in serum bile acid concentration occurs after 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 of administration of the IBAT inhibitor.

[0202] In some embodiments, the decrease in serum bile acid concentration occurs after 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., of administration of the IBAT inhibitor. In some embodiments, the decrease in serum bile acid concentration occurs after 4 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 12 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 24 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 48 weeks of administration. In some embodiments, the decrease in serum bile acid concentration occurs after 72 weeks of administration.

[0203] In some embodiments, after 12 weeks of administration of an IBAT inhibitor, serum bile acid concentrations are reduced by about 50 μmol / L to about 90 μmol / L. For example, after 12 weeks of administration of an IBAT inhibitor, serum bile acid concentrations are reduced by about 65 μmol / L to about 85 μmol / L. In some embodiments, after 12 weeks of administration of an IBAT inhibitor, serum bile acid concentrations are reduced by about 70 μmol / L (e.g., about 73 μmol / L).

[0204] In some embodiments, after 24 weeks of administration of the IBAT inhibitor, serum bile acid concentrations are reduced by about 100 μmol / L to about 130 μmol / L. For example, after 24 weeks of administration of the IBAT inhibitor, serum bile acid concentrations are reduced by about 110 μmol / L to about 120 μmol / L. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, serum bile acid concentrations are reduced by about 115 μmol / L.

[0205] In some embodiments, after 48 weeks of administration of the IBAT inhibitor, the serum bile acid concentration is reduced by about 150 μmol / L to about 180 μmol / L. For example, after 48 weeks of administration of the IBAT inhibitor, the 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 the IBAT inhibitor, the serum bile acid concentration is reduced by about 165 μmol / L (e.g., about 166 μmol / L).

[0206] In some embodiments, after at least 24 weeks of administration of the IBAT inhibitor, the subject exhibits a serum bile acid concentration of less than 70 μmol / L (eg, less than 60 μmol / L; less than 50 μmol / L, etc.).

[0207] In some embodiments, after at least 24 weeks of administration of an IBAT inhibitor, the subject exhibits at least a 50% (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%) decrease in serum bile acid concentration compared to baseline. In some embodiments, the subject exhibits at least a 60%, at least a 70%, or at least an 80% decrease in serum bile acid concentration compared to baseline.

[0208] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits an increase in mean height Z-score over baseline.

[0209] In some embodiments, after administration of the IBAT inhibitor, growth is improved relative to placebo. In some embodiments, after administration of the IBAT inhibitor, subjects exhibit an increase in mean height Z-score relative to baseline.

[0210] In some embodiments, the increase in mean height Z-score relative to baseline is 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 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.

[0211] In some embodiments, the increase in mean height Z-score occurs after about 20 weeks to about 72 weeks of administration of the IBAT inhibitor, e.g., about 20 weeks to about 24 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 36 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 48 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 60 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 28 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 40 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 52 weeks, about 24 weeks to about 60 weeks, about 24 weeks to about 72 weeks, about 28 weeks to about 36 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 48 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 60 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 40 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 52 weeks, about 36 weeks to about 60 weeks, about 36 weeks to about 72 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 48 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of the IBAT inhibitor. In some embodiments, the increase in mean height Z-score occurs after about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0212] In some embodiments, the increase in mean height Z-score occurs after 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 of administration of the IBAT inhibitor.

[0213] In some embodiments, the increase in mean height Z-score occurs after 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. of administration of the IBAT inhibitor. In some embodiments, the increase in mean height Z-score occurs after 24 weeks of administration. In some embodiments, the increase in mean height Z-score occurs after 48 weeks of administration. In some embodiments, the increase in mean height Z-score occurs after 72 weeks of administration.

[0214] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean height Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean height Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean height Z-score increases by about 1.1.

[0215] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits an increase in mean body weight Z-score.

[0216] In some embodiments, the increase in the mean body weight Z-score is 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 increased 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 increased by about 1.1.

[0217] In some embodiments, the increase in mean body weight Z-score occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 ... 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,after about 40 weeks to about 60 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 48 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 60 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 52 weeks, about 48 weeks to about 60 weeks, about 48 weeks to about 72 weeks, about 52 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks of administration of the IBAT inhibitor. In some embodiments, the increase in mean body weight Z-score occurs after about 5 weeks to about 8 weeks, about 9 weeks to about 12 weeks, or about 21 weeks to about 24 weeks of administration of the IBAT inhibitor.

[0218] In some embodiments, the increase in mean body weight Z-score occurs after 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 of administration of the IBAT inhibitor.

[0219] In some embodiments, the increase in mean weight Z-score occurs after 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. of administration of the IBAT inhibitor. For example, the increase in mean weight Z-score occurs after 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 of administration of the IBAT inhibitor. In some embodiments, the increase in mean weight Z-score occurs after 12 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 24 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 48 weeks of administration. In some embodiments, the increase in mean weight Z-score occurs after 72 weeks of administration.

[0220] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean body weight Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean body weight Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the mean body weight Z-score increases by about 1.1.

[0221] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits an increase in height Z-score relative to baseline. In some embodiments, the increase in height Z-score relative to baseline is 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.

[0222] In some embodiments, the increase in height Z-score occurs after about 20 weeks to about 72 weeks of administration of the IBAT inhibitor, e.g., 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, In some embodiments, the increase in height Z-score occurs after 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 of administration of the IBAT inhibitor.

[0223] In some embodiments, the increase in height Z-score occurs after 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 of administration of the IBAT inhibitor.

[0224] In some embodiments, the increase in height Z-score occurs after 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. of administration of the IBAT inhibitor. In some embodiments, the increase in height Z-score occurs after 24 weeks of administration. In some embodiments, the increase in height Z-score occurs after 48 weeks of administration. In some embodiments, the increase in height Z-score occurs after 72 weeks of administration.

[0225] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the height Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the height Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the height Z-score increases by about 1.1.

[0226] In some embodiments, after administration of the IBAT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in body weight Z-score.

[0227] In some embodiments, the increase in weight Z-score is 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.

[0228] In some embodiments, the increase in body weight Z-score occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 ... 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,The increase in body weight Z-score occurs after 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 of administration of the IBAT inhibitor. In some embodiments, the increase in body weight Z-score occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0229] In some embodiments, the increase in weight Z-score occurs after 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 of administration of the IBAT inhibitor.

[0230] In some embodiments, the increase in weight Z-score occurs after 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., of administration of the IBAT inhibitor. For example, the increase in weight Z-score occurs after 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 of administration of the IBAT inhibitor. In some embodiments, the increase in weight Z-score occurs after 12 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 24 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 48 weeks of administration. In some embodiments, the increase in weight Z-score occurs after 72 weeks of administration.

[0231] In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the body weight Z-score increases by about 0.9 to about 1.3. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the body weight Z-score increases by about 1.0 to about 1.2. In some embodiments, after 48 weeks of administration of an IBAT inhibitor, the body weight Z-score increases by about 1.1.

[0232] In some embodiments, after administering IBAT inhibitor, subject shows improvement in sleep parameters.Improvement in sleep parameters can include, for example, the percentage of caregiver-reported number of days with bleeding scratching behavior, number of days that need sleep assistance, number of days that need sedation, number of days that sleep with caregiver or number of days that take medication to induce sleep, and the percentage of caregiver-reported number of days that experience daytime fatigue, and the average number of caregiver-reported awakenings per night.As described in Example, at 24 weeks after starting IBAT inhibitor, the sleep parameters of most patients are significantly improved.

[0233] 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, which is associated with the intensity of cholestatic pruritus, and / or the level of plasma 7α-hydroxy-4-cholesten-3-one (p-C4), a marker of bile acid synthesis, is improved.

[0234] In some embodiments, serum ALT levels are improved after administration of the IBAT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, serum total bilirubin levels are reduced after administration of the IBAT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, serum AST levels are improved after administration of the IBAT inhibitor or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, after administration of the IBAT inhibitor, the subject exhibits a decrease in serum cholesterol levels (mmol / L).

[0236] In some embodiments, the reduction in cholesterol levels is 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 reduction in cholesterol levels is from about 0.2 to about 2.5 mmol / L (e.g., from about 0.2 to about 2.0; from about 0.2 to about 1.5; from about 0.2 to about 1.2; from about 0.2 to about 1.0; from about 0.2 to about 0.8; from about 0.2 to about 0.5; from about 0.5 to about 2.5; from about 0.5 to about 2.0; from about 0.5 to about 1.5; from 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 reduction in cholesterol levels is about 0.5 mmol / L. In some embodiments, the reduction in cholesterol levels is about 0.6 mmol / L.

[0237] In some embodiments, the reduction in cholesterol levels occurs after about 1 week to about 72 weeks of administration of the IBAT inhibitor, e.g., 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 12 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 Between about 12 weeks and about 72 weeks, between about 16 weeks and about 20 weeks, between about 16 weeks and about 24 weeks, between about 16 weeks and about 28 weeks, between about 16 weeks and about 36 weeks, between about 16 weeks and about 40 weeks, between about 16 weeks and about 48 weeks, between about 16 weeks and about 52 weeks, between about 16 weeks and about 60 weeks, between about 16 weeks and about 72 weeks, between about 20 weeks and about 24 weeks, between about 20 weeks and about 28 weeks, between about 20 weeks and about 36 weeks, between about 20 weeks and about 40 weeks, between about 20 weeks and about 48 weeks, between about 20 weeks and about 52 weeks, between about 20 weeks and about 60 weeks, between about 20 weeks and about 72 weeks, between about 24 weeks and about 28 weeks, between about 24 weeks ~ 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,after 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 of administration of the IBAT inhibitor. In some embodiments, the reduction in cholesterol levels occurs after about 5 to about 8 weeks, about 9 to about 12 weeks, or about 21 to about 24 weeks of administration of the IBAT inhibitor.

[0238] In some embodiments, the reduction in cholesterol levels occurs after 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 of administration of the IBAT inhibitor.

[0239] In some embodiments, the reduction in cholesterol levels occurs after administration of the 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. For example, the reduction in cholesterol levels may occur after administration of the IBAT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks. In some embodiments, the reduction in cholesterol levels occurs after 4 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 24 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 48 weeks of administration. In some embodiments, the reduction in cholesterol levels occurs after 72 weeks of administration.

[0240] In some embodiments, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced by about 0.4 to about 1 mmol / L. For example, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced by about 0.5 to about 0.8 mmol / L. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced by about 0.6 mmol / L.

[0241] In some embodiments, after 48 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced by about 0.5 to about 2.0 mmol / L, for example, after 48 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced by about 0.8 to about 1.5 mmol / L.

[0242] In some embodiments, after administration of an IBAT inhibitor, the subject exhibits a decrease in cholesterol levels relative to baseline. In some embodiments, the decrease in cholesterol levels relative to baseline is 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 decrease in cholesterol levels relative to baseline is 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 decrease in cholesterol levels relative to baseline is about 0.5 mmol / L. In some embodiments, the decrease in cholesterol levels is about 0.6 mmol / L.

[0243] In some embodiments, the reduction in cholesterol levels relative to baseline occurs after administration of the 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. For example, the reduction in cholesterol levels relative to baseline may occur after administration of the IBAT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 4 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 24 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 48 weeks of administration. In some embodiments, the reduction in cholesterol levels relative to baseline occurs after 72 weeks of administration.

[0244] In some embodiments, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced from baseline by about 0.4 to about 1 mmol / L. For example, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced from baseline by about 0.5 to about 0.8 mmol / L. In some embodiments, after 24 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced from baseline by about 0.6 mmol / L.

[0245] In some embodiments, after 48 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced from baseline by about 0.5 to about 2.0 mmol / L, for example, after 48 weeks of administration of the IBAT inhibitor, cholesterol levels are reduced from baseline by about 0.8 to about 1.5 mmol / L.

[0246] In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is not a pediatric subject.

[0247] In some embodiments, the subject is administered about 20 to about 800 μg / kg / day of an IBAT inhibitor, e.g., 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, or 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 14 The IBAT inhibitor is administered at a dose of 0 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. In some embodiments, the subject is administered about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 400, about 600, or about 800 μg / kg / day of the IBAT inhibitor, hi some embodiments, the subject is administered 120 μg / kg / day of the IBAT inhibitor.In some embodiments, the subject is administered 800 μg / kg / day of the IBAT inhibitor.

[0248] In some embodiments, the subject is administered an IBAT inhibitor in an amount not exceeding 6 mg per day.

[0249] In some embodiments, the IBAT inhibitor is administered as a unit dose ranging 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 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, or from about 50 μg to about 100 μg. g ~ 8 mg, approximately 50 μg ~ 7 mg, 50 μg ~ 6 mg, 50 μg ~ 5 mg, 50 μg ~ 4 mg, 50 μg ~ 3 mg, 50 μg ~ 2 mg, 50 μg ~ 1 mg, 50 μg ~ 800 μg, 50 μg ~ 600 μg, approx. 5 0 μg to about 400 μg, about 50 μg to about 200 μg, about 50 μg to about 100 μg, about 100 μg to about 10 mg, about 100 μg to about 9 mg, about 100 μg to about 8 mg, about 100 μg to about 7 mg, about 100 μg to about 6 mg, about 100 μg to about 5 mg, about 10 0 μg to approx. 4 mg, approx. 100 μg to approx. 3 mg, approx. 100 μg to approx. 2 mg, approx. 100 μg to approx. 1 mg, approx. 100 μg to approx. 800 μg, approx. 100 μg to approx. 600 μg, approx. g, approx. 200 μg ~ approx. 9 mg, approx. 200 μg ~ approx. 8 mg, approx. 200 μg ~ approx. 7 mg, approx. 200 μg ~ approx. 6 mg, approx. 200 μg ~ approx. 5 mg, approx. 0 μg to about 800 μg, about 200 μg to about 600 μg, about 200 μg to about 400 μg, about 200 μg to about 10 mg, about 200 μg to about 9 mg, about 400 μg to about 8 mg, about 400 μg to about 7 mg, about 400 μg to about 6 mg, about 400 μg to about 5 mg, Approximately 400μg to approximately 4mg, approximately 400μg to approximately 3mg, approximately 400μg to approximately 2mg, approximately 400μg to approximately 1mg, approximately 400μg to approximately 800μg, approximately 400μg to approximately 600μg, approximately 600μg to approximately 10mg, approximately 600μg to approximately 9mg, approximately 600μg to approximately 8mg,Approximately 600μg to approximately 7mg, approximately 600μg to approximately 6mg, approximately 600μg to approximately 5mg, approximately 600μg to approximately 4mg, approximately 600μg to approximately 3mg, approximately 600μg to approximately 2mg, approximately 600μg to approximately 1mg, approximately 60 0μg to about 800μg, about 800μg to about 10mg, about 800μg to about 9mg, about 800μg to about 8mg, about 800μg to about 7mg, about 800μg to about 6mg, about 800μg to about 5mg, about 80 0 μg to about 4 mg, about 800 μg to about 3 mg, about 800 μg to about 2 mg, about 800 μg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2mg to about 6mg, about 2mg to about 5mg, about 2mg to about 4mg, about 2mg to about 3mg, about 3mg to about 10mg, about 3mg to about 9mg, about 3mg to about 8mg, about 3mg to about 7mg, about 3m g ~ about 6mg, about 3mg - about 5mg, about 3mg - about 4mg, about 4mg - about 10mg, about 4mg - about 9mg, about 4mg - about 8mg, about 4mg - about 7mg, about 4mg - about 6mg, about 4mg - about 5mg , about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg. In some embodiments, the IBAT inhibitor is administered as a unit dose 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.

[0250] 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.

[0251] The administration frequency can vary from once or twice a week to once or more times a day, for example, twice or three times a day. In some embodiments, the IBAT inhibitor is administered once a day. Furthermore, the administration frequency can remain constant or can vary during the treatment period. Several factors, such as the severity of the condition being treated, the duration of treatment, and the age, weight, sex, diet, and general health of the patient being treated, can affect the administration frequency and effective amount of the formulation to be used for a particular treatment.

[0252] In some embodiments, the IBAT inhibitor is administered at a unit dose of about 200 μg per day. In some embodiments, the IBAT inhibitor is administered at a unit dose of about 400 μg per day. In some embodiments, the IBAT inhibitor is administered at a unit dose of about 600 μg per day. In some embodiments, the IBAT inhibitor is administered at a unit dose of about 1200 μg per day.

[0253] In some embodiments, the unit dose of the IBAT inhibitor does not exceed 6 mg per day.

[0254] In some embodiments, the subject was IBAT inhibitor naive prior to the first administration of the pharmaceutical formulation comprising the IBAT inhibitor.

[0255] formulation The IBAT inhibitors provided herein can be formulated as previously described. See, e.g., International Publications WO2019 / 245449; WO2020 / 0167981; WO2020 / 0167985; WO2020 / 0167964; U.S. Patent No. 10,709,755; and U.S. Patent Application Publication US2017 / 0143738.

[0256] For example, odevixibat exhibits high potency and should be administered at low doses, e.g., in the range of about 40 μg / kg / day to about 120 μg / kg / day. This may correspond to doses such as 200 μg to 7200 μg in the treatment of pediatric patients weighing about 4 kg to 55.5 kg. In some embodiments, this may correspond to doses as low as 200 μg to 800 μg in the treatment of pediatric patients (e.g., infants and young children) weighing about 4 kg to 20 kg. It is desirable that odevixibat formulations be able to be administered to young patients in small dosage sizes. Furthermore, it is desirable that the formulation exhibit good palatability, be not perceived as gritty, and be well tolerated by infants and small children.

[0257] When administered with a liquid, multiparticulates may be administered to infants from birth. For children aged approximately 6 months or older (i.e., after weaning), solid multiparticulates may be administered directly into the mouth or mixed with semi-solid food. Particle size, shape, texture, hardness, taste, and dosage (i.e., number of particles) have been reported to be important for the acceptability of multiparticulates by infants and children (Kozarewicz, Int. J. Pharm. 2014, vol. 469, pp 245-248). Although various literature reviews have been conducted regarding the tolerability of various oral dosage forms in pediatric and older adult patients (e.g., Liu et al., Drugs 2014, vol. 74, pp. 1871-1889; Drumond et al., Int. J. Pharm. 2017, vol. 521, pp. 294-305; Mistry et al., J. Pharm. Pharmacol. 2017, vol. 69, pp. 361-376; Walsh et al., Int. J. Pharm. 2017, vol. 536, pp. 547-562), these reviews do not always report the particle size and / or dose (amount) of the multiparticulates investigated.

[0258] The perception of grittiness can be influenced by a range of factors, including particle size, amount, and administration 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 particle hardness and shape (Tyle, Acta Psychologica 1993, vol. 84, pp. 111-118), and the fact that irregular particles are perceived as larger than round (spherical) particles of the same size (Engelen et al., J. Text. Studies 2005, vol. 36, pp. 373-386). Studies on perception of grittiness have shown that grittiness scores can increase with increasing multiparticulate particle size and dose, while grittiness scores can decrease with increasing medium viscosity (Lopez et al., Eur. J. Pharm. Sci. 2016, vol. 92, pp. 156-162).

[0259] Capsules may be tolerated by children aged approximately 6 years and older. The ease of swallowing a capsule may depend on the dimensions (i.e., size) of the dosage form and the child's ability. Size, shape, taste, and aftertaste are important capsule characteristics that may affect patient acceptability (Kozarewicz, Int. J. Pharm. 2014, vol. 469, pp. 245-248). In some embodiments, capsule size is kept as small as possible, and the number of capsules required per administration is kept to a minimum, e.g., 1-3 capsules or less.

[0260] Provided herein is a multiparticulate formulation comprising a low dose of odevixibat.In some embodiments, the formulation is a pediatric formulation.In some embodiments, the formulation allows for weight-based dosing and can be sprinkled on food.The formulation can be designed to exhibit good palatability with an optimal balance between particle size and dosage.

[0261] Provided herein is a pharmaceutical formulation of odevixibat comprising a plurality of particles, each particle comprising odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / w to about 5.0% w / w, based on the total mass of the particle.

[0262] Because odevixibat is to be administered at low doses and, furthermore, because it is administered in multiparticulate form, each particle of the formulation contains only a very small amount of the active ingredient. For example, the amount of odevixibat or a pharmaceutically acceptable salt thereof in each particle can be about 0.2% w / w to about 3.5% w / w, e.g., about 0.3% w / w to about 3.0% w / w, about 0.4% w / w to about 2.5% w / w, or about 0.5% w / w to about 2.0% w / w, based on the total mass of the particle. In some embodiments, each particle contains odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w, based on the total mass of the particle. In another embodiment, each particle contains odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 1.0% w / w, based on the total mass of the particle. In yet another embodiment, each particle comprises odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 1.5% w / w based on the total mass of the particle.

[0263] As used herein, the term "particle" refers to small particles ranging in size from about 0.1 to about 1.5 mm. These particles are essentially spherical, although elongated or oblong particles may also be used. Particles may be, for example, pellets, beads, microparticles, microspheres, granules, or minitablets, and may optionally be coated with one or more coating layers surrounding each pellet, bead, microparticle, microsphere, granule, or minitablet.

[0264] In some embodiments, the particles of the formulation are small enough to be sprinkled on food and easily swallowed. In some embodiments, the particles can be swallowed without causing a perceived grittiness. In some embodiments, the particles do not induce the patient's urge to chew them. Thus, the particles are about 0.1 to about 1.5 mm in diameter, e.g., about 0.1 to about 1.0 mm, or about 0.1 to 0.8 mm, e.g., 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 about 0.4 to about 0.8 mm, e.g., about 0.5 mm, or e.g., about 0.6 mm, or e.g., about 0.7 mm. In some embodiments, the particles are about 0.7 mm.

[0265] In some embodiments, provided herein are odevixibat formulations, wherein each particle comprises a core and a coating layer surrounding the core, and the core of each particle can be a pellet, granule, minitablet, bead, microparticle, or microsphere.

[0266] In some embodiments, the core of each particle comprises the active pharmaceutical ingredient (odevixibat), while the coating layer of each particle does not comprise the active pharmaceutical ingredient. In some embodiments, the core of each particle comprises from about 0.1% to about 5% w / w of the active pharmaceutical ingredient relative to the total weight of the particle, e.g., from about 0.1% to about 2% w / w, e.g., from about 0.1% to about 1% w / w, or e.g., from about 0.1% to about 0.5% w / w of the active pharmaceutical ingredient relative to the total weight of the particle.

[0267] In some embodiments, the coating layer of each particle comprises the active pharmaceutical ingredient (odevixibat), while the core of each particle does not comprise the active pharmaceutical ingredient. In some embodiments, the coating layer of each particle comprises from about 0.1% to about 5% w / w of the active pharmaceutical ingredient relative to the total weight of the particle, e.g., from about 0.1% to about 2% w / w, e.g., from about 0.1% to about 1% w / w, or e.g., from about 0.1% to about 0.5% w / w of the active pharmaceutical ingredient relative to the total weight of the particle.

[0268] The core may be orally dispersible and comprise a soluble component, such as a sugar (e.g., sucrose) or a soluble polymer (e.g., hydroxypropylmethylcellulose), or parenterally dispersible and comprise an insoluble component, such as an insoluble polymer (e.g., microcrystalline cellulose). In some embodiments, the core comprises microcrystalline cellulose. In some embodiments, the core is a microcrystalline cellulose sphere.

[0269] The coating layer may further comprise a film-forming polymer, such as a cellulose-based polymer, a polysaccharide-based polymer, an N-vinylpyrrolidone-based polymer, an acrylate, an acrylamide, or a copolymer 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 comprises a film-forming polymer selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), starch, hydroxypropyl starch, and hydroxypropyl cellulose (HPC). For example, the coating layer may comprise hydroxypropyl methylcellulose as the film-forming polymer.

[0270] The coating layer may optionally include one or more additional ingredients, such as a plasticizer (e.g., polyethylene glycol, triacetin, or triethyl citrate), an anti-blocking agent (e.g., talc or magnesium stearate), or a colorant (e.g., titanium dioxide, iron oxide, riboflavin, or turmeric).

[0271] In some embodiments, the formulation contains odevixibat in a crystalline form. In some embodiments, the formulation contains a crystalline hydrate of odevixibat. In some embodiments, the formulation contains crystalline modification 1 of odevixibat. This stable crystalline modification can be obtained from a slurry of odevixibat in a mixture of water and an organic solvent, such as ethanol. Under these conditions, a mixed solvate (e.g., dihydrate-diethanolate or dihydrate-triethanolate) containing about 2 moles of water and about 1 to about 3 moles, e.g., about 2 to about 3 moles, of ethanol per mole of odevixibat is initially formed. This mixed solvate is referred to herein as crystalline modification 2. When dried, for example, under reduced pressure (e.g., less than 5 mbar) or under a nitrogen stream, crystalline modification 2 loses its organic solvent molecules to crystalline modification 1. In some embodiments, the conversion of crystalline modification 2 to crystalline modification 1 proceeds via a crystalline intermediate. This crystalline intermediate is a dehydrated form that is believed to rapidly pick up water from the air. Without wishing to be bound by theory, it is believed that the solvent molecules can be removed without dissolving and recrystallizing the crystals.

[0272] Crystalline modification 1 of odevixibat can be obtained not only from a mixture of water and ethanol as described above, but also from a slurry of odevixibat in a mixture of water and an organic solvent selected from the group consisting of methanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, DMF, and DMSO. Upon drying of the various mixed solvates (crystal modification 2) obtained under these conditions, the same crystalline hydrate of odevixibat, namely crystal modification 1, is obtained.

[0273] Crystalline modification 1 contains a void volume capable of containing up to about 2 moles of water bound to the crystal per mole of odevixibat, depending on the relative humidity. Morphologically, this form is therefore a channel hydrate. However, at a relative humidity of about 30%, crystal modification 1 contains a substantially stoichiometric amount of water, about 1.5 moles per mole of organic compound, and is therefore a sesquihydrate. This substantially stoichiometric amount of water is considered advantageous because the water content of the crystals remains substantially constant even with humidity changes within the normal relative humidity range of about 30% to about 70% RH. Indeed, at normal humidity levels, such as about 30% to about 70% RH, crystal modification 1 exhibits relatively low hygroscopicity.

[0274] In one embodiment, the formulation comprises crystalline modification 1 of odevixibat having an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, comprising at least the following specific peaks at °2θ positions: 5.6±0.2, 6.7±0.2, and / or 12.1±0.2.

[0275] In a specific embodiment, the formulation comprises crystalline modification 1 having an XRPD pattern obtained with CuKα1 radiation comprising specific peaks at °2θ positions of 5.6±0.2, 6.7±0.2, and 12.1±0.2, and one or more of the characteristic peaks of 4.1±0.2, 4.6±0.2, 9.3±0.2, 9.4±0.2, and 10.7±0.2.

[0276] In a more specific embodiment, the formulation comprises crystalline modification 1 having an XRPD pattern obtained with CuKα1 radiation comprising specific peaks at °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.

[0277] In a more specific embodiment, the formulation has characteristic peaks at °2θ positions of 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, as well as 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.

[0278] In a more specific embodiment, the formulation exhibits characteristic peaks at °2θ positions obtained with CuKα1 radiation: 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. 2, containing crystalline modification 1, having XRPD patterns including 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.

[0279] In another embodiment, the formulation comprises crystalline modification 1 having an XRPD pattern obtained with CuKα1 radiation substantially as shown in FIG.

[0280] Crystalline modification 1 is a sesquihydrate containing about 3.5% (w / w) water (based on the total crystal mass) at a relative humidity of about 30%, but it has been observed that the crystals can take up an additional 1.5% (w / w) water when the humidity is increased to 95% RH. The adsorption and desorption of this additional water is fully reversible. The additional water may be adsorbed on the surface or may further fill the channels of the structure. In some embodiments, the term "superhydrated" means that the crystal modification 1 contains about 1.5 to about 4 moles of water per mole of odevixibat, such as about 1.5 to about 3.5 moles, or such as about 1.5 to 3 moles, or such as about 1.5 to about 2.5 moles, or such as about 1.5 to about 2 moles of water per mole of odevixibat. In some embodiments, the term "superhydrated" means that the crystalline modification 1 contains from about 2 to about 4 moles of water per mole of odevixibat, such as from about 2 to about 3.5 moles of water per mole of odevixibat, or such as from about 2 to about 3 moles, or such as from about 2 to 2.5 moles of water.

[0281] It has been observed that the XRPD pattern of the perhydrated crystalline modification 1 changes slightly upon drying, for example, at 50 °C under reduced pressure. Small shifts of the peaks are most evident in the 2θ ranges 5-13° and 18-25°, as shown in Figures 3 and 4, respectively. Exposing the dried modification to high relative humidity, for example, up to 95% RH, causes the XRPD pattern of the perhydrated modification to reappear. This peak shift is the result of a change in the unit cell volume that occurs as water molecules enter and leave the crystal structure.

[0282] Thus, in another embodiment, the formulation comprises the perhydrated crystalline modification 1 having an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation comprising at least the specific peaks at °2θ positions 5.7±0.2, 6.7±0.2, and / or 12.0±0.2.

[0283] In a specific embodiment, the formulation comprises the perhydrated crystalline modification 1 having an XRPD pattern obtained with CuKα1 radiation comprising specific peaks at °2θ positions of 5.7±0.2, 6.7±0.2, and 12.0±0.2, and one or more of the characteristic peaks of 4.0±0.2, 9.4±0.2, 9.6±0.2, and 10.8±0.2.

[0284] In a more specific embodiment, the formulation comprises the perhydrated crystalline modification 1 having an XRPD pattern obtained with CuKα1 radiation comprising specific peaks at °2θ positions of 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.

[0285] In a more specific embodiment, the formulation exhibits characteristic peaks at °2θ positions of 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, as well as 4.7±0.2, 8.0±0.2, 8.6±0.2, 13.3±0.2, 14.1±0.2, and 15.3±0.2, as measured with CuKα1 radiation. 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.

[0286] In a more specific embodiment, the formulation has characteristic peaks of 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, 16.0±0.2, 17.0±0.2, 18.0±0.2, 19.0±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0± and perhydrated crystalline modification 1, having XRPD patterns including: 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.

[0287] In another embodiment, the formulation comprises the perhydrated crystalline modification 1 of odevixibat having an XRPD pattern obtained with CuKα1 radiation substantially as shown in FIG.

[0288] 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 the preparation of the formulation. It has been determined that odevixibat is only slightly soluble in water, with a low solubility of approximately 30 μg / mL at pH 7 and 37° C. Due to this low water solubility, an aqueous suspension of odevixibat may contain large aggregates of odevixibat, which may result in an uneven distribution of the active pharmaceutical ingredient on the cores, i.e., the cores may contain different amounts of odevixibat, which in turn affects the uniformity of the dose. Therefore, in some embodiments, the aqueous suspension of odevixibat is homogeneous. In some embodiments, a homogeneous aqueous suspension of odevixibat is sprayed onto the cores.

[0289] Odevixibat exhibits high potency and should be administered at low doses, particularly in the treatment of pediatric patients weighing approximately 4 to 55.5 kg. To achieve high dose uniformity with the multiparticulate formulations disclosed herein, it is important that each particle of the formulation contains substantially the same amount of odevixibat, i.e., the variability in odevixibat content of the particles of the formulation should be as small as possible.

[0290] As used herein, the term "uniform" means that the suspension does not contain odebixibat aggregates larger than about 200 μm, e.g., odebixibat aggregates larger than about 100 μm, or odebixibat aggregates larger than about 50 μm. The size of the odebixibat aggregates in the coating suspension can be determined by light microscopy as described in the experimental section, using a method based on monograph 2.9.37 of the European Pharmacopoeia 9.0. Alternatively, the size of the odebixibat aggregates in the coating suspension can be determined by light scattering techniques, such as low-angle laser light scattering (LALLS). In some embodiments, the particle size distribution of the coating suspension can be determined by light scattering techniques, such as low-angle laser light scattering (LALLS). 90 The value may be less than 15 μm, such as less than 14 μm, for example less than 13 μm, such as less than 12 μm, for example less than 11 μm, or such as less than 10 μm.

[0291] In some embodiments, a uniform suspension of odevixibat can be prepared by dispersing the compound in water by wet milling. Wet milling is a process in which a solid substance is dispersed in a liquid by shearing, crushing, or grinding. Examples of wet milling equipment include colloid mills, conical mills, ball mills, disk mills, and high-shear dispersers. A specific example of a wet milling equipment for use in the formulations provided herein is a colloid mill.

[0292] In some embodiments, the crystallinity of odevixibat increases during wet milling.

[0293] In some embodiments, odevixibat is first wetted in a small amount of water using a homogenizer, and then dispersed in water using a colloid mill. The homogenous dispersion is sprayed onto the cores, allowing for uniform distribution of the active pharmaceutical ingredient.

[0294] It is desirable that the formulation does not contain any components that are not strictly 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.

[0295] In one embodiment, the particles are contained in a sachet. In another embodiment, the particles are contained in a capsule. Such capsules can be made from gelatin, cellulosic polymers such as hydroxypropylmethylcellulose (hypromellose), or polysaccharide polymers such as pullulan. The capsules can be swallowed whole or can be designed to be opened so that the contents (i.e., particles) can be sprinkled into a food medium for administration. In the latter case, the number of particles per capsule should correspond to one tablespoon of food. In some embodiments, the capsules contain about 20 to about 100 mg of particles, e.g., about 30, about 40, about 50, about 60, about 70, about 80, or about 90 mg of particles.

[0296] For younger pediatric patients, such as infants, toddlers, and children under about 6 years of age, the particles can be sprinkled onto foods that are easy to swallow and do not require chewing, such as yogurt, applesauce, fruit puree, or oatmeal. For older pediatric patients, such as children over about 6 years of age, adolescents, and young adults, capsules containing the particles can be swallowed whole, i.e., unopened. For neonatal patients under about 6 months of age who have not yet weaned or are unable to consume semi-solid foods, the formulation can be administered by dispersing the particles in a suitable liquid medium, such as breast milk, formula, or water. When dispersed in a liquid medium, the particles can be administered to the patient within 30 minutes of dispersion without loss of active ingredient or signs of degradation. In some embodiments, the amount of liquid medium used to administer odevixibat particles, including rinsing, can be less than about 20 mL, such as less than about 15 mL, such as less than about 10 mL, or such as less than about 5 mL. In some embodiments, the dispersed particles are administered directly into the mouth using an oral syringe.

[0297] Although several embodiments of the present invention have been described, it will 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 following claims. [Example]

[0298] Example 1 A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Odevixibat in Patients with Alagille Syndrome (ASSERT) Alagille syndrome (ALGS) is a rare multisystem disorder with a wide variety of clinical manifestations affecting the liver, heart, skeleton, eyes, central nervous system, kidneys, and facial features. It is an autosomal dominant disorder caused in approximately 90% of patients by deficiencies in components of the NOTCH signaling pathway, most commonly due to mutations in JAG1. A minority of patients with ALGS have mutations in the gene for the NOTCH2 receptor. Approximately 60% of cases exhibit de novo mutations. The majority of patients present early, often within the first three months of life, with jaundice or cardiac symptoms.

[0299] Diagnosis of ALGS has traditionally been difficult due to the variable clinical manifestations. Findings based on histological examination of liver biopsy specimens can be inconclusive. With the introduction of genetic testing, detection of mutations in JAG1 or NOTCH2 sequence analysis can confirm or even make the clinical diagnosis of ALGS.

[0300] The majority of patients with ALGS present with severe, refractory pruritus that can be disabling. Attempts to manage pruritus have been made by including ursodeoxycholic acid, cholestyramine, rifampin, ondansetron, or naltrexone in patient treatment regimens, but these medications are only partially effective at best. Occasionally, bile duct diversion is used to treat refractory pruritus with some success. Treatment of persistent cholestasis and advanced cirrhosis is supportive and usually involves choleretic agents. Kasai portoenterostomy (HPE) has been attempted in an effort to increase bile flow from the liver to the intestine, but unlike patients with biliary atresia, patients with ALGS who undergo this procedure show worse outcomes. Approximately 15% to 25% of patients with ALGS will require liver transplantation during childhood. Patients with ALGS have a positive response to transplantation, with approximately 90% showing improvement in liver parameters and some degree of catch-up growth. The 5-year post-transplant survival rate in this population is approximately 80%.

[0301] Besides cholestasis and pruritus, other characteristic findings of ALGS include jaundice, elevated bile acid and liver biochemistry parameters, cardiovascular abnormalities, xanthomas, and fat-soluble vitamin deficiencies.

[0302] IBAT, also known as the apical sodium-dependent bile acid transporter (SLC10A2), is located on the luminal side of enterocytes in the terminal ileum and mediates the reabsorption of conjugated bile acids for recirculation to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and results in fecal excretion of bile acids similar to surgical interruption of the enterohepatic circulation.

[0303] method Study Design and Procedures Odevixibat is an investigational, orally administered, potent, luminal-limited, selective IBAT inhibitor for the treatment of cholestatic liver disease. This Phase 3, double-blind, randomized, 24-week study (ASSERT) evaluated the efficacy and safety of odevixibat compared with placebo in patients with Alagille syndrome (ALGS). The efficacy of odevixibat in patients with ALGS was evaluated in a 24-week, randomized, double-blind, placebo-controlled study (NCT04674761; ASSERT) conducted in 52 patients with a confirmed diagnosis of 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 repeated daily dosing of odebixibat 120 μg / kg / day in reducing pruritus in patients with ALGS, to evaluate the effect of odebixibat on serum bile acid levels in patients with ALGS, and to evaluate the safety and tolerability of odebixibat in patients with ALGS.

[0304] The study consisted of a screening phase and a parallel-design treatment period. Two screening visits were conducted. The first occurred between 56 and 21 days before the first dose of study medication, and the second occurred between 49 and 14 days before. On Day 0, all eligible patients were randomized in a 2:1 ratio to receive oral odevixibat 120 μg / kg / day or placebo once daily. Eligibility for randomization was confirmed using observer-reported outcomes (ObsRO) / patient-reported outcomes (PRO) data for the assessment of pruritus (PRO), scratching (ObsRO), and sleep disturbance (PRO and ObsRO) within the 14 days prior to Study Day 1, clinical genetic confirmation of diagnosis, and liver biochemistry assessment from a previous screening visit. After obtaining written informed consent, patients were assigned to treatment using an interactive web response system (IWRS). Randomization codes were computer-generated by Albireo or a certified randomization vendor.

[0305] Odevixibat and placebo were supplied as capsules for oral administration. Patients were given white, opaque capsules filled with pellets containing odevixibat or placebo. Two different capsule sizes were available: size 0, which could be opened, and size 3, which could be swallowed whole. Size 3 capsules were opened only under exceptional circumstances (e.g., if the patient was unable to swallow the capsule whole). To ensure blinding of treatment assignment, the study drug and matching placebo were of the same shape and size, and the study drug containers were labeled without identifying the randomized treatment assignment. Dispensing of study drug was coordinated by the IWRS.

[0306] Treatment was dispensed during a local clinic visit, and patients or caregivers were instructed to take or administer the study medication at home each morning as a whole capsule (swallowed with a glass of water and food). Alternatively, the capsule could be opened and the contents sprinkled and mixed into a small amount of soft, room-temperature food (e.g., applesauce, followed by water). The double-blind ASSERT treatment period lasted 24 weeks.

[0307] Patients who completed the treatment period had a follow-up visit 28 days (±7) after the last dose of study drug or could continue to enter an optional open-label extension study (ASSERT-EXT; ClinicalTrials.gov identifier: NCT05035030) in which all patients received odevixibat. Up to 10 clinic visits, including screening, treatment, and follow-up visits, were scheduled, along with one phone call at week 2, midway between randomization and the week 4 visit.

[0308] Patients - Key Eligibility Criteria Patients (of any age) with a genetically confirmed diagnosis of ALGS met the eligibility criteria. Patients had to have a history of significant pruritus, elevated baseline serum bile acid levels, and a mean caregiver-reported score for observed scratching behavior or a patient-reported score for pruritus of 2 or greater (on a scale of 0 to 4) within 14 days prior to randomization, as measured by the ObsRO device (for patients under 18 years of age) or the PRO device (for patients 18 years of age or older). In addition, caregivers or eligible patients (aged 8 years or older) consented to use an electronic diary (eDiary) device to record symptoms.

[0309] Exclusion criteria included the following: history or ongoing 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 based on imaging studies); diseases or conditions known to interfere with intestinal drug absorption, distribution, metabolism (especially bile acid metabolism), or excretion (e.g., inflammatory bowel disease); chronic (i.e., >3 months) diarrhea; active, clinically significant acute or chronic infection, or infection requiring hospitalization or parenteral anti-infective treatment within 4 weeks of treatment initiation; cancer within the past 5 years, excluding basal cell carcinoma; cancer more than 5 years before screening, excluding non-liver cancer, without evidence of recurrence; or chronic kidney disease. Patients were excluded from the study if they had undergone a bile duct drainage system within 6 months prior to the start of the screening period; had undergone a liver transplant or were scheduled for a liver transplant within 6 months of randomization; showed signs of decompensated liver disease (e.g., ascites); or showed pruritus caused by any condition other than ALGS (e.g., refractory atopic dermatitis, other primary pruritic skin diseases). Use of resins or medications that slow gastrointestinal motility was not permitted. Patients were excluded if they had laboratory parameters exceeding the following thresholds: international normalized ratio (INR) >1.4, serum alanine aminotransferase (ALT) >10x the upper limit of normal (ULN) at screening, serum ALT >15x the ULN in the past 6 months, and total bilirubin >15x the ULN at screening. Additional exclusion criteria included any patient who was pregnant or breastfeeding or planning to become pregnant within 24 weeks of randomization; patients with a history of alcohol or substance abuse; and patients with investigational exposure to any drug, biologic, or medical device within 30 days or within 5 half-lives of the study agent, whichever was longer, prior to screening.

[0310] evaluation One primary endpoint was assessed in this study: the change from baseline to 6 months (weeks 21-24) in scratching behavior, as measured by the Observer-Reported Outcomes (ObsRO) instrument.

[0311] The study was also conducted for a second primary endpoint, namely, the change from baseline to the mean of weeks 20 and 24 in serum bile acid levels. Additional secondary efficacy endpoints were: Change in pruritus from baseline to month 6 (weeks 21-24) as measured by the Albireo PRO device. · Percentage of patients who achieved a clinically significant reduction in pruritus (pruritus responders) as measured by the ObsRO / PRO instrument. Changes from baseline to week 24 in patient-reported and observer-reported itch and scratching severity scores for morning and evening assessments, respectively; sleep parameters (e.g., fatigue and number of awakenings) measured by Albireo's ObsRO / PRO device; and PedsQL subdomain scores. Patient, caregiver, and clinician assessments of overall symptom relief as measured by items from the Global Impression of Symptoms GIS (PGIS, CaGIS, CGIS) from baseline to 4, 12, and 24 weeks. Change from baseline to week 24 in xanthomatosis as assessed by the Clinician Xanthomatosis Scale; serum bile acid levels; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels; gamma-glutamyltransferase levels; and total bilirubin levels. Changes from baseline in biochemical markers and measures of bile acid synthesis (autotaxin, p-C4, and patients >10 kg only); and total cholesterol levels.

[0312] Itch parameters, scratching behavior parameters, and sleep parameters Itch, observed scratching behavior, and sleep disturbance were recorded twice daily via eDiary. Patients and / or caregivers were instructed to complete the eDiary every morning after the patient woke up and in the evening just before the patient went to bed throughout the study. The eDiary included ObsRO and PRO items. The PRO items assessed itch severity, aspects of sleep disturbance (morning diary only), and fatigue. The ObsRO items assessed observed scratching severity, aspects of sleep disturbance (morning diary only), and signs of fatigue (evening diary only). See Figure 26. The scratching behavior and itch severity items in ObsRO and PRO used a response scale of 0 to 4.

[0313] serum bile acids At each clinic visit, blood samples were collected for analysis of fasting total serum bile acids. All post-baseline serum bile acid analyses were blinded. Samples were processed and shipped to a central laboratory according to instructions in the laboratory manual.

[0314] Biochemical markers and PK samples Blood samples for clinical chemistry analysis were collected between Screening Visits 1 and 2, as well as at randomization (Study Day 1), Weeks 4 to 24 / EOT, and safety follow-up visits. As outlined in Table 1, assessments of total bilirubin, AST, ALT, and γ-glutamyltransferase were included as part of routine laboratory parameters. Blood samples for autotaxin and p-C4 were collected at randomization (Study Day 1), Week 12, and Week 24 / EOT for children weighing >10 kg only. Blood for odevixibat PK evaluation was collected at Weeks 4, 20, and EOT (for children weighing >10 kg only). Samples were processed and transported to the laboratory according to instructions in the laboratory manual.

[0315] [Table 1]

[0316] Global Impression of Change and Global Impression of Symptoms Measurement Items Patients (ages 8 years and older), caregivers, and clinicians completed Global Impression of Change (GIC) measures (Patient Global Impression of Change (PGIC), Caregiver Global Impression of Change (CaGIC), and Clinician Global Impression of Change (CGIC)) and Global Impression of Symptoms (GIS) measures (Patient Global Impression of Symptoms (PGIS), Caregiver Global Impression of Symptoms (CaGIS), and Clinician Global Impression of Symptoms (CGIS)) at randomization (Study Day 1; PGIS only), 4 weeks, 12 weeks, and 24 weeks / EOT.

[0317] GIC items assessed change in itch (patient version), scratching behavior (caregiver and clinician versions), and sleep (all versions) since initiation of study medication. GIS items assessed itch (patient version), scratching behavior (caregiver and clinician versions), and sleep (all versions) over the past week. Caregivers and clinicians completed the GIC and GIS for all patients, and patients aged 8 years and older completed the patient version.

[0318] Clinical evaluation of xanthomas Changes in xanthomas, as assessed by the Clinician Xanthomas Scale, were measured at randomization (Study Day 1), Week 12, and Week 24 / EOT visits. Clinicians' assessment of participants' xanthomas focused on the number of lesions present and the extent to which the participants' lesions interfered with or limited their activities. The Clinician Xanthomas Scale used a 5-point scale, where 0 represented no evidence of xanthomas, 1 represented fewer than 20 scattered individual lesions, 2 represented more than 20 lesions that did not interfere with or limit activities, 3 represented numerous lesions that were large in number or size, causing facial or limb distortion, and 4 represented xanthomas that were excessive in size or number, interfering with function (e.g., hand use or ability to walk).

[0319] safety The primary safety analyses in this study included the overall incidence of treatment-emergent adverse events (AEs) and the incidence of treatment-emergent adverse events (TEAEs) categorized by investigator assessment of causality, severity, and seriousness comparing study drug exposure with placebo. Other safety endpoints included physical examination, concomitant medications, vital signs, laboratory tests, and liver ultrasound and hepatic elastography.

[0320] statistical analysis A sample size of 45 patients under the age of 18 years was randomized in a 2:1 allocation ratio to experimental medication versus control, designed to yield approximately 36 completers, assuming a dropout rate of approximately 20%. Subjects under the age of 18 years were randomized according to one age stratification factor: age <10 years and ages 10 to <18 years. This stratification factor was based on demonstrating increased prevalence and severity of pruritus in children under the age of 10 years. At an α1-sided one-sided significance level of 0.025, assuming a pooled standard deviation (SD) of 1.0 and a difference between treatment groups in the change in pruritus that would promote response of 1.2, the power of the study using exact methods (SAS, Proc Power v.9.4, Cary, NC) was 0.909. A standardized treatment effect (treatment effect / SD) of 1.2 was also used to demonstrate power for the primary secondary endpoint. To assess the need for sample size re-estimation after a minimum of 18 patients completed the 16-week visit, an independent statistician calculated the pooled SD of the change in mean monthly scratching scores from baseline to Month 4 (assessment at Weeks 13–16) and the available change from baseline to Month 6 (assessment at Weeks 21–24). Sample size re-estimation was based on unblinded data that did not require alpha adjustment. If the pooled SD was underestimated in this sample size calculation, an adjustment would have been made to maintain the power of the study, assuming a treatment effect of 1.2. The SDs at Weeks 16 and 24 were assumed to be equivalent; however, a multiplication factor (1.07) may have been used for the calculated SD based on current understanding of the instrument at the time of sample size re-estimation. If the SD was overestimated in this initial sample size calculation, the sample size would not have been reduced. Planned sample size re-estimation was performed based on Figure 21. The sample size was increased to a goal of 48 completers (i.e., approximately 32 and 16 patients in the odevixibat and placebo groups, respectively, based on a 2:1 randomization ratio). Due to the low dropout rate at that time, 7 patients were added to the study. A total of 52 patients were enrolled.

[0321] result patient patient placement Study design and baseline characteristics are shown in Figures 1-3. A total of 52 patients were randomized: 17 to placebo and 35 to odevixibat 120 μg / kg / day, respectively. Overall, all 52 (100%) patients completed the 24-week treatment period (Figure 2).

[0322] Figure 3 summarizes the patient demographics and baseline characteristics. The mean age of the patients was 6.3 years, and 27 (52%) were male. 92% of patients had JAG1 mutations, and 8% had NOTCH2 mutations. At baseline (study entry), 89% of patients were treated with ursodeoxycholic acid (UDCA), and 98% were treated with antipruritic medications. The baseline mean (SD) pruritus score (range: ...

Claims

1. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject, the subject exhibits a decrease in pruritus score compared to baseline.

2. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating pruritus associated with Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject, the subject exhibits a decrease in pruritus score compared to baseline.

3. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in reducing pruritus scores compared to baseline in a subject with Alagille syndrome (ALGS).

4. 4. The formulation for use according to any one of claims 1 to 3, wherein the reduction in pruritus score is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.

0.

5. 5. The formulation for use according to any one of claims 1 to 4, wherein the reduction in pruritus score compared to baseline is from about 1.2 to about 2.

0.

6. 6. The formulation for use according to any one of claims 1 to 5, wherein the reduction in pruritus score compared to baseline is about 1.

6.

7. 7. The formulation for use according to any one of claims 1 to 6, wherein the reduction in pruritus score compared to baseline occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

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

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

10. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in reducing serum bile acid concentrations in a subject with Alagille syndrome (ALGS).

11. 11. The formulation for use according to any one of claims 8 to 10, wherein the reduction in serum bile acid concentration is 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 compared to baseline.

12. 11. The formulation for use according to any one of claims 8 to 10, wherein the reduction in serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L compared to baseline.

13. 11. The formulation for use according to any one of claims 8 to 10, wherein the reduction in serum bile acid concentration is from about 70 μmol / L to about 120 μmol / L compared to baseline.

14. 14. The formulation for use according to any one of claims 8 to 13, wherein the reduction in serum bile acid concentration occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

15. 1. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating Alagille Syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject for at least 24 weeks, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

16. 1. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating pruritus associated with Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject for at least 24 weeks, the subject exhibits a serum bile acid concentration of less than 70 μmol / L.

17. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject for at least 24 weeks, the subject exhibits at least a 50% reduction in serum bile acid concentration compared to baseline.

18. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in treating pruritus associated with Alagille syndrome (ALGS), wherein after oral administration of the pharmaceutical formulation to a subject for at least 24 weeks, the subject exhibits at least a 50% reduction in serum bile acid concentration compared to baseline.

19. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in reducing serum bile acid concentrations by at least 50% compared to baseline in subjects with Alagille syndrome (ALGS) by oral administration of the pharmaceutical formulation for at least 24 weeks.

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

21. 10. A pharmaceutically acceptable salt thereof for use in improving sleep parameters in a subject with ALGS.

22. 22. The formulation for use according to claim 21, wherein the sleep parameters are selected from the group consisting of percent of days with scratching accompanied by bleeding, percent of days needing assistance in falling asleep, percent of days needing sedation, fatigue, and percent of days needing to sleep with a caregiver.

23. 23. The formulation for use according to claim 21 or 22, wherein the improvement in sleep parameters occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, 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.

24. A pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof for use in improving a liver parameter or liver biomarker in a subject with ALGS.

25. 25. The formulation for use according to claim 24, wherein the liver parameter or liver biomarker is selected from the group consisting of autotaxin level, plasma C4 level, total bilirubin level, serum alanine aminotransferase (ALT) level, serum gamma-glutamyltransferase (GGT) level, and serum aspartate transaminase (AST) level.

26. 26. The formulation for use according to claim 24 or 25, wherein the improvement in the liver parameter occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, 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.

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

28. 28. The formulation for use according to any one of claims 1 to 27, wherein the subject is administered 120 μg / kg / day of odevixibat or a pharmaceutically acceptable salt thereof.

29. 29. The formulation for use according to any one of claims 1 to 28, wherein the subject was odevixibat naive prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

30. 30. The pharmaceutical formulation of odevixibat or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein the formulation comprises a plurality of particles, each particle having a particle size of about 0.1 to about 1.5 mm, and comprising odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / w to about 5.0% w / w, based on the total mass of the particle.

31. 31. The formulation for use according to claim 30, wherein each particle comprises odevixibat 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 mass of the particle.

32. 32. The formulation for use according to claim 30 or 31, wherein each particle comprises odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w relative to the total mass of the particle.

33. 33. The formulation for use according to any one of claims 30 to 32, wherein each particle comprises odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 1.5% w / w relative to the total mass of the particle.

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

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

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

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

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

39. The formulation for use according to any one of claims 34 to 38, wherein the coating layer is sprayed onto the particles as a homogeneous aqueous suspension of odevixibat.

40. 40. The formulation for use according to claim 39, wherein the uniform suspension is prepared by dispersing odevixibat or a pharmaceutically acceptable salt thereof in water by wet milling.

41. 41. A formulation for use according to claim 39 or 40, wherein the homogeneous suspension does not contain odevixibat aggregates larger than 200 μm.

42. The formulation for use according to any one of claims 34 to 41, wherein the coating layer is free of surfactants.

43. 43. The formulation for use according to any one of claims 30 to 42, wherein the particles have a particle size of about 0.1 to about 1.0 mm.

44. 44. The formulation for use according to any one of claims 30 to 43, wherein odevixibat is present as a crystalline hydrate of odevixibat.

45. 45. The formulation for use according to any one of claims 30 to 44, wherein odevixibat is present as crystalline modification 1 of odevixibat.

46. 46. ​​A formulation for use according to claim 45, wherein the crystalline modification 1 of odevixibat has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, comprising at least the specific peaks at °2θ positions of 5.6±0.2, 6.7±0.2, and / or 12.1±0.

2.

47. A formulation for use according to any one of claims 30 to 46, wherein the particles are contained within a sachet or capsule.

48. 30. The formulation for use according to any one of claims 1 to 29, wherein odevixibat is present as a hydrate of odevixibat.

49. 49. The formulation for use according to claim 48, wherein odevixibat is present as a sesquihydrate.

50. 50. The formulation for use according to any one of claims 1 to 29 and 48 to 49, wherein odevixibat is present as a crystalline hydrate of odevixibat.

51. 51. The formulation for use according to claim 50, wherein odevixibat is present as crystalline modification 1 of odevixibat.

52. 52. A formulation for use according to claim 51, wherein the crystalline modification 1 of odevixibat has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, comprising at least the specific peaks at °2θ positions of 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, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in pruritus score compared to baseline.

54. A method for treating pruritus associated with Alagille Syndrome (ALGS) in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation, the subject exhibits a decrease in pruritus score compared to baseline.

55. 1. A method for reducing pruritus scores relative to baseline in a subject with Alagille Syndrome (ALGS), comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

56. 56. The method of any one of claims 53 to 55, wherein the reduction in itch score from baseline is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.

0.

57. 57. The method of any one of claims 53 to 56, wherein the reduction in itch score compared to baseline is from about 1.2 to about 2.

0.

58. 58. The method of any one of claims 53 to 57, wherein the reduction in itch score compared to baseline is about 1.

6.

59. 59. The method of any one of claims 53-58, wherein the reduction in pruritus score compared to baseline occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

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

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

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

63. 63. The method of any one of claims 60-62, wherein the reduction in serum bile acid concentration is 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. 63. The method of any one of claims 60-62, wherein the reduction in serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L compared to baseline.

65. 63. The method of any one of claims 60-62, wherein the reduction in serum bile acid concentration is from about 70 μmol / L to about 120 μmol / L compared to baseline.

66. 66. The method of any one of claims 60-65, wherein the reduction in serum bile acid concentration occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

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

68. 1. A method for treating pruritus associated with Alagille Syndrome (ALGS) in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of 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, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof, wherein after administration of the pharmaceutical formulation for at least 24 weeks, the subject exhibits at least a 50% reduction in serum bile acid concentration compared to baseline.

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

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

72. 72. The method of any one of claims 69-71, wherein the subject exhibits at least a 60%, at least a 70%, or at least an 80% decrease in serum bile acid concentration compared to baseline.

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

74. 74. The method of claim 73, wherein the sleep parameters are selected from the group consisting of percent of days with scratching accompanied by bleeding, percent of days requiring assistance with falling asleep, percent of days requiring sedation, fatigue, and percent of days requiring sleep with a caregiver.

75. 75. The method of claim 73 or 74, wherein the improvement in sleep parameters occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, 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.

76. 1. A method for improving a liver parameter or liver biomarker in a subject with ALGS, comprising orally administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

77. 77. The method of claim 76, wherein the liver parameter or liver biomarker is selected from the group consisting of autotaxin level, plasma C4 level, total bilirubin level, serum alanine aminotransferase (ALT) level, serum gamma-glutamyltransferase (GGT) level, and serum aspartate transaminase (AST) level.

78. 78. The method of claim 76 or 77, wherein the improvement in the liver parameter occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, 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.

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

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

81. 81. The method of any one of claims 53 to 80, wherein the subject was odevixibat naive prior to the first administration of the pharmaceutical formulation comprising odevixibat or a pharmaceutically acceptable salt thereof.

82. 82. The method of any one of claims 53 to 81, wherein the pharmaceutical formulation of odevixibat or a pharmaceutically acceptable salt thereof comprises a plurality of particles, each particle having a particle size of about 0.1 to about 1.5 mm, and comprising odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% w / w to about 5.0% w / w, based on the total mass of the particle.

83. 83. The method of claim 82, wherein each particle comprises odevixibat 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 mass of the particle.

84. 84. The method of claim 82 or 83, wherein each particle comprises odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 0.5% w / w relative to the total mass of the particle.

85. 85. The method of any one of claims 82 to 84, wherein each particle comprises odevixibat or a pharmaceutically acceptable salt thereof in an amount of about 1.5% w / w relative to the total mass of the particle.

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

87. 87. The method of any one of claims 82 to 86, wherein the core does not comprise odevixibat or a pharmaceutically acceptable salt thereof.

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

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

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

91. 91. The method of any one of claims 86 to 90, wherein the coating layer is sprayed onto the particles as a homogeneous aqueous suspension of odevixibat.

92. 92. The method of claim 91, wherein the uniform suspension is prepared by dispersing odevixibat or a pharmaceutically acceptable salt thereof in water by wet milling.

93. 93. The method of claim 91 or 92, wherein the uniform suspension does not contain odevixibat aggregates greater than 200 μm.

94. The method of any one of claims 86 to 93, wherein the coating layer is surfactant-free.

95. 95. The method of any one of claims 82 to 94, wherein the particles are about 0.1 to about 1.0 mm in size.

96. 96. The method of any one of claims 82 to 95, wherein odevixibat is present as a crystalline hydrate of odevixibat.

97. 97. The method of any one of claims 82 to 96, wherein odevixibat is present as crystalline modification 1 of odevixibat.

98. 98. The method of claim 97, wherein the crystalline modification 1 of odevixibat has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, comprising at least the following specific peaks at °2θ positions: 5.6±0.2, 6.7±0.2, and / or 12.1±0.

2.

99. 99. The method of any one of claims 82 to 98, wherein the particles are contained in a sachet or capsule.

100. 82. The method of any one of claims 53 to 81, wherein odevixibat is present as a hydrate of odevixibat.

101. 133. The method of claim 132, wherein odevixibat is present as a sesquihydrate.

102. 102. The method of any one of claims 53 to 81 and 100 to 101, wherein odevixibat is present as a crystalline hydrate of odevixibat.

103. 103. The method of claim 102, wherein odevixibat is present as crystalline modification 1 of odevixibat.

104. 104. The method of claim 103, wherein the crystalline modification 1 of odevixibat has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, comprising at least the following specific peaks at °2θ positions: 5.6±0.2, 6.7±0.2, and / or 12.1±0.

2.

105. The method of any one of claims 60 to 104, wherein the subject exhibits a decrease in itch score compared to baseline.

106. 106. The method of claim 105, wherein the reduction in itch score from baseline is at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or at least 2.

0.

107. 107. The method of any one of claims 53 to 59 and 105 to 106, wherein the reduction in itch score compared to baseline is from about 1.5 to about 4.

108. 108. The method of any one of claims 53 to 59 and 105 to 107, wherein the reduction in itch score compared to baseline is about 1.5 to about 2.

5.

109. 109. The method of any one of claims 53 to 59 and 105 to 108, wherein the reduction in itch score compared to baseline is about 2.

110. 110. The method of any one of claims 105-109, wherein the reduction in pruritus score compared to baseline occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

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

0.

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

5.

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

0.

114. 113. The method of any one of claims 53-59 and 105-112, wherein the baseline pruritus score is about 2.

8.

115. 115. The method of any one of claims 53-59 and 73-114, wherein the subject exhibits a decrease in serum bile acid concentration compared to baseline.

116. 116. The method of claim 115, wherein the decrease in serum bile acid concentration is 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.

117. 117. The method of any one of claims 115-116, wherein the reduction in serum bile acid concentration is from about 50 μmol / L to about 180 μmol / L compared to baseline.

118. 118. The method of any one of claims 115-117, wherein the reduction in serum bile acid concentration is from about 70 μmol / L to about 120 μmol / L compared to baseline.

119. 119. The method of any one of claims 60-72 and 115-118, wherein the reduction in serum bile acid concentration is from about 80 μmol / L to about 110 μmol / L compared to baseline.

120. 120. The method of any one of claims 115-119, wherein the reduction in serum bile acid concentration occurs after administration of the pharmaceutical formulation for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

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

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

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

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