Treatment with ileal bile acid transporter (IBAT) inhibitors to increase event-free survival (EFS)

Abstract

The present invention generally relates to a method for treating cholestatic liver disease by administering an ileal bile acid transporter (IBAT) inhibitor, which treatment results in an increase in event-free survival (EFS).The present invention also relates to a method for predicting EFS, thereby providing a prediction of response to IBAT inhibitor therapy for the treatment of cholestatic liver disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 315,762, filed March 2, 2022, and U.S. Provisional Application No. 63 / 276,480, filed November 5, 2021, the disclosures of which are incorporated by reference in their entireties herein. [Technical field]

[0002] The present invention relates generally to a method for treating cholestatic liver disease by administering an ileal bile acid transporter (IBAT) inhibitor, which treatment results in an increase in event-free survival (EFS).The present invention also relates to a method for predicting EFS, thereby providing a prediction of response to IBAT inhibitor therapy for the treatment of cholestatic liver disease. [Background technology]

[0003] Hypercholestasis and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis), often associated with and secondary to intracellular accumulation of bile acids / salts in hepatocytes. Hypercholestasis is characterized by elevated serum concentrations of bile acids or bile salts. Cholestasis can be classified clinically and pathologically into two major categories: obstructive, often extrahepatic, cholestasis, and nonobstructive or intrahepatic cholestasis. Nonobstructive intrahepatic cholestasis can be further classified into two major subgroups: primary intrahepatic cholestasis, resulting from constitutively defective bile secretion, and secondary intrahepatic cholestasis, resulting from hepatocellular injury. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, a predominantly adult form with similar clinical manifestations, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which are diseases that affect children.

[0004] Background: Pediatric cholestatic liver disease affects a small percentage of children, but treatment incurs substantial healthcare costs each year. Currently, many pediatric cases of cholestatic liver disease require invasive and costly procedures, such as liver transplantation and surgery. There is a need for effective, minimally invasive transplant-free survival (TFS) procedures that result in long-term event-free survival (EFS). Summary of the Invention [Means for solving the problem]

[0005] Various non-limiting aspects and embodiments of the present invention are described below.

[0006] In one aspect, the present invention provides a method of treating cholestatic liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ileal bile acid transporter (IBAT) inhibitor, the treatment comprising: a) Total bilirubin (TB); b) total serum bile acids (sBA); and c) Itch score measured by the Itch Reported Outcome (ItchRO) severity assessment tool The present invention provides a method for increasing a subject's event-free survival (EFS) by reducing one or more of the following:

[0007] In one embodiment, TB is reduced to about 6.5 mg / dL or less.

[0008] In one embodiment, sBA levels are reduced to about 200 μmol / L or less.

[0009] In one embodiment, the ItchRO score for pruritus is reduced by at least about 1 point compared to the first administration of the IBAT inhibitor.

[0010] In one embodiment, the TB, sBA, or pruritus score is determined 18 weeks after the start of IBAT inhibitor treatment. In one embodiment, the TB, sBA, or pruritus score is determined 24 weeks after the start of IBAT inhibitor treatment. In one embodiment, the TB, sBA, or pruritus score is determined 48 weeks after the start of IBAT inhibitor treatment.

[0011] In one embodiment, the TB, sBA or pruritus score is reduced compared to the first administration of the IBAT inhibitor.

[0012] In one aspect, the present invention provides a method for providing a prediction of response to IBAT inhibitor therapy for the treatment of cholestatic liver disease in a subject in need thereof by predicting event-free survival (EFS), the method comprising obtaining one or more of total bilirubin (TB) data, total serum bile acid (sBA) data, pruritus relief data, and age of the subject at the start of treatment with the IBAT inhibitor, and predicting EFS using the data obtained for the subject.

[0013] In one embodiment, EFS is predicted when TB is less than about 6.5 mg / dL.

[0014] In one embodiment, TB is determined 48 weeks after the initiation of IBAT inhibitor treatment.

[0015] In one embodiment, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 200 μmol / L.

[0016] In one embodiment, the sBA level is determined 18 weeks after the start of IBAT inhibitor treatment. In one embodiment, the sBA level is determined 24 weeks after the start of IBAT inhibitor treatment. In one embodiment, the sBA level is determined 48 weeks after the start of IBAT inhibitor treatment.

[0017] In one embodiment, EFS is predicted by a reduction in pruritus after treatment with the IBAT inhibitor compared to pruritus upon first administration of the IBAT inhibitor of at least about 1 point, where pruritus is measured by the Itch Reported Outcomes (ItchRO) severity assessment tool.

[0018] In one embodiment, pruritus is determined 18 weeks after the start of IBAT inhibitor treatment. In one embodiment, pruritus is determined 24 weeks after the start of IBAT inhibitor treatment. In one embodiment, pruritus is determined 48 weeks after the start of IBAT inhibitor treatment.

[0019] In one embodiment, EFS is predicted when the subject's age at the start of treatment is about 36 months or greater.

[0020] In one embodiment, EFS includes the time to survival free of one or more of hepatic decompensation, surgical biliary diversion, liver transplant, or death.

[0021] In one embodiment, EFS includes the length of time a subject survives in the absence of a liver transplant.

[0022] In one embodiment, treatment with an IBAT inhibitor further results in relief of cholestatic pruritus.

[0023] In one embodiment, administration is sufficient to cause the subject to have an event-free survival of at least 18 months after the first administration of the IBAT inhibitor.In one embodiment, administration is sufficient to cause the subject to have an event-free survival of at least 2 years after the first administration of the IBAT inhibitor.In one embodiment, administration is sufficient to cause the subject to have an event-free survival of at least 6 years after the first administration of the IBAT inhibitor.

[0024] In one embodiment, the cholestatic liver disease is pediatric cholestatic liver disease.

[0025] In one embodiment, the cholestatic liver disease is adult cholestatic liver disease.

[0026] In one embodiment, the cholestatic liver disease is selected from the group consisting of nonobstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-related (TPN-related) cholestasis, and / or cholestasis. The following conditions are considered to be associated with cholestasis: paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, drug-associated cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome (ALGS), biliary atresia, biliary atresia after Kasai operation, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant associated liver disease, intestinal failure associated liver disease, bile acid-mediated liver disease, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

[0027] In one embodiment, the cholestatic liver disease is ALGS, PFIC, BRIC, PSC, PBC, or biliary atresia.

[0028] In one embodiment, the sBA comprises one or more of TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA.

[0029] In another aspect, the present invention provides a method of treating cholestatic liver disease associated with pruritus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an IBAT inhibitor or a pharma- ceutically acceptable salt thereof, which administration reduces the pruritus score by at least about 1 point as measured by the Itch Reported Outcomes (ItchRO) severity assessment tool, thereby increasing the subject's event-free survival (EFS) for at least 18 months after the first administration of the IBAT inhibitor.

[0030] In one embodiment, the cholestatic liver disease associated with pruritus is selected from the group consisting of ALGS, PFIC, BRIC, PSC, PBC and biliary atresia.

[0031] In one embodiment, the pruritus score is determined 18 weeks after the start of IBAT inhibitor treatment. In one embodiment, the pruritus score is determined 24 weeks after the start of IBAT inhibitor treatment. In one embodiment, the pruritus score is determined 48 weeks after the start of IBAT inhibitor treatment.

[0032] In another aspect, the present invention provides a method of treating a cholestatic liver disease associated with elevated total serum bile acids (sBA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an IBAT inhibitor or a pharma- ceutically acceptable salt thereof, which administration reduces sBA to about 200 μmol / L or less, thereby increasing the subject's event-free survival (EFS) for at least 18 months after the first administration of the IBAT inhibitor.

[0033] In one embodiment, the cholestatic liver disease associated with elevated sBA is selected from the group consisting of ALGS, PFIC, BRIC, PSC, PBC, and biliary atresia.

[0034] In one embodiment, the sBA is determined 18 weeks after the initiation of IBAT inhibitor treatment. In one embodiment, the sBA is determined 24 weeks after the initiation of IBAT inhibitor treatment. In one embodiment, the sBA is determined 48 weeks after the initiation of IBAT inhibitor treatment.

[0035] In one embodiment, the sBA comprises one or more of TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA.

[0036] In another embodiment, the present invention provides a method of treating a cholestatic liver disease associated with elevated total bilirubin (TB) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an IBAT inhibitor or a pharma- ceutically acceptable salt thereof, which administration increases the subject's event-free survival (EFS) for at least 18 months after the first administration of the IBAT inhibitor by reducing TB to about 6.5 mg / dL or less.

[0037] In one embodiment, the cholestatic liver disease associated with elevated TB is biliary atresia (BA).

[0038] In one embodiment, TB is determined 48 weeks after the initiation of IBAT inhibitor treatment.

[0039] In one embodiment, the administration is sufficient to result in event-free survival of the subject for at least 2 years after the first administration of the IBAT inhibitor. In one embodiment, the administration is sufficient to result in event-free survival of the subject for 6 years after the first administration of the IBAT inhibitor.

[0040] In one embodiment, the IBAT inhibitor is administered once daily.

[0041] In one embodiment, the IBAT inhibitor is administered twice daily.

[0042] In one embodiment, the IBAT inhibitor is administered in an amount of about 0.1 mg to about 100 mg per dose. In one embodiment, the IBAT inhibitor is administered in an amount of about 10 mg to about 100 mg per dose. In one embodiment, the IBAT inhibitor is administered in an amount of about 20 mg to about 80 mg per dose.

[0043] In one embodiment, the IBAT inhibitor is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day. In one embodiment, the IBAT inhibitor is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day.

[0044] In one embodiment, the subject has a BSEP deficiency.

[0045] In one embodiment, the IBAT inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0046] In one embodiment, the IBAT inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0047] In one embodiment, the IBAT inhibitor is [ka] It is.

[0048] In one embodiment, the IBAT inhibitor is [ka] It is.

[0049] In some embodiments, the subject is a pediatric subject. In one embodiment, the pediatric subject is 0-18 years old.

[0050] In one embodiment, the IBAT inhibitor is administered orally.

[0051] In one embodiment, less than 10% of the IBAT inhibitor is absorbed systemically.In one embodiment, less than 30% of the IBAT inhibitor is absorbed systemically.

[0052] In yet another aspect, the present invention provides a method of treating Alagille syndrome in a pediatric subject in need thereof, comprising administering to the subject a therapeutically effective amount of maralixibat or a pharma- ceutical acceptable salt thereof, said administration comprising: a) reducing total bilirubin (TB) to approximately 6.5 mg / dL or less; b) reducing total serum bile acids (sBA) to about 200 μmol / L or less; and c) A reduction in itch score of at least about 1 point as measured by the Itch Reported Outcomes (ItchRO) severity assessment tool. The present invention provides a method for increasing a subject's event-free survival (EFS) for at least 18 months after the first dose of maralixibat by one or more of the following:

[0053] In one embodiment, the treatment increases liver-free transplant survival (TFS) for at least 18 months after the first dose of maralixibat.

[0054] In yet another aspect, the present invention provides a method for providing a prediction of response to maralixibat therapy for the treatment of Alagille syndrome in a subject in need thereof by predicting event-free survival (EFS) for 6 years after the first administration of maralixibat, the method comprising obtaining one or more of total bilirubin (TB) data, total serum bile acid (sBA) data, pruritus relief data, and age of the subject at the start of treatment with maralixibat, and predicting EFS using the data obtained for the subject.

[0055] In one embodiment, the maralixibat is maralixibat chloride.

[0056] In one embodiment, the sBA comprises one or more of TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA.

[0057] These and other aspects of the present invention will become apparent to those of ordinary skill in the art after reading the following detailed description of the invention, including the appended claims.

[0058] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0059] [Figure 1] Kaplan-Meier Plot for event-free survival in the maralixibat cohort versus the GALA control group. [Figure 2A] Kaplan-Meier plots of EFS by variable (total bilirubin at week 48) are shown. Data values ​​below each panel indicate the number of patients at each time point. EFS = event-free survival. [Figure 2B] Kaplan-Meier plots of EFS by variable (sBA at week 48) are shown. Data values ​​below each panel indicate the number of patients at each time point. EFS = event-free survival; sBA = serum bile acids. [Figure 2C] Kaplan-Meier plots of EFS by variable (change in ItchRO(Obs) at week 48 from baseline). Data values ​​below each panel indicate the number of patients at each time point. EFS: event-free survival; ItchRO(Obs): itch-reported outcome (observer); pt: score. [Figure 2D] Kaplan-Meier plots of EFS by variable (age at initiation of maralixibat) are shown. Data values ​​below each panel indicate the number of patients at each time point. EFS: event-free survival. [Figure 3A]HRQoL scores at baseline and week 48 by ItchRO response status are shown. Figure 3A shows PedsQL Generic Core Total Scale scores. In Figures 3A-C, open squares and green arrows represent the mean treatment response and HRQoL values ​​for all responders and non-responders at baseline and week 48. Individual changes from baseline (open circles) to week 48 (filled circles) are shown for responders (pink circles and arrows) and non-responders (blue circles and arrows). All arrows indicate the directionality between baseline and week 48. [Figure 3B] HRQoL scores at baseline and week 48 are shown by ItchRO response status. Figure 3B shows Family Impact Total Scale scores. [Figure 3C] HRQoL scores at baseline and week 48 by ItchRO response status are shown. Figure 3C shows Multidimensional Fatigue Total Scale scores. [Figure 4A] HRQoL scores at baseline and week 48 by sBA response status are shown. Figure 4A shows PedsQL Generic Core Total Scale scores. In Figures 4A-C, open squares and green arrows represent the mean treatment response and HRQoL values ​​for all responders and non-responders at baseline and week 48. Individual changes from baseline (open circles) to week 48 (filled circles) are shown for responders (pink circles and arrows) and non-responders (blue circles and arrows). All arrows indicate the directionality between baseline and week 48. [Figure 4B] HRQoL scores at baseline and week 48 are shown by sBA response status. Figure 4B shows Multidimensional Fatigue Total Scale scores. [Figure 4C]HRQoL scores at baseline and week 48 are shown by sBA response status. Figure 4C shows Family Impact Total Scale scores. [Diagram 5] Figure 13. Plot of patient disposition during the study. Abbreviations: AE = adverse event, BSEP = bile salt export pump; FIC = familial intrahepatic cholestasis; nt-BSEP = nontruncating BSEP; t-BSEP = truncating BSEP. [Figure 6A] Individual changes in sBA levels from baseline to week 240 in sBA responders are shown. The filled circle indicates when the seventh responder started twice daily dosing at week 97. Abbreviations: sBA = serum bile acids. [Figure 6B] Individual changes from baseline to week 240 in sBA levels in sBA non-responders are shown. [Figure 7A] Figure 1 shows individual changes in ItchRO(Obs) scores from baseline to week 240 in sBA responders. Abbreviations: ItchRO(Obs) = itch reported outcome (observer); sBA = serum bile acids. [Figure 7B] Individual changes from baseline to week 240 in ItchRO(Obs) scores in sBA non-responders are shown. Three non-responders achieved a >1.0 point change in ItchRO(Obs) considered clinically significant. Abbreviations: ItchRO(Obs) = itch reported outcome (observer); sBA = serum bile acids. [Figure 8A] (A) Mean change in height z-score from baseline to week 240 in sBA responders and sBA non-responders is plotted. Abbreviations: sBA = serum bile acids; SE = standard error. [Figure 8B] Plots the mean change in weight z-score from baseline to week 240 in sBA responders and sBA non-responders. Abbreviations: sBA = serum bile acids; SE = standard error. [Figure 9]1 shows the change in mean PedsQL™ scores from baseline to week 240 in sBA responders vs. sBA non-responders (BSEP-deficient patients, n=25). Abbreviations: PedsQL™ = Pediatric Quality of Life inventory™; sBA = serum bile acids; SE = standard error. [Figure 10-1] Figure 1 shows the change in ALT and AST over the study period in seven sBA responders. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; U = units; L = liters. [Figure 10-2] 1 shows the change in bilirubin (total and direct bilirubin) over the study period in seven sBA responders. [Figure 11] Changes in individual 7α-C4 / sBA ​​ratios from baseline to week 240 in sBA responders and sBA non-responders (BSEP-deficient patients; n=25) are shown. Abbreviations: sBA = serum bile acids; 7α-C4 = 7α-hydroxy-4-cholesten-3-one. [Figure 12] Transplant-free survival rates in sBA responders and sBA non-responders are shown. Abbreviations: sBA = serum bile acids. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] Detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are merely exemplary of the present invention, which may be embodied in various forms. Moreover, each of the examples given in relation to the various embodiments of the present invention is intended to be illustrative, not limiting. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art to use the present invention in various ways.

[0061] Bile acids / salts play an important role in activating digestive enzymes and solubilizing fats and fat-soluble vitamins, and are involved in liver, biliary and intestinal diseases. Bile acids are synthesized in the liver by a multistep, multiorganelle pathway. Hydroxyl groups are added to specific sites on the steroid structure, the double bond in the B ring of cholesterol is reduced, the hydrocarbon chain is shortened by three carbon atoms, and a carboxyl group is generated at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before leaving the hepatocyte to form bile, bile acids are conjugated to glycine (to produce glycocholic acid or glycochenodeoxycholic acid) or taurine (to produce taurocholic acid or taurochenodeoxycholic acid). The conjugated bile acids are called bile salts, and their amphiphilic nature makes them more efficient surfactants than bile acids. Bile salts, but not bile acids, are found in bile.

[0062] Bile salts are secreted by hepatocytes into the bile canaliculi to form bile. The canaliculi empty into the left and right hepatic ducts, and the bile flows to the gallbladder. Bile is released from the gallbladder and travels to the duodenum, where it contributes to fat metabolism and breakdown. Bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted via the feces. A small proportion of bile salts can be reabsorbed in the proximal intestine by either passive or carrier-mediated transport processes. Most bile salts are retrieved in the distal ileum by a sodium-dependent, apically located bile acid transporter called the ileal bile acid transporter (IBAT). At the basolateral surface of the enterocyte, a truncated version of IBAT is involved in the vectorial transport of bile acids / salts to the portal circulation. Completion of the enterohepatic circulation occurs at the basolateral surface of hepatocytes by a transport process mediated primarily by sodium-dependent bile acid transporters. Intestinal bile acid transport plays a key role in the enterohepatic circulation of bile salts. Molecular analysis of this process has recently led to important advances in our understanding of the biology, physiology, and pathophysiology of intestinal bile acid transport.

[0063] In the intestinal lumen, bile acid concentrations fluctuate, with the majority of reuptake occurring in the distal intestine. Described herein are specific compositions and methods that are administered in the fasting state to control the concentration of bile acids in the intestinal lumen, thereby controlling hepatocellular damage caused by bile acid accumulation in the liver, and further minimizing gastrointestinal adverse effects.

[0064] The subject matter of the present disclosure is based, at least in part, on the surprising discovery that treatment of a subject in need thereof with an IBAT inhibitor results in long-term event-free survival (EFS) in patients in which a reduction in one or more of: a) total bilirubin levels, b) total serum bile acid levels, and c) pruritus scores is met.

[0065] Classes of Cholestasis and Cholestatic Liver Disease As used herein, "cholestasis" refers to a disease or condition involving impaired bile formation and / or bile flow. As used herein, "cholestatic liver disease" refers to a liver disease associated with cholestasis. Cholestatic liver disease is often accompanied by jaundice, fatigue, and pruritus (itching). Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyl transpeptidase, elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.

[0066] Cholestatic liver diseases can be divided clinicopathologically into two main categories: obstructive, often extrahepatic, and nonobstructive or intrahepatic cholestasis, in which cholestasis occurs when bile flow is mechanically blocked, for example by gallstones or tumors, or in extrahepatic biliary atresia.

[0067] The latter group with nonobstructive intrahepatic cholestasis is further divided into two main subgroups. In the first subgroup, cholestasis occurs when the processes of bile secretion and modification or synthesis of bile components are secondarily involved in hepatocellular injury so severe that nonspecific impairment of many functions, including those subserving bile formation, can be expected. In the second subgroup, no presumed cause of hepatocellular injury can be identified. Cholestasis in such patients appears to occur when one of the steps in bile secretion or modification or synthesis of bile components is constitutively impaired. Such cholestasis is considered primary.

[0068] Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with hypercholesterolemia and / or cholestatic liver disease. In some such embodiments, the methods include increasing bile acid and / or GLP-2 concentrations in the intestinal lumen.

[0069] Elevated bile acid levels and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase) and 5'-nucleotidase are biochemical characteristics of cholestasis and cholestatic liver disease.Therefore, methods and compositions are provided herein for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancement of adaptive process in the intestine in individuals with hypercholesterolemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase or GGT) and / or 5'-nucleotidase.In some of such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen. Provided herein are methods and compositions for alleviating hypercholesterolemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase or GGT), and / or 5'-nucleotidase, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0070] Pruritus is often associated with hypercholesterolemia and cholestatic liver disease. It has been suggested that pruritus is due to bile salts acting on peripheral pain afferents. The severity of pruritus varies from individual to individual (i.e., some individuals are more sensitive to elevated levels of bile acids / salts).

[0071] Administration of an agent that reduces serum bile acid concentration has been shown to reduce pruritus in certain individuals.Therefore, provided herein are methods and compositions for stimulating intestinal epithelial proliferation and / or intestinal lining regeneration and / or enhanced adaptive processes in individuals with pruritus.In some such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen.Further provided herein are methods and compositions for treating pruritus, comprising reducing total serum bile acid load by excreting bile acid in feces.

[0072] Another symptom of hypercholesterolemia and cholestatic liver disease is an elevated serum concentration of conjugated bilirubin. Elevated serum concentration of conjugated bilirubin results in jaundice and dark urine. The magnitude of the elevation is not diagnostically significant, since no relationship has been established between serum levels of conjugated bilirubin and the severity of hypercholesterolemia and cholestatic liver disease. Conjugated bilirubin concentrations rarely exceed 30 mg / dL. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with elevated serum concentrations of conjugated bilirubin. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of conjugated bilirubin, including reducing overall serum bile acid load by excreting bile acids in feces.

[0073] Elevated serum concentration of unconjugated bilirubin is also considered to be a sign of hypercholesterolemia and cholestatic liver disease. A portion of serum bilirubin is covalently bound to albumin (delta (δ) bilirubin or biliprotein). This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of δ-bilirubin indicates long-term cholestasis. δ-bilirubin in umbilical cord blood or newborn blood is an indicator of cholestasis / cholestatic liver disease occurring before birth. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhanced adaptive processes in the intestine in individuals with elevated serum concentration of unconjugated bilirubin or δ-bilirubin. In some such embodiments, the method comprises increasing bile acid concentration in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of unconjugated bilirubin and delta-bilirubin, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0074] Cholestasis and cholestatic liver disease cause hypercholesterolemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts reflux from hepatocytes into serum, resulting in increased concentrations of bile salts in peripheral circulation. In addition, the uptake of bile salts entering the liver in portal blood is inefficient, resulting in spillover of bile salts into peripheral circulation. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with hypercholesterolemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating hypercholesterolemia, including reducing overall serum bile acid load by excreting bile acids in feces.

[0075] Hyperlipidemia is characteristic of some, but not all, cholestatic diseases. Serum cholesterol is elevated in cholestasis due to a decrease in circulating bile salts, which contribute to cholesterol metabolism and degradation. Cholesterol retention is associated with increased membrane cholesterol content and decreased membrane fluidity and membrane function. Furthermore, because bile salts are metabolic products of cholesterol, decreased cholesterol metabolism leads to decreased bile acid / salt synthesis. Serum cholesterol observed in children with cholestasis ranges between about 1,000 mg / dL and about 4,000 mg / dL. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with hyperlipidemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating hyperlipidemia, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0076] In individuals with hypercholesterolemia and cholestatic liver disease, xanthomas develop from the deposition of excess circulating cholesterol in the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Planar xanthomas develop first around the eyes, then in the creases of the palms and soles, and then on the neck. Nodular xanthomas are associated with chronic and long-term cholestasis. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with xanthomas. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating xanthomas, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0077] In children with chronic cholestasis, one of the major consequences of hypercholesterolemia and cholestatic liver disease is failure to thrive. Failure to thrive is the result of reduced delivery of bile salts to the intestine, which contributes to inefficient digestion and absorption of fats and reduced intake of vitamins (vitamins E, D, K, and A are all malabsorbed in cholestasis). In addition, delivery of fats to the colon can cause colonic secretions and diarrhea. Treatment of failure to thrive includes dietary substitution and supplementation with long-chain triglycerides, medium-chain triglycerides, and vitamins. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and does not affect fat absorption. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or regeneration of the intestinal lining and / or enhancement of adaptive processes in individuals (e.g., children) with failure to thrive. In some such embodiments, the method comprises increasing the concentration of bile acids in the intestinal lumen.Further provided herein are methods and compositions for treating growth disorders comprising reducing overall serum bile acid load by excreting bile acids in the feces.

[0078] Primary Biliary Cirrhosis (PBC) Primary biliary cirrhosis is an autoimmune disease of the liver characterized by the destruction of the bile ducts. Damage to the bile ducts results in the accumulation of bile in the liver (i.e., cholestasis). Retention of bile in the liver can damage liver tissue, leading to scarring, fibrosis, and cirrhosis. PBC usually develops in adulthood (e.g., over age 40). Individuals with PBC often present with fatigue, pruritus, and / or jaundice. PBC is diagnosed when an individual has elevated AP concentrations, elevated γGT levels, antimitochondrial antibodies (AMA) in serum (>1:40), and florid bile duct lesions for at least 6 months. Serum ALT and serum AST and conjugated bilirubin may also be elevated, but these are not considered diagnostic. Cholestasis associated with PBC has been treated or ameliorated by administration of ursodeoxycholic acid (UDCA or ursodiol). Corticosteroids (e.g., prednisone and budesonide) and immunosuppressants (e.g., azathioprine, cyclosporine A, methotrexate, chlorambucil, and mycophenolate) have been used to treat cholestasis associated with PBC. Sulindac, bezafibrate, tamoxifen, and lamivudine have also been shown to treat or ameliorate cholestasis associated with PBC.

[0079] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a group of rare autosomal recessive disorders caused by defects in bile formation. PFIC causes progressive liver disease that typically results in liver failure. In people with PFIC, liver cells have a reduced ability to secrete bile. The resulting accumulation of bile causes liver disease in affected individuals. Signs and symptoms of PFIC typically begin during infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increased liver dysfunction (hepatic failure). The disease is estimated to affect 1 in 50,000 to 100,000 people in the United States and Europe. Six types of PFIC have been genetically identified, all of which are similarly characterized by impaired bile flow and progressive liver disease.

[0080] Children typically present initially with jaundice in the first year of life, followed by other cholestatic features: particularly pruritus and deficiency of fat-soluble vitamins (FSVs). Some subtypes of PFIC are associated with a significant risk of hepatocellular carcinoma. Failure of aggressive management in addressing symptoms leads many patients to undergo surgical interruption of the enterohepatic circulation of bile acids or liver transplantation. There is clearly a significant unmet need for treatment of both pruritus and the underlying liver disease.

[0081] Although prevention of progression of liver disease is always paramount, early management of PFIC relies heavily on nutritional support and treatment of pruritus. Medical treatment of cholestatic pruritus is not particularly satisfactory and includes the use of rifampicin, ursodeoxycholic acid, bile acid-binding resins, serotonin reuptake inhibitors, opioid antagonists (naloxone), and antipruritic drugs (especially antihistamines). Failure of medical treatment of pruritus has led to surgical intervention. Apart from transplantation, the mainstay of surgical treatment has been depletion of bile salt pool size by surgical biliary diversion (SBD). Recently, a large retrospective analysis showed that SBD extends transplant-free survival up to 15 years in patients with nt-BSEP deficiency (van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Sokal E, Grammatikopoulos T, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol 2020;73:84-93). Furthermore, this study also showed that a 75% reduction in serum bile acids (sBA) or a drop to <102 μmol / L after surgery was associated with long-term native liver survival. Bile salt depletion by externalization of bile or by preventing uptake at the terminal ileum depends on some residual bile salt excretion in the bile. A retrospective analysis of surgical management of PFIC confirmed this hypothesis, showing that patients with t-BSEP did not respond and progressed to require liver transplantation.

[0082] Given the limited efficacy of currently available antipruritic medications, as well as the risks and burdens of surgical intervention, there remains a high unmet need for alternative treatments for patients with PFIC. Pharmacological blockade of enterohepatic bile acid recirculation has the potential to reduce the size of the bile salt pool, alleviate cholestatic pruritus, prevent liver damage, and reduce the need for surgical intervention. Malalixibat, a minimally absorbed selective inhibitor of the ileal bile acid transporter (IBAT), reduces sBA levels and improves growth in patients with cholestatic liver disease, as demonstrated in a previous study in children with Alagille syndrome. Malalixibat is currently FDA approved for the treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older.

[0083] PFIC1 PFIC1 (also known as Byler's disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also called FIC1). This gene, which encodes a P-type ATPase, is located on human chromosome 18 and is also mutated in the milder phenotypes, benign recurrent intrahepatic cholestasis type 1 (BRIO) and Greenland familial cholestasis. The FIC1 protein is located in the canalicular membrane of hepatocytes, but is expressed primarily in cholangiocytes in the liver. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining an abundance of phosphatidylserine and phosphatidylethanolamine in the inner leaflet of the plasma membrane compared to the outer leaflet. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high bile salt concentrations in the canalicular lumen. Abnormal protein function may indirectly interfere with biliary secretion of bile acids. Abnormal secretion of bile acids / salts results in hepatocyte bile acid overload.

[0084] PFIC1 typically presents in infants (e.g., 6-18 months of age). Infants may show signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. Individuals may also have liver fibrosis. Individuals with PFIC1 typically do not have bile duct proliferation. Most individuals with PFIC1 develop end-stage liver disease by age 10. No medical treatment has proven beneficial for the long-term treatment of PFIC1. Children are often given medium-chain triglycerides and fat-soluble vitamins to reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive). Ursodiol has not been demonstrated to be effective in individuals with PFIC1.

[0085] PFIC2 PFIC2 (also known as Byler syndrome, BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) in human liver and is located on human chromosome 2. The BSEP protein, expressed in the hepatocyte canalicular membrane, is the major exporter of primary bile acids / salts against extreme concentration gradients. Mutations in this protein are responsible for the reduced bile salt secretion described in affected patients, leading to reduced bile flow with ongoing severe hepatocellular damage and accumulation of bile salts inside hepatocytes.

[0086] PFIC2 typically presents in infants (e.g., 6-18 months of age). Infants may show signs of pruritus. Biochemically, individuals with PFIC2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. Individuals may also have portal inflammation and giant cell hepatitis. Additionally, individuals often develop hepatocellular carcinoma. No medical treatment has proven beneficial for the long-term treatment of PFIC2. Children are often given medium-chain triglycerides and fat-soluble vitamins to reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive). The PFIC2 patient population represents approximately 60% of the PFIC population.

[0087] PFIC3 PFIC3 (also known as MDR3 deficiency) is caused by a genetic deficiency in the ABCB4 gene (also called MDR3) located on chromosome 7. Class III multidrug resistance (MDR3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the export of bile phospholipids (phosphatidylcholine) at the canalicular membrane of hepatocytes. PFIC3 results from bile toxicity, where detergent bile salts are not inactivated by phospholipids, causing damage to the canaliculi and bile duct epithelium.

[0088] PFIC3 also develops in early childhood. In contrast to PFIC1 and PFIC2, individuals have elevated γGT levels. Individuals also have portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol is effective in treating or ameliorating PFIC3.

[0089] Benign recurrent intrahepatic cholestasis (BRIC) BRIC1 BRIC1 results from a genetic deficiency of the FIC1 protein in the canalicular membrane of hepatocytes. BRIC1 is typically associated with normal serum cholesterol and gamma-glutamyl transpeptidase levels, but elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite repeated attacks of cholestasis or cholestatic liver disease, there is no progression to chronic liver disease in the majority of patients. During attacks, patients develop severe jaundice and have pruritus, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

[0090] BRIC2 BRIC2 is caused by mutations in ABCB11, leading to defective BSEP expression and / or function in the bile canalicular membrane of hepatocytes.

[0091] BRIC3 BRIC3 is associated with defective MDR3 expression and / or function in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically show elevated serum gamma-glutamyl transpeptidase levels in the presence of normal or slightly elevated bile acid levels.

[0092] Dubin-Johnson Syndrome (DJS) DJS is characterized by conjugated hyperbilirubinemia due to inherited dysfunction of MRP2. Liver function is preserved in affected patients. Several different mutations have been associated with the condition, resulting in either a complete absence of immunohistochemically detectable MRP2 in affected patients or impaired maturation and sorting of the protein.

[0093] Acquired cholestatic disorders Primary Biliary Cirrhosis (PBC) PBC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected patients. In PBC, the inflammatory process primarily affects the bile ducts.

[0094] Primary sclerosing cholangitis (PSC) PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected patients. Fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic bile ducts predominates in PSC inflammation.

[0095] PSC is characterized by progressive cholestasis, which can often lead to severe pruritus that significantly impairs quality of life.

[0096] Intrahepatic cholestasis of pregnancy (ICP) ICP is characterized by the development of transient cholestasis or cholestatic liver disease in pregnant women, typically occurring in the third trimester of pregnancy, when circulating levels of estrogen are high. ICP is associated with pruritus and biochemical cholestasis or cholestatic liver disease of various severity and constitutes a risk factor for prematurity and intrauterine fetal death. A genetic predisposition has been suspected based on the strong regional clustering, the high prevalence in women of ICP patients' families, and the susceptibility of ICP patients to developing intrahepatic cholestasis or cholestatic liver disease under other hormonal challenges, such as oral contraceptives. The heterogeneous state of MDR3 gene deficiency may represent a genetic predisposition.

[0097] cholelithiasis Cholelithiasis is one of the most common and costly of all gastrointestinal diseases, with a prevalence of up to 17% in white women. Cholesterol-containing gallstones are the predominant form of gallstones, and therefore supersaturation of bile with cholesterol is a prerequisite for gallstone formation. ABCB4 mutations may be involved in the pathogenesis of cholesterol cholelithiasis.

[0098] Drug-induced cholestasis Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis, leading to hepatic accumulation of bile salts and subsequent hepatocellular injury. Several drugs are involved in BSEP inhibition. Most of these agents, such as rifampicin, cyclosporine, glibenclamide, or troglitazone, directly cis-inhibit ATP-dependent taurocholate transport in a competitive manner, whereas estrogen and progesterone metabolites indirectly trans-inhibit BSEP after secretion into the bile canaliculi by Mrp2. Alternatively, drug-mediated stimulation of MRP2 can promote cholestasis or cholestatic liver disease by altering bile composition.

[0099] Total Parenteral Nutrition-Associated Cholestasis TPNAC represents one of the most serious clinical scenarios in which cholestatic or cholestatic liver disease develops rapidly and is highly associated with early mortality. Infants who are usually premature and have undergone intestinal resection are dependent on TPN for growth and frequently develop cholestatic or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The extent of cholestatic or cholestatic liver disease and chances of survival in these infants are related to the number of septic episodes, likely initiated by repeated bacterial translocation across the intestinal mucosa. Although there is also a cholestatic effect from intravenous preparations, septic mediators are most likely to contribute to altered liver function in these infants.

[0100] Total Parenteral Nutrition-Associated Cholestasis TPNAC represents one of the most serious clinical scenarios in which cholestatic or cholestatic liver disease develops rapidly and is highly associated with early mortality. Infants who are usually premature and have undergone intestinal resection, dependent on TPN for growth, frequently develop cholestatic or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The extent of cholestatic or cholestatic liver disease and chances of survival in these infants are related to the number of septic episodes, likely initiated by repeated bacterial translocation across the intestinal mucosa. Although there is also a cholestatic effect from intravenous preparations, septic mediators are most likely to contribute to altered liver function in these infants.

[0101] Alagille Syndrome (ALGS) Alagille syndrome is a genetic disease that affects the liver and other organs. ALGS is also known as syndromic intrahepatic cholangiopancreas or arteriohepatic dysplasia. ALGS is a rare genetic disorder in which bile ducts are abnormally narrow, malformed, and reduced in number, leading to bile accumulation in the liver and ultimately progressive liver disease. ALGS is autosomal dominant, caused by mutations in JAG1 (>90% of cases) or NOTCH2. The estimated incidence of ALGS is 1 in 30,000 or 50,000 in the United States and Europe. In patients with ALGS, multiple organ systems can be affected by the mutations, including the liver, heart, kidneys, and central nervous system. The accumulation of bile acids prevents the liver from functioning properly to clear waste products from the bloodstream, resulting in progressive liver disease that ultimately requires a liver transplant in 15% to 47% of patients. Signs and symptoms resulting from liver damage in ALGS can include jaundice, pruritus, and xanthomas, as well as reduced growth. The pruritus experienced by people with ALGS is one of the most severe manifestations of chronic liver disease and is present in most affected children by the third year of life.

[0102] ALGS often presents during infancy (e.g., 6-18 months) to early childhood (e.g., 3-5 years) and may stabilize after age 10. Symptoms may include chronic progressive cholestasis, cholangiocele, jaundice, pruritus, xanthomas, congenital heart defects, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmurs, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot. Individuals diagnosed with Alagille syndrome have been treated with ursodiol, hydroxyzine, cholestyramine, rifampicin, and phenobarbital. Due to a decreased ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally given high doses of multivitamins.

[0103] biliary atresia Biliary atresia is a life-threatening condition in infants who do not have normal openings in the bile ducts inside or outside the liver. In biliary atresia, bile becomes trapped, builds up, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver will eventually fail and the infant will require a liver transplant to stay alive. The two types of biliary atresia are fetal and perinatal. Fetal biliary atresia is present while the baby is in the womb. Perinatal biliary atresia is more common and does not become evident until 2-4 weeks after birth.

[0104] Biliary atresia after Kasai operation Biliary atresia is treated with a surgical procedure called the Kasai procedure, or with a liver transplant. The Kasai procedure is usually the first method of treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and replaces them with elevated loops of intestine. Although the Kasai procedure can restore biliary flow and correct many problems caused by biliary atresia, the surgery does not cure biliary atresia. If the Kasai procedure is unsuccessful, the infant will usually require a liver transplant within one to two years. Even after successful surgery, most infants with biliary atresia will slowly develop cirrhosis over the course of years and require a liver transplant by adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

[0105] Biliary atresia after liver transplantation Once complete, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can lead to complications, such as organ rejection, and there are also cases where a donor liver is no longer available. Additionally, in some patients, liver transplantation may not be successful in curing biliary atresia.

[0106] xanthomas Xanthomas are skin conditions associated with cholestatic liver disease in which certain fats accumulate under the skin's surface. Cholestasis causes several disturbances in lipid metabolism, leading to the formation of abnormal lipid particles in the blood called lipoprotein X. Lipoprotein X is formed by the reflux of bile lipids from the liver into the blood, and does not bind to LDL receptors and deliver cholesterol to cells throughout the body as normal LDL does. Lipoprotein X increases hepatic cholesterol production five-fold and blocks the liver's normal removal of lipoprotein particles from the blood.

[0107] General 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.

[0108] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "method" includes one or more methods, and / or steps of the type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0109] The term "baseline" or "pre-administration baseline" as used herein refers to information collected at the beginning of a study or a known initial value used for comparison with later data. A baseline is an initial measurement of a measurable condition taken at an initial time point and used to compare over time to look for changes in the measurable condition. For example, a patient's serum bile acid concentration before drug administration (baseline) and after drug administration. A baseline is an observation or value that represents a normal or starting level of a measurable quality that is used for comparison with a value that represents a response to an intervention or environmental stimulus. A baseline is time "zero" before a study participant receives an experimental drug or intervention, or a negative control. For example, "baseline" can refer in some instances to 1) the state of a measurable quantity immediately prior to the start of a clinical trial, or 2) the state of a measurable quantity immediately prior to changing the dosage level or composition administered to a patient from a first dosage level or composition to a second dosage level or composition.

[0110] As used herein, the terms "level" and "concentration" are used interchangeably. For example, "high serum bilirubin level" can be replaced with "high serum bilirubin concentration."

[0111] As used herein, the term "normalized" or "normal range" refers to an age-specific value that is within a range applicable to healthy individuals (i.e., a normal or normalized value). For example, the phrase "serum bilirubin concentration was normalized within 3 weeks" means that the serum bilirubin concentration was within a range known in the art to be within a healthy individual's concentration (i.e., within a normal range, e.g., not an elevated range) within 3 weeks. In various embodiments, the normalized serum bilirubin concentration is from about 0.1 mg / dL to about 1.2 mg / dL. In various embodiments, the normalized serum bile acid concentration is from about 0 μmol / L to about 25 μmol / L.

[0112] As used herein, the terms "ITCHRO(OBS)" and "ITCHRO" (or "ItchRO(Pt)") are used interchangeably, with the proviso that the ITCHRO(OBS) scale is used to measure the severity of pruritus in children under 18 years of age, and the ITCHRO scale is used to measure the severity of pruritus in adults 18 years of age or older. Thus, when the ITCHRO(OBS) scale is referred to in relation to adult patients, the ITCHRO scale is the indicated scale. Similarly, when the ITCHRO scale is referred to in relation to pediatric patients, the ITCHRO(OBS) scale is usually the indicated scale (some older children were allowed to report their scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[0113] The term "bile acid(s)" as used herein includes steroid acids (and / or their carboxylate anions) found in the bile of animals (e.g., humans), and their salts, including, by way of non-limiting example, cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and / or taurocholate are referred to herein as TCA. Any reference to a bile acid as used herein includes reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Thus, the terms "bile acid", "bile salt", "bile acid / salt", "bile acids", "bile salts", and "bile acid / salt" are used interchangeably herein unless otherwise indicated. Any reference to a bile acid as used herein includes a reference to a bile acid or its salt. Additionally, pharma- ceutically acceptable bile acid esters are optionally utilized as "bile acids" as described herein, e.g., bile acids / salts conjugated to an amino acid (e.g., glycine or taurine). Other bile acid esters include, e.g., substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, and the like. For example, the term "bile acid" includes cholic acid conjugated to either glycine or taurine: glycocholic acid and taurocholic acid (and their salts), respectively. Any reference to a bile acid as used herein includes a reference to the same compound, whether naturally or synthetically prepared. Furthermore, any singular reference to a component (bile acid or otherwise) as used herein should be understood to include a reference to one and only one, one or more, or at least one of such components.Similarly, a plurality of references to elements as used herein includes a reference to one and only one, one or more, or at least one of such elements unless specifically stated otherwise.

[0114] The terms "subject", "patient", "participant", or "individual" are used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein. Examples of mammals include, but are not limited to, any member of the class Mammalia (humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic animals such as cows, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs). Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0115] As used herein, the term "about" includes any value within 10% of the stated value.

[0116] The term "composition" as used herein includes disclosure of both compositions and compositions administered in the manner described herein. Furthermore, in some embodiments, the compositions of the invention are or include a "formulation," an oral dosage form, or a rectal dosage form, as described herein.

[0117] The terms "treat", "treating" or "treatment" and other grammatical equivalents used herein include alleviating, suppressing or relieving symptoms, reducing or suppressing the severity of a disease or condition, reducing the occurrence of a disease or condition, reducing or suppressing the recurrence of a disease or condition, delaying the onset of a disease or condition, delaying the recurrence of a disease or condition, ameliorating or ameliorating a disease or condition, ameliorating the underlying cause of symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or halting the symptoms of a disease or condition. These terms further include achieving a therapeutic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated and / or the eradication or amelioration of one or more physiological symptoms associated with the underlying disease such that an improvement is observed in the patient.

[0118] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of at least one agent (e.g., a therapeutically active substance) being administered to achieve a desired result in a subject or individual, such as, for example, alleviating to some extent one or more symptoms of the disease or condition being treated. In certain instances, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. In certain instances, an "effective amount" for therapeutic use is the amount of a composition comprising an agent as described herein that is required to provide a clinically significant reduction in a disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" or "effective amount" of an IBAT inhibitor refers to an amount of an IBAT inhibitor sufficient to treat cholestasis or cholestatic liver disease in a subject or individual.

[0119] The terms "administer", "administering", "administration" and the like used herein refer to the methods that can be used to allow delivery of an agent or composition to the site where biological action is desired. These methods include, but are not limited to, oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical administration and rectal administration. The administration techniques that are optionally used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa, all of which are incorporated herein by reference in their entirety for all purposes. In certain embodiments, the agents and compositions described herein are administered orally.

[0120] The term "IBAT inhibitor" refers to a compound that inhibits ileal bile acid transport or any recuperative bile salt transport. The term "ASBT inhibitor" refers to a compound that inhibits ileal bile acid transport or any recuperative bile salt transport. The term apical sodium-dependent bile acid transporter (or transporter) (ASBT) is used interchangeably with the term ileal bile acid transporter (IBAT).

[0121] The phrase "pharmacologically acceptable" when used in connection with the compositions of the present invention refers to molecular entities and other components of such compositions that are physiologically tolerated and do not normally produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmacologically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals, more specifically, in humans.

[0122] In various embodiments, pharma- ceutically acceptable salts described herein include, by way of non-limiting example, nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, salicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-toluenesulfonate, mesylate, etc. Additionally, pharma-ceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium or potassium), ammonium salts, etc.

[0123] As used herein, the term "fasted state" is defined as a state in which a subject has completely assimilated and digested their last meal, and the subject's insulin level is at a low or baseline level. In some embodiments, fasted state is defined as a state in which no food has been consumed for at least 4 hours for subjects aged 18 years or older. In some embodiments, fasted state is defined as a state in which no food has been consumed for at least 2 hours for pediatric subjects. In some embodiments, fasted state is defined as a state about 30 minutes before a meal.

[0124] As used herein, a fasting patient is defined as a patient who has not eaten any food, i.e., fasting for at least 4 hours (for subjects aged 18 years or older) or at least 2 hours (for pediatric subjects) before administration of the IBAT inhibitor and at least 30 minutes after administration of the IBAT inhibitor. The IBAT inhibitor is optionally administered with water during the fasting period, which can be consumed ad libitum.

[0125] bile acids Bile contains water, electrolytes, and numerous organic molecules (such as bile acids, cholesterol, phospholipids, and bilirubin). Bile is secreted from the liver and stored in the gallbladder, and upon contraction of the gallbladder due to ingestion of a fatty meal, bile passes through the bile duct into the intestine. Bile acids / salts are important for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400-800 mL of bile per day. Bile secretion can be thought of as occurring in two steps. First, hepatocytes secrete bile into the bile canaliculi, from which it flows into the bile ducts; this hepatic bile contains large amounts of bile acids, cholesterol, and other organic molecules. Second, as the bile flows through the bile ducts, it is modified by the addition of watery bicarbonate-rich secretions from the bile duct epithelial cells. Bile is typically concentrated five-fold during its storage in the gallbladder.

[0126] Bile flow is lowest during fasting, with most of it being directed to the gallbladder for concentration. When the chyme of an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both of which are important for bile secretion and flow. Cholecystokinin (cholecyst = gallbladder and kinin = motor) is a hormone that stimulates contraction of the gallbladder and common bile duct, resulting in the delivery of bile to the intestine. The most powerful stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acid in the duodenum that stimulates cholangiocytes to secrete bicarbonate and water, thereby expanding the volume of bile and increasing its outflow to the intestine.

[0127] Bile acids / salts are derivatives of cholesterol. Cholesterol, either ingested as part of the diet or derived from synthesis in the liver, is converted to bile acids / salts in hepatocytes. Examples of such bile acids / salts include cholic acid and chenodeoxycholic acid, which are then conjugated to amino acids (such as glycine or taurine) to produce conjugated forms that are actively secreted into the bile canaliculi. The most abundant bile salts in humans are cholate and deoxycholate, which are usually conjugated with either glycine or taurine to produce glycocholate or taurocholate, respectively.

[0128] Free cholesterol is practically insoluble in aqueous solutions, but is soluble in bile due to the presence of bile acids / salts and lipids. Hepatic synthesis of bile acids / salts accounts for the majority of cholesterol breakdown in the body. In humans, approximately 500 mg of cholesterol is converted to bile acids / salts and excreted in bile each day. Thus, secretion into bile is the major route for cholesterol elimination. Although large amounts of bile acids / salts are secreted into the intestine each day, relatively small amounts are lost from the body. This is because approximately 95% of the bile acids / salts delivered to the duodenum are absorbed back into the blood in the ileum by a process known as the "enterohepatic circulation".

[0129] Venous blood from the ileum goes straight into the portal vein and thus passes through the hepatic sinusoids. Hepatocytes extract bile acids / salts from the sinusoidal blood very efficiently, and very little escapes from a healthy liver into the systemic circulation. The bile acids / salts are then transported past the hepatocytes and re-secreted into the bile canaliculi. The net effect of this enterohepatic circulation is that each bile salt molecule is reused approximately 20 times, and often 2-3 times, during one digestive stage. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for just over half of the approximately 800 mg / day of cholesterol consumed by the average adult in metabolic processes. In comparison, the biosynthesis of steroid hormones consumes only about 50 mg of cholesterol per day. Much more than 400 mg of bile salts per day are required and secreted into the intestine, and this is achieved by recycling the bile salts. Most of the bile salts secreted into the upper region of the small intestine are absorbed along with the dietary lipids they emulsify at the lower end of the small intestine. They are separated from dietary lipids and returned to the liver for reuse, thus allowing 20-30 g of bile salts to be secreted into the small intestine each day.

[0130] Bile acids / salts are amphiphilic, the cholesterol-derived moieties contain both hydrophobic (fat-soluble) and polar (hydrophilic) moieties, whereas amino acid conjugates are generally polar and hydrophilic. This amphiphilicity allows bile acids / salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids to aqueous environments. Bile acids / salts have a detergent action on particles of dietary fat, breaking down or emulsifying fat globules. Emulsification is important because it greatly increases the surface area of ​​fat available for digestion by lipases that cannot access the interior of the lipid droplets. In addition, bile acids / salts are lipid carriers and can solubilize many lipids by forming micelles, which are important for the transport and absorption of fat-soluble vitamins.

[0131] The term "non-systemic" or "minimally absorbed" as used herein refers to low systemic bioavailability and / or absorption of an administered compound. In some embodiments, a non-systemic compound is a compound that is not substantially absorbed systemically. In some embodiments, the IBAT inhibitor composition described herein delivers the IBAT inhibitor to the distal ileum, colon, and / or rectum and not systemically (e.g., a significant portion of the IBAT inhibitor is not absorbed systemically). In some embodiments, the systemic absorption of the non-systemic compound is <0.1%, <0.3%, <0.5%, <0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%, <3%, or <5% (wt% or mol%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than ten percent (<10%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than fifteen percent (<15%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 25% (<25%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 30% of the administered dose. In another approach, the non-systemic IBAT inhibitor is a compound that has a lower systemic bioavailability compared to the systemic bioavailability of the systemic IBAT inhibitor (e.g., compounds 100A, 100C). In some embodiments, the bioavailability of the non-systemic IBAT inhibitor described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of the systemic IBAT inhibitor (e.g., maralixibat or vorixibat).

[0132] In another alternative approach, the compositions described herein are formulated to deliver less than 10% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 20% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 30% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 40% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 50% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 60% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the compositions described herein are formulated to deliver less than 70% of the administered dose of the IBAT inhibitor to the system. In some embodiments, the systemic absorption is determined in any suitable manner, including total circulating amount, amount cleared after administration, etc.

[0133] Event-free survival (EFS) In various embodiments of the method of the present invention, administering an IBAT inhibitor to a subject increases event-free survival (EFS).In certain embodiments, administering an IBAT inhibitor increases the event-free survival (EFS) of a subject by reducing one or more of the following: a) total bilirubin (TB); b) total serum bile acid (sBA); and c) pruritus score measured by Itch Reported Outcome (ItchRO) severity assessment tool.

[0134] In certain embodiments, EFS includes survival without one or more of hepatic decompensation, surgical biliary diversion, liver transplant, or death. In certain embodiments, hepatic decompensation includes variceal bleeding and / or ascites requiring treatment.

[0135] In a particular embodiment, the present disclosure provides a method for providing a prediction of response to IBAT inhibitor therapy for treatment of cholestatic liver disease in a subject in need thereof by predicting event-free survival (EFS), the method comprising obtaining one or more of total bilirubin (TB) data, total serum bile acid (sBA) data, pruritus relief data, and subject's age at initiation of treatment with the IBAT inhibitor, and predicting EFS using the data obtained for the subject.

[0136] In certain embodiments, EFS is predicted when TB is less than about 6.5 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 6 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 5 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 4 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 3 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 2 mg / dL. In certain embodiments, EFS is predicted when TB is less than about 1 mg / ml. In certain embodiments, EFS is predicted when TB is less than about 0.1 mg / ml.

[0137] In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 200 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 150 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 100 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 50 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 20 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 10 μmol / L. In certain embodiments, EFS is predicted when the sBA level after treatment with an IBAT inhibitor is less than about 5 μmol / L.

[0138] In certain embodiments, the sBA level is determined 18 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined 24 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined 48 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 100 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 150 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 200 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 250 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 300 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 300 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 350 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 400 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 450 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 500 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 18 weeks to about 500 weeks after the start of IBAT inhibitor treatment. In certain embodiments, the sBA level is determined about 48 weeks to about 500 weeks after the start of IBAT inhibitor treatment.

[0139] In certain embodiments, EFS is predicted by a reduction in pruritus after treatment with the IBAT inhibitor compared to pruritus upon first administration of the IBAT inhibitor of more than about 1 point, where pruritus is measured by the Itch Reported Outcomes (ItchRO) severity assessment tool.

[0140] In certain embodiments, the pruritus is determined 18 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined 24 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined 48 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 100 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 150 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 200 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 250 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 300 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 300 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 350 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 400 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 450 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 500 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 18 weeks to about 500 weeks after the initiation of IBAT inhibitor treatment. In certain embodiments, the pruritus is determined about 48 weeks to about 500 weeks after the initiation of IBAT inhibitor treatment.

[0141] In certain embodiments, EFS is predicted when the subject's age at the start of treatment is about 36 months or greater.

[0142] In various embodiments of the methods of the present invention, administration of an IBAT inhibitor to a subject results in an improvement in health-related quality of life (HRQoL).

[0143] In certain embodiments, HRQoL is determined by using Itch Reported Outcome (ItchRO), Pediatric Quality of Life Inventory Generic Core (PedsQL), Family Impact (FI), and Multidimensional Fatigue (MF) scale scores.

[0144] In certain embodiments, the ItchRO scale score ranges from 0 (0=none) to 4 (4=very severe). In certain embodiments, a clinically meaningful pruritus response is defined as a ≧1 point reduction in the ItchRO from baseline to week 48 of treatment.

[0145] In certain embodiments, the PedsQL scale score ranges from 0 to 100, with 100 = best quality of life.

[0146] IBAT inhibitors In various embodiments of the method of the present invention, an IBAT inhibitor is administered to the subject. An IBAT inhibitor (ASBT inhibitor) reduces or inhibits the recycling of bile acids in the distal gastrointestinal tract (GI), including the distal ileum, colon and / or rectum. Inhibition of ileal bile acid transport disrupts the enterohepatic circulation of bile acids, resulting in more bile acids being excreted in feces, leading to a reduction in bile acid levels in the whole body, thereby reducing bile acid-mediated liver damage and associated effects and complications. In certain embodiments, the IBAT inhibitor is absorbed systemically. In certain embodiments, the IBAT inhibitor is not absorbed systemically. In some embodiments, the IBAT inhibitor described herein is modified or substituted to be non-systemic.

[0147] In certain embodiments, the compounds described herein have one or more chiral centers. Thus, all stereoisomers are contemplated herein. In various embodiments, the compounds described herein exist in optically active or racemic forms. It is understood that the compounds of the present invention encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, by way of non-limiting examples, by resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases. In some embodiments, a mixture of one or more isomers is utilized as a therapeutic compound described herein. In certain embodiments, the compounds described herein include one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers is accomplished by any means, including, by way of non-limiting examples, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

[0148] In some embodiments, the IBAT inhibitor is [ka] It is.

[0149] In some embodiments, the IBAT inhibitor is [ka] (maralixibat chloride, LUM-001, SHP625, ropixibat chloride) or an alternative pharma- ceutically acceptable salt thereof.

[0150] In some embodiments, the IBAT inhibitor is [ka] (volixibat, (2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate), or a pharma- ceutically acceptable salt thereof.

[0151] In some embodiments, the IBAT inhibitor is

[0152] [ka] (LUM-002; SHP626; SAR548304; vorixibat potassium), or an alternative pharma- ceutically acceptable salt thereof.

[0153] In various embodiments, the IBAT inhibitor is [ka] (odevixibat; AZD8294; WH010706; AR-H064974; SCHEMBL946468; A4250; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-a-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine), or a pharma- ceutically acceptable salt thereof.

[0154] In some embodiments, the IBAT inhibitor is [ka] (elobixibat; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,5-benzothiazepin-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid), or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, the IBAT inhibitor is [ka] (GSK2330672; linerixibat; 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid), or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is maralixibat (e.g., as maralixibat chloride), vorixibat (e.g., as vorixibat potassium), or odevixibat (A4250), or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is maralixibat, or a pharma- ceutically acceptable salt thereof.

[0158] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is vorixibat, or a pharma- ceutically acceptable salt thereof.

[0159] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is odevixibat, or a pharma- ceutically acceptable salt thereof.

[0160] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is elobixibat, or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the IBAT inhibitor used in the methods or compositions of the invention is GSK2330672, or a pharma- ceutically acceptable salt thereof.

[0162] In some embodiments, the IBAT inhibitor may comprise a mixture of different IBAT inhibitors; for example, the IBAT inhibitor may be a composition comprising maralixibat, vorixibat, odebixibat, GSK2330672, elobixibat, or various combinations thereof.

[0163] Methods for Treating Cholestasis and Minimizing Adverse Gastrointestinal Effects - Patent application Provided herein is a method for treating cholestasis in a subject with liver disease, where the treatment increases the subject's event-free survival (EFS). The method includes administering an apical sodium-dependent bile acid transporter inhibitor (IBAT inhibitor) to a subject in need of treatment. The IBAT inhibitor is malalixibat or vorixibat, or a pharma- ceutically acceptable salt thereof. The IBAT inhibitor is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day.

[0164] Provided herein are methods of treating cholestatic liver disease in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of an ileal bile acid transporter inhibitor (IBAT inhibitor), the treatment resulting in one or more of: 1) increased event-free survival (EFS); and 2) improved health-related quality of life (HRQoL).

[0165] Provided herein are methods of treating cholestatic liver disease in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of an ileal bile acid transporter (IBAT) inhibitor, the treatment comprising: a) Total bilirubin (TB); b) total serum bile acids (sBA); and c) Pruritus score measured by the Itch Reported Outcomes (ItchRO) severity assessment tool By reducing one or more of the following, the subject's event free survival (EFS) is increased.

[0166] Provided herein is a method of treating Alagille syndrome in a pediatric subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of maralixibat, or a pharma- ceutically acceptable salt thereof, wherein the administration increases the subject's event-free survival (EFS) for at least 18 months following a first dose of the IBAT inhibitor.

[0167] Provided herein is a method of providing a prediction of response to IBAT inhibitor therapy for treatment of cholestatic liver disease in a subject in need thereof by predicting event free survival (EFS), the method comprising obtaining one or more of total bilirubin (TB) data, total serum bile acid (sBA) data, pruritus relief data, and age of the subject at the start of treatment with the IBAT inhibitor, and predicting EFS using the data obtained for the subject.

[0168] Provided herein is a method for providing a prediction of response to maralixibat therapy for the treatment of Alagille syndrome in a subject in need thereof by predicting event-free survival (EFS) for 6 years after the first dose of maralixibat, the method comprising obtaining total bilirubin (TB) data, total serum bile acid (sBA) data, pruritus relief data, and the subject's age at the start of treatment with an IBAT inhibitor, and predicting EFS using the data obtained for the subject.

[0169] Provided herein is a method for treating cholestatic liver disease in a subject in need thereof, comprising administering a therapeutically effective amount of an IBAT inhibitor to the subject prior to food intake, wherein the subject experiences a reduction in the frequency and / or severity of one or more side effects associated with administration of the IBAT inhibitor, and the treatment increases the subject's event-free survival (EFS). The method comprises administering an IBAT inhibitor to a subject in need of treatment prior to food intake. In certain embodiments, the IBAT inhibitor is malalixibat or vorixibat, or a pharma-ceutically acceptable salt thereof. The IBAT inhibitor is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day.

[0170] In certain embodiments, the IBAT inhibitor is administered to subject in fasting state (or fasting state).In certain embodiments, the IBAT inhibitor is administered less than about 1 minute, less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 30 minutes, or less than about 60 minutes before eating food.In certain embodiments, the IBAT inhibitor is administered immediately before eating food.

[0171] In various embodiments, the liver disease is cholestatic liver disease.In some embodiments, the liver disease is PFIC, ALGS, PSC, biliary atresia, intrahepatic cholestasis of pregnancy, PBC, any of the above-mentioned cholestatic liver diseases, or various combinations thereof.

[0172] In certain embodiments, the cholestatic liver disease is selected from the group consisting of progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant associated liver disease, intestinal failure associated liver disease, and the like. The present invention relates to a bile acid-mediated liver disease, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric obstructive cholestasis, pediatric nonobstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIP type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis. In some embodiments, the biliary liver disease is a pediatric type of liver disease. In some embodiments, the subject has intrahepatic cholestasis of pregnancy (ICP).

[0173] In certain embodiments, the cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, elevated serum concentrations of bile acids, elevated hepatic concentrations of bile acids, elevated serum concentrations of bilirubin, hepatocellular injury, hepatic scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, anorexia, abnormal odor, dark urine, light stools, steatorrhea, failure to thrive, and / or renal failure.

[0174] In various embodiments, the liver disease is PFIC2, and the subject has a non-truncating mutation in the ABCB11 gene. In various embodiments, the non-truncating mutation in the ABCB11 gene is a missense mutation. In various embodiments, the missense mutation can be selected from one of the mutations listed in Byrne, et al., "Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messanger RNA Splicing," Hepatology, 49:553-567 (2009), which is incorporated herein by reference in its entirety for all purposes.

[0175] In various embodiments, the subject has a condition related to BSEP deficiency, caused by BSEP deficiency, or partially caused by BSEP deficiency.In certain embodiments, the condition related to BSEP deficiency, caused by BSEP deficiency, or partially caused by BSEP deficiency is neonatal hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC2, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary atresia, or combinations thereof.

[0176] In various embodiments, the patient is a pediatric patient under the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, a preschooler, a school-age child, a prepubescent child, a postpubescent child, an adolescent, or a teenager under the age of 18. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, a preschooler, or a school-age child. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, or a preschooler. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, or a toddler. In some embodiments, the pediatric subject is a newborn, a premature infant, or an infant. In some embodiments, the pediatric subject is a newborn. In some embodiments, the pediatric subject is an infant. In some embodiments, the pediatric subject is a toddler. In various embodiments, the pediatric patient has PFIC2, PFIC1, or ALGS. In some embodiments, the patient is an adult over 18, 20, 30, 40, 50, 60, or 70 years old. In some patients, the adult patient has PSC. In some patients, the adult patient has PBC. In some patients, the adult patient has ICP. In some embodiments, the pediatric patient has a pediatric cholestatic condition that results in less than normal growth, height, or weight.

[0177] In certain embodiments, the method of the present invention comprises non-systemic administration of a therapeutically effective amount of an IBAT inhibitor.In certain embodiments, the method comprises contacting the gastrointestinal tract, including the distal ileum and / or colon and / or rectum, of an individual in need thereof with an IBAT inhibitor.In various embodiments, the method of the present invention results in a reduction in bile acids in intraenterocytes, or a reduction in damage to liver cells or intestinal structures caused by cholestasis or cholestatic liver disease.

[0178] In various embodiments, the methods of the invention comprise delivering a therapeutically effective amount of any IBAT inhibitor described herein to the ileum or colon of an individual.

[0179] In various embodiments, the methods of the invention include reducing damage to liver cells or intestinal structures or cells due to cholestasis or cholestatic liver disease, comprising administering a therapeutically effective amount of an IBAT inhibitor. In certain embodiments, the methods of the invention include reducing bile acids / salts in intestinal cells by administering a therapeutically effective amount of an IBAT inhibitor to an individual in need thereof.

[0180] In some embodiments, the method of the present invention provides inhibition of bile salt recycling by administering any of the compounds described herein to an individual. In some embodiments, the IBAT inhibitors described herein are absorbed systemically upon administration. In some embodiments, the IBAT inhibitors described herein are not absorbed systemically. In some embodiments, the IBAT inhibitors described herein are orally administered to an individual. In some embodiments, the IBAT inhibitors described herein are delivered to and / or released in the distal ileum of an individual.

[0181] In various embodiments, contacting an individual's distal ileum with an IBAT inhibitor (e.g., any IBAT inhibitor described herein) inhibits reuptake of bile acids, increases the concentration of bile acids / salts in the vicinity of L-cells in the distal ileum and / or colon and / or rectum, thereby reducing bile acids in enterocytes, lowering serum and / or liver bile acid levels, reducing overall serum bile acid load, and / or reducing damage to ileal structure caused by cholestasis or cholestatic liver disease. Without being limited to any particular theory, reducing serum and / or liver bile acid levels ameliorates hypercholesterolemia and / or cholestatic disease.

[0182] Administration of the compounds described herein can be accomplished in any suitable manner, including, by way of non-limiting examples, oral, enteric, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Any compound or composition described herein can be administered in a suitable manner or formulation for treating a neonate or infant. Any compound or composition described herein can be administered in an oral formulation (e.g., solid or liquid) for treating a neonate or infant. Any compound or composition described herein can be administered before, with, or after the ingestion of food.

[0183] In certain embodiments, the compounds or compositions comprising the compounds described herein are administered for preventive and / or therapeutic treatment.In therapeutic applications, the compositions are administered to individuals who are already suffering from disease or condition in an amount sufficient to cure or at least partially prevent the symptoms of disease or condition.In various cases, the amount effective for this use depends on the severity and course of disease or condition, previous treatment, individual's health condition, weight, and response to drugs, and the judgment of the treating physician.

[0184] In preventive applications, the compounds or compositions containing the compounds described herein may be administered to individuals susceptible to or otherwise at risk of a particular disease, disorder or condition.In certain embodiments of this use, the exact amount of compound administered depends on the individual's health condition, weight, etc.Furthermore, in some cases, when the compounds or compositions described herein are administered to an individual, the effective amount for this use depends on the severity and course of the disease, disorder or condition, previous treatment, the individual's health condition and response to the drug, and the judgment of the treating physician.

[0185] In certain embodiments of the methods of the invention where the individual's condition does not improve following administration of a selected dose of a compound or composition described herein, at the physician's discretion, the compound or composition described herein is optionally administered chronically, i.e., administered for an extended period of time, including over the course of the individual's life, to ameliorate or otherwise control or limit the symptoms of the individual's disorder, disease, or condition.

[0186] In certain embodiments of the method of the present invention, the effective amount of a given agent varies depending on one or more of several factors, such as the specific compound, the disease or condition and its severity, the identity (e.g., weight) of the subject or host requiring treatment, and is determined according to the specific circumstances surrounding the case, such as the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In some embodiments, the dose administered comprises a dose up to the maximum tolerated dose. In some embodiments, the dose administered comprises a dose up to the maximum tolerated dose by a newborn or infant.

[0187] In various embodiments of the method of the present invention, the desired dose is conveniently provided in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more subdoses per day.In various embodiments, a single dose of the IBAT inhibitor is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or once a week.In some embodiments, the total single dose of the IBAT inhibitor is within the ranges described below.

[0188] In various embodiments of the methods of the invention, if the patient's condition improves, at the discretion of the physician, the IBAT inhibitor is optionally given continuously; alternatively, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, such as, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100% of the original dose, such as, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the original dose. In some embodiments, the total single dose of the IBAT inhibitor is within the ranges set forth below.

[0189] Once improvement of the patient's condition occurs, a maintenance dose is administered as necessary.Then, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder or condition is maintained.In some embodiments, the patient requires long-term intermittent treatment upon recurrence of any symptoms.

[0190] In certain instances, there are many variables with respect to individual treatment regimens, and significant deviations from these recommendations are contemplated within the ranges described herein. The dosages described herein are optionally varied depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0191] The toxicity and therapeutic efficacy of such treatment regimens are 50 (lethal dose for 50% of the population) and ED 50The LD50 is optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the 50% therapeutically effective dose in the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The therapeutic index can be expressed as a ratio of ED to ED. Compounds that exhibit high therapeutic indices are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a range of dosages for use in humans. In certain embodiments, dosages of the compounds described herein are administered at ED 100 mg / kg with minimal toxicity. 50 The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0192] In certain embodiments, the composition used or administered includes an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0193] In some embodiments of the method of the present invention, the composition used to prepare an oral dosage form or orally administered comprises an absorption inhibitor, an orally suitable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional wetting agent. In certain embodiments, the orally administered composition induces an anorectal response. In certain embodiments, the anorectal response is an increase in the secretion of one or more enteroendocrine secretions by cells in the colon and / or rectum (e.g., L cells in the epithelial layer of the colon, ileum, rectum, or combinations thereof). In some embodiments, the anorectal response lasts for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In other embodiments, the anorectal reaction lasts for between 24 hours and 48 hours, while in other embodiments, the anorectal reaction lasts for a period of more than 48 hours.

[0194] Dosage In various embodiments, the IBAT inhibitor is maralixibat or vorixibat, or a pharma- ceutically acceptable salt thereof.

[0195] In various embodiments, the IBAT inhibitor is administered to a subject prior to ingestion of food.

[0196] In various embodiments, the efficacy and safety of administering an IBAT inhibitor to a patient is monitored by measuring the serum level of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum conjugated bilirubin concentration, serum autotaxin concentration, serum bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum ALT concentration, serum AST concentration, or combinations thereof.In various embodiments, the efficacy of administering an IBAT inhibitor is measured by monitoring Itch Reported Outcome (Observer) (ITCHRO (OBS)) score, HRQoL (e.g., PedsQL) score, CSS score, xanthomas score, height Z score, weight Z score, or various combinations thereof. In various embodiments, the method includes monitoring the serum level of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum conjugated bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum autotaxin concentration, serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof.In various embodiments, the method includes monitoring the Itch Reported Outcome (Observer) (ITCHRO (OBS)) score, weight Z score, HRQoL (e.g., PedsQL) score, xanthomas score, CSS score, height Z score, or various combinations thereof.

[0197] In some embodiments, the IBAT inhibitor is about or at least about 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 100 μg / kg, 140 μg / kg, 150 μg / kg, 200μg / kg, 240μg / kg, 250μg / kg, 280μg / kg, 300μg / kg, 360μg / kg, 380μg / kg, 400 μg / kg, 500μg / kg, 560μg / kg, 600μg / kg, 700μg / kg, 800μg / kg, 880μg / kg, 900μg / k g, 1,000μg / kg, 1,100μg / kg, 1,200μg / kg, 1,300μg / kg, 1,400μg / kg, 1500μg / kg, Administered at doses of 1,600μg / kg, 1,700μg / kg, 1,800μg / kg, 1,900μg / kg, or 2,000μg / kg.In various embodiments, the IBAT inhibitor is about 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / k g, 40μg / kg, 45μg / kg, 50μg / kg, 55μg / kg, 60μg / kg, 65μg / kg, 70μg / kg, 75μg / kg, 80μg / kg, 85μg / kg, 90μg / kg, 100μg / kg, 140μg / kg, 150μg / kg, 200μg / kg, 240μg / The drug is administered at a dose not exceeding 250 μg / kg, 280 μg / kg, 300 μg / kg, 360 μg / kg, 380 μg / kg, 400 μg / kg, 500 μg / kg, 560 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 880 μg / kg, 900 μg / kg, 1,000 μg / kg, 1,100 μg / kg, 1,200 μg / kg, 1,300 μg / kg, 1,400 μg / kg, 1,500 μg / kg, 1,600 μg / kg, 1,700 μg / kg, 1,800 μg / kg, 1,900 μg / kg, 2,000, or 2,100 μg / kg. In various embodiments, the IBAT inhibitor is administered at a dose of about or at least about 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, 30 mg / day, 31 mg / day, 32 mg / day, 33 mg / day, 34 mg / day, 35 mg / day, 36 mg / day, 37 mg / day, 38 mg / day, 39 mg / day, 40 mg / day, 41 mg / day, 42 mg / day, 43 mg / day, 44 mg / day, 45 mg / day, 46 mg / day, 47 mg / day, 48 mg / day, 49 mg / day, 50 mg / day, 51 mg / day, 52 mg / day, 53 mg / day, 54 mg / day, 55 mg / day, 56 mg / day, 57 mg / day, 58 mg / day, 59 mg / day, 60 mg / day, 61 mg / day, 62 mg / day, 63 mg / day, 64 mg / day, 65 mg / day, 66 mg / day, 67 mg / day, 68 mg / day, 69 mg / day, 70 mg / day, 7 daily, 19mg / day, 20mg / day, 30mg / day, 40mg / day, 50mg / day, 60mg / day, 70mg / day, 80mg / day, 90mg / day, 100mg / day, 150mg / day, 200mg / day, 300mg / day, 500mg / day, 600mg / day, 700mg / day, 800mg / day, 900mg / day, 1000mg / day.In various embodiments, the IBAT inhibitor is administered at a dose of about 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day , 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1,000 mg / day, or 1,100 mg / day.

[0198] In some embodiments, the IBAT inhibitor is administered at a dose of about 140 μg / kg / day to about 1400 μg / kg / day. In various embodiments, the IBAT inhibitor is administered at a dose of about or at least about 0.5 μg / kg / day, 1 μg / kg / day, 2 μg / kg / day, 3 μg / kg / day, 4 μg / kg / day, 5 μg / kg / day, 6 μg / kg / day, 7 μg / kg / day, 8 μg / kg / day, 9 μg / kg / day, 10 μg / kg / day, 15 μg / kg / day, 20 μg / kg / day, 25 μg / kg / day, 30 μg / kg / day, 35 μg / kg / day, 40 μg / kg / day, 45 μg / kg / day, 50 μg / kg / day, 100 μg / kg / day, 140 μg / kg / day, 150 μg / kg / day, 20 The drug is administered at doses of 0 μg / kg / day, 240 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 250 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 360 μg / kg / day, 380 μg / kg / day, 400 μg / kg / day, 500 μg / kg / day, 560 μg / kg / day, 600 μg / kg / day, 700 μg / kg / day, 800 μg / kg / day, 880 μg / kg, 900 μg / kg / day, 1,000 μg / kg / day, 1,100 μg / kg / day, 1,200 μg / kg / day, or 1,300 μg / kg / day.In various embodiments, the IBAT inhibitor is administered at about 1 μg / kg / day, 2 μg / kg / day, 3 μg / kg / day, 4 μg / kg / day, 5 μg / kg / day, 6 μg / kg / day, 7 μg / kg / day, 8 μg / kg / day, 9 μg / kg / day, 10 μg / kg / day, 15 μg / kg / day, 20 μg / kg / day, 25 μg / kg / day, 30 μg / kg / day, 35 μg / kg / day, 40 μg / kg / day, 45 μg / kg / day, 50 μg / kg / day, 100 μg / kg / day, 140 μg / kg / day, 150 μg / kg / day, 200 μg / kg / day, 240 μg / kg / day , 280 μg / kg / day, 300 μg / kg / day, 250 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 360 μg / kg / day, 380 μg / kg / day, 400 μg / kg / day, 500 μg / kg / day, 560 μg / kg / day, 600 μg / kg / day, 700 μg / kg / day, 800 μg / kg / day, 880 μg / kg / day, 900 μg / kg / day, 1,000 μg / kg / day, 1,100 μg / kg / day, 1,200 μg / kg / day, 1,300 μg / kg / day, or 1,400 μg / kg / day.In various embodiments, the IBAT inhibitor is administered at a dose of from about 0.5 μg / kg / day to about 500 μg / kg / day, from about 0.5 μg / kg / day to about 250 μg / kg / day, from about 1 μg / kg / day to about 100 μg / kg / day, from about 10 μg / kg / day to about 50 μg / kg / day, from about 10 μg / kg / day to about 100 μg / kg / day, from about 0.5 μg / kg / day to about 2000 μg / kg / day, from about 280 μg / kg / day to about 1400 μg / kg / day, from about 420 μg / kg / day to about 500 μg / kg / day, from about 50 ... / day~about 1400μg / kg / day, about 250~about 550μg / kg / day, about 560μg / kg / day~about 1400μg / kg / day, from700μg / kg / day~about 1400μg / kg / day, about 560μg / kg / day~ Approximately 1200μg / kg / day, approximately 700μg / kg / day to approximately 1200μg / kg / day, approximately 560μg / kg / day to approximately 1000μg / kg / day, approximately 700μg / kg / day to approximately 1000μg / kg / day, approximately 800μg / kg / day ~1000μg / kg / day, approx. 200μg / kg / day ~ approx. 600μg / kg / day, approx. 300μg / kg / day ~ approx. 600μg / kg / day, approx. 400μg / kg / day ~ approx. 500μg / kg / day, approximately 400μg / kg / day ~600μg / kg / day, ~400μg / kg / day~700μg / kg / day, ~400μg / kg / day~800μg / kg / day, ~500μg / kg / day~800μg / kg / day, ~500μg / kg / day The compound is administered at a dose of about 900 μg / kg / day, about 600 μg / kg / day to about 900 μg / kg / day, about 700 μg / kg / day to about 900 μg / kg / day, about 200 μg / kg / day to about 600 μg / kg / day, about 800 μg / kg / day to about 900 μg / kg / day, about 100 μg / kg / day to about 1500 μg / kg / day, about 300 μg / kg / day to about 2,000 μg / kg / day, or about 400 μg / kg / day to about 2000 μg / kg / day.

[0199] In some embodiments, the IBAT inhibitor is administered at a dose of about 30 μg / kg to about 1400 μg / kg per administration. In some embodiments, the IBAT inhibitor is administered at a dose of about 0.5 μg / kg to about 2000 μg / kg per administration, about 0.5 μg / kg to about 1500 μg / kg per administration, about 100 μg / kg to about 700 μg / kg per administration, about 5 μg / kg to about 100 μg / kg per administration, about 10 μg / kg to about 500 μg / kg per administration, about 50 μg / kg to about 1400 μg / kg per administration, about 300 μg / kg to about 2000 μg / kg per administration, about 60 μg / kg to about 1200 μg / kg per administration, about 70 μg / kg to about 1000 μg / kg per administration, about 70 The dose is administered at a dose of about 700 μg / kg, about 80 μg / kg, about 1000 μg / kg, about 80 μg / kg, about 800 μg / kg, about 100 μg / kg, about 800 μg / kg, about 100 μg / kg, about 600 μg / kg, about 150 μg / kg, about 700 μg / kg, about 150 μg / kg, about 500 μg / kg, about 200 μg / kg, about 400 μg / kg, about 200 μg / kg, about 300 μg / kg, or about 400 μg / kg.

[0200] In some embodiments, the IBAT inhibitor is administered at a dose of about 0.5 mg / day to about 550 mg / day. In various embodiments, the IBAT inhibitor is administered at a dose of about 1 mg / day to about 500 mg / day, about 1 mg / day to about 300 mg / day, about 1 mg / day to about 200 mg / day, about 2 mg / day to about 300 mg / day, about 2 mg / day to about 200 mg / day, about 4 mg / day to about 300 mg / day, about 4 mg / day to about 200 mg / day, about 4 mg / day to about 150 mg / day, about 5 mg / day to about 150 mg / day, about 5 mg / day to about 100 mg / day, about 5 mg / day to about 80 mg / day, about 5 mg / day to about 50 mg / day, about 5 mg / day to about 40 mg / day. daily, about 5 mg / day to about 30 mg / day, about 5 mg / day to about 20 mg / day, about 5 mg / day to about 15 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 80 mg / day, about 10 mg / day to about 50 mg / day, about 10 mg / day to about 40 mg / day, about 10 mg / day to about 20 mg / day, about 20 mg / day to about 100 mg / day, about 20 mg / day to about 80 mg / day, about 20 mg / day to about 50 mg / day, or about 20 mg / day to about 40 mg / day, or about 20 mg / day to about 30 mg / day.

[0201] In some embodiments, the IBAT inhibitor is administered twice daily (BID) in an amount of about 200 μg / kg to about 400 μg / kg per dose. In some embodiments, the IBAT inhibitor is administered in an amount of about 280 μg / kg / day to about 1400 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 20 mg / day to about 50 mg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 5 mg / day to about 15 mg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 560 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 700 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 700 μg / kg / day to about 900 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 560 μg / kg / day to about 1400 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of 700 μg / kg / day to about 1400 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 200 μg / kg / day to about 600 μg / kg / day. In some embodiments, the IBAT inhibitor is administered in an amount of about 400 μg / kg / day to about 600 μg / kg / day.

[0202] In various embodiments, the dose of the IBAT inhibitor is at a first dose level. In various embodiments, the dose of the IBAT inhibitor is at a second dose level. In some embodiments, the second dose level is higher than the first dose level. In some embodiments, the second dose level is about or at least about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or 100 times higher than the first dose level. In some embodiments, the second dose level is not more than about 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 15x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, or 150x the first dose level.

[0203] In various embodiments, the IBAT inhibitor is administered once a day (QD) at one of the doses or within one of the dose ranges above. In various embodiments, the IBAT inhibitor is administered twice a day (BID) at one of the doses or within one of the dose ranges above. In various embodiments, the dose of the IBAT inhibitor is administered daily, every other day, twice a week, or once a week.

[0204] In various embodiments, the IBAT inhibitor is administered periodically for about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, or 800 weeks. In various embodiments, the IBAT inhibitor is administered for a period not exceeding about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, or 1000 weeks. In various embodiments, the IBAT inhibitor is administered periodically for a period of about or at least about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In various embodiments, the IBAT inhibitor is administered periodically for a period of not more than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

[0205] Relief of symptoms of cholestatic liver disease or changes in disease-related laboratory values In various embodiments of the above-mentioned methods of the present invention, administration of an IBAT inhibitor results in a reduction in symptoms of cholestatic liver disease or a change in a disease-relevant laboratory measure (i.e., an improvement in the patient's condition) that occurs within about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks maintained for 5 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years, or 10 years. In various embodiments, the symptom reduction or disease-related laboratory change comprises a reduction in sBA concentration, an increase in serum 7αC4 concentration, an increase in 7αC4:sBA ratio, an increase in fBA excretion, a reduction in pruritus, a reduction in serum total cholesterol concentration, a reduction in serum LDL-C cholesterol concentration, a reduction in ALT level, an increase in quality of life inventory score, an increase in quality of life inventory score for fatigue, a reduction in xanthomas score, a reduction in serum autotaxin concentration, an increase in growth, or a combination thereof. In various embodiments, the symptom reduction or disease-related laboratory change is determined relative to baseline levels. That is, the symptom reduction or disease-related laboratory change is determined relative to the symptom measurement or disease-related laboratory change 1) before a change in the dose level of the IBAT inhibitor administered to the patient, 2) before a change in the dosing regimen followed by the patient, 3) before the start of administration of the IBAT inhibitor, or 4) before various other changes made to reduce symptoms or change disease-related laboratory changes in the patient. In various embodiments, the symptom reduction or disease-related laboratory change is a statistically significant reduction.

[0206] In various embodiments, the reduction in symptoms of cholestatic liver disease or change in disease-related laboratory values ​​is achieved within about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, , 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years, or 10 years.

[0207] In some embodiments, the patient is a pediatric patient and the reduction in symptoms or change in disease-related laboratory value comprises an increase or improvement in growth. In some embodiments, the increase in growth is measured compared to baseline. In various embodiments, the increase in growth is measured as an increase in height Z-score or weight Z-score. In various embodiments, the increase in height Z-score or weight Z-score is statistically significant. In various embodiments, the increase in height Z-score, weight Z-score, or both is at least 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17., 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, or 0.9 increase. In some embodiments, the height Z-score, weight Z-score, or both, increase progressively during administration of the IBAT inhibitor over a period of about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 48, 50, 60, 70, or 72 weeks.

[0208] In various embodiments, administration of IBAT inhibitor leads to increase in serum 7αC4 concentration.In various embodiments, serum 7αC4 concentration increases by about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 times compared to baseline.In various embodiments, serum 7αC4 concentration increases by about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, or 10,000% compared to baseline.

[0209] In various embodiments, administration of an IBAT inhibitor increases the 7αC4:sBA ratio by about 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 fold or times relative to baseline.

[0210] In various embodiments, administration of an IBAT inhibitor results in an increase in fBA excretion. In some embodiments, administration of an IBAT inhibitor results in an increase in fBA excretion of about or at least about 100%, 110%, 115%, 120%, 130%, 150%, 200%, 250%, 275%, 300%, 400%, 500%, 600%, 700%, 800%, 1,000%, 5,000%, 10,000% or 15,000% relative to baseline. In various embodiments, fBA excretion is increased by about or at least about 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times relative to baseline. In some embodiments, fBA excretion is increased by about or at least about 100 μmol, 150 μmol, 200 μmol, 250 μmol, 300 μmol, 400 μmol, 500 μmol, 600 μmol, 700 μmol, 800 μmol, 900 μmol, 1,000 μmol, or 1,500 μmol relative to baseline. In various embodiments, administration of an IBAT inhibitor results in a dose-dependent increase in fBA excretion, with administration of a higher dose of an IBAT inhibitor resulting in a corresponding higher level of fBA excretion. In various embodiments, an IBAT inhibitor is administered at a dose sufficient to result in an increase in bile acid secretion of at least about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times relative to baseline.

[0211] In various embodiments, administration of an IBAT inhibitor results in a reduction in sBA concentrations of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 31%, 35%, 40%, 45%, 50%, 55%, 57%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% relative to baseline.

[0212] In some embodiments, administration of an IBAT inhibitor results in a reduction in the severity of pruritus. In various embodiments, the severity of pruritus is measured using ITCHRO (OBS) score, ITCHRO score, CSS score, or a combination thereof. In various embodiments, administration of an IBAT inhibitor results in a reduction in ITCHRO (OBS) score on a scale of 1 to 4 of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3, relative to baseline. In various embodiments, administration of the IBAT inhibitor results in a decrease in the ITCHRO score on a scale of 1 to 10 of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. In various embodiments, administration of the IBAT inhibitor results in a decrease in the ITCHRO(OBS) score, the ITCHRO score, or both, to zero. In various embodiments, administration of the IBAT inhibitor results in a decrease in the ITCHRO(OBS) score or the ITCHRO score to 1.0 or less. In various embodiments, administration of an IBAT inhibitor results in a reduction in the CSS score relative to baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3. In various embodiments, administration of an IBAT inhibitor results in a reduction in the CSS score to zero. In various embodiments, administration of an IBAT inhibitor results in a reduction in the CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof of about or at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline.In various embodiments, a reduction in CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof versus baseline is observed on 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of days.

[0213] In some embodiments, patients with a higher baseline ITCHRO (OBS) score show a greater reduction in symptoms or a greater change in disease-related laboratory values ​​than patients with a lower baseline ITCHRO (OBS) score. In some embodiments, patients with a baseline ITCHRO (OBS) score of at least 2, 3, or 4 or an ITCHRO score of at least 4, 5, 6, 7, 8, 9, or 10 have a greater reduction in symptoms or a greater change in disease-related laboratory values ​​relative to baseline compared to the smaller reduction in patients with a lower baseline severity of pruritus scores. In various embodiments, patients with PSC and a baseline ITCHRO score of at least 4 show a greater reduction in symptoms or a greater change in disease-related laboratory values ​​than patients with a baseline ITCHRO score of less than 4. In various embodiments, the method includes predicting that a patient will have a greater reduction in symptoms or a greater change in disease-related laboratory values ​​if the patient's baseline ITCHRO score is at least 4 compared to patients with a baseline ITCHRO score of less than 4. In various embodiments, the smaller reduction is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% or less of the larger reduction. In various embodiments, the difference in symptom relief or disease-related laboratory change (i.e. the difference between the greater and lesser reduction) between patients with an ITCHRO score of at least 4 at baseline and patients with an ITCHRO score of less than 4 at baseline is about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks after the first administration of the IBAT inhibitor at the first dose or the second dose.are measured after 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years or 10 years.

[0214] In various embodiments, the reduction in severity of pruritus resulting from administration of an IBAT inhibitor to a patient is positively correlated with a reduction in the concentration of sBA in the patient. In various embodiments, a greater reduction in the concentration of sBA in a patient is correlated with a corresponding greater reduction in the severity of pruritus.

[0215] In various embodiments, administration of an IBAT inhibitor results in a reduction in serum LDL-C concentrations compared to baseline. In some embodiments, serum LDL-C concentrations are reduced by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline.

[0216] In some embodiments, administration of an IBAT inhibitor results in a reduction in serum total cholesterol concentration compared to baseline. In some embodiments, administration of an IBAT inhibitor results in a reduction in serum LDL-C levels compared to baseline. In some embodiments, serum total cholesterol concentration, serum LDL-C levels, or both are reduced by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline. In various embodiments, administration of an IBAT inhibitor results in a reduction in serum total cholesterol concentration, serum LDL-C levels, or both, of about or at least about 1 mg / dL, 2 mg / dL, 3 mg / dL, 4 mg / dL, 5 mg / dL, 10 mg / dL, 12.5 mg / dL, 15 mg / dL, 20 mg / dL, 30 mg / dL, 40 mg / dL or 50 mg / dL relative to baseline.

[0217] In various embodiments, administration of IBAT inhibitor leads to a decrease in serum autotaxin concentration.In some embodiments, administration of IBAT inhibitor leads to about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% decrease in autotaxin concentration compared to baseline.

[0218] In various embodiments, administration of an IBAT inhibitor results in an increase in a quality of life scale score, or an increase in a quality of life scale score for fatigue. The quality of life scale score can be a health-related quality of life (HRQoL) score. In some embodiments, the HRQoL score is a PedsQL score. In various embodiments, administration of an IBAT inhibitor results in an increase in a PedsQL score or a PedsQL score for fatigue of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to baseline.

[0219] In various embodiments, administration of an IBAT inhibitor results in a decrease in xanthomas score compared to baseline. In some embodiments, the xanthomas score is decreased by about or at least about 2.5%, 5%, 10%, 15%, 20%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline.

[0220] In various embodiments, administration of the IBAT inhibitor is for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 or by 1 week, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or by 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years, there is a reduction in symptoms or a change in disease-related laboratory values.

[0221] In various embodiments, the serum bilirubin concentration is about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, pre-dose baseline levels or normal levels at or by week, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years.

[0222] In various embodiments, the serum ALT concentration is measured at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks , 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years, or pre-administration baseline levels or normal levels at or by. In some embodiments, administration of an IBAT inhibitor results in a reduction in ALT levels of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% relative to baseline.

[0223] In various embodiments, the serum ALT concentration, serum AST concentration, serum bilirubin concentration, serum conjugated bilirubin concentration, or various combinations thereof, is about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, within the normal range or pre-dose baseline levels at or by week, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years. In various embodiments, administration of the IBAT inhibitor is for at least about or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks , 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years, do not result in a statistically significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof. In various embodiments, for adult patients with an ITCHRO score of at least 4 at baseline, administration of the IBAT inhibitor is for at least about or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks.does not result in a significant change from baseline in serum conjugated bilirubin concentrations at 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year, or 2 years, or 3 years, or 4 years, or 5 years, or 6 years.

[0224] In various embodiments of the above method of the present invention, administration of the IBAT inhibitor results in the reduction, prevention, amelioration or elimination of one or more side effects associated with administration of the IBAT inhibitor in a subject in need thereof.In various embodiments, the frequency and / or severity of side effects is reduced compared to the side effects when the IBAT inhibitor is administered after ingestion of food, simultaneously with food, or mixed with food.In various embodiments, the one or more side effects are diarrhea, loose stool, nausea, gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

[0225] Dose adjustment In various embodiments, the method comprises adjusting the dosage of the IBAT inhibitor administered to the patient. The adjustment comprises determining the patient's 7αC4:sBA ratio at baseline (e.g., before administering the IBAT inhibitor or before adjusting (e.g., increasing) the dosage of the IBAT inhibitor), and further determining the 7αC4:sBA ratio after administering the IBAT inhibitor at a first dose or adjusting (e.g., increasing) the dosage of the IBAT inhibitor to a second dose. If the 7αC4:sBA ratio does not increase by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000-fold from baseline, the ratio is considered to be The dose of the IBAT inhibitor is increased until the IBAT inhibitor has increased by at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 fold relative to the baseline. In various embodiments, the dose of the IBAT inhibitor is increased or decreased to achieve and maintain a particular 7αC4:sBA ratio.

[0226] In various embodiments, modulating includes an initial increase in the 7αC4:sBA ratio of at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 fold from baseline and then begins to decrease or return to baseline. In one embodiment, the method comprises increasing the dose of the IBAT inhibitor from the first dose level to a second dose level higher than the first dose level if the IBAT inhibitor has decreased to less than 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times higher than the first dose level. Dose levels are escalated until the 7αC4:sBA ratio increases from baseline by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000-fold.

[0227] In some embodiments, the modulation comprises administering a first dose of an IBAT inhibitor to the patient. If the 7αC4:sBA ratio does not increase or does not increase from baseline by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times, the patient is then administered a second dose of the IBAT inhibitor that is greater than the first dose. The dose administered to the patient continues to be escalated until the 7αC4:sBA ratio increases from baseline by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000-fold.

[0228] In various embodiments, the 7αC4:sBA ratio is measured about daily, biweekly, weekly, bimonthly, monthly, every two months, every three months, every four months, every five months, every six months, or yearly, and the dose of the IBAT inhibitor is adjusted as needed each time the ratio is measured.

[0229] Pharmaceutical Compositions In some embodiments, the IBAT inhibitor is administered as a pharmaceutical composition (composition or pharmaceutical composition) comprising the IBAT inhibitor. Any composition described herein may be formulated for ileal, rectal and / or colonic delivery. In more specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon. As used herein, delivery to the colon is understood to include delivery to the sigmoid colon, transverse colon and / or ascending colon. In even more specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon and administered rectally. In other specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon and administered orally.

[0230] In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein. In certain examples, the pharmaceutical composition comprises an IBAT inhibitor (e.g., any of the IBAT inhibitors described herein).

[0231] In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and auxiliaries that facilitate the processing of active compounds into preparations suitable for pharmaceutical use.In certain embodiments, suitable formulations depend on the route of administration selected.Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all of which are incorporated herein in their entirety for all purposes.

[0232] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. In certain instances, the pharmaceutical composition facilitates administration of the compound to an individual or cell. In certain embodiments of carrying out the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to an individual having a disease, disorder, or condition to be treated. In certain embodiments, the individual is a human. As discussed herein, the compounds described herein are utilized alone or in combination with one or more additional therapeutic agents.

[0233] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual by any manner, including one or more of a variety of routes of administration, such as, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.

[0234] In certain embodiments, the pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of free acid or free base, or in the form of pharma- ceutically acceptable salt. In some embodiments, the compounds described herein are utilized as N-oxides, or in crystalline or amorphous forms (i.e., polymorphs). In some situations, the compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in unsolvated or solvated forms, and the solvated forms include any pharma- ceutically acceptable solvent, such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.

[0235] "Carriers" in some embodiments include pharma- ceutically acceptable excipients, selected based on compatibility with the compounds described herein, such as any of the compounds of Formulae I-VI, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999); all of which are incorporated herein in their entireties for all purposes.

[0236] Furthermore, in certain embodiments, the pharmaceutical compositions described herein are formulated as dosage forms.Thus, in some embodiments, dosage forms comprising the compounds described herein are provided herein that are suitable for administration to individuals.In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast-dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0237] In some embodiments, provided herein is a composition for alleviating a symptom of cholestasis or cholestatic liver disease in an individual, the composition comprising an enteroendocrine peptide secretion enhancing agent, and optionally a pharma- ceutically acceptable carrier.

[0238] In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue and an absorption inhibitor. In certain embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of the particular enteroendocrine peptide secretagogue (or at least one of) with which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, and a carrier (e.g., a carrier suitable for oral administration or a carrier suitable for rectal administration, depending on the intended method of administration). In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0239] In other embodiments, the compositions described herein are administered orally for non-systemic delivery of the IBAT inhibitor to the rectum and / or colon, including the sigmoid colon, transverse colon, and / or ascending colon. In certain embodiments, the compositions formulated for oral administration are enteric coated or enteric formulated oral dosage forms, such as, by way of non-limiting example, tablets and / or capsules.

[0240] Absorption inhibitors In certain embodiments, the compositions described herein as formulated for non-systemic delivery of an IBAT inhibitor further comprise an absorption inhibitor. As used herein, absorption inhibitors include an agent or agents that inhibit the absorption of bile acids / salts.

[0241] Suitable bile acid absorption inhibitors (also referred to herein as absorption inhibitors) may include, by way of non-limiting example, anion exchange matrices, polyamines, quaternary amine-containing polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam, colesevelam hydrochloride, CholestaGel (polymer of N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium chloride with (chloromethyl)oxirane, 2-propen-1-amine, and N-2-propenyl-1-decaneamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, carbohydrates that bind bile acids, lipids that bind bile acids, proteins and proteinaceous substances that bind bile acids, and antibodies and albumins that bind bile acids. Suitable cyclodextrins include, by way of non-limiting example, those that bind bile acids / salts, such as β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include, by way of non-limiting example, those that bind bile acids / salts, such as bovine serum albumin, egg albumin, casein, alpha-acid glycoprotein, gelatin, soy protein, peanut protein, almond protein, and wheat plant protein.

[0242] In certain embodiments, the absorption inhibitor is cholestyramine. In certain embodiments, cholestyramine binds bile acids. The ion exchange resin cholestyramine is a styrene polymer containing quaternary ammonium groups crosslinked by divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In certain embodiments, colestipol binds bile acids. The ion exchange resin colestipol is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[0243] In certain embodiments of the compositions and methods described herein, the IBAT inhibitor is linked to a resorption inhibitor, while in other embodiments, the IBAT inhibitor and the resorption inhibitor are separate molecular entities.

[0244] Cholesterol absorption inhibitors In certain embodiments, the compositions described herein optionally include at least one cholesterol absorption inhibitor.Suitable cholesterol absorption inhibitors include, but are not limited to, ezetimibe (SCH58235), ezetimibe analogs, ACT inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, sulfated polysaccharides, neomycin, phytosponin, phytosterol, phytostanol preparation FM-VP4, sitostanol, β-sitosterol, acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, avasimibe, implitapide, steroid glycosides, etc.Suitable ezetimibe analogs include, but are not limited to, SCH48461, SCH58053, etc. Suitable ACT inhibitors include, but are not limited to, trimethoxy fatty acid anilides such as Cl-976, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide, melinamide, etc. Beta-lactam cholesterol absorption inhibitors include, but are not limited to, (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-beta-phenylpropyl)-2-azetidinone, etc.

[0245] Peptidase inhibitors In some embodiments, the compositions described herein optionally comprise at least one peptidase inhibitor, including, but not limited to, dipeptidyl peptidase-4 inhibitors (DPP-4), neutral endopeptidase inhibitors, and convertase inhibitors. Suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include, by way of non-limiting example, Vildagliptin, (2S)-1-{2-β-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile, Sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetraazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, Saxagliptin, and (1S,3S,5S)-2-[(2S)-2-amino-2-β-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile. Such neutral endopeptidase inhibitors include, but are not limited to, Candoxatrilat and Ecadotril.

[0246] Spreading agent / wetting agent In certain embodiments, the compositions described herein optionally include a spreading agent. In some embodiments, the spreading agent is utilized to improve the spreadability of the composition in the colon and / or rectum. Suitable spreading agents include, by way of non-limiting example, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrin, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbophil, di-n-octyl ether, Cetiol™ OE, fatty alcohol polyalkylene glycol ether, Aethoxal™ B, 2-ethylhexyl palmitate, Cegesoft™ C24, and isopropyl fatty acid esters.

[0247] In some embodiments, the compositions described herein optionally include a wetting agent. In some embodiments, the wetting agent is utilized to improve the wettability of the composition in the colon and rectum. Suitable wetting agents include, by way of non-limiting example, surfactants. In some embodiments, the surfactants include, by way of non-limiting example, polysorbates (e.g., 20 or 80), stearyl heptanoate, chain length C 12 ~C 18 caprylic / capric fatty acid esters of saturated fatty alcohols, isostearyl diglycerol isostearic acid, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate, and a mixture of isopropyl myristate / isopropyl stearate / isopropyl palmitate.

[0248] vitamin In some embodiments, the methods provided herein further comprise administering one or more vitamins.

[0249] In some embodiments, the vitamin is vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, phylloquinone, menaquinone.

[0250] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, phylloquinone, etc. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0251] Bile Acid Sequesterants / Binding Agents In some embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum compared to concentrations found in the small intestine. Examples of microflora activation systems include dosage forms that include pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gastrointestinal microflora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0252] In certain embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases the bile acid or is degraded after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of sequestration, in some embodiments, the labile bile acid sequestrant releases the bile acid or is degraded after 1, 2, or 3 days of sequestration.

[0253] In some embodiments, the labile bile acid sequestrant has a low affinity for bile acids, hi certain embodiments, the labile bile acid sequestrant has a high affinity for primary bile acids and a low affinity for secondary bile acids.

[0254] In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6 or less and a low affinity for bile acids at a pH of greater than 6. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6.5 or less and a low affinity for bile acids at a pH of greater than 6.5. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7 or less and a low affinity for bile acids at a pH of greater than 7. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.1 or less and a low affinity for bile acids at a pH of greater than 7.1. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.2 or less and a low affinity for bile acids at a pH of greater than 7.2. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.3 or less and a low affinity for bile acids at a pH greater than 7.3. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.4 or less and a low affinity for bile acids at a pH greater than 7.4. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.5 or less and a low affinity for bile acids at a pH greater than 7.5. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.6 or less and a low affinity for bile acids at a pH greater than 7.6. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.7 or less and a low affinity for bile acids at a pH greater than 7.7. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.8 or less and a low affinity for bile acids at a pH greater than 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 6.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.1. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.2. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.3. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.4. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.7. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.9.

[0255] In certain embodiments, the labile bile acid sequestrant is lignin or modified lignin.In some embodiments, the labile bile acid sequestrant is a polycationic polymer or copolymer.In certain embodiments, the labile bile acid sequestrant is a polymer or copolymer that comprises one or more N-alkenyl-N-alkylamine residues; one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkyl-azanium residues; one or more N,N,N-trialkyl-N-alkenyl-azanium residues; one or more alkenylamine residues; or combinations thereof. In some embodiments, the bile acid binder is cholestyramine and various compositions containing cholestyramine, which are described, for example, in U.S. Pat. Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336, all of which are incorporated by reference herein in their entireties for all purposes. In some embodiments, the bile acid binding agent is colestipol or colesevelam.

[0256] Route of Administration, Dosage Forms, and Dosing Regimen In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reuptake or reduce serum or hepatic bile acid levels. In certain embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for localized delivery of the composition to the rectum and / or colon (sigmoid, transverse, or ascending colon). In certain embodiments, for rectal administration, the compositions described herein are formulated as enemas, rectal gels, enema foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. In some embodiments, for oral administration, the compositions described herein are formulated for oral administration and enteral delivery to the colon.

[0257] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver the IBAT inhibitor to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In some embodiments, the oral compositions described herein deliver the IBAT inhibitor to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In some embodiments, the rectal compositions described herein deliver the IBAT inhibitor to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In certain embodiments, the non-systemic compositions described herein deliver less than 90% w / w of the IBAT inhibitor to the systemic. In certain embodiments, the non-systemic compositions described herein deliver less than 80% w / w of the IBAT inhibitor to the systemic. In certain embodiments, the non-systemic compositions described herein deliver less than 70% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 60% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 50% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 40% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 30% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 25% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 20% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 15% w / w of the IBAT inhibitor to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 10% w / w of the IBAT inhibitor systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 5% w / w of the IBAT inhibitor systemically.In some embodiments, systemic absorption is determined in any suitable manner, including total circulating amount, amount cleared following administration, etc.

[0258] In certain embodiments, the compositions and / or formulations described herein are administered at least once a day.In certain embodiments, the formulations comprising an IBAT inhibitor are administered at least twice a day, and in other embodiments, the formulations comprising an IBAT inhibitor are administered at least three times a day.In certain embodiments, the formulations comprising an IBAT inhibitor are administered up to five times a day.It should be understood that in certain embodiments, the administration regimen of the compositions comprising an IBAT inhibitor described herein is determined by considering various factors such as the age, sex, and diet of the patient.

[0259] The concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 1 mM to about 1M. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulation described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of the IBAT inhibitor administered in the formulations described herein ranges from about 200 mM to about 500 mM.

[0260] In certain embodiments, by targeting the distal digestive tract (e.g., the distal ileum, colon, and / or rectum), the compositions and methods described herein provide efficacy (e.g., efficacy in reducing microbial growth and / or alleviating symptoms of cholestasis or cholestatic liver disease) at reduced doses of enteroendocrine peptide secretagogues (e.g., compared to oral doses that do not target the distal digestive tract).

[0261] Oral Administration for Colonic Delivery In certain aspects, compositions or formulations comprising one or more compounds described herein are administered orally for local delivery of the IBAT inhibitor or compounds described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets or capsules formulated for enteral delivery to the colon. In certain embodiments, such pills, tablets or capsules comprise the compositions described herein encapsulated or embedded in microspheres. In some embodiments, the microspheres include, by way of non-limiting examples, chitosan micro-core HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known in the field of pharmaceutical formulation. For example, in certain embodiments, tablets are manufactured using standard tablet processing procedures and equipment. An exemplary method for forming tablets is by direct compression of a powdered, crystalline, or granular composition comprising the above-mentioned active agent, alone or in combination with one or more carriers, additives, and the like. In alternative embodiments, tablets are prepared using wet granulation or dry granulation processes. In some embodiments, tablets are molded rather than compressed, starting with a moist or otherwise tractable material.

[0262] In certain embodiments, tablets prepared for oral administration contain various excipients, including, by way of non-limiting example, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavoring agents, and the like. In some embodiments, binders are used to impart cohesion to the tablet and ensure that it remains intact after compression. Suitable binder materials include, by way of non-limiting example, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, such as acacia, sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, and the like), Veegum, and combinations thereof. In certain embodiments, diluents are utilized to increase the bulk of the tablet to provide a tablet of practical size. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. In certain embodiments, lubricants are used to facilitate tablet manufacture; suitable lubricants include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, disintegrants are used to facilitate tablet disintegration, but are not limited to, starch, clay, cellulose, algin, gum, cross-linked polymer, and combinations thereof. Fillers include, but are not limited to, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.In certain embodiments, stabilizers are used to inhibit or retard drug decomposition reactions, including, by way of example, oxidation reactions, hi certain embodiments, the surfactant is an anionic, cationic, amphoteric or nonionic surfactant.

[0263] In some embodiments, the IBAT inhibitor, or other compound described herein, is administered orally with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and / or rectum).

[0264] In certain embodiments, the compositions described herein comprise an IBAT inhibitor or other compound described herein in association with a matrix (e.g., a matrix comprising hypermellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or the colon. In some embodiments, the compositions comprise a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH sensitive polymers suitable for controlled release include those that contain acidic groups (e.g., -COOH, -SO 3Examples of suitable polymers for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain methacrylic acid (H) and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the composition suitable for controlled release in the distal ileum comprises a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of an enteroendocrine peptide secretagogue to the distal ileum. In some embodiments, the dosage form containing an enteroendocrine peptide secretagogue is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, the bacterial activation system is suitable for targeted delivery to the distal part of the ileum.Examples of the microflora activation system include dosage forms that contain pectin, galactomannan, and / or Azo hydrogel and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.).Examples of the digestive tract microflora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0265] The pharmaceutical compositions described herein optionally include an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a permeation enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, or one or more combinations thereof. In some embodiments, a film coating is provided around the formulation of the compound of formula I using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0266] In further embodiments, the tablet or capsule containing the IBAT inhibitor or other compounds described herein is film-coated for delivery to target sites in the gastrointestinal tract.Examples of enteric film coating include, but are not limited to, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, etc.

[0267] Pediatric Formulations and Compositions In certain embodiments, provided herein is a pediatric formulation or composition comprising a therapeutically effective amount of any of the compounds described herein. In certain examples, the pharmaceutical composition comprises an IBAT inhibitor (e.g., any of the IBAT inhibitors described herein).

[0268] In certain embodiments, dosage forms suitable for pediatric formulations or compositions include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candies, orally disintegrating tablets, powders for reconstitution as suspensions or solutions, sprinkle oral powders or granules, sugar-coated tablets, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. In some embodiments, provided herein are pharmaceutical compositions in which the pediatric dosage form is selected from solutions, syrups, suspensions, elixirs, powders for reconstitution as suspensions or solutions, dispersible / effervescent tablets, chewable tablets, gummy candies, lollipops, freezer pops, lozenges, oral flakes, orally disintegrating tablets, orally disintegrating strips, sachets, and sprinkle oral powders or granules.

[0269] In another aspect, provided herein is a pharmaceutical composition in which at least one excipient is a flavoring or sweetening agent.In some embodiments, provided herein is a coating.In some embodiments, provided herein is a taste masking technology selected from: coating drug particles with taste-neutral polymers by spray drying, wet granulation, fluid bed, and microencapsulation; coating a mixture of molten wax and other pharmaceutical auxiliary with molten wax; entrapment of drug particles by complexation, aggregation, or solidification of aqueous polymer dispersions; adsorption of drug particles to resins and inorganic supports; and solid dispersions in which drug and one or more neutral taste compounds are melted and cooled or co-precipitated by solvent evaporation.In some embodiments, provided herein is a delayed or sustained release formulation comprising drug particles or granules in a rate-controlling polymer or matrix.

[0270] Suitable sweeteners include sucrose, glucose, fructose, or high-intensity sweeteners, i.e., agents having a high sweetening power compared to sucrose (e.g., at least 10 times sweeter than sucrose). Suitable high-intensity sweeteners include aspartame, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidin dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, Magnasweet®. The total concentration of sweeteners can range from substantially zero to about 300 mg / ml, based on the liquid composition upon reconstitution.

[0271] In order to enhance the palatability of the liquid composition when reconstituted with an aqueous medium, one or more taste-masking agents can be added to the composition to mask the taste of the IBAT inhibitor. The taste-masking agent can be a sweetener, a flavoring agent, or a combination thereof. The taste-masking agent typically provides up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the present invention, the composition includes both a sweetener and a flavoring agent.

[0272] Flavoring agents herein are substances capable of enhancing the taste or aroma of a composition. Suitable natural or synthetic flavoring agents can be selected from standard reference books, such as Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of flavoring and / or sweetening agents useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois cream, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, and the like. , cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed base Lee, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Prosweet® Powder, Raspberry, Root Beer, Rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Talin, Silitol, Sucralose, Sorbitol Tall, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. The flavoring agents may be used alone or in combination of two or more. In some embodiments, the aqueous liquid dispersion includes a sweetener or flavoring agent at a concentration ranging from about 0.001% to about 5.0% by volume of the aqueous dispersion.In one embodiment, the aqueous liquid dispersion comprises a sweetening or flavoring agent at a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion comprises a sweetening or flavoring agent at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetening or flavoring agent at a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetening or flavoring agent at a concentration ranging from about 0.01% to about 0.5% by volume of the aqueous dispersion.

[0273] In certain embodiments, the pediatric pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of free acid or free base, or in the form of a pharma- ceutically acceptable salt. In some embodiments, the compounds described herein are utilized as N-oxides, or in crystalline or amorphous forms (i.e., polymorphs). In some situations, the compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in unsolvated or solvated forms, where the solvated forms include any pharma- ceutically acceptable solvent, e.g., water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.

[0274] "Carriers" for pediatric pharmaceutical compositions, in some embodiments, comprise pharma- ceutically acceptable excipients and are selected based on compatibility with the compounds described herein, such as any of the compounds of Formulae I-VI, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999); all of which are incorporated by reference in their entireties for all purposes.

[0275] Furthermore, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated as dosage forms.Thus, in some embodiments, dosage forms are provided herein that contain the compounds described herein and are suitable for administration to individuals.In certain embodiments, suitable dosage forms include, by way of non-limiting examples, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, sustained release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0276] In certain embodiments, pediatric compositions or formulations comprising one or more compounds described herein are orally administered for local delivery of an IBAT inhibitor or a compound described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets or capsules formulated for enteral delivery to the colon.

[0277] In some embodiments, the IBAT inhibitor, or other compound described herein, is administered orally with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and / or rectum).

[0278] In certain embodiments, the pediatric compositions described herein comprise an IBAT inhibitor or other compound described herein in association with a matrix (e.g., a matrix comprising hypermellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or colon. In some embodiments, the composition comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH sensitive polymers suitable for controlled release include those that contain acidic groups (e.g., -COOH, -SO 3Examples of suitable polymers for controlled release in the distal ileum include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain methacrylic acid and / or methacrylic acid esters and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the composition suitable for controlled release in the distal ileum comprises a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of an enteroendocrine peptide secretagogue to the distal ileum. In some embodiments, the dosage form containing the enteroendocrine peptide secretagogue is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, the bacterial activation system is suitable for targeted delivery to the distal part of the ileum.Examples of the microflora activation system include dosage forms that contain pectin, galactomannan, and / or Azo hydrogel and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.).Examples of the digestive tract microflora enzymes include bacterial glycosidases such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0279] The pediatric pharmaceutical compositions described herein optionally include an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a permeation enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, or one or more combinations thereof. In some aspects, a film coating is provided around the formulation of the compound of formula I using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0280] Liquid dosage forms Liquid pharmaceutical dosage forms of the present invention can be prepared according to techniques well known in the art of pharmacy.

[0281] A solution refers to a liquid formulation in which the active ingredient is dissolved in a liquid. Pharmaceutical solutions of the present invention include syrups and elixirs. A suspension refers to a liquid formulation in which the active ingredient is in precipitate in a liquid.

[0282] It is desirable for liquid dosage forms to have a particular pH and / or be maintained within a particular pH range. To control the pH, an appropriate buffer system can be used. Additionally, the buffer system must have sufficient capacity to maintain the desired pH range. Examples of buffer systems useful in the present invention include, but are not limited to, citrate buffer, phosphate buffer, or any other suitable buffer known in the art. Preferably, the buffer system includes sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. The concentration of the buffer system in the final suspension will vary depending on factors such as the strength of the buffer system and the pH / pH range required for the liquid dosage form. In one embodiment, the concentration is in the range of 0.005-0.5 w / v% in the final liquid dosage form.

[0283] Pharmaceutical compositions, including liquid dosage forms of the present invention, may also contain suspending / stabilizing agents to prevent sedimentation of the active substance. Over time, sedimentation may cause the active substance to cake on the inner walls of the product pack, making redispersion and accurate dispensing difficult. Suitable stabilizers include, but are not limited to, polysaccharide stabilizers such as xanthan, guar and tragacanth gum, as well as cellulose derivatives HPMC (hydroxypropylmethylcellulose), methylcellulose and Aviccel RC-591 (microcrystalline cellulose / sodium carboxymethylcellulose). In another embodiment, polyvinylpyrrolidone (PVP) may also be used as a stabilizer.

[0284] In addition to the aforementioned ingredients, the IBAT inhibitor oral suspension formulation may optionally contain alternative solvents, flavoring agents, antioxidants, bulking agents, acidifiers, enzyme inhibitors, and other additives as described in Handbook of Pharmaceutical Excipients, Rowe et al., Eds., 4 thThe composition may include other excipients commonly found in pharmaceutical compositions, such as those described in U.S. Pat. No. 6,313,311, published in US Pat. No. 6,252,311 and incorporated herein by reference in its entirety for all purposes.

[0285] The addition of alternative solvents can help to increase the solubility of the active ingredient in the liquid dosage form, thereby increasing its absorption and bioavailability in the subject's body.Preferably, the alternative solvents include methanol, ethanol, or propylene glycol, etc.

[0286] In another aspect, the present invention provides a process for preparing a liquid dosage form. This process includes mixing an IBAT inhibitor or a pharma- ceutically acceptable salt thereof with ingredients including glycerol or syrup or mixtures thereof, preservatives, buffer systems and suspending / stabilizing agents in a liquid medium. In general, the liquid dosage form is prepared by uniformly and homogeneously mixing these various ingredients in a liquid medium. For example, ingredients such as glycerol or syrup or mixtures thereof, preservatives, buffer systems and suspending / stabilizing agents can be dissolved in water to form an aqueous solution, and then the active ingredient can be dispersed in the aqueous solution to form a suspension.

[0287] In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 50 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.2 ml and about 40 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.5 ml and about 30 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the amount of the IBAT inhibitor may range from about 0.001% to about 90% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 0.01% to about 80% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 0.1% to about 70% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 60% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 50% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 40% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 30% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 20% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 1% to about 10% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 70% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 60% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 50% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 40% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 30% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 20% of the total volume.In some embodiments, the IBAT inhibitor may be in an amount ranging from about 5% to about 10% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 10% to about 50% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 10% to about 40% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 10% to about 30% of the total volume. In some embodiments, the IBAT inhibitor may be in an amount ranging from about 10% to about 20% of the total volume. In one embodiment, the resulting liquid dosage form has a liquid volume of 0.1 ml to 30 ml, preferably 0.1 ml to 20 ml, and the active ingredient is in an amount ranging from about 0.001 mg / ml to about 16 mg / ml, or from about 0.025 mg / ml to about 8 mg / ml, or from about 0.1 mg / ml to about 4 mg / ml, or in an amount of about 0.25 mg / ml, or about 0.5 mg / ml, or about 1 mg / ml, or about 2 mg / ml, or about 4 mg / ml, or about 5 mg / ml, or about 8 mg / ml, or about 9 mg / ml, or about 10 mg / ml, or about 12 mg / ml, or about 14 mg / ml, or about 16 mg / ml.

[0288] Bile acid sequestrants In certain embodiments, the oral formulation for use in any of the methods described herein is, for example, an IBAT inhibitor with a labile bile acid sequestrant.A labile bile acid sequestrant is a bile acid sequestrant that has an unstable affinity for bile acid.In certain embodiments, the bile acid sequestrant described herein is an agent that sequesters (e.g., adsorbs or loads) bile acid and / or its salt.

[0289] In certain embodiments, the labile bile acid sequestrant sequester (e.g., adsorb or load) bile acids and / or their salts and releases at least a portion of the adsorbed or loaded bile acids and / or their salts in the distal digestive tract (e.g., colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof). In certain embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in higher concentrations in the human colon or rectum compared to concentrations found in the small intestine. Examples of microflora activation systems include dosage forms that include pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gut microflora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase. In some embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant (i.e., the bile acid sequestrant sequesters bile acids and / or their salts and releases at least a portion of the bile acids and / or their salts after a period of time). In some embodiments, the time-dependent bile acid sequestrant is an agent that degrades over time in an aqueous environment. In certain embodiments, the labile bile acid sequestrants described herein are bile acid sequestrants that have a low affinity for bile acids and / or their salts, thereby allowing the bile acid sequestrant to continue to sequester bile acids and / or their salts in environments where the bile acids / salts and / or their salts are present in high concentrations and release them in environments where the bile acids / salts and / or their salts are present in lower relative concentrations. In some embodiments, the labile bile acid sequestrant has a high affinity for a primary bile acid and a lower affinity for a secondary bile acid, and the bile acid sequestrant sequesters the primary bile acid or salt thereof and subsequently releases the secondary bile acid or salt thereof as the primary bile acid or salt thereof is converted (e.g., metabolized) to the secondary bile acid or salt thereof.In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6 or less and a lower affinity for bile acids at a pH of greater than 6. In certain embodiments, the pH-dependent bile acid sequestrant decomposes at a pH of greater than 6.

[0290] In some embodiments, the labile bile acid sequestrants described herein include any compound, e.g., macrostructure compounds, that can sequester a bile acid / salt and / or its salt through any suitable mechanism. For example, in certain embodiments, the bile acid sequestrant sequesters a bile acid / salt and / or its salt through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, steric interactions, etc. In certain embodiments, the macrostructure compounds sequester the bile acid / salt and / or sequestrant by trapping the bile acid / salt and / or its salt in a pocket of the macrostructure compound, and optionally through other interactions such as those described above. In some embodiments, bile acid sequestrants (e.g., labile bile acid sequestrants) include, by way of non-limiting example, lignin; modified lignin; polymers; polycationic polymers and copolymers; polymers and / or copolymers comprising any one or more of N-alkenyl-N-alkylamine residues, one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkyl-azanium residues, one or more N,N,N-trialkyl-N-alkenyl-azanium residues, one or more alkenylamine residues, or combinations thereof; or any combination thereof.

[0291] Covalent binding of drug to carrier In some embodiments, strategies utilized for colon targeted delivery include, by way of non-limiting example, covalent attachment of the IBAT inhibitor or other compounds described herein to a carrier, coating the formulation with a pH sensitive polymer for delivery upon reaching the pH environment of the colon, use of redox (oxidation-reduction) sensitive polymers, use of time-released formulations, use of coatings that are specifically degraded by colonic bacteria, use of bioadhesive systems, and use of osmotically controlled drug delivery systems.

[0292] In certain embodiments of such oral administration of compositions comprising IBAT inhibitors or other compounds described herein, covalent bonds to carriers are included, and upon oral administration, the bound moieties remain intact in the stomach and small intestine. Upon entering the colon, the covalent bonds are cleaved by pH changes, enzymes, and / or degradation by intestinal microflora. In certain embodiments, the covalent bonds between IBAT inhibitors and carriers include, by way of non-limiting examples, azo bonds, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates, and amino acid conjugates (high hydrophilicity and long chain length of carrier amino acids).

[0293] Coating with polymers: pH-sensitive polymers In some embodiments, the oral dosage forms described herein are coated with an enteric coating to facilitate delivery of the IBAT inhibitor or other compounds described herein to the colon and / or rectum. In certain embodiments, the enteric coating is a coating that remains intact in the low pH environment of the stomach, but dissolves readily when the optimum dissolution pH of the particular coating is reached, which depends on the chemical composition of the enteric coating. The thickness of the coating depends on the dissolution properties of the coating material. In certain embodiments, the thickness of the coating used in such formulations described herein ranges from about 25 μm to about 200 μm.

[0294] In certain embodiments, the compositions or formulations described herein are coated so that the IBAT inhibitors or other compounds described herein of the compositions or formulations are delivered to the colon and / or rectum without being absorbed in the upper part of the intestine. In certain embodiments, specific delivery to the colon and / or rectum is achieved by coating the formulation with a polymer that degrades only in the pH environment of the colon. In alternative embodiments, the compositions are coated with an enteric coat that dissolves at intestinal pH and an outer layer matrix that slowly erodes in the intestine. In some such embodiments, the matrix slowly erodes until only the core composition comprising the enteroendocrine peptide secretagogue (and, in some embodiments, the drug absorption inhibitor) remains, and the core is delivered to the colon and / or rectum.

[0295] In certain embodiments, the pH-dependent system takes advantage of the progressively increasing pH along the human gastrointestinal tract (GIT), from the stomach (pH 1-2, rising to 4 during digestion), to the small intestine at the site of digestion (pH 6-7), and to 7-8 at the distal ileum. In certain embodiments, dosage forms for oral administration of the compositions described herein are coated with a pH-sensitive polymer to provide delayed release and protect the enteroendocrine peptide secretagogue from gastric fluids. In certain embodiments, such polymers can tolerate the lower pH values ​​of the stomach and proximal portions of the small intestine, but disintegrate at the neutral or slightly alkaline pH of the terminal ileum and / or ileocecal region. Thus, in certain embodiments, provided herein are oral dosage forms comprising a coating, the coating comprising a pH-sensitive polymer. In some embodiments, polymers used for colon and / or rectal targeting include, by way of non-limiting example, methacrylic acid copolymers, methacrylic acid and methyl methacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit L-30D, Eudragit FS-30D, Eudragit L100-55, polyvinyl acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, cellulose acetate trimellitate, cellulose acetate phthalate (cellulose acetate phthalate), and combinations thereof.

[0296] In certain embodiments, oral dosage forms suitable for delivery to the colon and / or rectum include a coating having a biodegradable and / or bacteriodegradable polymer(s) that are degraded by the microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, by way of non-limiting example, azopolymers, linear segmented polyurethanes containing azo groups, polygalactomannans, pectins, glutaraldehyde cross-linked dextran, polysaccharides, amylose, guar gum, pectins, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextran, locust bean gum, chondroitin sulfate, chitosan, poly(-caprolactone), polylactic acid, and poly(lactic-co-glycolic acid).

[0297] In certain embodiments of such oral administration of compositions comprising one or more IBAT inhibitors or other compounds described herein, the compositions are delivered to the colon without being absorbed in the upper intestine by coating the formulation with a redox (oxidation-reduction) sensitive polymer that is degraded by the colonic microflora (bacteria). In such biodegradable systems, such polymers include, by way of non-limiting example, redox sensitive polymers that contain azo and / or disulfide bonds in the backbone.

[0298] In some embodiments, compositions formulated for delivery to the colon and / or rectum are formulated for time release, hi some embodiments, the time release formulation resists the acidic environment of the stomach, thereby delaying release of the enteroendocrine peptide secretagogue until the formulation enters the colon and / or rectum.

[0299] In certain embodiments, the time-release formulations described herein include a capsule (containing an enteroendocrine peptide secretagogue and an optional absorption inhibitor) with a hydrogel plug. In certain embodiments, the capsule and hydrogel plug are covered with a water-soluble cap, and the entire unit is coated with an enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves, and the hydrogel plug swells and detaches from the capsule after a period of time, releasing the composition from the capsule. The amount of hydrogel is used to adjust the period of content release.

[0300] In some embodiments, oral dosage forms are provided herein that include multiple coatings, the coatings comprising different layers of polymers with different pH sensitivities. As the coated formulation moves along the GIT, the different layers dissolve depending on the pH encountered. Polymers used in such formulations include, by way of non-limiting example, polymethacrylates with suitable pH solubility properties, Eudragit® RL and Eudragit® RS (inner layer), and Eudragit® FS (outer layer). In other embodiments, the dosage form is an enteric coated tablet with an outer shell of hydroxypropyl cellulose or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0301] In some embodiments, provided herein are oral dosage forms comprising a coating with cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate; polymers and copolymers formed from acrylic acid, methacrylic acid, and combinations thereof.

[0302] Combination therapy In some embodiments, the methods provided herein include administering a compound (e.g., an IBAT inhibitor) or composition described herein in combination with one or more additional agents. In some embodiments, the present invention also provides compositions comprising a compound (e.g., an IBAT inhibitor) together with one or more additional agents.

[0303] Fat-soluble vitamins In some embodiments, the methods provided herein further comprise administering one or more vitamins, in some embodiments, the vitamins are vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, phylloquinone, menaquinone.

[0304] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, phylloquinone, etc. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0305] IBAT inhibitors and PPAR agonists In various embodiments, the present invention provides methods of using a combination of an IBAT inhibitor and a PPAR (peroxisome proliferator-activated receptor) agonist. In various embodiments, the PPAR agonist is a fibrate. In some embodiments, the fibrate is clofibrate, gemfibrozil, ciprofibrate, benzafibrate, fenofibrate, or various combinations thereof. In various embodiments, the PPAR agonist is aleglitazar, muraglitazar, tesaglitazar, saroglitazar, GW501516, GW-9662, a thiazolidinedione (TZD), an NSAID (e.g., IBUPROFEN), an indole, or various combinations thereof.

[0306] IBAT inhibitors and FXR drugs In various embodiments, the present invention provides methods of using a combination of an IBAT inhibitor and a farnesoid X receptor (FXR) targeted drug. In various embodiments, the FXR targeted drug is avermectin B1a, bepridil, fluticasone propionate, GW4064, gliquidone, nicardipine, triclosan, CDCA, ivermectin, chlorotrianisene, tribenoside, mometasone furoate, miconazole, amiodarone, butoconazole, bromocriptine mesylate, pizotifen malate, or various combinations thereof.

[0307] Partial External Biliary Diversion (PEBD) In some embodiments, the methods provided herein further include using partial external biliary drainage as a treatment for patients who have not yet developed cirrhosis. This treatment method helps to reduce bile acid / salt circulation in the liver to reduce complications and prevent the need for early transplant in many patients.

[0308] This surgical technique involves isolating a 10 cm long section of intestine from the rest of the intestine to be used as a bile conduit (a passageway for the passage of bile). One end of the conduit is attached to the gallbladder, and the other end is brought out to the skin to form a stoma (a surgically constructed opening to allow the passage of waste). Partial external biliary stomy may be used in patients who do not respond to all medical treatments, especially older, larger patients. This technique may not be helpful in younger patients, such as infants. Partial external biliary stomy may reduce pruritus intensity and lower blood cholesterol levels.

[0309] IBAT inhibitors and ursodiol In some embodiments, the IBAT inhibitor is administered in combination with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, tauroursodeoxycholic acid. In some instances, increasing the concentration of bile acids / salts in the distal gut induces intestinal regeneration, reduces intestinal damage, reduces bacterial translocation, inhibits the release of free radical oxygen, inhibits the production of inflammatory cytokines, or any combination thereof.

[0310] In certain embodiments, a patient receives about or at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 ... Ursodiol is administered at daily doses of 0 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, or 3,000 mg. In certain embodiments, a patient receives about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg , 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, 3,000 mg, or 3,500 mg or less per day. In various embodiments, patients are administered ursodiol at a daily dose of about or at least about 3 mg to about 300 mg, about 30 mg to about 250 mg, about 36 mg to about 200 mg, about 10 mg to about 3000 mg, about 1000 mg to about 2000 mg, or about 1500 to about 1900 mg.

[0311] In various embodiments, the ursodiol is administered as a tablet. In various embodiments, the ursodiol is administered as a suspension. In various embodiments, the concentration of ursodiol in the suspension is about 10 mg / mL to about 200 mg / mL, about 50 mg / mL to about 150 mg / mL, about 10 mg / mL to about 500 mg / mL, or about 40 mg / mL to about 60 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about or at least about 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, or 80 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about 25 mg / mL or less, 30 mg / mL or less, 35 mg / mL or less, 40 mg / mL or less, 45 mg / mL or less, 50 mg / mL or less, 55 mg / mL or less, 60 mg / mL or less, 65 mg / mL or less, 70 mg / mL or less, 75 mg / mL or less, 80 mg / mL or less, or 85 mg / mL or less.

[0312] The IBAT inhibitor and the second active ingredient are used such that the combination is present in a therapeutically effective amount. The therapeutically effective amount may result from the use of the combination of the IBAT inhibitor and the other active ingredient (e.g., ursodiol), each of which may be used in a therapeutically effective amount, or each of which may be used in a subclinical therapeutically effective amount, i.e., an amount that would be less effective for the therapeutic purpose described herein if used alone, provided that the combination is therapeutically effective due to the additive or synergistic effects resulting from the combination. In some embodiments, the use of the combination of the IBAT inhibitor and any other active ingredient described herein encompasses combinations in which the IBAT inhibitor or other active ingredient is present in a therapeutically effective amount and the other is present in a subclinical therapeutically effective amount, provided that the combination is therapeutically effective due to their additive or synergistic effects. As used herein, the term "additive effect" describes a combined effect of two (or more) pharma- ceutical active agents that is equal to the sum of the effects of each agent given alone. A synergistic effect is one in which the combined effect of two (or more) pharma- ceutically active agents is greater than the sum of the effects of each agent given alone. Any suitable combination of an IBAT inhibitor with one or more of the other active ingredients described above, and optionally with one or more other pharmacologically active substances, is considered to be within the scope of the methods described herein.

[0313] In some embodiments, the specific selection of compounds depends on the diagnosis of the attending physician and the attending physician's judgment regarding the individual's condition and the appropriate treatment protocol. Compounds are optionally administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the individual's condition, and the actual selection of compounds used. In certain instances, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment protocol is based on the evaluation of the disease being treated and the individual's condition.

[0314] In some embodiments, the therapeutically effective dosage changes when drugs are used in a combination treatment. Methods for experimentally determining the therapeutically effective dosages of drugs and other agents for use in combination therapy regimens are described in the literature.

[0315] In some embodiments of the combination therapy described herein, the dosage of the co-administered compound varies depending on the type of co-drug used, the specific drug used, the disease or condition being treated, etc. Furthermore, when co-administered with one or more biologically active agents, the compounds provided herein are optionally administered simultaneously or sequentially with the biologically active agents. In certain instances, when administered sequentially, the attending physician will determine the appropriate sequence of the therapeutic compounds described herein and the additional therapeutic agent.

[0316] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or simultaneously. When administered simultaneously, multiple therapeutic agents are optionally provided in a single, integrated form, or in multiple forms (by way of example only, either as a single pill or two separate pills). In certain examples, one of the therapeutic agents is optionally given in multiple doses. In other examples, both are optionally given as multiple doses. If not simultaneously, the timing between the multiple doses is any suitable timing, for example, more than 0 weeks to less than 4 weeks. Furthermore, the combination methods, compositions and formulations are not limited to the use of only two agents; multiple therapeutic combinations are also envisioned (including those that include more than two compounds described herein).

[0317] In certain embodiments, the dosage regimen for treating, preventing or improving the condition that is sought to be alleviated is modified according to various factors.These factors include the disorder that the subject suffers from, as well as the subject's age, weight, sex, diet and medical condition.Therefore, in various embodiments, the dosage regimen that is actually used varies and deviates from the dosage regimen described herein.

[0318] In some embodiments, the pharmaceutical agents constituting the combination therapy described herein are provided in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents constituting the combination therapy are administered sequentially, with either therapeutic compound being administered by a regimen requiring two-step administration. In some embodiments, the two-step administration regimen requires sequential administration of the active agents or spaced administration of the separate active agents. In certain embodiments, the period between the multiple administration steps varies from minutes to hours, depending on the properties of each pharmaceutical agent, such as, by way of non-limiting example, the potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

[0319] In certain embodiments, combination therapy is provided herein. In certain embodiments, the composition described herein comprises an additional therapeutic agent. In some embodiments, the method described herein comprises administering a second dosage form comprising an additional therapeutic agent. In certain embodiments of combination therapy, the composition described herein is administered as part of a regimen. Thus, the additional therapeutic agent and / or additional pharmaceutical dosage form can be applied to the patient either directly or indirectly, simultaneously or sequentially with the composition and formulation described herein.

[0320] kit In another aspect, provided herein is a kit comprising a device for oral administration and a pharmaceutical composition as described herein. In certain embodiments, the kit comprises a prefilled sachet or bottle for oral administration. In certain embodiments, the kit comprises a prefilled syringe for oral or enema administration.

[0321] Release in the distal ileum and / or colon In certain embodiments, the dosage form comprises a matrix (e.g., a matrix comprising hypromellose) that allows for controlled release of the active agent in the distal jejunum, proximal ileum, distal ileum and / or colon. In some embodiments, the dosage form comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the ileum and / or colon. Examples of such pH sensitive polymers suitable for controlled release include those that contain acidic groups (e.g., -COOH, -SC 3Examples of suitable polymers for controlled release in the distal ileum include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain a hydroxypropyl ester (H) and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the dosage form suitable for controlled release in the distal ileum comprises a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of the IBAT inhibitor to the distal ileum. In some embodiments, the dosage form containing the IBAT inhibitor is coated with an enteric polymer (e.g., an anionic polymer such as Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid or methacrylic acid esters) for site-specific delivery to the ileum and / or colon. In some embodiments, a bacterial activation system is suitable for targeted delivery to the ileum. Examples of microflora activation systems include dosage forms containing pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gastrointestinal microflora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0322] The pharmaceutical solid dosage forms described herein optionally comprise an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a permeation enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, or one or more combinations thereof. In some aspects, a film coating is provided around the formulation of the IBAT inhibitor using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0323] IBAT inhibitors can be used to prepare medicaments for the prophylactic and / or therapeutic treatment of cholestasis or cholestatic liver disease.The method of treating any of the diseases or conditions described herein in an individual in need of such treatment can comprise administering to said individual a therapeutically effective amount of a pharmaceutical composition comprising at least one IBAT inhibitor described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate. EXAMPLES

[0324] The following examples are provided to further illustrate some of the embodiments disclosed herein. The examples are intended to illustrate, but not limit, the disclosed embodiments.

[0325] Example 1. Six-year event-free survival analysis of Alagille syndrome in the GALA clinical research database and in patients treated with maralixibat Real-world evidence (RWE) analyses continue to advance natural history comparisons in rare diseases. GALA is the largest global clinical research database on Alzheimer's syndrome (ALGS). Malalixibat (MRX) is an ileal bile acid transporter inhibitor being studied in ALGS. A pre-specified analysis plan applied novel analytical techniques to compare RWE with the MRX cohort with the aim of comparing event-free survival (EFS) in patients with ALGS.

[0326] GALA contains retrospective data on clinical parameters, biochemistry and outcomes. The MRX database includes 84 ALGS patients with up to 6 years of data. EFS was defined as the time to the first event of liver decompensation (variceal bleeding, ascites requiring treatment), surgical biliary diversion, liver transplant (LT), or death. GALA was filtered to align to the main MRX eligibility criteria. Index time was determined via maximum likelihood estimation. Balance between baseline (BL) variables was assessed. Patient selection and index time were blinded to clinical outcomes. Sensitivity and subgroup analyses, as well as adjustment for covariates, were applied. Missing outcome data were censored at last contact.

[0327] Of 1,438 patients in GALA, 469 were eligible. Age, total bilirubin (TB), gamma-glutamyltransferase (GGT), and alanine aminotransferase (ALT) were balanced between the groups, and no statistical differences were observed for age, mutation, region, TB, GGT, and ALT. Median serum bile acids (sBA) in BL were significantly higher in the MRX cohort (p=0.003); 85% sBA data were unavailable in GALA. EFS rates in the MRX cohort were significantly better than those reported in GALA controls, crude 6-year EFS: 73% and 50%, respectively (Figure 1), adjusted for age, sex, TB, and ALT: HR=0.305; 95% CI: 0.189-0.491; p<0.0001. The various index times, weighted inverse probability of treatment weights, mean treatment effects across treatment groups, LT and death only, regions, sBA subgroups, and pruning events up to 12 months were consistent with the primary results.Limitations included the lack of a standardized measure of pruritus, limited sBA data in GALA, and inherent bias in patients participating in clinical trials.

[0328] This 6-year analysis suggested a possible improvement in EFS with MRX in patients with ALGS. This RWE analysis provided a potential method for evaluating outcomes in long-term interventional trials where placebo comparisons are not feasible. Limitations always exist given the lack of prospective conduct and inherent biases, but sensitivity analyses can help mitigate them and aid interpretation.

[0329] Example 2. Response to treatment with maralixibat in Alagille syndrome is associated with improved health-related quality of life Alzheimer's syndrome (ALGS) is associated with a high disease burden and reduced health-related quality of life (HRQoL) due to pruritus, growth failure, and xanthomas. There are no approved pharmacological therapies for ALGS. Malalixibat (MRX), an oral minimally absorbed inhibitor of ileal bile acid transporters, has been evaluated for the treatment of cholestatic pruritus in children with ALGS. We assessed the impact of MRX treatment response on changes in HRQoL in patients with ALGS.

[0330] We conducted a retrospective analysis of 48-week data from the phase 2 ICONIC study, a double-blind, placebo-controlled, randomized washout trial with a 4-week washout period in patients with ALGS. Patients had moderate to severe pruritus, measured using a validated caregiver-reported Itch Reported Outcomes (ItchRO) severity assessment tool (0 = none to 4 = very severe). A clinically meaningful pruritus response was defined as a decrease of ≥ 1 point on the ItchRO from baseline to week 48. HRQoL was assessed using the Pediatric Quality of Life Inventory Generic Core (PedsQL; 0-100 scale, 100 = best quality of life), Family Impact (FI), and Multidimensional Fatigue (MF) scale scores and collected via caregivers. The minimal clinically important difference (MCID) for HRQoL assessments is 5 points. A subset of individual items from the HRQoL scale was also independently selected to assess treatment response. HRQoL scores and selected variables were assessed at baseline and week 48 and stratified by treatment response status. P values ​​were calculated using t-tests or ANOVA. Multivariate linear regression models were used to evaluate the relationship between the mean change in HRQoL score from baseline (dependent variable) and measures of treatment response (independent variables), adjusting for baseline HRQoL. Adjustment for additional baseline covariates was also considered for the following variables: age, sex, bilirubin, rifampicin use, height z-score, weight z-score, ItchRO, and serum bile acids.

[0331] A total of 27 ALGS patients were included, with mean ± SD baseline age 5.7 ± 4.3 years, ItchRO score 2.90 ± 0.56, PedsQL score 59.40 ± 16.97, FI score 55.14 ± 18.61, MF score 50.95 ± 23.08, and 67% were male. Baseline patient characteristics, including HRQoL and pruritus scores, were similar between responders and nonresponders (Table 1). At week 48, 20 (74%) patients achieved an ItchRO treatment response. Responders had a greater mean HRQoL score than nonresponders (Table 2). Furthermore, responders experienced a greater mean increase in HRQoL from baseline to week 48 compared to nonresponders (Table 2).

[0332] [Table 1]

[0333] Numerically, responders had improved HRQoL measures compared with nonresponders across all scales (Table 2). Changes in Multidimensional Fatigue Total Scale scores from baseline to week 48 were significantly higher in responders compared with nonresponders (Table 2). No clinically meaningful changes were observed from baseline to week 48 across all scales in nonresponders.

[0334] This multivariate regression analysis demonstrated that ItchRO treatment response was associated with clinically meaningful improvements in HRQoL at week 48 compared with baseline. Results were strongest for FI scores; controlling for baseline FI scores, responders' scores increased by a mean of 17 points over 48 weeks compared with non-responders (p<0.05). Smaller, statistically non-significant point estimates were observed for PedsQL and MF scores. Of the 19 HRQoL items selected for individual analysis, six sleep-related items showed significantly greater change from baseline to week 48 in responders compared to non-responders: Trouble sleeping (p=0.001), Feeling tired (p=0.030), Sleeping a lot (p=0.014), Difficulty sleeping through the night (p=0.003), Feeling tired upon waking (p<0.001), and Taking a lot of naps (p=0.020).

[0335] [Table 2]

[0336] Baseline and week 48 HRQoL scores by ItchRO response status are shown in Figure 3. PedsQL Generic Core Total Scale scores (Figure 3A), Family Impact Total Scale scores (Figure 3B) and Multidimensional Fatigue Total Scale scores (Figure 3C) all indicate that ItchRO treatment response at week 48 was consistently associated with clinically meaningful improvements in all measures of HRQoL. Multivariate regression analyses demonstrated that ItchRO treatment response was associated with clinically meaningful improvements in all three measures of HRQoL from baseline to week 48.

[0337] Responders' Family Impact Scale scores increased by a mean of 16.9 points over 48 weeks compared with nonresponders, more than three times the MCID (p=0.05) (Table 3). Responders' PedsQL Generic Core Total Scale scores increased by a mean of 8.8 points (p=0.19) compared with nonresponders, nearly twice the MCID. Similarly, for Multidimensional Fatigue scores, responders had a mean total score increase of 13.9 points compared with nonresponders, more than twice the MCID (p=0.11) (Table 3). Results remained robust even after adjusting for demographic and clinical characteristics. Of the 19 HRQoL items selected for individual analysis, six sleep-related items showed significantly greater change from baseline to week 48 in responders compared with nonresponders (Table 4).

[0338] [Table 3]

[0339] [Table 4]

[0340] In conclusion, ALGS patients who experienced a pruritus response while receiving maralixibat treatment achieved, on average, greater improvements in HRQoL from baseline to week 48 compared with pruritus nonresponders. Changes in the Family Impact Scale were statistically significant and clinically meaningful using multivariate regression analysis. Improvements in the PedsQL Generic Core Scale were nearly twice the MCID. Changes in the Multidimensional Fatigue Scale were more than twice the MCID.

[0341] The significant improvements in the six sleep-related items of the HRQoL scale seen in responders versus pruritus non-responders warrant further investigation of the relationship between response to maralixibat and improvement in sleep disturbance.

[0342] These data demonstrate that the significant improvement in pruritus seen with maralixibat at week 48 in the ICONIC trial is clinically meaningful and associated with improved quality of life (QOL) for patients.

[0343] Example 3. Predictors of 6-year event-free survival in patients with Alagille syndrome treated with the IBAT inhibitor maralixibat Refractory pruritus and progression of liver disease are indications for liver transplantation (LTx) in patients with Alagille syndrome (ALGS). Predictors of long-term event-free survival (EFS) and transplant-free survival (TFS) were investigated in patients with ALGS enrolled in three clinical trials of the ileal bile acid transporter (IBAT) inhibitor maralixibat (MRX) with up to 6 years of follow-up.

[0344] MRX-treated ALGS patients from three long-term clinical trials were followed for the occurrence of clinically significant events (LTx, biliary diversion surgery [SBD], hepatic decompensation [ascites requiring treatment, and variceal bleeding], and death) for up to 6 years. TFS (LTx and death only) was also assessed. Those who received MRX for 48 weeks from first dose and had laboratory results at week 48 were included in the analysis. Variables considered in the model included: liver biochemistry, platelets, pruritus (assessed by the ItchRO(Obs) 0-4 scale), total serum bile acids (sBA), and age. Goodness of fit was assessed using Harrell's concordance statistic (C-statistic). Cutoffs were determined by grid search. P values ​​are from the log-rank test.

[0345] ALGS patients (N=76) aged 14-207 months with moderate to severe pruritus were included in this analysis. Maralixibat-treated ALGS patients from three long-term clinical trials (ClinicalTrials.gov ID: NCT02047318; ClinicalTrials.gov ID: NCT02160782; ClinicalTrials.gov ID: NCT02117713) were followed up to 6 years for the occurrence of a first clinically significant event (LT, biliary diversion surgery, hepatic decompensation [ascites requiring treatment, and variceal bleeding], or death). TFS (LT and death only) was also assessed. Patients who received maralixibat for 48 weeks from the first dose and had laboratory results after 48 weeks were included in this analysis.

[0346] Variables considered in the model included: liver biochemistry, platelets, pruritus (assessed by the Itch Reported Outcome [Observer] [ItchRO(Obs)] 0-4 scale), total sBA, and age at entry. These were examined at baseline, week 48, and change from baseline to week 48. Goodness of fit was assessed using Harrell's concordance statistic (C-statistic). Cutoffs were determined by grid search. Statistical comparisons between cutoff groups were calculated using the log-rank test.

[0347] This analysis included 76 maralixibat-treated patients with a median follow-up period of 266 weeks (range: 53-380). Baseline characteristics of patients are shown in Table 5.

[0348] [Table 5]

[0349] Sixty of the 76 patients remained event-free at the time of analysis. Sixteen patients experienced clinical events: LT (n=10), decompensation (n=3), death (n=2), and biliary diversion (n=1). Variables predictive of EFS included: total bilirubin at week 48, sBA at week 48, change from baseline to week 48 in pruritus (ItchRO[Obs]), and age at initiation of maralixibat (Table 6; Figure 2).

[0350] [Table 6]

[0351] The four variables identified as predictors of EFS had high C-statistics over time, indicating that these cutoffs were stable predictors for an additional 2 to 5 years after 48 weeks of maralixibat treatment. These four variables and cutoffs were similarly predictive for TFS.

[0352] Fifty-nine (79.7%) patients had two or fewer predictors of poor EFS at the end of 48 weeks of maralixibat treatment (Table 7). The 6-year EFS rate in this group was 88%. Fifteen (20.3%) patients had three or more predictors of poor EFS. The 6-year EFS rate in this group was 31%.

[0353] [Table 7]

[0354] In patients with ALGS, predictors of EFS with maralixibat treatment included (Figures 2A-2D): total bilirubin and sBA (both at week 48); reduction in pruritus (baseline to week 48); and age at initiation of maralixibat. Pruritus is a frequent indication for liver transplantation (LT) in patients with ALGS, and the data demonstrated that improvement in pruritus with maralixibat was significantly associated with improved event-free survival (EFS) and transplant-free survival (TFS). The data identified potential prognostic markers that may better inform patient / provider discussions about clinical outcomes in patients undergoing maralixibat treatment.

[0355] Example 4. Serum bile acid (sBA) control in patients treated with long-term maralixibat correlates with native liver survival in children with progressive familial intrahepatic cholestasis (PFIC) due to bile salt export pump (BSEP) deficiency Children with progressive familial intrahepatic cholestasis (PFIC) due to bile salt export pump (BSEP) deficiency present with debilitating pruritus, short stature, and progressive liver disease. The NAPPED study (NCT03930810) shows that although approximately 50% of patients undergo liver transplantation by age 10, patients who achieve serum bile acid (sBA) levels of <100 μmol / L after partial external biliary diversion show improved autologous liver survival, as well as reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin.

[0356] Malalixibat (MRX) is an ileal bile acid transporter (IBAT) inhibitor approved for the treatment of pruritus in patients with Alagille syndrome aged 1 year and older and is being evaluated in patients with PFIC. MRX blocks enterohepatic recirculation and reduces pruritus and cholestasis and improves growth at 72 weeks in an open-label, long-term study (INDIGO; NCT02057718). This example describes treatment of a patient with PFIC with MRX for >4.5 years.

[0357] MRX was administered at 280 μg / kg once daily for 48 weeks, increasing to 280 μg / kg twice daily in the extension. NAPPED sBA thresholds (≦100 μmol / L) were applied in patients remaining on study for >4.5 years. Transaminases, bilirubin, and growth were assessed through 237 weeks.

[0358] Of patients (n=19) with non-truncating BSEP mutations enrolled (median age 4.1 years, range 1-13 years; 32% male), 7 achieved sBA control and remained on study at week 237. The mean (SE) reduction in sBA was 234.4 (80.5) μmol / L (p<0.05), with a mean of 44.2 (38.8) μmol / L (baseline [BL] 299.6 μmol / L). The mean reductions in AST and ALT were 35.4 (11.5) and 41.1 (14.3) U / L, with a mean of 26.7 (62.1 at BL) and 16.7 (57.9 at BL), respectively (both p<0.05). The mean reduction in total and direct bilirubin was 0.1 (0.3) and 0.4 (0.2) mg / dL, respectively, with mean values ​​of 0.7 (0.8 in BL) and 0.1 (0.6 in BL), respectively (p=0.8 and 0.13). Those with abnormal bilirubin normalized. No ongoing patients were eligible for liver transplantation after >4.5 years of MRX. Growth (height z score; p<0.01) and pruritus (p<0.001) improved significantly. Long-term MRX was safe and well tolerated; the most common treatment-emergent adverse events were mild to moderate in severity.

[0359] Patients who achieved control of sBA during MRX treatment had autologous liver survival of more than 4.5 years, improved liver biochemistry, and improved growth, suggesting the disease-modifying potential of MRX. These data support MRX as a potential alternative to surgery for children with PFIC due to non-truncated BSEP deficiency.

[0360] Example 5. Treatment response to maralixibat is associated with improved health-related quality of life in patients with BSEP deficiency Bile salt export pump (BSEP) deficiency is the most common genetic cause of progressive familial intrahepatic cholestasis (PFIC). This disease adversely affects patients' health-related quality of life (HRQoL). Malalixibat (MRX) is an oral, minimally absorbed inhibitor of the ileal bile acid transporter (IBAT) that was recently approved for the treatment of pruritus in patients with Alagille syndrome aged 1 year and older and is under evaluation in patients with PFIC. This study evaluated the impact of MRX treatment response on HRQoL in patients with BSEP deficiency.

[0361] This retrospective analysis included data from patients with BSEP deficiency from the INDIGO phase 2 open-label trial of MRX in children with PFIC. Pruritus was measured using the validated caregiver-reported Itch Reported Outcomes (ItchRO) severity assessment tool (0=none to 4=very severe). Serum bile acid (sBA) response with MRX was defined as a reduction of >75% from baseline or a decline from baseline to <102 μmol / L from week 48. HRQoL was assessed using the Pediatric Quality of Life Inventory Generic Core (PedsQL), Family Impact (FI), and Multidimensional Fatigue (MF) scale scores and was collected by caregivers. The minimal clinically important difference (MCID) for HRQoL assessments is 5 points. A subset of individual items from the HRQoL scale was also selected for assessment by treatment response. HRQoL was assessed at baseline and week 48, and scores were stratified by treatment response. p values ​​were calculated using t tests or ANOVA.Multivariate linear regression models were used to assess the relationship between the mean change from baseline in HRQoL scores and measures of treatment response, adjusting for baseline HRQoL.

[0362] Twenty-two patients from the INDIGO trial of PFIC2 had available HRQoL data at week 48 and were included in this analysis (patient baseline characteristics are shown in Table 8 below).

[0363] [Table 8]

[0364] At week 48, six patients (28.6%) achieved a treatment response; one patient's sBA response status at week 48 was unknown and therefore was excluded; 15 participants did not meet the criteria for sBA response and were classified as nonresponders. Baseline HRQoL was lower in the responder group than in the nonresponders. Other baseline characteristics were similar between the two groups.

[0365] Mean HRQoL scores by treatment-reported status are presented in Table 9 below.

[0366] [Table 9]

[0367] Twenty-two patients with BSEP deficiency were included, with mean ± SD baseline age of 4.7 ± 3.4 years, sBA of 359.18 ± 148.76 μmol / L, ItchRO(Obs) score of 2.20 ± 0.86, PedsQL score of 64.34 ± 13.54, FI score of 61.22 ± 15.75, and MF score of 60.87 ± 22.78; 31.8% were male. At 48 weeks, six patients achieved a treatment response, and baseline HRQoL was lower in the responder group than in nonresponders. Responders experienced greater changes from baseline to 48 weeks across all HRQoL measures versus nonresponders (Table). Multivariate regression analysis found that sBA response at 48 weeks was associated with clinically meaningful improvements in HRQoL from baseline to 48 weeks. Adjusting for baseline scores, sBA responders' PedsQL scores increased by a mean of 17 points over 48 weeks versus nonresponders (p=0.012), and MF scale scores increased by a mean of 22 points versus nonresponders (p=0.037). Nonsignificant differences were observed for FI scores. Five of 10 preselected individual HRQoL items, primarily related to sleep, showed significant changes from baseline to 48 weeks in sBA responders versus nonresponders: feeling tired during the day (p=0.032), worrying about how their child's illness is affecting other family members (p=0.004), difficulty sleeping through the night (p=0.002), feeling tired on waking in the morning (p=0.005), and taking frequent naps (p=0.004).

[0368] Responders experienced improvements from baseline to week 48 across all HRQoL measures compared to non-responders. Statistically significant differences between responders and non-responders were observed in PedsQL Generic Core and Multidimensional Fatigue scores (Table 9 above). The change in Family Impacte score from baseline to week 48 for responders was clinically significant at >1.5 times the MCID, while the difference between responders and non-responders was not statistically significant.

[0369] Adjusting for baseline PedsQL Generic Core Total Scale scores, multivariate regression analysis found that sBA responders' scores increased by a mean of 17 points over 48 weeks compared with nonresponders, more than three times the MCID (p<0.05) (Table 10). Similarly, on the Multidimensional Fatigue Scale, responders' total scores increased by a mean of 22 points compared with nonresponders (p<0.05). Smaller, non-statistically significant differences were observed for Family Impact Total Scale scores.

[0370] Five of 10 individual HRQoL items in the PedsQL Family Impact Scale showed significant change from baseline to week 48 in sBA responders compared with non-responders: feeling tired during the day (p=0.03); worrying about how their child's illness is affecting other family members (p<0.01); difficulty sleeping through the night (p<0.01); feeling tired on waking (p<0.01); and taking frequent naps (p<0.01).

[0371] [Table 10]

[0372] Significant differences were found in PedsQL Generic Core Total Scale and Multidimensional Fatigue Total Scale scores, with mean (standard deviation) change in score from baseline to week 48 being 20.3 (17.7) and 35.8 (15.1) for responders compared with -0.8 (10.9) and 0.7 (16.7) for non-responders; p=0.01 and p<0.01, respectively.

[0373] Compared with non-responders, more responders experienced a ≥ 5-point change in PedsQL Generic Core Total Scale score (80.0%* vs. 15.4%; p = 0.02). A ≥ 10-point change in PedsQL Multidimensional Fatigue Total Scale score was experienced by all responders (100%) and two non-responders (16.7%).

[0374] HRQoL scores at baseline and week 48 by sBA response status are shown in Figure 4. PedsQL Generic Core Total Scale scores (Figure 4A), Multidimensional Fatigue Total Scale scores (Figure 4B), and Family Impact Total Scale scores (Figure 4C) all indicate that sBA treatment response at week 48 for individual patients was strongly associated with clinically meaningful improvements in PedsQL Generic Core Total Scale Score and Multidimensional Fatigue Total Scale scores (Figure 4). * One patient and three patients, respectively, had missing data on these metrics.

[0375] MRX treatment response at 48 weeks in patients with BSEP deficiency, as measured by sBA and pruritus, is associated with statistically significant and clinically meaningful improvements in HRQoL across multiple dimensions.

[0376] Patients with BSEP deficiency (PFIC2) who responded to maralixibat treatment had statistically significant and clinically meaningful improvements in HRQoL (PedsQL Generic Core Total Scale score, Multidimensional Fatigue Total Scale score). Clinically meaningful improvements were also found in Family Impact Total Scale score. Statistically significant improvements were also seen in sleep and fatigue measures in maralixibat responder patients compared to non-responders.

[0377] This analysis demonstrates that maralixibat treatment response at week 48, as measured by sBA, in patients with BSEP deficiency (PFIC2), is associated with statistically significant and clinically meaningful improvements in HRQoL across multiple dimensions.

[0378] Example 6: Longitudinal serum bile acid profiling by UHPLC-MS / MS predicts relief of cholestatic pruritus in maralixibat-treated patients with bile salt export pump deficiency Progressive familial intrahepatic cholestasis (PFIC) due to bile salt export pump (BSEP) deficiency is a distressing disease manifested by intractable pruritus, growth retardation, and ultimately liver failure. Bile acids have long been implicated in the pathogenesis of pruritus, but the exact role they play is unclear. Malalixibat (MRX) is a nonabsorbable apical sodium-dependent bile acid (BA) transport inhibitor that interferes with the enterohepatic circulation of BAs. It was recently FDA approved for the treatment of pediatric cholestasis-associated pruritus due to its ability to reduce the accumulation of circulating and hepatic BAs. Not all patients respond to treatment, and the reasons for this are unclear. This example describes a targeted metabolomics approach to explore the association between the bile acid metabolome and cholestatic pruritus and its potential to predict relief of pruritus in response to MRX treatment.

[0379] Total and individual serum BAs (sBAs), including the major subspecies of TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA, as well as 7α-hydroxy-4-cholesten-3-one (sterol-C4), a surrogate marker of BA synthesis, were measured using a validated ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS / MS) assay. A cocktail of internal deuterium-labeled standards was added to serum, calibrators, and QC samples. sBAs were extracted and separated by gradient elution on a Kinetex C18 (2.6 μm, 100 × 3.0 mm) column (Phenomenex, Torrance, CA). Quantification of individual sBAs was performed by multiple reaction monitoring (MRM) of selected transitions. Total C24 bile acid concentrations were calculated from the sum of the individual species. We applied these assays to the analysis of serum from 19 patients with genetically confirmed PFIC due to BSEP deficiency treated with MRX (open-label, phase 2 INDIGO study; NCT02057718). Changes in the composition of sBA associated with improvement in pruritus, as measured by observer-reported outcomes (ItchRO[Obs] scores, were monitored at intervals over 72 weeks, and pruritus responders, defined as a reduction of ≥1 scale, were compared with non-responders. We also modeled the longitudinal profile of sBA and pruritus reduction over time using a linear mixed model framework.

[0380] Of 19 patients, 11 met criteria for a pruritic response, which correlated with a decrease from baseline in total sBAs that was significantly greater in the longitudinal data than in nonresponders (p<0.05). Changes were also observed in individual BA subtypes. Decreases in glycine- and taurine-conjugated cholic acid (TCA) were associated with a reduction in pruritus after MRX treatment and correlated with the percentage reduction in ItchRO(Obs) scores (Pearson correlation coefficients: 0.58, 0.50, and 0.53 for TCA, glycocholic acid, and total cholic acid [CA], respectively). A trend toward an increased proportion of unconjugated BAs was observed in responders (9.84±4.87%) compared with nonresponders (0.61±0.24%, p=0.09). More importantly, changes in longitudinal sBA profiles, including GUDCA, GCDCA, and TCDCA, were significantly correlated with reduction in pruritus (χ 2 = 13.35, P < 0.001; χ 2 = 12.86, P < 0.001; χ 2 = 19.50, P < 0.001). A concomitant increase in serum sterol-C4 was observed in pruritus responders (χ 2 = 4.70, P < 0.05), consistent with the biological action of MRX in blocking intestinal reabsorption of bile acids.

[0381] Targeted analysis of the bile acid metabolome by mass spectrometry revealed significant changes associated with the pruritic response to MRX therapy in children with BSEP deficiency, and measurement of serum sterol-C4 further confirmed the efficacy of the drug. These findings provide further interpretation regarding the BA subspecies profile associated with relief of cholestasis and pruritus, and strengthen the data demonstrating that MRX is an effective pharmacotherapy for BSEP deficiency.

[0382] Example 7: Pruritus intensity is associated with cholestatic biomarkers and quality of life measures after maralixibat treatment in children with Alagille syndrome Previously, absolute values ​​of pruritus intensity and cholestatic biomarkers have been shown to correlate poorly in children with ALGS. This study evaluates how changes in pruritus intensity correlate with changes in cholestatic biomarkers in children with ALGS who received maralixibat (ICONIC trial; NCT02160782, supra).

[0383] The goal of this study was to characterize the correlation between pruritus, as measured by the Itch Reported Outcomes (Observer) (ItchRO) tool, and various parameters, including sBA and sBA subspecies, autotaxin (ATX), and quality of life measures, following maralixibat treatment in children with ALGS.

[0384] Of the 31 participants enrolled, 29 completed 48 weeks of treatment, and 27 were evaluable for this analysis. Baseline characteristics of the analysis population are shown in Table 11.

[0385] [Table 11]

[0386] As shown in Table 12, at 48 weeks, statistically significant correlations with ItchRO score included CSS score, sBA, growth (height z-score), and ATX, and trended toward significance with PedsQL™ Family Impact Total Scale (PedsQL™ Impact) score.

[0387] Taurocholic acid (TCA) and glycocholic acid (GCA) also showed significant correlation with pruritus in patients with ALGS (Table 12). A statistically significant correlation was also observed between ItchRO and PedsQL™ Multidimensional Fatigue Scale (PedsQL™ Fatigue) scores as change from baseline to week 48 (r=-0.59, p=0.0053; Table 12).

[0388] [Table 12]

[0389] The overall mean ItchRO score reduction was 1.6 points at Week 48. Proportional increases in sBA reduction beyond 50% appear to be associated with greater ItchRO score reduction (Table 13 below). One participant normalized with an ItchRO score reduction of -3.5 points.

[0390] [Table 13]

[0391] Malalixibat treatment in ALGS study participants resulted in significant and clinically meaningful improvements in pruritus using ItchRO and CSS scores. Reductions in sBA correlated with reduced pruritus intensity, further supporting a causal relationship between the two. Significant correlations were also observed with ATX and height z scores, and there was a trend toward significance with PedsQL™ Impact scores. When assessed as change from baseline to week 48, pruritus correlated significantly with PedsQL™ Fatigu scores, suggesting improved sleep accompanied by reduced pruritus.

[0392] Overall, the positive treatment effect of maralixibat in patients with ALGS demonstrates significant correlations with various clinically relevant parameters at 48 weeks.

[0393] Example 8: Maralixibat for the treatment of progressive familial intrahepatic cholestasis: A long-term, open-label, phase 2 study Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiencies, suffer from debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Dependence on surgical interventions, including liver transplantation, highlights an unmet therapeutic need. INDIGO was an open-label, phase 2, international, long-term study evaluating the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiency, conducted in 12 hospitals. Thirty-three patients aged 12 months to 18 years were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency; six had biallelic, protein truncating mutation (t)-BSEP, and 19 had ≥1 non-truncating mutation (nt)-BSEP. Patients received maralixibat 266 μg / kg orally once daily from baseline through week 72, after which twice-daily dosing was permitted. Long-term efficacy was determined at week 240. During the study, serum bile acid (sBA) response (>75% sBA reduction from baseline or sBA concentration <102.0 μmol / L) was achieved in seven patients with nt-BSEP (six during once-daily dosing and one after switching to twice-daily dosing). sBA responders showed significant reductions in sBA and pruritus, as well as increases in height, weight, and QoL. All sBA responders remained liver transplant-free >5 years later. No patients with FIC1 or t-BSEP deficiency met sBA responder criteria during the study. Maralixibat was generally well tolerated throughout the study.

[0394] Response to maralixibat was dependent on PFIC subtype; 6 of 19 patients with nt-BSEP experienced a rapid and sustained decline in sBA levels. Seven responders were alive with autologous liver at last follow-up and experienced clinically significant relief of pruritus as well as meaningful improvements in growth and QoL. The results indicate that maralixibat is a well-tolerated alternative to surgical intervention.

[0395] Most forms of PFIC are caused by mutations in transporters expressed in the canalicular membrane of hepatocytes. Two of the major forms of PFIC, bile salt export pump (BSEP) deficiency or familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiency, were included in this study. BSEP deficiency (or PFIC type 2) is caused by mutations in ATP-binding cassette subfamily B member 11 (ABCB11). BSEP is the major bile acid transporter from hepatocytes to the bile canaliculi, and BSEP deficiency is the most common PFIC type. The majority of patients with BSEP deficiency have at least one nonprotein truncating mutation (nt-BSEP) with the possibility of some residual BSEP function, but approximately 15% have two mutants predicted to cause protein truncation (truncated BSEP [t-BSEP]), resulting in the absence of BSEP function. FIC1 is encoded by P-type ATPase phospholipid transporting 8B1 (ATP8B1), a lipid transporter expressed in multiple epithelia, including the bile canalicular membrane. FIC1 deficiency (or PFIC1 type) is associated with extrahepatic manifestations, including chronic diarrhea, pancreatic insufficiency, renal tubular dysfunction, and growth failure.

[0396] Here, we present data from INDIGO (Open-Label Study of the Efficacy and Long-Term Safety of LUM001 in the Treatment of Cholestatic Liver Disease in Pediatric Patients with Progressive Familial Intrahepatic Cholestasis; LUM001-501; NCT02057718), an open-label phase 2 study of the long-term efficacy and safety of maralixibat in children with BSEP or FIC1 deficiency. INDIGO investigated the effect of maralixibat on sBA levels and cholestatic pruritus, along with other biochemical markers of cholestasis and liver disease in these patients.

[0397] INDIGO was an open-label, phase 2, international, long-term, multicenter study designed to evaluate the efficacy and safety of maralixibat (previously known as LUM001-501 or SHP625) in children with FIC1 or BSEP deficiency. The study was conducted in 12 hospitals in France, Poland, the UK, and the USA. Screening assessments were performed 6 weeks before study initiation. Genetic testing was performed in patients without documented ATP8B1 or ABCB11 mutations. The study included an initial maralixibat dose-escalation period, followed by a long-term stable treatment period (up to 266 μg / kg maralixibat orally once daily [equivalent to 280 μg / kg maralixibat chloride, hereafter referred to as "266 μg / kg"]). An amendment to the study protocol allowed for an increase in dose to 266 μg / kg twice daily if the prespecified sBA and pruritus benefits were not achieved by week 72, as well as transition to a long-term extension period of the study.

[0398] The primary efficacy endpoint was the change in mean fasting sBA levels from baseline to week 13 in the entire intent-to-treat (ITT) study population. The key secondary efficacy endpoint was the mean change in observer-assessed pruritus (Itch Reported Outcomes (Observers) [ItchRO(Obs)]) score from baseline to week 13 in the entire ITT study population. Other secondary efficacy endpoints included the mean change from baseline to week 13 in total cholesterol, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and serum triglyceride levels in the entire ITT study population. Further efficacy and safety analyses included changes from baseline to weeks 72 and 240 in sBA levels, patient height and weight, bile acid synthesis (determined by the ratio of sBA levels to 7α-hydroxy-4-cholesten-3-one [7α-C4] levels), quality of life as measured by the Pediatric Quality of Life Inventory™ (PedsQL™), mean changes in ALT, aspartate aminotransferase (AST), and bilirubin (total and direct bilirubin), lipid profile, and FSV levels. ItchRO assessments were not performed at week 72, so data from week 48 were used instead.

[0399] Efficacy and safety analyses were performed for the entire ITT study population and separately for the two PFIC subtypes (FIC1 deficiency and BSEP deficiency). Patients with BSEP deficiency were analyzed overall and by variant type (t-BSEP and nt-BSEP). Long-term changes in pruritus scores, patient height, blood lipids, liver parameters, and transplant-free survival were evaluated according to the responder analysis. Analyses were performed at week 72 (due to the natural break between the two main periods of the study) and week 240 (selected to provide long-term data while minimizing the impact of small patient numbers and missing data observed at later time points).

[0400] Quantitative analysis of the 15 major sBAs and serum 7α-C4 was performed at a single institution (Cincinnati) by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry (LCMS / MS) using a fully validated proprietary assay that complies with the College of American Pathologists / Clinical Laboratory Improvement Amendments certification. The study protocol defined a composite response to maralixibat as achieving a ≥1.0 point reduction in the ItchRO(Obs) score and a ≥70% reduction or normalization of sBA levels from baseline. Following publications reporting improved transplant-free survival in individuals who achieved a >75% reduction in sBAs from baseline or a concentration of <102.0 μmol / L after surgical interruption of the enterohepatic circulation, we modified the threshold to use this new definition in the post-hoc responder analysis for this study. Regardless of the definition, the number of responders remained the same. Pruritus was measured using the ItchRO tool, which was specifically developed and validated to assess pruritus in children with cholestatic liver disease based on a 5-point scale of 0 = "none" and 4 = "very severe." This tool has been shown to detect clinically relevant changes in cholestatic pruritus in children across all ages, with a change of ≥ 1.0 points being clinically meaningful. ItchRO measurements were completed twice daily via eDiary. Parents / caregivers completed the ItchRO(Obs) assessment for all patients. In addition, children aged 9 years and older completed the ItchRO(Pt) assessment. ALT, AST, bilirubin (total and direct bilirubin), lipids, and FSV levels were assessed using standard clinical laboratory techniques. Quality of life was assessed using the PedsQL™ questionnaire. The minimal clinically important difference in child-reported and parent / caregiver-reported scores was a change of 4.4 or 4.5 points in the Total Scale Score, respectively. The occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) was assessed throughout the study.

[0401] Thirty-seven patients were screened between February 2014 and July 2015. Three patients had low sBA (sBA < 3 × ULN (8.5 μmol / L)) and one participant had an elevated INR, which were not included in the study. Thirty-three patients were enrolled; a total of eight (24%) had FIC1 deficiency and 25 (76%) had BSEP deficiency (six had t-BSEP and 19 had nt-BSEP; Figure 5). Of the 33 patients enrolled: all completed study treatment through week 13; 22 (67%) completed study treatment through week 72 (six had FIC1 deficiency and 16 had BSEP deficiency); 11 (33%) discontinued treatment. Eighteen patients agreed to continue study treatment beyond week 72; six patients discontinued during this period (Figure 5). The mean study week when dose escalation to 266 μg / kg twice daily occurred was 110 weeks (range 94-152 weeks). At the end of the study (week 240), a total of 12 patients had been on maralixibat treatment for >4 years each.

[0402] Both short-term (13 weeks) and long-term (up to 72 weeks) efficacy results are described below. Notable differences in short-term and long-term efficacy results were observed between disease subtypes, with patients with nt-BSEP deficiency showing significant improvements in various parameters (shown below).

[0403] Within the entire ITT study population (all 33 enrolled patients; PFIC1 and PFIC2 combined), there was no significant decline in sBA levels from baseline to week 13 (-16.9 μmol / L [95% confidence interval (CI) -74.830, 41.070; P = 0.884]). However, pruritus improved significantly by week 13 in the ITT population, with a mean reduction from baseline of -0.8 (95% CI -1.04, -0.53; P < 0.001) in ItchRO(Obs) score and -1.0 (95% CI -1.55, -0.47; P = 0.002) in ItchRO(Pt) score.

[0404] Patients with BSEP deficiency responded differently to treatment as expected depending on disease type, with patients with nt-BSEP (n=19) showing the greatest response. During the study, sBA response (>75% reduction in sBA from baseline or concentration <102.0 μmol / L) was achieved by a subset of seven patients (37%) with nt-BSEP (hereafter referred to as "sBA responders"). These sBA responders showed significant and sustained reduction in sBA, as well as reduction in pruritus and other parameters. Six achieved a response while receiving 266 μg / kg once daily, and one achieved a response while receiving 266 μg / kg twice daily after week 97. No patient with t-BSEP met sBA responder criteria at any time during the study, and all patients with t-BSEP discontinued before week 240. The following results summarize the long-term efficacy for all patients with BSEP deficiency and summarize the data for sBA responders vs. sBA non-responders.

[0405] Baseline serum ALT, AST, total and direct bilirubin, cholesterol, and triglycerides were all significantly lower in responders than in nonresponders. Changes in mean sBA levels are shown in Figure 6. Compared to baseline, sBA levels in sBA responders declined rapidly (within 2-4 weeks) upon initiating treatment, with a mostly sustained response maintained long-term throughout the study (Figure 6A). This pattern of response was not observed in sBA nonresponders (Figure 6B).

[0406] The change in mean ItchRO(Obs) score is shown in Figure 7. All seven sBA responders experienced a clinically meaningful reduction in ItchRO(Obs) score of >1.0 points after achieving an sBA response (Figure 7A), and three additional sBA nonresponders achieved clinically meaningful reductions in ItchRO(Obs) score (Supporting Figure 7B).

[0407] The changes in mean height and weight z scores are shown in Figure 8. sBA responders had a progressive increase in mean height and weight z scores from baseline to week 72 (0.67, 95% CI 0.369, 0.976; P = 0.0016 and 0.30, 95% CI -0.001, 0.603; P = 0.051, respectively, which was maintained through week 240; Figure 8A and Figure 8B). This growth benefit contrasted with the decrease in height and weight z scores in sBA non-responders when assessed at week 72 (0.49, 95% CI -0.948, -0.041; P < 0.001 vs. sBA responders, and -0.30, 95% CI -0.606, -0.012; P = 0.013 vs. sBA responders, respectively).

[0408] The change in mean PedsQL™ score is shown in Figure 9. A clinically meaningful improvement in mean PedsQL™ score was observed among sBA responders upon initiation of treatment and was consistently maintained throughout the study (change from baseline to week 240: 24 points, 95% CI 6.7, 40.6; P=0.014; Figure 9).

[0409] Biochemical assessments are shown in Figure 10. sBA responders experienced improvement and / or normalization of serum ALT, AST, and bilirubin levels (if elevated at baseline; Figure 10). With treatment with maralixibat, mean serum 7α-C4 levels increased in patients with nt-BSEP, increasing progressively throughout the study and reaching statistical significance at week 240 (+26.29 ng / mL, 95% CI 4.07, 48.50; P=0.027).

[0410] Evidence of biological response after treatment can be assessed by examining the increase in bile acid synthesis reflected by an increase in serum 7α-C4. When combined with a decrease in sBA, the 7α-C4 / sBA ​​ratio compared to baseline is a sensitive marker of biological response. The 7α-C4 / sBA ​​ratio in patients with BSEP deficiency generally increased compared to baseline in sBA responders, in contrast to sBA nonresponders (Figure 11). Of note, the 7α-C4 / sBA ​​ratio in the seventh sBA responder fluctuated during once-daily dosing but showed a clear increase when twice-daily dosing was initiated.

[0411] All sBA responders demonstrated transplant-free survival after receiving maralixibat for >5 years, compared with none of the sBA nonresponders (P<0.001; Figure 12). Two sBA responders who were candidates for liver transplantation (for the indication of refractory pruritus) at the start of the study improved sufficiently to be removed from the transplant waiting list.

[0412] Data describing additional long-term efficacy analyses in FIC1-deficient patients show that mean levels of sBA, ItchRO(Obs) scores, and PedsQL™ scores did not change significantly from baseline. No FIC1-deficient patients met sBA responder criteria over the course of the study. Four FIC1-deficient patients continued to receive the study drug, likely due to receiving some pruritus benefit.

[0413] Throughout the study, maralixibat was generally safe and well tolerated (Figure 5). All patients experienced one or more TEAEs, most of which were mild or moderate (58%) and transient. The most common TEAEs were fever (20 [61%] patients), diarrhea (19 [58%] patients), and cough (18 [55%] patients). Eight patients (one with FIC1 deficiency and seven with BSEP deficiency) discontinued maralixibat due to adverse events during the study (four due to a non-serious event of increased serum bilirubin; one due to a non-serious event of pancreatitis; one due to a non-serious event of decreased vitamin E; one due to a non-serious event of pruritus; and one due to a non-serious event of a liver mass [reported as a grade 1 event of a liver nodule, which led to the patient subsequently undergoing liver transplantation]). Patients with pancreatitis were reported to have a history of pancreatitis occurring within 2 years prior to starting maralixibat (3 previous episodes). A total of 15 patients had serious TEAEs reported during the study, of which abdominal pain, diarrhea, and gastroenteritis were the only SAEs reported in more than one patient (2 patients each). No deaths were reported during the study.

[0414] This study reports the results of up to 5 years of treatment with maralixibat, a minimally absorbed IBAT inhibitor with the potential to mimic the effects of partial external biliary diversion, in children with FIC1 or BSEP deficiency. The study did not meet the primary endpoint of sBA reduction in the entire ITT study population over the first 13 weeks of treatment; however, importantly, the response to treatment was found to be dependent on the different PFIC subtypes. A group of 7 patients (37%; 7 / 19) with nt-BSEP (considered treatment sBA responders) experienced a sustained, clinically relevant, and statistically significant response with improvement in multiple parameters. In addition to the reduction in sBA levels, the response included a ≥ 1.0 point reduction in the ItchRO(Obs) score, improvement in serum transaminases and bilirubin, and improvement in quality of life and growth parameters. Notably, these patients have remained transplant-free and partial external biliary diversion-free for more than 5 years. These findings are consistent with those of the NAPPED Consortium on SBD, which showed that lowering threshold sBA after SBD resulted in similar biochemical and long-term outcomes and improved natural history benefit.

[0415] In contrast to all sBA responders with at least one non-protein truncating mutation within ABCB11, none of the six patients with t-BSEP achieved an sBA response. These observations strongly suggest that residual BSEP function is necessary for maralixibat response. This contention is strongly supported by the differences seen in baseline biochemistry, with lower levels of bilirubin, liver enzymes, and lipids seen in the subsequent responders. All these parameters suggest a milder degree of cholestasis, consistent with a greater degree of preserved BSEP function. There were sBA non-responders in patients with nt-BSEP. Although it is possible that these patients had insufficient BSEP function, other factors may have determined the lack of response. These factors may include the degree to which the farnesoid X receptor (FXR) controls bile acid synthesis, the level of IBAT expression, the dose of maralixibat, and even the low intestinal fluid volume. It is not immediately clear why the patients with FIC1 deficiency in this study did not respond to maralixibat. The factors mentioned above may also have played a role. Furthermore, the decrease in FXR expression observed in these patients may lead to an increase in ASBT expression, which would result in the need for higher doses of maralixibat in this subgroup.

[0416] The 7α-C4 / sBA ​​ratio increased rapidly in sBA responders upon initiation of treatment and persisted throughout the study, suggesting that this ratio may be a sensitive predictor of response to treatment with maralixibat, better than changes in serum 7α-C4 alone. The seventh sBA responder had a fluctuating 7α-C4 / sBA ​​ratio during once-daily dosing, but it clearly increased with twice-daily dosing, and thus became an sBA responder. Correspondingly, several patients who discontinued at this stage had 7α-C4 / sBA ​​ratios similar to those of the sBA responders, suggesting that these patients may respond similarly if they received twice-daily dosing. Thus, the 7α-C4 / sBA ​​ratio may be used to identify sBA nonresponders who would benefit from dose escalation.

[0417] Maralixibat was generally well tolerated in patients with PFIC after up to 5 years of treatment, even in patients receiving twice-daily dosing. Twelve patients discontinued treatment with maralixibat due to adverse events or liver transplantation after disease progression, which was not unexpected given the progressive nature of PFIC. The majority of TEAEs reported during the study were mild-to-moderate, transient gastrointestinal TEAEs, likely due to increased colonic bile acid flux after IBAT inhibition, and did not result in treatment discontinuation. These results were consistent with the safety profile observed in previous studies of maralixibat.

[0418] Treatment with maralixibat did not have any significant adverse effects on FSV or liver transaminase levels. Limitations of this study include the lack of a placebo-controlled component and the relatively small sample size. Given the rare nature of PFIC and the dramatic treatment effect on sBA responders who avoided possibly life-threatening surgery, these findings are considered highly relevant and clinically significant. The primary endpoint was based on response in the entire cohort. However, it is now clear that there was a dichotomous response to treatment, and thus a responder analysis would have been more appropriate. Finally, the open-label design limits some of the conclusions that can be drawn from this study in the absence of a control group, although it would not have been feasible to generate placebo-controlled data >5 years. The absence of a control group is mitigated by the dramatic and sustained treatment effect seen in sBA responders compared to baseline.

[0419] In conclusion, this study demonstrates that maralixibat can produce a rapid and sustained reduction in sBA levels in patients with nt-BSEP resulting in transplant-free survival, as well as reduced pruritus and significant improvements in growth and quality of life. These data support the NAPPED findings on the use of therapeutic bile acid depletion in nt-BSEP and the observation that reduced sBA is a prognostic marker for autologous liver survival. Thus, maralixibat can be considered a realistic and effective treatment strategy, benefiting the lives of patients and caregivers by alleviating disease symptoms, increasing transplant-free survival, and even providing a well-tolerated non-surgical alternative to biliary diversion surgery. References

[0420] TIFF2024540306000025.tif121161 TIFF2024540306000026.tif228163 TIFF2024540306000027.tif230164 TIFF2024540306000028.tif72157

[0421] All references cited anywhere within this specification are incorporated herein by reference in their entirety for all purposes.

[0422] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only.

[0423] Recitation of ranges of values ​​herein, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value and each endpoint falling within the range, and each separate value and endpoint is incorporated herein as if it were individually set forth herein.

[0424] Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A composition comprising an ileal bile acid transporter (IBAT) inhibitor for use in a method for treating cholestatic liver disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an IBAT inhibitor, said treatment comprising: a) reducing total bilirubin (TB) to about 6.5 mg / dL or less; b) reducing total serum bile acids (sBA) to about 200 μmol / L or less; and c) A reduction in pruritus score as measured by the Itch Reported Outcomes (ItchRO) severity assessment tool of at least about 1 point compared to the first dose of the IBAT inhibitor. increasing the subject's event-free survival (EFS) by one or more of: TB, sBA, or pruritus scores are reduced compared to when the IBAT inhibitor was first administered; The IBAT inhibitor is 【Chemical 1】 or a pharmaceutically acceptable salt thereof; The IBAT inhibitor is 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

2. 2. The composition of claim 1, wherein the TB, sBA, or pruritus score is determined (i) 18 weeks, (ii) 24 weeks, or (iii) 48 weeks after initiation of IBAT inhibitor treatment.

3. 10. The composition of claim 1, wherein EFS comprises the length of time to survive free of one or more of hepatic decompensation, biliary diversion surgery, liver transplant, or death.

4. 10. The composition of claim 1, wherein treatment with an IBAT inhibitor further results in relief of cholestatic pruritus.

5. 10. The composition of claim 1, wherein said administration is sufficient to result in event-free survival of the subject for (i) at least 18 months, or (ii) at least 2 years, or (iii) 6 years after the first administration of the IBAT inhibitor.

6. The composition of claim 1 , wherein the cholestatic liver disease is pediatric cholestatic liver disease.

7. The composition of claim 1 , wherein the cholestatic liver disease is adult cholestatic liver disease.

8. The cholestatic liver disease includes non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, and drug-related cholestasis. The composition of claim 1, wherein the disease is selected from the group consisting of hepatitis, hepatitis B, hepatitis C, hepatitis B-related cholestasis, hepatitis C-related cholestasis ...

9. 9. The composition of claim 8, wherein the cholestatic liver disease is ALGS, PFIC, BRIC, PSC, PBC, or biliary atresia.

10. 2. The composition of claim 1, wherein the sBA comprises one or more of TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA.

11. 10. The composition of claim 1, wherein the IBAT inhibitor is administered (i) once daily, or (ii) twice daily.

12. 10. The composition of claim 1, wherein the IBAT inhibitor is administered in an amount of (i) about 10 mg to about 100 mg per dose, or (ii) about 20 mg to about 80 mg per dose.

13. 12. The composition of any one of claims 1-11, wherein the IBAT inhibitor is administered in an amount of (i) about 100 μg / kg / day to 1400 μg / kg / day, or (ii) about 400 μg / kg / day to about 800 μg / kg / day.

14. The IBAT inhibitor is 【Chemistry 3】 The composition according to any one of claims 1 to 12, wherein

15. The IBAT inhibitor is 【Chemistry 4】 The composition according to any one of claims 1 to 12, wherein

16. The composition of any one of claims 1 to 12, wherein the IBAT inhibitor is administered orally.

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