Methods of treating progressive familial intrahepatic cholestasis

Abstract

Provided herein are methods for treating cholestasis in an individual having a liver disease. More specifically, the present invention relates to a method for treating progressive familial intrahepatic cholestasis (PFIC) in a subject wherein the method comprises administering to a subject in need thereof maxicabate.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of the provisional applications Ser. No. 63 / 418,589, filed Oct. 23, 2022; Ser. No. 63 / 423,310, filed Nov. 7, 2022; Ser. No. 63 / 471,291, filed Jun. 6, 2023; and Ser. No. 63 / 522,355, filed Jun. 21, 2023, which are hereby incorporated by reference in their entireties, and we claim the priority of these applications. Technical Field

[0003] The present invention generally relates to methods for treating cholestasis in an individual suffering from liver disease. More specifically, the present invention relates to methods for treating progressive familial intrahepatic cholestasis (PFIC) in an individual, wherein the methods comprise administering maralixibat to an individual in need thereof. Background Art

[0004] Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive liver disease characterized by intrahepatic cholestasis due to defective microtubular bile transport. Based on different mutations, there are more than 4 subtypes of PFIC. PFIC 1, 2, and 3 are caused by mutations in the genes ATPase phospholipid transporter 8B1 (ATP8B1), ATP-binding cassette subfamily B member 11 (ABCB11), and ATP-binding cassette subfamily B member 4 (ABCB4), respectively, and all share the main clinical manifestations of cholestasis and pruritus. PFIC 4 is based on a mutation in the tight junction protein 2 gene (TJP2) and causes protein mislocalization, disruption of tight junction structure, and severe cholestatic liver disease. In children, PFIC accounts for 10%-15% of the causes of cholestasis and 10%-15% of the causes of liver transplantation. PFIC 2 is the most common subtype and is diagnosed in about 50% to 60% of PFIC patients, while PFIC 1 (also known as Byler's disease) and PFIC 3 account for about 10%-20% and 30%-40% of the PFIC population, respectively.

[0005] PFIC is associated with early mortality, morbidity, and devastating consequences for the quality of life of patients. Without surgery, PFIC 1 and PFIC 2 are highly aggressive diseases, and only 10%-15% of individuals with PFIC 1 and PFIC 2 (depending on the variant) survive to 18 years of age. PFIC 2 is associated with a continuous progression of symptoms. Although PFIC 1 may be characterized by extrahepatic involvement, such as pancreatitis or diarrhea, the initial presentation and progression of the disease in PFIC 2 tend to be more severe than in PFIC 1. Patients present with persistent jaundice within a few months after birth and rapidly progress to cirrhosis and liver failure within a few years after birth. Interrupting the enterohepatic circulation of bile acids by partial external biliary diversion (PEBD) surgery can produce promising results for the pruritus, jaundice, and histology of patients with PFIC 1 and PFIC 2. Previous studies reported that patients undergoing PEBD had significant treatment outcomes within 1 year, with serum bile acids (sBA) and liver function returning to normal in 13 / 21 (62%) of the patients; however, other groups reported a total failure rate of PEBD as high as 30%, and 30%-50% of the patients required repeat surgery. In addition, PEBD must be performed before liver fibrosis and cirrhosis are established to obtain the best benefits. For the vast majority of patients who do not undergo PEBD or do not respond, liver transplantation may be the only treatment option. Given the clinical outcomes associated with PFIC, including the profound negative impact on the quality of life of patients and caregivers, and the fact that there is no approved treatment, the medical need for novel treatments for this disease remains unmet.

[0006] Marseglurant (in the form of marseglurant chloride) is the only currently approved pharmaceutical therapy for the treatment of pruritus in people with Alagille syndrome. Marseglurant chloride is known to inhibit apical sodium-dependent bile acid transport (U.S. Patent No. 5,994,391). The synthesis of marseglurant chloride was previously disclosed in U.S. Patent Application Publication No. 2003 / 0199515A1. SUMMARY OF THE INVENTION

[0007] The following describes various non-limiting aspects and embodiments of the present invention.

[0008] In one aspect, the present invention provides a method for treating progressive familial intrahepatic cholestasis (PFIC) in an individual in need thereof, the method comprising administering marseglurant or a pharmaceutically acceptable salt thereof to the individual.

[0009] In one embodiment, the pharmaceutically acceptable salt of marseglurant is marseglurant chloride, marseglurant bromide, marseglurant acetate, or marseglurant mesylate. In one embodiment, the pharmaceutically acceptable salt of marseglurant is marseglurant chloride.

[0010] In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is administered in an amount of from about 10 μg / kg per day to about 1400 μg / kg per day. In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is administered in an amount of from about 300 μg / kg per day to about 1200 μg / kg per day. In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is administered in an amount of from about 600 μg / kg per day to about 1200 μg / kg per day. In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is marciprant chloride, and marciprant chloride is administered in an amount of about 1200 μg / kg per day.

[0011] In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is administered in an amount of from about 0.5 mg per day to about 100 mg per day.

[0012] In one embodiment, the PFIC is PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5 or PFIC 6. In one embodiment, the PFIC is PFIC 1. In one embodiment, the PFIC is PFIC 2. In one embodiment, the PFIC 2 is untruncated PFIC 2. In one embodiment, the PFIC 2 is truncated PFIC 2. In one embodiment, the PFIC is PFIC 3. In one embodiment, the PFIC is PFIC 4. In one embodiment, the PFIC is PFIC 5. In one embodiment, the PFIC is PFIC 6.

[0013] In one embodiment, the PFIC is heterozygous. In one embodiment, the individual has intermittent cholestasis. In one embodiment, the individual has undergone a biliary shunt operation.

[0014] In one embodiment, the individual is a pediatric individual. In one embodiment, the age of the individual is greater than 1 year and less than 18 years. In one embodiment, the age of the individual is less than 12 months.

[0015] In one embodiment, the individual has a mutation in a gene selected from the group consisting of ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B.

[0016] In one embodiment, marciprant or a pharmaceutically acceptable salt thereof is administered once daily (QD). In one embodiment, the marciprant or a pharmaceutically acceptable salt thereof is administered twice daily (BID).

[0017] In one embodiment, the marcipitant or a pharmaceutically acceptable salt thereof is marcipitant chloride, and marcipitant chloride is administered at 600 μg / kg BID, with a total daily dose of 1200 μg / kg per day.

[0018] In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 2 months. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 4 months. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 6 months. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 1 year.

[0019] In one embodiment, the reduction in the symptoms or disease-related laboratory measures is determined relative to a baseline level.

[0020] In one embodiment, the reduction in the symptoms or disease-related laboratory measures includes a decrease in sBA concentration, a reduction in pruritus, a decrease in total bilirubin, a decrease in direct bilirubin, an improvement in growth, or a combination thereof.

[0021] In one embodiment, administration of the marcipitant reduces the intensity of pruritus. In one embodiment, reducing the intensity of pruritus is reducing the ItchRO(Obs) score, reducing the CSS score, or a combination thereof.

[0022] In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to decrease by at least 1.0 point relative to the baseline. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to decrease by at least 1.2 points relative to the baseline. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to decrease by at least 1.4 points relative to the baseline. In one embodiment, administration of the marcipitant or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to decrease by at least 1.6 points relative to the baseline.

[0023] In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 1.0 point in the CSS score of the individual relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 1.2 points in the CSS score of the individual relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 1.4 points in the CSS score of the individual relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 1.6 points in the CSS score of the individual relative to baseline.

[0024] In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 50 μmol / L in the sBA concentration of the individual relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof results in a reduction of at least 100 μmol / L in the sBA concentration of the individual relative to baseline.

[0025] In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction in total bilirubin. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 0.2 mg / dL in total bilirubin relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 0.5 mg / dL in total bilirubin relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 1.0 mg / dL in total bilirubin relative to baseline.

[0026] In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction in direct bilirubin. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 0.2 mg / dL in direct bilirubin relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 0.5 mg / dL in direct bilirubin relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes a reduction of at least 1.0 mg / dL in direct bilirubin relative to baseline.

[0027] In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes improvement in the height Z-score or weight Z-score or both of the individual relative to baseline. In one embodiment, administering the maribavir or a pharmaceutically acceptable salt thereof causes an increase of at least 0.2 points in the weight Z-score relative to baseline.

[0028] In one embodiment, the method further comprises administering a fat-soluble vitamin (LSV) to an individual suffering from LSV deficiency. In one embodiment, the LSV is selected from the group consisting of vitamin A, vitamin D, and vitamin E.

[0029] In one embodiment, maribavir or a pharmaceutically acceptable salt thereof is administered before a meal. In one embodiment, maribavir or a pharmaceutically acceptable salt thereof is administered about 30 minutes before a meal. In one embodiment, wherein maribavir or a pharmaceutically acceptable salt thereof is BID, i.e., administered about 30 minutes before breakfast and about 30 minutes before dinner.

[0030] In one embodiment, maribavir is administered in the form of a pharmaceutical composition comprising maribavir or a pharmaceutically acceptable salt thereof, an antioxidant, and a preservative. In one embodiment, the pharmaceutical composition is a liquid composition for oral administration. In one embodiment, the liquid composition is an aqueous solution.

[0031] In one embodiment, maribavir is present in the composition in an amount of about 2 mg / mL to about 100 mg / mL. In one embodiment, maribavir is present in the composition in an amount of about 5 mg / mL to about 50 mg / mL. In one embodiment, maribavir is present in the composition in an amount of about 8 mg / mL to about 20 mg / mL. In one embodiment, maribavir is present in the composition in an amount of about 9.5 mg / mL to about 10 mg / mL.

[0032] In one embodiment, the preservative is an antimicrobial preservative. In one embodiment, the antimicrobial preservative is selected from the group consisting of propylene glycol, ethanol, glycerol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimide (cetyltrimethylammonium bromide), cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof. In one embodiment, the preservative is propylene glycol. In one embodiment, the preservative is present in the composition in an amount of about 30% w / w to about 40% w / w. In one embodiment, the preservative is present in the composition in an amount of about 300 mg / mL to about 400 mg / mL.

[0033] In one embodiment, the antioxidant is selected from the group consisting of amino carboxylic acids, amino polycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or its derivatives, propyl gallate, and combinations thereof.

[0034] In one embodiment, the antioxidant is an amino polycarboxylic acid selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), nitrilotriacetic acid (NTA), 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), tetraazacyclododecanetetraacetic acid (DOTA), and ethylenediamine-N,N'-bis(2-hydroxy phenylacetic acid) (EDDHA). In one embodiment, the antioxidant is EDTA. In one embodiment, the antioxidant is present in the composition in an amount of about 0.01% w / w to about 0.5% w / w.

[0035] In one embodiment, the pharmaceutical composition further comprises a sweetening agent, a taste masking ingredient, or a combination thereof.

[0036] In one embodiment, the pharmaceutical composition comprises:

[0037] a. Maralixibat at about 8 mg / mL to about 20 mg / mL;

[0038] b. Propylene glycol at about 330 mg / mL to about 380 mg / mL;

[0039] c. EDTA at about 1 mg / mL;

[0040] d. A sweetening agent, taste masking ingredient, or combination thereof, and

[0041] e. Water.

[0042] These and other aspects of the invention will become apparent to those skilled in the art after reading the following embodiments of the invention, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 A schematic diagram is provided that outlines the physiological effects of administering maralixibat to a patient. IBAT, ileal bile acid transporter.

[0044] Figure 2 A schematic diagram is shown that provides an overview of the dosing regimen used in a Phase 3 open-label extension clinical study of maralixibat in individuals with PFIC. The clinical study investigated the long-term exposure to maralixibat.

[0045] Figure 3 A flow chart is shown that represents the treatment and discontinuation protocol recommendations for the worsening of LSV deficiency.

[0046] Figure 4A Outlines the MARCH-PFIC Phase 3 study design. Figure 4B Shows the efficacy endpoints. *570 μg / kg maralixibat is equivalent to 600 μg / kg maralixibat chloride. Abbreviations: AE = adverse event; BSEP = bile salt export pump; BL = baseline; ItchRO(Obs) = itching reported outcome (observer); MMRM = mixed model repeated measures; R = randomization.

[0047] Figure 5 Describes 93 MARCH-PFIC study participants.

[0048] Figure 6A and 6B Shows the BSEP deficiency cohort ( Figure 6A ) and all PFIC cohorts ( Figure 6B):Mean change in ItchRO[Obs] (severity of itch score) relative to baseline. Abbreviations: LS = least squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval.

[0049] Figure 7A and 7B show the mean change in ItchRO[Obs] (severity of itch score) relative to baseline in the BSEP deficiency cohort at night ( Figure 7A ) and at daily maximum ( Figure 7B ).

[0050] Figure 8A and 8B show the mean change in ItchRO[Obs] (severity of itch score) relative to baseline in all PFIC cohorts at night ( Figure 8A ) and at daily maximum ( Figure 8B ).

[0051] Figure 9A and 9B show the mean change in ItchRO[Obs] (severity of itch score) relative to baseline in the FIC1 deficiency cohort ( Figure 9A ) and the MDR3 deficiency cohort ( Figure 9B ).

[0052] Figure 10A and 10B show the change over time in ItchRO[Obs] (severity of itch score) relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 10A ), PFIC cohorts ( Figure 10B ) and all study participants ( Figure 10C ).

[0053] Figure 11A and 11B show the key secondary efficacy endpoint in the BSEP deficiency cohort ( Figure 11A ) and all PFIC cohorts ( Figure 11B ): mean change in sBA content relative to baseline. Abbreviations: LS = least squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval.

[0054] Figure 12A and 12B show the mean change in sBA content relative to baseline in the FIC1 cohort ( Figure 12A ) and the MDR3 cohort ( Figure 12B ).

[0055] Figure 13A and 13BShow the percentage of pruritus ( Figure 13A ) and sBA ( Figure 13B ) responses in the BSEP deficiency cohort according to MARCH SAP.

[0056] Figure 14A And 14B Show the percentage of pruritus ( Figure 14A ) and sBA ( Figure 14B ) responses in all PFIC cohorts according to MARCH SAP.

[0057] Figure 15A And 15B Show the change in sBA over time relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 15A ), PFIC cohort ( Figure 15B ), and all study participants ( Figure 15C ).

[0058] Figure 16A And 16B Show the proportion of pruritus responses ≤ 1 evaluated in the BSEP deficiency cohort and PFIC cohort. The proportion of responders in the BSEP deficiency cohort is shown in Figure 16A ; the proportion of responders in all PFIC cohorts is shown in Figure 16B .

[0059] Figure 17A And 17B Show the proportion of pruritus responses ≤ 1 or decreased ≥ 1 evaluated in the BSEP deficiency cohort and PFIC cohort. The proportion of responders in the BSEP deficiency cohort is shown in Figure 17A ; the proportion of responders in all PFIC cohorts is shown in Figure 17B .

[0060] Figure 18A And 18B Show the clinician scratch scores over time for the BSEP deficiency (also known as primary) cohort ( Figure 18A ) and PFIC cohort ( Figure 18B ).

[0061] Figure 19A And 19B Show the mean change in clinician scratch scale scores relative to baseline for the BSEP deficiency (also known as primary) cohort ( Figure 19A ) and PFIC cohort ( Figure 19B ).

[0062] Figure 20A And 20B Show the BSEP deficiency cohort ( Figure 20A ) and PFIC cohort ( Figure 20BThe mean change in total bilirubin (mg / dL) relative to baseline.

[0063] Figure 21A and 21B Show the change in total bilirubin (mg / dL) over time relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 21A ) and the PFIC cohort ( Figure 21B ).

[0064] Figure 22A and 22B Show the mean change in direct bilirubin (mg / dL) relative to baseline in the BSEP deficiency cohort ( Figure 22A ) and the PFIC cohort ( Figure 22B ).

[0065] Figure 23A and 23B Show the change in direct bilirubin (mg / dL) over time relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 23A ) and the PFIC cohort ( Figure 23B ).

[0066] Figure 24A - 24C Show the change in height Z-score over time relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 24A ) and the PFIC cohort ( Figure 24B and 24C ).

[0067] Figure 25A - 25C Show the change in weight Z-score over time relative to baseline in the BSEP deficiency (also known as primary) cohort ( Figure 25A ) and the PFIC cohort ( Figure 25B and 25C ).

[0068] Figure 26A and 26B Show the change in ALT relative to baseline in all PFIC cohorts.

[0069] Figure 27A Show a schematic diagram providing an overview of the method. *ItchRO(Obs) score ≥ 1.5; Marsebil is equivalent to 600 μg / kg of Marsebil chloride. Figure 27B Show that patients receiving Marsebil had significantly more days with mild itching or no itching compared to patients receiving placebo. Error bars represent SE. Percentage values represent the proportion of assessments from baseline to week 26. *Increment (Delta) at 95% CI. CI, confidence interval. SE is the standard error. Figure 27CShow that in patients receiving maribavir, itching was significantly reduced compared to placebo, regardless of when and how it was measured. Figure 27D Show that changes in sleep induced by maribavir compared to placebo were significantly improved relative to baseline, as measured by EDQ(Obs). *Increment at 95% CI. Figure 27E Show that changes in itching were closely related to changes in sleep. Abbreviations: BL = baseline; CSS = Clinician Scratch Scale; EDQ(Obs) = Exploratory Diary Questionnaire (Observer); ItchRO(Obs) = Itching Report Outcome (Observer); R = randomization.

[0070] Figure 28 Show the incidence of gastrointestinal events.

[0071] Figure 29A Show a schematic diagram providing the study design. Figure 29B and 29C Show that in the MRX-MRX group, the severity of itching ( Figure 29B ) and the content of serum bile acids (sBA) ( Figure 29C ) continued to improve significantly. Figure 29D and 29E Show that in the PBO-MRX group, a significant decrease was newly observed in the severity of itching ( Figure 29D ) and the sBA content ( Figure 29E ).

[0072] Figure 30 Show a schematic diagram providing the study design. a All doses were presented as the MRX free base. All patients received a daily dose appropriate for their body weight, with a maximum dose of 28.5 mg / d for adult patients. b Before 16 years old was defined as the last data point before reaching 16 years old. After 16 years old was defined as the first data point after reaching 16 years old.

[0073] Figure 31A and 31B Show the changes in ItchRO(Obs) ( Figure 31A ) and sBA ( Figure 31B ) for participants (n = 11) who started MRX treatment at <16 years old. Among the 11 participants, 9 had ItchRO(Obs) scores available for all time points and were included in the analysis. b ItchRO(Obs) is a 0 to 4 scale, where a decrease of ≥1 point is considered clinically significant. The average ItchRO(Obs) was rounded to 1 decimal place. Error bars represent SE. Significance was determined using the Student's t-test. c The average sBA was rounded to the nearest integer. Error bars represent SE.d The average of the last 2 records before 16 years old. e The average of the first 2 records after 16 years old. f The average of the final 2 records.

[0074] Figure 32A and 32B Show the changes in ltchRO(Obs) ( Figure 32A ) and sBA ( Figure 32B ) for participants (n = 3) who started MRX treatment at ≥16 years old. a ItchRO(Obs) is a 0 - to - 4 scale, where a decrease of ≥1 point is considered clinically significant. b The average of the final two records.

[0075] Figure 33A and 33B Show the changes in the weekly ItchRO(Obs) scores for FIC1, MDR3, TJP2, and MYO5B.

[0076] Figure 34A and 34B Show the changes in serum bile acids relative to baseline for FIC1, MDR3, TJP2, and MYO5B.

[0077] Figure 35A - 35H Show the changes in the weekly ltchRO(Obs) scores and serum bile acids (sBA) in the full study cohort ( Figure 35A and 35B ), the cohort without identified variants ( Figure 35C and 35D ), the FIC1 cohort ( Figure 35E and 35F ), and MDR3 ( Figure 35G and 35H ).

[0078] Figure 36A and 36B Show the changes in total bilirubin ( Figure 36A ) and direct bilirubin ( Figure 36B ) relative to baseline in all PFIC cohorts.

[0079] Figure 37A and 37B Show the changes relative to baseline for patients with abnormal total bilirubin ( Figure 37A ) and direct bilirubin ( Figure 37B ) at baseline.

[0080] Figure 38A and 38B Show the normalization of total bilirubin.

[0081] Figure 39 Demonstrate the normalization of direct bilirubin.

[0082] Figure 40 Demonstrate the relationship between the normalization of total bilirubin and the changes in serum bile acids.

[0083] Figure 41A - 41D Demonstrate the changes over time in the morning pruritus severity at the patient level measured by the pruritus report results (observer). Demonstrate the individual participants in the BSEP cohort (Figure 41A); participants with FIC1, MDR3, TJP2, and MYO5B deficiencies (Figure 41B); participants in whom no pathogenic variants were identified (Figure 41C); and participants with truncated BSEP (BSEP3) deficiency (Figure 41D) in the change in morning pruritus severity over time (baseline to 26 weeks) relative to baseline (blue = maralixibat and red = placebo group). BSEP represents bile salt export pump, FIC1 represents familial intrahepatic cholestasis-related protein 1, MDR3 represents multidrug resistance protein 3, MYO5B represents myosin VB, t represents truncated, and TJP2 represents tight junction protein 2.

[0084] Figure 42A - 42D Demonstrate the changes over time in the BA content at the patient level. Demonstrate the change in sBA content (baseline to 26 weeks) relative to baseline in the participants in the BSEP cohort (Figure 42A); participants with FIC1, MDR3, TJP2, and MYO5B (Figure 42B); participants in whom no pathogenic variants were found (Figure 42C); and truncated BSEP (BSEP3; Figure 42D) (blue = maralixibat and red = placebo group). BSEP represents bile salt export pump, FIC1 represents familial intrahepatic cholestasis-related protein 1, MDR3 represents multidrug resistance protein 3, MYO5B represents myosin VB, and t represents truncated. *The patient had a decrease in both total bilirubin (from 3.85 mg / dL at baseline to 2.6 mg / dL at 26 weeks) and ALT (from 320 U / L at baseline to 183 U / L at 26 weeks). Detailed implementation mode

[0085] The detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments only illustrate that the present invention can be implemented in various forms. In addition, each example provided in connection with the various embodiments of the present invention is intended to be illustrative rather than restrictive. Therefore, the specific structural and functional details disclosed herein should not be construed as restrictive, but only as a representative basis for teaching those skilled in the art to use the present invention in different ways.

[0086] Marcybutat is an IBAT inhibitor. IBAT is a transmembrane protein present in the terminal ileum and is located on the luminal surface of ileal epithelial cells. IBAT mediates the absorption of conjugated bile acids across the brush border membrane of enterocytes. Ninety-five percent of the bile acids entering the intestinal lumen are recycled to the gallbladder, where they are stored for future release into the duodenum. Additional proteins and transporters carry bile acids across enterocytes and across the basolateral membrane into the bloodstream, where they are circulated to the liver via the portal vein and then re-secreted into the intestine, which is called the enterohepatic circulation( Figure 1 ). Blockade of intestinal bile acid reabsorption by marcybutat via IBAT interrupts the enterohepatic circulation, thereby increasing fBA secretion and decreasing sBA content.

[0087] "Marcybutat" refers to 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium, which is the free form of marcybutat chloride. The structure of marcybutat is represented as follows:

[0088]

[0089] "Marcybutat chloride" (also known as LUM-001, SHP625 or lopixibatchloride) refers to 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride. The structure of marcybutat chloride is represented as follows:

[0090]

[0091] IBAT is ideally suited for pharmacological modulation of bile acid transport by compounds that can be confined to the intestinal lumen (i.e., compounds that do not require systemic exposure to exert activity). Marcybutat is designed to minimize absorption due to its large molecular weight (approximately 710 Da) and the presence of a positively charged quaternary nitrogen atom, thus maximizing local exposure of the molecule to its target and minimizing unnecessary systemic exposure.

[0092] Since it has been demonstrated that a decrease in sBA concentration following interruption of the enterohepatic circulation during surgery is associated with improved cholestasis and clinical outcomes in several pediatric cholestatic liver diseases, pharmacological interruption of the enterohepatic circulation by IBAT inhibition represents a potentially non-surgical and easily reversible alternative to achieve a similar sBA decrease and thus potentially improve the outcomes of diseases such as PFIC, ALGS, and biliary atresia.

[0093] Bile acids / salts play a key role in activating digestive enzymes and solubilizing fats and fat-soluble vitamins and are associated with liver, bile, and intestinal diseases. Bile acids are synthesized in the liver via a multi-step, multi-organelle pathway. Hydroxyl groups are added to specific sites on the steroid structure, the double bond in the B ring of cholesterol is reduced, and the hydrocarbon chain is shortened by three carbon atoms, generating a carboxyl group at the chain terminus. The most common bile acids are cholic acid and chenodeoxycholic acid ("primary bile acids"). Before bile acids leave the hepatocyte and form bile, they conjugate with 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 amphoteric nature makes them more efficient detergents than bile acids. Bile salts, not bile acids, are present in bile.

[0094] Bile salts are secreted by hepatocytes into canaliculi to form bile. The canaliculi drain into the right and left hepatic ducts, and bile flows into the gallbladder. Bile is released from the gallbladder and travels to the duodenum, where it facilitates the metabolism and degradation of fats. Bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts typically undergo multiple enterohepatic circulations before excretion via feces. A small amount of bile salts can be reabsorbed in the proximal intestine by passive or carrier-mediated transport processes. Most bile salts are reclaimed in the distal ileum by an apical sodium-dependent bile acid transporter called apical sodium-dependent bile acid transporter (ASBT). At the basolateral surface of the enterocyte, a truncated form of ASBT is involved in the carrier-mediated transfer of bile acids / salts into the portal circulation. The enterohepatic circulation is completed at the basolateral surface of hepatocytes by a transport process mediated mainly by sodium-dependent bile acid transporters. Intestinal bile acid transport plays a key role in the enterohepatic circulation of bile salts. Recently, molecular analysis of this process has led to important advances in the understanding of the biology, physiology, and pathophysiology of intestinal bile acid transport.

[0095] Within the intestinal lumen, the concentration of bile acids varies, with most reabsorption occurring in the distal intestine. Certain compositions and methods are described herein that control the concentration of bile acids in the intestinal lumen and thereby control hepatocyte damage caused by bile acid accumulation in the liver.

[0096] General Definitions

[0097] Unless otherwise specified, 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.

[0098] Unless the context clearly dictates otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include plural referents. 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 one of ordinary skill in the art after reading this disclosure.

[0099] As used herein, the term "baseline" or "pre - administration baseline" refers to information collected at the start of a study or an initial known value used for comparison with subsequent data. A baseline is an initial measurement of a measurable condition taken at an early time point and is used for comparison over time to detect changes in the measurable condition. For example, the serum bile acid concentration in a patient before (baseline) and after administration of a drug. A baseline is an observation or value representing the normal or starting level of a measurable quality, used for comparison with values representing a response to an intervention or environmental stimulus. A baseline is time "zero", i.e., before a participant in a study receives an experimental agent or intervention or a negative control. For example, in some cases, "baseline" can refer to 1) the state of a measurable quantity immediately before the start of a clinical study, or 2) the state of a measurable quantity before the dose level or composition to be administered to a patient is changed from a first dose level or composition to a second dose level or composition.

[0100] As used herein, the terms "content" and "concentration" are used interchangeably. For example, "high serum content of bilirubin" may alternatively be expressed as "high serum concentration of bilirubin".

[0101] As used herein, the terms "normalize" or "normal range" indicate age - specific values within a range corresponding to healthy individuals (i.e., normal or normalized values). For example, the phrase "serum bilirubin concentration normalizes within three weeks" means that the serum bilirubin concentration decreases within three weeks to a range known in the art to correspond to healthy individuals (i.e., within the normal and, for example, non - elevated range). 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.

[0102] As used herein, the terms “ITCHRO(OBS)” and “ITCHRO” (alternatively, “ItchRO(Pt)”) are used interchangeably provided that the caregiver uses the ITCHRO(OBS) scale to measure the severity of itching in all patients, and the ITCHRO scale to measure the severity of itching in adults at least 18 years of age. Thus, when the ITCHRO(OBS) scale is mentioned with respect to adult patients, the scale indicated is the ITCHRO scale. Similarly, whenever the ITCHRO scale is mentioned with respect to pediatric patients, the scale generally indicated is the ITCHRO(OBS) scale. Some children at least 9 years of age report their own scores as ITCHRO(Pt) scores. For the ALGS and PFIC studies, patients at least 9 years of age perform ITCHRO(Pt) and patients under 9 years of age use ITCHRO(OBS). The ITCHRO(OBS) scale ranges from 0 to 4, the ITCHRO(Pt) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[0103] As used herein, the terms “EDQ(Obs)”, “EDQ(Pt)”, and “EDQ” refer to an Exploratory Diary Questionnaire used to assess itching in children under 18 years of age or adults at least 18 years of age. The EDQ is a caregiver / patient-reported outcome measure administered in the form of an electronic diary twice daily. The EDQ contains a sleep problem related to itching: “My child has trouble falling asleep because of itching. 1 - Never, 2 - Rarely, 3 - Sometimes, 4 - Often, or 5 - Almost always.”. Caregivers of all individuals less than 9 years of age complete the observer instrument: EDQ(Obs). Individuals 9 years of age and older complete the patient instrument: EDQ(Pt). The EDQ includes questions related to sleep disorders associated with itching.

[0104] As used herein, the term "bile acid" or "bile acids" includes steroid acids (and / or their carboxylate anions) and their salts found in the bile of animals (e.g., humans), and as non-limiting examples, includes cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodeoxycholic acid, tauro-ursodeoxycholic acid, glycoursodeoxycholic acid, 7-β-methylcholic acid, lithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, etc. Taurocholic acid and / or taurocholate are referred to herein as TCA. Any reference to "bile acid" as used herein includes reference to a bile acid, one bile acid and only one bile acid, one or more bile acids or at least one bile acid. Thus, unless otherwise indicated, the terms "bile acid", "bile salt", "bile acid / salt", "bile acids", "bile salts" and "bile acid / salts" are used interchangeably herein. Any reference to a bile acid as used herein includes reference to a bile acid or its salt. In addition, a pharmaceutically acceptable "bile acid ester" is optionally used as the bile acid described herein, for example, a bile acid / salt conjugated with an amino acid (e.g., glycine or taurine). Other bile acid esters include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, etc. For example, the term "bile acid" includes cholic acid conjugated with glycine or taurine: glycocholate and taurocholate (and their salts). Any reference to a bile acid as used herein includes reference to the same compound prepared naturally or synthetically. In addition, it should be understood that any singular reference to a component (bile acid or otherwise) used herein includes reference to one and only one of the components, one or more or at least one of the components. Similarly, unless otherwise indicated, any plural reference to a component used herein includes reference to one and only one of the components, one or more or at least one of the components.

[0105] The terms "subject", "patient", "participant", or "individual" are used interchangeably herein and refer to, for example, mammalian and non-mammalian subjects suffering from a disorder described herein. Examples of mammals include (but are not limited to) any member of the mammalian class: humans, non-human primates (such as chimpanzees and other ape and monkey species); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc. Examples of non-mammals include (but are not limited to) birds, fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0106] As used herein, the term "about" includes any value within 10% of the recited value.

[0107] As used herein, the term "composition" includes the composition and the disclosure of the composition administered in the methods described herein. Further, in some embodiments, the compositions of the invention are or comprise the "formulations", oral dosage forms, or rectal dosage forms described herein.

[0108] As used herein, the terms "treat / treating / treatment" and other grammatical equivalents include alleviating, inhibiting, or reducing symptoms; reducing the severity of symptoms of a disease or condition; reducing its incidence; reducing or inhibiting its recurrence; delaying its onset; delaying its recurrence; alleviating or improving the symptoms of a disease or condition; improving the underlying cause of the symptoms; inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition. The terms further include achieving a therapeutic benefit. A therapeutic benefit means eradicating or improving the underlying disorder being treated, and / or eradicating or improving one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient.

[0109] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of at least one agent (e.g., a therapeutic active agent) that is sufficient to achieve a desired result when administered to a subject or individual, such as alleviating to some extent one or more symptoms of the disease or condition being treated. In some cases, the result is the reduction and / or alleviation of the signs, symptoms or cause of the disease, or any other desired alteration of a biological system. In some cases, the "effective amount" for therapeutic use is the amount of the composition comprising the agent as set forth herein required to effect a clinically significant reduction in the disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies. In some embodiments, the "therapeutically effective amount" or "effective amount" of ASBTI refers to the amount of ASBTI sufficient to treat cholestasis or cholestatic liver disease in a subject or individual.

[0110] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to enable an agent or composition to be delivered to a desired biological site of action. These methods include (but are not limited to) oral, duodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intracascular or infusion), topical and rectal administration. Administration techniques optionally used with the agents and methods described herein are found in sources such as Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon Press; 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 some embodiments, the agents and compositions described herein are administered orally.

[0111] The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile transport or any restitution of bile salt transport. The term "IBAT inhibitor" refers to a compound that inhibits ileal bile acid transport or any restitution of bile salt transport. The term apical sodium-dependent bile transporter (ASBT) may be used interchangeably with the term ileal bile acid transporter (IBAT). The term "ASBT inhibitor" may be used interchangeably with the term "IBAT inhibitor".

[0112] The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention means that the molecular entities and other ingredients in such compositions are physiologically tolerable and generally produce no adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeias for use in mammals, and more particularly in humans.

[0113] In various embodiments, non-limiting examples of pharmaceutically acceptable salts described herein include nitrates, chlorides, bromides, phosphates, sulfates, acetates, hexafluorophosphates, citrates, gluconates, benzoates, propionates, butyrates, subsalicylates, maleates, laurates, malates, fumarates, succinates, tartrates, aminosulfonates, pamoates, tosylates, mesylates, and the like. In addition, non-limiting examples of pharmaceutically acceptable salts include alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), ammonium salts, and the like.

[0114] Bile acid

[0115] Bile contains water, electrolytes, and many organic molecules, including bile acids, cholesterol, phospholipids, and bilirubin. Bile is secreted from the liver and stored in the gallbladder, and when the gallbladder contracts in response to the ingestion of a fatty meal, bile passes through the bile duct into the intestine. Bile acids / salts are essential for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400 to 800 mL of bile per day. Bile secretion can be considered to occur in two stages. First, hepatocytes secrete bile into the bile canaliculi, and the bile flows from the bile canaliculi into the bile duct, and this hepatic bile contains a large amount of bile acids, cholesterol, and other organic molecules. Subsequently, as the bile flows through the bile duct, it is modified by the addition of a bicarbonate-rich aqueous secretion from the bile duct epithelial cells. Bile is concentrated during storage in the gallbladder, typically by a factor of five.

[0116] Bile flow is lowest during fasting, and most of the bile is diverted to the gallbladder for concentration. When chyme from the ingested food enters the small intestine, acid and partially digested fat and protein stimulate the secretion of cholecystokinin and secretin, both of which are essential for bile secretion and flow. Cholecystokinin (cholecysto = gallbladder, and kinin = move) is the hormone that stimulates the contraction of the gallbladder and the common bile duct, thereby delivering bile to the intestine. The most effective 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, and it mimics the secretion of bicarbonate and water by cholangiocytes, thereby expanding the bile volume and increasing its flow into the intestine.

[0117] Bile acids / salts are derivatives of cholesterol. Cholesterol is either ingested as part of the diet or synthesized by the liver, and it is converted into bile acids / salts in hepatocytes. Examples of such bile acids / salts include cholic acid and chenodeoxycholic acid, which are subsequently conjugated with amino acids (such as glycine or taurine) to produce the conjugated forms that are actively secreted into the canaliculi. The most abundant bile salts in the human body are cholate and deoxycholate, and they are usually conjugated with glycine or taurine to obtain glycocholate or taurocholate, respectively.

[0118] Free cholesterol is almost insoluble in aqueous solutions. However, in bile, it becomes soluble due to the presence of bile acids / salts and lipids. Bile acids / salts synthesized by the liver account for most of the cholesterol breakdown in the body. In humans, approximately 500 mg of cholesterol is converted into bile acids / salts and eliminated in bile every day. Therefore, secretion into bile is the main route for cholesterol elimination. A large amount of bile acids / salts is secreted into the intestine every day, but only a relatively small amount of bile acids / salts is 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 through a process called "enterohepatic circulation".

[0119] Venous blood from the ileum enters directly into the portal vein and thus passes through the sinusoids of the liver. Hepatocytes extract bile acids / salts very efficiently from the sinusoidal blood and little bile acids / salts escape from the healthy liver into the systemic circulation. Subsequently, bile acids / salts are transported across the hepatocytes for re-secretion into the bile canaliculi. The net effect of this enterohepatic recirculation is that each bile salt molecule is reused approximately 20 times during a single digestive phase, often two or three times. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the approximately 800 mg of cholesterol consumed by the average adult during metabolism. In contrast, steroid hormone biosynthesis consumes only approximately 50 mg of cholesterol per day. More than 400 mg of bile salts are required and secreted into the intestine each day, and this is achieved by recycling the bile salts. Most of the bile salts secreted in the upper region of the small intestine are absorbed together with the dietary lipids emulsified in the lower end of the small intestine. It is separated from the dietary lipids and returned to the liver for reuse. Thus, recycling enables 20 - 30 g of bile salts to be secreted into the small intestine each day.

[0120] Bile acids / salts are amphiphilic, with the cholesterol-derived moiety containing both a hydrophobic portion (lipophilic) and a polar portion (hydrophilic), while the amino acid conjugates are generally polar and hydrophilic. This amphiphilic nature enables bile acids / salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids in an aqueous environment. Bile acids / salts have a detergent action on dietary fat particles, causing the fat globules to break down or emulsify. Emulsification is important because it greatly increases the surface area of the fat available for digestion by lipase, which cannot access the interior of the lipid droplet. In addition, bile acids / salts are lipid carriers and can solubilize many lipids by forming micelles, and are essential for the transport and absorption of fat-soluble vitamins.

[0121] As used herein, the terms "non-systemic" or "minimally absorbed" refer to the lower systemic bioavailability and / or absorption of an administered compound. In some embodiments, a non-systemic compound is a compound that is substantially not systemically absorbed. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, with non-systemic delivery (e.g., the majority of ASBTI is not systemically absorbed). In some embodiments, the systemic absorption of a 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 a non-systemic compound is <10% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <15% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <25% of the administered dose. In an alternative approach, a non-systemic ASBTI (e.g., maribavir) is a compound that has a lower systemic bioavailability relative to the systemic bioavailability of a systemic ASBTI. In some embodiments, the bioavailability of a non-systemic ASBTI (e.g., maribavir) described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of a systemic ASBTI.

[0122] In another alternative approach, the compositions described herein are formulated for systemic delivery of <10% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <20% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <30% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <40% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <50% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <60% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated for systemic delivery of <70% of the administered dose of ASBTI. In some embodiments, systemic absorption is determined in any suitable manner, including total circulating volume, amount cleared after administration, etc.

[0123] Categories of cholestasis and cholestatic liver diseases

[0124] As used herein, "cholestasis" means a disease or condition involving impaired bile formation and / or bile flow. As used herein, "cholestatic liver disease" means a liver disease associated with cholestasis. Cholestatic liver disease is typically associated with jaundice, fatigue, and pruritus. Biomarkers of cholestatic liver disease include elevated serum bile acid concentration, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyl transpeptidase (gammaGT), elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.

[0125] Cholestatic liver disease can be clinically and pathologically classified into two major categories: obstructive (usually extrahepatic) cholestasis and non-obstructive (or intrahepatic) cholestasis. In the former, cholestasis results when bile flow is mechanically obstructed (e.g., by gallstones or tumors) or when there is extrahepatic biliary atresia.

[0126] The latter group of patients with non-obstructive intrahepatic cholestasis is further divided into two main subgroups. In the first subgroup, cholestasis results when the processes of bile secretion and modification or the synthesis of bile components are impaired due to hepatocyte injury that is so severe that non-specific impairment of many functions (including those involved in promoting bile formation) can be expected. In the second subgroup, no putative cause of hepatocyte injury can be identified. Cholestasis in such patients appears to result when one step in bile secretion or modification or the synthesis of bile components is constitutively impaired. Such cholestasis is considered primary.

[0127] Progressive familial intrahepatic cholestasis (PFIC)

[0128] PFIC is a rare genetic disorder that causes progressive liver disease and typically leads to liver failure. In individuals with PFIC, hepatocytes have a reduced ability to secrete bile. The resulting bile accumulation causes liver disease in affected individuals. The signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, failure to grow at an expected rate (failure to thrive), and progressive loss of liver function (liver failure). It is estimated that one in 50,000 to 100,000 newborns in the United States and Europe has the disease. Six types of PFIC have been genetically identified, all similarly characterized by impaired bile flow and progressive liver disease.

[0129] PFIC types include familial intrahepatic cholestasis related protein 1 (FIC1) deficiency (PFIC1), bile salt export pump (BSEP) deficiency (PFIC2), multidrug resistance 3 protein (MDR3) deficiency (PFIC3), tight junction protein 2 (TJP2) deficiency (PFIC4), farnesoid X receptor (FXR) deficiency (PFIC5), and myosin VB (MYO5B) deficiency (PFIC6), which are discussed in more detail below.

[0130] PFIC 1

[0131] PFIC 1 (also known as Byler disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also known as FIC1). This gene encodes a P-type ATPase, is located on human chromosome 18, and mutations are also present in the milder phenotypes, namely benign recurrent intrahepatic cholestasis (BRIC) type 1 and Greenland familial cholestasis. The FIC1 protein is located on the canalicular membrane of hepatocytes, but in the liver, it is mainly expressed in bile duct epithelial cells. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane compared to the outer leaflet. In some cases, PFIC 1 mutations are homozygous. In other cases, PFIC 1 mutations are heterozygous. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against the high bile salt concentration in the canalicular lumen. Abnormal protein function can indirectly interfere with the choleretic secretion of bile acids. Abnormal secretion of bile acids / salts leads to bile acid overload in hepatocytes.

[0132] PFIC 1 usually presents in infants (e.g., aged 6 to 18 months). Infants may show signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC 1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. Individuals may also have liver fibrosis. Individuals with PFIC 1 usually do not have bile duct hyperplasia. Most individuals with PFIC 1 will develop end-stage liver disease by the age of 10. No medical treatment has been proven beneficial for the long-term treatment of PFIC 1. To reduce extrahepatic symptoms (e.g., malnutrition and stunted growth), medium-chain triglycerides and fat-soluble vitamins are usually administered to children. Ursodeoxycholic acid has not been proven effective in individuals with PFIC 1.

[0133] PFIC 2

[0134] PFIC 2 (also known as Byler syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also known as BSEP). The ABCB11 gene encodes the ATP-dependent bile salt export pump (BSEP) of the human liver and is located on human chromosome 2. The BSEP protein is expressed at the canalicular membrane of hepatocytes and is the major exporter of primary bile acids / salts against extreme concentration gradients. Mutations in this protein cause the described decrease in biliary bile salt secretion in affected patients, leading to reduced bile flow and bile salt accumulation within hepatocytes, and resulting in persistent severe hepatocyte injury. In some cases, the PFIC2 mutations are homozygous. In other cases, the PFIC 2 mutations are heterozygous.

[0135] Previously, BSEP deficiency has been classified into three subtypes, named BSEP1, BSEP2, and BSEP3, based on the type and severity of the resulting deficiency. The BSEP1 genotype denotes patients with at least one D482G or E297G mutation. BSEP1 is considered the least severe genotype as the responsible mutations still allow the BSEP protein to function partially. The BSEP2 genotype denotes patients with at least one missense mutation that is not a D482G or E297G mutation. The BSEP3 genotype is the most severe and denotes patients with mutations that are known or predicted to result in a non-functional BSEP protein or absent BSEP expression. BSEP3 is associated with a relatively high incidence of hepatocellular carcinoma (HCC). It has also been demonstrated that the severity of BSEP deficiency strongly predicts long-term autologous liver survival.

[0136] PFIC 2 typically presents in infants (e.g., aged 6 to 18 months). Infants may exhibit signs of pruritus. Biochemically, individuals with PFIC 2 present with elevated serum transaminases, elevated bilirubin, elevated serum bile acid content, and a lower γGT content. Individuals may also have portal inflammation and giant cell hepatitis. In addition, individuals often develop hepatocellular carcinoma. No medical treatment has been proven beneficial for the long-term treatment of PFIC 2. To reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive), medium-chain triglycerides and fat-soluble vitamins are typically administered to children. The PFIC 2 patient population accounts for approximately 60% of the PFIC population.

[0137] PFIC 3

[0138] PFIC 3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also known as MDR3) located on chromosome 7. Class III multi-drug resistance (MDR3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the secretion of biliary phospholipids (phosphatidylcholine) in the canalicular membrane of hepatocytes. PFIC 3 is caused by bile toxicity in which the detergent bile salts are not activated by phospholipids, leading to damage to bile canaliculi and biliary epithelial cells.

[0139] PFIC 3 also presents in early childhood. In contrast to PFIC 1 and PFIC 2, individuals have elevated gamma-glutamyl transferase (γGT) levels. Individuals also suffer from portal inflammation, fibrosis, cirrhosis, and massive ductal proliferation. Individuals may also develop intrahepatic gallstone disease. Ursodeoxycholic acid has been effective in treating or improving PFIC 3.

[0140] PFIC 4

[0141] PFIC 4 (also known as TJP2 deficiency) is caused by a genetic defect in the TJP2 gene (also known as zonula occludens protein 2) located on chromosome 9. In the liver, tight junction protein 2 (TJP2) is involved in the formation of tight junctions by interacting with transmembrane tight junction proteins and the actin cytoskeleton. Tight junctions are essential in the liver as they help prevent the leakage of biliary components into the hepatic parenchyma. Normally, these proteins are located in the canalicular membrane, but in TJP2 mutations, they fail to localize, especially in the parenchyma of the hepatic lobule. These damaged tight junctions then allow cytotoxic bile salts to leak into the paracellular space, causing damage to the surrounding hepatocytes and biliary epithelial cells.

[0142] PFIC 4 presents as severe cholestasis and lower γGT levels. Patients lack mutations in the ATP8B1 and ABCB11 genes, ruling out the diagnosis of PFIC 1 and PFIC 2. Some patients have been reported to have extrahepatic symptoms, mainly in the neurological and respiratory systems. There have been several reports of HCC in patients with TJP2 deficiency.

[0143] PFIC 5

[0144] PFIC 5 (also known as FXR deficiency) is caused by a genetic defect in the NR1H4 gene (also known as FXR) located on chromosome 12. Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and directly involved in the expression of both BSEP and MDR3 (proteins affected in PFIC 2 and PFIC 3, respectively). FXR is activated by an increased bile acid content in the ileum, leading to the expression of fibroblast growth factor 19 (FGF19). In the liver, FGF19 binds to the fibroblast growth factor receptor 4 / β-Klotho complex, which in turn inhibits cytochrome P450 7A1 (CYP7A1). Inhibition of this enzyme will reduce de novo bile acid synthesis.

[0145] PFIC 5 presents as neonatal-onset normal γGT-related cholestasis, elevated serum bilirubin, elevated serum AFP levels, undetectable BSEP expression in bile canaliculi, and vitamin K-independent coagulopathy. This vitamin K-independent coagulopathy is specific to PFIC 5 and has been shown to be a direct consequence of FXR mutations. Three fibrinogen genes, as well as some coagulation factors, are related to FXR-dependent induction, which does not occur in PFIC 5 patients. NR1H4 / FXR-related PFIC is extremely rare, with only eight cases reported in the literature.

[0146] PFIC 6

[0147] PFIC 6 (also known as MYO5B deficiency) is caused by a genetic defect in the MYO5B gene located on chromosome 18. The interaction between myosin 5B (MYO5B) and RAS-related GTP-binding protein 11A (RAB11A) is crucial for epithelial cell polarization and the localization of BSEP to the bile canalicular membrane. Reduced activity of the MYO5B / RAB11A recycling endosome pathway is associated with disruption of BSEP localization. Mutations in this gene are associated with microvillus inclusion disease (MVID), which affects intestinal epithelial cells and causes diarrhea and malabsorption. The presence of mislocalized apical brush border proteins, ciliary atrophy, and microvillus inclusion disease are all associated with MVID. Total parenteral nutrition (TPN) is required throughout life, but this is associated with a high risk of sepsis and small bowel transplantation.

[0148] MVID has been associated with cholestatic liver disease, which may occur as a result of TPN. In fact, MYO5B gene mutations can account for 20% of idiopathic low γGT-related cholestasis in pediatric patients. This cholestasis presents with low or even normal γGT levels, jaundice, pruritus, mild elevation of alanine transaminase and aspartate transaminase, elevated serum BS levels, hepatomegaly, portal and lobular fibrosis, and giant cell transformation.

[0149] Other PFIC Subtypes

[0150] The phenotypes of PFIC types that have not been genetically characterized are generally presented by clinical manifestations similar to those of other PFIC subtypes described herein. These phenotypes may include jaundice, cholestasis (confirmed by elevated serum bile acids), elevated liver enzymes, and other symptoms associated with cholestasis, including pruritus, growth defects, and poor quality of life. New phenotypes associated with mutations in each gene are still emerging.

[0151] Intermittent cholestasis or elevated serum bile acids may be present in patients with BSEP deficiency or other genetic subtypes. Symptoms associated with intermittent sBa elevation may include pruritus and poor quality of life, and may affect children and adults. Patients may have elevated liver enzymes spontaneously or persistently.

[0152] Patients who have undergone a bile diversion surgery to divert bile acids may still present symptoms associated with PFIC, including pruritus, poor quality of life, and poor growth and nutrition. In some patients who experience recurrent elevated serum bile acids and recurrence of pruritus, as well as other symptoms of elevated related liver enzymes or cholestasis, the surgical diversion that usually successfully reduces bile acids and improves symptoms may lose its effectiveness.

[0153] In some cases, PFIC mutations can be heterozygous. Any one of PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5, PFIC 6, or other PFIC subtypes can have heterozygosity. In non-limiting examples, an individual can have non-truncated PFIC 2 with heterozygosity. In another example, an individual can have PFIC 1 with heterozygosity. In one embodiment, an individual can have a heterozygous ABCB11 mutation. In another embodiment, an individual can have a heterozygous ATP8B1 mutation.

[0154] ASBT inhibitor

[0155] In various embodiments of the methods of the present invention, an ASBT inhibitor is administered to an individual. In some embodiments, the ASBTI inhibitor is maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBTI inhibitor is maribavir chloride. The ASBT inhibitor (ASBTI) reduces or inhibits bile acid recirculation in the distal gastrointestinal (GI) tract, including the distal ileum, colon, and / or rectum. Inhibiting apical sodium-dependent bile acid transport will interrupt the enterohepatic circulation of bile acids and result in more bile acids being excreted in the feces, see Figure 1, causing a decrease in the total body bile acid content, thereby reducing bile acid-mediated liver injury and related effects and complications. In certain embodiments, the ASBTI is systemically absorbed. In certain embodiments, the ASBTI is not systemically absorbed. In one embodiment, maralixibat is a non-systemically absorbed ASBTI. In some embodiments, the ASBTI used in the methods or compositions of the present invention is maralixibat or a pharmaceutically acceptable salt thereof.

[0156] In one embodiment, the ASBTI used in the methods or compositions of the present invention is

[0157] (maralixibat chloride, LUM-001, SHP625, lopixibat chloride).

[0158] In one embodiment, the ASBTI used in the methods or compositions of the present invention is maralixibat bromide.

[0159] In one embodiment, the ASBTI used in the methods or compositions of the present invention is maralixibat acetate.

[0160] In one embodiment, the ASBTI used in the methods or compositions of the present invention is maralixibat mesylate.

[0161] Method for treating cholestasis

[0162] The present disclosure provides methods for treating cholestasis in an individual suffering from a liver disease. The methods include administering an apical sodium-dependent bile acid transporter inhibitor (ASBTI) to an individual in need of treatment. The ASBTI is maralixibat, maralixibat chloride, or an alternative pharmaceutically acceptable salt. The ASBTI is administered in an amount of from about 140 μg / kg per day to about 1400 μg / kg per day.

[0163] In various embodiments, the liver disease is a cholestatic liver disease. In some embodiments, the liver disease is PFIC, ALGS, PSC, biliary atresia, intrahepatic cholestasis of pregnancy, PBC, any one of the cholestatic liver diseases discussed above, or various combinations thereof. In some embodiments, the liver disease is PFIC.

[0164] In certain embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, PFIC type 4, PFIC type 5, PFIC type 6, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, after Kasai operation for biliary atresia, after liver transplantation for biliary atresia, after liver transplantation for cholestasis, post-liver transplantation related liver disease, intestinal failure related liver disease, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric obstructive cholestasis, pediatric non-obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, BRIC, BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition related cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-related cholestasis, infection-related cholestasis or gallstone disease. In some embodiments, the cholestatic liver disease is a pediatric form of liver disease. In some embodiments, the individual has intrahepatic cholestasis of pregnancy (ICP).

[0165] In certain embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC). In certain embodiments, the cholestatic liver disease is PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5 or PFIC 6. In one embodiment, the cholestatic liver disease is PFIC 1. In one embodiment, the cholestatic liver disease is PFIC 2. In one embodiment, the cholestatic liver disease is PFIC 3. In one embodiment, the cholestatic liver disease is PFIC 4. In one embodiment, the cholestatic liver disease is PFIC 5. In one embodiment, the cholestatic liver disease is PFIC 6.

[0166] In one embodiment, the cholestatic liver disease is non-truncated PFIC 2. In one embodiment, the cholestatic liver disease is truncated PFIC 2.

[0167] In one embodiment, the cholestatic liver disease is heterozygous PFIC.

[0168] In certain embodiments, cholestatic liver disease is characterized by one or more symptoms selected from the following: jaundice, pruritus, cirrhosis, hyperkalemia, neonatal respiratory distress syndrome, pneumonia, increased serum concentration of bile acids, increased liver bile acid concentration, increased serum bilirubin concentration, hepatocyte injury, liver scarring, liver failure, hepatomegaly, xanthoma, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocyte necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, abnormal taste, dark urine, loose stools, steatorrhea, failure to thrive, and / or renal failure.

[0169] In various embodiments, the liver disease is PFIC 1, and the individual has a mutation in the ATP8B1 gene. In various embodiments, the mutation in the ATP8B1 gene is a missense mutation. In various embodiments, the mutation in the ATP8B1 gene is a nonsense mutation. In various embodiments, the mutation can be selected from one of the mutations listed in the following: Klomp et al., "Characterization of mutations in ATP8B1 associated with hereditary cholestasis", Hepatology, 40:27-38 (2004), which is incorporated herein by reference in its entirety for all purposes.

[0170] In various embodiments, the liver disease is PFIC 2, and the individual 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 the following: Byrne et al., "Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messenger RNA Splicing", Hepatology, 49:553-567 (2009), which is incorporated herein by reference in its entirety for all purposes.

[0171] In various embodiments, the liver disease is PFIC 3, and the individual has a mutation in the ABCB4 gene. In various embodiments, the mutation in the ABCB4 gene is a missense mutation. In various embodiments, the mutation in the ABCB4 gene is a nonsense mutation. In various embodiments, the mutation can be selected from one of the mutations listed below: Degiorgio et al., "Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC 3)", Eur J Hum Genet, 15:1230-1238 (2007), which is incorporated herein by reference in its entirety for all purposes.

[0172] In various embodiments, the liver disease is PFIC 4, and the individual has a truncating mutation in the TJP2 gene. In various embodiments, the truncating mutation in the TJP2 gene can be selected from one of the mutations listed below: Sambrotta et al., "Mutations in TJP2 cause progressive cholestatic liver disease", Nat Genet, 46:326-328 (2014), which is incorporated herein by reference in its entirety for all purposes.

[0173] In various embodiments, the liver disease is PFIC 5, and the individual has a mutation in the NR1H4 gene. In various embodiments, the mutation in the NR1H4 gene is a nonsense mutation. In various embodiments, the mutation can be selected from one of the mutations listed below: Gomez-Ospina et al., "Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis", Nat Commun, 7:1-8 (2016), which is incorporated herein by reference in its entirety for all purposes.

[0174] In various embodiments, the liver disease is PFIC 6 and the individual has a non-truncating mutation in the MYO5B gene. In various embodiments, the non-truncating mutation in the MYO5B gene is a missense mutation. In various embodiments, the missense mutation can be selected from one of the mutations listed in the following: Overeem, et al., "A Molecular Mechanism Underlying Genotype-Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations", Hepatology, 72:213-229 (2020), which is incorporated herein by reference in its entirety for all purposes.

[0175] In various embodiments, the individual has a condition associated with, caused by, or partially caused by BSEP deficiency. In certain embodiments, the condition associated with, caused by, or partially caused by BSEP deficiency is PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5, PFIC 6, or a combination thereof. In certain embodiments, the BSEP deficiency is BSEP1, BSEP2, or BSEP3 as defined herein and in the following: van Wessel, et al., "Genotype Correlates with the Natural History of Severe Bile Salt Export Pump Deficiency", Journal of Hepatology, 73(1):84-93 (2020), which is incorporated herein by reference in its entirety for all purposes. In various embodiments, the individual has heterozygous PFIC. In some embodiments, the individual has PFIC characterized by intermittent cholestasis. In some embodiments, the individual with PFIC has undergone a biliary diversion surgery.

[0176] In various embodiments, the patient is a pediatric patient less than 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, or 18 years of age. In certain embodiments, the pediatric individual is a neonate, a premature infant, an infant, a toddler, a preschooler, a school-age child, a preadolescent, a postadolescent, an adolescent, or a juvenile under the age of eighteen. In some embodiments, the pediatric individual is a neonate, a premature infant, an infant, a toddler, a preschooler, or a school-age child. In some embodiments, the pediatric individual is a neonate, a premature infant, an infant, a toddler, or a preschooler. In some embodiments, the pediatric individual is a neonate, a premature infant, an infant, or a toddler. In some embodiments, the pediatric individual is a neonate, a premature infant, or an infant. In some embodiments, the pediatric individual is a neonate. In some embodiments, the pediatric individual is an infant. In some embodiments, the pediatric individual is a toddler. In various embodiments, the pediatric patient has PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5, or PFIC 6. In various embodiments, the pediatric patient has heterozygous PFIC or PFIC associated with intermittent cholestasis, or the pediatric PFIC individual has undergone a biliary shunt procedure. In some embodiments, the patient is an adult over 18 years, 20 years, 30 years, 40 years, 50 years, 60 years, or 70 years of age.

[0177] In certain embodiments, the method of the invention comprises non-systemic administration of a therapeutically effective amount of maralixibat or maralixibat chloride. 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 with maralixibat or maralixibat chloride. In various embodiments, the method of the invention results in a reduction of bile acids within enterocytes, or a reduction of damage to hepatocytes or the intestinal architecture caused by cholestasis or cholestatic liver disease.

[0178] In various embodiments, the method of the invention comprises delivering a therapeutically effective amount of maralixibat or maralixibat chloride to the ileum or colon of an individual.

[0179] In various embodiments, the method of the invention comprises reducing damage to hepatocytes or the intestinal architecture caused by cholestasis or cholestatic liver disease by administering a therapeutically effective amount of maralixibat or maralixibat chloride. In certain embodiments, the method of the invention comprises reducing bile acids / salts within enterocytes by administering a therapeutically effective amount of maralixibat or maralixibat chloride to an individual in need.

[0180] In some embodiments, the method of the present invention provides inhibition of bile salt recycling after administration of any of the compounds described herein to an individual. In some embodiments, maribavir or maribavir chloride is not systemically absorbed. In some embodiments, maribavir or maribavir chloride is administered orally to an individual. In some embodiments, maribavir or maribavir chloride is delivered and / or released in the distal ileum of the individual.

[0181] In various embodiments, contacting the distal ileum of an individual with an ASBTI (e.g., maribavir or maribavir chloride) will inhibit bile acid reabsorption and increase the bile acid / salt concentration near L cells in the distal ileum and / or colon and / or rectum, thereby reducing intracellular bile acids in enterocytes, lowering serum and / or liver bile acid content, reducing the overall serum bile acid load, and / or reducing damage to the intestinal architecture caused by cholestasis or cholestatic liver disease. Without being limited by any particular theory, reducing serum and / or liver bile acid content will improve hyperkalemia and / or cholestatic diseases.

[0182] The compounds described herein are administered in any suitable manner, by way of non-limiting example, including 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 method or formulation suitable for treating neonates or infants. Any compound or composition described herein can be administered in the form of an oral formulation (e.g., solid or liquid) to treat neonates or infants. Any compound or composition described herein can be administered before, during, or after a meal.

[0183] In certain embodiments, the compounds described herein or compositions comprising the compounds are administered for prophylactic and / or therapeutic treatment. In a therapeutic application, the composition is administered to an individual having a disease or condition in an amount sufficient to cure or at least partially inhibit the symptoms of the disease or condition. In each case, the amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the health status, weight, and response of the individual to the drug, and the judgment of the treating physician.

[0184] In a prophylactic application, the compounds described herein or compositions comprising the compounds can be administered to individuals predisposed to or otherwise at risk of developing a particular disease, disorder, or condition. In certain embodiments regarding this use, the precise amount of the compound administered depends on the health status, weight, etc. of the individual. Additionally, in some cases, when the compounds or compositions described herein are administered to an individual, the amount effective for this use depends on the severity and course of the disease, disorder, or condition, previous therapy, the health status of the individual, and the response to the drug and the judgment of the treating physician.

[0185] In certain embodiments of the method of the present invention, if the condition of an individual does not improve after administration of a selected dose of the compounds or compositions described herein, then, at the discretion of the physician, administration of the compounds or compositions described herein is optionally continued for a long term, i.e., for a prolonged period of time, including the entire duration of the individual's life, in order to improve 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 a variety of factors, such as the particular compound, the disease or condition and its severity, the identity (e.g., weight) of the individual or host to be treated, and is determined according to the specific circumstances of the case, including, for example, the particular agent administered, the route of administration, the condition being treated and the individual or host being treated. In some embodiments, the dose administered comprises a dose up to the maximum tolerable dose. In some embodiments, the dose administered comprises a dose up to the maximum tolerable dose for a neonate or infant.

[0187] In various embodiments of the method of the present invention, the required dose is preferably presented as a single dose or as divided doses administered simultaneously (or over a shorter time period) or at appropriate time intervals (e.g., two, three, four or more sub-doses per day). In various embodiments, a single dose of maribavir or maribavir chloride 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 maribavir or maribavir chloride is within the ranges described below.

[0188] In various embodiments of the method of the present invention, in the event that the patient's condition does improve, maribavir or maribavir chloride is optionally administered continuously at the discretion of the physician; or, the dose of the drug administered is temporarily reduced or temporarily suspended for a length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including, for example, 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. The dose reduction during the drug holiday includes 10%-100% of the initial dose, by way of example only, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the initial dose. In some embodiments, the total single dose of ASBTI is within the ranges described below.

[0189] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the administered dose or frequency or both are reduced to an extent that maintains the improved disease, disorder, or condition, depending on the symptoms. In some embodiments, the patient requires long-term intermittent treatment upon any recurrence of symptoms.

[0190] In certain cases, there are a large number of variables in the individual treatment regimens, and a significant deviation from these recommended values is considered to be within the scope described herein. The doses described herein are optionally varied depending on a number of variables such as, by way of non-limiting example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual patient, the severity of the disease or condition being treated, and the judgment of the physician.

[0191] Dose

[0192] In various embodiments, the ASBTI is maribavir or a pharmaceutically acceptable salt thereof.

[0193] In various embodiments, the efficacy and safety of the ASBTI administered to a patient are monitored by measuring the serum content of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), the conjugated bilirubin concentration of the serum, the serum autotaxin concentration, the serum fibroblast growth factor (FGF-19) concentration, the serum bilirubin concentration, the serum total cholesterol concentration, the serum LDL-C concentration, the serum ALT concentration, the serum AST concentration, or a combination thereof. In various embodiments, the efficacy of ASBTI administration is measured by monitoring the observer-reported itch report outcome (ITCHRO(OBS)) score, HRQoL (e.g., PedsQL) score, CSS score, xanthoma score, height Z-score, weight Z-score, or various combinations thereof. In various embodiments, the method includes monitoring the serum content of 7αC4, sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), the conjugated bilirubin concentration of the serum, the serum total cholesterol concentration, the serum LDL-C concentration, the serum autotaxin concentration, the serum bilirubin concentration, the serum ALT concentration, the serum AST concentration, or a combination thereof. In various embodiments, the method includes monitoring the observer-reported itch report outcome (ITCHRO(OBS)) score, weight Z-score, HRQoL (e.g., PedsQL) score, xanthoma score, CSS score, height Z-score, or various combinations thereof.

[0194] In some embodiments, ASBTI is administered at a dose of 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, 200 μg / kg, 240 μg / kg, 280 μg / kg, 300 μg / kg, 250 μg / kg, 280 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 560 μg / kg, 600 μg / kg, 700 μg / kg, 800 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, 1500 μg / kg, 1,600 μg / kg, 1,700 μg / kg, 1,800 μg / kg, 1,900 μg / kg or 2,000 μg / kg.In various embodiments, ASBTI is administered at a dose not exceeding the following: 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 / 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, 200 μg / kg, 240 μg / kg, 280 μg / kg, 300 μg / kg, 250 μg / kg, 280 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 560 μg / kg, 600 μg / kg, 700 μg / kg, 800 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, ASBTI is administered at a dose of about or at least about the following: 0.5 mg per day, 1 mg per day, 2 mg per day, 3 mg per day, 4 mg per day, 5 mg per day, 6 mg per day, 7 mg per day, 8 mg per day, 9 mg per day, 10 mg per day, 11 mg per day, 12 mg per day, 13 mg per day, 14 mg per day, 15 mg per day, 16 mg per day, 17 mg per day, 18 mg per day, 19 mg per day, 20 mg per day, 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 300 mg per day, 500 mg per day, 600 mg per day, 700 mg per day, 800 mg per day, 900 mg per day, 1000 mg per day.In various embodiments, ASBTI is administered at a dose not exceeding the following: about 1 mg per day, 2 mg per day, 3 mg per day, 4 mg per day, 5 mg per day, 6 mg per day, 7 mg per day, 8 mg per day, 9 mg per day, 10 mg per day, 11 mg per day, 12 mg per day, 13 mg per day, 14 mg per day, 15 mg per day, 16 mg per day, 17 mg per day, 18 mg per day, 19 mg per day, 20 mg per day, 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 300 mg per day, 500 mg per day, 600 mg per day, 700 mg per day, 800 mg per day, 900 mg per day, 1,000 mg per day, 1,100 mg per day.

[0195] In some embodiments, maribavir is administered at a dose of from about 140 μg / kg per day to about 1400 μg / kg per day. In various embodiments, maribavir is administered at a dose of about or at least about the following: 0.5 μg / kg per day, 1 μg / kg per day, 2 μg / kg per day, 3 μg / kg per day, 4 μg / kg per day, 5 μg / kg per day, 6 μg / kg per day, 7 μg / kg per day, 8 μg / kg per day, 9 μg / kg per day, 10 μg / kg per day, 15 μg / kg per day, 20 μg / kg per day, 25 μg / kg per day, 30 μg / kg per day, 35 μg / kg per day, 40 μg / kg per day, 45 μg / kg per day, 50 μg / kg per day, 100 μg / kg per day, 140 μg / kg per day, 150 μg / kg per day, 200 μg / kg per day, 240 μg / kg per day, 250 μg / kg per day, 280 μg / kg per day, 300 μg / kg per day, 400 μg / kg per day, 500 μg / kg per day, 560 μg / kg per day, 600 μg / kg per day, 700 μg / kg per day, 800 μg / kg per day, 900 μg / kg per day, 1,000 μg / kg per day, 1,100 μg / kg per day, 1,200 μg / kg per day, or 1,300 μg / kg per day. In various embodiments, maribavir is administered at a dose not exceeding the following: about 1 μg / kg per day, 2 μg / kg per day, 3 μg / kg per day, 4 μg / kg per day, 5 μg / kg per day, 6 μg / kg per day, 7 μg / kg per day, 8 μg / kg per day, 9 μg / kg per day, 10 μg / kg per day, 15 μg / kg per day, 20 μg / kg per day, 25 μg / kg per day, 30 μg / kg per day, 35 μg / kg per day, 40 μg / kg per day, 45 μg / kg per day, 50 μg / kg per day, 100 μg / kg per day, 140 μg / kg per day, 150 μg / kg per day, 200 μg / kg per day, 240 μg / kg per day, 280 μg / kg per day, 300 μg / kg per day, 250 μg / kg per day, 280 μg / kg per day, 300 μg / kg per day, 400 μg / kg per day, 500 μg / kg per day, 560 μg / kg per day, 600 μg / kg per day, 700 μg / kg per day, 800 μg / kg per day, 900 μg / kg per day, 1,000 μg / kg per day, 1,100 μg / kg per day, 1,200 μg / kg per day, 1,300 μg / kg per day, or 1,400 μg / kg per day.In various embodiments, maribavir is administered at the following doses: from about 0.5 μg / kg per day to about 500 μg / kg per day, from about 0.5 μg / kg per day to about 250 μg / kg per day, from about 1 μg / kg per day to about 100 μg / kg per day, from about 10 μg / kg per day to about 50 μg / kg per day, from about 10 μg / kg per day to about 100 μg / kg per day, from about 0.5 μg / kg per day to about 2000 μg / kg per day, from about 280 μg / kg per day to about 1400 μg / kg per day, from about 420 μg / kg per day to about 1400 μg / kg per day, from about 250 to about 550 μg / kg per day, from about 560 μg / kg per day to about 1400 μg / kg per day, from 700 μg / kg per day to about 1400 μg / kg per day, from about 560 μg / kg per day to about 1200 μg / kg per day, from about 700 μg / kg per day to about 1200 μg / kg per day, from about 560 μg / kg per day to about 1000 μg / kg per day, from about 700 μg / kg per day to about 1000 μg / kg per day, from about 800 μg / kg per day to about 1000 μg / kg per day, from about 200 μg / kg per day to about 600 μg / kg per day, from about 300 μg / kg per day to about 600 μg / kg per day, from about 400 μg / kg per day to about 500 μg / kg per day, from about 400 μg / kg per day to about 600 μg / kg per day, from about 400 μg / kg per day to about 700 μg / kg per day, from about 400 μg / kg per day to about 800 μg / kg per day, from about 500 μg / kg per day to about 800 μg / kg per day, from about 500 μg / kg per day to about 900 μg / kg per day, from about 600 μg / kg per day to about 900 μg / kg per day, from about 700 μg / kg per day to about 900 μg / kg per day, from about 200 μg / kg per day to about 600 μg / kg per day, from about 800 μg / kg per day to about 900 μg / kg per day, from about 100 μg / kg per day to about 1500 μg / kg per day, from about 300 μg / kg per day to about 2,000 μg / kg per day or from about 400 μg / kg per day to about 2000 μg / kg per day.

[0196] In some embodiments, maribavir is administered at a dose of about 30 μg / kg to about 1400 μg / kg per dose. In some embodiments, maribavir is administered at the following doses: about 0.5 μg / kg to about 2000 μg / kg per dose, about 0.5 μg / kg to about 1500 μg / kg per dose, about 100 μg / kg to about 700 μg / kg per dose, about 5 μg / kg to about 100 μg / kg per dose, about 10 μg / kg to about 500 μg / kg per dose, about 50 μg / kg to about 1400 μg / kg per dose, about 300 μg / kg to about 2,000 μg / kg per dose, about 60 μg / kg to about 1200 μg / kg per dose, about 70 μg / kg to about 1000 μg / kg per dose, about 70 μg / kg to about 700 μg / kg per dose, 80 μg / kg to about 1000 μg / kg per dose, 80 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 600 μg / kg per dose, 150 μg / kg to about 700 μg / kg per dose, 150 μg / kg to about 500 μg / kg per dose, 200 μg / kg to about 400 μg / kg per dose, 200 μg / kg to about 300 μg / kg per dose, or 300 μg / kg to about 400 μg / kg per dose.

[0197] In some embodiments, maribavir is administered at a dose of about 0.5 mg to about 550 mg per day. In various embodiments, maribavir is administered at the following doses: about 1 mg to about 500 mg per day, about 1 mg to about 300 mg per day, about 1 mg to about 200 mg per day, about 2 mg to about 300 mg per day, about 2 mg to about 200 mg per day, about 4 mg to about 300 mg per day, about 4 mg to about 200 mg per day, about 4 mg to about 150 mg per day, about 5 mg to about 150 mg per day, about 5 mg to about 100 mg per day, about 5 mg to about 80 mg per day, about 5 mg to about 50 mg per day, about 5 mg to about 40 mg per day, about 5 mg to about 30 mg per day, about 5 mg to about 20 mg per day, about 5 mg to about 15 mg per day, about 10 mg to about 100 mg per day, about 10 mg to about 80 mg per day, about 10 mg to about 50 mg per day, about 10 mg to about 40 mg per day, about 10 mg to about 20 mg per day, about 20 mg to about 100 mg per day, about 20 mg to about 80 mg per day, about 20 mg to about 50 mg per day, or about 20 mg to about 40 mg per day, or about 20 mg to about 30 mg per day.

[0198] In some embodiments, maribavir is administered twice daily (BID) in an amount of about 150 μg / kg to about 600 μg / kg per dose. In some embodiments, maribavir is administered in an amount of about 280 μg / kg to about 1400 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 400 μg / kg to about 800 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 20 mg to about 50 mg per day. In some embodiments, maribavir is administered in an amount of about 5 mg to about 15 mg per day. In some embodiments, maribavir is administered in an amount of about 560 μg / kg to about 1,400 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 700 μg / kg to about 1,400 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 400 μg / kg to about 800 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 700 μg / kg to about 900 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 560 μg / kg to about 1400 μg / kg per day. In some embodiments, maribavir is administered in an amount of 700 μg / kg to about 1400 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 200 μg / kg to about 600 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 400 μg / kg to about 600 μg / kg per day. In some embodiments, maribavir is administered in an amount of about 1100 μg / kg to about 1200 μg / kg per day. In some embodiments, maribavir as the maribavir free base is administered twice daily (BID) in an amount of about 570 μg / kg per day of maribavir, which is equivalent to an amount of about 600 μg / kg per day of maribavir chloride twice daily (BID).

[0199] In various embodiments, the dose of maribavir is a first dose level. In various embodiments, the dose of maribavir is a second dose level. In various embodiments, the dose of maribavir is a third dose level. In various embodiments, the dose of maribavir is a fourth dose level. In some embodiments, the second dose level is greater than the first dose level. In some embodiments, the second dose level is 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, or 100 times greater than the first dose level. In some embodiments, the second dose level is no more than about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times greater than the first dose level. In some embodiments, the third dose level is greater than the second dose level. In some embodiments, the third dose level is 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, or 100 times greater than the second dose level. In some embodiments, the third dose level is no more than about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times greater than the second dose level. In some embodiments, the fourth dose level is greater than the third dose level. In some embodiments, the fourth dose level is 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, or 100 times greater than the third dose level. In some embodiments, the fourth dose level is no more than about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times greater than the third dose level.

[0200] In various embodiments, maribavir is administered once daily (QD) at one of the above doses or one of the above dose ranges. In various embodiments, maribavir is administered twice daily (BID) at one of the above doses or one of the above dose ranges. In various embodiments, the ASBTI dose is administered daily, every other day, twice a week, or once a week.

[0201] In various embodiments, maribavir is administered periodically for a period of 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, maribavir is administered for no more than 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, maribavir 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, maribavir is administered periodically for no more than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

[0202] Reduction in symptoms of cholestatic liver disease or disease-related laboratory measure changes

[0203] In various embodiments of the methods of the present invention described above, administration of maribavir or maribavir chloride results in a reduction in symptoms of cholestatic liver disease or changes in disease-related laboratory measures (i.e., improvement in the patient's condition) that is maintained for about the following or at least about the following: 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. In various embodiments, the reduction in changes in symptoms or disease-related laboratory measures comprises a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the 7αC4:sBA ratio, an increase in fBA secretion, a decrease in pruritus, a decrease in serum total cholesterol concentration, a decrease in serum LDL-C cholesterol concentration, a decrease in ALT content, an increase in quality of life questionnaire score, an increase in quality of life questionnaire score related to fatigue, a decrease in xanthoma score, a decrease in serum autotaxin concentration, an increase in growth, or a combination thereof. In various embodiments, the reduction in changes in symptoms or disease-related laboratory measures comprises a decrease in sBA concentration, a reduction in pruritus, a decrease in total bilirubin, a decrease in direct bilirubin, an improvement in growth, or a combination thereof. In various embodiments, the reduction in changes in symptoms or disease-related laboratory measures is determined relative to a baseline level. That is, the reduction in changes in symptoms or disease-related laboratory measures is determined relative to the measurement of changes in symptoms or disease-related laboratory measures prior to: 1) changing the dose level of the ASBTI administered to the patient; 2) changing the dosing regimen followed by the patient; 3) starting administration of the ASBTI; or 4) any other various changes made to reduce the changes in symptoms or disease-related laboratory measures in the patient. In various embodiments, the reduction in changes in symptoms or disease-related laboratory measures is a statistically significant reduction.

[0204] In various embodiments, the reduction in symptoms of cholestatic liver disease or disease-related laboratory measure changes is measured by a reduction in progressive symptoms or disease-related laboratory measure changes persisting for about the following or at least about the following times: 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.

[0205] In some embodiments, the patient is a pediatric patient, and the reduction in symptoms or disease-related laboratory measure changes includes an increase or improvement in growth. In some embodiments, the increase in growth is measured relative to a baseline. In various embodiments, the increase in growth is measured by 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 height Z-score, weight Z-score, or both increase by 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, 0.4, 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 points relative to the baseline. In some embodiments, the height Z-score, weight Z-score, or both increase gradually during ASBTI administration for 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.

[0206] In various embodiments, administration of ASBTI causes an increase in serum 7αC4 concentration. In various embodiments, the 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-fold relative to baseline. In various embodiments, the 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% relative to baseline.

[0207] In various embodiments, administration of ASBTI causes a decrease in total bilirubin. In various embodiments, the total bilirubin decreases by about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9-fold relative to baseline. In various embodiments, the total bilirubin decreases by about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to baseline. In various embodiments, the total bilirubin decreases by about or at least about 0.1 mg / dL, 0.2 mg / dL, 0.3 mg / dL, 0.4 mg / dL, 0.5 mg / dL, 0.6 mg / dL, 0.7 mg / dL, 0.8 mg / dL, 0.9 mg / dL, 1.0 mg / dL, 1.1 mg / dL, or 1.2 mg / dL.

[0208] In various embodiments, administration of ASBTI causes a decrease in direct bilirubin. In various embodiments, the direct bilirubin decreases by about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9-fold relative to baseline. In various embodiments, the direct bilirubin decreases by about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to baseline. In various embodiments, the direct bilirubin decreases by about or at least about 0.1 mg / dL, 0.2 mg / dL, 0.3 mg / dL, 0.4 mg / dL, 0.5 mg / dL, 0.6 mg / dL, 0.7 mg / dL, 0.8 mg / dL, 0.9 mg / dL, 1.0 mg / dL, 1.1 mg / dL, or 1.2 mg / dL.

[0209] In various embodiments, administration of ASBTI causes the 7αC4:sBA ratio to increase relative to baseline to about or 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.

[0210] In various embodiments, administration of ASBTI causes an increase in fBA secretion. In some embodiments, administration of ASBTI causes fBA secretion to increase relative to baseline by 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%. In various embodiments, fBA secretion increases relative to baseline 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-fold. In some embodiments, fBA secretion increases relative to baseline 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. In various embodiments, administration of ASBTI causes a dose-dependent increase in fBA secretion such that administration of a higher dose of ASBTI causes a correspondingly higher level of fBA secretion. In various embodiments, ASBTI is administered at a dose sufficient to cause an increase in bile acid secretion relative to baseline that is 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-fold relative to baseline.

[0211] In various embodiments, administration of ASBTI causes the sBA concentration to decrease relative to baseline by 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%.

[0212] In some embodiments, administration of ASBTI results in a reduction in the severity of itching. In various embodiments, the severity of itching is measured using the ITCHRO(OBS) score, the ITCHRO score, the CSS score, or a combination thereof. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO(OBS) score on a 1 to 4 scale by 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 points relative to baseline. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO score on a 1 to 10 scale by 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 points. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO(OBS) score, the ITCHRO score, or both to zero. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO(OBS) score or the ITCHRO score to 1.0 or lower. In various embodiments, administration of ASBTI results in a reduction of the CSS score by 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 points relative to baseline. In various embodiments, administration of ASBTI results in a reduction of the CSS score to zero. In various embodiments, administration of ASBTI results in a reduction of the CSS score, the ITCHRO(OBS) score, the ITCHRO score, or a combination thereof by about or at least about 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 the CSS score, the ITCHRO(OBS) score, the ITCHRO score, or a combination thereof relative to 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 the days.

[0213] In some embodiments, patients with a higher baseline ITCHRO (OBS) score exhibit a greater reduction in symptom - or disease - related laboratory measures compared to 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 exhibit a greater reduction in symptom - or disease - related laboratory measures relative to baseline compared to patients with a lower baseline pruritus severity score. In various embodiments, patients with PSC and a baseline ITCHRO score of at least 4 exhibit a greater reduction in symptom - or disease - related laboratory measures compared to patients with a baseline ITCHRO score of less than 4. In various embodiments, the method includes predicting that a patient has a greater reduction in symptom - or disease - related laboratory measures when the patient's baseline ITCHRO score is at least 4 compared to a patient with a baseline ITCHRO score of less than 4. In various embodiments, a lower reduction is about or less than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the greater reduction. In various embodiments, the difference in the reduction of symptom - or disease - related laboratory measures between patients with an ITCHRO score of at least 4 at baseline and patients with an ITCHRO score of less than 4 at baseline (i.e., between the greater reduction and the lower reduction) is measured at 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 after the first administration of the first or second dose of ASBTI.

[0214] In various embodiments, the reduction in pruritus severity caused by administering ASBTI to a patient is positively correlated with a reduction in the patient's sBA concentration. In various embodiments, a greater reduction in the patient's sBA concentration is associated with a corresponding greater reduction in pruritus severity.

[0215] In various embodiments, administration of ASBTI causes a decrease in serum LDL-C concentration relative to baseline. In some embodiments, the serum LDL-C concentration is decreased 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 ASBTI causes a decrease in serum total cholesterol concentration relative to baseline. In some embodiments, administration of ASBTI causes a decrease in serum LDL-C content relative to baseline. In some embodiments, the serum total cholesterol concentration, the serum LDL-C content, or both are decreased 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 ASBTI causes the serum total cholesterol concentration, the serum LDL-C content, or both to be decreased by 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 ASBTI causes a decrease in serum autotaxin concentration. In some embodiments, administration of ASBTI causes the serum autotaxin concentration to be decreased by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline.

[0218] In various embodiments, administration of ASBTI causes improvement in sleep. In some embodiments, sleep is evaluated using the Exploratory Diary Questionnaire (EDQ(Obs)). In some embodiments, the average morning EDQ(Obs) sleep disorder score is decreased 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.

[0219] In some embodiments, administration of ASBTI results in improved sleep, as measured by a reduction of at least 1.0 point in an individual's EDQ(Obs) or EDQ(Pt) score relative to baseline. In some embodiments, administration of ASBTI results in improved sleep, as measured by a reduction of at least 1.2 points in an individual's EDQ(Obs) or EDQ(Pt) score relative to baseline. In some embodiments, administration of ASBTI results in improved sleep, as measured by a reduction of at least 1.4 points in an individual's EDQ(Obs) or EDQ(Pt) score relative to baseline. In some embodiments, administration of ASBTI results in improved sleep, as measured by a reduction of at least 1.6 points in an individual's EDQ(Obs) or EDQ(Pt) score relative to baseline.

[0220] In various embodiments, administration of ASBTI results in an increase in a quality of life questionnaire score or a quality of life questionnaire score related to fatigue. The quality of life questionnaire 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 ASBTI results in a PedsQL score or a PedsQL score related to fatigue increasing by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to baseline.

[0221] In various embodiments, administration of ASBTI results in a reduction in xanthoma score relative to baseline. In some embodiments, the xanthoma score is reduced 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.

[0222] In various embodiments, administration of ASBTI results in a decrease in a symptom- or disease-related laboratory measure 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, or 1 year.

[0223] In various embodiments, the serum bilirubin concentration is at the pre - administration baseline level or normal level at or by 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 or 1 year.

[0224] In various embodiments, the serum ALT concentration is at the pre - administration baseline level or normal level at or by 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. In some embodiments, administration of ASBTI causes a decrease in ALT content of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% relative to the baseline.

[0225] In various embodiments, the serum ALT concentration, serum AST concentration, serum bilirubin concentration, conjugated bilirubin concentration of the serum, or various combinations thereof are within the normal range or at the pre - administration baseline level at or by about the following times: 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. In various embodiments, administration of ASBTI does not cause a statistically significant change in the serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or a combination thereof relative to the baseline for at least about or about the following time periods: 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. In various embodiments, for adult patients with an ITCHRO score of at least 4 at baseline, administration of ASBTI does not cause a significant change in the conjugated bilirubin concentration of the serum relative to the baseline for at least about or about the following time periods: 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.

[0226] Dose adjustment

[0227] In various embodiments, the method includes adjusting the dose of maribavir administered to a patient. In some embodiments, adjusting the dose of maribavir may include increasing the dose of maribavir. In some embodiments, adjusting includes administering a first dose level of maribavir to a patient in a first week. If the patient tolerates the first dose level, the dose level is increased to a second dose level in a second week. If the patient tolerates the second dose level, the dose level is increased to a third dose level in a third week. If the patient tolerates the third dose level, the dose level is increased to a fourth dose level for the remainder of the treatment study.

[0228] In some embodiments, the method includes a dose escalation period. In one non-limiting embodiment, the dose escalation period includes the following weekly steps: a) Dose level 1: 150 μg / kg maribavir BID for 1 week; b) Dose level 2: 300 μg / kg maribavir BID for 1 week; c) Dose level 3: 450 μg / kg maribavir BID for 1 week; d) Dose level 4: 600 μg / kg maribavir BID for the remaining duration of administration. In another non-limiting embodiment, the dose escalation steps may be delayed or reversed to improve tolerance.

[0229] Drug composition

[0230] In some embodiments, maribavir is administered in the form of a drug composition comprising maribavir or maribavir chloride. 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 local delivery to the rectum and / or colon. It should be understood that as used herein, delivery to the colon includes delivery to the sigmoid colon, transverse colon, and / or ascending colon. In even more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and / or colon by rectal administration. In other specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and / or colon by oral administration.

[0231] In certain embodiments, a drug composition is provided herein that comprises a therapeutically effective amount of any compound described herein. In certain cases, the drug composition comprises an ASBT inhibitor (e.g., maribavir or maribavir chloride).

[0232] In certain embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, which carriers include, for example, excipients and auxiliaries that assist in processing the active compound into a formulation suitable for pharmaceutical use. In certain embodiments, the appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Dekker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins, 1999), all of the above references being incorporated herein by reference in their entirety for all purposes.

[0233] 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 some cases, the pharmaceutical composition facilitates the administration of the compound to an individual or a cell. In certain embodiments of practicing the therapeutic or use methods provided herein, a therapeutically effective amount of the compound described herein is administered to an individual suffering from a disease, disorder, or condition to be treated in the form of a pharmaceutical composition. In a particular embodiment, the individual is a human. As discussed herein, the compounds described herein are used alone or in combination with one or more additional therapeutic agents.

[0234] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual in any manner, including one or more of a variety of routes of administration, such as (by way of non-limiting examples) oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.

[0235] In certain embodiments, the pharmaceutical compositions described herein include one or more of the compounds described herein in the form of the free acid or free base or in the form of a pharmaceutically acceptable salt as the active ingredient. In some embodiments, the compounds described herein are used in the form of the N-oxide or in crystalline or amorphous form (i.e., polymorphs). In some cases, the compounds described herein exist in tautomeric forms. 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, wherein the solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be described herein.

[0236] In some embodiments, the "carrier" includes pharmaceutically acceptable excipients and is selected based on compatibility with the compounds described herein (such as compounds of any of Formulas 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, etc. See, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, PA: Mack Publishing Company, 1995); John E. Hoover, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 1975; Lieberman H.A. and Lachman L., eds., Pharmaceutical Dosage Forms, Marcel Dekker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), all of the above references being incorporated herein by reference in their entirety for all purposes.

[0237] In addition, in certain embodiments, the pharmaceutical compositions described herein are formulated into a dosage form. Thus, in some embodiments, the present disclosure provides a dosage form comprising a compound described herein, which is suitable for administration to an individual. 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, sprays, controlled release formulations, fast-melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0238] Route of Administration, Dosage Form, and Dosage Regimen

[0239] In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reabsorption or to reduce serum or hepatic bile acid levels. In certain embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, these formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for local delivery of the composition to the rectum and / or colon (sigmoid colon, transverse colon, or ascending colon). In certain embodiments, for rectal administration, the compositions described herein are formulated as enemas, rectal gels, rectal 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 intestinal delivery to the colon.

[0240] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and are non-systemic (e.g., the majority of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the oral compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and are non-systemic (e.g., the majority of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the rectal compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and are non-systemic (e.g., the majority of the enteroendocrine peptide secretagogue is not systemically absorbed). In certain embodiments, the non-systemic compositions described herein systemically deliver less than 90% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 80% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 70% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 60% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 50% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 40% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 30% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 25% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 20% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 15% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 10% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 5% w / w of ASBTI. In some embodiments, systemic absorption is determined in any suitable manner, including total circulating volume, amount cleared after administration, etc.

[0241] In certain embodiments, the compositions and / or formulations described herein are administered at least once a day. In certain embodiments, formulations containing ASBTI are administered at least twice a day, while in other embodiments, formulations containing ASBTI are administered at least three times a day. In certain embodiments, formulations containing ASBTI are administered at most five times a day. It should be understood that in certain embodiments, the dosing regimen of the compositions containing ASBTI described herein is determined by considering various factors such as patient age, sex, and diet.

[0242] The concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.

[0243] In certain embodiments, by targeting the distal gastrointestinal tract (e.g., distal ileum, colon, and / or rectum), the compositions and methods described herein provide efficacy (e.g., reducing microbial growth and / or alleviating symptoms of cholestasis or cholestatic liver disease) at a reduced dose of an enteroendocrine peptide secretagogue (e.g., compared to an oral dose that does not target the distal gastrointestinal tract).

[0244] Liquid dosage form

[0245] The pharmaceutical liquid dosage forms of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0246] A solution refers to a liquid pharmaceutical preparation in which the active ingredient is dissolved in a liquid. The pharmaceutical solutions of the present invention include syrups and elixirs. A suspension refers to a liquid pharmaceutical preparation in which the active ingredient is in the form of a precipitate in a liquid.

[0247] In liquid dosage forms, it is desirable to have a specific pH and / or maintain it within a specific pH range. To control the pH, a suitable buffer system can be used. Additionally, the buffer system should have the ability to maintain the desired pH range. Examples of buffer systems suitable for the present invention include (but are not limited to) citrate buffers, phosphate buffers, or any other suitable buffers known in the art. Preferably, the buffer system includes sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, etc. The concentration of the buffer system in the final suspension varies 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 in the final liquid dosage form ranges from 0.005 to 0.5 w / v%.

[0248] The pharmaceutical composition containing the liquid dosage form of the present invention may also include a suspending agent / stabilizer to prevent the active material from settling. Over time, settling may cause the active substance to agglomerate on the inner wall of the product packaging, resulting in difficulty in redispersing and accurate dispensing. Suitable stabilizers include (but are not limited to) polysaccharide stabilizers such as xanthan gum, guar gum, and tragacanth gum; and cellulose derivatives HPMC (hydroxypropyl methylcellulose), methylcellulose, and Avicel RC-591 (microcrystalline cellulose / sodium carboxymethylcellulose). In another embodiment, polyvinylpyrrolidone (PVP) can also be used as a stabilizer.

[0249] In addition to the foregoing components, the ASBTI oral suspension form may optionally contain other excipients commonly found in pharmaceutical compositions, such as alternative solvents, taste-masking agents, antioxidants, fillers, acidifying agents, enzyme inhibitors, and other components described in the Handbook of Pharmaceutical Excipients, edited by Rowe et al., 4th edition, Pharmaceutical Press (2003), which is incorporated herein by reference in its entirety for all purposes.

[0250] Adding alternative solvents can help increase the solubility of the active ingredient in the liquid dosage form and thus improve absorption and bioavailability in the individual's body. Preferably, the alternative solvents include methanol, ethanol, or propylene glycol, etc.

[0251] In another aspect, the present invention provides a method for preparing a liquid dosage form. The method comprises the step of mixing maribavir or a pharmaceutically acceptable salt thereof with components including glycerol or syrup or a mixture thereof, a preservative, a buffer system, and a suspending / stabilizing agent, etc. in a liquid medium. Generally, the liquid dosage form is prepared by uniformly and intimately mixing these various components in the liquid medium. For example, components such as glycerol or syrup or a mixture thereof, a preservative, a buffer system, and a suspending / stabilizing agent can be dissolved in water to form an aqueous solution, and subsequently the active ingredient can be dispersed in the aqueous solution to form a suspension.

[0252] In some embodiments, the volume of the liquid dosage form provided herein can be between about 5 ml and about 50 ml. In some embodiments, the volume of the liquid dosage form provided herein can be between about 5 ml and about 40 ml. In some embodiments, the volume of the liquid dosage form provided herein can be between about 5 ml and about 30 ml. In some embodiments, the volume of the liquid dosage form provided herein can be between about 5 ml and about 20 ml. In some embodiments, the volume of the liquid dosage form provided herein can be between about 10 ml and about 30 ml. In some embodiments, the volume of the liquid dosage form provided herein can be about 20 ml. In some embodiments, the amount of maribavir can range from about 0.001% to about 90% of the total volume. In some embodiments, the amount of maribavir can range from about 0.01% to about 80% of the total volume. In some embodiments, the amount of maribavir can range from about 0.1% to about 70% of the total volume. In some embodiments, maribavir can be in the range of about 1% to about 60% of the total volume. In some embodiments, the amount of maribavir can range from about 1% to about 50% of the total volume. In some embodiments, the amount of maribavir can range from about 1% to about 40% of the total volume. In some embodiments, the amount of maribavir can range from about 1% to about 30% of the total volume. In some embodiments, the amount of maribavir can range from about 1% to about 20% of the total volume. In some embodiments, the amount of maribavir can range from about 1% to about 10% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 70% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 60% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 50% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 40% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 30% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 20% of the total volume. In some embodiments, the amount of maribavir can range from about 5% to about 10% of the total volume. In some embodiments, the amount of maribavir can range from about 10% to about 50% of the total volume. In some embodiments, the amount of maribavir can range from about 10% to about 40% of the total volume. In some embodiments, the amount of maribavir can range from about 10% to about 30% of the total volume. In some embodiments, the amount of maribavir can range from about 10% to about 20% of the total volume.In one embodiment, the resulting liquid dosage form can be from 10 ml to 30 ml, preferably a liquid volume of 20 ml, and the amount of the active ingredient can be in the range of about 0.001 mg / ml to about 25 mg / ml, or about 0.025 mg / ml to about 8 mg / ml, or about 0.1 mg / ml to about 4 mg / ml, or 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 10 mg / ml, or about 12 mg / ml, or about 14 mg / ml, or about 16 mg / ml, or about 18 mg / ml, or about 20 mg / ml, or about 25 mg / ml. In one embodiment, the active ingredient is marciprant present in an amount of 9.5 mg / ml. In one embodiment, the active ingredient is marciprant chloride present in an amount of 10 mg / ml.

[0253] Oral solution

[0254] In some embodiments, the pharmaceutical composition is formulated as an oral solution comprising marciprant chloride, a preservative, an antioxidant, a flavoring agent, a sweetening agent, and water.

[0255] Preservative

[0256] In certain embodiments, the composition of the present invention comprises a preservative. In certain embodiments, the preservative is an antimicrobial preservative.

[0257] In certain embodiments, the antimicrobial preservative is selected from the group consisting of propylene glycol, ethanol, glycerol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimonium bromide (hexadecyltrimethylammonium bromide), cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof.

[0258] In certain embodiments, the preservative is propylene glycol.

[0259] In certain embodiments, the preservative is present in an amount of at least about 10% w / w of the composition. In certain embodiments, the preservative is present in an amount of at least about 20% w / w of the composition. In certain embodiments, the preservative is present in an amount of at least about 25% w / w of the composition. In certain embodiments, the preservative is present in an amount of at least about 30% w / w of the composition.

[0260] In certain embodiments, the preservative is present in an amount of about 30% to about 40% of the composition.

[0261] In certain embodiments, the preservative is present in an amount of from about 32% to about 37% of the composition. In certain embodiments, the preservative is present in an amount of from about 33% to about 36% of the composition.

[0262] In certain embodiments, the preservative is present in an amount of about 33% of the composition. In certain embodiments, the preservative is present in an amount of about 34% of the composition. In certain embodiments, the preservative is present in an amount of about 35% of the composition.

[0263] Antioxidant

[0264] In certain embodiments, the composition of the present invention comprises an antioxidant. In certain embodiments, the antioxidant is selected from the group consisting of: amino carboxylic acids, aminopolycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or its derivatives, propyl gallate, and combinations thereof.

[0265] In certain embodiments, the antioxidant is an aminopolycarboxylic acid selected from the following: ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), nitrilotriacetic acid (NTA), 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), tetraazacyclododecanetetraacetic acid (DOTA), and ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid) (EDDHA).

[0266] In certain embodiments, the antioxidant is EDTA.

[0267] In certain embodiments, the antioxidant is present in an amount of from about 0.001% to about 1% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of from about 0.005% to about 0.75% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of from about 0.01% to about 0.5% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of from about 0.05% to about 0.25% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of from about 0.075% to about 0.2% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.1% w / w of the composition.

[0268] In some embodiments, the pharmaceutical composition comprises maribavir chloride at about 5 mg / mL to about 50 mg / mL; propylene glycol at about 300 mg / mL to about 400 mg / mL; disodium edetate at about 1 mg / mL; a sweetening agent, a flavoring agent, or a combination thereof, and water.

[0269] In some embodiments, the pharmaceutical composition comprises maribavir chloride at about 5 mg / mL to about 50 mg / mL; propylene glycol at about 300 mg / mL to about 400 mg / mL; disodium edetate at about 1 mg / mL; sucralose at about 10 mg / mL, grape flavor at about 5 mg / mL, and water.

[0270] In some embodiments, the pharmaceutical composition comprises maribavir chloride at about 10 mg / mL; propylene glycol at about 360 mg / mL; disodium edetate at about 1 mg / mL; sucralose at about 10 mg / mL, grape flavor at about 5 mg / mL, and water.

[0271] Pediatric dosage formulations and compositions

[0272] In certain embodiments, provided herein are pediatric dosage formulations or compositions comprising a therapeutically effective amount of any of the compounds described herein. In certain cases, the pharmaceutical composition comprises an ASBT inhibitor (e.g., maribavir or maribavir chloride).

[0273] In certain embodiments, dosage forms suitable for pediatric dosage 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, quick melt formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candies, orally disintegrating tablets, powders for reconstitution into suspensions or solutions, dispersible oral powders or granules, dragees, delayed release formulations, sustained release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release and controlled release formulations. In some embodiments, provided herein is a pharmaceutical composition, wherein the pediatric dosage form is selected from solutions, syrups, suspensions, elixirs, powders for reconstitution into suspensions or solutions, dispersible tablets / effervescent tablets, chewable tablets, gummy candies, lollipops, freezer pops, troches, oral thin strips, orally disintegrating tablets, orally disintegrating strips, sachets, and dispersible oral powders or granules.

[0274] In another aspect, the present disclosure provides a pharmaceutical composition, wherein at least one excipient is a flavoring agent or a sweetening agent. In some embodiments, the present disclosure provides a coating. In some embodiments, the present disclosure provides a taste masking technique selected from: coating drug particles with a neutral-tasting polymer by spray drying, wet granulation, fluidized bed, and microencapsulation; melt wax coating using a mixture of molten wax and other pharmaceutical adjuvants; encapsulating drug particles by complexation, flocculation, or coagulation of an aqueous polymer dispersion; adsorption of drug particles onto resins and inorganic carriers; and solid dispersions, wherein the drug and one or more neutral-tasting compounds are melted and cooled, or co-precipitated by solvent evaporation. In some embodiments, the present disclosure provides a delayed or sustained release formulation comprising drug particles or granules in a rate controlling polymer or matrix.

[0275] Suitable sweetening agents include sucrose, glucose, fructose, or intense sweetening agents, i.e., agents having a higher sweetness when compared to sucrose (e.g., at least 10 times sweeter than sucrose). Suitable intense sweetening agents include aspartame, saccharin, sodium saccharin, potassium saccharin, or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidin dihydrochalcone, or mixtures thereof, thaumatin, isomaltitol, stevioside, rebaudioside, The total concentration of the sweetening agent can effectively range from zero to about 300 mg / ml, based on the reconstituted liquid composition.

[0276] To improve the palatability of the liquid composition after reconstitution with an aqueous medium, one or more taste masking agents can be added to the composition to mask the taste of the ASBT inhibitor. The taste masking agent can be a sweetening agent, a flavoring agent, or a combination thereof. The taste masking agent generally comprises up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the present invention, the composition contains a sweetening agent and a flavoring agent.

[0277] The flavoring agents of the present invention are substances capable of enhancing the taste or aroma of the 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 agents and / or sweeteners suitable for the formulations described herein include, for example, gum arabic syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, red currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus paste, marshmallow, cocoa, cola, cool cherry, cool citrus, cyclamate, dextrose, eucalyptus oil, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid ester, licorice (Glycyrrhiza glabra) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, ammonium glycyrrhizinate maltitol, mannitol, maple, marshmallow, menthol, peppermint paste, mixed berries, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint paste Powders, raspberries, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberries, strawberry paste, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, 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 can be used alone or in combination of two or more. In some embodiments, the aqueous liquid dispersion comprises a sweetening or flavoring agent at a concentration in the range of 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 in the range of 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 in the range of 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 in the range of 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 in the range of about 0.01% to about 0.5% by volume of the aqueous dispersion.

[0278] In certain embodiments, the pediatric pharmaceutical compositions described herein include one or more of the compounds described herein in the form of the free acid or free base or in the form of a pharmaceutically acceptable salt as the active ingredient. In some embodiments, the compounds described herein are used in the N - oxide or crystalline or amorphous form (i.e., polymorphs). In some cases, the compounds described herein exist in the tautomeric form. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in the non - solvated or solvated form, wherein the solvated form comprises any pharmaceutically acceptable solvent, such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be described herein.

[0279] In some embodiments, the carrier for the pediatric pharmaceutical composition includes pharmaceutically acceptable excipients and is selected based on compatibility with the compounds described herein (such as compounds of any of Formulas 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, 19th Edition (Easton, PA: Mack Publishing Company, 1995); John E. Hoover, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 1975; Lieberman H.A. and Lachman L., eds., Pharmaceutical Dosage Forms, Marcel Dekker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), all of which are incorporated herein by reference in their entireties for all purposes.

[0280] In addition, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated as a dosage form. Thus, in some embodiments, there is provided a dosage form comprising a compound described herein, which is suitable for administration to an individual. 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, sprays, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0281] In certain aspects, the pediatric composition or formulation containing one or more compounds described herein is orally administered for local delivery of maribavir, maribavir chloride, or other 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 contain the composition described herein coated or encapsulated in microspheres. In some embodiments, the microspheres include (by way of non-limiting example) chitosan microcores HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, the oral dosage forms are prepared using conventional methods known in the pharmaceutical formulation art. For example, in certain embodiments, tablets are manufactured using standard tableting procedures and equipment. An exemplary method for forming tablets is from a powder, crystalline, or granular composition containing only the active agent or a combination of the active agent with one or more carriers, additives, and the like. In alternative embodiments, tablets are prepared using wet granulation methods or dry granulation methods. In some embodiments, tablets are molded rather than compressed starting from a moist or otherwise easily handled material.

[0282] In certain embodiments, tablets for oral administration are prepared containing various excipients, by way of non-limiting examples, including binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavorants, and the like. In some embodiments, binders are used to impart cohesive qualities to the tablets, ensuring that the tablets remain intact after compression. Suitable binder materials include, by way of non-limiting examples, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrin, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums such as gum arabic, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, etc.), Veegum, and combinations thereof. In certain embodiments, diluents are utilized to increase the volume of the tablets in order to provide tablets of practical size. Suitable diluents include, by way of non-limiting examples, 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; examples of suitable lubricants include, by way of non-limiting examples, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, disintegrants are used to facilitate tablet disintegration and include, by way of non-limiting examples, starches, clays, celluloses, algins, gums, cross-linked polymers, and combinations thereof. Fillers include, by way of non-limiting examples, materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrin, sodium chloride, and sorbitol. In certain embodiments, stabilizers are used to inhibit or delay drug decomposition reactions including, for example, oxidation reactions. In certain embodiments, the surfactant is an anionic, cationic, amphoteric, or nonionic surfactant.

[0283] In some embodiments, maribavir, maribavir chloride, or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and / or rectum).

[0284] In certain embodiments, the pediatric compositions described herein comprise maribavir, maribavir chloride, or other compounds described herein in combination with a matrix (e.g., a matrix comprising hydroxypropyl methylcellulose) such that the active agent is released in a controlled manner in the distal portion of the ileum and / or colon. In some embodiments, the composition comprises a pH-sensitive polymer (e.g., MMX from Cosmo Pharmaceuticals) TMa matrix) 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 (but are not limited to) polyacrylic acid polymers (e.g., anionic methacrylic acid and / or methacrylate polymers, such as polymers) that contain acid groups (e.g., -COOH, -SO 3 H) and swell at the alkaline 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 contains particulate active agents (e.g., micronized active agents). In some embodiments, a non-enzymatically degradable poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivering 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., S-100; cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, phthalates, anionic methacrylic acid, methacrylate polymers, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, a bacterial activation system is suitable for targeted delivery to the distal portion of the ileum. Examples of the microbiota activation system include dosage forms of active agents that contain pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, etc.). Examples of gastrointestinal microbiota enzymes include bacterial glycosidases such as D-galactose, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranoside, etc.

[0285] The pediatric pharmaceutical compositions described herein optionally include the additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or a combination of one or more thereof. In some aspects, using standard coating procedures such as those described in the 20th Edition of Remington's Pharmaceutical Sciences (2000), a film coating is provided around the formulation of the compound of Formula I. In one embodiment, the compounds described herein are in particulate form and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compounds described herein are microencapsulated. In some embodiments, the particles of the compounds described herein are not microencapsulated and not coated.

[0286] In other embodiments, tablets or capsules containing ASBTI or other compounds described herein are coated with a film coating for delivery to a target site within the gastrointestinal tract. Examples of enteric film coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 4500, polyethylene glycol 8000, methylcellulose, hypromellose, amylopectin, etc.

[0287] Solid dosage forms for pediatric administration

[0288] The solid dosage forms for pediatric administration of the present invention can be manufactured by standard manufacturing techniques. Non-limiting examples of oral solid dosage forms for pediatric administration are described below.

[0289] Effervescent compositions

[0290] The effervescent compositions of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0291] Effervescent preparations contain an effervescent pair of a base component and an acid component, which components come into contact in the presence of water to produce a gas. In some embodiments, the base component can include, for example, alkali metal or alkaline earth metal carbonates or bicarbonates. The acid component can comprise, for example, aliphatic carboxylic acids or their salts, such as citric acid. The base component and the acid component can each independently constitute, for example, 25% to 55% (w / w) of the effervescent composition. The ratio of the acid component to the base component can be in the range of 1:2 to 2:1.

[0292] The effervescent compositions of the present invention can be formulated with additional pharmaceutically acceptable carriers or excipients as appropriate. For example, one or more taste-masking agents can be used. Dyes can also be used, as pediatric patients generally prefer brightly colored drug combinations. The compositions can be in the form of, for example, tablets, granules or powders, granules or powders provided in sachets.

[0293] Chewable tablets

[0294] The chewable tablets of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0295] Chewable tablets are tablets intended to disintegrate in the mouth under chewing or sucking action, and thus, the active ingredient has a greater chance of contacting the bitter receptors on the tongue in the mouth.

[0296] One way to overcome this problem is to absorb the active ingredient onto a suitable matrix. This method is known in the art and is described, for example, in U.S. Patent No. 4,647,459, which is incorporated herein by reference in its entirety for all purposes.

[0297] Another method involves forming aggregates of the active ingredient with a pre-swollen substantially anhydrous hydrocolloid. The hydrocolloid absorbs saliva and acquires a smooth texture, enabling it to lubricate the aggregate particles and mask the taste of the active ingredient. This method is known in the art and is described, for example, in European Patent Application 0190826, which is incorporated herein by reference in its entirety for all purposes.

[0298] Another method involves using a water-insoluble hygroscopic excipient such as microcrystalline cellulose. This method is known in the art and is described, for example, in U.S. Patent No. 5,275,823, which is incorporated herein by reference in its entirety for all purposes.

[0299] In addition to the above methods, the chewable tablets of the present invention may also contain other standard tablet excipients such as disintegrants and taste masking agents.

[0300] Orally Disintegrating Tablets

[0301] The orally disintegrating tablets of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0302] In the orally disintegrating tablets of the present invention, the excipient mixture gives them a certain disintegration rate, whereby their disintegration in the buccal cavity occurs in an extremely short time and especially in less than sixty seconds. In some embodiments, the excipient mixture is characterized by the fact that the active substance is in the form of microcrystals, either coated or uncoated, in particulate form. In some embodiments, the orally disintegrating tablets contain one or more carboxymethyl cellulose type or insoluble network PVP type disintegrants, one or more swelling agents, which may include carboxymethyl cellulose, starch, modified starch or microcrystalline cellulose, or optionally directly compressible sugar.

[0303] Powders for Reconstitution

[0304] The powder for reconstitution pharmaceutical compositions of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0305] In some embodiments, the powder for reconstitution compositions of the present invention contain an effective amount of at least one internal dehydrating agent. The internal dehydrating agent can enhance the stability of the powder. In some embodiments, the internal dehydrating agent is magnesium citrate or disodium carbonate. In some embodiments, the powder composition contains a pharmaceutically acceptable diluent such as sucrose, dextrose, mannitol, xylitol or lactose.

[0306] The powder compositions of the present invention can be placed in a sachet or bottle for simultaneous dissolution or short-term storage in liquid form (e.g., for 7 days).

[0307] Gummy Candies

[0308] The gummy candies of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[0309] Traditional gummy candies are made from a gelatin matrix. Gelatin imparts elasticity, the desired chewiness, and a longer shelf life to the candies. In some embodiments, the gummy candy pharmaceutical composition of the present invention comprises a binder, a sweetener, and an active ingredient.

[0310] In some embodiments, the binder is pectin gel, gelatin, food starch, or any combination thereof.

[0311] In some embodiments, the gummy candies contain a sweetener, a binder, natural and / or artificial flavorings, as well as colorants and preservatives. In some embodiments, the gummy candies contain glucose syrup, natural cane juice, gelatin, citric acid, lactic acid, natural colorants, natural flavorings, fractionated coconut oil, and carnauba wax.

[0312] An ASBT inhibitor (e.g., marciprant) can be used to prepare a medicament for prophylactic and / or therapeutic treatment of cholestasis or cholestatic liver diseases (e.g., PFIC). A method for treating any one of the diseases or conditions described herein in an individual in need of such treatment can involve administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising at least one ASBT inhibitor or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof as described herein.

[0313] Examples

[0314] The following examples are provided to further describe some embodiments disclosed herein. The examples are intended to illustrate and not limit the disclosed embodiments.

[0315] Example 1. A randomized, double - blind, placebo - controlled Phase 3 clinical study to evaluate the efficacy and safety of maralixibat in individuals with PFIC Figure 2

[0316] Study Overview

[0317] Based on standard of care genotyping (primary cohort criteria), a primary analysis was conducted in a population of intention-to-treat (ITT) individuals with documented ABCB11 (PFIC 2) bi-allelic gene mutations. Individuals predicted to have complete absence of bile salt export pump (BSEP) function based on the ABCB11 mutation type (PFIC 2) determined by standard of care genotyping were excluded from the primary cohort and could only be included in the supplemental cohort. Individuals with other PFIC subtypes (e.g., PFIC 1 / 3 / 4 / 5 / 6 or novel PFIC mutation variants) or post-surgical individuals (e.g., after intra- or extrahepatic biliary shunt surgery or individuals who have undergone reversal of biliary shunt surgery) were included in separate supplemental cohorts and were evaluated as part of secondary and exploratory analyses.

[0318] Individuals in the main cohort were randomized to receive marciprant or placebo at a 1:1 ratio. Individuals in the supplemental cohort were randomized to receive marciprant or placebo within the following subcohorts at a 1:1 ratio: a) PFIC 1; b) PFIC 3; c) all other supplemental cohort individuals. All individuals received study treatment, including antipruritic concomitant treatment, in addition to standard care therapy.

[0319] In the main cohort, 31 individuals were recruited to have at least 26 individuals complete the study. In the supplemental cohort, a total of 62 individuals were recruited.

[0320] An overview of the Phase 3 clinical study is outlined in Figure 5 . The study was divided into 4 parts: 1) screening period (up to 6 weeks); 2) dose escalation period (4 - 6 weeks); 3) steady - state dosing period (20 - 22 weeks); 4) safety follow - up period (7 days).

[0321] Study population

[0322] The key inclusion criteria for the Phase 3 clinical study were as follows: 1) individuals aged 1 - 18 years with a body weight ≥ 5.0 kg at baseline; 2) cholestasis with a total sBA ≥ 3 × ULN; 3) an average AMItchRO(Obs) score ≥ 1.5 during 4 consecutive weeks of the screening period, leading to entry into the baseline visit; 4) completion of at least 21 valid morning ItchRO(Obs) records during 4 consecutive weeks of the screening period, leading to entry into the baseline visit; 5) diagnosis of PFIC based on: chronic cholestasis with persistent (> 6 months) pruritus, and biochemical abnormalities and / or pathological signs of progressive liver disease and: a) main cohort: individuals with gene test results consistent with biallelic pathogenic changes in ABCB11 (PFIC 2) based on standard care genotyping; b) supplemental cohort: i) individuals with gene test results consistent with biallelic pathogenic changes in ATP8B1 (PFIC 1), ABCB4 (PFIC 3), or TJP2 (PFIC4) based on standard care genotyping; ii) individuals with a PFIC phenotype but without a known mutation or with another known mutation not described above or with intermittent cholestasis characterized by fluctuating sBA levels; iii) individuals with PFIC who had undergone intra - or extra - hepatic portosystemic shunt surgery or whose intra - or extra - hepatic portosystemic shunt surgery had been reversed.

[0323] A valid record is one that has been completed and does not answer "I don't know"; a maximum of 7 invalid reports are allowed, with no more than 2 invalid reports within the last 7 days before randomization.

[0324] The key exclusion criteria for the Phase 3 study were as follows: 1) predicted complete absence of bile salt export pump (BSEP) function based on the ABCB11 mutation type (PFIC 2) determined by standard of care genotyping (only applicable to the primary cohort); 2) recurrent intrahepatic cholestasis indicated by sBA levels < 3 × ULN or a history of intermittent pruritus (only applicable to the primary cohort); 3) current or recent history (< 1 year) of atopic dermatitis or other non-cholestatic diseases associated with pruritus; 4) history of interruption of enterohepatic circulation surgery (only applicable to the primary cohort); 5) chronic diarrhea occurring at screening or within 6 months prior to screening that required intravenous fluid or nutritional intervention to treat the diarrhea and / or its sequelae; 6) prior or need for immediate liver transplantation; 7) decompensated cirrhosis (international normalized ratio [INR] > 1.5, and / or albumin < 30 g / L, with a history or presence of clinically significant ascites and / or variceal bleeding and / or encephalopathy); 8) ALT or TSB > 15 × ULN at screening; 9) presence of other liver diseases; 10) any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of the study drug, including bile salt metabolism in the gut (e.g., inflammatory bowel disease), as judged by the investigator; 11) imaging (including screening ultrasound) showing a possible malignant liver mass; 12) known diagnosis of human immunodeficiency virus (HIV) infection; 13) any prior cancer diagnosis (except carcinoma in situ) within 5 years prior to the screening visit; 14) any known history of alcohol or substance abuse; 15) administration of bile acids or lipid-binding resins or phenylbutyrate during the screening period; 16) administration of any study drug, biologic, or medical device during the screening period; 17) prior use of ileal bile acid transporter inhibitor (IBATi); 18) history of non-compliance with medical regimens, unreliability, medical conditions, mental instability, or cognitive impairment that, in the opinion of the investigator or sponsor medical monitor, may compromise the validity of informed consent, compromise the safety of the individual, or lead to non-compliance with the study protocol or inability to conduct study procedures; 19) known allergy to maralixibat or any of its excipients.

[0325] Study drug

[0326] The study drug administered was maralixibat chloride, provided as an oral solution (e.g., 5, 10, 15, and 20 mg / mL) with dosing dispensers in sizes of 0.5, 1.0, or 3.0 mL. The reference / comparator product was placebo, also provided as an oral solution with dosing dispensers of the same sizes (0.5 mL, 1.0 mL, or 3.0 mL). Maralixibat and placebo (study drug) were provided in 30 mL volumes, packaged in 30 mL amber PET bottles and required refrigerated storage conditions (2°C - 8°C).

[0327] One excipient in maribavir oral solution is propylene glycol (PG); to limit individual exposure to PG, a specific concentration of the oral solution is prescribed for a given individual based on body weight and the target dose. The dosing schedule limits PG exposure to ≤26 mg / kg per day while providing a reasonable (not too high or too low) dosing volume to ensure accurate administration.

[0328] The placebo solution contains all components of the investigational drug except the active pharmaceutical ingredient. To maintain blinding, all packaged components of the investigational drug (including the dosing dispenser) are identical.

[0329] Investigational drug administration

[0330] Individuals are screened and recruited, randomized, supplied and managed with investigational drug, inventory managed and supplied sequenced, investigational drug expiration tracked and managed, and emergency unblinding using Interactive Response Technology (IRT). Individual subject processing is automatically assigned by IRT. After confirmation of study eligibility, individuals are randomized in a 1:1 ratio to receive maribavir or placebo, stratified by cohort, via a computer-generated randomization schedule.

[0331] Starting from the baseline visit (Visit 1), different volumes of ready-to-use oral solution investigational drug are administered (or self-administered) to individuals at each dosing visit. The dosing volume is determined based on the individual's body weight, the dose level (150, 300, 450, or 600 μg / kg) according to the dose escalation plan, and the concentration of the solution administered (5, 10, 15, or 20 mg / mL).

[0332] Based on the BID regimen, investigational drug administration occurs during the dose escalation and steady-state dosing periods of the study. The morning dose is administered approximately 30 minutes before breakfast, and the evening dose is administered approximately 30 minutes before the main evening meal. Throughout the study, the investigational drug is administered at approximately the same time each day.

[0333] For individuals assigned to maribavir, the dose escalation period consists of the following weekly steps: dose level 1, 150 μg / kg maribavir BID for 1 week; dose level 2, 300 μg / kg maribavir BID for 1 week; dose level 3, 450 μg / kg maribavir BID for 1 week; dose level 4, 600 μg / kg maribavir BID for the remaining duration of the study.

[0334] Study schedule

[0335] The study procedures and assessments conducted throughout the study are visible in the assessment schedule in Table 1.

[0336] Genetic test results. Mutations in ATP8B1 (PFIC 1), ABCB11 (PFIC 2), ABCB4 (PFIC 3), TJP2 (PFIC4), NR1H4 (PFIC 5), and MYO5B (PFIC 6) predict PFIC. Review the standard-of-care genotyping results and record them by the sponsor or designee to confirm the PFIC subtype and determine cohort assignment.

[0337] Efficacy. Assess the severity of itching using the Itch Caregiver / Patient Report Outcome Measure (ItchRO TM ) administered in the form of an electronic diary twice daily. Caregivers of all individuals completed the observer tool: ItchRO (Obs). ItchRO (Obs) was completed by the same caregiver whenever possible to maintain consistency. Only individuals aged ≥9 years at screening completed the patient tool: ItchRO (Pt). If an individual turned 9 years old at any time point after screening, they were not required to complete ItchRO (Pt). Itching was assessed via ItchRO starting on the day after the screening visit and every day throughout the duration of the study, and recorded twice daily. The severity of itching was measured by completing the first question in ItchRO (Obs) (How severe are your child's itching-related symptoms) or ItchRO (Pt) (How itchy do you feel). The frequency of itching was measured by completing the third question in ItchRO (Obs) (How many times has your child rubbed or scratched) or ItchRO (Pt) (How much time last night / today did you rub or scratch because you felt itchy). Caregivers and individuals rated the severity and frequency of itching using 5 options to describe their itching condition. ItchRO (Pt) and ItchRO (Obs) have been previously described in the following: Kamath et al., "Development of a Novel Tool to Assess the Impact of Itching in Pediatric Cholestasis", Patient, 11:69-82 (2018), which is hereby incorporated by reference in its entirety for all purposes.

[0338] Table 1. Assessment schedule

[0339]

[0340]

[0341] AFP = alpha-fetoprotein; C4 = 7alpha-hydroxy-4-cholesten-3-one; CBC = complete blood count; CIS = caregiver impression of severity; CIC = caregiver impression of change; ECG = electrocardiogram; EDQ = Exploratory Diary Questionnaire; EOT = end of treatment; ET = early termination; FGF-19 = fibroblast growth factor-19; ItchRO = itching report outcome; P = provided; PedsQL = Pediatric Quality of Life Questionnaire; PIC = patient impression of change; PIS = patient impression of itching severity; PK = pharmacokinetics; R = return; S = serum; U = urine; V = visit

[0342] a Individuals who initially do not meet the eligibility criteria may be re-evaluated during the 6-week screening period before being considered screening failures. Individuals may also be re-screened.

[0343] b If PFIC is known at this visit, the study site should record the dates of any future scheduled procedures related to PFIC (e.g., PEBD, ileal bypass, liver transplantation, or listing for liver transplantation).

[0344] c Blood pressure, heart rate, body temperature, respiratory rate, height, and weight will be measured by trained staff using standardized methods, including a calibrated range finder or headboard and a calibrated scale.

[0345] d If there is an ultrasound or liver MRI within 6 months, screening ultrasound is not required.

[0346] e For fertile females only; results must be reviewed before study drug is assigned.

[0347] f Genotyping results will be reviewed by the sponsor or designee.

[0348] g Caregivers and appropriate-aged individuals are asked to complete an electronic diary twice daily (morning and evening).

[0349] h Will be completed by the caregiver of all individuals

[0350] i Will be completed by individuals aged ≥9 years at screening

[0351] j Will be completed by individuals and caregivers using the age-appropriate PedsQL module

[0352] kIndividuals should fast for at least 6 hours prior to collection, if possible. Water intake is permitted if necessary, but this is not recommended.

[0353] l Blood samples must be drawn prior to vitamin supplement administration.

[0354] m PK samples will be drawn before dosing and at approximately 2.5 hours after morning dosing.

[0355] n If needed, study medication may be provided to patients by direct delivery between site visits.

[0356] o Individuals will self-administer (or be administered) the first dose of study medication at the clinic, supervised by the investigator or trained site staff, after breakfast on Day 0 / Visit 1.

[0357] Serum bile acids and other cholestasis biomarkers. As described in Table 1, blood samples are collected to measure cholestasis biomarker levels, including total sBA, sBA subspecies, C4, FGF-19, and autotaxin, as well as liver-related parameters. Individuals are encouraged to fast for at least 6 hours prior to collection (water intake is permitted if necessary, but this is not recommended). Total sBA and target bile acid subspecies are quantified by liquid chromatography mass spectrometry (LC-MS) for exploratory evaluation. Additionally, screening total sBA will be evaluated by enzymatic assay to assess inclusion criteria. The key intermediate C4 in the bile acid synthesis pathway from cholesterol will be determined by a validated LC-MS / MS method.

[0358] Clinical laboratory evaluations. Clinical laboratory assessments are performed as listed in Table 2. Serum bile acid results are confidential to the study site and the blinded study team, except for results at screening, until after database lock for Study MRX-502. Anion gap and osmolar gap, as well as corrected sodium, alpha-tocopherol / total lipid ratio, retinol / RBP molar ratio, FIB-4, and APRI are calculated.

[0359] Health-related quality of life and pruritus assessments. Throughout the study, health-related quality of life (HRQoL) assessments are also administered to patients. PedsQL TM is a questionnaire administered to individuals and caregivers using the age-appropriate PedsQL module. Individuals aged 8 to 12 years and 13 to 18 years complete the PedsQL Child Report and PedsQL Adolescent Report, respectively, on their own. Caregivers of individuals complete the age-appropriate Parent PedsQL Report (i.e., reports for infants, toddlers, young children, children, and adolescents).

[0360] Caregiver Impression of Itch Severity (CIS). The CIS is a questionnaire administered to caregivers, as outlined in Table 2. The CIS is designed to assess the caregiver's perception of the itch severity in their child. The questionnaire is provided over a 1-week recall period.

[0361] Patient Impression of Itch Severity (PIS). The PIS is a questionnaire administered to caregivers, as outlined in Table 2. Individuals aged ≥9 years complete the questionnaire themselves. The PIS is designed to assess the individual's perception of their itch severity. The questionnaire is provided over a 1-week recall period.

[0362] Clinician Scratch Scale (CSS). The CSS provides an assessment of itch severity. The clinician's assessment of individual pruritus focuses on scratching observed by the physician and visible skin damage. The CSS uses a 5-point scale, where 0 indicates no signs of scratching and 4 indicates skin damage with bleeding, heavy bleeding, and scar formation. As outlined in Table 2, the clinician's assessment of itch using the CSS is recorded by the principal investigator or an assistant investigator at screening, baseline, and additional study visits.

[0363] Table 2. List of Laboratory Analytes

[0364]

[0365] AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; β-hCG = beta-human chorionic gonadotropin; FGF-19 = fibroblast growth factor 19; FIB-4 = fibrosis-4; GGT = gamma-glutamyltransferase; PT = prothrombin time; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBP = retinol-binding protein; SGOT = serum glutamate-oxaloacetate transaminase; SGPT = serum glutamate-pyruvate transaminase; WBC = white blood cells.

[0366] a Blood samples for the analysis of cholestasis biomarkers, lipid panels, and fat-soluble vitamins should be drawn before the administration of vitamin supplements and, whenever possible, approximately 6 hours after food or formula (drinking water is permitted if necessary, but not recommended). Other biomarkers [e.g., lysophosphatidic acid (LPA)] may be measured. When necessary, at the discretion of the sponsor, samples will be collected and appropriately stored for subsequent analysis.

[0367] b Unless otherwise specified, it will be performed upon abnormal findings.

[0368] Patient's Impression of Change (PIC). PIC is designed to assess an individual's perception of his / her pruritus at Week 26 (EOT) compared to his / her pruritus before starting treatment with the study drug. PIC is completed by individuals 9 years of age or older at the Week 26 (EOT) visit.

[0369] Caregiver's Impression of Change (CIC). CIC is designed to assess a caregiver's perception of an individual's pruritus-related symptoms and xanthoma severity at Week 26 (EOT) compared to his / her pruritus-related symptoms and xanthoma severity before starting treatment with the study drug. CIC is completed by all caregivers at the Week 26 (EOT) visit.

[0370] Exploratory Diary Questionnaire. Pruritus is assessed using the EDQ caregiver / patient-reported outcome measure administered in the form of an electronic diary twice daily. Caregivers of all individuals <9 years of age complete the observer tool: EDQ (Obs). Individuals ≥9 years of age complete the patient tool: EDQ (Pt). During the screening visit (Visit 0), individuals and caregivers are trained on how to use the electronic diary. As described in Table 2, starting the day after the screening visit and every day throughout the duration of the study, pruritus is assessed and recorded twice daily by the individual or caregiver via the EDQ.

[0371] Clinical Pharmacology Assessment. Blood samples (anticoagulant K3 EDTA) are drawn before dosing and at 2.5 hours (with a 30-minute window) after morning dosing at Week 10 (Visit 5) and Week 26 (Visit 9; EOT / ET) to assess maribavir plasma levels. The actual PK blood sample collection time and dosing time are recorded.

[0372] Healthcare Utilization. During post-baseline visits, the number of hospitalizations, length of hospital stay, and emergency room visits (days) related to the underlying disease, as well as any surgeries and procedures specific to the individual's PFIC condition, are collected as outlined in Table 2. Visit / admission dates, discharge dates, relationship / problem, and discharge status are collected.

[0373] PFIC Population Analyzed

[0374] The following definitions are used for the PFIC population in the analysis of various endpoints in this study, as Figure 5As outlined in. Primary and secondary endpoints: 1) PFIC 2, participants with PFIC 2 who meet the main cohort criteria; 2) PFIC, participants with PFIC1, PFIC 2 (who meet the criteria of the main cohort), PFIC 3, PFIC 4, PFIC 5, and PFIC 6. Exploratory endpoints: PFIC 2 and PFIC 1, PFIC 2, PFIC 4, PFIC 5, PFIC 6, truncated PFIC 2.

[0375] In the PFIC population (PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5, and PFIC 6), participants include those with bi-allelic pathogenic changes in ATP8B1 (PFIC 1), ABCB11 (PFIC 2, truncated and non-truncated variants), ABCB4 (PFIC 3), TJP2 (PFIC4), MYO5B (PFIC 6), as well as PFIC patients with a history of biliary shunt or Kasai surgery, PFIC 1 and PFIC 2 patients with heterozygosity, and participants with unknown variants. The number of participants with each variant depends on the incidence of genotypes within the recruited study population, see Example 2. Primary Efficacy Endpoint and Tables 3 and 4.

[0376] Unless otherwise indicated, percentages are 100*n / N. Individuals with PFIC 1 to PFIC 6 all have bi-allelic diseases. [1] nt-PFIC 2 = non-truncated PFIC 2 (main cohort); nt-PFIC 2-IsBA = non-truncated PFIC 2 with low or fluctuating serum bile acids; nt-PFIC 2-surgery = non-truncated PFIC 2 with a history of surgery; t-PFIC 2 = truncated PFIC 2; PFIC 1-surgery = PFIC 1 with a history of surgery; PFIC 4-surgery = PFIC 4 with a history of surgery; nt PFIC 2-het = non-truncated PFIC 2 with heterozygosity; PFIC 1-het = PFIC 1 with heterozygosity; no variant found = no identified variant associated with PFIC disease. [2] nt PFIC 2 = partial loss of BSEP function; t-PFIC 2 = complete loss of BSEP function. Only applicable to PFIC 2 individuals, except for one nt PFIC 2 individual (015002) who has a heterozygous ABCB11 mutation; all other individuals are not applicable. [3] One individual (015002) has a heterozygous ABCB11 mutation, and another individual (021006) has a heterozygous ATP8B1 mutation.

[0377] Table 3 provides an overview of the participant disposition and demographic data in the MARCH clinical study. Table 4 provides an overview of the baseline health-related parameters of the participants in the MARCH clinical study. The tabular results described in Tables 3 and 4 include individual disposition, demographic data and baseline characteristics, history of PFIC disease, prior treatments, and treatment exposures and adherence. Table 3 shows that the baseline characteristics and demographic data are balanced among the cohorts.

[0378] Table 3. Demographic Data of Participants in the Clinical Study

[0379]

[0380] [1] Age at baseline visit.

[0381] [2] Height, weight, and BMI Z-scores are based on the individual's sex and age at baseline visit. Z-scores for individuals younger than 24 months of age were derived using World Health Organization (WHO) growth charts, and Z-scores for individuals 24 months of age and older were derived using Centers for Disease Control and Prevention (CDC) growth charts.

[0382] Table 4. Baseline Disease Characteristics of Participants in the Clinical Study

[0383]

[0384] Table 5. Baseline Characteristics and Demographic Data Among the Cohorts

[0385]

[0386]

[0387] Figure 6A

[0388] For this study, the primary estimation objective was the improvement in pruritus measured as the change from baseline in the mean morning ItchRO(Obs) severity score in the marcipitant treatment group relative to the placebo group. The primary analysis for the primary efficacy endpoint was conducted in the following: 1) participants with PFIC 2 who met the criteria of the primary cohort in the ITT population (the non-truncated "primary BSEP cohort" or "primary cohort", where N = 31); 2) all PFIC participants (excluding participants with a history of prior surgery, heterozygous participants, and participants of unknown type, the "all PFIC cohort" or "PFIC cohort", where N = 64); and 3) the all-study participant cohort, including participants with a history of prior surgery, heterozygous participants, and participants of unknown type. The repeated measures mixed effects model (MMRM) based on the restricted maximum likelihood method (REML) was used as the primary analysis method. The repeated measures included post-baseline visits during the dose escalation period (i.e., week 6) and the steady-state dosing period (i.e., weeks 10, 14, 18, 22, and 26), with the change from baseline in the mean morning ItchRO(Obs) severity score over 6 weeks or 4 weeks as the dependent variable. The MMRM model included fixed categorical effects for treatment group, visit, and treatment group-visit interaction, as well as continuous fixed covariates for the baseline 4-week mean morning ItchRO(Obs) severity score and the baseline score-visit interaction.

[0389] The primary efficacy analysis used contrasts (differences in least squares [LS] means) between treatment groups in the last 12 weeks of the study (i.e., combining weeks 15 to 18, weeks 19 to 22, and weeks 23 to 26) to compare marcipitant and placebo. The analytical solution for the overall treatment effect obtained from the MMRM was the equally weighted mean of the 3 individually specified period estimates within the period of interest (i.e., the last 12 weeks of the study). The significance test was based on the LS means, using a two-sided significance level (two-sided 95% confidence interval [CI]). The null hypothesis for the primary efficacy endpoint of equal marcipitant and placebo was: H 01 : the mean change in the mean morning ItchRO(Obs) severity score from baseline to between weeks 15 and 26 was equal in the 2 treatment groups.

[0390] The primary efficacy endpoint (mean change in pruritus severity score (ItchRO[Obs]) from baseline) in the BSEP deficiency cohort and the all PFIC cohort is summarized in Figures 6 - 8. The BSEP deficiency cohort showed a 1.7-point decrease in the morning ItchRO[Obs] score for pruritus relative to baseline, with a 1.089-point difference from the placebo group ( Figure 7A)。The BSEP deficiency cohort showed that the evening ItchRO[Obs] score for pruritus decreased by 1.7 points relative to baseline, with a difference of 1.111 points compared to the placebo group ( Figure 7B )。The BSEP deficiency cohort showed that the maximum daily ItchRO[Obs] score for pruritus decreased by 1.8 points relative to baseline, with a difference of 1.130 points compared to the placebo group ( Figure 6B )。

[0391] All PFIC cohorts showed that the morning ItchRO[Obs] score for pruritus decreased by 1.8 points relative to baseline, with a difference of 1.20 points compared to the placebo group ( Figure 8A )。All PFIC cohorts showed that the evening ItchRO[Obs] score for pruritus decreased by 1.8 points relative to baseline, with a difference of 1.157 points compared to the placebo group ( Figure 8B )。All PFIC cohorts showed that the maximum daily ItchRO[Obs] score for pruritus decreased by 1.9 points relative to baseline, with a difference of 1.198 points compared to the placebo group ( Figure 9A )。

[0392] The primary efficacy endpoints (mean change in pruritus severity score (ItchRO[Obs]) relative to baseline) in the FIC1 (PFIC 1) cohort and the MDR3 (PFIC 3) cohort are summarized in Figure 9. The FIC1 cohort showed that the morning ItchRO[Obs] score for pruritus decreased by 1.4 points relative to baseline, with a difference of 1.136 points compared to the placebo group ( Figure 9B )。The MDR3 cohort showed that the morning ItchRO[Obs] score for pruritus decreased by 1.8 points relative to baseline, with a difference of 0.594 points compared to the placebo group ( Figure 10A )。

[0393] The change over time in the weekly morning mean ItchRO[Obs] score in the BSEP deficiency (also known as major) group relative to baseline is shown in Figure 10B . The change over time in the weekly morning mean ItchRO[Obs] score in the PFIC group relative to baseline is shown in Figure 10C . The change over time in the weekly morning mean ItchRO[Obs] score in all study participants relative to baseline is shown in Example 3. Secondary Efficacy Endpoint . It is evident from these figures that the ItchRO[Obs] scores of marcipitant-treated participants were significantly lower at each time point from week 2 to week 26, indicating a strong response of all PFIC types to marcipitant treatment.

[0394] These results confirm that marciprant is highly effective in significantly reducing pruritus in all PFIC patients compared to placebo, including PFIC 1 participants, PFIC 2 participants, PFIC 3 participants, and all PFIC groups combined.

[0395] Figure 13A

[0396] The secondary efficacy endpoints were defined as the mean change in total serum bile acid (sBA) content between baseline and the mean of weeks 18, 22, and 26 (Figure 11 - 12); 2) the percentage of ItchRO(Obs) responders from week 15 to week 26 ( Figure 13B and 14A ); 3) the percentage of sBA responders from week 18 to week 26 ( Figure 11A and 14B ). Pruritus responders were defined as individuals with a change in the mean morning ItchRO(Obs) severity over 4 weeks relative to baseline ≤ 1.0 or a mean severity score ≤ 1.0 points. For the purpose of determining response, the mean severity scores from three 4 - week periods (weeks 15 to 18, weeks 19 to 22, and weeks 23 to 26) were used. If the 4 - week mean baseline score was missing or all three 4 - week mean (post - baseline) scores were missing, the individual was defined as an ItchRO non - responder. sBA responders were defined as individuals with a mean sBA content < 102 μmol / L (only applicable when baseline sBA ≥ 102 μmol / L) or a mean percentage change relative to baseline ≤ - 75%. For the purpose of determining response, the mean sBA values from weeks 18, 22, and 26 were used. If the baseline sBA value was missing or the sBA values at all 3 time points (i.e., weeks 18, 22, and 26) were missing, the individual was defined as an sBA non - responder. Barnard's exact test was used to calculate the p - value comparing the marciprant and placebo treatment groups.

[0397] The key secondary efficacy endpoint (mean change in sBA content relative to baseline) is shown in Figures 11 - 12. The BSEP deficiency cohort achieved a reduction in sBA content of nearly 200 μmol / L, a difference of 186.723 μmol / L from placebo ( Figure 11B ). All PFIC cohorts achieved a reduction in sBA content of more than 150 μmol / L, a difference of 160.403 μmol / L from placebo ( Figure 12A ). The FIC1 cohort achieved a reduction in sBA content of nearly 100 μmol / L, a difference of 126.382 μmol / L from placebo ( Figure 12B ). The MDR3 cohort achieved a reduction in sBA content of 150 μmol / L, a difference of 135.089 μmol / L from placebo ( Figure 13A)。

[0398] The percentages of pruritus and sBA response in the BSEP deficiency cohort are shown in Figure 13. The percentage of pruritus response in the BSEP deficiency cohort taking marcipitant was 57.1%, while that in the placebo group was 23.5%, indicating a p-value of 0.0736( Figure 13B )。The percentage of sBA response in the BSEP deficiency cohort taking marcipitant was 35.7%, while that in the placebo group was 5.9%, indicating a p-value of 0.0410( Figure 14A )。

[0399] The percentages of pruritus and sBA response in all PFIC cohorts are shown in Figure 14. The percentage of pruritus response in all PFIC cohorts taking marcipitant was 63.6%, while that in the placebo group was 25.8%, indicating a p-value of 0.0023( Figure 14B )。The percentage of sBA response in the BSEP deficiency cohort taking marcipitant was 45.5%, while that in the placebo group was 6.5%, indicating a p-value of 0.0004( Figure 15A )。

[0400] The change in sBA content (μmol / L) over time relative to baseline in the BSEP deficiency (also known as major) group is shown in Figure 15B . The change in sBA content (μmol / L) over time relative to baseline in the PFIC group is shown in Figure 15C . The change in sBA content (μmol / L) over time relative to baseline in all study participants is shown in Example 4. Additional Efficacy Assessments . It is obvious from these figures that the sBA content of the participants treated with marcipitant was more than 100 μmol / L lower at each time point from week 2 to week 26, indicating a very strong response of all PFIC types to marcipitant treatment.

[0401] These results confirm that marcipitant is very effective in significantly reducing serum bile acids in all PFIC patients, including PFIC 1 patients, PFIC 2 patients, PFIC 3 patients, and all PFIC groups together. The results also confirm that marcipitant can effectively reduce pruritus and sBA in most participants, and the percentage of participants is much higher than that of the placebo, with a very high confidence level.

[0402] Figure 16A

[0403] Additional efficacy endpoints were defined as: 1) pruritus response: assessment ratio ≤ 1; 2) pruritus response: assessment ratio ≤ 1 or reduction ≥ 1; 3) mean change in the Clinical Physician Scratch Scale (CSS) score relative to baseline; 4) mean change in total bilirubin relative to baseline; and 5) mean change in direct bilirubin relative to baseline.

[0404] The pruritus responses with an assessment ratio ≤ 1 in the BSEP deficiency cohort and the PFIC cohort are shown in Figure 16. Responders were defined as having a scratching score ≤ 1 on the ItchRO(Obs) severity score. The ratios were calculated using morning and evening values. [1] The model included treatment group, baseline morning pruritus score, and baseline evening pruritus score. [2] The model included treatment group, baseline morning pruritus score, baseline evening pruritus score, and PFIC type. The proportion of pruritus responders among participants in the BSEP deficiency cohort taking marcipitant exceeded 0.6, while that in the placebo group was 0.3, indicating a difference in the proportion of pruritus responders taking marcipitant of 0.344( Figure 16B ). The proportion of pruritus responders among participants in the PFIC cohort taking marcipitant exceeded 0.6, while that in the placebo group was 0.3, indicating a difference in the proportion of pruritus responders taking marcipitant of 0.345( Figure 17A ).

[0405] The pruritus responses with an assessment ratio ≤ 1 or a decrease ≥ 1 in the BSEP deficiency cohort and the PFIC cohort are shown in Figure 17. Responders were defined as having a scratching score ≤ 1 point or the ItchRO(Obs) severity score decreasing by at least one point relative to baseline. At each assessment, the morning severity score was compared with the average baseline morning severity score, and the evening severity score was compared with the average baseline evening severity score. The ratios were calculated using morning and evening values. [1] The model included treatment group, baseline morning pruritus score, and baseline evening pruritus score. [2] The model included treatment group, baseline morning pruritus score, baseline evening pruritus score, and PFIC type. The proportion of pruritus responders among participants in the BSEP deficiency cohort taking marcipitant exceeded 0.7, while that in the placebo group was 0.3, indicating a difference in the proportion of pruritus responders taking marcipitant of 0.398( Figure 17B ). The proportion of pruritus responders among participants in the PFIC cohort taking marcipitant was over 0.7, while that in the placebo group was 0.3, indicating a difference in the proportion of pruritus responders taking marcipitant of 0.380( Figure 18A ).

[0406] The changes over time in the CSS scores of the BSEP deficiency (also known as primary) group are shown in Figure 18B . The changes over time in the CSS scores of the PFIC group are shown in Figure 19A . It is evident from these figures that the CSS scores of the participants treated with marcipitant were significantly lower at each time point from week 2 to week 26.

[0407] The mean change from baseline in the Clinician Scratch Scale (CSS) score is shown in Figure 19. Estimates were from a mixed model repeated measures (MMRM), using the change from baseline as the dependent variable, and fixed categorical effects for treatment group, analysis visit, and treatment-by-visit interaction, and continuous fixed covariates for baseline score and baseline score-by-visit interaction. For the PFIC cohort, PFIC type was included in the model as an additional covariate. The improvement in CSS score relative to baseline in the BSEP deficiency cohort was approximately 1.7 points, while in the placebo group it was approximately 0.4 points, representing an improvement difference of 1.328 points in the maribavir treatment group ( Figure 19B ). The improvement in CSS score relative to baseline in the PFIC cohort was approximately 1.8 points, while in the placebo group it was approximately 0.5 points, representing an improvement difference of 1.247 points in the maribavir treatment group ( Figure 20A ).

[0408] These additional efficacy endpoint results further underscore the unexpected and unanticipated efficacy of maribavir in reducing pruritus in all PFIC patients. Additionally, in a previous study of odevixibat in PFIC, efficacy measurements of pruritus and serum bile acids did not increase the efficacy of either endpoint. The higher dose groups had lower efficacy parameters. Thus, it is assumed that this is the expected maximum effect size of IBAT inhibitors in PFIC. The magnitude of the reduction in pruritus and sBA observable in the MARCH study was greater than previous odevixibat data.

[0409] The mean change from baseline in total bilirubin is shown in Figures 20 - 21. Estimates were from a mixed model repeated measures (MMRM), using the change from baseline as the dependent variable, and fixed categorical effects for treatment group, time period, and treatment-by-time period interaction, and continuous fixed covariates for mean baseline score and baseline score-by-time period interaction. [2] The mean values for weeks 15 to 18, 19 to 22, and 23 to 26 of the time period obtained from the MMRM were used as the equally weighted mean of three individually specified visit estimates. The improvement (decrease) in total bilirubin relative to baseline in the BSEP deficiency cohort was approximately 1.2 mg / dL, while in the placebo group it increased by approximately 0.4 mg / dL, representing an improvement difference of 1.585 mg / dL in the maribavir treatment group ( Figure 20B ). The improvement (decrease) in total bilirubin relative to baseline in the PFIC cohort was approximately 1.2 mg / dL, while in the placebo group it increased by approximately 0.8 mg / dL, representing an improvement difference in total bilirubin of 2.000 mg / dL in the maribavir treatment group ( Figure 21A ). The change in total bilirubin over time relative to baseline in the BSEP deficiency (also known as major) group is shown in Figure 21B . The change in total bilirubin over time relative to baseline in the PFIC group is shown inFigure 22A Among them. It is obvious from these figures that the total bilirubin of the participants treated with maribavir is significantly lower than the baseline (at each time point from week 2 to week 26), and at week 18 and subsequent time points, it is at least 1.0 mg / dL lower than the baseline.

[0410] The mean change in direct bilirubin relative to the baseline is shown in Figures 22 - 23. The estimates are from a mixed model repeated measures (MMRM), using the change relative to the baseline as the dependent variable, and the fixed categorical effects of treatment group, time period, and the interaction of treatment and time period, as well as the continuous fixed covariates of the mean baseline score and the interaction of baseline score and time period. [2] The means for the time periods from week 15 to week 18, week 19 to week 22, and week 23 to week 26 obtained from the MMRM are used as the equally weighted mean of three uniquely defined visit estimates. The improvement (decrease) in direct bilirubin in the BSEP deficiency cohort relative to the baseline is more than 0.8 mg / dL, while it increases by approximately 0.3 mg / dL in the placebo group, indicating an improvement difference of 1.196 mg / dL in the maribavir treatment group ( Figure 22B ). The improvement (decrease) in direct bilirubin in the PFIC cohort relative to the baseline is approximately 0.9 mg / dL, while it increases by approximately 0.7 mg / dL in the placebo group, indicating an improvement difference in direct bilirubin of 1.608 mg / dL in the maribavir treatment group ( Figure 23A ). The change in direct bilirubin over time relative to the baseline in the BSEP deficiency (also known as the major) group is shown in Figure 23B . The change in direct bilirubin over time relative to the baseline in the PFIC group is shown in Figure 24A . It is obvious from these figures that the direct bilirubin of the participants treated with maribavir is significantly lower than the baseline (at each time point from week 2 to week 26), and at week 18 and subsequent time points, it is at least 1.0 mg / dL lower than the baseline.

[0411] The change in the height Z - score of the participants in the BSEP deficiency (also known as the major) group over time is shown in Figure 24B . The change in the height Z - score of the participants in the PFIC group over time is shown in Figure 25A and 24C . These figures show an overall positive trend in the increase in the height Z - score of the participants in the maribavir treatment group compared to the placebo group.

[0412] The change in the weight Z - score of the participants in the BSEP deficiency (also known as the major) group over time is shown in Figure 25B . The change in the weight Z - score of the participants in the PFIC group over time is shown in Figure 26A and 25CIn the marciprant treatment group and the placebo group, the children gained weight, but it is very obvious from these figures that the participants in the marciprant treatment group had significantly more weight gain compared to the placebo participants.

[0413] No significant changes in serum ALT were observed in all PFIC cohorts upon MRX treatment ( Example 5. Assessment of Adverse Events and Serious Adverse Events and 26B ).

[0414] In the indigo phase 2 study of marciprant, only participants with PFIC 2 had a response. Patients with PFIC 1 did not have a response. Therefore, this MARCH study was designed with independent cohorts because it was expected that other (non-PFIC 2) subtypes would not have a response.

[0415] However, unexpectedly, significant improvements in sBA, pruritus, total bilirubin, and direct bilirubin were observed in all PFIC types in this study.

[0416] In addition, the magnitude of the effect of non-PFIC 2 patients on the reduction of sBA and pruritus was the same as or stronger than that in PFIC 2 patients, which was unexpectedly contrary to the previous study results.

[0417] Another unexpected finding is that the complete population of the group includes not only another PFIC subtype but also PFIC patients after the operation. Given that the operation has the same mechanism of interrupting the enterohepatic circulation, we would not expect these patients to have a response at all. However, these patients unexpectedly showed a significant response to marciprant treatment.

[0418] Pharmacokinetic analysis

[0419] The systemic concentration of marciprant in plasma was determined before dosing and approximately 2.5 hours after morning dosing at week 10 and week 26 (EOT / ET). At each nominal time point and sampling time, the total statistics of marciprant concentration (number of observations, mean, standard deviation, coefficient of variation, median, minimum, maximum, and geometric mean) were determined.

[0420] Adverse Events

[0421] An adverse event (AE) or treatment-emergent adverse event (TEAE) is any untoward medical event that occurs in an individual being clinically investigated for a drug product and that does not necessarily have a causal relationship with this treatment. Thus, a TEAE can be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of the medicinal product (investigational), whether or not related to the medicinal product (investigational) (ICH guideline E2A 1995). All TEAEs are collected from the time of signing the informed consent until the defined follow-up period. This includes events that occur during the study screening period, whether or not the investigational drug is administered.

[0422] Table 6 below summarizes the TEAEs for all PFIC cohorts in the MARCH Phase 3 study. The most common TEAEs were GI disorders in 35 (74.5%) of maralixibat and 17 (37.0%) of placebo patients [n(%)]. In total, 90 patients experienced ≥1 TEAE, of which 84 had mild or moderate severity (93.3%) and were transient in nature. Among the 90 AE participants, 84 had a highest grade of mild or moderate.

[0423] Table 6. Summary of TEAEs for all PFIC cohorts

[0424] Maralixibat (n = 47) Placebo (n = 46) Any TEAE, n(%) Grade 3 / 4 TEAE, n(%) 47(100％) 43(93.5％) Serious TEAE, n(%) 3(6.4％) 3(6.5％) TEAE Leading to Discontinuation, n(%) 5(10.6％) 3(6.5％) TEAE Leading to Death, n(%) 1(2.1％) 0 TEAE Possibly Related to Study Drug, n(%) 0 0 GI Events Possibly Related to Study Drug, n(%) 18(38.3％) 2(4.3％) Diarrhea 14(29.8％) 2(4.3％) Diarrhea Related to Study Drug, n(%) 27(57.4％) 9(19.6％) Figure 28 13(27.7％) 1(2.2％)

[0425] A serious adverse event (SAE) is any untoward medical event (whether or not considered related to the investigational drug) that, at any dose, results in any of the following: 1) death; 2) life-threatening; 3) requires hospitalization or prolongation of existing hospitalization; 4) results in persistent or significant disability / incapacity; or 5) is an important medical event.

[0426] All SAEs (regardless of relationship to the study) are collected from the time an individual signs the informed consent until the defined follow-up period and must be reported within 24 hours of first awareness of the event.

[0427] Among the 47 maralixibat-treated participants, 5 experienced SAEs (10.6%). Among the 46 placebo participants, 3 experienced SAEs (6.5%).

[0428] TEAEs in the MRX group and placebo group included diarrhea (57.4% vs 19.6%) and abdominal pain (25.5% vs 13%) respectively (Table 7). Diarrhea was mainly grade 1, transient, and had a median duration of 5.5 days; there were no severe or serious events. One patient with mild diarrhea discontinued treatment (Table 6 and Example 6. Safety Monitoring of Selected Parameters )). Abdominal pain was also mainly mild and transient and, in almost all cases, was accompanied by diarrhea. No clinically significant changes in transaminase levels relative to baseline were observed in either group.

[0429] Table 7. Clinically relevant TEAEs occurring in ≥5% of participants in either arm, by FMQ and preferred terms

[0430]

[0431] Transaminase adverse events (AEs) were observed in 17% and 6.5% of MRX and PBO patients, respectively (Table 7). Among the 8 MRX-treated participants with elevated transaminases, 6 had resolution of elevated transaminases without drug interruption; 2 patients had persistent stable elevations even after drug interruption (n = 1) or dose reduction (n = 1), and both patients ultimately recovered before reaching the maximum dose. None of the patients discontinued MRX due to elevated transaminases.

[0432] There was no evidence that MRX treatment contributed to fat-soluble vitamin (FSV) deficiency. FSV deficiency (reported as an AE) was also less frequent in the MRX group than in the PBO group (27.7% vs 34.8%). With regular FSV supplementation due to chronic cholestasis, no clinically significant changes in serum levels of vitamins A, D, and E relative to baseline were observed in the study population. Bilirubin increases were less common in the MRX group than in the PBO group (14.9% vs 19.6%). At Week 26, the international normalized ratio (INR) decreased (improved) at each assessment time point, with a mean change relative to baseline of -0.3 in the MRX group and -0.03 in the placebo group at Week 26.

[0433] Fractures were observed in 6.4% of MRX and 0% of PBO; none were considered treatment-related as all fractures had clear alternative causes, including pre-existing vitamin D deficiency, which stabilized or improved after taking MRX. Serious AEs were reported in 10.6% of MRX patients and 6.5% of PBO patients; none were considered related (except for 1 event of mild bilirubin increase in the MRX group); all resolved without any dose modification.

[0434] MRX was well tolerated, with GI effects being the most frequent event but generally mild and self-limiting. FSV deficiency and bilirubin increases were frequently observed in the PBO group. Overall, no changes in liver enzymes were observed during the study, and individual elevations were mild and transient; there were no drug discontinuations.

[0435] Example 7. Additional Results for FIC1, MDR3, TJP2, and MYO5B Cohorts

[0436] Liver parameters

[0437] Table 8 provides guidelines for close monitoring of liver parameters.

[0438] For individuals with confirmed increases in ALT or TSB levels and who meet the criteria for close monitoring, consider the following studies as clinically indicated: 1) closely and frequently monitor the results of liver enzyme and serum bilirubin tests as clinically indicated; 2) symptoms, as well as past, current, and concurrent diseases / conditions; 3) concomitant treatments (including over-the-counter medications, herbal, and dietary supplement preparations), alcohol use, recreational drug use, and use or recent changes in specific diets; 4) history of exposure to environmental chemicals and travel history; 5) serology for viral hepatitis (panel of HAV IgM, HBsAg, HCV antibody, HCV RNA, CMV IgM, and EBV antibody tests); 6) serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]); 7) AST, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH); 8) CBC and differential blood count (eosinophils); 9) reticulocyte count, PT / INR.

[0439] Table 8. Guidelines for Close Monitoring of Treatment-Induced Elevations in ALT and TSB

[0440]

[0441] ALT = alanine aminotransferase; BL = baseline; TSB = total serum bilirubin.

[0442] Figure 33A

[0443] Treatment with MRX caused a statistically significant and clinically meaningful improvement in pruritus in the cohorts of familial intrahepatic cholestasis-related protein 1 (FIC1), multidrug resistance protein 3 (MDR3), tight junction protein 2 (TJP2), and myosin VB (MYO5B) ( Figure 34A and 33B ). A significant improvement in serum bile acid levels was observed in the FIC1, MDR3, TJP2, and MYO5B cohorts ( Figure 35A and 34B ).

[0444] Treatment with MRX caused a statistically significant and clinically meaningful improvement in pruritus severity and serum bile acid levels in the overall study population ( Figure 35C and 35B ). In patients without identified variants, MRX demonstrated improvement in pruritus and serum bile acid levels ( Figure 35E and 35D ). Changes in weekly ltchRO(Obs) scores and serum bile acids (sBA) were also observed in the FIC1 ( Figure 35G and 35F ) and MDR3 ( ​ and 35H ) cohorts.

[0445] Example 8. Marcipitant causes a significant reduction in pruritus and improvement in sleep in children with progressive familial intrahepatic cholestasis Figure 27A

[0446] Method: Participants were randomly assigned to receive MRX 570 μg / kg BID or placebo (PBO)( Figure 27B ). The primary analysis evaluated itch as assessed by caregivers using the ItchRO(Obs) 0 - 4 scale and by physicians using the Clinician Scratch Scale (CSS). Sleep was evaluated using the Exploratory Diary Questionnaire (Observer) (EDQ[Obs]). The responses for itch and sleep were determined as the mean of weekly scores using a mixed - effects model with repeated measures of change from baseline (CFB) up to 26 weeks.

[0447] The Itch Report Outcome (Observer) (ItchRO(Obs)) is a 0 - 4 scale where 0 = no itch, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. A decrease in ItchRO(Obs) of ≥1 point was considered clinically significant.

[0448] The Clinician Scratch Scale (CSS) is a 0 - 4 scale where 0 = none and 4 = skin damage, extensive bleeding, and scar formation (worst scratching).

[0449] The Exploratory Diary Questionnaire (Observer) (EDQ[Obs]) is a 1 - 5 scale (1 = never / no itch to 5 = always / very severe) that includes questions on sleep disturbances related to itch.

[0450] Results: Sixty - four patients (nt - BSEP [n = 31], FIC1 [n = 13], MDR3 [n = 9], TJP2 [n = 7], and MYO5B [n = 4]) were randomly assigned to the MRX group (n = 33) or the PBO group (n = 31). Baseline characteristics were well - balanced between treatment groups (Table 9). The baseline itch scores (ItchRO[Obs]) for MRX and PBO were 2.9 vs. 2.7. From baseline to 26 weeks, the proportion (SE) of itch assessments ≤1 was higher in the MRX group (0.62 [0.06]) than in the PBO group (0.27 [0.06]) and the difference was significant (increment [95% CI]: 0.35 [0.19, 0.50])( Figure 27C ). From weeks 15 to 26, the median proportion of days with an ItchRO(Obs) score of 0 - 1 reported in the MRX group was 95%, while in the PBO group it was 9% (p = 0.0005). When at morning (increment [95% CI]: - 1.20 [- 1.73, - 0.67]), evening (increment: - 1.16 [- 1.69, - 0.63]), or maximum daily (increment: - 1.20 [- 1.74, - 0.66])(Figure 27D ) The pruritus response obtained using ItchRO(Obs) from 15 to 26 weeks during measurement was greater in the MRX group. The pruritus response measured using CSS was greater and significantly different in the MRX group (Increment: -1.8 [-2.2, -1.53]) than in the PBO group (Increment: -0.7 [-1.1, -0.3]) (Increment: -1.1 [-1.7, -0.6]; p < 0.0002). The CFB of sleep was greater in the MRX group (Increment: -1.74 [-2.15, -1.33]) than in the PBO group (Increment: -0.55 [-0.99, -0.11]) and was significantly different (Increment: -1.19 [-1.78, -0.60]; p = 0.0002)( Figure 27E ). During the entire study period, there was a strong correlation between the absolute values of pruritus and sleep scores (Spearman's r = 0.93; p < 0.0001) and between the changes in pruritus and sleep relative to baseline (Spearman's r = 0.93; p < 0.0001)( Example 9. Long-term maintenance response and improvement in liver health with marcipitant in patients with progressive familial intrahepatic cholestasis (PFIC) ).

[0451] Table 9. Baseline characteristics between treatment arms

[0452]

[0453] Unless otherwise specified, all data are mean values. Percentages are 100×n / N. UDCA is ursodeoxycholic acid.

[0454] Conclusion: MRX is associated with complete or almost complete resolution of pruritus in most patients with PFIC, and the effect is independent of the method of measurement or the assessor. The changes in pruritus are strongly correlated with the changes in sleep, indicating that the use of MRX can cause a meaningful improvement in quality of life in this area.

[0455] Figure 29A Figure 29B

[0456] Eighty-five patients from the MARCH trial participated in MARCH-ON (Table 10, Figure 29D ). Forty-seven patients had received marciprant (MRX-MRX) during the MARCH trial and 38 had received placebo (PBO-MRX).

[0457] Table 10. Baseline characteristics between treatment arms

[0458]

[0459] Unless otherwise specified, all data are mean values. Percentages are 100×n / N. UDCA is ursodeoxycholic acid.

[0460] The PFIC subtypes of patients included in the study were: non-truncated bile salt export pump (nt-BSEP, n = 27), familial intrahepatic cholestasis related protein type 1 (F1C1, n = 13); multidrug resistance protein 3 (MDR3, n = 9); tight junction protein 2 (TJP2, n = 6); myosin VB (MYO5B, n = 2); heterozygous (n = 2); truncated BSEP (t-BSEP, n = 9); no variant found (n = 8), sBA fluctuation (n = 2) and surgery (n = 7). Efficacy analysis included n = 33 in the MRX-MRX group and n = 24 in the PRO-MRX group. Subtypes nt-BSEP, F1C1, MDR3, TJP2 and MYO5B were included in the efficacy analysis. Baseline was defined as the start of maralixibat (MRX) treatment in each group.

[0461] Methods: To evaluate the long-term maintenance of the response of patients initially randomized to receive MRX in MARCH and continued treatment in MARCH-ON (MRX-MRX group; n = 33). The MRX response of patients receiving PBO was evaluated in the MARCH study and switched to open-label MRX in MARCH-ON (PBO-MRX group; n = 24). The evaluations included: pruritus measured by the 0 to 4 subscale of ItchRO[Obs], sBA, bilirubin and growth z-score, and the incidence of treatment-emergent adverse events (TEAE). Baseline (BL) was defined as the start of MRX in each group.

[0462] Results: For the MRX-MRX group, the median (min, max) time of MRX was 394 days (108, 836). Twenty out of a total of 33 patients reached it at week 52 of the analysis. During the first 26 weeks of the MARCH study, the severity of pruritus (-2.17, p < 0.0001), sBA (-200 μmol / L, p = 0.0004), bilirubin (-2.64 mg / dL, p = 0.0084), height z-score (+0.54, p < 0.0001) and weight z-score (+0.44, p = 0.0010) observed in MARCH-ON improved significantly from baseline (BL) and continued until week 52 ( Example 10. Effect of marcipitant (MRX) on cholestatic pruritus in adults 16 years of age and older with Alagille syndrome (ALGS) -C, Table 11). In the PBO-MRX group, the median time of taking MRX was 256 days (29, 569). Fifteen out of a total of 24 patients reached it at week 26 of the analysis. From BL to week 26, a statistically significant decrease in pruritus (-1.05, p = 0.0017) and sBA (-141 μmol / L, p = 0.0003) was newly observed in the primary efficacy endpoints for pruritus and sBA ( Figure 30-E, Table 11), which is consistent with the observations from the initial MARCH MRX group. Overall, no new safety signals were identified (Table 12). The most common TEAE was related to the gastrointestinal (GI) tract and was accompanied by early diarrhea (51%), which is consistent with the mechanism of IBAT inhibition and is generally mild and transient. In the MRX-MRX subgroup, fewer patients experienced diarrhea in MARCH-ON, demonstrating that these effects are early and transient.

[0463] Table 11. Significant improvements in key endpoints were observed from baseline to week 52 in the MRX-MRX group and from baseline to week 26 in the PBO-MRX group

[0464]

[0465]

[0466] a The analysis included n = 20 patients in the MRX-MRX group, followed up to week 52.

[0467] b The analysis included n = 15 patients in the PBO-MRX group, followed up to week 26.

[0468] Table 12. No new safety signals were identified during treatment with maralixibat

[0469]

[0470] Percentages are 100×n / N. TEAE is treatment-emergent adverse effect.

[0471] Conclusion: In the broadest range of inherited PFIC types studied to date, significant and sustained responses in pruritus, sBA, bilirubin, and growth were observed under 52 weeks of MRX treatment. The PBO-MRX group demonstrated significant improvements in pruritus severity and sBA levels, similar to those observed in the initial MARCH maralixibat group. These data suggest that the overall improvement in liver health induced by MRX treatment can be maintained over time.

[0472] Figure 31A Example 11. Marcipitant causes a significant reduction in bilirubin in patients with progressive familial intrahepatic cholestasis (PFIC)

[0473] To study the efficacy and safety of MRX in participants with ALGS transitioning to adult care aged ≥16 years and in participants starting MRX treatment aged >16 years Figure 36A)。The median (min, max) duration of treatment for participants who initiated MRX before age 16 was 4.1 years (1.5, 5.9), with the oldest patient taking MRX at age 21 (Table 13). Three participants initiated MRX at age ≥16 and the median follow-up was 3.8 years.

[0474] Table 13. Key demographics and baseline characteristics (N = 14)

[0475]

[0476] ALT is alanine aminotransferase. Adverse events (AE) decreased with increasing patient age (Table 14).

[0477] Table 14. Overview of treatment-emergent adverse effects (TEAE) in the full study cohort (N = 14).

[0478]

[0479] a Individuals were only counted once per cycle for each preferred term. b Before 16 years old was defined as the last data point before reaching 16 years old. After 16 years old was defined as the first data point after reaching 16 years old.

[0480] b Treatment-related AE of grade ≥3 was increased pruritus (grade 3) that resolved without dose modification.

[0481] Pruritus and sBA improved significantly in patients receiving MRX during childhood, and the improvement was maintained into early adulthood ( Figure 36B -B and 32A-B). Participants receiving MRX in early adulthood showed significant improvement in pruritus and sBA after treatment, and the improvement was maintained throughout the therapy. MRX was generally well tolerated and demonstrated a safety and tolerability profile consistent with previously reported data.

[0482] These results provide key data on patients transitioning to adulthood while receiving MRX therapy. MRX shows potential for a positive impact on the management of adult patients with ALGS who can survive to adulthood with their native liver.

[0483] Figure 37A Figure 38A

[0484] Methods: MARCH enrolled patients with genetic diagnosis of PFIC, pruritus, and elevated sBA. Patients were randomized to receive MRX 570 μg / kg BID or placebo (PBO) for 26 weeks. Using a mixed-effects model with repeated measures, the change was determined as the difference in the change from baseline (CFB) of the mean of the final three measurements (weeks 18, 22, and 26) between the MRX group and the PBO group. The total / direct bilirubin (TB / DB) category was defined as normal (≤1.2 / 0.3 mg / dL) or abnormal (>1.2 / 0.3 mg / dL).

[0485] Results: The analysis included 64 patients from all PFIC cohorts (13 FIC1, 31 nt-BSEP, 9 MDR3, 7 TJP2, and 4 MYO5B); patients were randomized to the MRX group (n = 33) or the PBO group (n = 31). The median (Q1, Q3) TB at baseline in the MRX group and the PBO group was 2.8 (1.4, 5.5) and 2.6 (0.8, 5.5) mg / dL, respectively, and the DB was 2.1 (0.9, 4.0) mg / dL and 1.9 (0.5, 4.3) mg / dL, respectively. The study achieved a significant CFB between MRX and PBO for TB (-1.1 vs. +0.9 mg / dL; group difference: 2.0; p = 0.047)( Figure 38A ) and DB (-0.8 vs. +0.8 mg / dL; group difference: 1.5; p = 0.048)( Figure 39 ). Among individuals with abnormal baseline bilirubin (TB: n = 46; DB: n = 56), there was a significant CFB between the MRX group and the PBO group for DB (-0.8 vs. +1.0 mg / dL; group difference: -1.8; p = 0.042)( Figure 40 and 37B ). For the post hoc analysis evaluating bilirubin normalization, pre- and post-treatment bilirubin values were available for 60 individuals (32 MRX; 28 PBO). For the MRX group, TB normalized in 40% (10 / 25) of patients with abnormal baseline values, and no patient changed from normal TB to abnormal TB (0 / 7)( Example 12. Marcipitant causes unexpected and unanticipated improvement in patients with truncated BSEP (t-BSEP) and 38B ). For the PBO group, TB never normalized in patients with abnormal baseline values (0 / 18), and instead, 30% (3 / 10) of patients became abnormal( ​ and 38B ). For DB, the MRX group also showed a greater frequency of normalization compared to the PBO group (38% vs. 8%)( ​)。Among all individuals with normalized TB, sBA decreased by 94.9% (95% CI: 68.5%, 98.9%), while for individuals without normalized TB, sBA decreased by only 13.3% (95% CI: 1.4, 34.0); p < 0.0001( ​ )。For treatment-emergent adverse event reporting, an increase in bilirubin was observed less frequently in the MRX group than in the PBO group (14.9% vs. 19.6%).

[0486] Conclusion: MRX is the only IBAT inhibitor that demonstrated a significant reduction in TB / DB compared to PBO in children with PFIC and across various PFIC types. 40% of MRX patients with abnormal baseline bilirubin achieved normalization, while none of the patients in the PBO group did, indicating that MRX can produce clinically meaningful improvements in liver health in patients with PFIC. The reduction in bilirubin corresponded to a reduction in sBA.

[0487] ​

[0488] Unexpected findings were observed in patients with truncated BSEP (t-BSEP) deficiency (also known as truncated PFIC2 or t-PFIC2), where improvement was observed in individual patients, with sBA decreasing from baseline to week 26 and limited improvement in pruritus (Figures 41D and 42D). As shown in Figure 41D, a subset of t-BSEP patients experienced a reduction in pruritus, with t-BSEP patients reporting a decrease in morning pruritus severity over time, as measured by the Itch Report Outcome.

[0489] Table 15 below presents data for individual t-BSEP patients. All patients receiving maribavir (MRX-MRX) or switched from placebo (PBO-MRX) to maribavir demonstrated a meaningful reduction in sBA.

[0490] Table 15. Overview of sBA, total bilirubin, and ALT in t-BSEP patients at week 26 and week 58 of treatment

[0491]

[0492] [a] Week 52 values are from week 26 values of Study MRX-503 (representing 26 weeks of MRX treatment). Change from baseline (percentage) was calculated relative to week 26 results obtained from Study MRX-502.

[0493] [b] For participant 043-001, week 26 results were not available, so baseline values from MRX-503 were actually used.

[0494] [c]Use the 22-week results of the study of MRX-503.

[0495] This finding was very unexpected and beyond expectation given the predicted loss of function associated with this genotype.

[0496] All references cited anywhere in this specification are hereby incorporated by reference in their entirety for all purposes.

[0497] While the preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only.

[0498] Unless otherwise indicated herein, the recitation of a range of values herein is merely intended to be a shorthand method of individually referring to each individual value and each endpoint falling within the stated range, and each individual value and endpoint is incorporated into the specification as if it were individually recited herein.

[0499] Many variations, modifications, and substitutions may be made by those skilled in the art without departing from the invention. It is to be understood that various alternatives to the embodiments of the invention described herein may be employed to practice the invention. It is expected that the following claims define the scope of the invention and thereby cover methods and structures within the scope of these claims and their equivalents.

[0500] References

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Claims

1. A method for treating progressive familial intrahepatic cholestasis (PFIC) in an individual in need thereof, comprising administering maralixibat or a pharmaceutically acceptable salt thereof to the individual.

2. The method according to claim 1, wherein the pharmaceutically acceptable salt of maralixibat is maralixibat chloride, maralixibat bromide, maralixibat acetate or maralixibat mesylate.

3. The method according to claim 1, wherein the pharmaceutically acceptable salt of maralixibat is maralixibat chloride.

4. The method according to any one of claims 1 to 3, wherein the maralixibat or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 μg / kg per day to about 1400 μg / kg per day.

5. The method according to any one of claims 1 to 4, wherein the maralixibat or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 μg / kg per day to about 1200 μg / kg per day.

6. The method according to any one of claims 1 to 5, wherein the maralixibat or a pharmaceutically acceptable salt thereof is administered in an amount of about 600 μg / kg per day to about 1200 μg / kg per day.

7. The method according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt of maralixibat is maralixibat chloride, and maralixibat chloride is administered in an amount of about 1200 μg / kg per day.

8. The method according to any one of claims 1 to 7, wherein the maralixibat or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.5 mg per day to about 100 mg per day.

9. The method according to any one of claims 1 to 8, wherein the PFIC is PFIC 1, PFIC 2, PFIC 3, PFIC 4, PFIC 5 or PFIC 6.

10. The method according to claim 9, wherein the PFIC is PFIC 1.

11. The method according to claim 9, wherein the PFIC is PFIC 2.

12. The method according to claim 11, wherein the PFIC 2 is non-truncated PFIC 2.

13. The method according to claim 11, wherein the PFIC 2 is truncated PFIC 2.

14. The method according to claim 9, wherein the PFIC is PFIC 3.

15. The method according to claim 9, wherein the PFIC is PFIC 4.

16. The method according to claim 9, wherein the PFIC is PFIC 5.

17. The method according to claim 9, wherein the PFIC is PFIC 6.

18. The method according to any one of claims 1 to 17, wherein the PFIC is heterozygous.

19. The method according to any one of claims 1 to 18, wherein the individual has intermittent cholestasis.

20. The method according to any one of claims 1 to 19, wherein the individual has undergone biliary diversion surgery.

21. The method according to any one of claims 1 to 20, wherein the individual is a pediatric individual.

22. The method according to any one of claims 1 to 21, wherein the age of the individual is more than 1 year and less than 18 years.

23. The method according to any one of claims 1 to 22, wherein the age of the individual is less than 12 months.

24. The method according to any one of claims 1 to 23, wherein the individual has a mutation in a gene selected from the group consisting of: ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, and MYO5B.

25. The method according to any one of claims 1 to 23, wherein the mutation is a non-truncating mutation.

26. The method according to any one of claims 1 to 23, wherein the mutation is a truncating mutation.

27. The method according to any one of claims 1 to 23, wherein the individual has a truncated BSEP protein.

28. The method according to any one of claims 1 to 24, wherein the marciprant or a pharmaceutically acceptable salt thereof is administered once daily (QD).

29. The method according to any one of claims 1 to 28, wherein the marciprant or a pharmaceutically acceptable salt thereof is administered twice daily (BID).

30. The method according to any one of claims 1 to 29, wherein the marciprant or a pharmaceutically acceptable salt thereof is marciprant chloride, and marciprant chloride is administered BID at 600 μg / kg per day, and the total daily dose is 1200 μg / kg per day.

31. The method according to any one of claims 1 to 30, wherein administration of the marciprant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 2 months.

32. The method according to any one of claims 1 to 31, wherein administration of the marciprant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 4 months.

33. The method according to any one of claims 1 to 32, wherein administration of the marciprant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 6 months.

34. The method according to any one of claims 1 to 33, wherein administration of the marciprant or a pharmaceutically acceptable salt thereof results in a reduction in the symptoms of PFIC or changes in disease-related laboratory measures, maintained for at least 1 year.

35. The method according to any one of claims 31 to 34, wherein the reduction in the symptoms or disease-related laboratory measures is determined relative to a baseline level.

36. The method according to any one of claims 31 to 35, wherein the reduction in the change in the symptom or the disease-related laboratory measure comprises a decrease in sBA concentration, a decrease in itching, a decrease in total bilirubin, a decrease in direct bilirubin, an improvement in growth, or a combination thereof.

37. The method according to any one of claims 1 to 36, wherein administering the maribavir reduces the intensity of itching.

38. The method according to claim 37, wherein the reduction in the intensity of itching is a reduction in the ItchRO(Obs) score, a reduction in the CSS score, or a combination thereof.

39. The method according to any one of claims 1 to 38, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to be reduced by at least 1.0 point relative to the baseline.

40. The method according to any one of claims 1 to 39, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to be reduced by at least 1.2 points relative to the baseline.

41. The method according to any one of claims 1 to 40, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to be reduced by at least 1.4 points relative to the baseline.

42. The method according to any one of claims 1 to 41, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the ItchRO(Obs) score of the individual to be reduced by at least 1.6 points relative to the baseline.

43. The method according to any one of claims 1 to 42, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the CSS score of the individual to be reduced by at least 1.0 point relative to the baseline.

44. The method according to any one of claims 1 to 43, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the CSS score of the individual to be reduced by at least 1.2 points relative to the baseline.

45. The method according to any one of claims 1 to 44, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the CSS score of the individual to be reduced by at least 1.4 points relative to the baseline.

46. The method according to any one of claims 1 to 45, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes the CSS score of the individual to be reduced by at least 1.6 points relative to the baseline.

47. The method according to any one of claims 1 to 46, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes an improvement in sleep as measured by a reduction in the EDQ(Obs) or EDQ(Pt) score of the individual by at least 1.0 point relative to the baseline.

48. The method according to any one of claims 1 to 47, wherein administering the maribavir or a pharmaceutically acceptable salt thereof causes an improvement in sleep as measured by a reduction in the EDQ(Obs) or EDQ(Pt) score of the individual by at least 1.2 points relative to the baseline.

49. The method according to any one of claims 1 to 48, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes an improvement in sleep as measured by a reduction of at least 1.4 points in the individual's EDQ(Obs) or EDQ(Pt) score relative to baseline.

50. The method according to any one of claims 1 to 49, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes an improvement in sleep as measured by a reduction of at least 1.6 points in the individual's EDQ(Obs) or EDQ(Pt) score relative to baseline.

51. The method according to any one of claims 1 to 50, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the sBA concentration of the individual to be reduced by at least 50 μmol / L relative to baseline.

52. The method according to any one of claims 1 to 51, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the sBA concentration of the individual to be reduced by at least 100 μmol / L relative to baseline.

53. The method according to any one of claims 1 to 52, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes a reduction in total bilirubin.

54. The method according to any one of claims 1 to 53, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the total bilirubin to be reduced by at least 0.2 mg / dL relative to baseline.

55. The method according to any one of claims 1 to 54, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the total bilirubin to be reduced by at least 0.5 mg / dL relative to baseline.

56. The method according to any one of claims 1 to 55, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the total bilirubin to be reduced by at least 1.0 mg / dL relative to baseline.

57. The method according to any one of claims 1 to 56, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes a reduction in direct bilirubin.

58. The method according to any one of claims 1 to 57, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the direct bilirubin to be reduced by at least 0.2 mg / dL relative to baseline.

59. The method according to any one of claims 1 to 58, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the direct bilirubin to be reduced by at least 0.5 mg / dL relative to baseline.

60. The method according to any one of claims 1 to 59, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes the direct bilirubin to be reduced by at least 1.0 mg / dL relative to baseline.

61. The method according to any one of claims 1 to 60, wherein the administration of maribavir or a pharmaceutically acceptable salt thereof causes an improvement in the height Z-score or weight Z-score or both of the individual relative to baseline.

62. The method according to claim 61, wherein administration of the maribavir or a pharmaceutically acceptable salt thereof causes the body weight Z-score to increase by at least 0.2 relative to the baseline.

63. The method according to any one of claims 1 to 62, further comprising administering a fat-soluble vitamin (LSV) to an individual suffering from a deficiency of fat-soluble vitamins (LSV).

64. The method according to claim 63, wherein the LSV is selected from the group consisting of vitamin A, vitamin D, and vitamin E.

65. The method according to any one of claims 1 to 64, wherein the maribavir or a pharmaceutically acceptable salt thereof is administered before a meal.

66. The method according to claim 65, wherein the maribavir or a pharmaceutically acceptable salt thereof is administered about 30 minutes before a meal.

67. The method according to claim 65 or claim 66, wherein the maribavir or a pharmaceutically acceptable salt thereof is BID: i.e., administered about 30 minutes before breakfast and about 30 minutes before dinner.

68. The method according to any one of claims 1 to 67, wherein the maribavir is administered in the form of a pharmaceutical composition comprising maribavir or a pharmaceutically acceptable salt thereof, an antioxidant, and a preservative.

69. The method according to claim 68, wherein the pharmaceutical composition is a liquid composition for oral administration.

70. The method according to claim 69, wherein the liquid composition is an aqueous solution.

71. The method according to any one of claims 68 to 70, wherein the maribavir is present in the composition in an amount of about 2 mg / mL to about 100 mg / mL.

72. The method according to any one of claims 68 to 71, wherein the maribavir is present in the composition in an amount of about 5 mg / mL to about 50 mg / mL.

73. The method according to any one of claims 68 to 72, wherein the maribavir is present in the composition in an amount of about 8 mg / mL to about 20 mg / mL.

74. The method according to any one of claims 68 to 73, wherein the maribavir is present in the composition in an amount of about 9.5 mg / mL to about 10 mg / mL.

75. The method according to any one of claims 68 to 74, wherein the preservative is an antimicrobial preservative.

76. The method according to claim 75, wherein the antimicrobial preservative is selected from the group consisting of propylene glycol, ethanol, glycerol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimonium bromide (hexadecyltrimethylammonium bromide), cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof.

77. The method according to any one of claims 68 to 76, wherein the preservative is propylene glycol.

78. The method according to any one of claims 68 to 77, wherein the preservative is present in an amount of about 30% w / w to about 40% w / w of the composition.

79. The method according to any one of claims 68 to 78, wherein the preservative is present in an amount of about 300 mg / mL to about 400 mg / mL of the composition.

80. The method according to any one of claims 68 to 79, wherein the antioxidant is selected from the group consisting of: aminocarboxylic acids, aminopolycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or its derivatives, propyl gallate, and combinations thereof.

81. The method according to any one of claims 68 to 80, wherein the antioxidant is an aminopolycarboxylic acid selected from: ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), nitrilotriacetic acid (NTA), 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), tetraazacyclododecanetetraacetic acid (DOTA), and ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid) (EDDHA).

82. The method according to any one of claims 68 to 81, wherein the antioxidant is EDTA.

83. The method according to any one of claims 68 to 82, wherein the antioxidant is present in an amount of about 0.01% w / w to about 0.5% w / w of the composition.

84. The method according to any one of claims 68 to 83, wherein the pharmaceutical composition further comprises a sweetening agent, a taste masking component, or a combination thereof.

85. The method according to any one of claims 68 to 84, wherein the pharmaceutical composition comprises: a. about 8 mg / mL to about 20 mg / mL of maribavir; b. about 330 mg / mL to about 380 mg / mL of propylene glycol; c. about 1 mg / mL of EDTA; d. a sweetening agent, a taste masking component, or a combination thereof, and e. water.

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