Novel use of ileal bile acid transporter inhibitors for the treatment of pruritus

Abstract

The present invention relates to an IBAT inhibitor for use in the treatment of pruritus in certain chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD) [newly reclassified as metabolic dysfunction-related fatty liver disease (MASLD)], which includes non-alcoholic fatty liver disease (NAFLD) [newly reclassified as metabolic dysfunction-related fatty liver disease (MASLD)], which may or may not be accompanied by cirrhosis, and a method for treating pruritus in NAFLD (or MASLD), which includes NAFL and NASH (or MASH), which may or may not be accompanied by cirrhosis, comprising administering a therapeutically effective amount of an IBAT inhibitor such as linelixibat to the person.

Description

[Technical Field]

[0001] The present invention relates to an IBAT inhibitor for use in the treatment of pruritus in certain chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD) [newly reclassified as metabolic dysfunction-related fatty liver disease (MASLD)], which includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [newly reclassified as metabolic dysfunction-related fatty liver disease (MASH)], with or without cirrhosis, and a method for treating pruritus in NAFLD (or MASLD), which includes NAFL and NASH (or MASH), with or without cirrhosis, comprising administering a therapeutically effective dose of an IBAT inhibitor, such as linelixibat, to the person. [Background technology]

[0002] Pruritus (itching) is a well-recognized and characteristic symptom of chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and is known to affect quality of life (QoL). Primary Biliary Cholangitis:2018 Practice Guidance from the American Association for the Study of Liver Diseases [Lindor et al., 2019 Hepatology, 69(1), 394-419] states that "the cause of pruritus in PBC remains unclear. However, several important mediators in the pathophysiology of cholestatic pruritus have been identified, including lysophosphatidic acid, endogenous opioids, and bile acids, which offer opportunities for therapeutic intervention."

[0003] Cholestatic pruritus is a common debilitating condition that significantly impairs daily functioning, including sleep latency and disturbances, fatigue, depression, and suicidal ideation (Younossi, Kiwi et al. 2000; Montagnese, Nsemi et al. 2013; Hegade, Bolier et al. 2016; Jin and Khan 2016; Honig, Herder et al. 2018; Hegade, Mells et al. 2019; Mayo MJ, Dig Dis Sci. March 2023; 68(3):995~1005).

[0004] In patients with known cholestatic liver disease, such as in PBC, the itching is characterized as "relentless" or so severe that patients "want to peel off (their) skin" or scratch until they bleed (Rishe, Azarm et al. 2008). Furthermore, factors that exacerbate itching in cholestatic liver disease include heat, psychological stress, wearing certain clothing, and diurnal variation, which often worsens at night (Bergasa, Mehlman et al. 2000, Kremer, Beuers et al. 2008, Kremer, Oude Elferink et al. 2011, Lindor, Bowlus et al. 2019, Vander Does, Levy et al. 2022).

[0005] Drug development in liver disease has historically focused primarily on treating the underlying liver disease rather than symptoms such as itching. Interestingly, some approved and investigational treatments for chronic liver disease can actually cause itching as a side effect or increase, rather than alleviate, pre-existing itching. Oveticholic acid (OCA) (OCALIVA), approved for the treatment of PBC in patients with an inadequate response to or intolerance to ursodeoxycholic acid (UDCA), was associated with a higher incidence and severity of itching in PBC patients compared to placebo (Nevins et al., N Engl.J Med 2016;375:631~643), and has a warning and caution on the label about severe itching: [https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2022 / 207999s008lbl.pdf].

[0006] When used in this specification: "NAFLD" refers to non-alcoholic fatty liver disease, and until recently it was used to describe the histological spectrum of steatohepatitis and its subtypes "NAFL" (non-alcoholic fatty liver (simple steatohepatitis)) and "NASH" (non-alcoholic steatohepatitis).

[0007] "MASLD" refers to metabolic dysfunction-related fatty liver disease and represents a new classification of "NAFLD" diseases [Hepatology 78(6) 1966-1986], meaning that MASLD diseases were previously broadly classified using the term NAFLD.

[0008] "MASH" refers to metabolic disorder-associated steatohepatitis and is an alternative term for NASH (MERinella, JVLazarus, V.Ratziu et al. Annals of Hepatology 29(2024)101133).

[0009] Both the investigational products obeticholic acid and tropifexor have been found to cause increased pruritus in patients with NASH [Neuschwander et al., Lancet 2015;385:956~65; Patel K et al., Hepatology 2020;72:58~71.]

[0010] Recent studies are assessing the potential of ileal bile acid transporter (IBAT) inhibitors, also known as apical sodium-dependent bile acid transporter (ASBT) inhibitors, for the treatment of pruritus in some childhood cholestatic liver diseases. It has been hypothesized that excess systemic bile acids in cholestatic liver disease play a role in cholestatic pruritus, and the effects of reducing bile acids have supported this theory (Hepatology. 2019; 69(1): 394-419; Management of cholestatic liver diseases. J Hepatol. 2009; 51(2): 237-267). IBAT inhibitors block enterohepatic circulation of bile acids, thereby reducing circulating bile acid levels and increasing bile acid excretion in the stool (Lancet. 2017; 389(10074): 1114-1123). The molecular IBAT inhibitors malalixibat (LIVMARLI) and odevixibat (BYLVAY) were recently approved by the FDA for the treatment of cholestatic pruritus in Alagille syndrome and familial intrahepatic cholestasis (PFIC) in children, respectively. [LIVMARLI https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 214662s000lbl.pdf] [BYLVAY https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 215498s000lbl.pdf]. Odevixibat has also been approved by the European Medicines Agency [https: / / www.ema.europa.eu / en / documents / product-information / bylvay-epar-product-information_en.pdf].

[0011] Linelixibat, a minimally absorbed oral small molecule IBAT inhibitor, demonstrated significant improvement in pruritus and reductions in serum levels of bile acids and autotaxin (the enzyme that produces lysophosphatidic acid) compared to placebo in phase 2a and 2b studies in patients with PBC (Hegade, Kendrick et al. 2017) (Levy 2022 Clin Gastroenterol Hepatol. 2022, available online https: / / doi.org / 10.1016 / j.cgh.2022.10.032). The phase 2b GLIMMER study (NCT02966834) is currently the largest randomized trial in patients with PBC and cholestatic pruritus. In this study, linelixibat dose-dependently improved pruritus over 12 weeks of treatment (Levy et al., 2022). Furthermore, our own research (Example 5 in this specification) has shown that treatment with linelixibat in patients with pruritus in PBC leads to a decrease in total serum bile acids, which correlates with a reduction in itching in patients with cholestatic pruritus [Karatza et al., EASL abstract: Karatza E et al., J Hepatol 2023:78(S1):S367; Poster: Karatza et al., EASL Poster 2023 https: / / www.postersessiononline.eu / 173580348_eu / congresos / ILC2023 / aula / -TOP_62_ILC2023.pdf; Manuscript: https: / / doi.org / 10.1111 / liv.15982]. In summary, these findings suggest the potential of linelixibat as a future treatment option for cholestatic pruritus in PBC.

[0012] However, pruritus in other chronic liver diseases (CLDs) not classically considered cholestatic is not well recognized, as highlighted by the limited literature in this context. For example, there is limited, inconsistent data describing the presence and prevalence of pruritus in people with other CLDs such as chronic viral hepatitis (including viral hepatitis B and viral hepatitis C), autoimmune hepatitis (AIH), or NAFLD (or MASLD), and pruritus is often overlooked during treatment of liver disease (Biernacka, Nizynski et al. 2018). Where pruritus is reported to be present in these other CLDs, there is no consensus on the mechanisms modulating the pathogenesis of pruritus. Thus, the causes of pruritus in these other CLDs, such as viral hepatitis B (HepB), viral hepatitis C (HepC), AIH, and NAFLD (or MASLD), and particularly in NAFLD (or MASLD), e.g., NASH (or MASH), are not well understood.

[0013] Currently, there are no publications studying the prospective natural history of pruritus over time and its impact on patients, and our understanding of the underlying mechanisms of pruritus in this population of patients with CLD not classically considered cholestatic, namely those with HepB, HepC, AIH, and NAFLD (or MASLD), and especially in those with NAFLD (or MASLD), such as NASH (or MASH).

[0014] Furthermore, in chronic liver diseases such as NAFLD (or MASLD) and its progressive form NASH (or MASH) (Biomedicines 2022, 10, 451; Hepatology Communications, Vol. 4, No. 11, 2020), as well as in cholestatic liver diseases such as PBC and PSC, patients experience itching that significantly impairs their quality of life (Frontiers in Medicine 2021 Vol. 8: Article 639674; Proteome Res. 2021, 20, 2340~2351; European Journal of Gastroenterology & Hepatology: December 2014 - Vol. 26 - No. 12 - pp. 1374~1379).

[0015] Effective treatment for pruritus in HepB, HepC, AIH, and NAFLD (or MASLD), such as NASH (or MASH), is expected to significantly improve the quality of life in patients with pruritic elements in such CLDs. Therefore, effective treatment for pruritus in HepB, HepC, AIH, and NAFLD (or MASLD), such as NASH (or MASH), is highly desirable. [Overview of the project]

[0016] In a first aspect of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in NAFLD (or MASLD).

[0017] In a second aspect of the present invention, an IBAT inhibitor is provided for use in the treatment of cholestatic pruritus in NAFLD (or MASLD).

[0018] A third aspect of the present invention provides a method for treating pruritus in NAFLD (or MASLD) in a person in need thereof, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0019] In a fourth aspect of the present invention, there is provided a method for treating cholestatic pruritus in non-alcoholic fatty liver disease (NAFLD) (or metabolic dysfunction-associated steatohepatitis (MASLD)) in a human subject in need of treatment, the method comprising administering to the human subject a therapeutically effective amount of an IBAT inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] [Figure 1] FIG. 1 shows a 5D-itch plot of the results of a natural history study for NASH (or MASH), PBC, PSC, and AIH compared to a non-cholestatic prior art pruritus state from Example 2a. [Figure 1a] FIG. 1a shows a 5D-itch plot of the same natural history study results showing data for only NASH (or MASH) and PBC, and shows a 5D-itch plot of the same natural history study results for only NASH (or MASH) and PBC. [Figure 2] FIG. 2 is a Sankey diagram showing the change in itch severity over time in NASH (or MASH) and PBC from Example 1. [Figure 3] FIG. 3 shows a plot of individual Bayesian estimates of the change in TSBA from baseline AUC0-24 along with the change in weekly itch scores over a 12-week treatment period for PBC patients from Example 5. [Figure 4A] FIG. 4A shows a plot of the least squares mean ratio of ATX relative to baseline at week 16 in itch responders versus non-responders treated with 40 / 90 mg BID linoleic acid for PBC patients or placebo from Example 6. [Figure 4B] FIG. 4B shows a plot of the least squares mean ratio of ATX for linoleic acid versus placebo treatment in itch responders and non-responders in PBC patients from Example 6. DETAILED DESCRIPTION OF THE INVENTION

[0021] Measurement of Pruritus, Including Cholestatic Pruritus Pruritus may be measured using different assessment scales. For example, i) 0 - 10 point numerical rating scale (NRS): The patient-reported NRS scale measures the intensity or severity of itching (not the frequency of itching). For example, use of the NRS in measuring pruritus in PBC: "Development and adaptation of patient-reported outcome measures for patients who experience itch associated with primary biliary cholangitis." J Patient Rep Outcomes. 2019;3(1):2. ii) 5D itch scale: Elman et al., "The 5-D itch scale: a new measure of pruritus." Br J Dermatol. March 2010;162(3):587 - 93. The 5-D itch scale is a multidimensional patient-reported questionnaire designed to measure the following five dimensions: degree, duration, course, adverse effects, and distribution. iii) For patients with PBC: PBC - 40 (PBC - 40): Jacoby et al., "Development, validation, and evaluation of the PBC - 40, a disease specific health related quality of life measure for primary biliary cirrhosis." Gut. November 2005;54(11):1622 - 9. The six domains of the patient-reported questionnaire PBC - 40 relate to fatigue, emotional, social and cognitive function, systemic symptoms, and itching.

[0022] There are no well-established physical or physiological markers that can be observed or measured for the severity of pruritus associated with cholestatic liver disease or for the effectiveness of treatment. The assessment of pruritus is subjective, and each participant is likely to have a distinct response to any treatment for cholestatic pruritus. Therefore, patient-reported outcomes (PROs) are the best way to assess pruritus severity and measure treatment effectiveness. Treatment effectiveness may be measured by examining the change in pruritus from baseline with treatment and comparing it to the change in pruritus from baseline with placebo. Alternatively, the number of patients classified as responders to a given treatment can be compared to the number with placebo, where responders are defined as participants who improve beyond a predefined responder level.

[0023] In patients with HepB, HepC, AIH, and NAFLD (or MASLD), and CLDs such as NASH (or MASH), the pruritic component can be classified as mild, moderate, or severe using various different measurement tools and thresholds, such as numerical rating scales (NRS), visual analog scales (VAS), and verbal rating scales (VRS). Pruritus can result in a poor quality of life for patients, especially those with moderate to severe pruritus.

[0024] The following is a summary of the current understanding in the art of chronic liver diseases, including HepB, HepC, AIH, and NAFLD (or MASLD), as well as the extent to which pruritus has been reported in the art in patients with these diseases.

[0025] Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic disorder-associated fatty liver disease (MASLD), metabolic disorder-associated steatohepatitis (MASH) Non-alcoholic fatty liver disease (NAFLD) (newly classified as metabolic dysfunction-associated fatty liver disease (MASLD)) is the fastest-growing cause of chronic liver disease and a major cause of cirrhosis and hepatocellular carcinoma and the increasing number of liver transplant indications worldwide. MASLD is a new term used to refer to fatty liver disease associated with systemic metabolic dysregulation, encompassing patients with fatty liver who have at least one of the five cardiometabolic risk factors. Until recently, the term NAFLD was used to describe the histological spectrum of steatosis-steatohepatitis and its subtypes NAFL and NASH. NAFLD encompasses a disease continuum and exists in two clinical entities: non-alcoholic fatty liver (NAFL, simple steatosis) and non-alcoholic steatohepatitis (NASH), with or without cirrhosis. Classically, NAFL is considered a relatively benign disease that usually does not progress to NASH and liver fibrosis. However, recent clinical data from paired liver biopsy studies have shown that approximately 25% of patients with NAFL progress to NASH and bridging fibrosis (Pais R and Maurel TJClin.Med. 2021, 10, 1161). NASH, on the other hand, is characterized by necrotizing inflammation and simple steatosis, i.e., faster fibrotic progression than NAFL (Fiorucci, Biagioli et al. 2018, Powell, Wong et al. 2021). NASH (or MASH) is considered a progressive liver disease with a significant risk of developing cirrhosis and liver-related morbidity and mortality. Furthermore, cholestatic features may be observed in the end stages of certain chronic liver diseases, including NASH (Eur J Clin Invest 2013;43(10):1069~1083). Currently, it is estimated that 25% of the world's population has NAFLD (or MASLD), 20% to 30% of patients with NAFLD (or MASLD) have NASH (or MASH), and 10% to 15% of these may progress to cirrhosis (Armandi A and Bugianesi E. Liver International. 2021;41(Augmented 1):78-82).

[0026] Estimates from cross-sectional studies in published literature report that 14–55% of patients with NAFLD (or MASLD) or NASH (or MASH) experience pruritus at any given time. When limited to patients with moderate to severe pruritus, the prevalence at any given time ranges from 20–27% of patients. The literature typically describes pruritus in the broader NAFLD (or MASLD) population without specifically limiting it to a subset with NASH (or MASH).

[0027] To the best of our knowledge, there is no prior art that provides a comprehensive longitudinal evaluation of pruritus and its effects over time in the general NAFLD (or MASLD) or NASH (or MASH) population.

[0028] There is little or no documentation regarding the causes of pruritus in NASH (or MASH) (Vander Does, A., Levy, C. & Yosipovitch, G. Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments. Am J Clin Dermatol 23, 647-659 (2022)).

[0029] There is a lack of treatment for the unmet need for pruritus in NASH (or MASH). There are no official guidelines or approved therapies for the treatment of pruritus in NASH (or MASH) in the United States or the European Union. Based on the evidence from the literature and our own research, particularly from the examples described herein, there is an unmet medical need for the treatment of pruritus in NASH (or MASH).

[0030] [Table 1]

[0031] Viral hepatitis B Hepatitis B is a liver infection caused by the hepatitis B virus (HBV), which can result in acute or chronic infection. Acute liver injury is primarily caused by a protective immune response that destroys virus-infected liver cells. In the absence of an immune response sufficient to clear the virus, the infection becomes chronic (Fattovich 2003). Chronic HBV infection is defined as the persistence of hepatitis B surface antigen (HBsAg) for more than six months after acute HBV infection. Chronic HBV infection is associated with an increased risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), as well as an increased risk of associated mortality (NICE 2013, Tang, Covert et al. 2018). Cholestatic features may be observed in the end stages of certain chronic liver diseases, including HepB (Eur J Clin Invest 2013;43(10):1069~1083).

[0032] The primary therapeutic goal in HepB is to improve survival and quality of life by preventing disease progression and, consequently, the development of HCC. Long-term administration of nucleoside analogs, such as entecavir, tenofovir disoproxil, or tenofovir alafenamide, represents optimal treatment. Pegylated interferon-alpha therapy may also be considered in patients with mild to moderate chronic hepatitis B (European Association for the Study of the Liver. Electronic address and European Association for the Study of the 2017, Terrault, Lok et al. 2018).

[0033] Estimates from cross-sectional studies of published literature indicate that 20–32% of patients with chronic HBV experience pruritus at any given time point, and this figure drops to 8–12% when limited to patients reporting moderate to severe pruritus (NRS ≥ 4) or irritating pruritus.

[0034] [Table 2]

[0035] Viral hepatitis C Chronic hepatitis C virus (HCV) infection can lead to progressive liver disease with the development of cirrhosis and HCC, and is likely responsible for up to 500,000 deaths annually (Wedemeyer, Dore et al. 2015). Approximately 30% of infected individuals spontaneously clear the virus within 6 months of infection without treatment. The remaining 70% develop chronic HCV infection. Globally, an estimated 71 million people have chronic hepatitis C virus infection (WHO 2019). Cholestatic features may be observed in the late stages of certain chronic liver diseases, including HepC (Eur J Clin Invest 2013;43(10):1069~1083).

[0036] Six distinct genotypes (HCV-1 to HCV-6) and several subtypes have been identified, exhibiting different geographical and pathogenic patterns, as well as varying responses to conventional therapies. Genotype 1 (subtypes 1a and 1b) is by far the most common genotype worldwide. It is primarily transmitted through parenteral routes, but can also be transmitted through sexual contact and mother-to-child transmission (Zaltron, Spinetti et al. 2012).

[0037] Clinical care for patients with HCV-associated liver disease has advanced considerably in recent decades. The primary goal of HCV therapy is to cure the infection, i.e., to achieve sustained virological response (SVR), defined as the absence of detectable HCV RNA after completion of treatment (Journal of Hepatology 2020, Vol. 73, pp. 1170-1218). The WHO recommends the use of direct-acting antiviral (DAA) regimens for the treatment of all persons diagnosed with chronic hepatitis C virus infection (Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection, World Health Organization 2018). Overall, DAA regimens successfully cure HCV infection in >95% of treated individuals (Ann Intern Med 2017;166:637-648) (Hepatology, Vol. 71, No. 2, 2020).

[0038] Based on cross-sectional studies reported in the following published literature, pruritus has been reported to affect 15–58% of patients with chronic HCV, or 8–42% when limited to moderate to severe itching.

[0039] [Table 3]

[0040] Autoimmune hepatitis (AIH) Autoimmune hepatitis (AIH) is a globally occurring chronic autoimmune inflammatory liver disease that affects people of all ages and is predominantly female. AIH is a rare disease, estimated to affect approximately 20 people per 100,000 population in Europe (Mieli-Vergani, Vergani et al. 2018). By definition, AIH is a chronic disease that can lead to cirrhosis, HCC, liver transplantation, and / or death, but it can also present as fulminant hepatic failure and should therefore be considered in the differential diagnosis of acute hepatic failure (Manns, Lohse et al. 2015). The diagnosis of AIH is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (elevated serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels and increased serum IgG concentration), and the presence of one or more characteristic autoantibodies (Liberal, Krawitt et al. 2016; Hepatology, Vol. 72, No. 2, 2020).

[0041] AIH may have cholestatic features that fall outside the established diagnostic criteria. These features have uncertain implications for clinical symptoms and disease progression. Patients with AIH may have anti-mitochondrial antibodies and incidental bile duct injury or loss (2%–13% of patients), focal biliary stricture and dilation based on cholangiography (2%–11%), or histological changes of bile duct injury or loss in the absence of other features (5%–11%).

[0042] AIH is classified into two types: AIH-1, positive for antinuclear antibody (ANA) and / or anti-smooth muscle antibody (SMA); and AIH-2, positive for anti-hepatorheological microsomal antibody type 1 (anti-LKM1), anti-LKM3, and / or anti-hepatic cytosolic antibody type 1 (anti-LC1) (Manns, Lohse et al. 2015). AIH-1 affects people of all ages, with two peaks: one in adulthood between 10 and 18 years of age and the other around 40 years of age. AIH-2 primarily affects children, including infants, adolescents, and young adults defined as under 25 years of age (Muratori, Fabbri et al. 2015, Mieli-Vergani, Vergani et al. 2018).

[0043] AIH is asymptomatic in 25%–34% of patients. Fatsia is the primary complaint in 85% of patients, and jaundice may be present. The goal of first-line therapy is to improve symptoms, control liver inflammation, achieve biochemical remission, prevent disease progression, and promote fibrosis regression with the lowest risk of drug-induced complications. The ideal laboratory response is normalization of serum ALT, AST, and IgG levels. Remission-inducing drugs consist of either high-dose corticosteroids alone or in combination with azathioprine. Histological features of NAFLD (or MASLD) are present in 17%–30% of adult patients with AIH, and concomitant NAFLD (or MASLD) may affect the response to therapy (Hepatology, vol. 72, no. 2, 2020).

[0044] It has been reported that pruritus affects 4–55% of patients with AIH, or 18–42% when limited to moderate to severe or severe itching.

[0045] [Table 4]

[0046] Biomarkers for pruritus: Bile acids and autotaxin bile acids Bile acids (BAs) are the main components of bile and play an essential role in the emulsification and absorption of dietary fats and fat-soluble vitamins. Bile acids are also signaling molecules involved in their own biosynthesis and the regulation of energy, glucose, and lipid metabolism by acting on various BA receptors. The liver synthesizes primary BAs, cholic acid and chenodeoxycholic acid, which readily conjugate with glycine or taurine. Secondary BAs, deoxycholic acid and lithocholic acid, as well as tertiary bile acids such as ursodeoxycholic acid, are derived from primary BAs in the large intestine by enzymes produced by symbiotic bacteria and can also be converted to glycine or taurine conjugates. The resulting BA pool, consisting of primary, secondary, conjugated, and unconjugated BA species, is optimally balanced to facilitate multiple biological functions. The BA pool composition includes total serum bile acids (TSBA), total primary conjugated BA, total secondary conjugated BA, total primary BA, total secondary BA (Adams 2020 Liv Internat 40, 1356), molar concentration ratio of total primary to total secondary BA (Jiao 2018 Gut, 67, 1881-1891), molar concentration ratio of total conjugated to total unconjugated BA (Puri 2018 Hepatol 67(2) 534; Chen 2020 Clin Rev Allergy & Immunol, 58, 25-38), molar concentration ratio of total cholic acid to total chenodeoxycholic acid (Jurate 2017 16(4) 569-573), and molar concentration ratio of total glycine conjugates to total taurine conjugates (Yara 2019 It may be expressed in a number of ways, including but not limited to GastroHep, 1, 302-310), and "total" is the sum of multiple unconjugated (parental) and / or conjugated BAs [Fiorucci et al., Bile acids and their receptors in metabolic disorders. Progress in Lipid Research, 2021, 82, 101094].

[0047] The bile acid pool (BA) is efficiently utilized and recycled through a process known as enterohepatic recirculation, through which BA travels from the liver through bile and the gallbladder to the small intestine. Primary and conjugated BA are then largely absorbed in the terminal ileum by the ileal bile acid transporter (IBAT), also known as the apical sodium-dependent bile acid transporter (ASBT), while secondary and unconjugated BA are passively absorbed in the large intestine. After intestinal absorption, BA is returned to the liver via the hepatic portal vein and various other transporters. [Di Caula et al., Bile Acid Physiology, Ann. Hepatology 2017, 16(S1), s4~s14.]

[0048] In cholestatic states, the movement of bile acids (BAs) from the liver to the intestines via bile and the gallbladder is impaired, leading to BA accumulation in the liver and thus causing inflammation and injury. Under these conditions, the liver compensates by upregulating BA transporters responsible for efflux, downregulating BA transporters responsible for uptake, and downregulating the biosynthesis of new BAs [Langedijk, JA et al., Cholestasis-Associated Pruritus and its Pruritogens. Frontiers in Medicine, 2021, 8.639674]. These coordinated actions result in atypically high BA concentrations in the systemic circulation, typically reported as total serum bile acids (TSBA). Since primary and conjugated BAs are the dominant BA components in the liver, and because they are preferentially affected by changes in hepatocyte transporters during cholestasis, the systemic BA pool (i.e., serum concentrations of all BAs) is preferentially enriched with primary and conjugated BAs in patients with cholestasis. Normally, in healthy individuals, BA is substantially confined to enterohepatic recirculation, so serum concentrations of BA or TSBA are low.

[0049] While elevated bile acid levels in the body, as measured by serum concentration, are hypothesized to be one of several mediators of cholestatic pruritus, the lack of correlation between serum bile acid levels and cholestatic pruritus suggests that other factors may also contribute to pruritus. [Lindor 2019 Hepatology 69(1)].

[0050] Inhibition of IBAT with the inhibitor molecule linelixibat in adult PBC patients leads to a decrease in conjugated and total serum BA by preferential, increased clearance of primary and conjugated BA from the intestine to the stool, thereby reducing the overall burden of high BA concentrations in enterohepatic recirculation and the associated spillage into the systemic circulation in patients with cholestatic pruritus [Hegade et al. Lancet 2017, 389, 1114-1123; Hegade et al. Liver International, 2019, 39, 967-975]. In addition, differences in TSBA and BA pool composition are associated with the severity of PBC and NAFLD (or MASLD) [Chen et al. Clin Revs Allergy & Immunology 2020 February;58(1):25-38; Causesey et al. Gut 2019;68(10):1884-1892].

[0051] The clinical and biochemical manifestations of pregnancy-related intrahepatic cholestasis (ICP), the most common liver disorder associated with pregnancy in women, include pruritus and elevated levels of TSBA and autotaxin [Piechota J. Clin. Med. 2020, 9, 1361; Journal of Hepatology 2015 vol. 62 j897-904]. In well-recognized cholestatic disorders, both TSBA and BA pool composition are frequently measured because individual BA levels or the primary-to-secondary BA or conjugated-to-unconjugated BA ratio may be preferentially affected during cholestasis.

[0052] Increased levels of numerous potential pruritic substances, including BA, have been found in the serum of patients with cholestatic liver disease reporting severe generalized pruritus [PNAS 2019, 116(21);10525~10530]. TBSA has been found to be elevated in NASH (or MASH) compared to healthy subjects, attributable to increased conjugation and primary BA [Dig Dis Sci, 2015;60:3318~3328; GastroHep. 2019;1:302~310]. NASH (or MASH) is associated with elevated and significantly altered circulating BA composition compared to healthy controls [Puri P, Daita K, Joyce A et al. "The presence and severity of non-alcoholic steatohepatitis is associated with specific changes in circulating bile acids", Hepatology., 2018;67(2):534~548]. Elevated and altered BA composition has been observed in NASH (or MASH), but so far it has not been associated with itching. Example 4 of this specification demonstrates a new correlation between increased TSBA in NAFLD (or MASLD), particularly in NASH (or MASH), and reported itching severity.

[0053] In chronic HepB infection, while TBSA levels have not been found to increase, certain individual BA levels do increase, leading to an increase in the primary-to-secondary BA and conjugated-to-unconjugated BA ratios [Sun et al. Frontiers in Medicine, October 2021; Vol. 8: Article 708495].

[0054] Autoimmune hepatitis (AIH) is an autoimmune liver disease (AILD). TSBA and certain conjugated bile acids were found to be elevated in a Chinese AIH cohort [Lian et al., Hepatobiliary Pancreat Dis Int 2015 (August 15), Vol. 14(4):413-421].

[0055] Autotaxin Autotaxin (ATX) is a secretory enzyme that converts lysophosphatidylcholine to lysophosphatidic acid [Lindor 2019 Hepatology 69(1); J Biol Chem. 2002; 277: 39436~39442 Hepatology. 2012; 56: 1391~1400]. Serum ATX levels have been found to be significantly increased in patients with cholestatic liver disease who report pruritus compared to those patients without pruritus [Frontiers in Medicine 2021; Vol. 8: Article 639674]. ATX activity is significantly correlated with the intensity of pruritus, but this increase is mainly in cholestatic pruritus and not in pruritus of other causes [Gastroenterology 2010; 139: 1008~18; Hepatology 2012; 56: 1391~400]. Although ATX is not excreted into the bile [Gastroenterology 2010;139:1008~1848], interference with enterohepatic circulation, for example, by nasobiliary drainage and IBAT inhibition, reduces both circulating ATX levels and pruritus scores [Gastroenterology 2010;139:1008~1848; Sci Rep.2018 8:6658; Lancet 2017;389:1114~23; Liver Int.2019;39:967~75].

[0056] Inhibition of IBAT with linelixibat in adult PBC patients resulted in a decrease in serum autotaxin levels (Hegade 2017 Lancet, 389, 1114-1123; Levy 2022). In addition, correlations between the percentage change from baseline of ATX and the percentage change from baseline of some serum bile acids have been reported [Hegade et al. Liver International 2019, 39, 967-975], but no significant correlations were found between serum BA, autotaxin, and baseline pruritus scores, and a reduction in serum BA did not correlate with a reduction in pruritus scores.

[0057] IBAT inhibitors In cholestatic pruritus associated with cholestatic liver diseases such as PBC and PSC, attention has been drawn to the ileal bile acid transporter (IBAT), also known as the apical sodium-dependent bile acid transporter (ASBT), as a therapeutic target.

[0058] As mentioned above, the molecular IBAT inhibitors malalixibat (LIVMARLI) and odevixibat (BYLVAY) were recently approved by the FDA for the treatment of cholestatic pruritus in Alagille syndrome and familial intrahepatic cholestasis (PFIC) in children, respectively (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 214662s000lbl.pdf). (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 215498s000lbl.pdf). Odevixibat has also been approved by the European Medicines Agency: (https: / / www.ema.europa.eu / en / documents / product-information / bylvay-epar-product-information_en.pdf).

[0059] The present disclosures of this specification, particularly Examples 1-3, support the fact that pruritus experienced by patients with CLD such as HepB, HepC, AIH, and NAFLD (or MASLD), e.g., NASH (or MASH), is similar to cholestatic pruritus and therefore potentially cholestatic or bile acid-induced. Therefore, it is expected that pruritus may be treatable with therapies known to treat pruritus in cholestatic liver disease, e.g., treatment with IBAT inhibitors.

[0060] In addition, serum BA was found to be elevated in NAFLD (or MASLD) and NASH (or MASH). Considering that Example 4 newly demonstrates that increased TSBA in NAFLD (or MASLD), particularly in NASH (or MASH), correlates with reported pruritus severity, it is expected that pruritus may be treatable with therapies known to reduce bile acid levels, such as IBAT inhibitors.

[0061] Accordingly, in one embodiment of the present invention, an IBAT inhibitor for use in the treatment of pruritus in NAFLD (or MASLD) is provided. In another embodiment, a method of treatment of pruritus in NAFLD (or MASLD) in a human in need thereof is provided, comprising administering to said human a therapeutically effective amount of an IBAT inhibitor.

[0062] In another aspect of the present invention, an IBAT inhibitor is provided for use in the treatment of cholestatic pruritus in NAFLD (or MASLD). In a further aspect, a method of treatment of cholestatic pruritus in NAFLD (or MASLD) in a human in need thereof is provided, comprising administering to said human a therapeutically effective amount of an IBAT inhibitor.

[0063] In a further embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in HepB, for example, cholestatic pruritus in HepB. In a further embodiment, a method for treating pruritus in HepB, for example, cholestatic pruritus in HepB, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0064] In a further embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in HepC, for example, cholestatic pruritus in HepC. In a further embodiment, a method for treating pruritus in HepC, for example, cholestatic pruritus in HepC, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0065] In a further embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in AIH, for example, cholestatic pruritus in AIH. In a further embodiment, a method for treating pruritus in AIH, for example, cholestatic pruritus in AIH, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0066] In one aspect of the present invention, the use of an IBAT inhibitor in the manufacture of a medicament for use in the treatment of pruritus in NAFLD (or MASLD) is provided. In another aspect, the use of an IBAT inhibitor in the manufacture of a medicament for use in the treatment of cholestatic pruritus in NAFLD (or MASLD) is provided.

[0067] In one embodiment, the IBAT inhibitor is an antibody. The term “antibody” is used herein in the broadest sense to refer to a molecule having an immunoglobulin-like domain (e.g., IgG, IgM, IgA, IgD, or IgE), and includes multispecific antibodies, including monoclonal, recombinant, polyclonal, chimeric, human, humanized, bispecific and heteroconjugate antibodies, single variable domains (e.g., domain antibodies (DABs)), antigen-binding antibody fragments, Fab, F(ab')2, Fv, disulfide-linked Fv, single-stranded Fv, disulfide-linked scFv, diabody, TANDABS, etc., and any of the modified versions thereof (see Holliger and Hudson, Nature Biotechnology, 2005, vol. 23, no. 9, pp. 1126-1136, for a summary of alternative “antibody” formats).

[0068] In one embodiment, the IBAT inhibitor is a small molecule. In one embodiment, the IBAT inhibitor for use in the present invention is selected from malalixibat, vorixibat, odevixibat, elobixibat, linelixibat, Albireo A-3907 and CJ-14199 (by CJ Healthcare), or a pharmaceutically acceptable salt, solvate, or crystalline form thereof. In another embodiment, the IBAT inhibitor for use in the present invention is selected from malalixibat, vorixibat, odevixibat, elobixibat, linelixibat and Albireo A-3907, or a pharmaceutically acceptable salt or crystalline form thereof.

[0069] In one embodiment, the IBAT inhibitor for use in the present invention, or the IBAT inhibitor used in the therapeutic method of the present invention, exists as a free acid. In another embodiment, the IBAT inhibitor for use in the present invention exists in salt form. For example, malalixibat may exist in salt form, such as malalixibat chloride.

[0070] In further embodiments, the IBAT inhibitor for use in the present invention, or the IBAT inhibitor used in the therapeutic method of the present invention, exists in crystalline form.

[0071] IBAT inhibitors, such as linelixibat, have been shown to reduce serum bile acid concentrations. In this new Example 5, we demonstrate that linelixibat treatment results in a reduction of total serum bile acids that correlates with a reduction in itching in patients with cholestatic pruritus in PBC [Karatza et al., EASL abstract: Karatza E et al., J Hepatol 2023:78(S1):S367; Poster: Karatza et al., EASL Poster 2023 https: / / www.postersessiononline.eu / 173580348_eu / congresos / ILC2023 / aula / -TOP_62_ILC2023.pdf; Manuscript: https: / / doi.org / 10.1111 / liv.15982]. In Example 4, the present inventors also demonstrate that bile acids increase with the severity of itching in NAFLD (or MASLD), including NASH (or MASH). Therefore, treatment of patients experiencing or suffering from itching in NAFLD (or MASLD), including NASH (or MASH), with IBAT inhibitors such as linelixibat is expected to reduce serum bile acid concentrations and, consequently, reduce the severity of itching.

[0072] Accordingly, in one embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in NASH (or MASH), for example, cholestatic pruritus in NASH (or MASH). In another embodiment, a method for treating pruritus in NASH (or MASH), for example, cholestatic pruritus in NASH (or MASH), in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0073] In another embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in NAFL, for example, cholestatic pruritus in NAFL. In a further embodiment, a method for treating pruritus in NAFL, for example, cholestatic pruritus in NAFL, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0074] In another embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in NAFLD (or MASLD), for example, cholestatic pruritus in NAFLD (or MASLD). In a further embodiment, a method for treating pruritus in NAFLD (or MASLD), for example, cholestatic pruritus in NAFLD (or MASLD), in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0075] One embodiment provides the use of an IBAT inhibitor in the manufacture of a pharmaceutical product for use in the treatment of pruritus in NASH (or MASH). Another embodiment provides the use of an IBAT inhibitor in the manufacture of a pharmaceutical product for use in the treatment of cholestatic pruritus in NASH (or MASH).

[0076] In another embodiment of the present invention, the use of an IBAT inhibitor in the manufacture of a pharmaceutical for use in the treatment of pruritus in NAFL is provided. In yet another embodiment, the use of an IBAT inhibitor in the manufacture of a pharmaceutical for use in the treatment of cholestatic pruritus in NAFL is provided.

[0077] In another embodiment of the present invention, the use of an IBAT inhibitor in the manufacture of a medicament for use in the treatment of pruritus in NAFLD (or MASLD) is provided. In another embodiment, the use of an IBAT inhibitor in the manufacture of a medicament for use in the treatment of cholestatic pruritus in NAFLD (or MASLD) is provided.

[0078] In a further embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in non-cirrodeous NASH (or MASH), for example, cholestatic pruritus in non-cirrodeous NASH (or MASH). In a further embodiment, a method for treating pruritus in non-cirrodeous NASH (or MASH), for example, cholestatic pruritus in non-cirrodeous NASH (or MASH), in a person requiring treatment is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0079] In a further embodiment of the present invention, an IBAT inhibitor is provided for use in the treatment of pruritus in NASH (or MASH) with cirrhosis, for example, cholestatic pruritus in NASH (or MASH) with cirrhosis. In a further embodiment, a method for treating pruritus in NASH (or MASH) with cirrhosis, for example, cholestatic pruritus in NASH (or MASH) with cirrhosis, in a person in need of treatment, is provided, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0080] Linelixibat An example of an IBAT inhibitor, linelixibat is an orally small molecule with minimal absorption and demonstrated significant improvement in pruritus compared to placebo in a Phase 2a study of patients with PBC, reducing bile acid absorption in the terminal ileum and increasing bile acid excretion in the feces [Al-Dury S, Marschall HU. Front Pharmacol 2018;9:931 and Hegade VS et al., Lancet 2017;389:1114~23]. The Phase 2b GLIMMER study (NCT02966834) is currently the largest randomized trial of PBC patients with cholestatic pruritus. In this study, linelixibat dose-dependently improved pruritus over 12 weeks of treatment, demonstrating its potential as a future treatment option for cholestatic pruritus in PBC (Clin Gastroenterol Hepatol. 2022; in press).

[0081] Linelixibat, also known as GSK2330672, is the INN and USAN name of this compound, sometimes abbreviated as GSK672. The IUPAC name of the compound is rac-3-((((3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid. Its structure is:

[0082] [ka] It has.

[0083] Patent publication WO2011 / 137135 discloses, in particular, linelixibat among the compounds. WO2011 / 137135 also discloses a method for synthesizing the compound.

[0084] The preparation of linelixibat is disclosed in J.Med.Chem, Vol. 56, pp. 10, 5094-5114 (2013), J.Org.Chem., Vol. 78, pp. 12726-12734 (2013), and in Japanese Patent Publications WO2016 / 020785 and WO2018 / 002827.

[0085] Accordingly, in one embodiment, an IBAT inhibitor for use in the present invention or in the therapeutic method of the present invention is provided, the IBAT inhibitor being linelixibat or a pharmaceutically acceptable salt or crystalline form thereof.

[0086] In another embodiment, an IBAT inhibitor for use in the present invention or in the therapeutic method of the present invention is provided, wherein the IBAT inhibitor is linelixibat free acid.

[0087] Linelixibat has been shown to be generally well-tolerated in clinical studies in both the type 2 diabetes mellitus (T2DM) population [Nunez DJ et al., Diabetes Obes Metab 2016;18(7):654~662] and the PBC population, including patients with compensated cirrhosis [Levy 2022 Clin Gastroenterol and Hep, online: https: / / doi.org / 10.1016 / j.cgh.2022.10.032].

[0088] Potential metabolic effects of linelixibat that may be valuable in patients with NASH (or MASH) include reductions in fasting glucose and LDL cholesterol, as demonstrated in the T2DM population.

[0089] In both Phase 2 clinical studies of PBC patients with cholestatic pruritus, namely Phase 2a (Hegade, Kendrick et al., 2017) and Phase 2b GLIMMER (NCT02966834, results online: Levy 2002 https: / / doi.org / 10.1016 / j.cgh.2022.10.032), linelixibat reduced pruritus as well as serum concentrations / autotaxin activity of both TSBA and autotaxin, consistent with their roles as biomarkers in pruritus. Following discontinuation of linelixibat, there was evidence of recurrence of pruritus, as well as changes toward baseline levels of TSBA and autotaxin levels and autotaxin activity.

[0090] In Example 5 of this specification, the inventors demonstrate that changes in TSBA over the study treatment period are significantly correlated with and predictable to improvement in pruritus in patients with PBC. In Example 6 of this specification, the inventors demonstrate that serum ATX and FGF-19 can function as biomarkers of the pruritus response to linelixibat treatment, and that reductions in these biomarkers are associated with clinical response in patients with PBC and pruritus.

[0091] Accordingly, in a further embodiment of the present invention, linelixibat or a pharmaceutically acceptable salt or crystalline form thereof is provided for use in the treatment of pruritus in NASH (or MASH), for example, cholestatic pruritus in NASH (or MASH). In another embodiment, a method for treating pruritus in NASH (or MASH), for example, cholestatic pruritus in NASH (or MASH), in a person in need of treatment is provided, comprising administering a therapeutically effective amount thereof to the person. In one embodiment of the present invention, the use of linelixibat in the manufacture of a medicament for use in the treatment of pruritus in NASH (or MASH), for example, cholestatic pruritus, is provided.

[0092] In yet another embodiment of the present invention, linelixibat or a pharmaceutically acceptable salt or crystalline form thereof is provided for use in the treatment of pruritus in NAFL, for example, cholestatic pruritus in NAFL. In yet another embodiment, a method for treating pruritus in NAFL, for example, cholestatic pruritus in NAFL, in a person requiring treatment is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt or crystalline form thereof to the person. In one embodiment of the present invention, the use of linelixibat in the manufacture of a pharmaceutical for use in the treatment of pruritus in NAFL, for example, cholestatic pruritus, is provided.

[0093] In yet another embodiment of the present invention, linelixibat or a pharmaceutically acceptable salt or crystalline form thereof is provided for use in the treatment of pruritus in NAFLD (or MASLD), for example, cholestatic pruritus in NAFLD (or MASLD). In yet another embodiment, a method for treating pruritus in NAFLD (or MASLD), for example, cholestatic pruritus in NAFLD (or MASLD), in a person in need of treatment is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt or crystalline form thereof to the person. In one embodiment of the present invention, the use of linelixibat in the manufacture of a pharmaceutical for use in the treatment of pruritus in NAFLD (or MASLD), for example, cholestatic pruritus, is provided.

[0094] In a further embodiment of the present invention, linelixibat or a pharmaceutically acceptable salt or crystalline form thereof is provided for use in the treatment of pruritus in non-cirrodeous NASH (or MASH), for example, cholestatic pruritus in non-cirrodeous NASH (or MASH). In another embodiment, a method for treating pruritus in non-cirrodeous NASH (or MASH), for example, cholestatic pruritus in non-cirrodeous NASH (or MASH), in a person requiring treatment is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt or crystalline form thereof to the person. In one embodiment of the present invention, the use of linelixibat in the manufacture of a pharmaceutical for use in the treatment of pruritus in non-cirrodeous NASH (or MASH), for example, cholestatic pruritus, is provided.

[0095] In a further embodiment of the present invention, linelixibat or a pharmaceutically acceptable salt or crystalline form thereof is provided for use in the treatment of pruritus in NASH (or MASH) with cirrhosis, for example, cholestatic pruritus in NASH (or MASH) with cirrhosis. In another embodiment, a method for treating pruritus in NASH (or MASH) with cirrhosis, for example, cholestatic pruritus in NASH (or MASH) with cirrhosis, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt or crystalline form thereof to the person. In one embodiment of the present invention, the use of linelixibat in the manufacture of a pharmaceutical for use in the treatment of pruritus in NASH (or MASH) with cirrhosis, for example, cholestatic pruritus, is provided.

[0096] Linelixibat can exist in amorphous or crystalline forms as disclosed in Japanese Patent Publication WO2011 / 137135 and Japanese Patent Application PCT / EP2021 / 078734. Therefore, in one embodiment, the IBAT inhibitor for use in the present invention or in the therapeutic method of the present invention is linelixibat in crystalline form.

[0097] In one embodiment, the crystalline form of linelixibat may include one or more polymorphic crystalline forms. Linelixibat may exist in crystalline form I disclosed in WO2011 / 137135 and patent application PCT / EP2021 / 078734.

[0098] In one embodiment, linelixibat exists as a mixture of crystalline forms I and III disclosed in patent application PCT / EP2021 / 078734. In another embodiment, linelixibat is in an amorphous form.

[0099] PPAR agonist PPAR (peroxisome proliferator-activated receptor) agonists include selective activators of PPAR alpha and PPAR delta, as well as activators of both alpha and delta PPAR isoforms, and / or non-selective so-called "pan" PPAR activators.

[0100] PPAR agonists may reduce serum bile acid levels and alleviate itching in PBCs. PPAR agonists include, but are not limited to, ceradelpal, elafibranol, bezafibrate, and lanafibranol.

[0101] Therefore, treatment of patients experiencing or suffering from pruritus in NAFLD (or MASLD), including NASH (or MASH), with PPAR agonists that reduce serum bile acid concentration may reduce the severity of itching.

[0102] Accordingly, in one embodiment of the present invention, a PPAR agonist is provided for use in the treatment of pruritus in NAFLD (or MASLD), for example, in the treatment of cholestatic pruritus in NAFLD (or MASLD), or in the treatment of pruritus or cholestatic pruritus in NASH (or MASH).

[0103] In another embodiment of the present invention, a method for treating pruritus in NAFLD (or MASLD) in a person requiring treatment is provided, comprising administering a therapeutically effective amount of a PPAR agonist to the person. In certain embodiments of such a method, the treatment of pruritus in NAFLD (or MASLD) is the treatment of cholestatic pruritus in NAFLD (or MASLD) or the treatment of pruritus or cholestatic pruritus in NASH (or MASH).

[0104] In a further embodiment of the present invention, a PPAR agonist is provided for use in the treatment of pruritus in HepB, for example, cholestatic pruritus in HepB. In a further embodiment, a method for treating pruritus in HepB, for example, cholestatic pruritus in HepB, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of a PPAR agonist to the person.

[0105] In a further embodiment of the present invention, a PPAR agonist is provided for use in the treatment of pruritus in HepC, for example, cholestatic pruritus in HepC. In a further embodiment, a method for treating pruritus in HepC, for example, cholestatic pruritus in HepC, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of a PPAR agonist to the person.

[0106] In a further embodiment of the present invention, a PPAR agonist is provided for use in the treatment of pruritus in AIH, for example, cholestatic pruritus in AIH. In a further embodiment, a method for treating pruritus in AIH, for example, cholestatic pruritus in AIH, in a person requiring treatment is provided, comprising administering a therapeutically effective amount of a PPAR agonist to the person.

[0107] FGF-19 analogue FGF-19 (serum fibroblast growth factor-19) analogs, such as aldafermin, are known to suppress C4 and / or serum bile acid levels in patients with NASH (or MASH) and PSC [Harrison 2019 Hepatology; Sanyal 2021 JHEP Reports].

[0108] Therefore, treatment with FGF-19 analogs in patients experiencing or suffering from pruritus in NAFLD (or MASLD), including NASH (or MASH), is expected to reduce serum bile acid concentrations and, consequently, potentially reduce the severity of itching.

[0109] Accordingly, in one embodiment of the present invention, an FGF-19 analog is provided for use in the treatment of pruritus in NAFLD (or MASLD), for example, in the treatment of cholestatic pruritus in NAFLD (or MASLD) or in the treatment of pruritus in NASH (or MASH).

[0110] In another embodiment of the present invention, a method for treating pruritus in NAFLD (or MASLD) in a person requiring treatment is provided, comprising administering a therapeutically effective amount of an FGF-19 analog to the person. In certain embodiments of such a method, the treatment of pruritus in NAFLD (or MASLD) is the treatment of cholestatic pruritus in NAFLD (or MASLD) or the treatment of pruritus in NASH (or MASH).

[0111] In a further embodiment of the present invention, an FGF-19 analog is provided for use in the treatment of pruritus in HepB, for example, cholestatic pruritus in HepB. In a further embodiment, a method for treating pruritus in HepB, for example, cholestatic pruritus in HepB, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an FGF-19 analog to the person.

[0112] In a further embodiment of the present invention, an FGF-19 analog is provided for use in the treatment of pruritus in HepC, for example, cholestatic pruritus in HepC. In a further embodiment, a method for treating pruritus in HepC, for example, cholestatic pruritus in HepC, in a person in need of treatment is provided, comprising administering a therapeutically effective amount of an FGF-19 analog to the person.

[0113] In a further embodiment of the present invention, an FGF-19 analog is provided for use in the treatment of pruritus in AIH, for example, cholestatic pruritus in AIH. In a further embodiment, a method for treating pruritus in AIH, for example, cholestatic pruritus in AIH, in a person requiring treatment is provided, comprising administering a therapeutically effective amount of an FGF-19 analog to the person.

[0114] Consideration of the Examples As mentioned above, treating the underlying CLD condition does not necessarily lead to a reduction in itching, and in some cases, treating the underlying disease can worsen treatment-induced or associated itching.

[0115] In the natural history study described in Example 1 of this specification, data were collected regarding itching experienced by patients with widespread chronic liver disease. The results of this study support the literature's estimation that pruritus in NASH (or MASH) is common, similar in nature to pruritus observed in cholestatic liver disease, and represents an unmet medical need. The results of this study also provide some supporting evidence for the potential cholestatic nature of pruritus in chronic liver diseases that are not typically considered cholestatic, such as NAFLD (or MASLD), CLDs such as NASH (or MASH). Therefore, pruritus in NASH (or MASH) may be suitable for treatment with IBAT inhibitors.

[0116] Example 2a described herein is a comparison of pruritus experienced in PBC, PSC, AIH, HepB, HepC, and NASH (or MASH) conditions in the natural history study of Example 1 with pruritus reported in the literature in conditions where pruritus is known not to be of a cholestatic nature (i.e., pruritus in hemodialysis patient populations, patient populations with atopic dermatitis, and clinical trial patient populations with uremic pruritus). The comparison is presented in the form of a 5D-pruritus plot. It shows that pruritus in NASH (or MASH), AIH, HepB, and HepC is similar to pruritus in known cholestatic liver diseases or diseases with cholestatic features, in terms of degree and duration as measured by the 5D pruritus measurement device. This provides further supporting evidence relating to the similarity between pruritus in known cholestatic liver diseases and pruritus in AIH, HepB, HepC, and NASH (or MASH). Therefore, pruritus in AIH, HepB, HepC, and / or NASH (or MASH) may be suitable for treatment with IBAT inhibitors.

[0117] The PRO studies described in Examples 3 and 3a provide evidence that itching experienced by patients with HepB, HepC, AIH, DILI, NASH (or MASH), or NAFL (or MASLD) is qualitatively no different from itching in known cholestatic conditions such as PSC or PBC. Therefore, itching in these conditions, particularly HepB, HepC, AIH, NASH (or MASH), and NAFL (or MASLD), may be suitable for treatment with IBAT inhibitors.

[0118] Example 4 described in this specification is a study characterizing the pruritus burden and clinical trajectories in non-PBC / PSC chronic liver diseases including primary sclerosing cholangitis (PSC) and NAFLD (or MASLD) / NASH (or MASH). The results of the study in Example 4 support the finding that bile acids and autotaxin increase with itch severity in NAFLD (or MASLD) including NASH (or MASH). Thus, bile acids, alone or together with autotaxin, may play a role in the pathogenesis of pruritus in NASH (or MASH). Therefore, pruritus in NASH (or MASH) may be suitable for treatment with an IBAT inhibitor.

[0119] Example 5 of this specification is an analysis of the relationship between the linoleic acid dose and the change in TSBA over time and the change in pruritus in subjects with PBC. The inventors found that linoleic acid treatment leads to a rapid and dose-dependent reduction in TSBA. The baseline TSBA levels do not correlate with the changes in the NRS itch score during treatment, suggesting that they do not predict the linoleic acid response. However, the change in TSBA over the treatment period significantly correlates with and can predict the improvement of pruritus in patients with PBC.

[0120] Example 6 of this specification is an analysis of the relationship between the itch response after linoleic acid treatment and the changes in ATX and FGF-19 biomarker levels in patients with cholestatic pruritus associated with PBC. The inventors found that serum ATX and FGF-19 can function as biomarkers for the itch response to linoleic acid treatment. A reduction in these biomarkers has been found to be associated with the clinical response in patients with PBC and pruritus.

[0121] Medical Use Regarding an IBAT inhibitor, such as linoleic acid or a pharmaceutically acceptable salt thereof, for use in the treatments described in this specification or in treatment methods: In one embodiment, an IBAT inhibitor, such as linelixibat or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 3 mg to 100 mg, for example, 30 mg to 100 mg twice daily.

[0122] In one embodiment, an IBAT inhibitor, such as linelixibat or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of 40 mg to 90 mg.

[0123] In one embodiment, an IBAT inhibitor, such as linelixibat or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of approximately 90 mg.

[0124] In one embodiment, an IBAT inhibitor, such as linelixibat or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of approximately 40 mg.

[0125] Pharmaceutical composition With regard to IBAT inhibitors such as linelixibat or pharmaceutically acceptable salts thereof for use in the treatment or method of treatment described herein: In one embodiment, with respect to an IBAT inhibitor for use in the treatment or method of treatment described herein, the IBAT inhibitor is administered orally.

[0126] In one embodiment, the IBAT inhibitor is formulated into a solid dosage form such as a capsule or tablet. In one embodiment, the IBAT inhibitor is formulated into a tablet. In one embodiment, the IBAT inhibitor is administered as an immediate-release formulation such as an immediate-release tablet. In another embodiment, the tablet further comprises a filler, a disintegrant, and a lubricant. An example of a suitable tablet is one comprising the IBAT inhibitor, microcrystalline cellulose, and magnesium stearate. Another example of a suitable tablet is one comprising the IBAT inhibitor, microcrystalline cellulose, magnesium stearate, and croscarmellose sodium.

[0127] In one embodiment, the tablet contains 5 to 100 mg of IBAT inhibitor. In another embodiment, the tablet contains 20 to 90 mg of IBAT inhibitor. In yet another embodiment, the tablet contains 80 mg of IBAT inhibitor. In yet another embodiment, the tablet contains 90 mg of IBAT inhibitor. In yet another embodiment, the tablet contains 45 mg of IBAT inhibitor. In yet another embodiment, the tablet contains 40 mg of IBAT inhibitor. In yet another embodiment, the tablet contains 20 mg of IBAT inhibitor.

[0128] To avoid misunderstanding, it should be noted that any particular dose may be administered as a single tablet or oral dosage form, or as multiple tablets or other oral dosage forms. For example, a 40 mg dose may be administered as a single 40 mg tablet, or as two 20 mg tablets, or four 10 mg tablets, or eight 5 mg tablets, or, for example, as one 20 mg tablet and two 10 mg tablets.

[0129] It should be clear that dose adjustments result in increasing or decreasing the IBAT inhibitor dose by only one dose at a time. Patients receiving the highest (maximum) dose of an IBAT inhibitor who require a dose increase should maintain the same dose, while patients receiving the lowest dose of an IBAT inhibitor who require a dose decrease should discontinue therapy with the IBAT inhibitor.

[0130] In a first aspect of the present invention, an IBAT inhibitor for use in the treatment of pruritus in NAFLD or MASLD is provided. In another aspect, an IBAT inhibitor for use in the treatment of pruritus in NAFLD is provided. In a further aspect, an IBAT inhibitor for use in the treatment of pruritus in MASLD is provided.

[0131] In a second aspect of the present invention, an IBAT inhibitor is provided for use in the treatment of cholestatic pruritus in NAFLD or MASLD. In another aspect, an IBAT inhibitor is provided for use in the treatment of cholestatic pruritus in NAFLD. In yet another aspect, an IBAT inhibitor is provided for use in the treatment of cholestatic pruritus in MASLD.

[0132] A third embodiment of the present invention provides a method for treating pruritus in NAFLD or MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person. Another embodiment provides a method for treating pruritus in NAFLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person. A further embodiment provides a method for treating pruritus in MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0133] A fourth embodiment of the present invention provides a method for treating cholestatic pruritus in NAFLD or MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person. Another embodiment provides a method for treating cholestatic pruritus in NAFLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person. A further embodiment provides a method for treating cholestatic pruritus in MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

[0134] With respect to one or more of the first, second, third, and / or fourth embodiments, the following embodiments are included herein.

[0135] In one embodiment of the present invention, the IBAT inhibitor is selected from malalixibat, vorixibat, odevixibat, elobixibat, linelixibat, and Albireo A-3907, or a pharmaceutically acceptable salt or crystalline form thereof.

[0136] In another embodiment of the present invention, the IBAT inhibitor is linelixibat or a pharmaceutically acceptable salt or crystalline form thereof.

[0137] In another embodiment of the present invention, the IBAT inhibitor for use according to the first or second embodiment, or the first embodiment, is linelixibat or a pharmaceutically acceptable salt or crystalline form thereof.

[0138] In another embodiment of the present invention, NAFLD or MASLD is NASH or MASH. In another embodiment, NAFLD is NASH. In another embodiment, MASLD is MASH. In a further embodiment, NAFLD is NAFL.

[0139] In another embodiment of the present invention, NAFLD or MASLD is non-cirrhotic NASH or MASH. In a further embodiment, NAFLD is non-cirrhotic NASH. In another embodiment, MASLD is non-cirrhotic MASH.

[0140] In another embodiment of the present invention, NAFLD or MASLD is NASH or MASH with cirrhosis. In a further embodiment, NAFLD is NASH with cirrhosis. In another embodiment, MASLD is MASH with cirrhosis.

[0141] In another embodiment of the present invention, the IBAT inhibitor exists as a free acid.

[0142] In another embodiment of the present invention, the IBAT inhibitor exists in crystalline form.

[0143] In another embodiment of the present invention, the itching is moderate to severe, and is measured, for example, on an NRS scale of ≥4.

[0144] In another embodiment of the present invention, the pruritus is moderate to severe in patients with cirrhosis having, for example, a TSBA level of about 34.

[0145] In another embodiment of the present invention, the pruritus is moderate to severe in patients without cirrhosis, for example, with a TSBA level of about 11.

[0146] Abbreviation AIH autoimmune hepatitis ALD (Alcoholic Liver Disease) CLD chronic liver disease DILI (Drug-Induced Liver Injury) HepB viral hepatitis B HepC (Hepatitis C virus) MASLD (Metabolic Disorder-Related Fatty Liver Disease) MASH (Metabolic Steatohepatitis) NAFL (Non-Alcoholic Fatty Liver Disease) NAFLD (Non-Alcoholic Fatty Liver Disease) NASH (Non-Alcoholic Steatohepatitis) PBC (Primary Biliary Cholangitis) (formerly known as Primary Biliary Cirrhosis) PRO patient-reported outcomes PSC Primary Sclerosing Cholangitis TBSA (Total Serum Bile Acids) [Examples]

[0147] [Example 1] A natural history study on health-related quality of life in liver disease patients with pruritus. The overall goal of this completed study was to characterize the natural history of pruritus and associated health-related quality of life (HRQoL) in patients with any of nine types of chronic liver diseases (CLDs), namely CLDs known to be cholestatic or potentially having cholestatic features (PBC, PSC, AIH, DILI), as well as other chronic liver diseases not typically considered cholestatic, including NASH (or MASH) and NAFLD (or MASLD), HepB, and HepC. To the best of our knowledge, this was the first comprehensive longitudinal study to compare pruritus in patients with these different liver diseases. This study had the following specific objectives: Main objective 1. Prospectively document patient-reported changes in pruritus over a 1.6-month period, including frequency, severity, location, timing, and impact. 2. Retrospectively document the progression of pruritus in patients from its onset to the present, including diagnosis, treatment, severity, and impact. Secondary / exploratory objectives 1. To determine whether the disease course, including the progression of HRQoL, is similar across CLDs for the planning of future clinical trials, assess and document the differences in the retrospective and prospective courses of pruritus between CLDs. 2. Assess the prevalence of pruritus in CLD based on screening questions.

[0148] The characteristics and nature of itching were collected and evaluated for some of the nine CLDs, namely, across cholestatic CLDs and some CLDs with cholestatic features (PBC, PSC, AIH), compared to itching in patients with NASH (or MASH), HepB, HepC, and DILI, which are CLDs not typically considered cholestatic.

[0149] Patient experiences, frequency, impact, and duration of pruritus were assessed using the worst pruritus-NRS (WI-NRS) categories (no pruritus 0, mild 1-3, moderate 4-6, severe 7-10).

[0150] Results of Example 1 Support for the potential cholestatic nature of pruritus in NASH (or MASH), or for pruritus in NASH (or MASH) to be bile acid-induced, can be seen in the data collected from this natural history study, which highlights the widespread experience of pruritus across NASH (or MASH) and various CLDs, as well as the severity and debilitating burden of itching.

[0151] Focusing on NASH (or MASH), Table 1 shows that at screening, approximately 69% of NASH (or MASH) patients reported having pruritus, and 46% reported moderate to severe worst itching within the past three months. Table 2 shows the frequency of experiencing ≥2 days of itching or ≥2 days of peeling skin scratching in the past two weeks for each CLD. NASH (or MASH) patients with pruritus had a similar frequency of experiencing itching or peeling skin scratching compared to patients with pruritus originating from cholestatic liver disease or cholestatic liver disease (PBC, PSC, and AIH), as well as other CLDs and patients with pruritus.

[0152] Table 3 below shows the similar qualitative nature of the types of itching experienced by patients with NASH (or MASH) and patients with cholestatic liver disease or liver disease with cholestatic features (PBC, PSC, and AIH), when participants were asked to select which descriptive terms for itching applied to their experience of itching as a result of chronic liver disease. Overall, itching associated with NASH (or MASH) appeared similar to other known cholestatic itching conditions, with the majority of participants describing the itching as “deep” and “urgent.” Descriptive terms such as “carous” and “relentless” were also common experiences of itching in NASH (or MASH) and in itching conditions known to be cholestatic. The types of itching were found to differ across all conditions from the types of itching experienced in “urticaria.” Similarly, scratching did not relieve itching for a significant proportion of patients across all liver diseases. Importantly, these descriptive terms for itching are similar to those used by patients with PBC in externally published studies (Vander Does, Levy et al. 2022; Rishe, Azarm et al. 2008).

[0153] Table 4 shows that across liver disease, a similar proportion of patients reported that their itching worsened mostly at night or was equally bad both day and night.

[0154] Table 5 shows that heat, certain clothing, and stress worsen itching in both patients with cholestatic liver disease (PBC, PSC, AIH) and patients with NASH (or MASH) in the above natural history studies, similar to the factors reported by Vander Does et al. (Vander Does, Levy et al. 2022) to exacerbate itching.

[0155] Figure 2 shows that pruritus was generally persistent throughout a 6-month follow-up period in patients with NASH (or MASH) and PBC, particularly in patients with moderate to severe pruritus.

[0156] The data collected from this study demonstrated that antihistamines and topical therapies are commonly used by patients with NASH (or MASH) to treat their itching, and that while some improvement in itching is observed with these therapies, the reduction in itching is generally insufficient, suggesting that this patient population actively seeks treatment for their itching.

[0157] Conclusion of Example 1 This study found that patient experiences of pruritus and its impact on quality of life (QoL) were comparable for NASH (or MASH) and PBC. Nearly half (46%) of patients with screened NASH (or MASH) and 39% of screened patients with PBC reported moderate to severe pruritus. Patients with NASH (or MASH) and PBC used similar language to describe pruritus. Pruritus persisted over a 6-month study period for patients with both NASH (or MASH) and PBC. These data suggest that the assessed characteristics of pruritus in patients with NASH (or MASH) are qualitatively no different from those of pruritus in cholestatic liver diseases such as PBC and PSC, as well as in liver diseases with cholestatic features. Therefore, pruritus in NASH (or MASH) may be suitable for treatment with IBAT inhibitors.

[0158] [Table 5]

[0159] [Table 6]

[0160] [Table 7]

[0161] [Table 8]

[0162] [Table 9]

[0163] [Example 2a] Comparison of natural history research results with prior art states Figure 1 shows 5D-itch plots of natural history study results for HepB, HepC, NASH (or MASH), PBC, PSC, and AIH, contrasted with non-cholestasis-associated pre-arterial pruritus conditions (pruritus in hemodialysis, uremic pruritus, and atopic dermatitis). Figure 1a shows 5D-itch plots of the same natural history study results for NASH (or MASH) and PBC only. Participants in the natural history study of Example 1 completed 5D-itch measurements using the 5D-itch scale mentioned above; that is, they completed the questionnaire provided in Elman et al., "The 5-Ditch scale: a new measure of pruritus." Br J Dermatol. March 2010;162(3):587-93. The estimates shown are unadjusted, and patients do not account for differences in duration of liver disease or background among CLDs. Therefore, when comparing five scores across domains for different liver diseases, the severity and duration domains are given more weight because they best capture the itching experience in terms of severity and frequency, both of which are important when assessing symptoms.

[0164] The values ​​obtained from this assessment are plotted against 5D-itch measurements obtained from target prior art studies where the 5D-itch scale was used for pruritus in target populations where itching was known not to be of a cholestatic nature, namely hemodialysis patients, patients with atopic dermatitis, and clinical trial patients with uremic pruritus. All comparisons with these prior art studies are derived from non-intervention studies and include all pruritus severity levels (mild, moderate, and severe pruritus).

[0165] Results and Conclusions of Example 2a In Example 1, pruritus data from natural history studies originating from HepB, HepC, and NASH (or MASH), as well as from PBC, PSC, and AIH conditions, are included in Figure 1 because it is known that the pruritus associated with the latter group of conditions is of a cholestatic nature or has cholestatic characteristics. Non-cholestatic pruritus experienced in the three non-cholestatic conditions from the prior art differs from cholestatic pruritus conditions, particularly in terms of degree, duration, and distribution. In contrast, pruritus in NASH (or MASH), HepB, and HepC is similar in degree and course to PSC, PBC, and AIH. In addition, when comparing NASH (or MASH) and PBC (Figure 1a), the effects of pruritus were comparable across many 5-D pruritus domains, including duration, degree, and course.

[0166] This provides further supporting evidence relating to the similarity between itching in known cholestatic liver diseases and itching in NASH (or MASH), AIH, HepB, and HepC. Therefore, itching in NASH (or MASH), AIH, HepB, and HepC may be suitable for treatment with IBAT inhibitors.

[0167] [Example 3] Content validity of qualitative interviews and patient-reported outcomes (PROs) surveys to characterize patient experiences of cholestatic pruritus. Qualitative studies in patients with pruritus and chronic liver disease (CLD), including those with PSC, HepB, HepC, AIH, DILI, NASH (or MASH), or NAFL (or MASLD), were set up as part of a program to select and validate patient-reported outcomes (PROs) to assess the impact of pruritus and itching on patients with these conditions.

[0168] The main research objectives were as follows: To characterize patient experiences regarding symptoms and effects, and to identify concepts of interest to patients with CLD-associated pruritus living in Canada, China, Germany, Japan, the United Kingdom (UK), or the United States (US).

[0169] Individuals with pruritus were encouraged by third-party vendors or patient advocacy groups to participate in 90-minute one-on-one telephone or webcam interviews conducted by trained qualitative researchers. Each patient interview followed a standardized semi-structured interview guide that utilized both Concept Extraction (CE) and Cognitive Debriefing (CD) techniques to gather specific information relevant to the research objectives, while also allowing for open-end examination of their pruritus as needed. Table 4a outlines the sample distribution regarding CLD and country in the qualitative study.

[0170] [Table 10]

[0171] During the first part of the hybrid interview, participants were asked open-ended questions about what it felt like to have itching associated with their liver disease and how it affected their lives. Participants, regardless of whether they had CLD or their country of birth, agreed in their descriptions of itching as a persistent, irritating symptom that did not respond well to treatment and generally led to skin damage including scarring, worsening at night, disruption of sleep patterns, no clear pattern of itching associated with season or weather, feelings of embarrassment and discomfort in social and work settings, and the need to withdraw from recreational activities.

[0172] This study provides evidence that patient experiences of pruritus are similar among patients with different underlying liver conditions (PSC, AIH, HepB, HepC, DILI, NASH (or MASH), and NAFL) in Canada, China, Germany, Japan, the UK, and the US. PSC is widely recognized as cholestatic liver disease, and AIH has cholestatic features.

[0173] This evidence supports the qualitative findings from the natural history study in Example 1, in that patients with NASH (or MASH) describe their itching using similar terminology to patients with known cholestatic disorders.

[0174] [Example 3a] Qualitative interviews with patients experiencing pruritus secondary to primary biliary cholangitis. In the course of a drug development program for pruritus in PBC, a recognized cholestatic condition, another study very similar to Example 3 was also conducted. The primary objectives of this study were to confirm the satisfaction of a concept of interest and to cognitively test the English version of the PRO scale selected for use in PBC. A total of 15 participants were recruited in the US, with an additional 5 being English-speaking Canadians. All study subjects were adults aged 18–80 years with a self-reported formal diagnosis of PBC and at least moderate-intensity pruritus in the past 8 weeks.

[0175] This study helps to provide an approximate comparison of itching in PBC and itching in CLD in Example 3. The studies in Examples 3 and 3a were not conducted with the intention of cross-study comparisons, and therefore the data were not collected in a manner intended for direct comparison.

[0176] The following is a summary of data and findings from the studies of Examples 3 and 3a related to how patients described the severity, location, and frequency of itching.

[0177] 1. Severity of itching Table 8 shows the pruritus severity across the entire CLD population in the qualitative study of Example 3. The mean worst pruritus score over the past 8 weeks was either 7 or 8 depending on the country (range 4–10). In Example 3a of the PBC qualitative study, the mean worst pruritus score was 89 on the 0–100 NRS scale (range 50–100), Table 9.

[0178] [Table 11]

[0179] [Table 12]

[0180] 2. Explain the itching. In the broad CLD population of Example 3, participants consistently described the itching sensation as a burning itch that was not relieved by scratching and was often aggravated by scratching. It was also described as a tingling, stinging, or ticklish sensation. A small number of participants (n=3) likened it to being bitten by a red imported fire ant. Particularly in the NASH (or MASH) population (n=15), participants described the itching as a constant itch (n=13). It was also described as a hot, burning sensation (n=4), a crawling sensation on the skin (n=3), a tingling sensation (n=2), unbearable (n=2), a deep itch (n=1), and a ticklish sensation (n=1). Patients with NAFL (or MASLD) (n=10) described pruritus-associated itching as constant (n=8), deep (i.e., deep itching beneath the skin; n=4), and unbearable (n=2). When compared across CLD, there was no clear pattern in how participants in the CLD sample described their itching based on their liver condition. In the known cholestatic pruritus population of PBC in Example 3a, most expressions of the pruritus-associated sign and symptom subdomain generally referred to “pruritus” (by all 20 subjects), but other pruritus-associated concepts were also used, including “urticaria” (n=3), “burning” (n=3), “rash” (n=3), “stinging” (n=4), and “dry plaque” (n=1). Across both PBC and other CLD, burning and stinging were descriptions used by participants to elaborate on their itching.

[0181] 3. Body location Participants with CLD in Example 3 experienced itching in different locations on their bodies, and all experienced it in multiple locations. The majority of CLD participants experienced it on their torso (n=46), arms (n=43), and legs (n=41). Participants also reported experiencing it on their feet or toes (n=29), hands (n=24), head (n=17), face (n=7), and genital area (n=4). Most participants experienced itching in one or more of the same locations, but 15 participants reported that the location of the itching varied and there was no discernible pattern to predict where they might experience it next. The location of the itching, as well as the sensation of itching, was not predictable by liver status.

[0182] In patients with PBC in Example 3a, the most common location of itching detected by coding was the legs, affecting 15 subjects (75.0%), followed by the arms (13 or 65.0%), the torso including the back, abdomen, and chest (12 or 60.0%), and the feet (10 or 50.0%). Table 10 shows the frequency of subject representations of itching associated with specific locations. The itching patterns were similar between PBC and CLD, with the legs, arms, and torso being the most affected areas.

[0183] [Table 13]

[0184] Conclusion of Examples 3 and 3a In summary, within the CLD samples of Example 3, itching experienced across different CLDs (PSC, AIH, HepB, HepC, DILI, NASH (or MASH), and NAFL) was observed to be similar. In particular, PSC is widely recognized as cholestatic liver disease, AIH has cholestatic features, and certain other CLDs studied, including HepB, HepC, NASH (or MASH), and NAFL (or MASLD), are not considered classically cholestatic.

[0185] Furthermore, the itching associated with CLD in Example 3 was not found to be qualitatively different from that experienced in PBC in Example 3a. Therefore, there is reason to consider that the itching of CLD in AIH, HepB, HepC, NASH (or MASH), and NAFL (or MASLD) is qualitatively similar to the itching of PBC, which is widely recognized to be of a cholestatic nature. Thus, itching in CLD such as AIH, HepB, HepC, NASH (or MASH), and NAFL (or MASLD) may be suitable for treatment with IBAT inhibitors.

[0186] [Example 4] A study characterizing the burden of pruritus and the clinical trajectory in primary sclerosing cholangitis (PSC) and non-PBC / PSC chronic liver disease. This ongoing observational cohort study will include both cross-sectional and longitudinal assessments of patients with PSC, NAFLD (or MASLD) / NASH (or MASH), chronic HBV, chronic HCV, AIH, and DILI. Cross-sectional data will also be collected from patients with irritable bowel disease alone and from healthy volunteers. Patient assessments will be linked to routine standard treatment clinical visits (at least two measurements, up to 48 weeks).

[0187] Patients with NAFLD (or MASLD) and NASH (or MASH) formed a single cohort.

[0188] The common primary objective of this research is, a) Determine the proportion of patients with NAFLD (or MASLD) / NASH (or MASH) who are suffering from itching, and b) To quantify the intensity of pruritus and how this varies with the inherent clinical course of NAFLD (or MASLD) / NASH (or MASH). The prevalence and severity of pruritus were assessed using the NRS scale and the 5-D pruritus score. As described above, the 5-D pruritus scale is a multidimensional questionnaire designed to measure five magnitudes: degree, duration, course, adverse effects and distribution, while the NRS scale measures the intensity or severity of pruritus rather than the frequency of pruritus.

[0189] A secondary objective of this study is, • Correlate itching intensity with disease severity, serum liver biochemical parameters, and, if possible, serum bile acid levels. • To assess the current unmet needs for pruritus in NAFLD (or MASLD) regarding currently available medical therapies.

[0190] Results of Example 4 Baseline characteristics and severity of the disease This study was still recruiting patients when the interim data was reported, and at that stage, it had enrolled 91 patients with NAFLD (or MASLD) / NASH (or MASH). The baseline characteristics of the enrolled subjects at the time of the interim report can be found in Table 11. Of the 91 patients included in the interim results, more than half were classified as having severe disease (advanced fibrosis or cirrhosis), one-third were classified as having no fibrosis or mild fibrosis, and 11 patients remained unclassified regarding the severity of their disease.

[0191] At the end of enrollment, a total of 200 patients had been recruited for the study (including the initial 91 patients from the interim analysis). The baseline characteristics of the 200 enrolled subjects are shown in Table 11a. The data show similar trends in disease severity among patients as were observed in the interim stage.

[0192] [Table 14]

[0193] [Table 15]

[0194] Severity of itching Patient pruritus was measured using both a 0-10 NRS scale, which classifies pruritus severity as no pruritus (NRS=0), mild pruritus (NRS1-3), moderate pruritus (NRS4-6), and severe pruritus (NRS≧7), and the 5-D pruritus score. The 5-D pruritus score and the NRS scale were highly correlated (R in the interim analysis stage). spearman =0.921, p<0.0001, N=91, and R in all analyses spearman =0.8540, p<0.0001, N=200).

[0195] Of the initial 91 patients, when asked about their worst itching in the past two weeks, 62.64% (n=57) experienced itching of any severity, and 47.25% (n=43) experienced moderate to severe itching. When the mean itching was measured, 61.54% (n=56) experienced itching of any severity, and 40.66% (n=37) experienced moderate to severe itching, Table 12. Pruritus of all levels of severity was observed in patients with different stages of hepatic fibrosis and in both cirrhotic and non-cirrhotic NASH (or MASH) / NAFLD (or MASLD) patients.

[0196] A similar trend was observed in the data from the entire cohort of 200 enrolled patients. When asked about their worst itching in the past two weeks, 51.5% (n=103) of patients experienced itching of any severity, and 36.5% (n=73) experienced moderate to severe itching. When the mean itching was measured, 49.5% (n=99) of patients experienced itching of any severity, and 31.0% (n=62) experienced moderate to severe itching, Table 12a.

[0197] [Table 16]

[0198] [Table 17]

[0199] TSBA level Among the initial 91 patients (n=80 with TSBA measurement), mean non-overnight fasting TSBA levels were higher in patients with NAFLD (or MASLD) / NASH (or MASH) and increased with increasing pruritus severity, but were highly variable. TSBA levels were elevated in both cirrhotic and non-cirrhotic patients with moderate to severe pruritus (Table 13). In the non-cirrhotic subgroup, TSBA increased with increasing pruritus severity. Similar trends for TSBA levels and pruritus severity were observed across the entire cohort (n=171 with TSBA measurement), Table 13a.

[0200] [Table 18]

[0201] [Table 19]

[0202] Autotaxin (ATX) level Information on autotaxin was not available at the time of the interim analysis. Autotaxin levels were measured in a total of 64 patients from the entire cohort of 200 enrolled patients. Autotaxin levels were found to be higher among patients with moderate to severe pruritus, and particularly among patients with cirrhosis, compared to patients without pruritus (Table 14a), although the sample size was limited.

[0203] [Table 20]

[0204] Example 4 Conclusion Approximately one in three NAFLD (or MASLD) patients experience moderate to severe pruritus. Serum bile acid and autotaxin levels are significantly higher in patients with moderate to severe pruritus. In summary, the elevated TSBA and autotaxin levels in NAFLD (or MASLD), particularly in NASH (or MASH), correlate with reported pruritus severity, as supported by the results of the study in Example 4.

[0205] [Example 5] Analysis of the relationship between linelixibat dose, changes in TSBA over time, and changes in pruritus in subjects with PBC. We developed a population dose-pharmacodynamic (k-PD) model to characterize the linelixibat dose-TSBA relationship using the effects of linelixibat dose and regimen on the daily TSBA profile in phase 1 and 2 studies in patients with PBC. The following studies were included: Study NCT01899703, GLIMMER (NCT02966834), and healthy volunteers (NCT02801981, NCT01607385, NCT01416324).

[0206] Simulations were performed to investigate the effect of linelixibat dose and regimen on the daily TSBA profile. TSBA concentration-area under the curve (AUC) 0-24 To derive the results, individual Bayesian parameter estimates for subjects in the Phase 2b study of linelixibat in patients with GLIMMER, PBC, and moderate to severe pruritus (NCT02966834) were used. AUC 0-24These post - estimated values were correlated with itch reported on a 0 - 10 numerical rating scale (NRS). In GLIMMER, after 4 weeks of single - blind placebo (baseline = week 4), a randomized double - blind 12 - week treatment period (up to week 16) with linelixibat or placebo, and a further 4 - week single - blind placebo (up to week 20) followed. Mean worst - daily itch (MWDI) and monthly itch score (MIS) were calculated as previously described (Levy C et al., Clin Gastroenterol Hepatol 2022;S1542 - 3565(22)01021 - 7). Itch responders were defined as having a ≥ 2 - point improvement in itch score from baseline.

[0207] Results of Example 5 The final population k - PD model successfully explained the effect of linelixibat on TSBA in PBC. Linelixibat treatment resulted in a rapid dose - dependent decrease in TSBA AUC 0-24 and the reduction in TSBA AUC 0-24 reached steady state approximately 10 days later. Baseline TSBA concentration was not correlated with the change in MIS from baseline at week 16 (r = - 0.13, p = 0.14). At week 16, there was a moderate correlation between the change in TSBA AUC 0-24 and the change in MIS from baseline (r = 0.27, p = 0.002), which disappeared during the placebo wash - out period (week 20; r = 0.011, p = 0.91). The change in TSBA AUC 0-24 was strongly correlated with the improvement in MWDI score from baseline over the 12 - week treatment period (r = 0.52, p < 0.0001; Figure 3). A ≥ 30% decrease in TSBA AUC 0-24 was associated with approximately 64% of the itch response.

[0208] Conclusions of Example 5 Linelixibat treatment leads to a rapid, dose-dependent reduction in TSBA. Baseline TSBA levels do not correlate with changes in NRS pruritus scores during treatment, suggesting they do not predict the linelixibat response. Changes in TSBA over the double-blind treatment period significantly correlate with and can predict improvement in pruritus in patients with PBC.

[0209] [Example 6] Analysis of the association between pruritic response after linelixibat treatment and changes in ATX and FGF-19 biomarker levels in patients with cholestatic pruritus associated with PBC. The Phase 2b, placebo-controlled, dose-range GLIMMER study (NCT02966834) enrolled 147 adult patients with PBC and pruritus (Levy 2022 Clin Gastroenterol Hepatol.2022, available online https: / / doi.org / 10.1016 / j.cgh.2022.10.032). Patients were randomized to receive either linelixibat or placebo for 12 weeks (weeks 4–16). Patients reported pruritus on a 0–10 numerical rating scale. Due to the small number of patients, biomarkers could not be analyzed in individual dose groups; therefore, two twice-daily (BID) dose groups, 40 mg BID and 90 mg BID, which showed a greater response in pharmacodynamic markers compared to once-daily dosing, were combined. Serum ATX and FGF-19 levels were retrospectively compared in pruritus responders and non-responders at baseline versus week 16 in patients receiving linelixibat 40 / 90 mg BID or placebo. Analysis of responders from individual dose groups is not shown. Pruritus responders were defined as patients with a monthly pruritus score improvement of ≥2 at week 16 compared to baseline.

[0210] Example 6 Results The study included patients treated with linelixibat 40 / 90 mg BID (n=45) or placebo (n=36). Itch responders in the 40 / 90 mg BID group, compared to the placebo group, had a greater reduction in serum ATX at week 16 compared to baseline, Figure 4a. In linelixibat-treated patients, ATX levels at week 16 were reduced in itch responders compared to non-responders and compared to placebo, Figure 4b. Similarly, FGF-19 reduction was associated with itch response in patients receiving linelixibat 40 / 90 mg BID compared to placebo.

[0211] Conclusion of Example 6 Serum ATX and FGF-19 can serve as biomarkers of the pruritic response to linelixibat treatment. Reductions in these biomarkers are associated with clinical response in patients with PBC and pruritus.

[0212] References JPEG2026520031000022.jpg245170JPEG2026520031000023.jpg247170JPEG20265200310 00024.jpg237170JPEG2026520031000025.jpg236170JPEG2026520031000026.jpg168170

Claims

1. IBAT inhibitors for use in the treatment of pruritus in NAFLD or MASLD.

2. IBAT inhibitors for use in the treatment of cholestatic pruritus in NAFLD or MASLD.

3. The aforementioned IBAT inhibitor Malalixibat, Borixibat, Odebixibat, Elobixibat, Linelixibat and Albireo A-3907, or their pharmaceutically acceptable salts or crystalline forms An IBAT inhibitor for use according to claim 1 or claim 2, selected from the above.

4. The IBAT inhibitor for use according to any one of claims 1 to 3, wherein the IBAT inhibitor is linelixibat, or a pharmaceutically acceptable salt or crystalline form thereof.

5. An IBAT inhibitor for use according to any one of claims 1 to 4, wherein the NAFLD or MASLD is NASH or MASH.

6. An IBAT inhibitor for use according to any one of claims 1 to 4, wherein the NAFLD is NAFL.

7. An IBAT inhibitor for use according to any one of claims 1 to 4, wherein the NAFLD or MASLD is non-cirrhotic NASH or MASH.

8. An IBAT inhibitor for use according to any one of claims 1 to 4, wherein the NAFLD or MASLD is NASH or MASH associated with cirrhosis.

9. An IBAT inhibitor for use according to any one of claims 1 to 8, wherein the IBAT inhibitor exists as a free acid.

10. The IBAT inhibitor for use according to any one of claims 1 to 9, wherein the IBAT inhibitor exists in crystalline form.

11. An IBAT inhibitor for use according to any one of claims 1 to 10, wherein the pruritus is moderate to severe, for example, 4 or greater as measured on the NRS scale.

12. An IBAT inhibitor for use according to any one of claims 1 to 11, wherein the pruritus is moderate to severe, for example, in a patient with cirrhosis having a TSBA level of about 34.

13. An IBAT inhibitor for use according to any one of claims 1 to 11, wherein the pruritus is moderate to severe and, for example, in a patient without cirrhosis having a TSBA level of about 11.

14. A method for treating pruritus in NAFLD or MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

15. A method for treating cholestatic pruritus in NAFLD or MASLD in a person requiring treatment, comprising administering a therapeutically effective amount of an IBAT inhibitor to the person.

16. The aforementioned IBAT inhibitor Malalixibat, Borixibat, Odebixibat, Elobixibat, Linelixibat and Albireo A-3907, or their pharmaceutically acceptable salts or crystalline forms A treatment method according to claim 14 or claim 15, selected from the above.

17. The therapeutic method according to any one of claims 14 to 16, wherein the IBAT inhibitor is linelixibat, or a pharmaceutically acceptable salt or crystalline form thereof.

18. The treatment method according to any one of claims 14 to 17, wherein the NAFLD or MASLD is NASH or MASH.

19. The treatment method according to any one of claims 14 to 17, wherein the NAFLD is NAFL.

20. The treatment method according to any one of claims 14 to 17, wherein the NAFLD or MASLD is non-cirrhotic NASH or MASH.

21. The treatment method according to any one of claims 14 to 17, wherein the NAFLD or MASLD is NASH or MASH accompanied by cirrhosis of the liver.

22. The therapeutic method according to any one of claims 14 to 21, wherein the IBAT inhibitor is present as a free acid.

23. The therapeutic method according to any one of claims 14 to 22, wherein the IBAT inhibitor exists in crystalline form.

24. The treatment method according to any one of claims 14 to 23, wherein the pruritus is moderate to severe, and for example, is 4 or greater as measured on the NRS scale.

25. The treatment method according to any one of claims 14 to 24, wherein the pruritus is moderate to severe, for example, in a patient with cirrhosis having a TSBA level of about 34.

26. The treatment method according to any one of claims 14 to 24, wherein the pruritus is moderate to severe, and in a patient without cirrhosis, for example, having a TSBA level of about 11.

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