Treatment of advanced primary biliary cholangitis

Abstract

The present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage primary biliary cholangitis (PBC).

Description

[0001] TREATMENT OF ADVANCED PRIMARY BILIARY CHOLANGITIS

[0002] TECHNICAL FIELD

[0003] The present invention relates to the field of medicine, in particular the treatment of cholestatic diseases, and more specifically PBC.

[0004] BACKGROUND

[0005] Primary biliary cholangitis (PBC) is a rare, chronic, progressive, cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that, in untreated patients, may progress to hepatic fibrosis, cirrhosis, hepatic decompensation, and death unless patients receive a liver transplant. PBC disproportionately affects women vs men (approximately 10: 1) and is typically diagnosed in patients between 40 years to 60 years of age. In Europe, North America, Asia, and Australia, the incidence and prevalence rates of PBC are reported as ranging from 0.33 to 5.8 per 100,000 inhabitants and 1.91 to 40.2 per 100,000 inhabitants, respectively.

[0006] Over 60% of the newly diagnosed cases are asymptomatic. The majority of asymptomatic patients become symptomatic within 10 years. The most common symptoms of PBC are generalized fatigue (in 70% of cases) and pruritus (Crosignani A, et al., World J Gastroenterol. 2008; 14(21):3313-3327). The mechanisms underlying these symptoms are not well elucidated and neither correlates with disease stage or clinical outcomes.

[0007] PBC represents one of the leading indications for liver transplantation. Despite its rarity, PBC remains therefore an important cause of morbidity in the Western world. PBC has also been identified as an important risk factor for hepatocellular carcinoma.

[0008] PBC is characterized by cholestasis caused by autoimmune destruction of biliary ductules with progressive impairment of bile flow in the liver. This results in increased hepatocellular bile acid concentrations which are toxic to the liver.

[0009] Such hepatocellular injury is associated with a local inflammatory response resulting early on in an abnormal elevation of serum alkaline phosphatase (ALP) levels. Therefore, biologically, PBC is manifested by an elevation of ALP levels of more than 1.5 times the upper limit of normal (ULN).

[0010] According to Lammers et al (Lammers et al, Gastroenterology. 2014;147(6): 1338-1349.e5), disease stage can be classified histologically as early (stage I and II) or late (stage III or IV), or biochemically using serum albumin and bilirubin levels. According to this biochemical classification, early stage was defined by normal bilirubin and albumin serum levels, moderately advanced disease was defined by an abnormal bilirubin or albumin serum level, and advanced disease was defined by abnormal bilirubin and albumin serum levels. A new staging system for PBC was recently proposed (https: / / rare-liver.eu / media / easl_pbc_patient- guidelines_aw-05-web-singles.pdf), which will help to predict how the PBC condition will develop over the next 10 years. In particular, it will help to predict the development of cirrhosis and associated complications. This new approach identifies four different stages of PBC by measuring the increase in bile duct damage, and providing a risk score:

[0011] Stage I: no or minimal progression;

[0012] Stage II: mild progression;

[0013] Stage III: moderate progression; and

[0014] Stage IV: advanced progression, indicating cirrhosis.

[0015] The terms “early disease” and “moderate to advanced disease” are also used depending on the following measures:

[0016] In early PBC, patients are usually asymptomatic despite underlying inflammatory injury of small bile ducts with cholangitis, and slight anomalies in serum liver biochemical tests; this phase (Stage I) may continue for decades (EASL 2017; Montano-Loza AJ and Corpechot C, Clinical Gastroenterology and Hepatology, 2021, 19(11):2241-225 lei). An intermediate phase of PBC (Stages II and III) follows, where biochemical and clinical symptoms of cholestasis develop, while underlying lesions progress to ductopenia and liver fibrosis; this phase can continue for up to 10 years or more (Montano-Loza 2021). In late stage PBC (Stage IV), patients may develop progressive jaundice, portal hypertension, and / or liver failure, sometimes deteriorating over the span of 2 to 4 years and progressing to liver-related death in the absence of liver transplant. Hepatocellular carcinoma also may develop in advanced stage PBC (EASL 2017; Montano-Loza AJ and Corpechot C, Clinical Gastroenterology and Hepatology, 2021, 19(11):2241-225 lei). In patients with advanced PBC and jaundice, fat-soluble vitamin malabsorption may occur due to a decrease in biliary secretion of bile acids (Lindor KD et al, Hepatology. 2019;69(l):394— 419). In PBC, ALP increases with disease progression, as does total bilirubin in more advanced disease. These markers are both highly predictive of long-term clinical outcomes (Lammers WJ et al., Gastroenterology, 2014;147(6): 1338).

[0017] Indeed, elevations in ALP level are associated with a risk of liver transplantation or death that is 2.0 to 2.5 times higher than the risk associated with normal levels. As shown in an international follow-up study, ALP >2x ULN is associated with a 2.2x greater risk for liver transplant or death at 1 year compared to those who remained <2x ULN (P<.0001) (Lammers WJ et al., Gastroenterology, 2014;147(6): 1338)

[0018] An abnormally elevated bilirubin level, which occurs later in disease progression, is also a strong predictor of outcomes, with a risk of liver transplantation or death that was 5.1 to 10.7 times the risk associated with normal levels.

[0019] The approved drugs to treat patients with PBC are ursodeoxycholic acid (UDCA), Ocaliva® (obeticholic acid, OCA), elafibranor (Iqirvo®) and seladelpar (Livdelzi®).

[0020] UDCA (Ursodeoxycholic acid) has been shown to improve ALP and bilirubin levels, and to delay histological progression, thereby increasing liver transplant-free survival. However, up to 40% of UDCA-treated patients have a suboptimal response (Ali AH, et al., Orphan Drugs: Research and Reviews, 2015;5:83-97). ALP has been shown to remain elevated in up to 70% of patients who are currently being treated or are intolerant to UDCA (Lammers WJ, et al., Gastroenterology. 2014; 147(6): 1338-1349.). Such patients remain at risk of disease progression and longer term adverse clinical outcomes. At present, 44% of UDCA-treated patients are progressing to liver transplant or death over 15 years.

[0021] Obeticholic acid (OCA) (Ocaliva ®), which has been shown to reduce ALP, has been recently approved in several countries as second line therapy for the treatment of PBC as monotherapy in adults unable to tolerate UDCA or in combination with UDCA in adults with an inadequate response to UDCA. A decrease in ALP levels is recognized as a particularly relevant surrogate marker for the treatment of PBC, and was recently used as the basis for conditional market approval of OCA in this indication.

[0022] However, two studies requested by the European Medicines Agency (EMA) in 2016 (studies 747-401 and 747-302), failed to show that OCA was more effective than placebo in terms of the number of patients with advanced PBC, whose disease worsened or who died. In addition, side effects, including serious ones, occurred more frequently in patients with advanced disease treated with OCA (https: / / www.ema.europa.eu / en / medicines / human / referrals / ocaliva).

[0023] Besides, on May 26, 2021 , FDA announced restricting the use of Ocaliva® (active ingredient obeticholic acid) in patients having primary biliary cholangitis or PBC with advanced cirrhosis of the liver because it can cause serious harm (https: / / www.fda.gov / drugs / fda-drug-safety-podcasts / due-risk-serious-liver- injury-fda-restricts-use-obeticholic-acid-ocaliva-primary-biliary-cholangitis).

[0024] Considering the efficacy and tolerability issues with OCA or UDCA treatments, there is an unmet need for therapeutic options for patients with advanced stage PBC, allowing a significant reduction in plasma ALP levels.

[0025] Elafibranor (2-(2,6-dimethyl-4- { 3 -[4-(methylsulfanyl)phenyl] -3 -oxopropen- 1 -yl }phenoxy)-2- methylpropanoic acid) (Iqirvo®) was evaluated in a phase 3 study for the treatment of PBC (ELATIVE®). The results of phase 3 on PBC show that the mean relative change (%) from baseline to endpoint in serum ALP was -48.3% for the elafibranor 80 mg treatment group, and 3.2% for placebo.

[0026] Thus, the treatment with elafibranor resulted in a consistent, statistically significant reduction in plasma ALP levels from baseline when compared to placebo. Moreover, elafibranor is safe and well-tolerated by the patients.

[0027] SUMMARY OF THE INVENTION

[0028] A phase 3 clinical study has surprisingly shown that the treatment of participants with 2-(2,6-dimethyl- 4- { 3 -[4-(methylsulfanyl)phenyl] -3 -oxoprop- 1 -en- 1 -yl }phenoxy)-2 -methylpropanoic acid (elafibranor, formerly called GFT505, now FDA approved as Iqirvo®) (80 mg daily) was also effective for participants having advanced stage PBC.

[0029] Of the 161 patients enrolled in this phase 3 clinical study (ELATIVE®), 54 had advanced disease (elafibranor n=35; placebo n=19), and 107 had early disease (elafibranor n=73; placebo n=34). Mean baseline values of liver disease markers were higher in patients with advanced disease than in early disease, except for ALB. Biochemical response at Week 52 in patients with advanced disease was achieved in 45.7% of patients receiving elafibranor and in 0% receiving placebo (risk difference: 0.457; 95% confidence interval [CI]: 0.230, 0.618).

[0030] The present invention thus relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy] -2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

[0031] The present invention further relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for treating advanced primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

[0032] The invention further relates to the use of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy] -2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for the manufacture of a medicament for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

[0033] The present invention further relates to the use of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy] -2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT 1007, for the manufacture of a medicament for use in a method for treating advanced primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

[0034] The present invention also relates to a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC, comprising administering to said subject, a therapeutic effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2 -methylpropanoic acid (GFT 1007), and a pharmaceutically acceptable salt of elafibranor or GFT 1007.

[0035] The present invention also relates to a method for treating advanced primary biliary cholangitis (PBC) in a subject having advanced stage PBC, comprising administering to said subject, a therapeutic effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007.

[0036] DESCRIPTION OF THE FIGURES

[0037] Figure 1 shows the mean change from baseline to Week 52 (MMRM (mixed model for repeated measures) model) in alkaline phosphatase (ALP) levels (U / L) for patients with or without advanced PBC disease and receiving elafibranor or placebo.

[0038] Figure 2 shows the mean change from baseline to Week 52 (MMRM model) in total bilirubin (TB) level for patients with or without advanced PBC disease and receiving elafibranor or placebo.

[0039] Figure 3 shows the mean change from baseline to Week 52 (MMRM model) in yGT (gamma-glutamyl transferase) levels (U / L) for patients with or without advanced PBC disease and receiving elafibranor or placebo. Figure 4 shows the mean change from baseline to Week 52 (MMRM model) in Stiffhess / Liver Stiffness (LSM) (kPa) for patients with or without advanced PBC disease and receiving elafibranor or placebo.

[0040] Figure 5 shows the mean change from baseline to Week 52 (MMRM model) in albumin (ALB) levels(g / L) for patients with or without advanced PBC disease and receiving elafibranor or placebo.

[0041] Figure 6 shows the percentage change from baseline in markers of immune response and inflammation by disease stage at Week 52: A) IgG, B) IgM, C) haptoglobin, D) CRP, E) Fibrinogen, F) TNFa, G) IL- 6. CfB: change from baseline; CRP: C reactive protein; IgG; immunoglobulin G; IgM: immunoglobulin M; IL-6: interleukin-6; LS: least square; TNF-a: tumor necrosis factor-alpha.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo- propyl]phenoxy] -2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

[0044] The term "treatment" or “treating” refers to therapy, prevention, or prophylaxis of a cholestatic disease in particular of PBC, more particularly of advanced stage PBC, in a subject in need thereof. The treatment involves the administration of elafibranor, GFT1007 or a pharmaceutically acceptable salt thereof (such as via the administration of a pharmaceutical composition comprising elafibranor) to a subject (e.g. a patient) having a declared disease to prevent, cure, delay, reverse, or slow down the progression of the disease, improving thereby the condition of patients. A treatment may be also administered to subjects that are either healthy or at risk of developing a cholestatic disease.

[0045] Whenever within this whole specification "treatment of advanced PBC" or the like is mentioned with reference to the pharmaceutical composition of the invention, there is meant: a) a method for treating advanced PBC, said method comprising administering an effective amount of the pharmaceutical composition of the invention to a subject in need of such treatment; b) the use of a pharmaceutical composition of the invention for the treatment of advanced PBC; c) the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of advanced PBC; and / or d) a pharmaceutical composition of the invention for use in a method for treating advanced PBC.

[0046] In particular, the term “treatment of advanced PBC” or “treating advanced PBC” includes an improvement or normalization of:

[0047] ALP plasma level; and

[0048] Total bilirubin plasma level; and yGT plasma level; and / or

[0049] AST (aspartate aminotransferase), 5 ’-nucleotidase, conjugated bilirubin, ALT (alanine aminotransferase) and albumin levels; and / or

[0050] Lipid parameters; and / or bile acids level; and / or

[0051] C4 (7-a-hydroxy-4-cholesten-3-one) levels; and / or

[0052] FGF19 levels; and / or

[0053] IgM (immunoglobulin M) levels; and / or

[0054] Paris I, Paris II, Toronto I, Toronto II or UK-PBC risk score; and / or 5D-itch scale, PBC 40 QOL, VAS (visual analog scale); and / or Promis Fatigue T-score, in a subject having advanced PBC.

[0055] The present invention further relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, GFT 1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for reducing baseline plasma ALP level in a subject having advanced PBC.

[0056] In the context of the invention, the terms “baseline plasma level” refer to the plasma level of a subject before starting any treatment with the composition of the invention. For example, “baseline ALP plasma level” refer to the ALP plasma level of a subject before starting any treatment with the composition of the invention.

[0057] In the context of the invention, the terms “reducing baseline plasma ALP level in a subject” means either a reduction of at least 15% of the baseline plasma ALP level of said subject or a reduction of the ALP level of the subject to no more than 1 ,67xULN, after 52 weeks of treatment with the composition of the invention. Reducing baseline plasma ALP level in a subject having advanced PBC helps to improve the condition of said subject, in particular signing a reduction in cholestasis.

[0058] In the context of the invention, the terms “advanced stage PBC” and “advanced PBC” can be used interchangeably. In particular, the advanced stage PBC can be defined as PBC stage III or PBC stage IV.

[0059] In a particular embodiment of the invention, the subject having advanced stage PBC has stage III PBC. In another particular embodiment of the invention, the subject having advanced stage PBC has stage IV PBC.

[0060] In a particular embodiment of the invention, the subject having advanced stage PBC has PBC with or without cirrhosis. In a particular embodiment of the invention, the subject having advanced stage PBC has: a baseline ALP level of more than 2xULN; and / or a baseline total bilirubin serum level higher than 0.6 times the upper limit of normal (ULN); and / or a baseline albumin serum level of less than the lower limit of normal (LLN); and / or a liver stiffness measurement (LSM) higher than 9.6 kPa, in particular higher than 10 kPa.

[0061] In a particular embodiment of the invention, the subject having advanced PBC has a baseline ALP level of more than 2xULN and baseline total bilirubin serum level higher than 0.6xULN, in particular more than 0.6 mg / dL. In a particular aspect, the subject to be treated is identified by testing the ALP level and TB level of a potential subject and then selecting the subject having baseline plasma ALP level of more than 2xULN and baseline total bilirubin serum level of more than 0.6xULN. The ALP and TB levels are testing using methods commonly known in the art. These tests require a blood sample from a vein.

[0062] In the context of the invention, ALP results are reported in international units per liter (IU / L or U / L). For males older than age 18, the upper limit of normal (ULN) related to the ALP level is 129 U / L. For females older than age 18, the upper limit of normal (ULN) related to the ALP level is 104 U / L.

[0063] In the context of the invention, TB results are reported in international units per liter (mg / dL). Different labs may have slightly different ranges for what they consider normal bilirubin levels. On average, total bilirubin levels between 0.2 and 1.3 mg / dL, preferably between 0.2 and 1 mg / dL, are considered normal for children and adults. The reference range of direct bilirubin is 0. 1-0.4 mg / dL.

[0064] In a particular embodiment of the invention, the subject having advanced stage PBC is identified by liver stiffness measurement (LSM) higher than 9.6 kPa, in particular higher than 10 kPa.

[0065] Liver stiffness measurement can be obtained by different methods (stand-alone bedside device : vibration controlled transient elastography [TE]; techniques integrated in ultrasound devices: point-shear wave elastography (pSWE), bidimensional shear wave elastography (2D-SWE); and MRE). TE is the most widely validated and available. TE using the appropriate probe and the other ultrasound-based measurements have an applicability of >95% (in patients who are not morbidly obese), provide results in real time and only take a few minutes to be performed. In the context of the invention, liver stiffness was measured by vibration controlled transient elastography [TE] using Fibroscan® (FibroScan® Testing is a recently FDA-approved non-invasive diagnostic device used to measure liver scarring or fibrosis caused by a number of liver diseases). The observed values and changes from baseline for liver stiffness are presented over time using mixed model for repeated measures (MMRM).

[0066] In a particular embodiment of the invention, the subject having advanced PBC has a baseline ALP level of more than 2xULN and baseline albumin (ALB) serum level lower than limit of normal (LLN), namely lower than 3.5 mg / dL. In a particular aspect, the subject to be treated is identified by testing the ALP level and ALB level of a potential subject and then selecting the subject having baseline plasma ALP level of more than 2xULN and baseline ALB serum level of less than LLN. The ALP and ALB levels are testing using methods commonly known in the art. These tests require a blood sample from a vein.

[0067] In the context of the invention, ALB results are reported in international units per liter (mg / dL). The reference range of ALB is 3.5 to 5.5 mg / dL.

[0068] In a particular embodiment of the invention, the subject having advanced stage PBC can also be identified by histology among patients who had a liver biopsy (absent or mild fibrosis versus presence of bridging fibrosis or cirrhosis). In a particular aspect, the subject having advanced stage PBC has liver scarring or severe liver scarring. In another particular aspect, the subject having advanced stage PBC has irreversible liver scarring.

[0069] In the context of the invention, the term “patient”, “subject” or “individual” are interchangeable and refer to a mammal and more particularly a human including adult and child. The subjects to be treated according to the invention can be appropriately selected on the basis of several criteria associated with cholestatic pathological processes such as previous and / or present drug treatments, associated pathologies, genotype, exposure to risk factors, as well as any other relevant biomarker that can be evaluated by means of any suitable immunological, biochemical, or enzymatic method. Typically, the subject to be treated is with advanced PBC, as characterized as follows:

[0070] - the presence of at least 2 of the following 3 diagnostic factors:

[0071] (i) history of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit),

[0072] (ii) positive Anti-Mitochondrial Antibodies (AMA) titers (> 1 / 40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies, and

[0073] (iii) liver biopsy consistent with PBC; and

[0074] - LSM liver stiffness measurement (LSM) by TE higher than 9.6 kPa (in particular higher than 10 kPa) or Nakanuma fibrosis score 2 or 3; and / or a baseline ALP level of more than 2xULN and baseline total bilirubin serum level of more than 0.6xULN; and / or a baseline ALP level of more than 2xULN and albumin serum level lower than lower limit of normal (LLN); and / or presence of liver scarring, bridging fibrosis or cirrhosis; and

[0075] - optionally, taking UDCA for at least 12 months (stable dose for > 6 months) prior to screening visit. In a particular embodiment, the subject to be treated is with advanced PBC before receiving the first administration of the pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, GFT1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007.

[0076] In a particular embodiment of the invention, the pharmaceutical composition of the invention can be used for normalizing ALP, albumin and / or bilirubin level(s) in a subject having advanced stage PBC.

[0077] In a particular embodiment, the treatment results in a level of ALP lower than 1.67 x ULN (upper limit of normal) and optionally total bilirubin within normal limit.

[0078] In a particular variant of this embodiment, the composition of the invention is administered to the subject having advanced stage PBC for decreasing ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, more preferably by at least 40%, in particular after at least 52 weeks of administration.

[0079] In a particular embodiment, the composition of the invention is administered to the subject having advanced PBC for improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxy cholic acid (DCA) levels.

[0080] In a further particular embodiment, the composition of the invention is administered to the subject having advanced PBC for improving Paris I, Paris II, Toronto I, Toronto II or UK-PBC risk score.

[0081] In another particular embodiment, the composition of the invention is administered to the subject having advanced stage PBC for: improving AST, yGT, 5 ’-nucleotidase, total bilirubin, conjugated bilirubin, ALT and albumin levels; and / or improving lipid parameters; and / or improving C4 and / or FGF19 levels; and / or improving IgM levels; and / or improving 5D-itch scale, PBC 40 QOL, VAS; and / or improving Promis Fatigue T-score.

[0082] In a further particular embodiment, the composition of the invention is for use in a method for treating advanced PBC in a subject having advanced stage PBC.

[0083] In some particular embodiments of the invention, GFT1007, the active metabolite of elafibranor, is used. GFT1007 is 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2 -methylpropanoic acid. Its properties and synthesis were described in PCT application WO2007 / 147879, where it is referred to as compound 1. According to the present invention, the pharmaceutical composition of the invention may include a stereoisomer of elafibranor, of GFT1007, or of a pharmaceutically acceptable salt of elafibranor or of GFT1007.

[0084] A stereoisomer is an isomeric compound that has the same molecular formula and sequence of bonded atoms, but differs in the 3D-dimensional orientations of its atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers and tautomers.

[0085] Elafibranor or GFT1007 can be formulated as pharmaceutically acceptable salt, particularly an acid or base salt compatible with pharmaceutical use. Salts of elafibranor or GFT1007 implemented herein include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.

[0086] In particular, “pharmaceutically acceptable salts” include inorganic as well as organic acids salts. Counter-ions may be selected from the following the non-exhaustive list : ammonia, L-arginine, benethamine, benzathine, tert-butylamine (erbumine), calcium hydroxide, choline hydroxide, deanol, diethanolamine (2,2’-iminobis(ethanol), diethylamine, epolamine (l-(2-hydroxyethyl)pyrrolidine), 2- (diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H- imidazole, L-Lysine, magnesium hydroxide, meglumine (N-methyl-glucamine), 4-(2-hydroxyethyl)- morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2"-nitrilo- tris(ethanol)), tromethamine, zinc hydroxide, in particular tromethamine, potassium, sodium, benethamine, benzathine, L-arginine, ethanolamine, meglumine, glycine, erbumine, L-lysine, epolamine, choline, preferably tromethamine, potassium, sodium, benethamine, benzathine, L-arginine, more preferably tromethamine, potassium, sodium, L-arginine, more particularly tromethamine.

[0087] In particular embodiments, the invention implements an ammonia, L-arginine, benethamine, benzathine, tert-butylamine (erbumine), calcium, choline, deanol, diethanolamine (2,2’-iminobis(ethanol), diethylamine, epolamine (l-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2- aminoethanol), ethylenediamine, glycine, hydrabamine, IH-imidazole, L-Lysine, magnesium, meglumine (N-methyl-glucamine), 4-(2-hydroxyethyl)-morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2"-nitrilo-tris(ethanol)), tromethamine or zinc salt of elafibranor or GFT1007. In a further particular embodiment, the salt of elafibranor or GFT1007 is selected from a tromethamine, potassium, sodium, L-arginine, benethamine, benzathine, ethanolamine, meglumine, glycine, erbumine, L-lysine, choline, epolamine, magnesium or 2-amino-2 -methyl -propan- l-ol.

[0088] In a preferred embodiment, the pharmaceutical composition of the invention comprises elafibranor or a pharmaceutically acceptable salt thereof. In a most preferred embodiment, the pharmaceutical composition of the invention comprises elafibranor.

[0089] Pharmaceutical composition used in the invention can comprise one or several excipients or vehicles, acceptable within a pharmaceutical context (e.g. saline solutions, physiological solutions, isotonic solutions, etc., compatible with pharmaceutical usage and well-known by one of ordinary skill in the art). This composition can also comprise one or several agents or vehicles chosen among dispersants, solubilisers, stabilisers, preservatives, etc. Agents or vehicles useful for these formulations (liquid and / or injectable and / or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc. Elafibranor or GFT1007 can be formulated for enteral or parenteral administration. For example, elafibranor or GFT1007 can be formulated for oral, intravascular (e.g. intravenous or intra-arterial), intramuscular, intraperitoneal, subcutaneous, transdermal or nasal administration. The pharmaceutical composition can be a solid or liquid dosage form. Illustrative formulations include, without limitation, an injectable suspension, or suspension for oral ingestion, a gel, an oil, a pill, a tablet, a suppository, a powder, a gel cap, a capsule, an aerosol, an oinment, a cream, a patch, or means of galenic forms for a prolonged and / or slow release.

[0090] In a preferred embodiment, the pharmaceutical composition of the invention is administered orally. Preferably, the composition is formulated in a form selected from the group consisting of a gel, an oil, a pill, a tablet, a powder, a gel cap, a capsule, and a galenic form or device assuring a prolonged and / or slow release.

[0091] In a preferred embodiment, the pharmaceutical composition of the invention is formulated in a tablet.

[0092] As used herein, the term “therapeutically effective amount” refers to a quantity of elafibranor or GFT1007 which prevents, removes or reduces PBC, in particular advanced stage PBC, and one of its adverse events, in particular a quantity of elafibranor or GFT1007 which prevents, removes or reduces PBC, in particular advanced stage PBC. In particular, the amount of pharmaceutical salt of elafibranor or GFT1007 is intended as the amount of free form of elafibranor or GFT1007 in this pharmaceutical salt.

[0093] The quantity to be administered can be adapted by a person skilled in the art. In particular, doses and regimen of administration may be function of the stage and of the severity of PBC to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.

[0094] In a particular embodiment, elafibranor, GFT1007, or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 10 mg and 200 mg per administration, preferentially between 40 mg and 120 mg per administration, more preferentially between 80 mg and 120 mg per administration. In a further particular embodiment, elafibranor, GFT1007, or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose of 80 mg per administration. In another particular embodiment, elafibranor, GFT1007 or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose of 120 mg per administration.

[0095] Preferably, the pharmaceutical composition of the invention is administered once a day, in particular is orally administered once a day.

[0096] According to a particular embodiment, the pharmaceutical composition is a solid dosage form, such as a tablet. In a further particular embodiment, said tablet comprises between 10 mg and 200 mg of elafibranor, GFT1007, or of a pharmaceutically acceptable salt of elafibranor or of GFT1007, such as between 80 mg and 120 mg of elafibranor, GFT1007, or of a pharmaceutical salt of elafibranor or of GFT1007. For example, a tablet may comprise 80 mg of elafibranor or GFT1007 or a pharmaceutical salt of elafibranor or of GFT1007 or 120 mg of elafibranor or GFT1007 or a pharmaceutical salt of elafibranor or of GFT1007.

[0097] In yet another particular embodiment, a tablet comprising 80 mg of elafibranor or GFT1007 is orally administered once a day.

[0098] In a more particular embodiment, a tablet comprising 80 mg of elafibranor is orally administered once a day.

[0099] In yet another particular embodiment, a tablet comprising 120 mg of elafibranor or GFT1007 is orally administered once a day.

[0100] In yet another particular embodiment, a tablet comprising 120 mg of elafibranor is orally administered once a day.

[0101] As used herein, the terms “patient”, “subject” or “individual” are interchangeable and refer to a human, including adult and child. In the context of the invention, the patient is suffering from advanced PBC.

[0102] In a particular embodiment, the patient has advanced PBC and responds at least partly to ursodeoxycholic acid (UDCA). In another particular embodiment, the subject having advanced PBC has an inadequate response to UDCA.

[0103] In a particular embodiment, the invention relates to the use of the pharmaceutical composition comprising a compound selected from elafibranor, GFT1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007, in combination with at least one other therapeutically active agent, in the method for treating PBC in a subject having advanced PBC, and an inadequate response to ursodeoxycholic acid. The other active agent may in particular be selected from other anti-cholestatic agents such as UDCA, OCA or seladelpar. The invention thus also relates to the combination of the pharmaceutical composition of the invention with UDCA, OCA or seladelpar, preferably UDCA. In particular, the method comprises administering elafibranor at a dose of 80 mg per administration and ursodeoxycholic acid (UDCA), to the subject in need thereof. More particularly, the method comprises administering elafibranor at a dose of 80 mg per administration and ursodeoxycholic acid (UDCA), to a subject having advanced primary biliary cholangitis (PBC) and an inadequate response to ursodeoxycholic acid. Even more particularly, the method comprises administering elafibranor at a dose of 80 mg per day and UDCA at a dose of 13-15 mg / kg / day, to a subject having advanced PBC and an inadequate response to ursodeoxycholic acid.

[0104] In another embodiment, the present invention also provides a kit for the treatment of PBC in a subject having advanced stage PBC, comprising the composition of the invention and another anti-cholestatic agent as described above, in particular UDCA.

[0105] The invention is further described with reference to the following, non-limiting, examples.

[0106] EXAMPLES

[0107] NCT04526665 clinical trial (ELATIVE®)

[0108] Participants aged 18 to 75 years, who had been diagnosed with primary biliary cholangitis according to established criteria, were recruited at 82 sites in 14 countries. Inclusion criteria were an alkaline phosphatase level of >1.67 times the upper limit of the normal range (ULN), and a total bilirubin level of <2 times the ULN. Prior to screening, eligible participants had received 13 to 15 mg / kg ursodeoxycholic acid treatment per day for at least 12 months (stable dose for at least 3 months) or were intolerant to ursodeoxycholic acid (no treatment for at least 3 months).

[0109] In this double-blind, placebo-controlled, phase 3 trial, participants with an inadequate response or intolerance to ursodeoxycholic acid were randomized 2: 1 to receive elafibranor 80 mg or placebo once daily. Participants receiving stable doses of ursodeoxycholic acid for at least three months prior to enrollment continued their treatment regimen throughout the trial. The overall double-blind treatment period consisted of two parts. In part one, all randomized participants received a minimum of 52 weeks of double-blind treatment. In part two, participants continued to receive double-blind treatment beyond Week 52 in a variable treatment period until all participants had completed their Week 52 assessment or until a maximum treatment duration of 104 weeks, whichever came first. The first database lock occurred after the last participant completed their Week 52 visit in the double-blind period. At the end of the double-blind period (lasting 52 to 104 weeks), participants could optionally enter an open-label extension where they would receive elafibranor 80 mg for up to five years.

[0110] The primary endpoint of Study NCT04526665 was response to treatment in the intent-to-treat population at Week 52, defined as ALP <1.67 x ULN, TB <ULN, and ALP decrease >15% from baseline. The primary endpoint was also analyzed according to baseline alkaline phosphatase levels of <3 times versus >3 times the ULN. From September 2020 through May 2023, 161 participants were randomly assigned to receive elafibranor 80 mg (108 participants) or placebo (53 participants); these participants made up the intent- to-treat (ITT) and safety populations.

[0111] As required by eligibility criteria, all participants had ALP levels >1.67 x ULN during screening. At baseline, 96.3% of participants had ALP levels >1.67 x ULN (97.2% and 94.3% of participants in the elafibranor 80 mg group and placebo groups, respectively) and 39.1% of participants had ALP levels >3 x ULN (39.8% and 37.7% in the elafibranor 80 mg and placebo groups, respectively).

[0112] Identification of participants with advanced PBC

[0113] PBC disease stage was categorized as early (absent or mild fibrosis, normal levels of biomarkers (TB, ALB) or advanced (advanced fibrosis or cirrhosis, abnormal levels of biomarkers (TB, ALB) based on liver stiffness measurement (LSM) <10 or >10 kPa by TE (Transient Elastography) using Fibroscan®, and / or bridging fibrosis or cirrhosis on histology among patients who had a liver biopsy.

[0114] Response for participants with advanced PBC

[0115] Of the 161 patients enrolled in ELATIVE®, 54 had advanced stage PBC (elafibranor n=35; placebo n=19), and 107 had early stage (elafibranor n=73; placebo n=34).

[0116] Mean baseline values of ALP, TB, GGT, and LSM were higher in patients with advanced stage than in early stage for both treatment arms. Among patients receiving elafibranor, biochemical response at Week 52 was achieved in 45.7% of patients with advanced stage and in 53.4% with early stage disease (risk difference: -0.016; 95% confidence interval [CI]: -0.216, 0.184). Among those receiving placebo, biochemical response occurred in 0% of patients with advanced stage PBC (risk difference versus elafibranor: 0.457; 95% CL 0.230, 0.618), and in 5.9% with early stage.

[0117] In addition, ALP normalization occurred in 8.6% of patients with advanced stage receiving elafibranor and in 17.8% with early stage disease also receiving elafibranor (in 0% of patients with advanced stage PBC and receiving placebo), with rapid, sustained reductions.

[0118] Figures 1 to 5 show that:

[0119] In patients with advanced stage PBC receiving elafibranor: o ALP levels (Figure 1) and GGT levels (Figure 3) substantially decreased; and o TB levels (Figure 2, LSM levels (Figure 4), and ALB levels (Figure 5) remained relatively unchanged,

[0120] In patients with advanced stage receiving placebo: o ALP level (Figure 1) remained stable; o TB (Figure 2) and LSM levels (Figure 4) showed trends for an increase; and o ALB level (Figure 5) decreased. Similar paterns were seen in patients with early stage PBC receiving elafibranor compared with placebo.

[0121] In addition, based on GLOBE and UK-PBC scores at Week 52, patients with early and advanced stage disease who received elafibranor had reduced risk change in transplant-free survival rates at 15 years (GLOBE: -3.87% and -7.00%, respectively; UK-PBC: -0.94% and -3.10%) compared with patients receiving placebo (-0.05% and 1.80%, respectively). There was no difference in risk assessed by GLOBE scores between advanced and early stage disease.

[0122] Figure 6 shows that there was also a significant difference in percentage change from in markers of immune response and inflammation between patients in advanced stage disease treated with elafibranor compared with placebo at Week 52.

[0123] The observed reduction in levels of multiple biochemical markers (ALP, GGT...) and inflammatory markers (IgG, IgM, and TNF-a), alongside the stability of others (TB and ALB), in patients with advanced stage PBC receiving elafibranor are encouraging, showing a positive impact on disease activity, and potentially slowed progression. Indeed, the improvements observed in biochemical, immune, and inflammatory markers resulted in improvement in predicted prognosis, according to UK-

[0124] PBC and GLOBE scores. Patients who received elafibranor had an increase in their predicted transplant- free survival compared with placebo, suggesting an improvement in prognosis, regardless of disease stage. Interestingly, the GLOBE scores revealed no significant difference in the risk between early and advanced disease, suggesting the treatment effect was similar across disease stages.

Claims

CLAIMS1. A pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2 -methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

2. The pharmaceutical composition for use according to claim 1, for use in a method for treating advanced PBC in a subject having advanced stage PBC.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the subject having advanced stage PBC is identified by liver stiffness measurement (LSM) higher than 10 kPa.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the subject having advanced stage PBC have a baseline total bilirubin serum level higher than 0.6 times the upper limit of normal (ULN).

5. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the subject having advanced PBC has a baseline ALP level of more than 2xULN and baseline total bilirubin serum level higher than 0.6xULN.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the subject having advanced stage PBC have a baseline albumin serum level of less than the lower limit of normal (LLN).

7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein the subject having advanced PBC has a baseline ALP level of more than 2xULN and baseline albumin (ALB) serum level lower than limit of normal (LLN).

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the subject having advanced PBC has a baseline ALP level of more than 2xULN.

9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the composition comprises elafibranor or a pharmaceutically acceptable salt thereof, in particular elafibranor.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein said composition is formulated in a form selected from the group consisting of a gel, an oil, a pill, a tablet, a powder, a gel cap, a capsule, and a galenic form or device assuring a prolonged and / or slow release.

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein said composition is formulated in a form of a tablet.

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein elafibranor is administered once a day.

13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the administration is oral.

14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the administration dose is of 80 mg or 120 mg per administration.

15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein elafibranor is administered at a dose of 80 mg per administration.

16. The pharmaceutical composition for use according to any one of claims 1 to 15, wherein the subject having advanced PBC has an inadequate response to ursodeoxycholic acid (UDCA).

17. The pharmaceutical composition for use according to any one of claims 1 to 16, the method comprising further administering to the subject in need thereof another anti -cholestatic agent, preferably the other anti-cholestatic agent being UDCA.

18. The pharmaceutical composition for use according to any one of claims 1 to 17, the method comprising administering elafibranor at a dose of 80 mg per administration and UDCA, to the subject in need thereof.

19. The pharmaceutical composition for use according to any one of claims 1 to 18, the method comprising administering elafibranor at a dose of 80 mg per administration and UDCA, to a subject having advanced stage PBC and an inadequate response to UDCA.

20. Use of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for the manufacture of a medicament for use in a method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC.

21. Use of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for the manufacture of a medicament for use in a method for treating advanced primary biliary cholangitis (PBC) in a subject having advanced stage PBC.1922. A method for treating primary biliary cholangitis (PBC) in a subject having advanced stage PBC, comprising administering to said subject, a therapeutic effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl- 4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007.

23. A method for treating advanced primary biliary cholangitis (PBC) in a subject having advanced stage PBC, comprising administering to said subject, a therapeutic effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl- 4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007.

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