Elafibranor for use for long-term treatment of 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 long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks, preferably 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

Description

[0001] ELAFIBRANOR FOR USE FOR LONG-TERM TREATMENT OF PRIMARY BILIARY CHOLANGITIS

[0002] TECHNICAL FIELD

[0003] The present invention relates to the field of medicine, in particular the long-term 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, etal.. 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. 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). The ALP levels are generally associated with disease progression. 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). 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.

[0009] The only approved drugs to treat patients with PBC are ursodeoxycholic acid (LIDCA) and Ocaliva® (obeticholic acid, OCA).

[0010] LIDCA (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.

[0011] 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.

[0012] Considering the efficacy and tolerability issues with the current treatment options available, there is an unmet need for therapeutic options for patients with PBC, allowing a significant reduction in plasma ALP levels.

[0013] Elafibranor (2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2- methylpropanoic acid) 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.

[0014] 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.

[0015] SUMMARY OF THE INVENTION

[0016] 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) (80 mg daily) provides a better efficacy after 78 weeks of treatment, than after 52 weeks of treatment: mean change from baseline to Week 78 in ALP plasma level was -135.3 ll / L in participants receiving elafibranor, compared with -117.7 ll / L from baseline to Week 52; mean change from baseline to Week 156 in ALP plasma level was -169.2 U / L in participants receiving elafibranor, compared with -119.6 U / L from baseline to Week 52; mean change from baseline to Week 78 in total bilirubin plasma level was -1 .2 pmol / L in participants receiving elafibranor, compared with -0.7 pmol / L from baseline to Week 52; mean change from baseline to Week 156 in total bilirubin plasma level was -1.23 pmol / L in participants receiving elafibranor, compared with -0.6 pmol / L from baseline to Week 52; mean change from baseline to Week 78 in yGT plasma level was -56.3 U / L in participants receiving elafibranor, compared with -44 U / L from baseline to Week 52; and mean change from baseline to Week 156 in yGT plasma level was -110 U / L in participants receiving elafibranor, compared with -52.3 U / L from baseline to Week 52.

[0017] The curves of mean change from baseline to Week 78 or to Week 130 or to Week 156 in ALP and yGT plasma level show a tendency to a loss of efficacy at 52 weeks, but then a strong improvement in efficacy is observed from 78 weeks onwards (see Figures 2 and 3).

[0018] 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 long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, wherein said pharmaceutical composition is administered for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. Administration can be performed daily or several times per day, if necessary. Preferably, the administration is performed once a day.

[0019] The invention further relates to a method for long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, comprising the administration of 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, in said subject, for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably 156 weeks. Preferably, the administration is a daily administration.

[0020] 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 the long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably 156 weeks.

[0021] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 reducing fatigue during at least 70 weeks in a subject having primary biliary cholangitis (PBC).

[0022] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.

[0023] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 reducing fatigue during at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks in a subject having primary biliary cholangitis (PBC).

[0024] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. DESCRIPTION OF THE FIGURES

[0025] Figure 1 a: Mean change from baseline to Week 78 in the cholestasis response. Figure 1 shows the proportion of patients with cholestasis response. A rapid improvement is observed from baseline through Week 4 in the elafibranor group (ELA), at levels significantly higher than the placebo group through Week 78.

[0026] Figure 1b: Mean change from baseline to Week 156 in the cholestasis response. Figure 1b shows the proportion of patients with cholestasis response in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.

[0027] Figure 2a: Mean change from baseline to Week 78 in ALP plasma level. Figure 2 shows rapid reductions in alkaline phosphatase (ALP) levels (U / L) observed from baseline through Week 4 in the elafibranor group (Ela), and sustained at levels significantly lower than the placebo group through Week 78.

[0028] Figure 2b: Mean change from baseline to Week 156 in ALP plasma level. Figure 2a shows reductions in alkaline phosphatase (ALP) levels (U / L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.

[0029] Figure 3a: Mean change from baseline to Week 78 in yGT plasma level. Figure 3a shows rapid reductions in yGT (gamma-glutamyl transferase) levels (U / L) observed from baseline through Week 4 in the elafibranor group (Ela), and sustained at levels significantly lower than the placebo group through Week 78.

[0030] Figure 3b: Mean change from baseline to Week 156 in yGT plasma level. Figure 3b shows reductions in yGT (gamma-glutamyl transferase) levels (U / L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.

[0031] Figure 4a: Mean change from baseline to Week 78 in total bilirubin plasma level. Figure 4 shows rapid reductions in total bilirubin levels (pmol / L) observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.

[0032] Figure 4b: Mean change from baseline to Week 156 in total bilirubin plasma level. Figure 4b shows reductions in total bilirubin levels (pmol / L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week Figure 5a: Mean change from baseline to Week 78 in 5-D itch total score. Figure 5a shows rapid reductions observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.

[0033] Figure 5b: Mean change from baseline to Week 156 in 5-D itch total score. Figure 5b shows rapid reductions observed from baseline through Week 156 in the elafibranor group (ELA) in the OLE study.

[0034] Figure 5c: Mean change from baseline to Week 156 in WI-NRS (Worst Itch Numeric Rating Scale) score. Figure 5c shows reductions in the elafibranor group (ELA) through Week 156.

[0035] Figure 5d: Mean change from baseline to Week 156 in PBC-40 itch score. Figure 5d shows rapid and constant reduction observed from baseline through Week 156 in the elafibranor group (ELA) in the OLE study.

[0036] Figure 6: Mean change from baseline to Week 78 in Promis Fatigue T-score. Figure 6 shows rapid reductions observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] 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 long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks. Preferably, said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0039] The term "treatment" or “treating” refers to therapy, prevention, or prophylaxis of a cholestatic disease 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.

[0040] Whenever within this whole specification “treatment of PBC" or the like is mentioned with reference to the pharmaceutical composition of the invention, there is meant: a) a method for treating 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 PBC; c) the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of PBC; and / or d) a pharmaceutical composition of the invention for use in a method for treating of PBC.

[0041] In particular, the term “treatment of PBC” or “treating PBC” includes an improvement or normalization of:

[0042] - ALP plasma level; and

[0043] Total bilirubin plasma level; and

[0044] - yGT plasma level; and / or

[0045] - AST (aspartate aminotransferase), 5’-nucleotidase, conjugated bilirubin, ALT (alanine aminotransferase) and albumin levels; and / or

[0046] Lipid parameters; and / or bile acids level; and / or

[0047] C4 (7-a-hydroxy-4-cholesten-3-one) levels; and / or

[0048] FGF19 levels; and / or

[0049] IgM (immunoglobulin M) levels; and / or

[0050] Paris I, Paris II, Toronto I, Toronto II or UK- PBC risk score; and / or

[0051] 5D-itch scale, PBC 40 QOL, VAS (visual analog scale), Wl NRS (Worst Itch Numeric Rating Scale); and / or

[0052] Promis Fatigue T-score (Fatigue Short Form 7a), and / or Epworth Sleepiness Scale (ESS) score.

[0053] The term “long-term treatment” refers to a treatment as defined above in which the therapy, prevention, or prophylaxis of the cholestatic disease, in particular PBC, in the subject in need thereof, lasts for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. This means that the treatment is able to be effective for a period of at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. In the context of the invention, the long-term treatment is obtained by administering elafibranor, GFT1007 or a pharmaceutically acceptable salt thereof during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. In that context, the administration is preferably a daily administration (once a day). Cholestasis or cholestatic disease is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepato-cellular cholestasis) or to obstruction of bile flow through intra- or extrahepatic bile ducts (obstructive cholestasis). In clinical practice, cholestasis is any condition in which the flow of bile from the liver is slowed or blocked.

[0054] Examples of cholestatic diseases are Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Intrahepatic Cholestasis of Pregnancy (ICP), Progressive Familial Intrahepatic Cholestasis (PFIC), Biliary atresia, Cholelithiasis, Infectious Cholangitis, Cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductal paucity, Drug-induced cholestasis, Total parenteral nutrition (TPN)-associated cholestasis.

[0055] In a particular embodiment, the subject to be treated has PBC. PBC is characterized by changes in many blood biochemical parameters. Patients’ sera show the enhanced activity of alkaline phosphatase (ALP), y-glutamyltransferase (gamma glutamyltranspeptidase, y-GT), 5’- nucleotidase (5’-NT), and leucineaminopeptidase (LAP), the higher levels of bile acids, cholesterol, phospholipids, copper, y-globulins, and bilirubin, and the lower level of total protein mainly at the expense of albumin fractions. In PBC, there is a decline in the levels of bile acids, cholesterol, and lecithin in the hepatic bile portion and their simultaneous rises in hepatocytes and blood (Reshetnyak VI, World J Gastroenterol. 2015; 21(25): 7683-7708). Changes in bile acid precursor C4 (7a-hydroxy-4-cholesten-3-one) (C4) can be assessed to characterize PBC.

[0056] The term “patient”, “subject” or “individual” are interchangeable and refer to a mammal and more particularly a human including adult and child. In the context of the invention, the patient is suffering from PBC. 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. The subject to be treated is with PBC, typically as characterized as follows:

[0057] - the presence of at least 2 of the following 3 diagnostic factors:

[0058] (i) history of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit)

[0059] (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

[0060] (iii) liver biopsy consistent with PBC

[0061] - ALP > 1.67x upper limit of normal (ULN) - optionally, taking LIDCA for at least 12 months (stable dose for > 6 months) prior to screening visit.

[0062] In a particular embodiment, the patient has PBC and responds at least partly to LIDCA. In another embodiment, the patient has PBC and does not respond adequately to LIDCA.

[0063] In a particular embodiment, the pharmaceutical composition of the invention can be used for reducing or normalizing ALP plasma level(s) in a subject having PBC for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0064] In a particular embodiment, the pharmaceutical composition of the invention can be used for reducing or normalizing ALP plasma level(s) in a subject having PBC after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.

[0065] In a particular embodiment, the pharmaceutical composition of the invention can be used for reducing or normalizing ALP, albumin and / or bilirubin level(s) in a subject having PBC for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0066] In a particular embodiment, the pharmaceutical composition of the invention can be used for reducing or normalizing ALP, albumin and / or bilirubin level(s) in a subject having PBC after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.

[0067] In a particular embodiment, the long-term treatment results in a level of ALP lower than 1.67 x ULN (upper limit of normal) for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0068] In a particular embodiment, the long-term treatment results in a level of ALP lower than 1.67 x ULN (upper limit of normal) after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.

[0069] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 %. Preferably, the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %. More preferably, the composition of the invention is administered to the subject once a day during at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 %.

[0070] According to the invention, the pharmaceutical composition of the invention is preferably for use for reducing plasma ALP level in a subject having PBC by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 % after at least 70 weeks, in particular after at least 78 weeks, in particular after at least 104 weeks, more particularly after at least 130 weeks, even more particularly after at least 156 weeks of administration.

[0071] Reducing baseline plasma ALP level in a subject having PBC helps to improve the condition of said subject, in particular signing a reduction in cholestasis.

[0072] In the context of the invention, ALP results are reported in international units per liter (I U / 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.

[0073] In a particular embodiment, the long-term treatment further results in a level of total bilirubin within normal limit for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks. The reference range of total bilirubin is 0.2-1.2 mg / dL. The reference range of direct bilirubin is 0.1-0.4 mg / dL.

[0074] In a particular embodiment, the long-term treatment further results in a level of total bilirubin within normal limit after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks of administration, in particular of daily administration. The reference range of total bilirubin is 0.1-1.2 mg / dL (1.71 to 20.5 pmol / L).

[0075] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %, more preferably by at least 8 %, even more preferably by at least 10 %. Preferably, the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %. More preferably, the composition of the invention is administered to the subject once a day during at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, for reducing baseline plasma total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %, more preferably by at least 8 %, even more preferably by at least 10 %.

[0076] According to the invention, the pharmaceutical composition of the invention is preferably for use for reducing plasma total bilirubin level in a subject having PBC by at least 5 % after at least 70 weeks, preferably after at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably after at least 156 weeks of administration.

[0077] In a particular embodiment, the long-term treatment further results in a level of y-GT within normal limit for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks. The common reference range for adults is 5 to 40 ll / L.

[0078] In a particular embodiment, the long-term treatment further results in a level of y-GT within normal limit after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks of administration, in particular of daily administration.

[0079] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %. Preferably, the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %. More preferably, the composition of the invention is administered to the subject once a day during at least 104 weeks, preferably at least 130 weeks, more preferably at least 156 weeks, for reducing baseline plasma y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %. According to the invention, the pharmaceutical composition of the invention is preferably for use for reducing plasma y-GT level in a subject having PBC by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %, after at least 70 weeks, preferably after at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably after at least 156 weeks, of administration.

[0080] In a further embodiment, the long-term treatment further results in improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.

[0081] In a particular embodiment, the long-term treatment further results in improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.

[0082] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels.

[0083] In a further embodiment, the long-term treatment further results in improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.

[0084] In a particular embodiment, the long-term treatment further results in improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration. In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score.

[0085] In a further embodiment, the long-term treatment further results in improving 5D-itch scale, PBC 40 QOL, VAS, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.

[0086] In a particular embodiment, the long-term treatment further results in improving 5D-itch scale, PBC 40 QOL, VAS, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.

[0087] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving 5D-itch scale, PBC 40 QOL, VAS.

[0088] In a further embodiment, the long-term treatment further results in improving Wl NRS score for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.

[0089] In a particular embodiment, the long-term treatment further results in improving Wl NRS score after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.

[0090] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Wl NRS score.

[0091] In a further embodiment, the long-term treatment further results in improving Promis Fatigue T-score, and / or Epworth Sleepiness Scale (ESS) score, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks. In a particular embodiment, the long-term treatment further results in improving Promis Fatigue T-score, and / or Epworth Sleepiness Scale (ESS) score, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.

[0092] In a particular embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Promis Fatigue T-score, and / or Epworth Sleepiness Scale (ESS) score.

[0093] In another embodiment, the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for further: improving AST, yGT, 5’-nucleotidase, total bilirubin, conjugated bilirubin, ALT and albumin levels; and 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 Wl NRS score; and / or improving Promis Fatigue T-score (Fatigue Short Form 7a), and / or Epworth Sleepiness Scale (ESS) score.

[0094] 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.

[0095] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 long-term reduction of fatigue in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks. Preferably, said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0096] The present invention also relates to a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, GFT1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term reduction of fatigue associated to PBC in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks. Preferably, said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0097] In the context of the invention, the terms “reducing fatigue” can refer to the decrease in the feeling of tiredness or sense of exhaustion. It can also refer to an increase in the sense of energy and in the ability to execute daily activities and function normally in family or social roles.

[0098] In the context of the invention, the terms “a method for long-term reduction of fatigue” refer to a method for reducing fatigue (as defined above) during at least 70 weeks, preferably during at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably during at least 156 weeks.

[0099] The patient’s fatigue can be measured using the PROMIS Short Form - Fatigue 7a questionnaire (V1 .0) to assess change from baseline in fatigue during treatment. The PROMIS Fatigue item banks assess a range of self-reported symptoms over the past seven days, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities. PROMIS instruments are scored using item-level calibrations. The final score is represented by the T- score, a standardized score with a mean of 50 and a standard deviation (SD) of 10. A 1 -point decrease of the PROMIS Fatigue T-score represents a meaningful change in fatigue. This improvement corresponds to changes in alertness and well-being that are easily noticeable. Likewise, a noticeable worsening corresponds to a 1 -point increase of the PROMIS Fatigue T- score (Schattenberg et al.; EASL 21-24 June 2023).

[0100] The patient’s fatigue can also be measured using the PBC-40 total fatigue score. The PBC- 40, consisting of 40 questions distributed across six domains: fatigue, emotional, social, cognitive function, general symptoms, and itch. Another way to mesure patient’s fatigue is to use the Epworth Sleepiness Scale. The Epworth Sleepiness Scale is widely used in the field of sleep medicine as a subjective measure of a patient's sleepiness. The test is a list of eight situations in which the patient rates his tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. The total score is based on a scale of 0 to 24.

[0101] In the context of the invention, the terms “reducing pruritus” can refer to the reduction in the intensity or severity of pruritus.

[0102] In the context of the invention, the terms “a method for long-term treatment of pruritus” refer to a method for reducing pruritus (as defined above) during at least 70 weeks, preferably during at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably during at least 156 weeks.

[0103] The patient’s pruritus can be measured using the 5D-itch score, the PBC-40 itch score or the Wl NRS score. The 5-D itch scale was developed as a brief but multidimensional questionnaire designed to be useful as an outcome measure in clinical trials. The five dimensions are degree, duration, direction, disability and distribution. The 5D-itch scale is the most comprehensive and provides an accurate snapshot of the impact of pruritus on the patient's daily life, thanks to its score: score ranging from 5 (no impact of pruritus) to 25 (pruritus having a severe impact on the patient). This scale has 5 dimensions (5D). Each of them will be evaluated from 1 to 5.

[0104] The PBC-40, consisting of 40 questions distributed across six domains: fatigue, emotional, social, cognitive function, general symptoms, and itch.

[0105] The Worst Itch Numeric Rating Scale (WI-NRS) has been developed as a simple, single item with which to assess the patient-reported severity of this symptom at its most intense during the previous 24-hour period. Scores are given from 0 to 10, higher scores indicating greater intensity of worst itching.

[0106] The invention further relates to a pharmaceutical composition comprising a compound selected from 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 long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks. Preferably, said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0107] In some 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 W02007 / 147879, where it is referred to as compound 1.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 (1-(2- hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1 H-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.

[0112] 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 (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)- ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1 H- 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-1-ol.

[0113] In a preferred embodiment, the pharmaceutical composition of the invention comprises elafibranor or a pharmaceutically acceptable salt thereof.

[0114] In a most preferred embodiment, the pharmaceutical composition of the invention comprises elafibranor.

[0115] 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.

[0116] 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.

[0117] In a preferred embodiment, the pharmaceutical composition of the invention is formulated in a tablet.

[0118] As used herein, the term “therapeutically effective amount” refers to a quantity of elafibranor or GFT1007 which prevents, removes or reduces PBC and one of its adverse events, in particular a quantity of elafibranor or GFT1007 which prevents, removes or reduces 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.

[0119] 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.

[0120] 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.

[0121] Preferably, the pharmaceutical composition of the invention is administered once a day for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. In particular, the pharmaceutical composition of the invention is orally administered once a day for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0122] According to an 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 GFT 1007, 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.

[0123] In yet another embodiment, a tablet comprising 80 mg of elafibranor or GFT1007 is orally administered once a day for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0124] In yet another embodiment, a tablet comprising 120 mg of elafibranor or GFT1007 is orally administered once a day for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

[0125] In a particular embodiment, the patient has PBC and responds at least partly to ursodeoxycholic acid (LIDCA). In another embodiment, the subject having PBC has an inadequate response to ursodeoxycholic acid (LIDCA).

[0126] In the context of the invention, the term “inadequate response to LIDCA” means that a treatment with LIDCA fails to significantly prevent, cure, delay, reverse, or slow down the progression of the disease, and / or fails to significantly improve the condition of the subject having PBC. In particular, the treatment with LIDCA fails to provide a significant improvement of:

[0127] - ALP plasma level; and

[0128] - Total bilirubin plasma level; and

[0129] - yGT plasma level; and / or

[0130] - AST (aspartate aminotransferase), 5’-nucleotidase, conjugated bilirubin, ALT (alanine aminotransferase) and albumin levels; and / or

[0131] Lipid parameters; and / or bile acids level; and / or

[0132] C4 (7-a-hydroxy-4-cholesten-3-one) levels; and / or

[0133] FGF19 levels; and / or

[0134] IgM (immunoglobulin M) levels; and / or

[0135] Paris I, Paris II, Toronto I, Toronto II or UK- PBC risk score; and / or

[0136] 5D-itch scale, PBC 40 QOL, VAS (visual analog scale), Wl NRS (Worst Itch Numeric Rating Scale); and / or

[0137] Promis Fatigue T-score (Fatigue Short Form 7a), and / or Epworth Sleepiness Scale (ESS) score.

[0138] 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 primary biliary cholangitis (PBC) in a subject having primary biliary cholangitis (PBC), and an inadequate response to ursodeoxycholic acid. The other active agent may in particular be selected from other anticholestatic agents such as UDCA, OCA or seladelpar (Livdelzi®). 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), once a day for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks 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), once a day for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks to a subject having 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 LIDCA at a dose of 13-15 mg / kg / day, for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks to a subject having PBC and an inadequate response to ursodeoxycholic acid.

[0139] In another embodiment, the present invention also provides a kit for the long-term treatment of PBC comprising the composition of the invention and another anti-cholestatic agent as described above, in particular LIDCA.

[0140] The invention is further described with reference to the following, non-limiting, examples.

[0141] EXAMPLES

[0142] NCT04526665 clinical trial (ELATIVE®)

[0143] 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).

[0144] In this multi-center, randomized, 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 (DBP). 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.

[0145] 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.

[0146] 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.

[0147] As required by eligibility criteria, all participants had ALP levels >1.67 x ULN during screening.

[0148] Of 161 randomised participants, 96 / 108 (89%) receiving elafibranor and 47 / 53 (89%) receiving placebo completed treatment in the common double-blind period (DBP) to Week 52. Beyond Week 52, in the variable double-blind period, 30 (28%) participants receiving elafibranor and 13 (25%) receiving placebo recorded a Week 78 visit.

[0149] Participants who completed the double-blind period of ELATIVE® clinical trial (participants who received 104 weeks of double-blind treatment or those who were in the double-blind period when the last participant completed 52 weeks of treatment) were eligible to enter the open label extension (OLE) part, where all participants received elafibranor 80 mg daily for up to 5 years.

[0150] 138 participants entered the OLE period: 93 participants were in the elafibranor group during the DBP and 45 were in the placebo group during the DBP. All 138 participants received at least one dose in the long term extension part of the study.

[0151] In total (DBP + OLE period), 153 participants have received ELA during more than one year; 108 had received ELA and 45 received placebo in the double-blind period (DBP). For participants receiving continuous ELA, data up to W156 are available. Baseline characteristics of participants receiving continuous ELA and participants switching from placebo to ELA were similar (mean ALP at 321 .3 U / L vs 335.8 U / L ; mean TB 0.57 mg / dL vs 0.64 mg / dL).

[0152] Cholestasis response at 52, 78, 104 and 156 weeks

[0153] At Week 52, 55 / 108 (51%) participants receiving elafibranor achieved cholestasis response versus 2 / 53 (4%) receiving placebo (p<0.0001). This was improved at Week 78, with 19 / 27 (70%) participants receiving elafibranor achieving cholestasis response versus 0 / 13 (0%) participants receiving placebo. In the participants receiving continuous ELA, 34 / 61 (56%) at Week 104 and 11 / 13 (85%) at Week 156 achieved cholestasis response (see Figure 1a and 1b).

[0154] Complete normalization of alkaline phosphatase at Week 52 occurred in 15% and 0% of patients receiving elafibranor and placebo, respectively (difference, 15%; odds ratio, infinity; 95% Cl, 2.8 to infinity; p=0.0019). This also was improved at Week 78, with ALP normalisation occurring in 5 / 27 (19%) participants receiving elafibranor versus 0 / 13 (0%) participants receiving placebo. ALP normalization occurred in 8 / 61 (13%) at Week 104 and 5 / 13 (39%) at Week 156.

[0155] Mean change from baseline to Week 78 in ALP was -135.3 U / L in participants receiving elafibranor (n=26), compared with 31.0 U / L in participants receiving placebo (n=12) (see Table 1a and Figure 2a).

[0156] In the OLE period, mean change from baseline to Week 130 in ALP plasma level was -156.7 U / L in participants receiving elafibranor (n=27) (see Table 1b and Figure 2b).

[0157] Mean change from baseline to Week 156 in ALP plasma level was -169.2 U / L in participants receiving elafibranor (n=13) (see Table 1 b and Figure 2b).

[0158] Mean change from baseline to Week 78 in gamma glutamyl transferase (yGT) was -56.3 U / L in participants receiving elafibranor (n=26) and -10.3 U / L in participants receiving placebo (n=12) (see Table 1 and Figure 3a).

[0159] In the OLE period, mean change from baseline to Week 130 in yGT (gamma glutamyl transferase) plasma level was -63.8 U / L in participants receiving elafibranor (n=27) (see Table 1b and Figure 3b).

[0160] Mean change from baseline to Week 156 in yGT plasma level was -110 U / L in participants receiving elafibranor (n=13) (see Table 1 b and Figure 3b).

[0161] Mean change from baseline to Week 78 in in total bilirubin levels (TB) was -1.2 pmol / L in participants receiving elafibranor (n=25), while participants receiving placebo had a worsening of mean TB levels with an increase of 3.1 pmol / L (n=12) (see Table 1 and Figure 4a).

[0162] In the OLE period, mean change from baseline to Week 156 in total bilirubin levels (TB) was - 110 pmol / L in participants receiving elafibranor (n=13) (see Table 1b and Figure 4b).

[0163] Mean change from baseline to Week 130 in total bilirubin plasma level was -0.64 pmol / L in participants receiving elafibranor (n=26) (see Table 1 b and Figure 4b). Table 1a summarizes mean changes from baseline to weeks 4, 13, 26, 39, 52 and 78, in participants receiving elafibranor or placebo.

[0164] Table 1b summarizes mean changes from baseline to weeks 4, 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, and 156 in participants receiving elafibranor (N=153), in the OLE study including 108 participants who received or not ELA during the double-blind period (108 participants having received ELA and 45 participants having received placebo).

[0165] NA : not applicable ; NE not evaluated

[0166] Conclusion: Following data up to Week 52, the results at Week 78 and Week 156 indicate that improvements in biomarkers of cholestasis in participants with PBC treated with elafibranor are sustained and even increased longer-term. Mean change from baseline to Week 130 in pruritus scores : 5-D itch total score PBC-40 itch score and Wl NRS score

[0167] Table 2a and Figures 5a summarize mean changes from baseline 4, 13, 26, 39, 5 and 78, in 5-D itch total score (Prurit) to weeks in participants receiving elafibranor or placebo. Table 2b and Figures 5b, 5c and 5d summarize mean changes from baseline from weeks 4, to week 156, in 5-D itch total score, PBC-40 itch score and Wl NRS score in participants receiving elafibranor comprising the participants including in the OLE period. A positive and sustained impact across different measures of pruritus (WI-NRS (Worst Itch-NRS), PBC-40, 5D-ltch) was observed.

[0168] NA : not applicable ; NE not evaluated

[0169] Following data up to Week 52, the results at Week 78 and through Week 156 indicate that improvements in pruritus as secondary endpoints in participants with PBC treated with elafibranor are sustained and even increased longer-term. Mean change from baseline to Week 130 in fatigue score: Fatigue Short Form 7a (PFSF 7a) and Epworth Sleepiness Scale (ESS)

[0170] Fatigue and sleep were assessed in ELATIVE® through the following instruments :

[0171] • Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a (PFSF 7a): consists of seven items measuring the experience of fatigue and its interference with daily activities over the past week. A 5-point Likert scale is used for individual items; scores can range from 7 (no fatigue) to 35 (always fatigue). Raw PROMIS Fatigue Short Form 7a scores are often converted to T-scores, which rescales the raw score into a standardized score with a mean of 50 and a standard deviation of 10. This allows for easier interpretation and comparison across different populations and measures. A T-score of 50 represents the average score for the United States general population. T-scores that are half a standard deviation worse than the mean (approximately 55-60 for negatively-worded concepts like fatigue) are often considered to indicate mild symptoms or impairment.

[0172] • Epworth Sleepiness Scale (ESS): used to assess daytime sleepiness, in which patients rate their usual chances of dozing off or falling asleep while engaged in eight different activities on a scale from zero to three. The ESS score can range from zero (no daytime sleepiness) to 24 (severe excessive daytime sleepiness). The scores from the ESS can also be categorized into different levels of sleepiness severity, which help in interpreting the results: 0 to 5 (lower normal daytime sleepiness), 6 to 10 (higher normal daytime sleepiness), 11 to 12 (mild excessive daytime sleepiness), 13 to 15 (moderate excessive daytime sleepiness), and 16 to 24 (severe excessive daytime sleepiness).

[0173] • PBC-40 Fatigue: one of the six domains of PBC-40, a disease-specific health-related quality of life measure developed for patients with PBC. The fatigue domain consists of 8 items / questions. Each item in the fatigue domain is scored on a 5-point Likert scale from 1 (never) to 5 (always). Patients are asked to reflect on their experiences over the past 4 weeks when answering the fatigue items. Domain scores range from 8 (never fatigued) to 40 (always fatigued). The PBC-40 Fatigue domain does not have specific categories like "normal," "mild," "moderate," or "severe". Sleep question of PBC-40 Itch: PBC-40 Itch is composed of three questions with one asking participants to rate the statement “itching disturbed my sleep” from 1 (never) to 5 (always), with an additional response option for did not apply / no itch.

[0174] • Sleep question of 5-D Itch: within the disability domain of 5-D Itch, participants are asked to rate the impact of itching on sleep over the last two weeks. Response options range from 1 (never affects sleep) to 5 (delays falling asleep and frequently wakes me up at night). T1

[0175] Table 3a and Figure 6a summarize mean changes from baseline from week 4 through week 78, in Promis Fatigues T-score, in participants receiving elafibranor comprising the participants including in the OLE period. Table 3b summarizes mean changes from baseline to week 104 and week 130 and the percentage of patients with improvement.

[0176] A positive and sustained impact across different measures of fatigue was observed.

[0177] Following data up to Week 52, the long term treatment at Week 78 and through Week 104 and Week 130, resulted in clinically improvements in fatigue and sleep in patients with PBC treated with elafibranor. Conclusion: Following data up to Week 52, the results at Week 78 and through Week 156 indicate that improvements in secondary endpoints in participants with PBC treated with elafibranor are sustained and even increased longer-term.

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 long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks.

2. The pharmaceutical composition for use according to claim 1 , for use for reducing baseline plasma ALP level in a subject having PBC by at least 35 % after at least 70 weeks, preferably after at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, of administration.

3. The pharmaceutical composition for use according to claim 1 or 2, for use for reducing baseline total bilirubin in a subject having PBC by at least 5 % after at least 70 weeks, preferably after at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, of administration.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, for use for reducing baseline y-GT level in a subject having PBC by at least 25 % after at least 70 weeks, preferably after at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, of administration.

5. A pharmaceutical composition comprising a compound selected from 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 long-term reduction of fatigue in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.

6. A pharmaceutical composition comprising a compound selected from 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 long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.

7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein said pharmaceutical composition is administered for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the composition comprises elafibranor or a pharmaceutically acceptable salt thereof, preferably elafibranor.

9. The pharmaceutical composition for use according to any one of claims 1 to 8, 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.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein said composition is formulated in a form of a tablet.

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein said composition is administered once a day during at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.

12. The pharmaceutical composition for use according to any one of claims 1 to 11 , wherein the administration is oral.

13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the administration dose is of 80 mg or 120 mg per administration, preferably 80 mg per administration.

14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein elafibranor is orally administered once a day during at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, at a dose of 80 mg or 120 mg per administration.

15. The pharmaceutical composition for use according to any one of claims 1 to 14, the method comprising further administering to the subject having PBC another anti-cholestatic agent, preferably the other anti-cholestatic agent being ursodeoxycholic acid (LIDCA).

16. The pharmaceutical composition for use according to any one of claims 1 to 15, the method comprising orally administering once a day during at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, elafibranor at a dose of 80 mg per administration and ursodeoxycholic acid (LIDCA), to the subject having PBC.

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

18. 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 the long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, for at least 70 weeks.

19. 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 long-term reduction of fatigue in a subject having primary biliary cholangitis (PBC), for at least 70 weeks.

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 long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), for at least 70 weeks.

21. A method for long-term treatment of primary biliary cholangitis (PBC) in a subject havingPBC, comprising the administration of 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, in said subject, for at least 70 weeks.

22. A method for long-term reduction of fatigue in a subject having primary biliary cholangitis (PBC), comprising the administration of 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, in said subject, for at least 70 weeks.

23. A method for long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), comprising the administration of 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, in said subject, for at least 70 weeks.

Images