ELAFIBRANOR FOR THE TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS.

Abstract

The present invention relates to elafibranor or its active metabolite, for use in a method for the treatment of primary sclerosing cholangitis.

Description

ELAFIBRANOR FOR THE TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS TECHNICAL FIELD The present invention relates to the field of medicine, in particular to the treatment of primary sclerosing cholangitis. BACKGROUND Bile is a digestive fluid produced in the liver. It travels through the bile ducts to the gallbladder and small intestine, where it helps digest fats and fatty acids. Cholestasis is a condition resulting from impaired bile formation or flow in the gallbladder and duodenum (the first section of the small intestine). The effects of cholestasis are severe and widespread, leading to worsening liver disease and systemic illness, liver failure, and the need for liver transplantation. Cholestasis can be classified as intrahepatic or extrahepatic. Intrahepatic cholestasis primarily affects the bile canaliculi and intrahepatic bile ducts. Extrahepatic cholestasis affects the extrahepatic ducts, the common hepatic duct, or the common bile duct. Primary sclerosing cholangitis (PSC) is a chronic, or long-term, disease that slowly damages the extrahepatic and intrahepatic bile ducts. In patients with PSC, the bile ducts become blocked due to inflammation and deteriorate. This causes bile to accumulate in the liver, where it gradually damages hepatocytes and leads to cirrhosis, or liver damage. Many people with PSC will eventually need a liver transplant, usually about 10 years after they are diagnosed with the disease. Primary sclerosing cholangitis can also lead to bile duct cancer. Currently, there is no therapy that significantly reduces the risk of death or the need for a liver transplant, which remains the only solution for patient survival. SUMMARY OF THE INVENTION A clinical study has surprisingly shown that the treatment of PCS can be achieved with a daily oral dose of elafibranor, (2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid), between 30 and 70 mg / day. Therefore, according to a first aspect, the present invention relates to pharmaceutical forms suitable for the oral administration of 30 to 70 mg / day of a selected compound of elafibranor (ELA) and its active metabolite GFT1007, or of a pharmaceutically acceptable salt thereof, in particular 40 to 60 mg / day. The invention relates more particularly to a pharmaceutical composition suitable for the oral administration of a daily dose of between 30 and 70 mg of a compound selected from elafibranor and 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]3-oxo-propyl]phenoxy]-2-methylpropanoic acid, or of a pharmaceutically acceptable salt of said compound, wherein said pharmaceutical composition is a unit pharmaceutical form. In one particular embodiment, the invention relates to a pharmaceutical composition comprising between 30 and 70 mg of elafibranor or GFT1007, wherein said pharmaceutical composition is a unit dosage form suitable for oral administration. In another embodiment, the pharmaceutical composition comprises between 40 and 60 mg of elafibranor or GFT1007. In a further embodiment, the pharmaceutical composition comprises approximately 40 mg of elafibranor or GFT1007, such as 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg of elafibranor or GFT1007. In one particular embodiment, the pharmaceutical composition comprises 40 mg of elafibranor or GFT1007. In a further embodiment, the unit dosage form is selected from solid and liquid dosage forms, the unit dosage form being more particularly a lozenge, tablet, or capsule, such as a hard gelatin capsule. In one particular embodiment, the pharmaceutical composition is a tablet. In another particular embodiment, the pharmaceutical composition is a tablet comprising 40 mg of elafibranor or GFT1007. According to another aspect, the invention relates to a compound selected from elafibranor and 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxopropyl]phenoxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof, in particular elafibranor, for use in a method for treating primary sclerosing cholangitis (PSC), said method comprising orally administering elafibranor or GFT1007 at a dose of between 30 mg / day and 70 mg / day. In another aspect, the invention relates to a method for treating a subject with PSC, wherein said method comprises administering to said subject a dose of elafibranor or GFT1007 of between 30 and 70 mg / day. In one particular embodiment, the method comprises administering the pharmaceutical composition of the first aspect. In another particular embodiment, the method comprises the oral administration of a single unit dosage form comprising the dose of the compound, in particular elafibranor, to be administered, or of several unit dosage forms comprising a fraction of the daily dose to be administered. In one particular embodiment, the method comprises administering said compound, in particular elafibranor or a pharmaceutically acceptable salt thereof, more particularly elafibranor, at a dose of 40 mg / day. In one specific embodiment, the method comprises the oral administration of a tablet comprising 40 mg of elafibranor or GFT1007, once daily. DETAILED DESCRIPTION OF THE INVENTION The term treatment refers to any action intended to improve an individual's health status, such as therapy, prevention, prophylaxis, or delaying the progression of a disease in an individual who requires it. Treatment involves administering elafibranor to an individual with a diagnosed illness to prevent, cure, delay, reverse, or slow the progression of the disease, thereby improving the individual's condition. Treatment may also be administered to individuals who are healthy or at risk of developing primary sclerosis (PSC). The term subject refers to a mammal, preferably a human being. The subjects to be treated according to the invention may be appropriately selected based on various criteria associated with the pathological processes of PCOS, such as previous and / or current drug treatments, associated pathologies, genotype, exposure to risk factors, as well as any other relevant biomarker that can be assessed by any suitable immunological, biochemical, or enzymatic method. Illustrative methods for synthesizing elafibranor include those described in PCT applications WO2004 / 005233 and WO2005 / 005369. 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 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 or GFT1007 or a salt of elafibranor or GFT1007. A stereoisomer is an isomeric compound that has the same molecular formula and sequence of bonded atoms, but differs in the three-dimensional orientations of its atoms in space. Stereoisomers include enantiomers, diastereomers, cis-trans and EZ isomers, conformers, and tautomers. Pharmaceutically acceptable salts include salts of inorganic as well as organic acids.Counterions may be selected from the following non-exhaustive list: ammonia, L-arginine, benetamine, benzathine, tert-butylamine (erbumin), calcium hydroxide, choline hydroxide, deanol, diethanolamine (2,2'-aminobis(ethanol)), diethylamine, epolamine (1-(2-hydroxyethyl)pyrolidine), 2-(diethylamino)ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, meglumine (N-methylglucamine), 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2-nitrilo-thos(ethanol)), tromethamine, zinc hydroxide, in particular tromethamine, potassium, sodium, benetamine, benzathine, L-arginine, ethanolamine, meglumine, glycine, erbumin, L-lysine, epolamine, choline, preferably tromethamine, potassium, sodium, benetamine, benzathine, L-arginine, more preferably tromethamine, potassium, sodium, L-arginine, more particularly tromethamine. In particular embodiments, the invention relates to an ammonia salt, L-arginine, benetamine, benzathine, tert-butylamine (erbumin), calcium, choline, deanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, epolamine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, magnesium, meglumine (N-methylglucamine), 4-(2-hydroxyethyl)morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2-nithol-ths(ethanol)), tromethamine or zinc salt of elafibranor. In a further particular embodiment, the elafibranor salt is selected from a salt of tromethamine, potassium, sodium, L-arginine, benetamine, benzathine, ethanolamine, meglumine, glycine, erbumine, L-lysine, choline, epolamine, magnesium or bort? ιη / ζζηζ / Β / γίΛΐ elafibranor 2-amino-2-methyl-propan-1-ol. The pharmaceutical composition of the invention may comprise one or more excipients or vehicles acceptable within a pharmaceutical context (e.g., saline solutions, physiological solutions, isotonic solutions, etc., compatible with pharmaceutical use and well known to a person skilled in the art). These compositions may also comprise one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Useful agents or vehicles for these formulations (liquid, injectable, and / or solid) include, in particular, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, gum arabic, liposomes, etc. These compositions may be formulated in solid or liquid unit dosage forms for oral administration.In one particular embodiment, the pharmaceutical composition of the invention is a solid dosage form, such as a lozenge, tablet, or capsule (e.g., a hard gelatin capsule). In one particular embodiment, the pharmaceutical composition is a tablet or capsule, in particular a hard gelatin tablet or capsule, more particularly a tablet. In one embodiment, the pharmaceutical composition is suitable for the oral administration of between 30 mg / day and 70 mg / day of a selected compound of elafibranor, GFT1007 and a pharmaceutically acceptable salt of elafibranor or GFT1007 to a subject with CEP. In another embodiment, the pharmaceutical composition of the invention comprises between 30 and 70 mg of a compound selected from elafibranor, GFT1007 and a pharmaceutically acceptable salt of elafibranor or GFT1007, wherein said pharmaceutical composition is a unit dosage form suitable for administering between 30 and 70 mg / day of said compound to a subject with CEP. In another particular embodiment, the pharmaceutical composition of the invention is suitable for administration to a subject with CEP, said pharmaceutical composition comprising between 30 and 70 mg of a compound selected from elafibranor, GFT1007 and a pharmaceutically acceptable salt of elafibranor or GFT1007, wherein said pharmaceutical composition is a unit dosage form suitable for administering between 30 mg / day and 70 mg / day of said compound to a subject with CEP. The pharmaceutical composition of the invention is a unit dosage form suitable for oral administration of 30 to 70 mg / day of elafibranor, GFT1007, a pharmaceutically acceptable salt of elafibranor, or a pharmaceutically acceptable salt of GFT1007. More particularly, the pharmaceutical composition of the invention is a unit dosage form suitable for oral administration of 30 to 70 mg / day of elafibranor or GFT1007. For example, in one particular embodiment, a single unit dosage form comprises the daily dose of elafibranor or GFT1007 to be administered. An illustration of this embodiment includes a unit dosage form of elafibranor or GFT1007 comprising 40 mg of elafibranor or GFT1007, where the daily dose to be administered to the subject is 40 mg / day. In another embodiment, the pharmaceutical composition is a unit pharmaceutical form comprising a fraction of the daily dose of elafibranor or GFT1007.In this embodiment, the pharmaceutical composition can be administered several times a day and / or several units of the pharmaceutical composition can be used concomitantly to achieve the desired daily dose. An illustrative, non-limiting embodiment of said unit dosage form comprises 10 mg of elafibranor or GFT1007, meaning that to achieve a dose of 30 to 70 mg / day, 3 to 7 unit dosage forms must be administered daily. Representative unit dosage forms, such as tablets or capsules (particularly hard gelatin capsules) useful in the context of the present invention, include oral dosage forms comprising 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 mg of elafibranor or GFT1007. According to another aspect, the invention relates to elafibranor or GFT1007 for use in the treatment of primary sclerosing cholangitis (PSC), said method comprising administering elafibranor or GFT1007 orally at a dose of between 30 mg / day and 70 mg / day. In another aspect, the invention relates to a method for treating a subject with PSC, wherein said method comprises administering to said subject a dose of elafibranor or GFT1007 of between 30 and 70 mg / day. In one particular embodiment, the method comprises administering the pharmaceutical composition of the invention. In another particular embodiment, the method comprises the oral administration of a single unit dosage form comprising the daily dose of elafibranor or GFT1007 to be administered, or of several unit dosage forms comprising a fraction of the daily dose to be administered. In one specific embodiment, the method comprises the oral administration of a tablet comprising 40 mg or 60 mg of elafibranor or GFT1007, once daily. In a more specific embodiment, the method comprises the oral administration of a tablet comprising 40 mg of elafibranor or GFT1007, once daily. In another additional embodiment, elafibranor or GFT1007 is administered in the morning, more particularly under fasting conditions. In a preferred variant of all aspects and embodiments disclosed above, the compound of the invention is elafibranor or a pharmaceutically acceptable salt thereof. The invention is described below with reference to the following non-limiting examples. EXAMPLES Example 1: Clinical trial in CEP Patients with clinical PSC have elevated levels of alkaline phosphatase (ALP) and bilirubin. Several studies show that ALP can serve as a stratifier and possibly as an alternative endpoint for clinical trials in primary sclerosing cholangitis (De Vries, EMG et al., Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value. Liver International (2016) pp. 1478-3223). Some studies also highlight elevated bilirubin levels (Denau, MR et al., The Natural History of Primary Sclerosing Cholangitis in 781 Children: A Multicenter, International Collaboration. Hepatology (2017), vol. 66, no. 2 pp. 518-527). This clinical trial was conducted to evaluate the tolerability, safety, and reduction of various parameters, including alkaline phosphatase, of once-daily oral administration of elafibranor (ELA) in patients with primary cutaneous sclerosis (PSC). It was a phase I, single-center, double-blind, placebo-controlled, randomized, multiple-dose escalation study in healthy male volunteers. Doses of 40 mg or 60 mg once daily for 14 days were tested. Thirty Caucasian male volunteers aged between 19 and 40 years were included: 9 in each treatment group and 12 in the placebo group. The compound used was ELA, presented in hard gelatin capsules dosed at 10 mg. The dose per administration was 40 mg or 60 mg. Administration was repeated once a day, with oral administration around 8 am with 200 ml of tap water, in a seated position, under fasting conditions, from day 1 to day 14. The corresponding placebo was presented in the form of identical capsules. Bort? ιη / ζζηζ / Β / γίΛΐ Assessment of ALP levels Amount of ALP (in mg / day) 40 60 - Number of patients 9 9 12 ALP measurement Change on day 15 from baseline -8.3 -20.7 -7.6 Table 1. Alkaline Phosphatase Dosage Patients with CEP treated with both doses of elafibranor (40 mg and 60 mg) showed improved alkaline phosphatase levels compared to the placebo group. Bilirubin level assessment Amount of ELA (in mg / day) 40 60 - Number of patients 9 9 12 Total bilirubin measurement Change on day 15 from baseline -2.07 -2.46 -0.72 Table 2. Bilirubin Dosage Patients with PSC treated with both doses of elafibranor (40 mg and 60 mg) showed improved total bilirubin levels compared to the placebo group No significant adverse events were reported. Repeat administration of ELA at any of the administered doses was clinically well tolerated in healthy volunteers. The results are summarized in Tables 1 and 2. Alkaline phosphatase levels were assessed at baseline (day 1) and on day 15. The results show that, compared with placebo, both doses of elafibranor reduced mean ALP (Table 1). Furthermore, patients with primary sclerosis treated with both doses of elafibranor showed improved total bilirubin levels compared with the placebo group (Table 2). Previous and ongoing clinical trials evaluating the efficacy of elafibranor in various diseases, particularly non-alcoholic steatohepatitis or primary biliary cholangitis, were conducted with a daily dose of 80 mg or 120 mg. This paper shows that, surprisingly, elafibranor can be used at a lower dose to treat primary biliary cholangitis.

Claims

1. A pharmaceutical composition suitable for the oral administration of a daily dose of between 30 and 70 mg of a compound selected from elafibranor and 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt of said compound, wherein said pharmaceutical composition is a unit pharmaceutical form.

2. The pharmaceutical composition according to claim 1, suitable for administering between 40 and 60 mg of said compound.

3. The pharmaceutical composition according to claim 1 or 2, suitable for administering 40 mg of said compound.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein said unit pharmaceutical form is selected from solid pharmaceutical forms and liquid pharmaceutical forms.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein said unit pharmaceutical form is a tablet.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein said compound is elafibranor or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising elafibranor, for the administration of a daily dose of 40 mg of elafibranor to a subject in need.

8. A compound selected from elafibranor and 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of primary sclerosing cholangitis (PSC), said method comprising administering said compound orally at a dose between 30 mg / day and 70 mg / day.

9. The compound for use according to claim 8, said method comprising administering the pharmaceutical composition according to any one of claims 1 to 7.

10. The compound for use according to claim 7, said method comprising administering said compound at a dose of 40 mg / day.

11. The compound for use according to claim 10, wherein said compound is elafibranor or a pharmaceutically acceptable salt thereof.

12. The compound for use according to claim 10 or 11, wherein said compound is elafibranor.

13. The compound for use according to claim 8 or 9, said method comprising administering a pharmaceutical composition comprising between 30 and 70 mg of said compound, wherein said pharmaceutical composition is a unit pharmaceutical form suitable for oral administration.

14. The compound for use according to claim 13, wherein the pharmaceutical composition comprises between 40 and 60 mg of said compound.

15. The compound for use according to claim 13 or 14, wherein the pharmaceutical composition comprises 40 mg of said compound.

16. The compound for use according to any one of claims 13 to 15, wherein said unit pharmaceutical form is selected from solid pharmaceutical forms and liquid pharmaceutical forms.

17. The compound for use according to any one of claims 13 to 16, wherein said unit dosage form is a tablet.

18. The compound for use according to any one of claims 13 to 16, wherein said method comprises the oral administration of a tablet comprising 40 mg of said compound once a day.

19. The compound for use according to any one of claims 13 to 16, wherein said compound is elafibranor or a pharmaceutically acceptable salt thereof.

20. The compound for use according to any one of claims 13 to 19, wherein said compound is elafibranor.