Lanifibranor for use in the treatment of splanchnic vasodilatation in a patient with a liver condition

Abstract

The present invention relates to the use of Lranilanol, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for the treatment of visceral vasodilation in patients with liver conditions.

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I 11111 In 111011 10 1111 0110 1111 1 0 H 11111 11111 1111 11111 11111 HI 1111111111111111111 International Bureau (10) International Publication Number (43) International Publication Date WO 2024 / 251730 Al 12 December 2024 (12.12.2024) WI POI PC T (51) International Patent Classification: A61K 31 / 381 (2006.01) A61P 1 / 00 (2006.01) A61K 31 / 428 (2006.01) A61P 1 / 16 (2006.01) A61K 31 / 5415 (2006.01) (21) International Application Number: PCT / EP2024 / 065324 (22) International Filing Date: 04 hake 2024 (04.06.2024) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 23305892.4 05 June 2023 (05.06.2023) EP (71) Applicant: INVENTIVA [FR / FR]; 50 rue de Dijon, 21121 DAIX (FR). (72) Inventors: WETTSTEIN, Guillaume; 50 rue de Dijon, DAIX 21121 (l'R). JUNIEN, Jean-Louis; 122 Boulevard Haussmann, 75008 Paris (fa). LEFERE, Sander; Corneel Heymanslaan 10, 9000 Ghent (BE). HELDENS, Anneleen; Corneel Heymanslaan 10, 9000 Ghent (BE). GEERTS, An- ja; Corneel Heymanslaan 10, 9000 Ghent (BE). (74) Agent: CABINET BEAU DE LOMENIE; 158, me de l'U- niversite, 75340 Paris Cedex 07 (FR). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, KH, KN, KR KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, _ ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, CV, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, ER, HU, LE, IS, IT, LT, LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). O rn Published: - with international search report (Art. 21(3)) 11▪ 1 " (54) Title: LANIFIBRANOR FOR USE IN THE TREATMENT OF SPLANCHNIC VASODILATATION IN A PATIENT WITH A rl LIVER CONDITION C (57) Abstract: The present invention relates to the use of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for the treatment of splanchnic vasodilatation in a patient with a liver condition. WO 2024 / 251730 1 PCT / EP2024 / 065324 LANIFIBRANOR FOR USE IN THE TREATMENT OF SPLANCHNIC VASODILATATION IN A PATIENT WITH A LIVER CONDITION Field of the invention The present invention relates to a method of treating splanchnic vasodilatation in a patient 5 with a liver condition, which method comprises administering lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof to the patient. Background of the invention Liver condition such as cirrhosis, Acute Liver Failure (ALF) or Acute on Chronic Liver Failure (ACLF) are end-stage diseases arising from multiple different hepatic and extra- 10 hepatic acute and chronical injuries. These injuries primarily impair the liver functions but also have systemic complications leading to multiple organ failure. One common driver of these extra-hepatic complications and organ failure is the alteration of the systemic haemodynamics. This is characterized by a splanchnic vasodilation leading to the formation of portal-systemic collaterals and other systemic haemodynamic alterations 15 leading to reduced total peripheral resistance and systemic hypotension. In addition, in case of hepatic disease leading to portal hypertension an increase in spleen size due to increase venous pressure causing congestive splenomegaly is observed. Finally, the systemic hypotension is responsible for renal dysfunction (one of the causes of ascites) as well as increase cardiac output and hepatic encephalopathy. In conclusion, splanchnic 20 vasodilation leads to hyperdynamic circulation which will in turn contribute to the maintenance and aggravation of liver failure. It is consequently of importance when treating advanced liver disease to be able to target the splanchnic vasodilation on top of the intrahepatic resistance. From a clinical point of view, the hyperdynamic syndrome mainly caused by splanchnic vasodilation can be considered a prerequisite for the 25 development of the multi-organ failure. Treatments for splanchnic vasodilation are known in the art and include, but are not limited to liver transplantation, dialysis, insertion of a transjugular intrahepatic portosystemic shunt (TIPS) (to reduce blood pressure in the portal vein), hemodialysis, liver dialysis, intravenous albumin infusion, splanchnic vasoconstrictors (e.g. vasopressin, 30 midodrine, somatostatin, ornipressin, terlipressin), albumin-bound membrane dialysis (e.g. molecular adsorbents recirculation system (MARS)), pentoxyfylline, acetylcysteine, and misoprostol. Treatment is currently limited to palliative care, which merely delays the eventual need for liver transplantation. The only effective treatment of liver condition is transplantation. The use of such transplants, however, is limited due to donor shortages, 35 high cost, and the requirement for life-long immunosuppression. Thus, there is a clear WO 2024 / 251730 2 PCT / EP2024 / 065324 need for alternative treatments for the treatment of splanchnic vasodilatation, in particular in patient with a liver condition. Lanifibranor {441-(1,3-benzothiazol-6-ylsulfony1)-5-chloroindol-2-yl] butanoic acid; CAS 927961-18-0} is a pan-PPAR agonist which is currently in clinical development for the 5 treatment of patients with non-alcoholic steatohepatitis (NASH). US patent 11,504,380 discloses a method for preventing a cirrhotic subject at risk of progressing from compensated stage to decompensated stage, the method comprising administering lanifibranor to the subject. It has now been found that lanifibranor can exert a vasoconstrictor effect in the splanchnic 10 compartment in patients with a liver condition. In particular it has been found that administration of lanifibranor improves mesenteric blood flow, mesenteric wall thickness, and spleen weight in such patients as well as reducing the mesenteric vasculature expansion, leading to reduce splanchnic vasodilatation in patients with a liver condition. Summary of the invention 15 The present disclosure relates to lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, for use in the treatment of splanchnic vasodilatation in a patient with a liver condition. In some embodiments, the liver condition is cirrhosis, acute liver failure, acute-on-chronic liver failure, 20 hepatopulmonary syndrome, hepatorenal syndrome and hepatic encephalopathy. In some embodiments, the liver condition is cirrhosis, advantageously decompensated cirrhosis. The present disclosure also relates to a method of treating splanchnic vasodilatation in a patient with a liver condition. In particular, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with a liver condition, the method comprising 25 administering lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, or a pharmaceutical composition comprising lanifibranor or deuterated form thereof or a pharmaceutical salt thereof, to the patient. Description of the drawings Figure 1: Evaluation of the spleen weight in animals with Partial portal vein ligation 30 (PPVL) treated or not with lanifibranor at 10 and 30 mg / kg. Figure 2: Evaluation of the mesenteric vascular wall thickness in animals with Partial portal vein ligation (PPVL) treated or not with lanifibranor at 10 and 30 mg / kg (quantification and pictures of the mesenteric vasculature by µCT). Figure 3: Evaluation of the flow superior mesenteric artery in animals with Partial portal 35 vein ligation (PPVL) treated or not with lanifibranor at 10 and 30 mg / kg. WO 2024 / 251730 3 PCT / EP2024 / 065324 Figure 4: Evaluation of the vasculature system using an immunohistochemistry staining for CD34 that is expressed on capillarized blood vessels in animals with Partial portal vein ligation (PPVL) treated or not with lanifibranor at 10 and 30 mg / kg. Detailed description of the invention 5 As used herein, the articles including "a" and "an", are understood to mean one or more of what is claimed or described. As used herein the term "about xx" includes the value "xx". As used herein, the term "from xx to yy" includes the end points xx and yy. As used herein, the term "prevent", "prevention" or "prophylaxis" or "preventive treatment" 10 or "prophylactic treatment" includes a treatment leading to the prevention of a disease as well as a treatment reducing and / or delaying the incidence of a disease or the risk of the disease occurring. As used herein, the term "treatment" or "curative treatment" is defined as a treatment leading to a cure or a treatment which alleviates, improves and / or eliminates, reduces 15 and / or stabilizes the symptoms of a disease or the suffering that it causes. According to the present invention, the term "for use in the treatment of splanchnic vasodilatation in a patient" or "for use in the curative treatment of splanchnic vasodilatation in a patient" means that the product used has a direct effect on splanchnic vasculature, and notably improves mesenteric blood flow, mesenteric wall thickness, spleen weight, and reduces 20 mesenteric vasculature expansion. As used herein, the term "splanchnic vasodilatation" refers to a widening of the vasculature supplying the intestines, e.g. by relaxation of the smooth muscle cells lining the vasculature. Splanchnic vasodilation includes venous splanchnic vasodilatation and / or arterial splanchnic vasodilatation. 25 The embodiments described herein can be combined. The present disclosure relates to lanifibranor or a deuterated derivative thereof or a pharmaceutical salt thereof for use in the treatment of splanchnic vasodilatation in a patient with a liver condition. Lanifibranor {4-(1-(1,3-benzothiazol-6-ylsulfony1)-5-chloroindol-2-ylibutanoic acid; CAS 30 927961-18-0} is a pan-PPAR agonist. Lanifibranor is described in example 117 of WO 2007 / 026097, where it is obtained as a pale-yellow powder having a melting point of 74-80°C, and has the following structure: N R2 O> SI WO 2024 / 251730 4 PCT / EP2024 / 065324 CI HO In some embodiments, lanifibranor is in crystalline form. Examples of crystalline forms of lanifibranor are described in WO 2023 / 194339, WO 2023 / 016319, WO 2022 / 122014, WO 2022 / 261410 or WO 2022 / 258060, all incorporated herein by reference. 5 In some embodiments, lanifibranor can be a deuterated form of lanifibranor. In some embodiments, a deuterated form of lanifibranor is a compound of formula (I): O H R7 0 R6 R5 R4 CI (I) wherein at least one of the groups R1 to R7 is a deuterium (D) atom and the other groups R1 to R7 are hydrogen (H) atoms, as described in FR-A-3084254. In some aspects, at 10 least group R1 is D. In some aspects at least one of the groups R2 to R7 is D, notably at least one of the groups R2 and R3 and / or at least one of the groups R4 and R5 and / or at least one of the groups R6 and R7 is D. In a preferred aspect each of R2, R3, R4, R5, R6 and R7 is D. In some embodiments, a deuterated form of lanifibranor is 4-(1-(2-deuterio-1,3- 15 benzothiazol-6-yl)sulfonyl)-5-chloro-1 H-indol-2-yl)butanoic acid. In other embodiments a deuterated form of lanifibranor is 441 -(1,3-benzothiazol-6-ylsulfony1)-5-chloro-indol-2-y1]- 2,2,3,3,4,4-hexadeuteriobutanoic acid. In some embodiments, lanifibranor or a deuterated form thereof is in the form of one of its pharmaceutically acceptable salts or solvates. The term" solvate" is used herein to 20 describe a molecular complex comprising lanifibranor or a deuterated form thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The WO 2024 / 251730 5 PCT / EP2024 / 065324 term" hydrate" is employed when said solvent is water. Pharmaceutically acceptable salts of lanifibranor or a deuterated form thereof include base addition salts thereof. Base addition salts may be prepared from inorganic and organic bases. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium 5 hydroxide. Examples of organic bases include amines, amino alcohols, basic amino acids such as lysine or arginine, and quaternary ammonium compounds such as betaine or choline. The inventors have shown that lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof is particularly useful for treating splanchnic 10 vasodilatation in patients with a liver condition. Indeed, lanifibranor has been tested in a mouse model in which the animals are free from a liver disorder or condition, in particular the animals are not cirrhotic. In this model, the portal vein of the animals has been partially ligated. Partial ligation of the portal vein leads to vasoconstriction (increase in portal pressure) without however inducing cirrhosis. In turn, vasoconstriction leads to a 15 deterioration of splanchnic circulation. The model thus mimics conditions which can develop in patients with a liver condition, such as hepatic or extra-hepatic precipitating events. Administration of lanifibranor improved mesenteric blood flow, mesenteric wall thickness, spleen weight and reduced mesenteric vasculature expansion in mice. The used mice model is known to reflect prehepatic portal hypertension with splanchnic 20 vasodilatation, hyperdynamics circulation and portal systemic shunts without hepatic impairment. The obtained data demonstrated a direct effect of lanifibranor on the splanchnic vasculature that is not consequent to a hepatic improvement. It therefore results that lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof can exert curative effects, in particular a vasoconstrictor effect in the splanchnic vasculature, 25 in patients with a liver condition. In one embodiment the patient is a human. In another embodiment the patient is a non- human animal, e.g., a dog, cat, horse, cow, pig, sheep, goat or primate. In some embodiments, the liver condition is cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome and hepatic 30 encephalopathy. In some embodiments, the liver condition is cirrhosis. In some embodiments, cirrhosis is decompensated cirrhosis. As used herein, the term "Acute Liver Failure" (ALF) is defined as a syndrome of rapid decline in liver function characterized by jaundice, coagulopathy (INR>1.5) and hepatic encephalopathy in patients with no evidence of prior liver disease. Acute liver failure is a 35 further condition where it is thought that non-apoptotic forms of cell death play an WO 2024 / 251730 6 PCT / EP2024 / 065324 important role in disease progression and development, and thus present likely therapeutic targets. There are many causes of ALF including drug toxicity, drug overdose, paracetamol overdose, autoimmune hepatitis, viral hepatitis, Wilson's disease, etc. As used herein, the term "acute-on-chronic liver failure" (ACLF) refers to a distinct clinical 5 entity encompassing an acute deterioration of the liver function in patients with cirrhosis, often decompensated cirrhosis, which is usually associated with a precipitating event and results in the failure of one or more organs and high short-term mortality. Unregulated inflammation is thought to be a major contributing factor. A characteristic feature of ACLF is its rapid progression, the requirement for multiple organ supports and a high incidence 10 of short- and medium-term mortality of 50-90%. As used herein, the term "cirrhosis" includes cirrhosis caused by alcohol use disorder, such as early stage alcoholism, chronic alcoholism or end-stage alcoholism; cirrhosis caused by chronic viral hepatitis; cirrhosis caused by Non-Alcoholic Fatty Liver Disease (NAFLD), and / or Non-Alcoholic SteatoHepatitis (NASH), and / or metabolic-associated fatty 15 liver disease (MAFLD), and / or metabolic-associated steatohepatitis (MASH); cirrhosis caused by primary biliary cirrhosis and / or primary sclerosing cholangitis or even cirrhosis caused by medication. In some embodiments, cirrhosis is compensated cirrhosis or decompensated cirrhosis. In some embodiments, decompensated cirrhosis includes decompensated cirrhosis caused by alcohol use disorder, such as early stage alcoholism, 20 chronic alcoholism or end-stage alcoholism; decompensated cirrhosis caused by chronic viral hepatitis; decompensated cirrhosis caused by Non-Alcoholic Fatty Liver Disease (NAFLD), and / or Non-Alcoholic Steatohepatitis (NASH), and / or metabolic-associated fatty liver disease (MAFLD), and / or metabolic-associated steatohepatitis (MASH); decompensated cirrhosis caused by primary biliary cirrhosis and / or primary sclerosing 25 cholangitis or even decompensated cirrhosis caused by medication. As used herein, "hepatorenal syndrome" (HRS) refers to a condition characterized by deterioration of the kidney function in patients with a liver disease (e.g. cirrhosis, alcoholic hepatitis or fulminant liver failure). HRS typically occurs when the liver suffers an acute injury, e.g. infection, bleeding in the gastrointestinal tract, and / or overuse of diuretic 30 medications. Hepatorenal syndrome is characterized by congestion and blockage of intrahepatic microvasculature, causing portal hypertension. As used herein, the term "hepatitis" refers to hepatitis A, B or C. In some embodiments, the patient with a liver condition is already being treated for that condition. In some embodiments, the pre-existing treatment includes anti-diabetic agents, WO 2024 / 251730 PCT / EP2024 / 065324 non-selective beta blockers, statins, anti-microbial agents, vasoconstrictor agents, lactulose therapy, or rifaximin. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically effective amount of lanifibranor or a deuterated form 5 thereof or a pharmaceutical salt thereof for use in the treatment of splanchnic vasodilatation in a patient with a liver condition. Advantageously, the pharmaceutical composition of the present disclosure comprises a pharmaceutically effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients. In some 10 embodiments, the present disclosure relates to a pharmaceutical composition consisting of a pharmaceutically effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients. In some embodiments, lanifibranor (or a deuterated form thereof or a pharmaceutical salt thereof) is formulated into a pharmaceutical composition comprising 15 one or more pharmaceutically acceptable excipients. Advantageously, the pharmaceutical composition comprising a therapeutically effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof as an active ingredient is administered to a patient suffering from or suspected of suffering from splanchnic vasodilatation. According to embodiments that involve administering to a patient in need of treatment a 20 therapeutically effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, "therapeutically effective" or "an amount effective to treat" or "pharmaceutically effective" denotes the amount of lanifibranor, or a deuterated form thereof or a pharmaceutical salt thereof, or of a pharmaceutical composition needed to inhibit or reverse a disease condition (e.g., to treat vasodilatation splanchnic in a patient 25 with a liver condition). Determining a therapeutically effective amount specifically depends on such factors as toxicity and efficacy of the medicament. These factors will differ depending on other factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and preferred mode of administration. Toxicity may be determined using methods well known in the art. Efficacy may be determined utilizing the 30 same guidance. A pharmaceutically effective amount, therefore, is an amount that is deemed by the clinician to be toxicologically tolerable, yet efficacious. Dosage may be adjusted appropriately to achieve desired lanifibranor (or a deuterated form thereof) level, local or systemic, depending upon the mode of administration. In the event that the response in a patient is insufficient at such doses, even higher doses (or 35 effective higher doses by a different, more localized delivery route) may be employed to WO 2024 / 251730 8 PCT / EP2024 / 065324 the extent that patient tolerance permits. Multiple doses per day may also be employed to achieve appropriate systemic levels of lanifibranor or a pharmaceutically salt thereof. Appropriate systemic levels can be determined by, for example, measurement of the patient's peak or sustained plasma level of the drug. "Dose" and "dosage" are used 5 interchangeably herein. In some embodiments, lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof is administered at a dose of from about 5 mg to about 1,200 mg. Advantageously, lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof is administered at least at a dose of about 5 mg, at least at a dose of about 10 mg, at least at a dose of 10 about 15 mg, at least at a dose of about 20 mg, at least at a dose of about 25 mg, at least at a dose of about 30 mg, at least at a dose of about 35 mg, at least at a dose of about 40 mg, at least at a dose of about 45 mg, at least at a dose of about 50 mg, at least at a dose of about 55 mg, at least at a dose of about 60 mg, at least at a dose of about 65 mg, at least at a dose of about 70 mg, at least at a dose of about 75 mg, at least at a dose of 15 about 80 mg, at least at a dose of about 85 mg, at least at a dose of about 90 mg, at least at a dose of about 95 mg, at least at a dose of about 100 mg, at least at a dose of about 150 mg, at least at a dose of about 200 mg, at least at a dose of about 250 mg, at least at a dose of about 300 mg, at least at a dose of about 350 mg, at least at a dose of about 400 mg, at least at a dose of about 450 mg, at least at a dose of about 500 mg, at least at 20 a dose of about 550 mg, at least at a dose of about 600 mg, at least at a dose of about 650 mg, at least at a dose of about 700 mg, at least at a dose of about 750 mg, at least at a dose of about at a dose of about 800 mg, at least at a dose of about 850 mg, at least at a dose of about 900 mg, at least at a dose of about 950 mg, at least at a dose of about 1,000 mg, at least at a dose of about 1,050 mg, at least at a dose of about 1,100 mg, at 25 least at a dose of about 1,150 mg, or at a dose of about 1,200 mg. Lanifibranor (or a deuterated derivative thereof) can be administered once daily ("QD"), twice daily ("BID"), three time daily ("TID") or four times daily ("QID") provided the daily dose does not exceed the maximum amount indicated herein, i.e. about 1,200 mg. In some embodiments, lanifibranor (or a deuterated form thereof or a pharmaceutical salt thereof) is administered 30 to a subject with a meal. In some embodiments, lanifibranor (or a deuterated form thereof or a pharmaceutical salt thereof) is administered to a subject under fasted conditions. In some embodiments, lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof is administered at a daily dosage of from about 5 mg to about 1,200 mg. Advantageously, lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof 35 is administered at least at a daily dose of about 5 mg, at least at a daily dose of about 10 WO 2024 / 251730 9 PCT / EP2024 / 065324 mg, at least at a daily dose of about 15 mg, at least at a daily dose of about 20 mg, at least at a daily dose of about 25 mg, at least at a daily dose of about 30 mg, at least at a daily dose of about 35 mg, at least at a daily dose of about 40 mg, at least at a daily dose of about 45 mg, at least at a daily dose of about 50 mg, at least at a daily dose of about 55 5 mg, at least at a daily dose of about 60 mg, at least at a daily dose of about 65 mg, at least at a daily dose of about 70 mg, at least at a daily dose of about 75 mg, at least at a daily dose of about 80 mg, at least at a daily dose of about 85 mg, at least at a daily dose of about 90 mg, at least at a daily dose of about 95 mg, at least at a daily dose of about 100 mg, at least at a daily dose of about 150 mg, at least at a daily dose of about 200 mg, 10 at least at a daily dose of about 250 mg, at least at a daily dose of about 300 mg, at least at a daily dose of about 350 mg, at least at a daily dose of about 400 mg, at least at a daily dose of about 450 mg, at least at a daily dose of about 500 mg, at least at a daily dose of about 550 mg, at least at a daily dose of about 600 mg, at least at a daily dose of about 650 mg, at least at a daily dose of about 700 mg, at least at a daily dose of about 15 750 mg, at least at a daily dose of about at a daily dose of about 800 mg, at least at a daily dose of about 850 mg, at least at a daily dose of about 900 mg, at least at a daily dose of about 950 mg, at least at a daily dose of about 1,000 mg, at least at a daily dose of about 1,050 mg, at least at a daily dose of about 1,100 mg, at least at a daily dose of about 1,150 mg, or at a daily dose of about 1,200 mg. 20 In some embodiments, the compositions provided are employed for in vivo applications. Depending on the intended mode of administration in vivo the compositions used may be in a solid dosage form, a semi-solid dosage form or a liquid dosage form, the list being not limitative. In some embodiments, the pharmaceutical composition is a solid dosage form. Exemplary solid dosage forms include tablets, capsules, stick-packs, sachets, lozenges, 25 powders, pills, or granules. Preferred solid dosage forms include tablets, capsules and stick-packs, tablets being especially preferred. Advantageously, the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts. The compositions may also include, depending on the formulation desired, one or more pharmaceutically acceptable excipient(s). The choice of excipient(s) will to a large 30 extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions of the invention can be prepared by conventional methods, as described e.g. in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), incorporated herein by reference. WO 2024 / 251730 10 PCT / EP2024 / 065324 In some embodiments, the pharmaceutical composition comprises from 5 mg to 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. Exemplary pharmaceutical compositions comprise at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at 5 least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 10 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. Exemplary pharmaceutical compositions comprise 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, at 65mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 15 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, or 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. In any of the embodiments described above, lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof either per se or when present in a pharmaceutical 20 composition, can be in crystalline form. Administration during in vivo treatment may be by any routes, including oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal. The skilled artisan will recognize that the route of administration may vary depending on the disorder to be treated. Advantageously, lanifibranor or a deuterated form thereof or a 25 pharmaceutical acceptable salt thereof, or the pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof may be administered to a patient via oral, parenteral or topical route. In some embodiments, the pharmaceutical compositions comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof are administered by oral route. 30 In some embodiments, the pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof can further comprise a second active ingredient, such as empagliflozin, firsocostat, resmetirom, efruxifermin, belapectin, ocaliva, vasopressin, midodrine, somatostatin, ornipressin, terlipressin, pentoxyfylline, acetylcysteine, misoprostol, an anti-diabetic agent, a non-selective beta WO 2024 / 251730 11 PCT / EP2024 / 065324 blocker, a statin, an anti-microbial agent, a vasoconstrictor agent, lactulose therapy, rifaximin or any suitable ingredient being effective in the treatment of such diseases. Another aspect of the present disclosure relates to a method for the curative treatment of splanchnic vasodilatation in a patient with a liver condition, the method comprising 5 administering an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, or of a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, to the patient. According to the present disclosure, lanifibranor or a deuterated form thereof or a 10 pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof is particularly effective in treating a liver condition such as cirrhosis, acute liver failure, acute- on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, and hepatic encephalopathy. Advantageously, lanifibranor or a deuterated form thereof or a 15 pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof is particularly useful to treat splanchnic vasodilatation. In some embodiments, the present disclosure relates to a method for the curative treatment of splanchnic vasodilatation in a patient with a liver condition, wherein the liver 20 condition is chosen among cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome and hepatic encephalopathy, the method comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or 25 a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. In some embodiments, the present disclosure relates to a method for the curative treatment of splanchnic vasodilatation in a patient with a liver condition, wherein the liver condition is cirrhosis, in particular decompensated cirrhosis, comprising administering to 30 the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of Ianifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. WO 2024 / 251730 12 PCT / EP2024 / 065324 In case of curative treatment, dosage, the administration mode and formulation as defined above are applicable. Another aspect of the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with a liver condition, the method comprising administering 5 lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical salt thereof, to the patient. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. In some embodiments, the present disclosure relates to a method of or treating splanchnic 10 vasodilatation in a patient with a liver condition, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined 15 above. In some embodiments, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with acute liver failure, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount 20 of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. In some embodiments, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with acute-on-chronic liver failure, comprising administering to 25 the patient an effective amount ,of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. Embodiments disclosed in relation to the methods 30 described above also apply to this aspect of the disclosure. In some embodiments, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with an hepatopulmonary syndrome, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an 35 effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical WO 2024 / 251730 13 PCT / EP2024 / 065324 acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. In some embodiments, the present disclosure relates to a method of treating splanchnic 5 vasodilatation in a patient with an hepatorenal syndrome, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable 10 excipient(s) as defined above. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. In some embodiments, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with an hepatic encephalopathy, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a 15 pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. 20 In some embodiments, the present disclosure relates to a method of treating splanchnic vasodilatation in a patient with cirrhosis, comprising administering to the patient an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as 25 active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above. In some embodiments, cirrhosis is caused by alcohol use disorder, such as early stage alcoholism, chronic alcoholism or end-stage alcoholism; by chronic viral hepatitis; by Non Alcoholic Fatty Liver Disease (NAFLD) and / or Non Alcoholic SteatoHepatitis (NASH); by primary biliary cirrhosis and / or primary sclerosing cholangitis or even by 30 medication. In some embodiments, cirrhosis is compensated cirrhosis or decompensated cirrhosis. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. Another aspect of the present disclosure relates to the use of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as defined above in the 35 manufacture of a medicament for treating a liver condition, in particular for treating WO 2024 / 251730 14 PCT / EP2024 / 065324 cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome or hepatic encephalopathy. Another aspect of the present disclosure relates to the use of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as defined above in the 5 manufacture of a medicament for treating cirrhosis, in particular for treating decompensated cirrhosis. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. Another aspect of the present disclosure relates to the use of an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, as 10 defined above, in the manufacture of a medicament for treating a liver condition, in particular for treating cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. Another aspect of the present disclosure relates to the use of an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, as defined above, 15 in the manufacture of a medicament for treating cirrhosis, in particular for treating decompensated cirrhosis. Embodiments disclosed in relation to the methods described above also apply to this aspect of the disclosure. Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or 20 a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above in the manufacture of a medicament for treating a liver condition, in particular for treating cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome or hepatic encephalopathy. Another aspect of the present disclosure relates to the use of 25 a pharmaceutical composition comprising an effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof as active ingredient and one or more pharmaceutically acceptable excipient(s) as defined above in the manufacture of a medicament for treating cirrhosis, in particular for treating decompensated cirrhosis. Embodiments disclosed in relation to the methods described 30 above also apply to this aspect of the disclosure. *** Aspects of the present disclosure are further illustrated by reference to the following, non- limiting embodiments. 1. A method of treating splanchnic vasodilatation in a patient with a liver condition, the 35 method comprising administering lanifibranor or a deuterated form thereof or a WO 2024 / 251730 15 PCT / EP2024 / 065324 pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, to the patient. 2. A method of treating splanchnic vasodilatation in a patient with a liver condition 5 according to item 1, wherein the liver condition is cirrhosis, acute liver failure, acute-on- chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome or hepatic encephalopathy. 3. A method of treating splanchnic vasodilatation in a patient with a liver condition according to item 2, wherein the liver condition is cirrhosis, in particular decompensated 10 cirrhosis. 4. A method of treating splanchnic vasodilatation in a patient with a liver condition according to any of items 1 to 3, wherein the administration of lanifibranor, a deuterated form thereof or a pharmaceutical acceptable salt thereof, or of a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical 15 acceptable salt thereof, improves mesenteric blood flow, mesenteric wall thickness and / or spleen weight in the patient. 5. A method of treating splanchnic vasodilatation in a patient with a liver condition according to any of items 1 to 4, wherein lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof is administered at a daily dose of from about 5 mg 20 to about 1,200 mg. 6. A method of treating splanchnic vasodilatation in a patient with a liver condition according to any of items 1 to 5, wherein the pharmaceutical composition is a solid dosage form. 7. A method of treating splanchnic vasodilatation in a patient with a liver condition 25 according to any of items 1 to 6, wherein the solid dosage form is a tablet, a capsule or a stick-pack. 8. A method of treating splanchnic vasodilatation in a patient with a liver condition according to any of items 1 to 7, wherein the pharmaceutical composition comprises from 5 mg to 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical 30 acceptable salt thereof. 9. A method of treating splanchnic vasodilatation in a patient with a liver condition according to any of items 1 to 8, wherein the pharmaceutical composition comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 35 mg, at least 65mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least WO 2024 / 251730 16 PCT / EP2024 / 065324 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 5 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. 10. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis, the method comprising administering lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising 10 lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, to the patient. 11. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to item 10, wherein the administration of lanifibranor, a deuterated form thereof or a pharmaceutical acceptable salt thereof, or of a pharmaceutical 15 composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, improves mesenteric blood flow, mesenteric wall thickness and / or spleen weight in the patient. 12. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to any of items 10 to 11, wherein lanifibranor or a deuterated form 20 thereof or a pharmaceutical acceptable salt thereof is administered at a daily dose of from about 5 mg to about 1,200 mg. 13. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to any of items 10 to 12, wherein the pharmaceutical composition is a solid dosage form. 25 14. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to any of items 10 to 13, wherein the solid dosage form is a tablet, a capsule or a stick-pack. 15. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to any of items 10 to 14, wherein the pharmaceutical composition 30 comprises from 5 mg to 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. 16. A method of treating splanchnic vasodilatation in a patient with decompensated cirrhosis according to any of items 10 to 15, wherein the pharmaceutical composition comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at 35 least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, WO 2024 / 251730 17 PCT / EP2024 / 065324 at least 60 mg, at least 65mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 5 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. The invention is illustrated by the following example. Example 10 Materials and methods Experiments were carried out using Swiss mice (7 to 10 animals per groups). Portal hypertension was induced using the partial portal vein ligation (PPVL) model. A midline abdominal incision was performed and the portal vein was separated from the surrounding tissue. A ligature (silk cut 5-0) was tied around both portal vein and adjacent 27-gauge 15 blunt-tipped needle. Subsequent removal of the needle yielded a calibrated stenosis of the portal vein. One week after the ligation mice received daily lanifibranor (10 mg / kg or 30 mg / kg) or vehicle in a therapeutic setting for 7 days. The effect of lanifibranor on angiogenesis was evaluated by analyzing hepatic and systemic hemodynamics, serum, hepatic and mesenteric histology. The vascular corrosion casting is a technic allowing the 20 capture of the 3D structure of the vascular bed. Briefly the vascular corrosion casts were obtained by inserting, after euthanasia, a 26-gauge catheter into the ileocolic vein, which was then perfused with Batson n°17 solution. The soft tissue was dissolved overnight in a 25% potassium hydroxide solution. The vascular corrosion casts of the venous mesenteric vasculature were analyzed using µCT. 25 Results Hemodynamic parameters Mice with PPVL demonstrated a significant and high increase in portal pressure in comparison to control animals (from 4.34 for control to 10.85 mmHg for PPVL mice). Mice with PPVL also demonstrated a significant increase in flow superior mesenteric artery that 30 was reduced by lanifibranor treatment at 30mg / kg (reduction of 51.7%), as can be seen from figure 3. Spleen weight The spleen weight was significantly increased in mice with PPVL in comparison to control animals (from 0.38% body weight for control to 0.63% body weight for PPVL mice) due to 35 the presence of portal hypertension. As can be seen from figure 1, lanifibranor dose- WO 2024 / 251730 18 PCT / EP2024 / 065324 dependently reduced spleen weight by 23.7% (0.57% body weight at 10 mg / kg) and 56.1% (0.49% body weight at 30 mg / kg), demonstrating the improvement of mesenteric vasculature. Corrosion vascular casting 5 Evaluation by µCT of the vasculature showed an expansion of the venous mesenteric vasculature and increased mesenteric vascular wall thickness in mice with PPVL in comparison to control mice (from 20.31 µM for control to 37.53 OA for PPVL mice). As can be seen from figure 2, mesenteric vascular wall thickness was reduced by lanifibranor either at 10 mg / kg (28.95 µM, 49.8% reduction) or at 30 mg / kg (28.53µM, 52.3% 10 reduction). Expansion of the venous mesenteric vasculature was also reduced (data not shown). Angiogenesis and vascular expansion Evaluation of the vasculature system with an immunohistochemistry staining for CD34 allow to highlight the increase of blood vessels in the mesenteric area in PPVL animals. 15 This reflect angiogenesis in this area due to increase mesenteric blood flow and portal pressure. This strength the data observed with the corrosion vascular casting showing an increase in the venous mesenteric vasculature. As observed with the corrosion casting technic the staining for CD34 significantly decreased in a dose dependent manner upon lanifibranor treatment (69.5% and 135.8% of reduction at 10 and 30mg / kg of lanifibranor 20 respectively) demonstrating the direct inhibition of angiogenesis and vascular expansion (figure 4). 0 CI WO 2024 / 251730 19 PCT / EP2024 / 065324 Claims 1. Lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use in the treatment of splanchnic vasodilatation in a patient with a liver 5 condition. 2. Lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use of claim 1, wherein the liver condition is cirrhosis, acute liver failure, acute- on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic 10 encephalopathy. 3. Lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use of any one of claims 1 to 2, wherein the liver condition is cirrhosis, in particular decompensated cirrhosis. 4. Lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use of any one of claims 1 to 3, wherein lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof is administered at a daily dose of from about 5 mg to about 1,200 mg. 5. Lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use according to any one of claims 1 to 4, wherein the deuterated form of lanifibranor is a compound of formula (I): OH (I) 25 wherein at least one of the groups R, to R7 is a deuterium (D) atom and the other groups R1 to R7 are hydrogen (H) atoms. 15 20 WO 2024 / 251730 20 PCT / EP2024 / 065324 6. A pharmaceutical composition comprising a pharmaceutically effective amount of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof for use in the treatment of splanchnic vasodilatation in a patient with a liver condition. 5 7. The pharmaceutical composition for use of claim 6, wherein the pharmaceutical composition is a solid dosage form, a semi-solid dosage form or a liquid dosage form, advantageously a solid dosage form. 8. The pharmaceutical composition for use of any one of claims 6 to 7, wherein the 10 solid dosage form is a tablet, a capsule, a stick-pack, a sachet, a lozenge, a powder, a pill or a granule, advantageously a tablet, a capsule or a stick-pack. 9. The pharmaceutical composition for use of any one of claims 6 to 8, wherein the pharmaceutical composition comprises from 5 mg to 1,200 mg of lanifibranor or a 15 deuterated form thereof or a pharmaceutical acceptable salt thereof. 10. The pharmaceutical composition for use of claim 9, wherein the pharmaceutical composition comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, 20 at least 55 mg, at least 60 mg, at least 65mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at 25 least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof. 11. The pharmaceutical composition for use of any one of claims 6 to 10, wherein the pharmaceutical composition is administered via oral, parenteral or topical route. 30 12. A method of treating splanchnic vasodilatation in a patient with a liver condition, the method comprising administering lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition comprising lanifibranor or a deuterated form thereof or a pharmaceutical acceptable salt thereof, to 35 the patient. WO 2024 / 251730 21 PCT / EP2024 / 065324 13. The method of claim 12, wherein the liver condition is cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome or hepatic encephalopathy. 5 14. The method of claim 13, wherein the liver condition is cirrhosis, in particular decompensated cirrhosis. 15. The method of any one of claim 12 to claim 14, wherein lanifibranor or a 10 deuterated form thereof or a pharmaceutical acceptable salt thereof is administered at a daily dose of from about 5 mg to about 1,200 mg. 16. The method of any of claims 12 to 15, wherein the pharmaceutical composition is a solid dosage form. 15 17. The method of claim 16, wherein the solid dosage form is a tablet, a capsule or a stick-pack. * ** 1.0 0.8 — (-35 3 3 0.6 — c 1:3 a) O. _0 0 0 0.4 — 0.2 — 0.0 S ha m + ve hi c ul e PP V L + v eh ic u le P P V L + la n i fi br an or 1 / 4 Fig.1 WO 2024 / 251730 PCT / EP2024 / 065324 V as cu la r w a l l th ic kn es s (p m ) 40 — 20 — 30 — 50 — 10 — 0 S ha m + v eh ic u le * * * * PP V L + v eh ic u le P P V L + la n if ib ra no r CA O P P V L + la n if ib ra n o r 0) E cp WO 2024 / 251730 PCT / EP2024 / 065324 214 * * Fig.2 P P V L + la n ifi b r a no r P P V L + ve h i cu le S ha m + v e h ic ul e WO 2024 / 251730 PCT / EP2024 / 065324 3 / 4 *** 0.07 2.5 2.0 1.5 1.0 0.5 0.0 F lo w S M A (m l / m in ) cn ... 0) E cp co Fig.3 20 - 40 - 0 S ha m + ve hi cu le eve tiff N. 0) E O O Et2 E _c U) P P V L + ve hi cu WO 2024 / 251730 PCT / EP2024 / 065324 4 / 4 CD34 IHC mesenteric **** * * 60 - cY 0 C D 3 4 ar ea Fig.4 IN 1- hliNA I 1(,)NAL btAlit.:1-1 Htl"Uti I International application No PCT / EP2024 / 065324 A. CLASSIFICATION OF SUBJECT MATTER INV. A61K31 / 381 A61K31 / 428 A61K31 / 5415 A61P1 / 00 A61P1 / 16 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal, WPI Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X X US 2021 / 137937 Al (WETTSTEIN GUILLAUME (FR] ET AL) 13 May 2021 (2021-05-13) cited in the application paragraph

[0064] ; claims FELLI ERIC ET AL: "Emerging Therapeutic Targets for Portal Hypertension", CURRENT HEPATOLOGY REPORTS vol. 22, no. 1 11 February 2023 (2023-02-11), pages 51-66, XP093085589, DOI: 10.1007 / s11901-023-00598-4 Retrieved from the Internet: URL:https: / / link.springer.com / article / 10.1 007 / s11901-023-00598-4 / fulltext.html page 56; table 1 1-17 1-17 documents are listed in the continuation of Box C. annex. Further r; See patent family ' Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered to be of particular relevance the principle or theory underlying the invention "E' earlier application or patent but published on or after the international "X" document of particular relevance;; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance;; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "0" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 7 August 2024 23 / 08 / 2024 Name and mailing address of the ISA / European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Authorized officer Zimmer, Barbara Form PCT / ISA / 210 (second sheet) (April 2005) page 1 of 3 INTERNATIONAL SEARCH lit} Ull I International application No PCT / EP2024 / 065324 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category` Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X A A A BOYER-DIAZ ZOE ET AL: "Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease", JOURNAL OF HEPATOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 74, no. 5, 2 December 2020 (2020-12-02), pages 1188-1199, XP086539001, ISSN: 0168-8278, DOI: 10.1016 / J.JHEP.2020.11.045 [retrieved on 2020-12-02] page 1188 page 1191, left-hand column BURRA PATRIZIA ET AL: "From the Editor's Desk", JOURNAL OF HEPATOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 73, no. 4, 15 September 2020 (2020-09-15), pages 745-748, XP086258592, ISSN: 0168-8278, DOI: 10.1016 / J.JHEP.2020.07.011 [retrieved on 2020-09-15] page 746 TSAI HUNG-CHENG ET AL: "Beneficial Effects of the Peroxisome Proliferator-Activated Receptor [alpha] / [gamma] Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension", THE AMERICAN JOURNAL OF PATHOLOGY, vol. 188, no. 7, 1 July 2018 (2018-07-01), pages 1608-1624, XP093040308, US ISSN: 0002-9440, DOI: 10.1016 / j.ajpath.2018.03.018 page 1608 GUPTA MONIKA ET AL: "Deuteration as a Tool for Optimization of Metabolic • Stability and Toxicity of Drugs", GLOBAL JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES vol. 1, no. 4 27 March 2017 (2017-03-27), XP055860642, DOI: 10.19080 / GJPPS.2017.01.555566 Retrieved from the Internet: URL:https: / / juniperpublishers.com / gjpps / pd f / GJPPS.MS.ID.555566.pdf page 1 - / -- 1-17 1-17 1-17 1-17 Form PCT / ISA / 210 (continuation of second sheet) (April 2005) page 2 of 3 INTERNATIONAL bhAHL:1-1 KtFUM I International application No PCT / EP2024 / 065324 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A A WO 2020 / 021215 Al (INVENTIVA [FR]) 30 January 2020 (2020- 01- 30) claims MARTELL MARIA ET AL: "Physiopathology of splanchnic vasodilation in portal hypertension", WORLD JOURNAL OF HEPATOLOGY vol. 2, no. 6 27 June 2010 (2010-06-27), page 208, XP093087896, ISSN: 1948-5182, DOI: 10.4254 / wjh.v2.16.208 Retrieved from the Internet: URL:https: / / www.ncbi.nlm.nih.gov / pmc / artic les / PMC2999290 / pdf / WJH-2-208.pdf page 208 1-17 1-17 Form PCTASA / 210 (continuation of second sheet) (April 2005) page 3 of 3 INTERNATIONAL SEARCH REPORT Information on patent family members International application No PCT / EP2024 / 065324 Publication date Patent family member(s) US 2021137937 Al 13-05-2021 NONE WO 2020021215 Al 30-01-2020 CN 112638911 A 09-04-2021 DK 3830085 T3 22-01-2024 EP 3830085 Al 09-06-2021 EP 4331584 Al 06-03-2024 ES 2970597 T3 29-05-2024 FI 3830085 T3 17-01-2024 FR 3084254 Al 31-01-2020 HR P20240157 Ti 12-04-2024 HU E065045 T2 28-04-2024 JP 7434278 B2 20-02-2024 JP 2021533101 A 02-12-2021 JP 2024036611 A 15-03-2024 LT 3830085 T 12-02-2024 PL 3830085 T3 15-04-2024 PT 3830085 T 24-01-2024 RS 65095 Bl 29-02-2024 SI 3830085 Ti 29-03-2024 US 2021300913 Al 30-09-2021 WO 2020021215 Al 30-01-2020 Patent document cited in search report Publication date Form PCT / ISA / 210 (patent family annex) (April 2005) 12 16 04 9 6 2 A (19) C11-1.1=btRA (10) 00ift&31F-q CN 121604962 A (43) 9 2026.03.03 (21)00144;2 202480050342.6 (22) Ha of 9 2024.06.04 (30)1)M tAtiz lia 23305892.4 2023.06.05 EP (85)PCTEinEtaiWillADVOSI. 2026.01.30 (86) PCTI=111;t149 IA EH MIME pcT / Ep2024 / 1365324 2024.06.04 (87) Pc-rElnE19 w02024 / 251730 EN 2024.12.12 (71) Ei9MA ithith (72) &HA A tEAM • *MOT ii--ig)th • ILM 4k,f,r-V.r< • tr* / . / F Vgla# • ;IVF:-3.-Iti • 1•1%.r<-7 3 (74) -V fill-U.-ICA lEJ4-1A-V71()M-IRctIfUT 11290 iff-taffi T / J\S tBM4..4 (51)Int.01. A61K 31 / 381(2006.01) A61K 31 / 428(2006.01) A61K W54 / 5(2006.01) A61P 1 / 00(2006.01) A61P 1 / 16(2006.01) *-0[1 .4Z-142X iAHMIT PflIE14T (54) AHA lin ME-K FYJ (57) AR CN 121604962 A ft] 133 1 / 2 1 TAIII1FIVA-gt Ill nti tt-MCIn )11 it '7f=1P It÷51AZttif-11-1, 4-1-- ±Tiff-kg:FMA 2. tHIEVfil * 1 Pfi.A. -T-wi,t)En riismuti 51,H, g4-4-± A ,11 r1=1 Pfi±FJY±Arftll-fait .;P_,sit-ATAA t .11T11% -d Art:AM. 3 *1-2 It' 11--T-ff±n p]-f-Pfi±)EHistrnt)t±t- t-gd V: Pi* JE1,- 1=1 ,P.RIHKATIYA-TR'Iti 4. tRIEWIJ - 31 1ff —mwitni=fiTFRitlillitItt1tif."1451r:VCA-Uf -t / at re-44- , 4±171j Sting. ._435mg.- .4_4j1,200mg itlt?-ti To 5. fEii}gtV1 5 *1-4 11:111-1-ff±nPIT-wi2triil E i pk11-W-UM51 *- ±r -4kni*,-,1E1:*,f-AltL-i-g-nti-utt (I) nit* OH R7 0 CI (I) 11 rti ,14-111R1 R74 in (D) „T,! J=1, fth-KlaiRIIIR7YA (H) 6. PIT [fri ttf PfiAilitt€1.*ttO, i'ari),J*-±AVEYJEL)ILL:i&li=1, 7 fRiEtVli A6PfiAn TH -f-w±pl tt 1:111 , PutfiCA--Itt MAORI .*PlizRAI.M.diA iti5j3P12101171.0 8 tRfiJ * 6 - FiThil ±wi?Efilitnvittta , kis*,Ffiii-qf2101.111 Yv -11.1.RAlf1 .-8M-1.1.:1AVRI.t.01.1.40.1.kAIMMCYFI , 9 . VIEW-1_1 V 6 811:1 ±WiztJt , , fr't'A-5mglY.1,200mgnItfit' L-i.fd,1=1,%-um5i,H, gid4_± TIT&54.[Iisjge 10 .fRtigtRf1.1 >R9Pfilinfil -T- Wiz_RfIli‘t c.pit , ,lah Jcot _ / ...1)5mg,I / .1.110mg,_1:15mg,I:ji20mg,YZ1 25mg, -g / P30mg,135mg,40mg,1_<.12 - _ / ..1)90mg,Y / ..1295mg ,_,.%12100mg,:ji150mg,!Ii200mg,Y.%1 250mg, --Y / P300mg,%1) 350mg,..1 400mg,Vi450mg,YZ.))500mg,Y / j)550mg, # .1)600mg, / .1)650mg,YZP700mg, # ..1 850mg,:ii900mg,YZ.1)950mg,1%.121,000mg,V)1,050mg,Y. ..1;1,150mg, ,200mgintijt,L-11:4141,rktFikl,;544-±Tql 'tk-9:n,to 11 tElgtRf.1_1 >R6 10 rrl —mwA.rn m1Jti=4*.t , , *WEI Nit.a 12. noiri rin -61M' nip ,PRA.Ju 2 CN 121604962 A fiJ .14 2 / 2 itLf_ti-Ad Vv-t3f -tpl,w, Tit -&--,3-Angnvittffi* 13. f-RfEtRfq *12Pfirr,J)Jit , J=1, , , _RA :Mt FAA ,1J+JI-03--,*d , FIR g;-T-t-,-- / (15111Tt 14. tRfigtRfli *13fiArrsJ , 11 , , t4 1.1t T AAFR 15. tiqiEVf1 * 12 — 14 11—mRiztinbit-,r: , , 200Ingn H 16 tRigtRfi1 V *12-151411 if , 1.41, 17. tRtgtRfE1 *10filtniu , It* , 3 CN 121604962 A IA FYI 1 / 11 f. _t-ti-S- J41 -51±WitITIA:Al#..4141tn nit[EVIT tKil'gft] tovsiia

[0001] 4.-t FIA-ia—friliemi-fog#_,1 J rfn rWKin (lani f i!Dranor) 55;34 i4. 71t

[0002] JfJ (Mil)iTRI-L,P,J111--.-5,14 (ALF) 5,k / If_Ylt.dtF-A-14 (AcLF)) VEtiT itThM- oiV,q51.•Tat , I A-*f±tf• V±T, *it it 'Aft)]* o-k_ J.'4EA-± JrtifriltM , 'Ys3f] -11- 41)1,1a1TW (portal-systemic col laterals) nffb--Mt1J-tf-t*tt k-,-4JtA*-5no3u_k_, 9-'R,1837HM1314)-il3kafFiAtterin .1E01, , r1IJ171(A-1-1h1:6?,-F , FLIT-011*E)] TI I rfn ft.lPt]rI3X , *-NOMJI*JittMAIX. , A-tteririi±±91tRTtfilMW 71(imuLt --)1),(Ezt, 4YtiVi Ar- ttlffit,f,R- -,- 313Kaft11-T-k-V-4W-Y-(±11)NE.111thE,A•jillrylitaiTIAOH-1- ,RTATIVEIJA,,ALVE L',-"(Ei=1109t1,YvAPT-I)Jht-*--At AA7-1,--ft-

[0003] i-- sfiniiirfriNEMifiNfr-T144±41=11EFin , =sA fli<JF it] n 3.A-A (TIPS) in IN X (1),13kiE f TAN* in E) rfn AMR . JF-EAffi ftE 'MIME / 4 finta „) g trti*Thlaffi (Mr13.3` 4)R13f1A-V6TFAM (MARS)) EfIVI701. Z P *at- PPfn **11101.10-. [Y,J ifik1113ZIRTILIM ,14.1R•IRICEYIJI-T-fMnA4FTE*.Firfo-wrgit Wi'Voff , EITT-VtiAtIA.*J1MA- P,a'A'VP,'M'tMr-M-1.1,,tow_ain 1:_\1f4Ye_Yilia J. Mft , Fin "64M-KrnWsY , Vftri& , M1 1 7:±1JT-liricig

[0004] ti-dtLig {4 -[1 - (1 , 3 '4- )1 PS - 6 -41-a If 4) - 5 - riAt [ig- - 2 - 41 TAP ; CAS 927961-18-01 kl —frliPPARitr4A11, Fin 0-k± 6.-Tt-iriglitAhEttjH(c (NAst-),tin fiJ11,504,3801LTT —#J11-fRIMf.61f-Efti4A- Tg-tit-ItAAR t*-Mt-ItArnxg-nb ,Mfr h7 ri`=i5ti-4Vti #1J L: Z.

[0005] al E , it1111±E rfn WLIWalifTH.t4VIAE AgE, -T -14. -*& M.Ak fl4rfn tsgAtil-K , J)k sitl.MI-MA-g,T.Z tiriVilitrfn NE

[0006] 4„ / L-)1 '-tfft5,U4-il,5)1i* .5;A illtz.1 1 ±4.igiid=1,tvft h-4 PfilififfiM 'at JEITRI-E . 4 CN 121604962 A 2 / 11 Ft-AM , ititt

[0007] )1 1Eita--;•-tqftqlF-AilikiltA. rm milt] trlf51VJ 4- Ez.---#1q8MIT-11,Mg,tin Kifilj-NE- n)-J , Vvf-U- t5-1 -t1.5)MA . t JA, --Afflgrlig ibiz*BA-to 131,1111% IV]

[0008] M 1 : R:4-110mg / kgfF130mg / kg#11tit-tigtTIA*•3711In 1'70)17M-it (PPVL)

[0009] Ei2:7- 1,10mg / kgfil30mg / kgri.,:t__Lig-tql3j4, kijint9,33u`1-10-agm(ppvort we.NgtniTit (itiLtucul-Efllifn gAiR-Itt-ILiffif5aft)

[0010] F 13: ..0.10mg / kgfuonig / kgE.- / .-_t-ig9,EqdkfTri<J01337`IIiilifJ171(tiit (PPVL) ttnIMJII±E)A71( [in AniT-G.

[0011] IN 4: cp 34 Ye. tfl, t5(710.10mg / kgf1130mg / kgtAjf,t_-`_intjTITT. nri[3]1'14-1iff171(nL (PPVL) f-Et Aftv-gZatTt )PRIS8ffi [1`7 , YLI-14N-t "a" fra "an" , ,±iVri0J-5,1pfi r fgml-v-Ei Lm Ip $4.pfiltgin,A-ifilixx-'WMP."xx" Y Y" 1=iAs.X.PRISt FY] , "NM." "M..LE" "1-)"" .R1 "NM-'h *T41" d "M. tPt rr--"wt-4-:aireimrr,y6r-faawurvgupt&-A-& -+,31)m-tt)54,kinierr--.

[0016] zi:14.-SOfittftln,ii -if, "i61-7" (W,I;Vt.Wr." f11 / 5-TiR.ifilifri / ,Aftl&472-1kidEtA-4-YA[1,Tirt-E ntr-r ‘ifiq-,ELItiin rin ttEKEY,])'Hit-"d ")EH±W-Azitiflif*V=1 n rfn iggEKEY]fflik" / NPR ftfl %-4-A AtVr ,r-t4P,1 1A03k,tHibtfriA.ENJIMNEt.P Jiragaagmmaite- Anto

[0017] .Pf:1 / 4_5(.fifif5VA "It] jrflf[114WK (splanchnic vasodi 1 atat ion) ''RfgrAg2-. rfri , fOniffid rfn nTAL1111,01'NklisJeLAYA it] It rfri ME-Mttiti Ogil(rin tM'

[0018] 4-S(WitnjaVJ [11),k iIrttfLfì

[0019] *.lz)16RIIIT- i6Irl-flitiAPA. itnt-A)-±-t-I.M1=1% -tVE17-1*.

[0020] fs-LYELL-i-t- {4 - [1 - (1 , 3 - -Xl( 6 A) -5- nglii2ic 2 --41 -Ilk; CAS 927961-18-01R—fria-PPARtftPjoil. -HifAWO 2007 / 026097 rj<A-,YMM117r1=141-pfiM , Ar3t-sERWRI14nt-1.1f,L1- -14-VirTP.74*c - 80 0C in& Y1 -OA*, 31 -A--A #zil-Ftrit : 5

[0012]

[0013]

[0014]

[0015] CN 121604962 A 3 / 11 T, CI

[0021] HO

[0022] rf.---13-',.1J -414:1,ti.)t -L1.--- -Viik -TRIEBoti.)t-t-1-.i4rfAirEt)Ttn'3-01.1?Iwo 2023 / 194339,WO 2023 / 016319,WO 2022 / 12201450 2022 / 261410gkWO 2022 / 258060*A I iERrivJ

[0023] ,(±--il-'Ps-%h , PLi 1511%,( rsyr-v-ty - tri=1,EL fEttiam-tytt (I) f-Et-'0: OH

[0024] (I)

[0025] J , oFR -A- 3084254Pat , , R7 (H) 1,-LIIR2RR3rornY_ --iN.fr1 / 51UPIIR4fnR5r1 n_,—t.fri / cm2fiR6friR7rri n ftAR`V, , R2. R3.R4. R5 .R6f111-

[0026] ISLIELLVIA-t -tt 4- (1- (2 - 1 , 3 - X)1 [IS11-6-)7tA PAZ) -5- - 1H -11 14 -2 -4) Tw. ,1-ii.--i±14 -- ri<m-utt4- [1- (1 , 3 - T-)1 arlt -6 -*WrEt4) -5 -a- oqi -2 - J -2 , 2 , 3 , 3 , 4,4 -- )Vr-V-tT

[0027] ?±-1 MNiu , *-Uft371-T- J-t g-f-*±)-51-41--engd4-11.11-Ett in-fTilmmozaiNJ1U-IA"i-g-P11-Ltt"106,71±'N-tql-ilE-Ltil'di=!VA-Uf1)),R--%'md Viqt.f*-±TiTikIll<11-A1 3.3` (f-moLn) "7.1<*tt" otATE:1_414-55,M-Ufn.474-__E-P1-4kEng. fitaMg WAVEL151 VARA KfolIJ LtIL 73-, N ItZ_AltiP4.Z,11-LiVrIVA A CAI n3r,IMIt)ii7,VAV4,attiV-ti414 (9110#1.-AdIV- Prt (N011:1-X01, 51E01)

[0028] RA E UR)] , tAit:1_-=-̀_i&A,}=!ti-- 35d=1,64-4--±1-5-M1111,]*A-Tfiftlffilrfft- g-..T.,trmiKrfri'ft-Mkrri`41.1AJt 0'7)-1±,ETI. / J\ITAt-4 rti -±± a4=1.- T , 1=11izint-MtLFJ111-*4LATKTI, t4 1.1).1i<-4Y40XAT*1-L, TlitEfAM , &tin fig+1171(E#Ar% 3--iiLorli*J171(nfzil3ft YA rin fraLlt (HOMat II rfri 4Y it] Jitlifit44M-E. ft , T fl-filtrAgt-aTIV 6 CN 121604962 A 4 / 11 A. 11-tidli}3a$40t, A T \ ri<]mtm rfn , 11 047.1114rfrit- 3--ttriE.EUPfiftf-Fin / i\VCORWT. FIVItlilAni(Ail (prehepatic portal hypertension) , it,jr-ficg-w-LE,A4hgtif\frififtin'A,fig.IBT f'51.10PRPT4[1',AttEt.F1)1 , Klub' P. A&- , -iAfF f=fi T17. Eh JITT)ig' I lEfi'J fiL 1-M4[7_11 t:titt_Lig rAjt. -A- )41 gii-PI-FJ11041,t AiViflft-fff4J , }AA.iiilili-friVitit#'*'n`nr,

[0029] ?±-1`'P,M,JJ , Pfits-a ,Fht-atix4,kat , 94.

[0030] , %L.g11=11±Agt t ,19.)JiltfiETAkt ,11T)1 , fiLRJiTJIVAjlt *--tftiVil-T4C-L,

[0031] 1-_f )Z.PfiftfNn ,iA "t„itlITICA" (ALF) tM" , v ntzrrini-vititaiATan%-tia , J=1. wvt±ggi.r [In TjAVV-51 (INR>1 . 5) tsitfEFAAAT_ --f1=4.CXYulrm-Lni,JM1Telk-L-(±A'AiRafrikNift*Efr og., igifutitv±nifirvErg O ALFinm , / fR , V:

[0032] 04.5cfilt1'11Flt , tt-j]iftV" (ACLF) , raFaft (i1*-t*A-UtIVITR,f-E) ,T,VITT)Antt.E•ft , iAt*ft*F1Y.- , 11 AuFYYWIARINCEA,Ar 411 t-'*44.1),R50%-90%InAMPAIftirl=iltJJk-t*.

[0033] Fl4aPRit111n,if -1,4"ETRI-E"tf- : Wilit)41133441 (Olt TAW / II:P-4. VA Aliti-I95A7-KMAIrti-14) EMP*It AAA tig-TA- (NAFLD) fri / R14VAItt.liHfihtt.FAc (NASH) fri / gU-tirti japaft.jj}A- (nap) fr_Vd)- iAlf-HfUNEttF (MASH) I ; WAttaq'tEtill-TR:1-Efri / dgttialt. MATRI-ERSAi-M4- JIT-Rito thP3--;Ah -Arri , 'f-titits)111}Ri-ErWt. lit)Thil3k54 (91.11 Wifitkiti-I,IttAxtiii=45-AsitAAMr=1=4) 1 -kar,A)- 1tIMETKI-E; Stiff ; (NAFLD) RI / di VAIMIffihnfilfF (NASH) fr1 / 911-WV:Viiiht_l-TA (NAFLD) fF-1 / 5111- 1V-VJINM't_11--* (MASH) I tint.)-t it-1 11F-aft; Vt.RittiPtt I krn , pk M.- Eli lAtt I kn't-tft-4,41iii-TRI-L

[0034] tAsaW158ffl J , "Fifft;-1-:*d" (HRS) J=[.t.V.EA'±)F-111AA (At inAltF- Lli-V-Attlif -A-A) tr% 2.1-E FiRsa-g r*AFKin:p_„fitlyr, ,00118. rfn fnMdilitffl 'ffn Wi.R±±11=F rin AtifFPlia, rtrlfRAT1.

[0035] Z4,)).FRIVIn , J "ETA'

[0036] F-Jr±Arf.tt EA-4'1'd )(7-WAMM6rY. J. Yfibiti-J-1-tyt,rov-tk.riripAgg L Vtkr-fiO, 111 •Tr,Ti 36E HA CN 121604962 A -IA 0)1 4'3 5 / 11 X

[0037] 4-1t_71- n --)J a.' —frii)1 14f A .Z`Fk7Mr±rfn *7-u9M4tr--1--t &11- ntattf--.-1:4- 51-14,-37(i-U5- 9 / 14., VE , I nPs'itttEti---tSEai-*-±A ttgllfit 1719 -- [Miff itttA 3-J` B / N-it-It.L.-J4-91 A tk,fUM5-Tii,JEt fi:IPT*-±171.&-iFe_inklAFP.171 / M bkh t1=1:1 , figi tME$1.1YA P-IlfillrfiltFAIIntiufMLfrfrizo'ft rp],t it5F6)1A

[0038] tafix4arpiir- Am-Ah , "&;-t-A 5'a" "A-we)-t- I" 54 "P5-14-±A lthtcp$15,111)PRI,5 #cQ, n It] ritcttmo fr B<JEL.)±±-14-5-ii J=1, izKI.MtnIL.06kT6-11-{zi W1-A-fzKFMATI-g-forn-B-Sitfurf)'a k-k[X1Aft rta , iM#zi-A5tec,i-ENT#i-ttftifflik.1-V2KI,TP_Eiliffmni-vrig_frlitaneTh ''OVZor-fcATJI -3-011t PI friqlf 9.11,14toliE , Pu*-±,h --4q44-±1=71M-9:11-fi Zzn

[0039] TITI)),# / tEtft Th (AA, rk,A-um) firattl.7.1<otx.f_,-a-LituftraT&I3L-Tz, r,wwf,,,TA-Etk / fgliitlicEliz-wpi cd Mit ri<J T=E 5t61 n ZAIRE ) a -t 1-51-3RTH tA-11 Li AP, Pi*-ILIn liNJ--A-tt.7.1( \ I / 0d iii,Ji - Ail=-7.1<\1' firikavitimg tt-nVitaffi. 5-14.1-tfri 71<7..*.$fit "p,11 (dos e) " "yfiji (dosage) " A.Asarti

[0040] ft' ,EVELL-ti44,V;Vvf- 31,1;Pb")1,1g1),t.',J5mg g4j1,200mgn NefToitiAit ,ttlit_rt-L.-Z3143TA.UP, ;UHL OTP11.gft- - : giNj5mgn ifij 1thfignI911,Ygt 15nignIf[19. - t / ,j2oinginna..- .t4j25mgnyFijig nypicy_t_4335mgn33 J ig., ,it. / 1A1,345ffignP1m, - .Jigisj5oingnP1-M, - .• gt55ingrrom ..Y..1;g4760mginna-, _ / ...1;g1T75mg EY,JP,I-M-..YZ.A<J80mginblig ,_- 9t.)J100mgri<J1f111, .1;_tl,j200mgrryjNI,Yzjigt250mgri<jAM,yzA4j 30orngin3i1ja,y / j)35onignMar,,yzAt40oingn31ER,yzAisj45oingrsim nv .. yam gt550mgn31J ET , %.itt600mgnPja,y._65omgrilPja,y.tt7oomgnP1 .Ptl,j75oifignP.11,1.- .,1;t4jsoomginP11, -yzjitt85orngri<JAija,f..- 9oornginP16.̀ , %.liesT950mgrAI.YZA431,000majPIM,..igt1,050mgrra114.yzjA4-ji, oomerim yz.); t4j 1 , 150m g rrATIM rg.V.!sj 1 , 200m g ri<j Alj atLP1-14 (4,1tr-V--t1)il-TFI—& ("QD") itkf& ("BID") FIE& ("Tip") ,95(1Ella& ("QID") , ailAsairiFIA max , EP 200mgo-L---4-P kh 411:1 ,)14ttattig (rA,L=1:tAT4i A Et* •.T'z$1.41- '3-qVJ rti rhol-±,Att- _,5--F- n§:i4vf,- a A.--1.'%qtrftli ---_.L.14-5-1,1.-Vvi-UFA.E-450-1 V51114 l),(n5mgV,4J1 , 200ffign4 Fri 4A T oftiAtt, IsiTE r;j7t / -U. gQ f J aPFIT H NaMsT : Y-A-4J5ingn Fl Y.,A1,J H yfija.y.g4ji5mgrn Ei ij , 8 CN 121604962 A b 0A +3 6 / 11 7. gt20rilgIn4 H 191 - , Yz_M 25mgnt H , , / ,.M30mgn-fra H , _I).es-J35mgrjt • , t4J 40m gn H J t',J 45 mgn H Pj , ,i.A.4j 50m g 79 H lj , g4i 55mgnt H Am, .,1)gi,J60mgn 4 = P1 .- itis-J65mgnt .1A,j70mgnisjt pi -1'J751EgrI<Jta H Yfil Fa' / A1 80m g Flisj H F , gt °mg rn4 H PM, . / %gl95Ingnt H H Yfija,..gisji5omgo<J4 H yfij H pi*, t4j250mgnt H #_i_pesjamment IfIft,YZ.iti 350mg H pit -.<.1)ti,3400mgrn-t H pi , #_,J;gi,j450ffign4H H .... / ...1A4J550mgnH pi ,-1.- Agj600ment. H # ..)Aisj650ingin4 Et pi w ,:y..<M700mg nt H H 800mgn4 H j)gJ850mgnt H pi , tJ~t4J900mgn4 H H , moment H , 050majt H pi , ,100mgn4H VA'sji ,150mgrn4H pi ig , 200mgn 4HP.W.

[0041] -(± 'Pc Ai] r1:1 ,Pfif ikLAM-11AltfHT-121NATIJotatJANAinfilKitit*Th , Ffr itfllntlitctzTliP),t 4 '1201 1i. , 113RWS.-- rn h rti PRiLR 4.A / MEL*ttt -1'f7KIfl.Mg .71=11 n '1* J tTtP.1,1-Z31Y9.1, 4(,- WT1 (s t i ck - packs) ,4 ,1vfil (sachets) ,vz-Pi,tP.I.klUalltffiloitiln fAKIREt.-itT.1.1i5- #1flifi-1 Llf1 t ft It it , Pfi ilm.tcttt 1),k a- ± wmf,- IAA n CiLL -1,1 111 tk'i TottigPMT6n8IJIN,PRilffiftti.III) ,,,1--fn51.V41 .414-:±J5TfOn An- ampt wA-f i q gr -Th ril,AYFAiite4g)ft.fott.tt.nfrIP RP] ft.ffl - MA 04-tliAn -gjttilti- tfq- adiLtAAlh'ini*,Att((Remington' s Pharmaceutical Sc iences))g19 (Mack Publishing Company ,1995) itiPfiLR I ffinh -4 / 1 AAK).

[0042] Yffh , gftir J1J 5mg 1, 200mgIntil -±4iX-14P, ;434,A*-±1-4kngot, 20mg.Y.%,[225mg,Y.!..1)30mg, -1-Y.i35mg,y,j)40mg,YZ945mg,YZ.I;50mg,Y.Z1255mg, 60mg, Y-1 / ...1265mg.yz_.1)70mg,LY%1:75mg,-yz;80mg,-52985mg,j)90mg,YZI)95mg,.j)loomg,:_l: 150mg, 1)250mg,YZi300mg,T29350mg,YZA00mg,V.:450mg, 1:%>550mg, !... 1)600mg,11..12650mg,Y%1)700mg , , 000mg , yzpi. , 050mg yz.pi , 100mg , yz..1; , 150mg, l ,200mgrnit. i-5mg,10mg;15mg, 20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg,65mg,70mg,75mg,80mg,85mg,90mg, 95mg,100mg,150mg,200mg,250mg,300mg,350mg,400mg.450mg,500mg,550mg,600mg,650mg, 700mg,750mg,800mg,850mg,900mg,950mg,1,000mg,1,050mg,1,100mg,1,150mg,d1,200mg

[0043] *=1:1 ±t- pk H. Tc, -49:n 44,9ilt*LT-FAMH-t 1 :1111,A01Thtlialff -40

[0044] 'fait] iRr-fliAlfflin?-ft TI41)).1111111qc 'Wt17I 'Al .111LN . it] . T it] . PRA . , I3A igfr-IAII6.a*x_raTvwnkt Tiet-alTI)).[N4ieft-ryA-A-n • rto PRgF' , LI N. 1%%M.IRM:sizta tIgft 9 CN 121604962 A -1,P, HA 4') 7 / 11 T., 451 -±14,35c ,, Yz_ nlittitgo. A~t— IttGrakh , LI ±7

[0045] 37r4z_n_gn-Pritt.C.Prizo

[0045] T1 , ft-U54950, P54-±J=11 - 9-1,7*01,7A-MEI. 111- il',̀%=-#11ttimI3J` , 4N . tIV.T4 r s °cos tat) Jr`tu X# (resmetirom) • ft i**BA (efruxifermin) 13,1itifT (be lapect in) (ocaliva) CJIIEA , (E KIPA • AU& • )NEA tVEDNEA • EAT:1-155A, Z., *kV • *T1U-NP blAgYRA .1A*Istr3.54:124K13fiAtP1 #Cilt ran V,

[0046] I in —13 A.:4R 1.1031F-JITAgt n tgEtqlig JJ , 'N tt 01 V.* )7'& 61. 1 / S] Lit ±----Ljg 51 Mc-- J=1, P3141 it • IAa '3<s-t inflrEt.-'4714.1-Z,"-UM3111 n

[0047] P4.-'1`)1ft1 ,filt-±.-_14145c,J=1,%"-U45-1!=i, t14 .4±JIT-411Engs • tilitt.'4,35(, 4A--UM5-14P5*-±.111-4ftng-nt ti*ItA'ififffflIt0-41 OFTRI-L, P_ATER. .tiff Fa-m*a 'ref ATE pi tilM) h m*14,1-h 1+4-511Itt"--50-1,',47 / b---44-±.13TIOIng..5-i',1,-E-dt,̀±-ti45-, / ,1=1,44,,t;;:62*±Td-f- EngnAttft*t`V-tiftliitifRrfri ift-±-04'fitl 41 it

[0048] T1----1-9-s-Ah , .̀)IAs, itR—#f] rfn tf4-knh , )-,* JITRI-E • ttlIT-A . ICH IttilTRA li+JIM*E . n-dfri1F-tigA ,PRizEh ikNMrriitVt, TtLE.WEA3.̀&-gT-n11.)t-L-1--1-41,-1,tryLt ff45-1 warnlifftimt.ftntttiE±-_--L- VRW-U45-711=1. Pit-±.17M-9:ng.1%).R.—fudVEM-4-4-±.1"449_11<JW0f1 n*vtizta*to

[0049] ?..±-.--JAP,A1u , 4-1L-71- —#)41 ft111:ft'iriNiqilftIVEtAZ-141 rfn tfRq=n JJ ,J=1, , , *)-tftiVIATRI-E [tli ,1 *A-Tt_hfifill'AVInfl-LfEr A-*-± fifftt- tth--MA,JP.f,'LL--Vh-dirtVd-tJ41214P5-4-4±. PA-&-x J 1)).R—fitidfEM2Y-'±_ FA- f-VInril,AVRIn.-AttEt*-to

[0050] rfizeiettienigtm-r, M=1±PRi`1Ati tfiT754fatIPITLI 1E11 riisj

[0051] ils. / z>mrsi —)'J OCR --frtqfgl)F-filAgP_,,g tin It] Ar±- 163M-Knh 7 , Pfi}J ft] g ri<3 rt-ttfl_ Pfi I _ft.d.h dtH -±-* / z) I [0052 ] 4*, )1 ita—friqfITHITIAg,_,WrPW,Jiviri rin NE / inh , kith roLitzgti -T-tFLEFfrizErn 71--(A--uytyl Pi*-±.TiT

[0053] TI----.1-PAJJ , As, nrti rin itiff11,]h , Ffid.IVkM. PAWNTLEPRin-A ityh Ez.—#A#11.4.1•3-*-±r-iff-OfdYARFAIJnPi-tgin-tto 10 CN 121604962 A IR FIJI 4; 8 / 11

[0054] T.-±.--t--Ahtrizi, / )T6R---friqF:iitiCritt JJTA1t7,A- tirriNiirirfri fni7 fi)J -A 23M nErit±±-i.f- 41-,4,- -)-TA )51J-{, V-544-± Tirt:51 / .At ti4554,1Et-t-'-tfti-iir,"vg*-±T=1-1457_n goa—f415-ift:A*-1.PA-45_1<grliJ-Mflini),Jtc*.tow*Fn-±A.JJ:itto:Fli th- h ) I niz--IJ go

[0055] -41171 , ANE-Krith ss& , 11=11 *7-01fifi n Wintif.L.L 5144-rt,'-t):tdizt Pi* __E.P T ;'&N nfov-i-mtvA<Jisiti-z-51J=1,r-v-UF4F-14=1, P5*-±TITV9Ak1), --filadVPKA-14-_LTITtkInMyofiin v-JIttc go

[0056] A—itP-.AJJ -ititr, 4- / L-MdEz.--f-4q6TMITA--1*-dt-ar1=1 rfri -c 3h , FR. -fikwt- r=i, Wailistrf -ftliffJ± I nia--JJ go

[0057] tit! ,i4s.- / z_ )1 R—frilifi4iFft.IMP, It!Jr])t. rfri tt-fg-Kn h 's& , PRizth 's / kwtrrtii ti• M-±t±Pir ;ESA -̀x k JJ1P±tg JA:Al-U -414.1,14- 4: ± [Tit -4 kEt<A..dt R—#11dfrrit*-±17]-4-1, nr),1-4%IfiinPittta*t 0Pfilz_;- )1 ry,"-±.3±Ju 'Path [0058 ] A— '3-0th ti=11 , 4- / L)=Fit mr±- rfn tf , fi h ±frfilin 3`&1.1 WffilnliftiMtmI3-A<JtA)t±,Liti-F-ii,H7v- -1J-1,A*--±TfiTtVIAPEIzt)kEz. —#5-71frII-.44,51-4-±Yii_31:rnfiljtffMf111<iiijtItg_EVOt A.— t F171 ,ffaft t "in ItUt 13-e-M (NO Winlitirs.'MttiP***--7k1t)Fig101-14) I ; 14ftA rtft.11-P( I ; Eti I rtElfiltliNftqttFiA (NAFLD) fA / T3-14iPtitt.AVAtt.)1- (NASH) Imo; jg&ttliEriftt.F Ritfil / digkItRittitifit j<.̀ , I if! ,lifRfEt RitItAlITRI-E51*Rit- filz_;) I ±.A. / J'& Thia- f1F-F,Lls. / L;71-11<i

[0059] 4- / L) I resJ—}Jfii33,hati±frfiA.illtilt-L-.-̀- iffdll'iTv-U -4171,1 -A*--±1-1 -tvAln w±mIl]]Ti6INMFF111011-rn*':ift r1=1 n )1] , *PI TleMITRI-E tttfFFAIVCri t±fiTitA .)1-Tirm*E *Tut

[0060] 4.1.-TT -0.45Fi±Pfii±nt1ttlacV:riC1-V -44.4V±.17If.rit L-LVIILE.111±"OliffRI-E[rAtrP , Tfi ifvft-*-titiVETRI-En h

[0061] 4&)1 fi4RZI.Pfiliri<JA aT iQ .1.))11 fff -Alt • fff10%.*-ff Pb-tt 0A / L-, JT Mita t±fifirit-A WintStit- 14.9iATLI- dA-P5*-±1711&§-z-tingAVITHT- firlIFR 111 11 CN 121604962 A V. OP 9 / 11 i-Engt 1,*#,111.±*fr-t.i-tft-4)1JiTRI-EnkbitoPFLJT _Lizth

[0062] * / Z-)I ,AXffita.Z_LWri<TN 41-.rni / Fti-mtftnt-iut,.-'- ix-c=1. llivq-IF*41-timg±-1-mary\ivit 1•4 1.1 '1f41T A ;',caInfiPttl'IVAlfit)trt-±-.Z5-11Etry- AA- P544-±)-5}-&.5.tngast--A:15fn ±A-w-Ai4nmym ivtci. toAmitd11±-mrr-FaibmvizrPnffil,t4A 1A141± ieflt:-Mt-10111-TFC-tni.-45-t ..PfilL-) I in-±iztiu'it-tHXM-Alu - ifiER±As,. / 29=FiniI— h.g.

[0063] ***

[0064] i),Tiramitn5-akTiTuT. Jz_THYA-1-J-3 i3tE91

[0065] 1. ---frkifirt-ffamItzrrintAtrinviEuism&,PRA. ,Nw=i, t-`* T 11U,114511Et 1 IL JG i yV 51,1; Pi*-±TiTtOft.. . 1:14141 AZ,A-t3fil J=1, ),34-± 1051:n nP3-1-tgE.Prfrt

[0066] 2 fE8g4 1 W[MfIft1T-11tf04-1,T.A. rIcin it] NI rfri Vgg-kniu , J4, , fitfiT 11-fRI-E.PAtil-TAA.t1Puttill+RA.TffirM

[0067] 3 ifgunh , ao-vuETRI-L ,* 1.1YAA-tft- 41J1+FC-E.

[0068] 4 MEM 1 [tiff —aFfiLm mfr-FK-A-g.tAiti [1',J ill rin , ,gffltz.1 1 -̀-_ig.1=1,71i-UFAdJ=1 , Pgd*-±qc&fz:ing.',91'N ilf-filfE -±fcg-3-117trv-UA ±TiTt01-n_grn;,̀ / ittliPt-tiV3z FA-1" [14-Jag4 Fin . Mfl4.e.1-9:11tf[1 / dPNIA

[0069] 5. MET-D1 PI 1 41 :111—apRitnierf-1---aogitz- iti rn rtri rtf-Knh , , tat-2±- i-ggutry-urp, gi,j1 , 200mgk J9 H

[0070] 6. ftqfg411f11# 51 2111—MffitriTieMITIMIPAlti FYI Pk] E rfn g-krin , 14, rri , Alt tln-10 ff.9

[0071] 7. &I-Ea F 1 6 '11-11MAriTifTr-fFEriCt-fltrrIn WfifiLMM(n-15& ,

[0072] 8. tRiET-M E 1 701•11 —4Pfi zEn fl)Filt I, ,W*k 7I JAlf rfn Ng RrevJ , J=1, , 5mg # 1, 200mgn11E jris rrCf3f,td j=1,

[0073] 9 . *Riga 1 # 8 1 111—afitn'6s-ry-tfargItA- ronitifrf rfri tE- [I" / 1215mg,YZ.i20mg, . / ..1)25mg,V)30mg, - ... / ...1:35mg,YZ.P40mg,1)45mg,Z_I)50mg,YZ955mg, 75mg,YZ980mg,f. / 985mg,i_990mg,1- 95mg,Y.!.12100mg.Y. / i150mg,Y.200mg. 250mg,. / .9300mg,y,j)350mg,y.400mg,V)450mg,Y1)500mg,...12550mg,YZ.P600mg, / ..1:650mg,Y700mg,YZ9750mg, - .1)800mg,A50mg, , 000mg,yz);1 ,050mg,y / ...1)1 , 100mg , i5omg , Noma / sin-au, 12 CN 121604962 A IR PP '1'3 10 / 11 TA

[0074] 10. t.-u-1-4 4m+h-ctst- rrintigirfritlfg-KniJ , ,A4,- / AL-t-_-̀.irg51 '3-YLI-UftEli-IEt -.4't---44-±T:1-&5tni,JPEIAPittg€1.

[0075] 11. fRIAM F 1 ciPiEii•J IENTv-t.E-il 14- t.t4--4±1-51tOfe_ Jiitt rin l]inqeS-Vribkgirtia

[0076] 12 fatEM IMTRI-L,A- mnitia.rfri tcg g-Kn)J&, Jr! , -Vvf- 5.1, J=1, *5•.)*-± ggj 5mg , 200mgn 1E1 Vat- I-

[0077] 13. taiga 10_121=1=11I—I-PLPfiizEiMfrit-t.ftitiViffal-L,Ltli=1:1nitla- rin

[0078] 14. taiga loy1314:iff—a%±ni8T-M"--ti-DtAff+RittA. nitiariegg

[0079] 15. fRtET-P.= 10Y.14 nit] rin JJ , ,H, , Wit 4, itt ta*t 5m g 1, 200mgmt.ftL-4-,Imrkr-Fdj=1, -A-44_± -ffriogAgo

[0080] 16. MEM f- 10Y.151=M—mphArnKisilt.i-tft- FnE)11-1-fritif nvu'i,,I1,*,PRLr-ph-ttft tZP35mg, %1:60mg, 70mg , - 1,1..1290mg ,YZ995mg, / i100mg,Y%12150mg,Zi 200mg,Y / 9250mg,Yj:300mg,V)350mg,,Y400mg,YZI)450mg,1)500mg,9550mg, 700mg,-- / .P750mg, -.9800mg„ - !1;850mg, - 9900mg, 950mg, , 050mg , ,100mg,--zpi,150mg,F11 [0081 ] 1tdo,-P4s-roNs-

[0082]

[0083] ff*344 pjj

[0084] `4-s-K-15t)T-A± / 1\ (gE.7.-1. 10;=:it%) iNt.301A33J`1101171(MIL (PPVL) t4W3 f701171cAr E rigkR-Vi , r] g+Thic Aejm (5- o_gt) rsigAn Mlfkl(fiV4'13rfi 2 7-14qi-igfr- rff.144- I fN3 , ft, nil TOE71(1A °Mt —JR , fir-f. T §_a -±-414 (10mg / kg13130mg / kg) Fir-6-V, 7X. tfiliTNIfri*hirfn rfri il-N,J1TafriEflVELF,44Z-RftficiErftlftiegt rryrf rfn tWitt4t. —ft r=71)),RRIELVMEgtg.,ifiqna. iff(4426 9 -atAA fix , J Batsonfflj n°1711-aWitZR'14t W,- 25% fflipcul-E*JIIA-V171(ifift Anifietfattomia4-i*tfi- 0

[0085] my,.

[0086] rin Aft t 4_4t-qt

[0087] 4- M7-Vj t-E..LE,PPvLij\kkniigfil(Et _T_TAT2.1P fignyi osxi-ffin 13 CN 121604962 A b 0)1 4'3 11 / 11 4.34mmHgNPPVL / JMn10.85mmHg) o#TAM31-51-1)),E• ME75E_A-Vir , un lJrtig ( 51.7%)

[0088] piitza

[0089] ThIcAril. J t, PPVIA`ranMilff +1-P- T-37 t )711 u9u4.D. n,s,f2r0.38%-YIPPVIJ,Nrixrni*.10.63%) I)JC- ismaza3-;-Apm 23.7% (AlOmg / kgT ,= . (z1Kto . 57%) f1156.1% (-{±30mg / kg-T I:$12M 0.49%)

[0090] ifritfAct,till

[0091] ailtuMl- rfri n-R-ftE.71s , ,PPvLij.mfy.-A,-*J140110,, *gAff-- telf-IFIPA u,x -rfflo120.31PM.YliPPVIANMn37.531.11\0 otaM217ITI<E± n,i1Li-,(±10mg / kg (28 . 95pM,(49.8%) Til,,72(±30mg / kg (28.530 ,13-m52.3%) Vtit'As-M )11- rfri MI -10E1461-fii(tat Arnff-3- m-(ai

[0092] :deg hf.,,,[fctli-q

[0093] JfNNaizJX 7 11101(E f T (In m itn[i[rim tiffl t (A10ing / kg Omg / kgn tmti ,tHATAfLtig-ti 1011 117 rfrf fikforiltrif-AE (IRO 14 iR HA 123 PI El 1;4 CN 121604962 A * * 1 .0 0.8 --I 0.6 0.2 0.0 11 -6) E n E =0 '0 =t S a_ a_ 'V 4- * I+ ig 4 P P V L + g A 15 2 / 4 w, 4= [WI •,N CN 121604962 A * * 50 — 40 — E 30 ti Itun 20 — 10 — P P V L + ',4 g A a_ a_ lk • 10 3 / 4 CN 121604962 A 2.5 2.0 1.5 1.0 0.5 0.0 0.07 14 .1. E 0 CI. 3 17 CN 121604962 A fikf.aCD34 IHC **** 0) 0) E co 4a; 11 4- a_ P P V L + 1 0 m g / kg P P V L + 3 0 m g / k g

Claims

1. Lanilanol or its deuterated form or a pharmaceutically acceptable salt thereof for use in the treatment of visceral vasodilation in patients with liver disease.

2. Lanilandrol or its deuterated form or a pharmaceutically acceptable salt thereof for the purpose according to claim 1, wherein, The liver conditions mentioned are cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy.

3. Lanilandrol or its deuterated form or a pharmaceutically acceptable salt thereof for the purposes described in any one of claims 1-2, wherein, The liver condition described is cirrhosis, particularly decompensated cirrhosis.

4. Lanilandrol or its deuterated form or a pharmaceutically acceptable salt thereof for the purposes described in any one of claims 1-3, wherein, Lanilanol or its deuterated form or a pharmaceutically acceptable salt thereof is administered at daily doses of about 5 mg to about 1,200 mg.

5. Lanilandol or its deuterated form or a pharmaceutically acceptable salt thereof for the purposes described in any one of claims 1-4, wherein, Lanilano in its deuterated form is a compound of formula (I): （I） Among them, at least one of the groups R1 to R7 is a deuterium (D) atom, and the other groups R1 to R7 are hydrogen (H) atoms.

6. A pharmaceutical composition for use in treating visceral vasodilation in patients with liver disease, said pharmaceutical composition comprising a pharmaceutically effective amount of lanyllanol or its deuterated form or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition for said use according to claim 6, wherein, The pharmaceutical composition is in the form of a solid dosage form, a semi-solid dosage form, or a liquid dosage form, preferably a solid dosage form.

8. The pharmaceutical composition for the said use according to any one of claims 6-7, wherein, The solid dosage form is a tablet, capsule, strip, bag, lozenge, powder, pill, or granule, preferably a tablet, capsule, or strip.

9. The pharmaceutical composition for the said use according to any one of claims 6-8, wherein, The pharmaceutical composition comprises 5 mg to 1,200 mg of lanyllanol or its deuterated form or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition for said use according to claim 9, wherein, The pharmaceutical composition comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 30 mg. 0 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of lanyllano or its deuterated form or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition for the said use according to any one of claims 6-10, wherein, The pharmaceutical composition is administered orally, parenterally, or locally.

12. A method for treating visceral vasodilation in a patient with liver disease, the method comprising administering to the patient lanilanol or its deuterated form or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising lanilanol or its deuterated form or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, wherein, The liver conditions mentioned are cirrhosis, acute liver failure, acute-on-chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy.

14. The method according to claim 13, wherein, The liver condition described is cirrhosis, particularly decompensated cirrhosis.

15. The method according to any one of claims 12-14, wherein, Lanilanol or its deuterated form or a pharmaceutically acceptable salt thereof is administered at daily doses of about 5 mg to about 1,200 mg.

16. The method according to any one of claims 12-15, wherein, The pharmaceutical composition is in solid dosage form.

17. The method according to claim 16, wherein, The solid dosage form is a tablet, capsule, or strip.

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