Method of treatment of cirrhosis

Abstract

The invention relates to a method of treating cirrhosis which comprises administering to a subject in need thereof lanifibranor or a deuterated derivative thereof.

Claims

1. A method of treating a cirrhotic subject at risk of progressing from compensated stage to decompensated stage, which comprises administering to the subject an effective amount of lanifibranor or of a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, whereby portal hypertension is decreased in the subject.

2. The method of claim 1, wherein the deuterated derivative of lanifibranor is a compound of formula (I): ##STR00002## wherein at least one of the groups R.sub.1 to R.sub.7 is a deuterium atom and the other groups R.sub.1 to R.sub.7 are hydrogen atoms.

3. The method of claim 2, wherein the deuterated derivative of lanifibranor is 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H -indol-2-yl)butanoic acid.

4. The method of claim 2, wherein the deuterated derivative of lanifibranor is 4-[1-(1,3-benzothiazol-6ylsulfonyl)-5-chloro-indol-2yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid.

5. The method of claim 1, wherein lanifibranor is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

6. The method of claim 5, wherein the pharmaceutical composition is a tablet.

7. The method of claim 6, wherein the tablet comprises from 100 mg to 1000 mg of lanifibranor or of a deuterated derivative thereof, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the extent of fibrosis, as demonstrated by collagen deposition, in rats treated with vehicle or lanifibranor.

(2) FIG. 2 shows TIMP1 and TIMP2 levels in rats treated with vehicle or lanifibranor.

(3) FIG. 3a shows α-SMA levels in rats treated with vehicle or lanifibranor.

(4) FIG. 3b shows Desmin levels in rats treated with vehicle or lanifibranor.

(5) FIG. 4 shows the percentage of fenestrae in rats treated with vehicle or lanifibranor.

(6) FIG. 5 shows levels of von Willebrand factor in rats treated with vehicle or lanifibranor.

(7) FIG. 6 shows ICAM-1, E-Selectin and VCAM-1 levels in rats treated with vehicle or lanifibranor.

(8) FIG. 7 shows IL-6 levels in rats treated with vehicle or lanifibranor.

(9) FIG. 8 shows AST levels in rats treated with vehicle or lanifibranor.

DETAILED DESCRIPTION OF THE INVENTION

(10) The invention relates to a method of treatment of advanced chronic liver disease which comprises administering to a subject in need thereof lanifibranor or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

(11) In some embodiments, advanced chronic liver disease is cirrhosis. In some embodiments, cirrhosis is caused by alcohol use disorder, such as early stage alcoholism, chronic alcoholism or end-stage alcoholism. In other embodiments, cirrhosis is caused by chronic viral hepatitis. In other embodiments cirrhosis is caused by NAFLD and/or NASH. In other embodiments cirrhosis is caused by primary biliary cirrhosis and/or primary sclerosing cholangitis. In other embodiments cirrhosis is caused by medication.

(12) In some embodiments, a deuterated derivative of lanifibranor is a compound of formula (I):

(13) ##STR00001##

(14) wherein at least one of the groups R.sub.1 to R.sub.7 is a deuterium (D) atom and the other groups R.sub.1 to R.sub.7 are hydrogen (H) atoms, as described in French patent application n° 18 57021. In some aspects, at least group R.sub.1 is D. In some aspects at least one of the groups R.sub.2 to R.sub.7 is D, notably at least one of the groups R.sub.2 and R.sub.3 and/or at least one of the groups R.sub.4 and R.sub.5 and/or at least one of the groups R.sub.6 and R.sub.7 is D. In a preferred aspect each of R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is D.

(15) In some embodiments, a deuterated derivative of lanifibranor is 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butanoic acid. In other embodiments a deuterated derivative of lanifibranor is 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid.

(16) In some embodiments, lanifibranor or a deuterated derivative thereof is in the form of one of its pharmaceutically acceptable salts or solvates. The term ‘solvate’ is used herein to describe a molecular complex comprising lanifibranor or a deuterated derivative thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. Pharmaceutically acceptable salts of lanifibranor or a deuterated derivative thereof include the acid addition and base salts thereof. In some aspects, the salts of lanifibranor or a deuterated derivative thereof include those formed with a non-toxic, pharmaceutically acceptable organic or inorganic base. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium 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.

(17) The invention also relates to a method of regulating portal hypertension which comprises administering to a subject in need thereof lanifibranor or a deuterated derivative thereof (as defined above), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

(18) Lanifibranor or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, can be formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. The choice of excipient(s) will to a large 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.

(19) In some embodiments, the pharmaceutical composition is suitable for oral administration. Examples of compositions suitable for oral administration include: tablets, soft or hard (gelatin) capsules, lozenges, gels, syrups, or suspensions.

(20) In some embodiments, the pharmaceutical composition comprises from about 1 to about 1000 mg of lanifibranor or deuterated derivative thereof, such as for example about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 750 mg or about 1000 mg of said compound.

(21) The invention is illustrated by the following example.

EXAMPLE

(22) Lanifibranor has been assessed in a rat model of cirrhosis induced by the administration of thioacetamide (TAA), which administration leads to the development of fibrosis in the early time points and then of cirrhosis in the late time points, turning for the majority of the animals to decompensated cirrhosis.

(23) Sprague Dawley rats (12-15 rats per groups) were intraperitoneally administered TAA (twice a week) for a period of twelve weeks to ensure reaching decompensated cirrhosis. At the end of this period, a TAA detoxification period of four days was observed. The rats were then orally administered for two weeks with either lanifibranor at 100 mg/kg/day in vehicle (methylcellulose 1%+poloxamer-188 0.1%), or with vehicle alone (control). At the end of the two weeks of treatment in vivo systemic and hepatic hemodynamics were determined and rats were then sacrificed, and plasma samples and liver tissue were harvested.

(24) The hemodynamics measurements were obtained as follow: mean arterial pressure (MAP) and heart rate (HR) were measured by cannulating the femoral artery; portal pressure (PP) was measured by cannulating the ileocolic vein, both with a heparinized p50 catheter (Portex) connected to a pressure probe; portal blood flow (PBF) was determined with the help of specific non-constrictive perivascular ultrasonic transit-time flow probe (Transonic Systems Inc.).

(25) Liver tissue samples for histology were fixed in 4% formaldehyde (Sigma), embedded in paraffin, sectioned and stained with 0.1% Sirius Red in picric acid aqueous solution (Sigma). Sinusoidal fenestrae were analyzed by electronic microscopy.

(26) Triton lysis buffer was used for protein extraction of liver tissue samples. Proteins were separated by molecular weight by electrophoresis using a sodium dodecylsulphate polyacrylamide gel, and transferred to a nitrocellulose membrane (Western blot).

(27) RNA was extracted from liver tissue using Trizol (Life Technologies), and quantified with the help of a NanoDrop spectrophotometer. Reverse transcription was carried out following QuantiTect reverse transcription kit (Qiagen). qPCR was performed using PowerUp SYBR Green Master Mix (Thermo Fisher) and specific primers.

(28) Hemodynamic Parameters and Ascites

(29) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced portal pressure (PP) (11.2±0.5 mmHg vs 13.1±0.4 mmHg, p<0.05), intrahepatic resistance (IHVR) (0.75±0.1 mmHg.Math.min/mL vs 0.53±0.06 mmHg.Math.min/mL, p<0.05) compared to vehicle. No change was observed regarding body weight, liver weight, spleen weight or heart rate as can be seen from Table 1. In TAA-exposed rats, lanifibranor at 100 mg/kg also significantly reduced ascites (16% Vs 67%; p=0.04) compared to vehicle (Table 1).

(30) TABLE-US-00001 TABLE 1 Vehicle Lanifibranor p-value MAP (mmHg) 81 ± 3 84 ± 2 0.4 PP (mmHg) 13.1 ± 0.4 11.2 ± 0.5 0.003 PBF (mL/min) 19.0 ± 1.7 23.5 ± 2.1 0.1 IHVR (mmHg .Math. min/mL) 0.75 ± 0.1  0.53 ± 0.06 0.02 Body weight (g) 485 ± 18 484 ± 16 >0.2 Liver weight (g) 14.4 ± 0.3 14.1 ± 0.7 >0.2 Spleen weight  1.6 ± 0.1  1.3 ± 0.1 0.08 HR (bpm) 328 ± 6  334 ± 8  >0.2 Ascites (%) 67 16 0.04

(31) Fibrosis

(32) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced established fibrosis as demonstrated by the histological decrease of 32% in collagen deposition (PicroSirius Red, PSR, staining 12.3% VS 18%, p<0.05) compared to vehicle. This histological observation was accompanied by a significant decrease in collagen 1a1 mRNA expression (p<0.005) (FIG. 1).

(33) Fibrosis Markers

(34) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced TIMP1 and TIMP2 mRNA expression, two markers of fibrosis, (p<0.001 and p<0.05 respectively) compared to vehicle (FIG. 2).

(35) Hepatic Stellate Cells (HSC) Activation

(36) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced the expression of α-SMA (alpha-Smooth Muscle Actin), the main marker of HSC activation both at mRNA and protein level, compared to vehicle (p<0.005 and p<0.05 respectively) (FIG. 3a).

(37) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced the protein level of Desmin (p<0.05) compared to vehicle (FIG. 3b)

(38) Sinusoidal Capillarization

(39) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced sinusoidal capillarization demonstrated by the increase in sinusoidal fenestrae (p<0.05) compared to vehicle (FIG. 4)

(40) Von Willebrand Factor

(41) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced the protein level of Von Willebrand factor (p<0.01) compared to vehicle (FIG. 5)

(42) Liver Sinusoidal Endothelial Cells (LSEC)

(43) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly reduced LSEC activated (pro-inflammatory) phenotype demonstrated by the significant decrease in ICAM-1 and E-Selectin (P<0.05) mRNA compared to vehicle and a trend for VCAM-1 mRNA expression (FIG. 6).

(44) IL-6 mRNA Expression

(45) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly decreased IL-6 mRNA expression, a pro-inflammatory cytokine (p<0.05) compared to vehicle (FIG. 7).

(46) AST Protein Content in Plasma

(47) In TAA-exposed rats, lanifibranor at 100 mg/kg significantly decreased AST protein content in plasma (p<0.005) compared to vehicle (FIG. 8).

(48) The above results show that cirrhotic rats administered with lanifibranor had significantly lower portal pressure (PP) than vehicle-treated animals with no significant changes in portal blood flow (PBF), thus indicating improved hepatic vascular resistance (HVR). In accordance with improved portal hypertension, ascites were absent in most animals treated with lanifibranor. No effects in systemic hemodynamics were observed. In addition, lanifibranor-treated rats showed significant fibrosis regression, inhibition of Hepatic Stellate cells (HSCs) activation, decrease of sinusoidal capillarization as well as improvement of liver inflammation and condition (AST). It is also worth noting that the inflammatory component of cirrhosis (expressed by IL-6 ARN levels) was significantly inhibited upon administration of lanifibranor.

(49) Without wishing to be bound by theory, it is believed that the fact that lanifibranor displays a well-balanced activation of PPARα and PPARδ, and a partial activation of PPARγ, accounts for the results obtained, notably the decrease in sinusoidal capillarization. To the Applicant's knowledge, such an effect on sinusoidal capillarization has not been reported thus far for PPAR agonists.

REFERENCES

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