Combination therapy for treatment of liver disease

Abstract

To provide a product for use in a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof.SOLUTION: Provided is a product comprising (i) lanifibranor or a deuterated derivative thereof, and (ii) firsocostat.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure provides combinations and methods for the treatment of liver disease, in particular the treatment of non-alcoholic fatty liver disease. [Background technology]

[0002] Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver without any other clear cause, such as alcoholism. There are two types of NAFLD: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), the latter of which also includes hepatitis. NAFLD is the most common liver disease worldwide, affecting approximately 25% of the world's population (Nutr Clin Pract 2020;Vol.35,n°1,pages72-84). NAFLD does not usually progress to NASH, but if it does progress to NASH, it can eventually lead to complications such as fibrosis, cirrhosis, liver cancer, liver failure, or cardiovascular disease. Due to its devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with annual direct medical costs estimated to exceed $100 billion in the United States alone. However, there are currently no approved treatments for NAFLD or NASH.

[0003] WO 2015 / 189401 discloses the use of pan-PPAR agonists, in particular 5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid (INN: Lanifibranol, CAS number: 927961-18-0), for the treatment of fibrotic conditions.

[0004] European Patent Publication No. 3597271 describes a method for treating or stabilizing non-alcoholic fatty liver disease or reducing its severity or progression, comprising administering to a patient a compound of the general formula: [ka] The use of a composition comprising an ACC inhibitor having one of the following is disclosed. The method comprises administering to a subject in need thereof a composition comprising an ACC inhibitor, which may be administered in combination with one or more other therapeutic agents. In some embodiments, the ACC inhibitor is: [ka] (INN: Filsocostat, CAS number: 1434635-54-7). In some embodiments, the ACC inhibitor is administered in combination with a PPARα / δ agonist such as GFT505, a PPARγ agonist such as pioglitazone, or a PPARδ agonist. However, the patent application does not contain any data to support the claimed treatment.

[0005] We found that coadministration of lanifibranor and filsocostat can effectively treat NAFLD. Summary of the Invention

[0006] In one aspect, the present disclosure provides a combination product comprising: (i) lanifibranor or a deuterated derivative thereof; and (ii) filsocostat.

[0007] In another aspect, the present disclosure provides a combination of lanifibranor (or a deuterated derivative thereof) and filsocostat for use in a method of treating NAFLD or a complication thereof.

[0008] In yet another aspect, the present disclosure provides a method of treating NAFLD or a complication thereof, comprising administering to a subject in need thereof a combination of lanifibranor (or a deuterated derivative thereof) and filscostat. [Brief description of the drawings]

[0009] [Figure 1]The average body weight of mice in each treatment group is shown: vehicle, lanifibranor alone, filsocostat alone, and the combination of lanifibranor and filsocostat. [Diagram 2] The mean weight of epididymal white adipose tissue (EWAT) per treatment group is shown. [Figure 3A] Liver fatty acid concentrations by treatment group are shown. [Figure 3B] Liver total cholesterol levels by treatment group are shown. [Figure 3C] Liver triglyceride concentrations by treatment group are shown. [Figure 4A] IL-1β RNA expression levels by treatment group are shown. [Figure 4B] MCP-1 RNA expression levels are shown by treatment group. [Figure 5A] Collagen-α1 RNA expression levels by treatment group are shown. [Figure 5B] The RNA expression levels of TGF-β1 are shown by treatment group. [Figure 6] Histological fatty liver scores by treatment group are shown. [Figure 7] Histological inflammation scores by treatment group are shown. [Figure 8A] Histological fibrosis scores by treatment group are shown. [Figure 8B] The histological fibrosis area rate is shown by treatment group. [Figure 9] The total histological score per treatment group, which corresponds to the sum of the fatty liver score, inflammation score, and fibrosis score, is shown.

[0010] In FIG. 1, the curves correspond, from top to bottom, to treatment with vehicle, treatment with lanifibranor, treatment with filsocostat, and treatment with lanifibranor + filsocostat.

[0011] In Figures 2 to 9, the points correspond, from left to right, to treatment with vehicle, treatment with lanifibranor, treatment with filsocostat, and treatment with lanifibranor + filsocostat. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In one aspect, the present disclosure provides a combination product comprising: (i) lanifibranor or a deuterated derivative thereof; and (ii) filsocostat.

[0013] In another aspect, the present disclosure provides a combination of (i) lanifibranor (or a deuterated derivative thereof) and (ii) filscostat for use in a method of treating nonalcoholic fatty liver disease (NAFLD) or a complication thereof.

[0014] In yet another aspect, the present disclosure provides a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof, comprising administering to a subject in need thereof a combination of (i) lanifibranor (or a deuterated derivative thereof) and (ii) filscostat. (definition)

[0015] As used herein, "complications of NAFLD" include, but are not limited to, fatty liver, steatohepatitis, nonalcoholic steatohepatitis (NASH), liver fibrosis due to NASH, liver cirrhosis due to NASH, liver failure due to NASH, cardiovascular disease due to NASH, and hepatocellular carcinoma (HCC) due to NASH.

[0016] As used herein, the term "subject" means mammalian and includes human and animal (eg, domestic animals such as horses, dogs, cats, etc.) subjects.

[0017] As used herein, the term "treatment" or "treating" refers to partially or completely alleviating, inhibiting, delaying the onset of, preventing, ameliorating, and / or alleviating a disease or disorder, or one or more symptoms of a disease or disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" encompasses preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., in light of a history of the condition and / or genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may be continued after symptoms have subsided, for example to prevent or delay recurrence. Thus, in some embodiments, the term "treating" encompasses preventing recurrence or recurrence of a disease or disorder.

[0018] In the context of this disclosure, each of the embodiments described herein can be combined.

[0019] As noted above, the present disclosure provides, in one aspect, a combination product comprising: (i) lanifibranor or a deuterated derivative thereof and (ii) filscostat, or a pharma- ceutically acceptable salt thereof.

[0020] The present disclosure also provides a combination of lanifibranor (or a deuterated derivative thereof) and filsocostat for use in a method of treating nonalcoholic fatty liver disease (NAFLD) or a complication thereof.

[0021] The present disclosure also provides a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof, comprising administering to a subject in need thereof a combination of lanifibranor (or a deuterated derivative thereof) and filscostat.

[0022] In some embodiments, the deuterated derivative of lanifibranor has formula (I): [ka] where 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 3 084 254 A1. In some embodiments, at least the group R1 is D. In some embodiments, at least one of the groups R2 to R7 is D, in particular 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 are D. In a preferred embodiment, R2, R3, R4, R5, R6, and R7 are each D. Preferred compounds of formula (I) include 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butanoic acid and 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid.

[0023] In some embodiments, Lanifibranor or its deuterated derivative is one of its pharmaceutically acceptable salts or solvates. The term "solvate" is used herein to refer to a molecular complex comprising Lanifibranor or its deuterated derivative and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable salts of Lanifibranor or its deuterated derivative include its acid and base addition salts. Acid addition salts can be prepared from inorganic and organic acids. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Base addition salts can be prepared from inorganic and organic bases. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide, etc. 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, etc.

[0024] In some embodiments, the filsocostat is one of its pharma- ceutically acceptable salts, as defined herein.

[0025] Lanifibranor (or its deuterated derivative) can be formulated as a pharmaceutical composition containing one or more pharma- ceutically acceptable excipients. The choice of excipients often depends on factors such as the particular mode of administration, the excipient's effect on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions can be prepared in a conventional manner, for example, as described in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), which is incorporated herein by reference.

[0026] In some embodiments, the pharmaceutical compositions are suitable for oral administration, such as, for example, tablets (optionally coated), soft or hard (gelatin) capsules, lozenges, gels, syrups, or suspensions.

[0027] In some embodiments, the pharmaceutical composition comprises about 100 to about 1200 mg of lanifibranor (or a deuterated derivative thereof), e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of the compound.

[0028] In some embodiments, Lanifibranor (or a deuterated derivative thereof) is administered in a daily amount of 200 mg to 1500 mg, such as a daily amount of 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1500 mg. Lanifibranor (or a deuterated derivative thereof) can be administered once daily ("QD"), twice daily ("BID"), three times daily ("TID"), or four times daily ("QID"), so long as the daily amount does not exceed the maximum amount provided herein (i.e., 1500 mg).

[0029] In some embodiments, Lanifibranor (or a deuterated derivative thereof) is administered to a subject with a meal, hi some embodiments, Lanifibranor (or a deuterated derivative thereof) is administered to a subject under fasting conditions.

[0030] Filsocostat can be formulated as a pharmaceutical composition containing one or more pharma- ceutically acceptable additives. The additives are often selected depending on factors such as the specific mode of administration, the additive's effect on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions can be prepared by conventional methods, as described herein.

[0031] In some embodiments, the pharmaceutical compositions are suitable for oral administration, such as, for example, tablets (optionally coated), soft or hard (gelatin) capsules, lozenges, gels, syrups, or suspensions.

[0032] In some embodiments, the pharmaceutical composition contains about 5 to about 200 mg of filsocostat, for example, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, or 200 mg of the compound.

[0033] In some embodiments, filsocostat is administered in a daily dose of 10 mg to 200 mg, for example, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, or 200 mg. Filscostat can be administered once daily ("QD"), twice daily ("BID"), three times daily ("TID"), or four times daily ("QID"), so long as the daily dose does not exceed the maximum amount provided herein (i.e., 200 mg).

[0034] In some embodiments, filsocostat is administered to a subject with a meal. In some embodiments, filsocostat is administered to a subject under fasting conditions.

[0035] In some embodiments, the lanifibranor (or a deuterated derivative thereof) and filsocostat are administered simultaneously. In some embodiments, the lanifibranor (or a deuterated derivative thereof) and filsocostat are administered sequentially. In some embodiments, the lanifibranor (or a deuterated derivative thereof) and filsocostat are administered over a period of time.

[0036] In some embodiments, lanifibranor (or its deuterated derivative) and filsocostat can be formulated in the same pharmaceutical composition, including one or more pharma- ceutically acceptable excipients. The pharmaceutical composition can be prepared as described herein. The amounts of lanifibranor (or its deuterated derivative) and filsocostat in such a pharmaceutical composition are each as described herein.

[0037] The present invention is illustrated by the following examples, but is not limited thereto. EXAMPLES

[0038] It has been reported that mice fed a high-fat / high-cholesterol / high-cholesterol diet and drinking water supplemented with 2% 2-hydroxypropyl β-cyclodextrin for 3 weeks rapidly developed liver complications such as fatty liver, inflammation, and fibrosis accompanied by elevated plasma ALT / AST concentrations (Duparc T et al., Am J Physiol Gasterointest Liver Physiol, 2019, Vol. 317, n° 4, pages G508-G517). In this model, the usefulness of a combination therapy containing lanifibranor and filsocostat was evaluated.

[0039] C57BL6 / J mice were fed a 60% high fat / 1.25% cholesterol / 0.5% cholic acid diet and drinking water supplemented with 2% 2-hydroxypropyl β-cyclodextrin (HFCC / CDX diet) for 3 weeks. After 1 week of food restriction, blood was collected (approximately 150 μL / ethylenediaminetetraacetic acid (EDTA)) in a non-fasting state to measure plasma ALT and AST concentrations. Mice were then randomized into four homogenous treatment groups (n=10 per group) according to (1) ALT concentration, (2) AST concentration, and (3) body weight. For the remaining 2 weeks, the four treatment groups received the following treatments in addition to the HFCC / CDX diet: Group 1: Solvent 1 + Solvent 2 Group 2: Lanifibranol + Solvent 2 Group 3: Solvent 1 + Filsocostat Group 4: Lanifibranor + Filsocostat

[0040] All treatments were administered orally QD. Solvent 1 was the solvent for lanifibranor (i.e., methylcellulose / poloxamer), and solvent 2 was the solvent for filsocostat (i.e., Tween® 80 / methylcellulose). Lanifibranor was administered at 10 mg / kg for 2 weeks, and filsocostat was administered at 30 mg / kg for the first 6 days and 15 mg / kg for the last 8 days. This was because the combined group showed a large weight loss, so the dose of filsocostat was changed to reduce toxicity. At the end of the treatment period, all mice were weighed and fasted for 4 hours before blood collection (maximum amount / EDTA). Plasma was separated and stored at -80°C. The remaining plasma was used to evaluate plasma triglycerides, cholesterol, and free fatty acids. After blood collection, the mice were euthanized by cervical dislocation under isoflurane anesthesia and exsanguinated with sterile saline.

[0041] After livers were harvested and weighed, liver samples were dissected for histological analysis (H&E, Sirius red staining, Sirius red labeling rate (%), and NAFLD activity score (NAS)) and hepatic lipid assays, and hepatic gene expression of IL-1b and MCP-1 for inflammation and Col1α1 and TGF-β for fibrosis were analyzed by qPCR.

[0042] (Weight monitoring) As expected, the HFCC+CDX diet had no effect on body weight during the 2 weeks of treatment. Lanifibranor caused a mild, but not significant, weight loss. On the other hand, filsocostat caused weight loss during the first week of treatment, which was even more pronounced in the combination group at 30 mg / kg, leading to a reduction in the dose to 15 mg / kg. This change in dose normalized body weight in both the filsocostat and filsocostat + lanifibranor groups (Figure 1).

[0043] (epididymal white adipose tissue) In the HFCC + CDX diet model, lanifibranor alone, filsocostat alone, and the combination of lanifibranor and filsocostat had no effect on the weight of epididymal white adipose tissue (EWAT) (Figure 2).

[0044] (liver lipids) In the HFCC+CDX diet model, lanifibranor alone did not affect liver fatty acid content (Figure 3A), and showed a tendency to decrease liver total cholesterol (-18%) and liver triglycerides (-7%), but this was not statistically significant (Figures 3B and 3C). Filsocostat showed a tendency to decrease liver fatty acid content (-16%), liver total cholesterol (-9%), and liver triglycerides (-14%), but this was not statistically significant (Figures 3A, 3B, and 3C). The combination of lanifibranor and filsocostat significantly reduced hepatic fatty acid content (-46%; p<0.001, vs. vehicle), hepatic total cholesterol (-43%; p<0.0001, vs. vehicle), and hepatic triglycerides (-48%; p<0.0001, vs. vehicle) (Figures 3A, 3B, and 3C).

[0045] (Hepatitis gene expression) In the HFCC+CDX diet model, lanifibranor statistically decreased IL-1β expression (p<0.001, vs. vehicle) and MCP-1 expression (p<0.01, vs. vehicle). Filsocostat also decreased both IL-1β and MCP-1 expression, but only the decrease in MCP-1 expression was significant (p<0.05, vs. vehicle). The combination of lanifibranor and filsocostat further decreased IL-1β and MCP-1 expression with higher statistical significance (p<0.0001, vs. vehicle, Figures 4A and 4B).

[0046] (Gene expression in liver fibrosis) In the HFCC+CDX diet model, lanifibranor and filsocostat statistically decreased collagen 1α1 expression (p<0.05, vs. vehicle) and TGF-β1 expression (p<0.001 for lanifibranor and p<0.01 for filsocostat, vs. vehicle). The combination of lanifibranor and filsocostat further decreased collagen 1α1 and TGF-β1 expression with higher statistical significance (p<0.001 and p<0.01, vs. vehicle, respectively, Figures 5A and 5B).

[0047] (Histological fatty liver) In the HFCC+CDX diet model, lanifibranor statistically reduced fatty liver (p<0.001, vs vehicle). In the vehicle group, all 10 animals scored 3 (3 being the highest), while in the lanifibranor-treated group, 8 animals scored 2 and 2 animals scored 1. Filsocostat reduced fatty liver to a score of 2 in 7 animals, but had no effect in 2 animals, so the effect was not significant. The combination of lanifibranor and filsocostat further reduced fatty liver, with all animals scoring 1, and thus more statistically significant (p<0.0001, vs vehicle) (Figure 6).

[0048] (histological inflammation) In the HFCC+CDX diet model, lanifibranor and filsocostat statistically reduced inflammation (p<0.01, vs vehicle). All vehicle-treated mice scored 3 (3 being the highest). Under lanifibranor treatment, 2 mice scored 3, 6 mice scored 2, and 2 mice scored 1. Under filsocostat treatment, 1 mouse scored 3, 7 mice scored 2, and 1 mouse scored 1. The combination of lanifibranor and filsocostat further reduced inflammation with higher statistical significance (p<0.0001, vs vehicle). Specifically, no animals scored 3, 4 mice scored 2, and 3 mice scored 1 (Figure 7).

[0049] (Histological fibrosis (number and percentage of fibrotic surface)) In the HFCC+CDX diet model, lanifibranor and filsocostat did not affect the fibrosis score compared to the vehicle group, but the combination of lanifibranor and filsocostat eliminated fibrosis in 5 of 7 mice (p<0.01, vs vehicle), while the remaining 2 mice had a score of 1, as observed in the vehicle group (Figure 8A).

[0050] In this model, lanifibranor and filsocostat tended to reduce the surface area of ​​fibrosis (measured by collagen deposition in the liver, 0.08% and 0.10%, respectively) compared to vehicle (0.14%), but this did not reach statistical significance. The combination of lanifibranor and filsocostat further reduced fibrosis, demonstrating a statistically significant effect (0.06%, p<0.05, vs vehicle, Figure 8B).

[0051] (Total Score) In the HFCC+CDX diet model, lanifibranor and filsocostat statistically reduced the total score of hepatic steatosis, inflammation, and fibrosis (4.7 and 5.1, respectively) compared to vehicle (6.9) (p<0.01 for lanifibranor, p<0.05 for filsocostat, vs vehicle). The combination of lanifibranor and filsocostat further reduced the total score (2.9) with higher statistical significance compared to vehicle (p<0.0001, vs vehicle, Figure 9).

[0052] These results indicate that the combination of Lanifibranor and Filsocostat is more effective in treated mice than Lanifibranor and Filsocostat alone, and is therefore suitable for the treatment of NAFLD and NASH. Markers of liver lipids, hepatic steatosis, inflammation (tissue and gene), and fibrosis (tissue and gene) were significantly improved in the combination compared to Lanifibranor and Filsocostat alone.

[0053] References Mundi M S et al.,Nutr Clin Pract 2020;Vol.35,n°1,pages72-84 International Publication No. 2015 / 189401 European Patent Application Publication No. 3597271 French Patent Application Publication No. 3084254 Duparc T et al.,Am J Physiol Gasterointest Liver Physiol.2019,Vol.317,n°4,pages G508-G517

Claims

1. A combination product comprising (i) lanifibranor or a deuterated derivative thereof, and (ii) filsocostat.

2. 2. The combination product of claim 1, wherein the lanifibranor or a deuterated derivative thereof is formulated in a first pharmaceutical composition and the filsocostat is formulated in a separate, second pharmaceutical composition.

3. The combination product of claim 2, wherein the first pharmaceutical composition comprises 100-1200 mg of lanifibranor or a deuterated derivative thereof.

4. The combination product according to claim 2 or 3, wherein the second pharmaceutical composition comprises 5 to 200 mg of filsocostat.

5. 2. The combination product of claim 1, wherein lanifibranor or a deuterated derivative thereof and filsocostat are formulated in the same pharmaceutical composition.

6. 6. The combination product of claim 5, wherein the pharmaceutical composition comprises 100-1200 mg of lanifibranor or a deuterated derivative thereof and 5-200 mg of filsocostat.

7. 1. A combination of (i) lanifibranor or a deuterated derivative thereof and (ii) filscostat for use in a method for treating nonalcoholic fatty liver disease (NAFLD) or a complication thereof.

8. 8. The combination for use according to claim 7, wherein the complication of NAFLD is at least one of fatty liver, steatohepatitis, nonalcoholic steatohepatitis (NASH), liver fibrosis due to NASH, liver cirrhosis due to NASH, liver failure due to NASH, cardiovascular disease due to NASH, and hepatocellular carcinoma due to NASH.

9. 9. The combination for use according to claim 7 or 8, wherein the lanifibranor or a deuterated derivative thereof is formulated in a first pharmaceutical composition and the filsocostat is formulated in a separate, second pharmaceutical composition.

10. The combination for use according to claim 7 or 8, wherein lanifibranor or a deuterated derivative thereof and filsocostat are formulated in the same pharmaceutical composition.

11. The combination for use according to claim 7 or 8, wherein lanifibranor or a deuterated derivative thereof and filsocostat are administered simultaneously.

12. The combination for use according to claim 7 or 8, wherein lanifibranor or a deuterated derivative thereof and filsocostat are administered sequentially.

13. The combination for use according to claim 7 or 8, wherein lanifibranor or a deuterated derivative thereof and filsocostat are administered over a period of time.

14. A method for treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof, comprising administering to a subject in need thereof a combination of (i) lanifibranor or a deuterated derivative thereof and (ii) filscostat.

15. 15. The method of claim 14, wherein the complication of NAFLD is at least one of fatty liver, steatohepatitis, nonalcoholic steatohepatitis (NASH), liver fibrosis due to NASH, liver cirrhosis due to NASH, liver failure due to NASH, cardiovascular disease due to NASH, and hepatocellular carcinoma due to NASH.

16. 16. The method of claim 14 or 15, wherein lanifibranor or a deuterated derivative thereof and filsocostat are administered simultaneously.

17. 16. The method of claim 14 or 15, wherein lanifibranor or a deuterated derivative thereof and filsocostat are administered sequentially.

18. 16. The method of claim 14 or 15, wherein the lanifibranor or deuterated derivative thereof and the filsocostat are administered over a period of time.

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