Combination therapy for treatment of liver disease

Abstract

The present invention relates to a pharmaceutical combination and a method for the treatment of liver disease, said combination comprising Lranilanol and firsostat.

Description

[0001] This application is a divisional application of the patent application with application number 202180079437.7, filed on November 16, 2021, and with the invention name “Combined therapy for the treatment of liver disease”. Technical Field

[0002] The present disclosure provides methods and pharmaceutical combinations for treating liver disease, particularly for treating nonalcoholic fatty liver disease. Background Art

[0003] Non-alcoholic fatty liver disease (NAFLD) refers to the excessive accumulation of fat in the liver in the absence of other clear causes, such as alcohol consumption. There are two types: non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis (NASH), the latter of which also includes liver inflammation. NAFLD is the most common liver disease in the world and is present in approximately 25% of the world's population (Nutr Clin Pract 2020; Volume 35, Issue 1, Pages 72-84). NAFLD does not usually progress to NASH. However, when NAFLD progresses to NASH, it may eventually lead to complications such as fibrosis, cirrhosis, liver cancer, liver failure, or cardiovascular disease. Due to the serious complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated direct medical costs exceeding $100 billion annually in the United States alone. However, to date, there are no approved treatments for NAFLD or NASH.

[0004] WO 2015 / 189401 discloses the use of pan-PPAR agonists, in particular 5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butyric acid (INN: Lanilanol; CAS No. 927961-18-0) for the treatment of fibrotic disorders.

[0005] EP-A-3 597 271 discloses a composition comprising an ACC inhibitor having one of the following general formulae for use in a method of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease:

[0006]

[0007] The method comprises administering to a patient in need thereof a composition comprising an ACC inhibitor, optionally wherein the ACC inhibitor is administered in combination with one or more additional therapeutic agents. In some embodiments, the ACC inhibitor is:

[0008]

[0009] (INN: firsocostat; CAS No. 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, this patent application does not contain any data supporting the claimed treatments.

[0010] It has now been discovered that the combined administration of Lanilanol and firsocostat provides an effective treatment for NAFLD. Summary of the Invention

[0011] In one aspect, the present disclosure provides a combination product comprising: (i) lanilanol or a deuterated derivative thereof, and (ii) firsocostat.

[0012] In another aspect, the present disclosure provides a combination of ranilano (or a deuterated derivative thereof) and firsocostat for use in a method of treating NAFLD or its complications.

[0013] In another aspect, the present disclosure provides a method of treating NAFLD or its complications, comprising administering to a subject in need thereof a combination of ranilanol (or a deuterated derivative thereof) and firsocostat. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown are the mean body weights of mice in each treatment group: vehicle, lanilanox alone, firsocostat alone, and the combination of lanilanox + firsocostat.

[0015] Figure 2 The mean weight of epididymal white adipose tissue (EWAT) for each treatment group is shown.

[0016] Figure 3 A shows the liver fatty acid levels of each treatment group.

[0017] Figure 3 B shows the liver total cholesterol levels in each treatment group.

[0018] Figure 3 C shows the liver triglyceride levels for each treatment group.

[0019] Figure 4 A shows the RNA expression level of IL-1β in each treatment group.

[0020] Figure 4 B shows the RNA expression level of MCP-1 in each treatment group.

[0021] Figure 5 A shows the RNA expression level of collagen-α1 in each treatment group.

[0022] Figure 5 B shows the RNA expression level of TGF-β1 in each treatment group.

[0023] Figure 6 Histological steatosis scores for each treatment group are shown.

[0024] Figure 7 Histological inflammation scores for each treatment group are shown.

[0025] Figure 8 A shows the histological fibrosis score for each treatment group.

[0026] Figure 8 B shows the histological percentage fibrosis area for each treatment group.

[0027] Figure 9 The total histological score for each treatment group, corresponding to the sum of the steatosis, inflammation, and fibrosis scores, is shown.

[0028] exist Figure 1 In the figure, from top to bottom, the curves correspond to: treatment with vehicle, treatment with lanilanox, treatment with firsocostat, and treatment with lanilanox + firsocostat.

[0029] exist Figures 2 to 9 Middle, from left to right, points correspond to: treatment with vehicle, treatment with lanilanox, treatment with firsocostat, and treatment with lanilanox + firsocostat. DETAILED DESCRIPTION

[0030] In one aspect, the present disclosure provides a combination product comprising: (i) lanilanol or a deuterated derivative thereof, and (ii) firsocostat.

[0031] In another aspect, the present disclosure provides a combination of (i) ranilano (or a deuterated derivative thereof) and (ii) firsocostat for use in a method of treating non-alcoholic fatty liver disease (NAFLD) or complications thereof.

[0032] In another aspect, the present disclosure provides a method of treating non-alcoholic fatty liver disease (NAFLD) or its complications, comprising administering to a subject in need thereof a combination of (i) ranilano (or a deuterated derivative thereof) and (ii) firsocostat.

[0033] definition

[0034] The term "NAFLD complications" as used herein includes, but is not limited to, steatosis, steatohepatitis, nonalcoholic steatohepatitis (NASH), NASH-induced liver fibrosis, NASH-induced cirrhosis, NASH-induced liver failure, NASH-induced cardiovascular disease, or NASH-induced hepatocellular carcinoma (HCC).

[0035] As used herein, the term "subject" means a mammal, and includes humans and animal subjects, such as livestock (eg, horses, dogs, cats, etc.).

[0036] As used herein, the term "treatment" refers to partially or completely alleviating, suppressing, delaying the onset of a disease or illness or one or more symptoms of the disease or illness, preventing, improving and / or alleviating a disease or illness or one or more symptoms of the disease or illness. In some embodiments, treatment can be administered after developing one or more symptoms. In some embodiments, the term "treatment" includes preventing or stopping the progression of a disease or illness. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals before the onset of symptoms (e.g., according to a history of symptoms and / or according to genetic or other predisposing factors). Treatment can also be continued after the symptoms resolve, for example, to prevent or delay the recurrence of symptoms. Therefore, in some embodiments, the term "treatment" includes preventing the recurrence or reappearance of a disease or illness.

[0037] In the context of the present disclosure, the various embodiments described herein may be combined.

[0038] As described above, in one aspect, the present disclosure provides a combination product comprising: (i) lanilanol or a deuterated derivative thereof and (ii) firsocostat, or a pharmaceutically acceptable salt thereof.

[0039] The present disclosure also provides a combination of lanilanol (or a deuterated derivative thereof) and firsocostat for use in a method of treating non-alcoholic fatty liver disease (NAFLD) or its complications.

[0040] The present disclosure also provides a method of treating non-alcoholic fatty liver disease (NAFLD) or its complications, comprising administering to a subject in need thereof a combination of ranilano (or a deuterated derivative thereof) and firsocostat.

[0041] In some embodiments, the deuterated derivative of Lanilanol is a compound of formula (I):

[0042]

[0043] 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-3 084 254. In some aspects, at least the group R1 is D. In some aspects, 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 is D. In a preferred aspect, each of R2, R3, R4, R5, R6 and R7 is D. Preferred compounds of formula (I) include 4-(1-(2-deutero-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-hexadeuterobutanoic acid.

[0044] In some embodiments, Lanilanol or its deuterated derivative 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 Lanilanol or its deuterated derivative and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. The pharmaceutically acceptable salts of Lanilanol or its deuterated derivative include its acid addition salts and base addition salts. Acid addition salts can be prepared by inorganic acids and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. 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. Base addition salts can be prepared by inorganic bases and organic bases. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide.Examples of the organic base include amines, amino alcohols, basic amino acids such as lysine or arginine, and quaternary ammonium compounds such as betaine or choline.

[0045] In some embodiments, firsocostat is in the form of one of its pharmaceutically acceptable salts, as defined herein.

[0046] Lanilanol (or its deuterated derivatives) can be formulated into pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients. The choice of excipient will depend largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions can be prepared by conventional methods, such as those described in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), which is incorporated herein by reference.

[0047] In some embodiments, the pharmaceutical composition is suitable for oral administration.Examples of compositions suitable for oral administration include: (optionally coated) tablets, soft or hard (gelatin) capsules, lozenges, gels, syrups or suspensions.

[0048] In some embodiments, the pharmaceutical composition comprises from about 100 mg to about 1200 mg of Lanilanol (or a deuterated derivative thereof), for example, 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.

[0049] In some embodiments, Lanilanol (or its deuterated derivative) is administered at a daily dose of 200 mg to 1500 mg, for example, 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1500 mg. Lanilanol (or its deuterated derivative) can be administered once a day ("QD"), twice a day ("BID"), three times a day ("TID"), or four times a day ("QID"), provided that the daily dose does not exceed the maximum dose shown herein, i.e., 1500 mg.

[0050] In some embodiments, Ranilanol (or a deuterated derivative thereof) is administered to a subject with a meal. In some embodiments, Ranilanol (or a deuterated derivative thereof) is administered to a subject under fasting conditions.

[0051] Firsocostat can be formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. The choice of excipient will depend largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions can be prepared by conventional methods described herein.

[0052] In some embodiments, the pharmaceutical composition is suitable for oral administration.Examples of compositions suitable for oral administration include: (optionally coated) tablets, soft or hard (gelatin) capsules, lozenges, gels, syrups or suspensions.

[0053] In some embodiments, the pharmaceutical composition comprises from about 5 mg to about 200 mg of firsocostat, for example, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, or 200 mg of the compound.

[0054] In some embodiments, firsocostat is administered at a daily dose of 10 mg to 200 mg, for example, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, or 200 mg. Firsocostat can be administered once daily ("QD"), twice daily ("BID"), three times daily ("TID"), or four times daily ("QID"), provided that the daily dose does not exceed the maximum dose set forth herein, i.e., 200 mg.

[0055] In some embodiments, firsocostat is administered to the subject with a meal. In some embodiments, firsocostat is administered to the subject under fasting conditions.

[0056] In some embodiments, Ranilanol (or a deuterated derivative thereof) and firsocostat are administered simultaneously. In some embodiments, Ranilanol (or a deuterated derivative thereof) and firsocostat are administered sequentially. In some embodiments, Ranilanol (or a deuterated derivative thereof) and firsocostat are administered over a period of time.

[0057] In some embodiments, lanilanol (or its deuterated derivative) and firsocostat can be formulated into the same pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. The pharmaceutical composition can be prepared as described herein. In such a pharmaceutical composition, the respective amounts of lanilanol (or its deuterated derivative) and firsocostat are as described herein.

[0058] The invention is illustrated by the following non-limiting examples.

[0059] Example

[0060] It has been reported (Duparc T et al., Am J Physiol Gasterointest Liver Physiol, 2019, Vol. 317, No. 4, pp. G508-G517) that mice fed a high-fat / high-cholesterol / high-choleate diet with 2% 2-hydroxypropyl β-cyclodextrin in drinking water for 3 weeks rapidly develop liver complications such as steatosis, inflammation, and fibrosis, accompanied by elevated plasma ALT / AST levels. The benefits of a combination therapy including lanilanol and firsocostat were evaluated in this model.

[0061] C57BL6 / J mice were fed a 60% high-fat / 1.25% cholesterol / 0.5% bile acid diet with 2% 2-hydroxypropyl β-cyclodextrin in drinking water for 3 weeks (HFCC / CDX diet). After one week of diet, blood was collected under non-fasting conditions (~150 μL / ethylenediaminetetraacetic acid (EDTA)) and plasma ALT and AST levels were measured. Mice were then randomly divided into four homogenous treatment groups (n=10 mice per group) based on 1) ALT levels, 2) AST levels, and 3) body weight.

[0062] Subsequently, the four groups received the following treatments on the basis of the HFCC / CDX diet for the remaining 2 weeks:

[0063] -Group 1: solvent 1 + solvent 2;

[0064] - Group 2: Lanilanol + vehicle 2;

[0065] - Group 3: Vehicle 1 + firsocostat;

[0066] - Group 4: Lanilanol + firsocostat.

[0067] All treatments were administered once daily (QD) os. Vehicle 1 represents the vehicle for Lanilanol (i.e., methylcellulose / poloxamer), and Vehicle 2 represents the vehicle for firsocostat (i.e., / methylcellulose). Lanilanol was administered at 10 mg / kg for 2 weeks, and firsocostat was administered at 30 mg / kg for the first 6 days and then at 15 mg / kg for the final 8 days: Due to the significant weight loss observed in the combination group, the dose of firsocostat was adjusted to limit toxicity. At the end of the treatment period, all mice were weighed and fasted for 4 hours (maximum capacity / EDTA) before blood collection. Plasma was separated and stored at -80°C. The remaining plasma was used to assess plasma triglycerides, cholesterol, and free fatty acids. After blood collection, mice were sacrificed by cervical dislocation under isoflurane anesthesia and bled with sterile saline.

[0068] The livers were collected and weighed, and liver samples were dissected for histological analysis (H&E, Sirius Red staining, Sirius Red labeling %, and NAFLD activity score (NAS)), liver lipid measurement, and qPCR analysis of hepatic gene expression of IL-1β, MCP-1 for inflammation, TGF-β for fibrosis, and Col1α1.

[0069] Weight follow-up

[0070] As expected, the HFCC+CDX diet did not affect body weight during the two weeks of treatment. Lanilanox caused a slight weight loss that was not significant. However, firsocostat caused weight loss during the first week of treatment, and when given at 30 mg / kg, the weight loss was more pronounced in the combination group, justifying the dose change to 15 mg / kg. Following this dose change, body weight normalized in both the firsocostat and firsocostat+lanilanox groups ( Figure 1 ).

[0071] Epididymal white adipose tissue

[0072] In the HFCC+CDX diet model, neither lanilanol alone, firsocostat alone, nor the combination of lanilanol and firsocostat had any effect on epididymal white adipose tissue (EWAT) weight ( Figure 2 ).

[0073] Liver lipids

[0074] In the HFCC+CDX diet model, Ranilanol alone had no effect on liver fatty acid levels ( Figure 3 A), and there was a trend towards lower liver total cholesterol (-18%) and liver triglycerides (-7%), but this did not reach statistical significance ( Figure 3 B and Figure 3 C). Firsocostat showed a trend toward a decrease in liver fatty acid levels (-16%), liver total cholesterol (-9%), and liver triglycerides (-14%), but these trends did not reach statistical significance ( Figure 3 A. Figure 3 B and Figure 3 The combination of lanilanol and firsocostat reduced liver fatty acid levels (-46%; p < 0.001 compared to vehicle), liver total cholesterol (-43%; p < 0.0001 compared to vehicle), and liver triglycerides (-48%; p < 0.0001 compared to vehicle) with high significance ( Figure 3 A. Figure 3 B and Figure 3 C).

[0075] Liver inflammatory gene expression

[0076] In the HFCC+CDX diet model, lanilanox statistically reduced the expression of IL-1β (p<0.001 compared to vehicle) and MCP-1 (p<0.01 compared to vehicle). Firsocostat also reduced the expression of both IL-1β and MCP-1, but only the reduction in MCP-1 expression reached significance (p<0.05 compared to vehicle). The combination of lanilanox and firsocostat further reduced the expression of IL-1β and MCP-1 with greater statistical significance (p<0.0001 compared to vehicle, Figure 4 A and Figure 4 B).

[0077] Liver fibrosis gene expression

[0078] In the HFCC+CDX diet model, lanilanox and firsocostat statistically reduced the expression of collagen 1α1 (p<0.05 compared to vehicle) and TGF-β1 (p<0.001 for lanilanox and p<0.01 for firsocostat compared to vehicle). The combination of lanilanox and firsocostat further reduced the expression of collagen 1α1 and TGF-β1 with higher statistical significance (p<0.001 and p<0.01, respectively, compared to vehicle). Figure 5 A and Figure 5 B).

[0079] Histological fatty degeneration

[0080] In the HFCC+CDX diet model, Lanilanox statistically (p<0.001 compared to vehicle) reduced steatosis. All 10 vehicle animals presented a score of 3 out of 3, while 8 of the animals on Lanilanox had a score of 2 and 2 animals had a score of 1. Frsocostat reduced steatosis to a score of 2 in 7 animals, but had no effect on 2 animals and therefore did not produce a significant effect. The combination of Lanilanox and firsocostat further reduced steatosis with greater statistical significance (p<0.0001 compared to vehicle), as all animals presented a score of 1 ( Figure 6 ).

[0081] Histological inflammation

[0082] In the HFCC+CDX diet model, lanilanox and firsocostat statistically reduced inflammation (p<0.01 compared to vehicle). All mice under vehicle treatment presented a score of 3 out of 3. Under lanilanox treatment, 2 animals had a score of 3, 6 animals had a score of 2, and 2 animals had a score of 1. Under firsocostat treatment, 1 animal had a score of 3, 7 animals had a score of 2, and 1 animal had a score of 1. The combination of lanilanox and firsocostat further reduced inflammation with higher statistical significance (p<0.0001 compared to vehicle): in fact, no animal had a score of 3, 4 animals had a score of 2, and 3 animals had a score of 1 ( Figure 7 ).

[0083] Histological fibrosis (% of fibrotic surface and score)

[0084] In the HFCC+CDX diet model, lanilanox and firsocostat had no effect on fibrosis scores compared to the vehicle group, but the combination of lanilanox and firsocostat abolished fibrosis in 5 of 7 mice (p < 0.01 compared to vehicle). The remaining two mice had a score of 1, which was the same as that observed in the vehicle group ( Figure 8 A).

[0085] In this model, lanilanox and firsocostat also tended to reduce the surface of fibrosis (measured by collagen deposition within the liver, 0.08% and 0.10%, respectively) compared to vehicle (0.14%), but the effect was not statistically significant. The combination of lanilanox and firsocostat further reduced fibrosis and showed a statistically significant effect (0.06%, p < 0.05 compared to vehicle). Figure 8 B).

[0086] Overall rating

[0087] In the HFCC+CDX diet model, compared to vehicle (6.9), lanilanox and firsocostat statistically reduced the total score (p<0.01 for lanilanox and p<0.05 for firsocostat compared to vehicle), which included steatosis, inflammation, and fibrosis scores (4.7 and 5.1, respectively). The combination of lanilanox and firsocostat further reduced the total score (2.9) compared to vehicle with higher statistical significance (p<0.0001, compared to vehicle). Figure 9 ).

[0088] The above results show that the combination of lanilanox and firsocostat provides beneficial effects in treated mice compared to lanilanox and firsocostat alone and is therefore suitable for the treatment of NAFLD and NASH. Compared with lanilanox and firsocostat alone, the combination improved liver markers of lipids, steatosis, inflammation (histological and genetic levels) and fibrosis (histological or genetic levels) to a greater extent.

[0089] References

[0090] Mundi MS et al.,Nutr Clin Pract 2020; Vol.35,n°1,pages 72-84

[0091] WO 2015 / 189401

[0092] EP-A-3 597 271

[0093] FR-A-3 084 254

[0094] Duparc T et al.,AmJPhysiol GasterointestLiverPhysiol. 2019,Vol.317,n°4, pages G508-G517

Claims

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

2. The combination product according to claim 1, wherein Lanilanol or a deuterated derivative thereof is formulated in a first pharmaceutical composition and firsocostat is formulated in a second, different pharmaceutical composition.

3. The combination product according to claim 2, wherein The first pharmaceutical composition comprises 400 mg to 1200 mg of Lanilanol or a deuterated derivative thereof.

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

5. The combination product according to claim 1, wherein Lanilanol or its deuterated derivative and firsocostat are formulated in the same pharmaceutical composition.

6. The combination product according to claim 5, wherein The pharmaceutical composition comprises 400 mg to 1200 mg of lanilla or a deuterated derivative thereof, and 5 mg to 200 mg of firsocostat.

7. Use of (i) lanilanol or a deuterated derivative thereof and (ii) firsocostat in the manufacture of a medicament for treating non-alcoholic fatty liver disease or its complications.

8. Use of Lanilanol or a deuterated derivative thereof in the manufacture of a medicament for treating non-alcoholic fatty liver disease or its complications in combination with firsocostat.

9. The use according to claim 7 or 8, wherein The complication of non-alcoholic fatty liver disease is at least one of steatosis, steatohepatitis, non-alcoholic steatohepatitis (NASH), liver fibrosis caused by NASH, cirrhosis caused by NASH, liver failure caused by NASH, cardiovascular disease caused by NASH, or hepatocellular carcinoma caused by NASH.

10. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is steatosis.

11. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is steatohepatitis.

12. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is nonalcoholic steatohepatitis.

13. The use according to claim 7 or 8, wherein The complication of non-alcoholic fatty liver disease is liver fibrosis caused by NASH.

14. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is liver cirrhosis caused by NASH.

15. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is liver failure caused by NASH.

16. The use according to claim 7 or 8, wherein The complication of non-alcoholic fatty liver disease is cardiovascular disease caused by NASH.

17. The use according to claim 7 or 8, wherein A complication of nonalcoholic fatty liver disease is hepatocellular carcinoma caused by NASH.

18. The use according to claim 7 or 8, wherein Lanilanol or a deuterated derivative thereof is formulated in a first pharmaceutical composition comprising 400 mg to 1200 mg of Lanilanol or a deuterated derivative thereof, and wherein firsocostat is formulated in a second pharmaceutical composition comprising 5 mg to 200 mg of firsocostat.

19. The use according to claim 7 or 8, wherein Lanilanol or a deuterated derivative thereof and firsocostat are formulated in the same pharmaceutical composition, which contains 400 mg to 1200 mg of Lanilanol or a deuterated derivative thereof and 5 mg to 200 mg of firsocostat.

20. Use of (i) lanilanol or a deuterated derivative thereof and (ii) firsocostat in the manufacture of a medicament for treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, wherein: Lanilanol or a deuterated derivative thereof is formulated in a first pharmaceutical composition comprising 400 mg to 1200 mg of Lanilanol or a deuterated derivative thereof, and wherein firsocosta is formulated in a second pharmaceutical composition comprising 5 mg to 200 mg of firsocostat.

21. The use according to claim 18 or 20, wherein The first pharmaceutical composition comprises 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg of Lanilanol or a deuterated derivative thereof.

22. The use according to claim 18 or 20, wherein The second pharmaceutical composition comprises 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, 100 mg or 200 mg of firsocostat.

23. The use according to claim 18 or 20, wherein The first pharmaceutical composition and the second pharmaceutical composition are prepared for simultaneous administration, sequential administration, or administration over a period of time.

24. Use of (i) lanilanol or a deuterated derivative thereof and (ii) firsocostat in the manufacture of a medicament for treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, wherein: Lanilanol or a deuterated derivative thereof and firsocostat are formulated in the same pharmaceutical composition, which contains 400 mg to 1200 mg of Lanilanol or a deuterated derivative thereof and 5 mg to 200 mg of firsocostat.

25. The use according to claim 19 or 24, wherein The pharmaceutical composition comprises 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg of Lanilanol or a deuterated derivative thereof.

26. The use according to claim 19 or 24, wherein The pharmaceutical composition comprises 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, 100 mg or 200 mg of firsocostat.

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