Patent Description:
Non-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with the latter also including liver inflammation. NAFLD is the most common liver disorder worldwide and is present in approximately <NUM>% of the world's population (<NPL>). NAFLD usually does not progress to NASH. However, when NAFLD does progress to NASH, it may eventually lead to complications such as fibrosis, cirrhosis, liver cancer, liver failure, or cardiovascular disease. Because of the devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated annual direct medical costs exceeding $<NUM> billion in the United States alone. Yet, as of today, there is no approved treatment for NAFLD or NASH.

<CIT> discloses the use of a pan-PPAR agonist, notably <NUM>-Chloro-<NUM>-[(<NUM>-benzothiazolyl)sulfonyl]-<NUM>-indole-<NUM>-butanoic acid (INN: lanifibranor; <NPL>) for the treatment of a fibrotic condition.

The results of a study assessing the efficacy of lanifibranor in adult subjects with NASH have been in published in <NPL>.

<CIT> discloses a composition comprising an ACC inhibitor having one of the general formulae below:
<CHM>
<CHM>
for use in a method of treating, stabilizing, or lessening the severity or progression of a non-alcoholic fatty liver disease comprising administering to a patient in need thereof the composition comprising the 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:
<CHM>
(INN: firsocostat; <NPL>). 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. This patent application does not, however, contain any data at all in support of the alleged treatment. An article published in <NPL> reports that GS-<NUM> reduces hepatic steatosis and fibrosis markers in patients with NAFLD.

It has now been found that the combined administration of lanifibranor and firsocostat provides an effective treatment against NAFLD.

In one aspect, the present disclosure provides a combination product comprising (i) lanifibranor or a deuterated derivative thereof, and (ii) firsocostat.

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

In <FIG> the curves correspond, from top to bottom, to: treatment with vehicle, treatment with lanifibranor, treatment with firsocostat, and treatment with lanifibranor + firsocostat. In <FIG> the dots correspond, from left to right, to: treatment with vehicle, treatment with lanifibranor, treatment with firsocostat, and treatment with lanifibranor + firsocostat.

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

As used herein, "a complication of NAFLD" includes, but is not limited to, steatosis, steatohepatitis, non-alcoholic steatohepatitis (NASH), liver fibrosis caused by NASH, liver cirrhosis caused by NASH, liver failure caused by NASH, cardiovascular disease caused by NASH or hepatocellular carcinoma (HCC) caused by NASH.

The term "subject", as used herein, means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).

The terms "treat" or "treating," as used herein, refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes 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 prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.

In the context of the present disclosure, the various embodiments described herein can be combined.

As mentioned above, the present disclosure provides in one aspect a combination product comprising (i) lanifibranor or a deuterated derivative thereof, and (ii) firsocostat, or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a combination of lanifibranor (or a deuterated derivative thereof) and firsocostat for use of in a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof.

A deuterated derivative of lanifibranor is a compound of formula (I):
<CHM>
wherein at least one of the groups R<NUM> to R<NUM> is a deuterium (D) atom and the other groups R<NUM> to R<NUM> are hydrogen (H) atoms, as described in <CIT>. In some aspects, at least group R<NUM> is D. In some aspects at least one of the groups R<NUM> to R<NUM> is D, notably at least one of the groups R<NUM> and R<NUM> and/or at least one of the groups R<NUM> and R<NUM> and/or at least one of the groups R<NUM> and R<NUM> is D. In a preferred aspect each of R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> is D. Preferred compounds of formula (I) include <NUM>-(<NUM>-(<NUM>-deuterio-<NUM>,<NUM>-benzothiazol-<NUM>-yl)sulfonyl)-<NUM>-chloro-<NUM>-indol-<NUM>-yl)butanoic acid and <NUM>-[<NUM>-(<NUM>,<NUM>-benzothiazol-<NUM>-ylsulfonyl)-<NUM>-chloro-indol-<NUM>-yl]-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-hexadeuteriobutanoic acid.

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 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 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.

In some embodiments, firsocostat is in the form of one of its pharmaceutically acceptable salts, said salts being as defined herein.

Lanifibranor (or a deuterated derivative 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 can be prepared by conventional methods, as described e.g. in <NPL>).

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.

In some embodiments, the pharmaceutical composition comprises from <NUM> to <NUM> of lanifibranor (or a deuterated derivative thereof), such as for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> of said compound.

In some embodiments, lanifibranor (or a deuterated derivative thereof) is administered at a daily dose of from <NUM> to <NUM>, such as for example a daily dose of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. 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. <NUM>.

In some embodiments, lanifibranor (or a deuterated derivative thereof) is administered to a subject with a meal. In some embodiments, lanifibranor (or a deuterated derivative thereof) is administered to a subject under fasted conditions.

Firsocostat 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 can be prepared by conventional methods, as described herein.

In some embodiments, the pharmaceutical composition comprises from <NUM> to <NUM> of firsocostat, such as for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> of said compound.

In some embodiments, firsocostat is administered at a daily dose of from <NUM> to <NUM>, such as for example a daily dose of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. Firsocostat 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. <NUM>.

In some embodiments, firsocostat is administered to a subject with a meal. In some embodiments, firsocostat is administered to a subject under fasted conditions.

In some embodiments, lanifibranor (or a deuterated derivative thereof) and firsocostat are administered simultaneously. In some embodiments, lanifibranor (or a deuterated derivative thereof) and firsocostat are administered sequentially. In some embodiment, lanifibranor (or a deuterated derivative thereof) and firsocostat are administered over a period of time.

In some embodiments, lanifibranor (or a deuterated derivative thereof) 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. The respective amounts of lanifibranor (or a deuterated derivative thereof) and firsocostat in such a pharmaceutical composition are as described herein.

The invention is illustrated by the following, non-limiting example.

It has been reported (<NPL>) that mice fed with a high fat/high cholesterol/high cholic acid diet with <NUM>% <NUM>-hydroxypropyl beta-cyclodextrin in drinking water for <NUM> weeks rapidly develops liver complications such as steatosis, inflammation and fibrosis with concomitant increase in plasma ALT/AST levels. The benefit of a combination therapy comprising lanifibranor and firsocostat was assessed in this model.

C57BL6/J mice were fed for <NUM> weeks with a <NUM>% high fat / <NUM>% cholesterol/<NUM>% cholic acid diet with <NUM>% <NUM>-hydroxypropyl beta-cyclodextrin in drinking water (HFCC/CDX diet). After <NUM> week of diet, blood was collected (~<NUM>µL/ethylenediaminetetraacetic acid (EDTA)) in non-fasting conditions and plasma ALT and AST levels were measured. Mice were then randomized into <NUM> homogenous treatment groups (n=<NUM> mice per group) according to their <NUM>) ALT levels, <NUM>) AST levels and <NUM>) body weight. The four groups received then their treatment for the remaining <NUM> weeks on top of the HFCC/CDX diet as follows:.

All treatments were given QD per os. Vehicle <NUM> stands for lanifibranor's vehicle (i.e. methyl cellulose/poloxamer), vehicle <NUM> stands for firsocostat's vehicle (i.e. Tween®<NUM>/methylcellulose). Lanifibranor was given at <NUM>/kg for <NUM> weeks and firsocostat was given at <NUM>/kg for the first <NUM> days and then at <NUM>/kg for the last <NUM> days: due to the high loss of weight observed in the combination group, the dose of firsocostat was adapted to limit toxicity. At the end of the treatment period all the mice were weighted and <NUM>-hour fasted prior to blood collection (maximal volume/EDTA). Plasma was isolated and stored at -<NUM>. Plasma leftover was used for evaluation of plasmatic triglycerides, cholesterols and free fatty acid. After blood collection, mice were sacrificed by cervical dislocation under isoflurane anaesthesia and exsanguinated with sterile saline.

The liver was collected and weighted then liver samples were dissected for histology analysis (H&E, Sirius Red staining, % Sirius Red labelling and NAFLD Activity Score (NAS)), liver lipids assay, hepatic gene expression of IL-1b, MCP-<NUM> for inflammation, Col1alpha1 and TGF-beta for fibrosis were analysed by qPCR.

As expected, HFCC+CDX diet did not impact the body weight during the two weeks of treatment. Lanifibranor induced a minor body weight loss that was not significant. Firsocostat however induced a body weight loss in the first week of treatment that was even more pronounced in the combination group when given at <NUM>/kg justifying a change in the dose that was reduced to <NUM>/kg. After this modification of dose both firsocostat and firsocostat + lanifibranor groups normalized their body weight (<FIG>).

In the HFCC+CDX diet model, neither lanifibranor alone, firsocostat alone nor the combination of lanifibranor and firsocostat had an effect of the epididymal white adipose tissue (EWAT) weight (<FIG>).

In the HFCC+CDX diet model, lanifibranor alone had no effect on hepatic fatty acids levels (<FIG>) and had a trend to decrease both hepatic total cholesterol (-<NUM>%) and hepatic triglycerides (-<NUM>%) however without reaching statistical significance (<FIG>). Firsocostat presented a trend in decreasing hepatic fatty acids levels (-<NUM>%), hepatic total cholesterol (-<NUM>%) and hepatic triglycerides (-<NUM>%) but without reaching statistical significance (<FIG>). The combination of lanifibranor and firsocostat decreased hepatic fatty acids levels (-<NUM>%; p<<NUM> vs vehicle), hepatic total cholesterol (-<NUM>%; p<<NUM> vs vehicle) and hepatic triglycerides (-<NUM>% p<<NUM> vs vehicle) with a high significance (<FIG>).

In the HFCC+CDX diet model, lanifibranor statistically decreased IL-1beta expression (p<<NUM> vs vehicle) and MCP-<NUM> expression (p<<NUM> vs vehicle). Firsocostat also decreased both IL-1beta and MCP-<NUM> expressions but only the decrease in MCP-<NUM> expression reached significance (p<<NUM> vs vehicle). The combination of lanifibranor and firsocostat further decreased the expression of IL-1beta and MCP-<NUM> with a higher statistical significance (p<<NUM> vs vehicle, <FIG>).

In the HFCC+CDX diet model, lanifibranor as well as firsocostat statistically decreased collagen 1alpha1 expression (p<<NUM> vs vehicle) and TGF-betal expression (p<<NUM> for lanifibranor and p<<NUM> for firsocostat vs vehicle). The combination of lanifibranor and firsocostat further decreased the expression of collagen 1alpha1 and TGF-beta1 with a higher statistical significance (p<<NUM> and p<<NUM> vs vehicle respectively, <FIG>).

In the HFCC+CDX diet model, lanifibranor statistically (p<<NUM> vs vehicle) decreased steatosis. All <NUM> vehicle animals presented a score of <NUM> (<NUM>, being the maximum) whereas the animals under lanifibranor had a score of <NUM> for <NUM> animals and of <NUM> for <NUM> animals. Firsocostat decreased the steatosis to a score of <NUM> in <NUM> animals but had no effect in <NUM> animals and consequently did not produce a significant effect. The combination of lanifibranor and firsocostat further decreased steatosis with a higher statistical significance (p<<NUM> vs vehicle) since all the animals presented a score of <NUM> (<FIG>).

In the HFCC+CDX diet model, lanifibranor as well as firsocostat statistically decreased inflammation (p<<NUM> vs vehicle). All mice under vehicle treatment presented a score of <NUM> (<NUM>, being the maximum). Under lanifibranor treatment <NUM> animals had a score of <NUM>, <NUM> animals had a score of <NUM> and <NUM> animals had a score of <NUM>. Under firsocostat treatment <NUM> animals had a score of <NUM>, <NUM> animals had a score of <NUM> and <NUM> animal had a score of <NUM>. The combination of lanifibranor and firsocostat further decreased inflammation with a higher statistical significance (p<<NUM> vs vehicle): indeed none of the animals had a score of <NUM>, <NUM> animals had a score of <NUM> and <NUM> animals had a score of <NUM> (<FIG>).

In the HFCC+CDX diet model, lanifibranor as well as firsocostat had no effect on the fibrosis score compared to the vehicle group but the combination of lanifibranor and firsocostat abolished the fibrosis in <NUM> mice out of <NUM> (p<<NUM> vs vehicle). The two remaining mice had a score of <NUM> such as observed in the vehicle group (<FIG>).

In this model, lanifibranor as well as firsocostat also tended to decrease the surface of fibrosis (<NUM>% and <NUM>% respectively, measured by the collagen deposition within the liver) compared to vehicle (<NUM>%) without being statistically significant. The combination of lanifibranor and firsocostat further decreased the fibrosis and demonstrated a statistically significant effect (<NUM>%, p<<NUM> vs vehicle, <FIG>).

In the HFCC+CDX diet model, lanifibranor as well as firsocostat statistically (p<<NUM> for lanifibranor and p<<NUM> for firsocostat vs vehicle) decreased the total scoring including steatosis, inflammation and fibrosis scoring (<NUM> and <NUM> respectively) compared to vehicle (<NUM>). The combination of lanifibranor and firsocostat further decreased the total scoring (<NUM>) with a higher statistical significance compared to vehicle (p<<NUM> vs vehicle, <FIG>).

Claim 1:
A combination product comprising (i) from <NUM> to <NUM>,<NUM> of lanifibranor or a deuterated derivative thereof, and (ii) from <NUM> to <NUM> of firsocostat, wherein the deuterated derivative of lanifibranor is a compound of formula (I):
<CHM>
wherein at least one of the groups R<NUM> to R<NUM> is a deuterium (D) atom and the other groups R<NUM> to R<NUM> are hydrogen (H) atoms.