CN116685321A - Methods for treating chronic kidney disease - Google Patents

Abstract

The present invention relates to a method for treating chronic kidney disease.

Description

Methods for treating chronic kidney disease

Technical Field

The present invention relates to the field of medicine, in particular Chronic Kidney Disease (CKD).

Background

Chronic Kidney Disease (CKD) is a long-term condition in which the kidneys fail to function properly. It has high popularity and estimated influence on hundreds of millions of people. Diabetes and hypertension are two major causes of CKD. Although kidneys have the ability to regenerate after an acute injury, regeneration and recovery are much more difficult in the case of chronic injury. Thus, this process is often irreversible, resulting in end stage renal disease, which requires dialysis or kidney transplantation.

CKD progression is characterized by the loss of the functional unit nephron of the kidney and its substitution by the extracellular matrix (ECM), independent of the concomitant disease. Thus, one of the consequences of CKD is glomerulosclerosis and tubular interstitial fibrosis, which are caused by an imbalance between the reduction of excessive synthesis and breakdown of ECM. There is currently no effective treatment to prevent the progression of renal fibrosis. The presence of fibrosis in CKD is strongly correlated with future manifestations of renal failure and thus with poor long-term prognosis.

More specifically, progressive CKD may be considered to have three phases. First, there is a cause-specific injury and an acute response to the injury. In the second stage, the misdirected repair produces fibrosis and dysfunction. At this stage, although fibrosis is a pathological and destructive event, it is essentially a self-limiting repair process, used to limit damage. The third and last stage is a relatively stable progressive loss of residual nephrons, which requires multiple neo-lesions per nephron or nephron cluster.

The Farnesoid X Receptor (FXR) is a Bile Acid (BA) activated nuclear receptor that is highly expressed in the liver, gall bladder, intestinal tract and kidneys, which regulates bile acid production, coupling and transport upon activation. FXR initiates a steady state response to control bile acid levels by inducing genes involved in bile acid excretion, coupling, detoxification and renal excretion. FXR agonists have been suggested for use in the treatment of diabetic nephropathy. More specifically, the FXR agonist, nidufexor (LMB 763), is currently being studied in phase II clinical trials for the treatment of NASH and diabetic nephropathy patients.

Many patent applications disclosing FXR agonists suggest their use in the treatment of kidney disease. For example, see, but not exclusively, WO2009/127321, WO2020/231917, WO2020/168143, WO2020/150136.

Current therapies have limited efficacy and can only delay disease progression, highlighting the need to develop new therapies to prevent or reverse progression. Thus, there is a strong unmet therapeutic need to achieve reversal/elimination of renal fibrosis.

Disclosure of Invention

The inventors have unexpectedly identified compounds (Vonafexor and dEF 2572) that are more effective in treating kidney disease than two reference FXR agonists, such as Nidufexor obeticholic acid. Indeed, although nidufenor is a stronger FXR agonist in the kidney than the identified compounds (fig. 4), these compounds showed better efficacy for unknown and unpredictable reasons. The same differential effect was observed in comparison with obeticholic acid (fig. 6). More specifically, the compounds of the present invention were able to partially but significantly reverse interstitial fibrosis without the significant effect of nidufenoor obeticholic acid being observed (fig. 1 and 6). The identified compounds, in particular Vonafexor, also show a higher beneficial effect than the CKD standard of care losartan. The therapeutic benefit of the Vonafexor on the kidney has been demonstrated in a clinical trial using it.

The present invention therefore relates to 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use in the treatment of kidney disease.

The 4-halogen-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid may be 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or 4-chloro-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

Preferably, the kidney disease is Chronic Kidney Disease (CKD).

Optionally, the subject to be treated has hypertension, type 2 diabetes, type 1 diabetes, obesity, non-alcoholic steatohepatitis (NASH), aging, infectious glomerulonephritis, focal segmental glomerulosclerosis, igA nephropathy, febrile disease, membranous nephropathy, renal small vessel inflammation, urinary tract obstruction, genetic alterations, autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and drug or toxin induced nephropathy. Optionally, the subject to be treated suffers from renal fibrosis, in particular tubular interstitial fibrosis.

Drawings

Fig. 1: compound dEF2572 treatment significantly reduced renal interstitial fibrosis in Nx mice. The mice were subjected to a kidney major excision (Nx). Treatment was started 5 weeks after Nx and continued for 3 weeks. Kidneys were collected at the time of sacrifice and fibrosis was assessed by quantification of the staining positive areas of sirius red (PSR). The p-values are noted on the graph.

Figure 2 treatment with compound dEF2572 significantly reduced tubular dilation in Nx mice. The mice were subjected to a kidney major excision (Nx). Treatment was started 5 weeks after Nx and continued for 3 weeks. Kidneys were collected at the time of sacrifice and tubular dilation was assessed by quantification of the staining positive areas of Periodic Acid Schiff (PAS). The p-values are noted on the graph.

Fig. 3: compound dEF2572 treatment significantly reduced glomerulopathy in Nx mice. The mice were subjected to a kidney major excision (Nx). Treatment was started 5 weeks after Nx and continued for 3 weeks. Kidneys were collected at the time of sacrifice and glomerular lesion extent was assessed using a semi-quantitative scoring system. Results are expressed as the average of scores of 40-60 glomeruli per mouse. The p-values are noted on the graph.

Fig. 4: both compound dEF2572 and Nidufexor treatment significantly increased kidney expression of both FXR target genes (OSTA and OSTB) in Nx mice. The mice were subjected to a kidney major excision (Nx). Treatment was started 5 weeks after Nx and continued for 3 weeks. Kidneys were collected at the time of sacrifice and OSTA and OSTB mRNA levels were assessed by quantitative RT-PCR. The p-values are noted on the graph.

Fig. 5: chronic kidney disease classification based on glomerular filtration rate and albuminuria. The data is from: kdaigo, recommended instruction digest (kdaigo. Summary of recommendation statements), kidney Int 2013,3 (suppl), 5; and national kidney disease foundation (National Kidney Foundation), guidelines for clinical practice of K/DOQI chronic kidney disease: evaluation, classification and stratification (K/DOQI clinical practice guidelines for chronic Kidney disease: evaluation, classification, and stratification), am J Kidney Dis 2002,39 (Suppl 1): S1.

Fig. 6: vonafexor treatment significantly reduced renal interstitial fibrosis in Nx mice. The mice were subjected to a kidney major excision (Nx). Treatment was started 5 weeks after Nx and continued for 3 weeks. Kidneys were collected at the time of sacrifice and fibrosis was assessed by quantification of the staining positive areas of sirius red (PSR). The p-values are noted on the graph.

Detailed Description

The examples show that in animal models, the compounds of the invention partially reverse renal fibrosis, in particular interstitial fibrosis, tubular dilation and glomerulopathy, all with significant effects.

The present invention relates to 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating kidney disease in a subject. It also relates to the use of 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating kidney disease in a subject. It also relates to a method of treating kidney disease in a subject in need thereof, comprising administering a therapeutic amount of 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

Thus, the compound for use according to the invention is 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof. More specifically, the compound may be 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid (dEF 2572) or a pharmaceutically acceptable salt thereof. Alternatively, the compound may be 4-chloro-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid (EYP 001) or a pharmaceutically acceptable salt thereof.

The compound 4-chloro-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid is also known as EYP001 or Vonafexor (CAS N. Degree. 1192171-69-9). The structure is as follows:

the compound 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid (CAS No 1192171-67-7) is also known as dEF2572 and has the structure:

definition of the definition

According to the invention, the following terms have the following meanings:

"pharmaceutically acceptable salts" include inorganic and organic acid salts. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, maleic acid, methanesulfonic acid, and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutical salts handbook, which is available in J.Pharm. Sci.1977,66,2 and in the main code of P.Heinrich Stahl and Camille G.Wermuth: properties, selection and Use (Handbook of Pharmaceutical Salts: properties, selection, and Use), the pharmaceutically acceptable salts listed in 2002. In a preferred embodiment, the salt is selected from the group consisting of maleate, hydrochloride, hydrobromide and mesylate salts. "pharmaceutically acceptable salts" also include inorganic and organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, or ammonium salts. Representative examples of suitable salts with organic bases include, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine. In a preferred embodiment, the salt is selected from sodium and potassium salts.

The term "treatment" as used herein refers to any action intended to improve the health state of a patient, such as the treatment, prevention, prophylaxis and delay of a disease. In certain embodiments, the term refers to the amelioration or eradication of a disease or symptom associated therewith. In other embodiments, the term refers to minimizing the spread or exacerbation of a disease as a result of administering one or more therapeutic agents to a subject suffering from the disease.

The terms "subject," "individual," or "patient" as used herein are interchangeable and refer to animals, preferably mammals, even more preferably humans, including adults and children. However, the term "subject" may also refer to non-human animals, particularly mammals such as dogs, cats, horses, cows, pigs, sheep, non-human primates, and the like.

The terms "amount," "amount," and "dose" are used interchangeably herein and may refer to an absolute quantification of a molecule.

The term "therapeutic effect" as used herein refers to an effect induced by the active ingredient or the pharmaceutical composition according to the present invention, which is capable of preventing or delaying the occurrence or development of a disease or disorder or curing or alleviating the effect of a disease or disorder.

The term "effective amount" as used herein refers to an amount of an active ingredient or pharmaceutical composition that prevents, removes, or mitigates the deleterious effects of a disease. Obviously, the amount to be administered may be adjusted by one skilled in the art depending on the subject to be treated, the nature of the disease, etc. In particular, the dosage and regimen of administration may vary with the nature, stage and severity of the disease to be treated and the weight, age and general health of the subject to be treated as well as the judgment of the physician.

The term "excipient or pharmaceutically acceptable carrier" as used herein refers to any ingredient other than the active ingredient present in the pharmaceutical composition. Its addition may be intended to provide a specific consistency or other physical or gustatory property to the final product. The excipient or pharmaceutically acceptable carrier must not interact, in particular chemically, with the active ingredient.

Kidney disease

In a particular aspect, the compounds of the invention are capable of reducing renal fibrosis. For example, the reduction may be a 20, 30, 40, 50, 60, 70, 80, 90, or 100% reduction in renal fibrosis as compared to renal fibrosis without treatment with the compound. The reduction may be measured by any method available to the person skilled in the art, for example in animal models as detailed in the examples. Optionally, the renal fibrosis is glomerulosclerosis. Optionally, the renal fibrosis is more particularly glomerulosclerosis. Optionally, the renal fibrosis is more particularly tubular interstitial fibrosis. Optionally, the renal fibrosis is both glomerulosclerosis and tubular interstitial fibrosis.

In addition, the compounds of the present invention are capable of reducing tubular dilation. For example, the reduction may be a 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% reduction in tubular dilation compared to tubular dilation without treatment with the compound. The reduction may be measured by any method available to the person skilled in the art, for example in animal models as detailed in the examples.

The compounds of the invention are capable of reducing glomerulopathy. For example, the reduction may be a 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% reduction compared to glomerulopathy without treatment with the compound. The reduction may be measured by any method available to the person skilled in the art, for example in animal models as detailed in the examples.

In one aspect, the subject to be treated has renal fibrosis. Renal fibrosis can be diagnosed on the basis of kidney biopsies. Alternatively, it may be diagnosed on the basis of alternative analyses such as Magnetic Resonance Imaging (MRI) or urethrai proteomics (e.g., CKD 273).

In a particular aspect, the renal fibrosis may include glomerulosclerosis. In another particular aspect, the renal fibrosis may include tubular interstitial fibrosis. In another particular aspect, the renal fibrosis may include both glomerulosclerosis and tubular interstitial fibrosis.

In a particular aspect, the kidney disease is chronic kidney disease. Preferably, the subject has kidney fibrosis and suffers from chronic kidney disease.

Chronic Kidney Disease (CKD) is defined as the presence of kidney injury (usually detected as urinary albumin excretion ≡30 mg/day or equivalent) or reduced renal function (defined as an estimated glomerular filtration rate [ eGFR ])]<60mL/min/1.73m ² ) Three months or more, regardless of the etiology.

In a particular aspect, the CKD is CKD based on glomerular filtration rate (evfr) as shown in fig. 5, having a stage selected from G1, G2, G3a, G3b, G4, or G5, preferably G1, G2, G3a, G3b, or G4, more preferably G2, G3a, or G3 b. Preferably, the subject has renal fibrosis.

In another particular aspect, the CKD is based on Albuminuria (ACR) as shown in fig. 5, having a CKD phase selected from A1, A2, or A3.

Table 1: CKD staging

Optionally, the CKD has a phase selected from phase 1 x, phase 1, phase 2, or phase 3 defined in table 1. Optionally, the CKD has a phase selected from phase 1, phase 2, or phase 3 defined in table 1. Optionally, the CKD has a phase selected from phase 1 or phase 2 defined in table 1.

In a first particular aspect, the CKD is CKD of stage 1 defined in table 1 or of the gfr-based G1 or G2 shown in fig. 5 and ACR-based A1 shown in fig. 5.

In a second particular aspect, the CKD is CKD of stage 1 defined in table 1 or of the gfr-based G1 or G2 shown in fig. 5 and of the ACR-based A2 or G3a shown in fig. 5 and of the ACR-based A1.

In a third particular aspect, the CKD is CKD of stage 2 defined in table 1 or of the G1 or G2 based on the eGFR shown in fig. 5 and of the G3 based on the ACR or G3a based on the eGFR and the A2 based on the ACR or G3b based on the gfr and the A1 based on the ACR shown in fig. 5.

In a fourth particular aspect, the CKD is CKD of stage 3 defined in table 1 or of the gfr-based G3a shown in fig. 5 and of the ACR-based A3 b shown in fig. 5 and of the ACR-based A2 or A3 or of the gfr-based G4 and of the ACR-based A1.

The effect of the compounds on the disease can be assessed, for example, by measurement of the eGFR or ACR. The therapeutic effect may be an improvement in the gfr and/or ACR. The therapeutic effect may be stabilization of the gfr and/or ACR. The therapeutic effect may also be a delay in disease progression or a slowing of disease progression, as assessed by e.g. gfr and/or ACR assays.

In a particular aspect, the subject has renal fibrosis and suffers from a disease selected from the group consisting of: hypertension, type 2 diabetes, type 1 diabetes, obesity, nonalcoholic steatohepatitis (NASH), aging, infectious glomerulonephritis (in particular infections such as syphilis, malaria, hepatitis b, hepatitis c or HIV), focal segmental glomerulosclerosis, igA nephropathy, slightly diseased glomerulopathy, membranous nephropathy, renal small vessel inflammation, urinary obstruction, genetic alterations, autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and drug or toxin induced renal disease such as those induced by drugs such as captopril, NSAIDs, penicillamine, probenecid, busidine, anti-TNF therapy and tiopronin or by toxins such as inorganic salts (e.g. gold, mercury).

Optionally, the subject has renal fibrosis and suffers from primary kidney disease such as focal segmental glomerulosclerosis, igA nephropathy, minuscule degenerative glomerulopathy, membranous nephropathy, urinary tract infection, stones, obstructive disease, and renal small vessel inflammation. Optionally, the subject has tubular interstitial fibrosis.

Optionally, the subject has CKD, particularly CKD of any particular stage as defined above, and suffers from primary kidney disease such as focal segmental glomerulosclerosis, igA nephropathy, morbid glomerulopathy, membranous nephropathy, urinary tract infection, calculi, obstructive disease, and renal small vessel inflammation. Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

In another particular aspect, the subject has renal fibrosis and suffers from a systemic disease affecting the kidney, such as a disease selected from the group consisting of: hypertension, type 2 diabetes, type 1 diabetes, non-alcoholic steatohepatitis (NASH), infectious glomerulonephritis (in particular infections such as syphilis, malaria, hepatitis b, hepatitis c or HIV), renal small vessel inflammation, autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and drug or toxin induced renal diseases such as those induced by drugs such as captopril, NSAIDs, penicillamine, probenecid, busyramine, anti-TNF therapies and tiopronin or by toxins such as inorganic salts (e.g. gold, mercury). Optionally, the subject has tubular interstitial fibrosis.

Optionally, the subject has CKD, particularly CKD at any particular stage as defined above, and suffers from a systemic disease affecting the kidneys, for example a disease selected from the group consisting of: hypertension, type 2 diabetes, type 1 diabetes, non-alcoholic steatohepatitis (NASH), infectious glomerulonephritis (in particular infections such as syphilis, malaria, hepatitis b, hepatitis c or HIV), renal small vessel inflammation, autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and drug or toxin induced renal diseases such as those induced by drugs such as captopril, NSAIDs, penicillamine, probenecid, busyramine, anti-TNF therapies and tiopronin or by toxins such as inorganic salts (e.g. gold, mercury). Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

Optionally, the subject suffers from hypertension. The subject may have CKD at stage 1, 2 or 3 as defined above in table 1. Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

Optionally, the subject has type 2 diabetes or type 1 diabetes. The subject may have CKD at stage 1, 2 or 3 as defined above in table 1. Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

Optionally, the subject has Systemic Lupus Erythematosus (SLE). The subject may have CKD at stage 1, 2 or 3 as defined above in table 1. In this case, the subject may have lupus kidney disease of class III, IV, V or VI. Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

Optionally, the subject has NASH or NAFLD. The subject may have CKD at stage 1, 2 or 3 as defined above in table 1. Nonalcoholic steatohepatitis (NASH) is a disease characterized by excessive accumulation of fat, inflammation and ballooning of hepatocytes, with or without liver fibrosis. In addition, some subjects affected by NASH may further develop chronic kidney disease. The compounds of the invention may be of particular interest for these particular subjects. In fact, the compounds of the invention are able to significantly reduce inflammation and fibrosis in the liver in a dose-dependent manner, and they are also able to significantly inhibit fibrosis in the kidney, even reverse existing fibrosis, and also able to reduce kidney inflammation. Thus, the compounds of the invention are useful for protecting a subject suffering from NASH from liver and kidney lesions or for treating a subject suffering from NASH so as to limit, slow or reverse liver and kidney lesions. Thus, the subject is in particular a subject suffering from NASH or NAFLD and having renal fibrosis. Optionally, the subject is a subject having NASH or NAFLD and having CKD. Optionally, the subject has renal fibrosis, in particular tubular interstitial fibrosis.

Optionally, the kidney disease is selected from AIDS-related kidney disease, ischemic kidney disease, tubular interstitial kidney disease, hepatorenal syndrome, hydronephrosis, renal dysplasia, medullary cystic kidney disease, medullary spongiform kidney, polycystic kidney dysplasia, podocytosis, papillary necrosis of the kidney, nephritis including glomerulonephritis, hereditary nephritis, interstitial nephritis, pyelitis, nephrocals, nephrosclerosis, alport syndrome, fabry disease, renal sarcoidosis, diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren syndrome, alar Ji Ouzeng syndrome, alpha 1 antitrypsin deficiency, and polycystic kidney disease.

Optionally, the kidney disease is selected from AIDS-related kidney disease, ischemic kidney disease, tubular interstitial kidney disease, hepatorenal syndrome, hydronephrosis, renal dysplasia, medullary cystic kidney disease, medullary spongiform nephrosis, polycystic kidney dysplasia, podocytosis, renal papillary necrosis, nephritis including glomerulonephritis, hereditary nephritis, interstitial nephritis, pyelitis, renal calcareous pigmentation disorder, nephrosclerosis, alport syndrome, fabry disease, and renal sarcoidosis.

Optionally, the kidney disease is selected from the group consisting of diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive glomerulosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1 antitrypsin deficiency and polycystic kidney disease.

In a particular aspect, the kidney disease is selected from diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive glomerulosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1-antitrypsin deficiency and polycystic kidney disease, and the compound is 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

In another particular aspect, the kidney disease is selected from the group consisting of diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive glomerulosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1-antitrypsin deficiency and polycystic kidney disease, and the compound is to be administered twice or three times daily.

Combination of

The compounds of the present disclosure may be used in combination with other therapeutic agents. The additional therapeutic agent may be selected from agents that have been used to treat one of the diseases described above. In particular, the additional therapeutic agent may be an anti-inflammatory agent.

Pharmaceutical composition

The pharmaceutical composition comprises a compound of the invention and optionally at least one pharmaceutically acceptable carrier or excipient.

The compounds according to the present disclosure or the pharmaceutical compositions according to the present disclosure may be administered by any conventional route of administration. In particular, the compounds or pharmaceutical compositions of the present disclosure may be administered by topical, enteral, oral, parenteral, intranasal, intravenous, intra-arterial, intramuscular, subcutaneous, or intraocular administration, and the like.

In particular, compounds according to the present disclosure or pharmaceutical compositions according to the present disclosure may be formulated for topical, enteral, oral, parenteral, intranasal, intravenous, intra-arterial, intramuscular, subcutaneous, or intraocular administration, and the like.

Preferably, the compounds according to the present invention or the pharmaceutical compositions according to the present disclosure are administered by enteral or parenteral routes of administration. When administered parenterally, the compounds according to the present disclosure or pharmaceutical compositions according to the present disclosure are preferably administered by intravenous route of administration. When enterally administered, the compounds according to the present disclosure or pharmaceutical compositions according to the present disclosure are preferably administered by the oral route of administration.

Pharmaceutical compositions comprising the molecules are formulated according to standard pharmaceutical practice known to those skilled in the art (Lippincott Williams & Wilkins,2000 and encyclopedia of pharmaceutical technology (Encyclopedia of Pharmaceutical Technology), J.Swarbrick and J.C.Boylan, inc., 1988-1999,Marcel Dekker,New York).

For oral administration, the compositions may be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs and concentrated drops. Non-toxic solid carriers or diluents can be used and include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. For compressed tablets, binders are also necessary as agents for imparting cohesive properties to the powdered material. For example, starches, gelatins, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also necessary in tablets to promote disintegration of the tablet. Disintegrants include starches, clays, celluloses, algins, gums and cross-linked polymers. Additionally, lubricants and glidants are included in the tablet to prevent the tablet material from adhering to surfaces during manufacture and to improve the flow characteristics of the powder material during manufacture. Colloidal silica is most commonly used as a glidant, and compounds such as talc or stearic acid are most commonly used as lubricants.

For transdermal administration, the composition may be formulated in the form of an ointment, cream or gel, and a suitable penetrant or detergent may be used to facilitate penetration, such as dimethyl sulfoxide, dimethylacetamide and dimethylformamide.

For transmucosal administration, nasal sprays, rectal or vaginal suppositories may be used. The active compounds may be incorporated into any known suppository base by methods known in the art. Examples of such binders include cocoa butter, polyethylene glycols (carbowax), polyethylene sorbitan monostearate and mixtures of these with other compatible materials which alter the melting point or dissolution rate.

The pharmaceutical compositions according to the present invention may be formulated to release the active agent substantially immediately after administration or at any predetermined time or period after administration.

The compounds according to the present invention or the pharmaceutical compositions according to the present disclosure may be administered as a single dose or in multiple doses.

Preferably, the treatment is administered periodically, preferably between daily and every month, more preferably between daily and every two weeks, more preferably between daily and weekly, even more preferably the treatment is administered daily.

In particular embodiments, the treatment is administered daily, optionally 1, 2 or 3 times daily. In a particular aspect, the treatment is administered at least twice daily, in particular 2 or 3 times daily. In an alternative aspect, the treatment is administered once daily.

The duration of treatment with the compounds according to the invention or the pharmaceutical compositions according to the invention may be weeks, months or even years. In particular, the duration of the treatment may be continued as long as the disease is continued.

The amount of a compound according to the present disclosure or a pharmaceutical composition according to the present disclosure to be administered must be determined by standard procedures well known to those of ordinary skill in the art. In order to determine the appropriate dosage, the patient's physiological data (e.g., age, body size, and weight) and route of administration must be taken into account so that a therapeutically effective amount can be administered to the patient.

In a particular aspect, the total compound dose per administration of a compound according to the present disclosure or a pharmaceutical composition according to the present disclosure is between 0.00001 and 1 g.

The form of the pharmaceutical composition, the route of administration and the dosage of the compound according to the present disclosure or the pharmaceutical composition according to the present disclosure may be adjusted by one skilled in the art according to the type and severity of the disease and according to the patient, in particular, the age, weight, sex and general physical condition thereof.

Other aspects and advantages of the invention are described in the following examples, which should be regarded as illustrative rather than limiting.

Examples

Example 1

Materials and methods

Experimental plan

Analysis focused on experimental models of CKD, i.e., kidney major excision (Nx). In this model, a "curative study" was studied, i.e. treatment was started 5 weeks after Nx, at which time lesions had developed.

42 9 week old FVB female mice were studied, 6 of which received sham surgery (control), 36 received major kidney resections (Nx), which included resecting both poles of the right and left kidneys to reduce total kidney mass by 75%. The procedure was performed under anesthesia with tolthiazine (Rompun 2%; bayer, leverkusen, france) (6. Mu.g/g body weight) and ketamine (Clorketam 1000;Vetoquinol SA,Lirre,France) (120. Mu.g/g body weight).

After 5 weeks, mice were divided into 4 groups:

sham operated mice treated with vehicle (n=6)

Nx mice treated with vehicle (n=10)

Nx mice treated with 100 mg/Kg/day dEF2572 FXR agonist (4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid) (n=11)

Nx mice treated with 30 mg/Kg/day of Nidufexor (LMB 763) FXR agonist (n=10)

The compounds were administered once daily (QD) via oral feeding tube.

Mice were sacrificed after 3 weeks. Blood was collected immediately before death. Kidneys were harvested at sacrifice for morphology and mRNA analysis.

Histological methods

Kidneys were fixed in 4% paraformaldehyde, paraffin embedded, and 4- μm sections were stained with Periodic Acid Schiff (PAS), parkinson's trichromat, hematoxylin and eosin, and sirius scarlet (PSR). Images were acquired using a Nikon digital camera Dx/m/1200. All sections were evaluated by pathologists blinded to the treatment group.

Glomerular lesion extent was assessed on Periodic Acid Schiff (PAS) staining using a semi-quantitative scoring method. Briefly, 40-60 glomeruli per mouse were scored at X400 magnification using the following scoring system: 0 = no lesions, 1 = mild sclerosis, involving 10-25% of glomeruli; 2 = moderate sclerosis, involving 25% -50% of glomeruli; 3 = severe sclerosis, involving 50% -75% of glomeruli; and 4 = global sclerosis, involving >75% glomeruli. Results are expressed as the average of scores of 40-60 glomeruli per mouse.

The extent of tubular dilation was quantified automatically on PAS staining using Image J/Fiji software version 2.1.0. The degree of interstitial fibrosis was also quantified using Image J/Fiji software. All kidney samples were stained with sirius scarlet (PSR) at the same time and red intensity above a prescribed threshold was defined as fibrosis. For tubular dilation and interstitial fibrosis, at least 10 to 15 randomly selected fields of view (magnification X200) across the pithelial junction were analyzed per kidney section and the results were expressed as a percentage of the total area of the selected fields of view.

Results

Two FXR agonists, namely compound EF2572 (4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid) and Nidufexor (also known as LMB 763), were evaluated in a mouse model of Chronic Kidney Disease (CKD). Mice were subjected to a major kidney resection (Nx) and treatment for 3 weeks was initiated 5 weeks after induction of disease. Kidneys were collected at the time of sacrifice to assess kidney lesions by histopathology. As shown on figures 1, 2 and 3, compound EF2572 treatment significantly reduced renal interstitial fibrosis, tubular dilation and glomerulopathy, respectively, in Nx mice.

It should be noted that those beneficial effects on the kidneys caused by compound dEF2572 were not observed after treatment with Nidufexor, although both compounds had strong renal FXR target engagement as shown by induction of OSTA and OSTB gene expression in the kidneys (fig. 4).

Example 2

Materials and methods

Experimental plan

Analysis focused on experimental models of CKD, i.e., kidney major excision (Nx). In this model, a "curative study" was studied, i.e. treatment was started 5 weeks after Nx, at which time lesions had developed.

54 9 week old FVB female mice were studied, 6 of which received sham surgery (control), 48 received major kidney resections (Nx), which included resecting both poles of the right and left kidneys to reduce total kidney mass by 75%. The procedure was performed under anesthesia with tolthiazine (Rompun 2%; bayer, leverkusen, france) (6. Mu.g/g body weight) and ketamine (Clorketam 1000;Vetoquinol SA,Lirre,France) (120. Mu.g/g body weight).

After 5 weeks, mice were divided into 5 groups:

sham operated mice treated with vehicle (n=6)

Nx mice treated with vehicle (n=9)

Nx mice treated with 100 mg/Kg/day of Vonafexor FXR agonist (n=12)

Nx mice treated with 30 mg/Kg/day obeticholic acid (OCA) FXR agonist (n=12)

Nx mice treated with losartan of 30 mg/Kg/day (n=12)

The compounds were administered once daily (QD) via oral feeding tube.

Mice were sacrificed after 3 weeks. Kidneys were harvested at sacrifice for morphological analysis.

Histological methods

Kidneys were fixed in 4% paraformaldehyde, paraffin embedded, and 4- μm sections were stained with sirius scarlet (PSR). Images were acquired using a Nikon digital camera Dx/m/1200. All sections were evaluated by pathologists blinded to the treatment group.

All kidney samples were stained with sirius scarlet (PSR) and red intensity above a specified threshold was defined as fibrosis. For interstitial fibrosis, at least 10 to 15 randomly selected fields of view (magnification X200) across the pithelial junction were analyzed per kidney section and the results were expressed as a percentage of the total area of the selected fields of view.

Results

Two FXR agonists Vonafexor and OCA and losartan were evaluated in a mouse model of Chronic Kidney Disease (CKD). Mice were subjected to a major kidney resection (Nx) and treatment for 3 weeks was initiated 5 weeks after induction of disease. Kidneys were collected at the time of sacrifice to assess interstitial fibrosis by histopathology. As shown on fig. 6, vonafexor treatment significantly reduced renal interstitial fibrosis in Nx mice.

It should be noted that those beneficial effects on the kidneys caused by Vonafexor were not observed after treatment with OCA, vonafexor being significantly better than OCA. In addition, vonafexor also shows higher beneficial effects compared to the standard of care losartan for CKD.

Example 3

Vonafexor-induced improvement of liver and kidney function in a randomized, double-blind placebo-controlled Livify NASH trial

Vonafexor has anti-fibrotic effects in NASH and Chronic Kidney Disease (CKD) models. Up to 64% of NASH patients have reduced estimated glomerular filtration rate (evfr<90mL/min/1.73m ² ) This may evolve into CKD. Stage 2a results in NASH patients treated with normal or slightly reduced egffr are reported below.

Method

96 patients were randomized 1:1:1 to daily oral placebo (PBO, n=32) or VONA (Vonafexor) mg (n=31) or 200mg (n=33) for 12 weeks (W12). Inclusion criteria required phenotype 2 or 3 stage fibrotic NASH, absolute liver fat content (LFC obtained by MRI-PDFF) > 10%, liver hardness by transient elastography [ LSTE ] > 8.5kPa or NASH confirmed by previous biopsies. Random groupings were stratified by diabetes and LFC.

Results

Baseline characteristics were similar between the two arms. In VONA treated patients there was a statistically significant decrease in absolute LFC (liver fat content) at W12 (100 mg used-6.3%, 200mg used-5.5%, PBO used-2.3%, p < 0.001) (table 2). 58% of patients in the 100mg group achieved an absolute LFC reduction of >5% compared to 22% of patients in the PBO group, and >30% relative LFC reduction in 50% of VONA treated patients compared to 13% of PBO patients.

VONA treatment significantly reduced ALT by 26% on average compared to 13% for PBO group. A rapid and sustained 42% average decrease in GGT (p < 0.001) was also observed in VONA treated subjects. The Liver fiber-inflammation marker cT1 (lever Multiscan) was reduced by 81msec in the 100mg VONA arm compared to 10msec (p < 0.001) in the PBO arm.

An increase of 34% in low density lipoprotein cholesterol (LDL-C) was observed. Statin dose adjustment normalized LDL-C levels to 70mg/dL.9% of patients cease to participate in VONA 100mg due to itching, which is mostly mild, transient and localized. No ALT increase was reported at No. 2. Serious adverse events associated with 5 non-drug were reported (1 in the PBO group and 2 in the VONA 100mg and 200mg groups each).

In kidney, a significant average increase in eGFR [ +5.6mL/min/1.73m was observed in subjects treated with VONA 100mg or 200mg ² ]Whereas a decrease in eGFR [ -2.8mL/min/1.73m was observed in the PBO group ² ]. eGFR improvement in 76% of patients receiving VONA during 12 weeks of treatment and in VONA 100mg of treated subjects>0.1mL/min/1.73m ² While 66% of patients receiving placebo had reduced renal function.

VONA treatment showed significant benefits for eGFR and also reduced alpha-2-macroglobulin (A2M) plasma levels. A2M and evfr are parameters for assessing kidney disease. A2M is a major human plasma protein with a variety of functions including ion transport, carrier protein and protease inhibition. Elevated levels are observed in clinical situations such as cirrhosis and liver fibrosis, nephrotic syndrome, severe burns, femoral head necrosis and diabetes. The A2M level is related to egffr but not to glycemic control parameters in diabetics with CKD. These patients had elevated A2M levels and urinary albumin: creatinine ratio (AcR) correlates with A2M levels. Surprisingly, FXR agonism by vonafor reduced A2M plasma levels in NASH patients and this decrease was associated with an increase in eGFR (p < 0.05). The A2M reduction can be considered a biomarker of renal function improvement caused by Vonafexor and can be used to monitor the therapeutic response to Vonafexor.

In summary and surprisingly, VONA treatment is also associated with renal benefit in addition to beneficial liver effects. Overall, VONA is safe and well tolerated, with a 100mg dose showing more favorable tolerability-efficacy profile.

Table 2: baseline value of key study results and change from baseline to W12

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Claims (15)

1. A compound for use in the treatment of kidney disease, wherein the compound is 4-halo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

2. The compound for use according to claim 1, wherein the compound is 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

3. The compound for use according to claim 1, wherein the compound is 4-chloro-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

4. A compound for use according to any one of claims 1-3, wherein the kidney disease is Chronic Kidney Disease (CKD).

5. The compound for use according to claim 4, wherein the CKD has a phase selected from phase 1, phase 2 or phase 3 defined in table 1.

6. The compound for use according to claim 4, wherein the CKD has a phase selected from phase 1, phase 2 or phase 3 defined in table 1.

7. The compound for use according to claim 4, wherein the CKD has a phase selected from phase 1 or phase 2 defined in table 1.

8. The compound for use according to any one of claims 1-7, wherein the subject has hypertension, type 2 diabetes, type 1 diabetes, obesity, non-alcoholic steatohepatitis (NASH), aging, infectious glomerulonephritis, focal segmental glomerulosclerosis, igA nephropathy, slightly-pathogenic glomerulopathy, membranous nephropathy, renal small vessel inflammation, urinary tract obstruction, genetic changes, autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and drug or toxin-induced kidney disease.

9. The compound for use according to any one of claims 1-7, wherein the subject has renal fibrosis, in particular tubular interstitial fibrosis.

10. A compound for use according to any one of claims 1-9, wherein the kidney disease is selected from AIDS-related kidney disease, ischemic kidney disease, tubular interstitial kidney disease, hepatorenal syndrome, hydronephrosis, renal dysplasia, medullary cystic kidney disease, medullary spongiform kidney, polycystic kidney dysplasia, podocytopathy, papillary necrosis of the kidney, nephritis including glomerulonephritis, hereditary nephritis, interstitial nephritis, pyelonephritis, nephrocalcanesis, nephrosclerosis, alport syndrome, fabry disease and sarcoidosis.

11. The compound for use according to any one of claims 1-9, wherein the kidney disease is selected from diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1 antitrypsin deficiency and polycystic kidney disease.

12. A compound for use according to any one of claims 1-9, wherein the kidney disease is selected from diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1-antitrypsin deficiency and polycystic kidney disease, and the compound is 4-bromo-5- [4- (2, 6-dichloro-benzenesulfonyl) -piperazin-1-yl ] -benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

13. The compound for use according to any one of claims 1-9, wherein the kidney disease is selected from diabetic nephropathy, focal Segmental Glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, sjogren's syndrome, alar Ji Ouzeng syndrome, alpha 1-antitrypsin deficiency and polycystic kidney disease, and the compound is administered twice or three times daily.

14. The compound for use according to any one of claims 1-13, wherein the compound is administered twice or three times daily.

15. The compound for use according to any one of claims 1-13, wherein the compound is administered once daily.