Pemafibrate and / or tofogliflozin for use in the treatment of liver disease

Abstract

Pemafibrate, tofogliflozin, or a combination thereof, for use in treating human patients with liver disease, particularly NASH patients with cirrhosis or liver fibrosis, NASH patients with lobular inflammation, NASH patients with elevated LDL-C, and NASH patients with healthy triglyceride levels.

Description

[Technical field]

[0001] Methods of using pemafibrate, tofogliflozin, and combinations thereof to treat human patients with liver disease, particularly NAFLD or NASH patients with cirrhosis or liver fibrosis, NAFLD or NASH patients with elevated ALT levels, NAFLD or NASH patients with elevated LDL-C, and NAFLD or NASH patients with healthy triglyceride levels. [Background technology]

[0002] Nonalcoholic fatty liver disease (NAFLD) is a medical condition in which excess fat accumulates in the liver. NAFLD includes nonalcoholic fatty liver ("NAFL"), in which there is no hepatocellular damage, and nonalcoholic steatohepatitis ("NASH"), which is characterized by steatosis, inflammation, and ballooning. Most cases of NAFLD develop as a result of obesity, diabetes mellitus, dyslipidemia, or hypertension. Due to the rise in the obese population, the number of patients with NAFLD and NASH is increasing worldwide, with the prevalence estimated to be 20-30% and 2-6%, respectively.

[0003] Pemafibrate is a selective PPARα modulator approved in Japan for the treatment of hyperlipidemia. Pemafibrate is chemically designated (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid and has the following chemical structure:

[0004] [ka] has.

[0005] Pemafibrate controls the expression of genes primarily involved in hepatic lipid and glucose metabolism. It also increases gene expression related to β-oxidation and lipid transport, and promotes energy metabolism by inducing mitochondrial uncoupling protein ("UCP") 3 gene expression. Preclinical studies in low-density lipoprotein ("LDL") receptor knockout mice and KK-A mice fed an MCD (methionine-choline deficient) diet showed that pemafibrate inhibited hepatocyte ballooning and fat accumulation, and reduced the number of Kupffer cells. See U.S. Patent Application Publication No. 2016 / 0136138 to Shibata et al.

[0006] Anhydrous tofogliflozin is chemically described as 6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol and has the following chemical structure:

[0007] [ka] The United States Nonproprietary Name ("USAN") tofogliflozin applies to the monohydrate, which is the form used as a drug. The International Nonproprietary Name ("INN") tofogliflozin applies to the anhydrous compound, and the drug form is called tofogliflozin hydrate. As used herein, tofogliflozin refers to the chemical compound 6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol, and thus includes all hydrated, solvated, crystalline, and amorphous forms of the compound.

[0008] Tofogliflozin was previously developed by Hoffman La-Roche Inc. and Chugai Pharmaceutical Co., Ltd. for the treatment of type 2 diabetes mellitus (T2DM). Tofogliflozin is a potent and selective inhibitor of SGLT2, which is localized in renal tubules and responsible for glucose reabsorption from renal filtrate. Preclinical studies in the HHC mouse model of NASH show that the combination of pemafibrate and tofogliflozin reduces lipid droplet size in animal hepatocytes, resulting in improved hepatocyte ballooning. See U.S. Patent Application Publication No. 2020 / 0022960 to Sasaki et al.

[0009] In addition to the steatosis, inflammation, and ballooning that characterize NASH and some NAFLD patients, there remains a need to treat and / or prevent cirrhosis and liver fibrosis in NASH and some NAFLD patients. There further remains a need to treat lipid and liver enzyme abnormalities in NAFLD and NASH patients and to characterize patients who would benefit most from such treatment, particularly in terms of lipid profile. Summary of the Invention

[0010] The inventors have unexpectedly discovered that pemafibrate, tofogliflozin, and their combinations can treat and / or prevent cirrhosis and liver fibrosis in NASH and some NAFLD patients.Accordingly, in a first main embodiment, the present invention provides a method for treating cirrhosis or liver fibrosis in patients with non-cirrhotic non-cirrhotic NASH or NAFLD and having a NASH CRN fibrosis score of 1 or more and less than 4, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharmaceutically acceptable salt thereof, (b) tofogliflozin or a pharmaceutically acceptable salt thereof, or (c) a combination thereof.

[0011] The inventors have further discovered that pemafibrate, tofogliflozin, and their combinations can treat NASH histology, particularly lobular inflammation, in NASH and NAFLD patients.Therefore, in a second main embodiment, the present invention provides a method for treating lobular inflammation in patients with non-cirrhotic NASH or NAFLD, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharmacologic acceptable salt thereof, (b) tofogliflozin or a pharmacologic acceptable salt thereof, or (c) a combination thereof.In a particularly preferred embodiment, the method is performed without worsening fibrosis in patients with a NASH CRN fibrosis score of 1 or more and less than 4.

[0012] The inventors have further discovered that the therapeutic methods described herein result in unexpected improvements in liver enzyme activity, particularly in patients with fibrosis and elevated alanine aminotransferase ("ALT") levels. Thus, in a third main embodiment, the present invention provides a method of improving liver function, as measured by ALT activity, in patients with non-cirrhotic NASH or NAFLD, with a NASH CRN fibrosis score of ≥1 and <4, and an ALT score of ≥2x ULN, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharma- ceutical acceptable salt thereof, (b) tofogliflozin or a pharma-ceutical acceptable salt thereof, or (c) a combination thereof.

[0013] The inventors have also discovered that the treatment methods described herein result in unexpected improvements in LDL-C, particularly in patients with fibrosis and high LDL-C levels.Accordingly, in a fourth main embodiment, the present invention provides a method of lowering LDL-C in a patient with non-cirrhotic NASH or NAFLD, having a NASH CRN fibrosis score of ≥1 and <4, and an LDL-C concentration of ≥100 mg / dL, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharma- ceutical acceptable salt thereof, (b) tofogliflozin or a pharma-ceutical acceptable salt thereof, or (c) a combination thereof.

[0014] Surprisingly, any of the above methods, including those that rely on pemafibrate, can be performed in patients with normal triglyceride levels.

[0015] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Definitions and Use of Terms As used in this specification and claims, the singular forms a, an, and the include plural references unless the context clearly dictates otherwise. For example, the term "a specification" refers to one or more specifications for use in the presently disclosed methods and systems. "An ingredient" includes mixtures of two or more such ingredients, and the like. The word "or" or similar terms are used herein to mean any one member of a particular list, and also include any combination of members of that list.

[0017] As used in this specification and the claims that follow, the word "comprise" and variations of that word, such as "comprising" and "comprises," mean "including but not limited to" and are not intended to exclude, for example, other additives, components, integers, or steps. It will be understood that when an element is described as comprising one or more components, steps, or conditions, the element can also be described as "consisting of" or "consisting essentially of" the component, step, or condition, or multiple components, steps, or conditions.

[0018] "Therapeutically effective amount" means an amount that, when administered to a human for supporting or affecting metabolic processes, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease, or to support or affect metabolic processes.

[0019] As "drug therapy," "drug administration," and similar terms are used herein, it will be understood that therapy may be accomplished through any suitable route of administration using any acceptable dosage form, and that drugs may be administered as a free base or acid, a salt, or an ester or other prodrug moiety.

[0020] When combination drug therapy is referred to herein for the achievement of a single endpoint or therapeutic objective, it will be understood that each of the individual active ingredients in the combination contributes to the achievement of the stated endpoint or therapeutic objective.Furthermore, in a preferred embodiment, it will be understood that each of the active ingredients contributes to a statistically significant clinical benefit in a properly powered patient population.When multiple endpoints or therapeutic objectives are to be achieved, it will be understood that both of the individual active ingredients contribute to the achievement of at least one endpoint or therapeutic objective, preferably all endpoints or therapeutic objectives, preferably to a statistically significant clinical benefit in a properly powered patient population, and any endpoints or therapeutic objectives that do not jointly contribute are preferably achieved by at least one active ingredient to a statistically significant clinical benefit.

[0021] As used herein, the term "about" is accepted in the pharmaceutical industry and compensates for variations inherent in products in this industry, such as differences in product strength due to manufacturing variations and product degradation caused by time, as well as differences due to water of hydration and different salts. This term allows for any variation in the implementation of pharmaceutical manufacturing and quality control standards, and allows the product being evaluated to be considered therapeutically equivalent or bioequivalent to the stated strength of the claimed product in humans. In one embodiment, this term allows for any variation within 5% of the stated specification or standard. In one embodiment, this term allows for any variation within 10% of the stated specification or standard.

[0022] Whenever a number is used to describe an element of the present invention, it will be understood that the number can be modified or replaced by a number modified by the term "about."

[0023] When published test methodologies and diagnostic devices are referred to herein, it will be understood that the test methodology or diagnostic device is performed based on the version in effect on May 1, 2021, unless specifically stated to the contrary in this specification.

[0024] When ranges are expressed herein by specifying alternative upper and lower limits of the range, it will be understood that the endpoints can be combined in any manner mathematically feasible. Thus, for example, a range of 50 or 80-100 or 70 can be expressed alternatively as a series of ranges of 50-100, 50-70, and 80-100. When a series of upper and lower limits are linked using the phrase "and" or "or", it will be understood that the upper limit is not limited by or can be combined with the lower limit, and vice versa. Thus, for example, a range of more than 40% and / or less than 80% includes the ranges of more than 40%, less than 80%, and more than 40% but less than 80%. Unless specified by the term "between", the boundaries of the range (lower and upper ends of the range) are included in the claims.

[0025] It will be understood that when an element of a process or thing is defined by reference to one or more examples, components, properties, or characteristics, any or any combination of these components, properties, or characteristics can also be used to define the matter in question. This can occur, for example, when specific examples of an element are recited in the claims (such as in a Markush group) or when an element is defined by multiple properties. Thus, for example, if a claimed system includes element A defined by elements A1, A2, and A3, in combination with element B defined by elements B1, B2, and B3, it will be understood that the invention also covers systems defined by element A without element B, systems in which element A is defined by elements A1 and A2, and combined with element B defined by elements B2 and B3, and all other possible permutations.

[0026] In the context of the present invention, the term "treatment" insofar as it relates to any pathology described herein means reducing the occurrence of symptoms or pathologies, or alleviating or relieving at least one symptom associated with such pathology, or slowing or reversing the progression of such pathology, or managing or influencing the metabolic processes underlying such pathology. Within the meaning of the present invention, the term also means preventing, or "preventing", i.e. delaying the onset (i.e., extending the period before the clinical manifestation of the disease) and / or reducing the risk of developing or worsening the disease. When a human having a pathology is stated in the affirmative, the term will be understood to require alleviation or reduction of at least one symptom associated with the pathology.

[0027] Biomarker Test Assays --Unless otherwise indicated herein, all biomarker test assays referred to herein are performed according to standard procedures adopted in the 2001-2002 cycle of the National Health and Nutrition Examination Survey.

[0028] Discussion of the Main Embodiment In a first primary embodiment, the present invention provides a method of treating cirrhosis or liver fibrosis in a patient with non-cirrhotic NASH or NAFLD and a NASH CRN fibrosis score of ≧1 and less than 4, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharma- ceutical acceptable salt thereof, (b) tofogliflozin or a pharma- ceutical acceptable salt thereof, or (c) a combination thereof.

[0029] In a second main embodiment, the invention provides a method of treating lobular inflammation in a patient with non-cirrhotic NASH or NAFLD, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharma- ceutical acceptable salt thereof, (b) tofogliflozin or a pharma- ceutical acceptable salt thereof, or (c) a combination thereof. In a particularly preferred embodiment, the method is performed without worsening fibrosis in patients with a NASH CRN fibrosis score of 1 or greater and less than 4.

[0030] In a third principal embodiment, the present invention provides a method of improving liver function, as measured by ALT activity, in a patient with non-cirrhotic NASH or NAFLD, with a NASH CRN fibrosis score of ≧1 and ≦4, and an ALT score of ≧2× the ULN, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharmaceutical acceptable salt thereof, (b) tofogliflozin or a pharmaceutical acceptable salt thereof, or (c) a combination thereof.

[0031] In a fourth principal embodiment, the invention provides a method of lowering LDL-C in a patient with non-cirrhotic NASH or NAFLD, with a NASH CRN Fibrosis Score of greater than or equal to 1 and less than 4, and an LDL-C level of greater than or equal to 100 mg / dL, comprising administering to the patient a therapeutically effective amount of (a) pemafibrate or a pharma- ceutical acceptable salt thereof, (b) tofogliflozin or a pharma-ceutical acceptable salt thereof, or (c) a combination thereof.

[0032] Subembodiment Considerations The present invention may be further understood with reference to various subembodiments that may modify any of the main embodiments, it being understood that these subembodiments may be combined in any manner that is mathematically and physically possible to produce additional subembodiments that, in turn, may modify any of the main embodiments.

[0033] As stated in the main embodiment, the method can be carried out using either pemafibrate alone, tofogliflozin alone, or a combination of pemafibrate and tofogliflozin. Thus, in one subembodiment, the method is carried out by administering to the patient a therapeutically effective amount of pemafibrate or a pharma- ceutically acceptable salt thereof. In another subembodiment, the method is carried out by administering to the patient a therapeutically effective amount of tofogliflozin or a pharma- ceutically acceptable salt thereof. In yet another subembodiment, the method is carried out by administering to the patient a therapeutically effective amount of the combination thereof.

[0034] A preferred therapeutically effective amount of pemafibrate, when administered orally, alone or in combination, is 0.1-0.8 mg / day, or 0.2-0.4 mg / day, administered in one, two or three divided doses. A particularly preferred dose is 0.4 mg / day. A preferred therapeutically effective amount of tofogliflozin, when administered orally, alone or in combination, is 5-60 mg / day, or 10-40 mg / day. A particularly preferred dose is 20 mg / day of tofogliflozin or a pharma- ceutically acceptable salt thereof. A preferred dosing regimen is a single dosage form, preferably a tablet, administered once a day. Thus, in a particularly preferred subembodiment, the present invention provides an orally administered unit dosage form comprising about 0.4 mg of pemafibrate or a pharma- ceutically acceptable salt thereof and about 20 mg of tofogliflozin or a pharma- ceutically acceptable salt thereof.

[0035] Patients treatable by the methods of the present invention can be characterized by several diagnostic criteria. Thus, in one subembodiment, at the time of starting the method, the patient has a vibration-controlled transient elastography CAP score of 290 dB / m or more. In another subembodiment, at the time of starting the method, the patient has an LSM of 7 kilopascals (kPa) or more and less than 19 kPa. In another subembodiment, at the time of starting the method, the patient has an AST concentration of 20 U / L, 30 U / L, 40 U / L, or 50 U / L or more. In yet another subembodiment, at the time of starting the method, the patient has (a) a vibration-controlled transient elastography CAP score of 290 dB / m or more, (b) an LSM of 7 kilopascals (kPa) or more and less than 19 kPa, and (c) an AST concentration of 20 U / L or more.

[0036] The patient may also be characterized histologically. Thus, in one subembodiment, at the time the method is initiated, the patient has a NAFLD activity score ("NAS") of 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8.

[0037] In another subembodiment, at the time of initiating the method, the patient has a NASH CRN steatosis score of 1 or greater, 2 or greater, or 3. In another subembodiment, at the time of initiating the method, the patient has a NASH CRN lobular inflammation score of 1 or greater, 2 or greater, or 3. In another subembodiment, at the time of initiating the method, the patient has a NASH CRN ballooning score of 1 or greater or 2. In yet another subembodiment, at the time of initiating the method, the patient has (a) an NASH CRN steatosis score of 4 or greater, (b) a NASH CRN lobular inflammation score of 1 or greater, (c) a NASH CRN lobular inflammation score of 1 or greater, and (d) a NASH CRN ballooning score of 1 or greater.

[0038] In addition to enzymatic liver activity, the patient can also be characterized histologically. Thus, in another subembodiment, at the time the method is initiated, the patient has (a) an NAS of 4 or greater, (b) an NASH CRN steatosis score of 1 or greater, (c) an NASH CRN lobular inflammation score of 1 or greater, (d) an NASH CRN ballooning score of 1 or greater, and (e) an ALT concentration of 1x, 2x, or 3x or greater than the ULN.

[0039] In other subembodiments, the patient can be characterized by liver imaging and / or liver enzyme activity. Thus, in another subembodiment, at the time of starting the method, the patient has a liver fat fraction of 10%, 12.5%, 15%, or 17.5% or more by MRI-PDFF. In another subembodiment, at the time of starting the method, the patient has a liver stiffness of 2.5 kPa, 2.75 kPa, or 3 kPa or more by MRE. In another subembodiment, at the time of starting the method, the patient has an ALT concentration of 1, 2, or 3 times or more than the ULN. In yet another subembodiment, at the time of starting the method, the patient has (a) a liver fat fraction of 10% or more by MRI-PDFF, (b) a liver stiffness of 2.5 kPa or more by MRE, and (c) an ALT level above the ULN.

[0040] Additional criteria can be used to characterize patients treatable by the methods of the invention. Thus, in one subembodiment, at the time the method is initiated, the patient has an LDL-C concentration greater than 110 or 120 mg / dL.

[0041] In another subembodiment, at the time the method is initiated, the patient is at least 22, 28, or 32 kg / m 2 Have a BMI above .

[0042] In another subembodiment, at the time the method is initiated, the patient has a fasting plasma glucose concentration of 100 mg / dL or greater.

[0043] In another subembodiment, at the time the method is initiated, the patient has a fasting TG level of less than 200, 175, or 150 mg / dL.

[0044] In yet another subembodiment, the patient has a NASH CRN fibrosis score of 1, 2, 3, greater than or equal to 1 and less than 4, or greater than or equal to 2 and less than 4, at the time the method is initiated.

[0045] In yet another subembodiment, at the time the method is initiated, the patient has an ALT concentration less than or equal to 5-fold the ULN.

[0046] A number of different measures can be used to determine the success of treatment with the methods of the invention. Thus, in one subembodiment, the method includes: (a) a 2 or more point histological improvement in the patient's NAS; and (b) no worsening of the patient's NASH CRN fibrosis score.

[0047] In another subembodiment, the method includes (a) (i) absence of fatty liver disease or (ii) isolated or simple steatosis without steatohepatitis and histological resolution of steatohepatitis defined as NAS of 0-1 for inflammation, 0 for ballooning, and any value for steatosis, and (b) no worsening of NASH CRN fibrosis score.

[0048] In another subembodiment, the method includes: (a) one or more improvements in the patient's NASH CRN inflammation score; (b) one or more improvements in the patient's NASH CRN ballooning score; and (c) one or more improvements in the patient's NASH CRN fatty tissue score.

[0049] In another subembodiment, the method comprises: (a) one or more improvements in the patient's NASH CRN fibrosis score; (b) no worsening of the patient's NASH CRN ballooning score; (c) no worsening of the patient's NASH CRN inflammation score; and (d) no worsening of the patient's NASH CRN steatosis score.

[0050] In yet another subembodiment, the method includes (a) a 30% or greater reduction in liver fat content as measured by MRI-PDFF, and / or a 30% or greater reduction in ALT to 40 U / L or less. EXAMPLES

[0051] In the following examples, efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated, and are intended to be purely illustrative of the invention and are not intended to limit the scope of what the inventors regard as their invention.

[0052] [Example 1] Improvement of liver stiffness and serum markers of liver and lipid metabolism in patients with NAFLD. This was a placebo-controlled, randomized, double-blind, parallel-group study in adults with NAFLD. Subjects received pemafibrate tablets (0.4 mg / day, BID) or placebo tablets for 72 weeks after a 2- to 8-week screening period. The primary outcome was the percentage change from baseline in liver fat content measured by MRI-PDFF at week 24. Key secondary outcome measures were the percentage change from baseline in liver stiffness and ALT levels from week 72 to week 24, respectively. The study was conducted in compliance with relevant guidelines, GCP guidance, and the Declaration of Helsinki.

[0053] Patients were enrolled if they had a liver fat fraction of ≥10% on MRI-PDFF, liver stiffness ≥2.5 kPa (measured using magnetic resonance elastography, MRE), and elevated ALT (>40 U / L for men and >30 U / L for women). 2 less than 30 mL min-1, poorly controlled diabetes (HbA1c 8% or more), renal dysfunction (estimated glomerular filtration rate, eGFR, 30 mL min-1) -11.73 -1 m -2 Patients were excluded if they had chronic liver disease other than NAFLD, cirrhosis, biliary obstruction, or NAFLD.

[0054] Subjects received their assigned medication (pemafibrate 0.2 mg tablet or placebo) orally twice daily for 72 weeks. Study visits were every 4 weeks from the start of treatment until week 24, and then every 8 weeks thereafter. Liver fat content and stiffness were measured at screening before randomization and then at weeks 0, 24, 48, and 72.

[0055] All imaging evaluation procedures were performed in a blinded manner. The equipment used in all facilities was standardized to a 3.0T MR Imaging System (GE Healthcare, Little Chalfont, UK). The applications used were IDEAL-IQ for MRI-PDFF and MR-touch for MRE. Detailed imaging conditions were described in the Imaging Procedure Manual, and the imaging procedures were standardized throughout all studies. Imaging was performed in the fasting state (4 hours or more after a meal), and the timing of the examination (before / after breakfast to before / after lunch) was standardized for each patient throughout the study.

[0056] The primary efficacy outcome was percent change in liver fat content, measured using MRI-PDFF. Liver stiffness, measured using MRE, was a secondary outcome, as was percent change from baseline. Other efficacy outcomes included liver function, fibrosis and inflammatory markers, and lipid markers.

[0057] Selected baseline characteristics of the study population are shown in Table 1. Selected outcomes are reported in Table 2.

[0058] [Table 1]

[0059] [Table 2]

[0060] The significant improvement in liver stiffness as measured by MRE, corresponding to an improvement in liver fibrosis, was an important surprising finding from this study. Other surprising findings from this study, especially when compared to the results reported by S. Ishibashi et al. / Atherosclerosis 249 (2016) 36-43, were: A significant improvement in liver function as measured by ALT (Ishibashi reported a much more modest decrease in ALT levels with pemafibrate administration), A significant reduction in total cholesterol and LDL cholesterol (Ishibashi reported a modest reduction in total cholesterol and an increase in LDL cholesterol with pemafibrate administration), and A significant reduction in HDL cholesterol, especially considering the HDL cholesterol and particle size data reported by Ishibashi 2016 The improvements in liver stiffness, liver function, and cholesterol degradation despite the reduction in HDL cholesterol were not predicted prior to this study.

[0061] [Example 2] A multicenter, placebo-controlled, randomized, double-blind, 48-week study evaluating pemafibrate, tofogliflozin, and the combination of pemafibrate and tofogliflozin in patients with NASH and liver fibrosis This is a double-blind, randomized, 48-week study evaluating the efficacy and safety of pemafibrate monotherapy (0.4 mg / day), tofogliflozin monotherapy (20 mg / day), and K-001 (combination therapy of pemafibrate 0.4 mg / day and tofogliflozin 20 mg / day) compared with placebo in patients with non-cirrhotic NASH and liver fibrosis.

[0062] Patients with possible noncirrhotic NASH with liver fibrosis are initially identified using a FibroScan vibration-controlled transient elastography-controlled attenuation parameter score of 290 dB / m or greater, a FibroScan liver stiffness measurement of 7 kilopascals (kPa) or greater and less than 19 kPa, and an aspartate aminotransferase (AST) of 20 U / L or greater. Patients with possible NASH undergo a confirmatory liver biopsy for eligibility, which is also used as a baseline assessment for histological evaluation. Key inclusion criteria are (i) an NAS of 4 or greater with each component of NAS (steatosis, lobular inflammation, and ballooning) having a score of at least 1, (ii) a fibrosis stage of 1 or greater and less than 4 on the NASH CRN fibrosis staging system, and (iii) a fasting plasma glucose of 100 mg / dL or greater.

[0063] The primary objective of this study was to evaluate efficacy in non-cirrhotic NASH patients with liver fibrosis. Efficacy was determined based on the primary endpoint of a ≥2-point improvement in liver histology in the NAFLD Activity Score (NAS) and no worsening of fibrosis score at 48 weeks.

[0064] The primary efficacy outcome measures were improvement from baseline in disease activity and no worsening of liver fibrosis as measured by the NASH Clinical Research Network (CRN) fibrosis score at week 48. Improvement in disease activity was defined as a ≥2-point improvement in the NASH CRN fibrosis score. Worsening fibrosis was defined as a numerical increase in disease stage.

[0065] The secondary efficacy endpoints of this study were: Resolution of steatohepatitis in global histopathological measurements and no worsening of liver fibrosis in NASH CRN fibrosis score at week 48. Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for ballooning, or any value for steatosis. At least one-point improvement from baseline in each of the NAS components (inflammation, ballooning, and steatosis) at week 48 -Improvement from baseline in liver fibrosis score of ≥1 and no worsening of steatohepatitis (defined as no increase in NAS in terms of ballooning, inflammation, or steatosis) at week 48 -Either improvement from baseline in liver fat content (MRI-PDFF) or improvement from baseline in ALT at week 48. Improvement in liver fat content or improvement in ALT is defined as meeting any of the following criteria: ALT level of 40 U / L or less and a 30% or greater decrease from baseline 〇Liver fat content (MRI-PDFF) reduced by 30% or more from baseline Improvement from baseline in liver fat content (defined as a ≥30% reduction) as measured by MRI PDFF at 48 weeks Improvement from baseline in ALT at week 48 (defined as ALT ≤40 U / L and a ≥30% decrease from baseline) Includes.

[0066] Table 3 describes the histological scoring system for NAFLD used in this example, as described by DE Kleiner et al. for the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatology 41:1313-1321, 2005.

[0067] [Table 3]

[0068] Abbreviation MRI-PDFF=magnetic resonance imaging-proton density fat fraction. MRE=magnetic resonance elastography. LSM=liver stiffness measurement. ALT=alanine transaminase. ALT ULN=30 IU / L for women and 40 IU / L for men AST=aspartate aminotransferase. LDL cholesterol = low-density lipoprotein cholesterol. HDL cholesterol = high-density lipoprotein cholesterol. M2BPGi = mac-2 binding protein glycosylation isomer. ELF test = enhanced liver fibrosis test. NASH CRN=Nonalcoholic Steatohepatitis Clinical Research Network. NAS = NAFLD activity score.

[0069] [Example 3] SGLT2 inhibitors versus sulfonylureas in type 2 diabetes with NAFLD Inclusion criteria 1. Biopsy consistent with a diagnosis of NAFLD 2.2 type diabetes, HbA1c 7.0% or higher

[0070] Exclusion criteria History of hepatic viral infections, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hemochromatosis, antitrypsin deficiency, Wilson's disease, parenteral nutrition, and substance abuse-induced use of drugs known to induce steatosis or liver damage, and / or current or past alcohol consumption >20 g / day Hypersensitivity or contraindication to glimepiride and tofogliflozin Not type 2 diabetes Poorly controlled diabetes Recurrent episodes of hypoglycemia of unknown cause Concomitant infection or scheduled surgery Uncontrolled high blood pressure Severe retinopathy Malignant tumors undergoing active treatment or that are not in complete remission or cured Severe health problems that make you unsuitable for this study Pregnant or breastfeeding women Inability to participate in the study as assessed by the researchers

[0071] Baseline characteristics A total of 40 patients were randomly assigned to receive either tofogliflozin at a dose of 20 mg once daily (20 patients) or glimepiride once daily (20 patients). All 40 patients (100%) completed the study. Demographic and baseline clinical characteristics, except for gender, were similar in both groups. All patients were Japanese and had type 2 diabetes. The mean age was 53.9 years, the mean weight was 82.0 kg, the mean hemoglobin A1c was 8.2%, and the mean NAS was 4.45. A total of 18 patients (45%) had stage F1 fibrosis, 11 (27.5%) had stage F2, and 5 (12.5%) had stage F3.

[0072] Participant flow A total of 40 patients were randomly assigned to receive tofogliflozin at a dose of 20 mg once daily (20 patients) or glimepiride once daily (20 patients). All 40 patients (100%) completed the study. Information on the primary outcome and confirmatory secondary outcomes on biopsy at week 48 was available for 39 patients (97.5%). Only one patient had a serious adverse event (2.5%).

[0073] Primary outcomes In the glimepiride group, the only histologic improvement from baseline to week 48 was a reduction in ballooning necrosis (P = .025). In contrast, subjects receiving tofogliflozin had significant histologic improvement from baseline to week 48 in all variables (proportions of patients with improvement in steatosis, ballooning necrosis, and lobular inflammation were 65, 55, and 50%, respectively). Fibrosis scores improved in the tofogliflozin group (60%, P = .001 for comparison of pretreatment and posttreatment scores), but the change from baseline was not significantly different between the tofogliflozin and glimepiride groups (P = .172).

[0074] Secondary outcomes Histological features The mean ballooning score was significantly reduced in both groups. The mean steatosis score, percentage of steatosis, lobular inflammation score, and fibrosis score were significantly reduced only in the tofogliflozin group. NAS was significantly improved in both groups compared with baseline values, and the beneficial effect was greater in the tofogliflozin group than in the glimepiride group (P = 0.002).

[0075] Serum enzyme levels and liver tests There was an early and highly significant decrease in aspartate aminotransferase and alanine aminotransferase levels in the tofogliflozin group. Changes from baseline were not significantly different between the tofogliflozin and glimepiride groups. The change in gamma-glutamyltransferase was significantly decreased in the tofogliflozin group (mean decrease at week 48 of 23.8 IU / L, P < 0.001 compared with glimepiride). In addition, the FIB-4 index was significantly decreased in the tofogliflozin group, and the effect was greater in the tofogliflozin group than in the glimepiride group.

[0076] Metabolic parameters Reductions in glycemic parameters such as FPG and HbA1c were similar. Weight, BMI, and percentage of body fat were significantly reduced in the tofogliflozin group (mean weight loss of 4.8 kg at week 48, P<0.001 compared with glimepiride). These changes occurred during the first 12 weeks and were sustained for the duration of the subjects' treatment. In contrast, CPR, lipid profile, oxidative stress markers, and cytokines were similar in both groups.

[0077] overview Among patients with biopsy-confirmed NAFLD and type 2 diabetes, the proportion of patients with improved liver histology through attenuation of beta-oxidation and hepatic inflammation, with similarly reduced glucose levels, was significantly higher with tofogliflozin than with glimepiride. Tofogliflozin had some favorable metabolic markers. SGLT2 inhibitors may have hepatoprotective effects.

[0078] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. A pharmaceutical composition comprising pemafibrate or a pharma- ceutical acceptable salt thereof for use in a method for treating cirrhosis or hepatic fibrosis in a human patient having non-cirrhotic NASH or NAFLD and having a NASH CRN fibrosis score of ≥1 and <4, said method comprising administering to said patient a therapeutically effective amount of pemafibrate or a pharma- ceutical acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein the method further comprises administering to the patient a therapeutically effective amount of tofogliflozin or a pharma- ceutically acceptable salt thereof.

3. At the start of the method, the patient: a) a vibration-controlled transient elastography CAP score of 290 dB / m or greater; b) an LSM of 7 kilopascals (kPa) or more and less than 19 kPa; and c) AST concentration of 20 U / L or more The pharmaceutical composition according to claim 1 or 2, having the formula:

4. At the start of the method, the patient: a) NAS of 4 or more; b) a NASH CRN steatosis score of 1 or greater; c) a NASH CRN lobular inflammation score of 1 or greater; and d) NASH CRN ballooning score of 1 or greater The pharmaceutical composition according to claim 1 or 2, having the formula:

5. At the start of the method, the patient: a) NAS of 4 or more; b) a NASH CRN steatosis score of 1 or greater; c) a NASH CRN lobular inflammation score of 1 or greater; d) a NASH CRN ballooning score of 1 or greater; and e) ALT concentration ≥1, ≥2, or ≥3 times the ULN The pharmaceutical composition according to claim 1 or 2, having the formula:

6. At the start of the method, the patient: a) liver fat fraction of 10% or more on MRI-PDFF; b) liver stiffness of 2.5 kPa or greater on MRE; and c) ALT level ≥1x ULN The pharmaceutical composition according to claim 1 or 2, having the formula:

7. At the start of the method, the patient: a) NASH CRN fibrosis score of 1, 2, 3, or ≥1 and <4, or ≥2 and <4, and b) ALT levels less than 5 times the ULN; The pharmaceutical composition according to claim 1 or 2, having the formula:

8. The method according to claim 1, a) a 2 or more point histological improvement in the patient's NAS; and b) There is no worsening of the patient's NASH CRN fibrosis score. The pharmaceutical composition according to claim 1 or 2, comprising:

9. The method according to claim 1, a) Histological resolution of steatohepatitis as defined below: i) Absence of fatty liver disease, or ii) isolated or simple steatosis without steatohepatitis, and NAS of 0-1 for inflammation, 0 for ballooning, and any value for steatosis; and b) No deterioration of NASH CRN fibrosis score The pharmaceutical composition according to claim 1 or 2, comprising:

10. The method of claim 1, a) an improvement in said patient's NASH CRN inflammation score of 1 or more; b) an improvement in one or more of the patient's NASH CRN ballooning scores; and c) an improvement in one or more of the patient's NASH CRN fatty tissue scores. The pharmaceutical composition according to claim 1 or 2, comprising:

11. The method according to claim 1, a) an improvement in said patient's NASH CRN fibrosis score of 1 or more; b) there is no worsening of the patient's NASH CRN ballooning score; c) no worsening of the patient's NASH CRN inflammation score; and d) There is no worsening of the patient's NASH CRN fatty tissue score. The pharmaceutical composition according to claim 1 or 2, comprising:

12. The method comprising: a) a 30% or greater reduction in liver fat content as measured by MRI-PDFF, and / or b) A 30% or greater decrease in ALT to 40 U / L or less; The pharmaceutical composition according to claim 1 or 2, comprising:

13. The method according to claim 1, a) 0.1 to 0.8 mg of pemafibrate or a pharma- ceutically acceptable salt thereof; b) 5 to 60 mg of tofogliflozin or a pharma- ceutically acceptable salt thereof, or c) Combinations thereof The pharmaceutical composition of claim 1 or 2, comprising administering to the patient daily orally.

14. The method of claim 1, a) 0.4 mg of pemafibrate or a pharma- ceutically acceptable salt thereof; b) 20 mg of tofogliflozin or a pharma- ceutically acceptable salt thereof, or c) Combinations thereof The pharmaceutical composition of claim 1 or 2, comprising administering to the patient daily orally.