Combinations for treatment of NAFLD/NASH and related diseases
Inventors
Amin, Neeta Balkrishan • Bergman, Arthur James • Calle, Roberto Arnaldo • Esler, William Paul • Kim, Albert Myung • Pfefferkorn, Jeffrey Allen • Verhoest, Patrick Robert
Assignees
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Publication Number
US-12472180-B2
Publication Date
2025-11-18
Expiration Date
Abstract
A method for treating fatty liver disease and related diseases or disorders with a therapeutically effective amount of a composition comprising from about 25 mg to about 1200 mg of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and from about 5 mg to about 40 mg of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.
Core Innovation
The document describes a pharmaceutical combination therapy for treating fatty liver and related diseases by administering to a human in need a therapeutically effective amount of a composition that comprises an ACC inhibitor, 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt, and a DGAT2 inhibitor, (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt. The composition is characterized by therapeutically effective amounts within specified ranges for each component.
The central problem addressed is treatment of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and related conditions, including forms with liver fibrosis, cirrhosis, and cirrhosis with hepatocellular carcinoma. The disclosed approach also covers fatty liver categories and related metabolic-related disease contexts, as well as alcoholic fatty liver disease and alcoholic steatohepatitis categories. The combination is positioned to manage disease outcomes in these patient populations through co-administration of the two named inhibitors.
The document further explains that ACC inhibition may raise circulating triglycerides and have platelet count effects, and proposes that co-administration with the DGAT2 inhibitor is intended to reverse triglyceride elevations and mitigate platelet decreases. The combination approach is additionally framed with patient identification and endpoint concepts using blood biomarker panels and imaging, and with regulatory surrogate markers and NAS component scoring.
Claims Coverage
Independent claims are provided for methods of treating selected conditions by administering a two-compound composition comprising specified therapeutically effective dose ranges. The supplied claim set contains four independent method claims covering liver-related diseases, additional alcohol-related and metabolic-related liver diseases, cardiovascular diseases, and metabolic diseases or conditions, each defined by the same two named active compounds and overlapping dosage ranges.
Treating selected liver diseases with a two-compound composition
A method for treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis with hepatocellular carcinoma or with a metabolic-related disease by administering to a human in need thereof a therapeutically effective amount of a composition comprising from about 5 mg to about 1200 mg of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and from about 5 mg to about 60 mg of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.
Treating selected alcohol- and metabolic-related liver diseases with a two-compound composition
A method for treating fatty liver, alcoholic fatty liver disease, alcoholic steatohepatitis, alcoholic steatohepatitis with liver fibrosis, alcoholic steatohepatitis with cirrhosis, and alcoholic steatohepatitis with cirrhosis with hepatocellular carcinoma or with a metabolic-related disease by administering to a human in need thereof a therapeutically effective amount of a composition comprising from about 5 mg to about 1200 mg of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and from about 5 mg to about 60 mg of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.
Treating selected cardiovascular diseases with a two-compound composition
A method for treating a cardiovascular disease or condition selected from atherosclerosis, stroke, myocardial infarction, aortic vascular disease, cerebral vascular disease, renal vascular disease, heart failure, atrial fibrillation, or coronary heart disease by administering to a human in need thereof a therapeutically effective amount of a composition comprising from about 5 mg to about 1200 mg of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and from about 5 mg to about 60 mg of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.
Treating selected metabolic diseases with a two-compound composition
A method for treating a metabolic disease or condition selected from obesity, dyslipidemia, type 2 diabetes mellitus, glycemic control in patients with type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, insulin resistance, or impaired glucose metabolism by administering to a human in need thereof a therapeutically effective amount of a composition comprising from about 5 mg to about 1200 mg of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and from about 5 mg to about 60 mg of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.
The independent claims consistently require a method of treatment in which a human is administered a therapeutically effective amount of a two-component composition containing the named DGAT2 inhibitor and ACC inhibitor, each optionally as pharmaceutically acceptable salts, with specified mg ranges and disease-condition selection spanning fatty liver categories, cardiovascular diseases, and metabolic diseases.
Stated Advantages
Reduces liver fat as measured by MRI-PDFF in NAFLD in the Phase 2A randomized double-blind placebo-controlled study with co-administration.
Mitigates triglyceride levels in the Phase 2A randomized double-blind placebo-controlled study with co-administration.
Provides safety/tolerability including reporting platelet effects.
ACC inhibition may raise circulating triglycerides and platelet count effects, and co-administration with the DGAT2 inhibitor is proposed to reverse triglyceride elevations and mitigate platelet decreases.
Documented Applications
Treating NAFLD in a Phase 2A randomized double-blind placebo-controlled study with co-administration of Compound A and Compound D, assessing liver fat (MRI-PDFF) and triglycerides, with safety/tolerability including platelet effects.
Pharmacological evaluation in animal studies using Western diet and choline-deficient high-fat diet models, comparing Compound A vs Compound D vs combination and measuring triglycerides, steatosis, SREBP-1 localization, lipogenic gene expression (ACC1, FASN, SCD1, SREBP1, PCSK9), and fibrosis markers (SWE, αSMA, collagen/PSR, Iba1).
Treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis with hepatocellular carcinoma or with a metabolic-related disease.
Treating alcoholic fatty liver disease, alcoholic steatohepatitis, alcoholic steatohepatitis with liver fibrosis, alcoholic steatohepatitis with cirrhosis, and alcoholic steatohepatitis with cirrhosis with hepatocellular carcinoma or with a metabolic-related disease.
Treating cardiovascular disease or conditions selected from atherosclerosis, stroke, myocardial infarction, aortic vascular disease, cerebral vascular disease, renal vascular disease, heart failure, atrial fibrillation, and coronary heart disease.
Treating metabolic disease or conditions selected from obesity, dyslipidemia, type 2 diabetes mellitus, glycemic control in patients with type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting plasma glucose, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, insulin resistance, and impaired glucose metabolism.
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