IP Library › Granted Patent US 12,485,106
Granted Patent B2
US 12,485,106 · App. 19/067,616 · Granted Dec 2, 2025

Methods of treating fibrotic liver diseases or conditions with indeglitazar

Inventors: Prasad Manchem (Carlsbad, CA); Joseph L. Evans (Saint Louis, MO)
Assignee: PLEIOGENIX INC.
A61K31/404A61K31/522A61K31/53A61K31/573A61P1/16
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Quick Facts
Patent No.
US 12,485,106
App. No.
19/067,616
Granted
Dec 2, 2025
Kind
B2
Abstract

The present invention relates to methods of treating metabolic dysfunction-associated steatohepatitis (MASH) in a human subject, comprising administering to the subject a therapeutically effective amount of indeglitazar or a pharmaceutically acceptable salt thereof.

Claims (20)

1 . A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a human subject, comprising administering to the subject a therapeutically effective amount of indeglitazar or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the treatment results in an improvement in a fibrosis marker selected from TIMP-1, TIMP-2, hyaluronic acid, P3NP, NFS, FIB-4 score, ELF score, Pro-C3, and combinations thereof.

3 . The method of claim 1 , wherein the treatment results in a reduction of alanine aminotransferase (ALT) activity in liver of the subject.

4 . The method of claim 1 , wherein the treatment results in a reduction of the fibrosis marker hepatic hydroxyproline.

5 . The method of claim 1 , wherein the treatment results in a reduction in a marker selected from bilirubin, plasma TGFβ1, plasma TNF-α, liver triglycerides, aspartate aminotransferase (AST) activity, alkaline phosphatase (ALP), and combinations thereof.

6 . The method of claim 1 , wherein the treatment results in an increase in plasma adiponectin of at least 30%.

7 . The method of the claim 1 , wherein the subject does not have type 2 diabetes.

8 . The method of claim 1 , wherein the subject has type 2 diabetes.

9 . The method of claim 1 , wherein the subject has an F2 or F3 grade of fibrosis using the NASH Clinical Research Network (CRN) fibrosis score.

10 . The method of claim 1 , wherein the subject has an AST level greater than the upper limit of normal.

11 . The method of claim 1 , wherein the subject has an ALT level greater than the upper limit of normal.

12 . The method of claim 1 , wherein the subject has an ALP level greater than the upper limit of normal.

13 . The method of claim 1 , wherein the therapeutically effective amount of indeglitazar or the pharmaceutically acceptable salt thereof comprises from about 20 mg/day to about 225 mg/day, wherein indeglitazar or the pharmaceutically acceptable salt thereof is administered orally.

14 . The method of claim 1 , wherein the method occurs without causing edema in the subject.

15 . The of claim 1 , wherein the method occurs without suppressing leptin concentrations in the subject.

16 . The method of claim 1 , wherein the method results in an improvement in liver fibrosis and no worsening of steatohepatitis, defined as no increase defined as no increase in NAFLD Activity Score for ballooning, inflammation or steatosis.

17 . The method of claim 1 , wherein the method results in both the resolution of steatohepatitis and improvement in fibrosis.

18 . The method of claim 1 , wherein indeglitazar or the pharmaceutically acceptable salt thereof is administered orally.

19 . The method of claim 1 , wherein the subject is administered one or more additional therapeutically active agents, selected from resmetirom, glucagon-like peptide-1 (GLP-1) receptor agonists, GLP-1 and gastric inhibitory polypeptide (GIP) receptor dual agonists, or GLP-1, GIP, and glucagon receptor triple agonists.

20 . The method of claim 1 , wherein the method results in reduction of the incidence of progression to cirrhosis.

Continuity (4)
Continuation 18771595 · Jul 12, 2024
Provisional Application 63532001 · Aug 10, 2023
Provisional Application 63526840 · Jul 14, 2023
Related Publication 20250319064A1 · Oct 16, 2025
References Cited (56)
US 7202266B2 · Arnold · 2007 [cited by applicant]
US 11241420B2 · Ciccocioppo · 2022 [cited by applicant]
US 20060252670A1 · Fiorucci · 2006 [cited by applicant]
US 20070072904A1 · Lin · 2007 [cited by applicant]
US 20200000772A1 · Lefebvre · 2020 [cited by applicant]
US 20230109432A1 · Gillberg · 2023 [cited by applicant]
US 20250017901A1 · Manchem et al. · 2025 [cited by applicant]
CN 115504925A · 2022 [cited by applicant]
EP 2990037A1 · 2016 [cited by applicant]
WO 2005009958A1 · 2005 [cited by applicant]
Kamata et al. (Antioxidants 2023, 12, 1523) (17 pages) (Year: 2023). [cited by examiner]
Kamata et al. (“Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease”, Biomolecules 2023,13, 1264) (21 pages) (Year: 2023). [cited by examiner]
Devchand PR et al., The Pioglitazone Trek via Human PPAR Gamma: From Discovery to a Medicine at the FDA and Beyond, Front Pharmacol, (2018), 9:1093. [cited by applicant]
Du J et al., Effects of pentoxifylline on nonalcoholic fatty liver disease: A meta-analysis, World J Gastroenterol, (2014), 20:569-77. [cited by applicant]
He L et al., Heart Failure Carnitine Palmitoyltransferase-1b Deficiency Aggravates Pressure Overload-Induced Cardiac Hypertrophy Caused by Lipotoxicity, Circulation, (2012), 126:1705-16. [cited by applicant]
Lamas-Paz et al., Alcoholic liver disease: Utility of animal models, World J Gastroenterol, (2018), 24:5063-75. [cited by applicant]
Louvet et al., Infection in Patients With Severe Alcoholic Hepatitis Treated With Steroids: Early Response to Therapy Is the Key Factor, Gastroenterology, (2009), 137:541-8). [cited by applicant]
Lucey et al., Alcoholic Hepatitis, N Engl J Med, (2009), 360:2758-69. [cited by applicant]
Mathurin et al., Early Liver Transplantation for Severe Alcoholic Hepatitis, N Engl J Med, (2011), 365:1790-800. [cited by applicant]
Moreau et al., Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis, Gastroenterology, (2013), 144:1426-37, 37 e1-9. [cited by applicant]
Nesto et al., Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure, Circulation, (2003), 108:2941-8. [cited by applicant]
Pouwels et al., on-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss, BMC Endocr Disord, (2022), 22:63. [cited by applicant]
Rao et al.,Recent Advances in Alcoholic Liver Disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease, Am J Physiol Gastrointest Liver Physiol, (2004), 286:G881-4. [cited by applicant]
Saha et al., Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis, Hepatology, (2019), 70:1134-49. [cited by applicant]
Sanyal et al., Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis, N Engl J Med, (2010), 362:1675-85. [cited by applicant]
Shah et al., Thymosin β4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice, Oxid Med Cell Longev, (2018), p. 1-2, 2018:9630175. [cited by applicant]
Szabo et al., Gut-liver axis and sterile signals in the development of alcoholic liver disease, Alcohol Alcohol, (2017), 52:414-24. [cited by applicant]
Tasdogan et al., Update on Immunosuppression in Liver TransplantatioN, Euroasian J Hepatogastroenterol, (2019), 9:96-101. [cited by applicant]
Thompson et al., Mortality and costs associated with alcoholic hepatitis: A claims analysis of a commercially insured population, Alcohol, (2018), 71:57-63. [cited by applicant]
Thursz et al., he clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2×2 factorial randomised controlled trial, Health Technol Assess, (2015), 19:1-104. [cited by applicant]
Tilg et al., Interleukin-1 and Inflammasomes in Alcoholic Liver Disease/Acute Alcoholic Hepatitis and Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Hepatology, (2016), 64:955-65. [cited by applicant]
Gul, et al., Deciphering the relational dynamics of AF-2 domain of PAN PPAR through drug repurposing and comparative simulations, PLOS One, (2023), p. 1-35. [cited by applicant]
Francque, et al., A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH, New England Journal of Medicine, (2021), 385:1547-1558. [cited by applicant]
Pawlak, et al., Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease, Journal of Hepatology, (2015), 62:720-733. [cited by applicant]
Barbosa-Da-Silva, et al., Singular effects of PPAR agonists on nonalcoholic fatty liver disease of diet-induced obese mice, Life Sciences, (2015), 127:73-81. [cited by applicant]
Chen et al., Design, synthesis, and biological evaluation of deuterated indolepropionic acid derivatives as novel long-acting pan PPARα/γ/δ agonists, Bioorganic & Medicinal Chemistry, (2023), 96:117533, p. 1-12. [cited by applicant]
English translation of CN115504925, Original Document dated Dec. 23, 2022. [cited by applicant]
Cheng et al., Exploration and Development of PPAR modulators in Health and Disease: An Update of Clinical Evidence. Int. J. Mol. Sci., (2019), 20:5055, p. 1-50. [cited by applicant]
Dolgin, NASH therapies head toward landmark approval, Nature Biotechnology, (2023), 41:587-590. [cited by applicant]
Kersten et al., The role and regulation of the peroxisome proliferator activated receptor alpha in human liver, Biochimie, (2017), 136:75-84. [cited by applicant]
International Search Report from Appl. No. PCT/US2024/037827, mail on Sep. 19, 2024. [cited by applicant]
Artis et al., Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent, PNAS, (2009), 106:262-267. [cited by applicant]
Sheka et al., Nonalcoholic Steatohepatitis, JAMA, (2020), 323:1175-1183. [cited by applicant]
Barrio et al., Liver Disease in Heavy Drinkers With and Without Alcohol Withdrawal Syndrome, Alcohol Clin Exp Res, (2004), 28:131-136. [cited by applicant]
Bataller et al., Alcohol-Associated Hepatitis, N Engl J Med, (2022), 387:2436-48. [cited by applicant]
Betteridge et al., Diabet. Med., (2011), 28:759-771. [cited by applicant]
Crews et at., Cytokines and Alcohol, Alcohol Clin Exp Res, (2006), 30: 720-730. [cited by applicant]
Kleiner et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, (2005), 41:1313-1321. [cited by applicant]
Morgan et al., Pentoxifylline and Alcoholic Hepatitis, Gastroenterology, (2000), 119: 1787-1790. [cited by applicant]
Yasir et al., Corticosteroid Adverse Effects, StatPearls. Treasure Island (FL): StatPearls PublishingCopyright © 2023, StatPearls Publishing LLC., (2023). [cited by applicant]
NCT00448032, Study Evaluating Multiple Oral Doses of PPM-204 in Healthy Japanese Male Subjects, (2007). [cited by applicant]
NCT00425919, Study Evaluating PPM-204 In Subjects With Type 2 Diabetes, (2007). [cited by applicant]
Jusudian et al., Acute alcoholic hepatitis as indication for liver transplantation, Curr Opin Organ Transplant, (2016), 21:107-10. [cited by applicant]
Mudaliar et al., Thiazolidinediones, Peripheral Edema, and Type 2 Diabetes: Incidence, Pathophysiology, and Clinical Implications, Endocr Pract, (2003), 9:406-16. [cited by applicant]
James O'Beirne J., Readmission Following Hospitalization for Alcoholic Hepatitis: Costly or Cost-Effective?, Dig Dis Sci., (2020), 65:920-1. [cited by applicant]
Son et al., Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice, J Clin Invest, (2007), 117:2791-801. [cited by applicant]
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