obeticholic-acid and cenicriviroc

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.

Topics: Adult; Benzhydryl Compounds; Chenodeoxycholic Acid; Child; Clinical Trials, Phase III as Topic; Fibroblast Growth Factors; Glucosides; Humans; Imidazoles; Isobutyrates; Liraglutide; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Oxazoles; Polyethylene Glycols; Pyridazines; Pyrimidines; Severity of Illness Index; Sulfoxides; Treatment Outcome; Uracil

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.

Topics: Antioxidants; Chalcones; Chenodeoxycholic Acid; Cytoprotection; Glucagon-Like Peptide 1; Humans; Imidazoles; Insulin Resistance; Metformin; Non-alcoholic Fatty Liver Disease; Patient Selection; Pharmaceutical Preparations; Propionates; Sulfoxides; Thiazolidinediones

NAFLD is a spectrum of liver disease starting with fatty liver at one end of the spectrum and cirrhosis or liver cancer at the other end. Worldwide, NAFLD has become one of the most common liver diseases and it has also become one of the leading indications for liver transplantation. Our understanding of the NAFLD epidemiology, pathogenesis and its progression to cirrhosis has improved over the last 2 decades. Currently, however, there are no FDA-approved treatment options for fibrosis resulting from NAFLD. A number of compounds targeting multiple pathways involved in the progression of NAFLD are currently in phase 2-3 trials. In this review, we will briefly discuss the epidemiology, the pathogenesis and the current status of treatment of NAFLD.

Topics: Benzamides; Chalcones; Chenodeoxycholic Acid; Disease Progression; Humans; Imidazoles; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Propionates; Pyridines; Risk Factors; Sulfoxides

This review discusses completed phase II randomized clinical trials with high-quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab's phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids).

Topics: Antibodies, Monoclonal, Humanized; CCR5 Receptor Antagonists; Chalcones; Chenodeoxycholic Acid; Clinical Trials, Phase II as Topic; Cysteamine; Cystine Depleting Agents; Humans; Imidazoles; Incretins; Liraglutide; Non-alcoholic Fatty Liver Disease; Propionates; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sulfoxides

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies.

Topics: Anti-Retroviral Agents; Chalcones; Chenodeoxycholic Acid; Cholic Acids; Clinical Trials, Phase III as Topic; Drug Interactions; HIV Infections; Humans; Imidazoles; Non-alcoholic Fatty Liver Disease; Propionates; Pyridazines; Sulfoxides; Uracil