Evolving Role for Pharmacotherapy in NAFLD/NASH

Abstract

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. Nonalcoholic fatty liver disease (NAFLD) affects up to 1 billion individuals worldwide 1 and is the most common cause of elevated liver enzymes in children. End-stage liver disease and/or hepatocellular carcinoma secondary to NAFLD are among the leading causes of liver failure in adults in the United States. Effective and affordable treatments to reduce the medical and societal burden of this increasingly prevalent condition are urgently needed. 2,3 NAFLD represents a spectrum of diseases ranging from hepatocellular fat deposition (nonalcoholic fatty liver) to steatohepatitis (nonalcoholic steatohepatitis (NASH) with or without fibrosis) to cirrhosis. NAFLD is a dynamic disease that can progress to cirrhosis,

Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

“…Research on the medical treatment of NASH consists of modulating either sugar or fat metabolism or targeting one of the downstream pathways associated with liver inflammation and fibrosis [4,5]. The largest class of molecular targets for hormone-based NASH therapies is nuclear receptors [6,7].…”

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

“…Several recent reviews have covered many aspects of NAFLD treatments, including plant-based compounds [ 210 ], DM-targeted drugs, lifestyle modifications, surgeries, and pharmacological approaches [ 211 , 212 , 213 ]. For those reasons, we will focus on the recent publications discussing NLRP3 inflammasome-oriented treatments ( Table 2 ).…”

Efficacy of Weight Reduction on Pediatric Nonalcoholic Fatty Liver Disease: Opportunities to Improve Treatment Outcomes Through Pharmacotherapy

“…Currently, there are no FDA-approved medications for pediatric NAFLD. However, the landscape of potential therapeutic agents for NAFLD is evolving rapidly and showing promise, as highlighted in recently published reviews (26,46) beyond the scope of this publication. In addition to novel therapeutic agents (e.g., obeticholic acid, fibroblast growth factor 19 & 21 analogs, thyroid hormone receptor-b agonists), there is also interest in repurposing existing drugs-already approved for pediatric obesity or obesity comorbidities-for the treatment of pediatric NAFLD (47).…”