Recent updates on pharmacologic therapy in non-alcoholic fatty liver disease

Since there are currently no US Food and Drug Administration (FDA)-approved drugs for the treatment of non-alcoholic steatohepatitis (NASH), various NASH treatments are under development for a wide range of targets.Several promising agents have recently failed in phase 3 trials, including selosertib, 1 elafibranor, and cenicriviroc, 2 and now five pharmacologic agents-obeticholic acid (OCA), resmetirom, aramchol, lanifibranor, and semaglutide-are being evaluated in large, histology-based phase 3 trials (Table 1).OCA, a farnesoid X receptor agonist, has been demonstrated to reduce hepatic fibrosis without worsening NASH in the 18-month interim analysis of the REGENERATE phase 3 trial, 3 and its anti-fibrotic effect and long-term favorable safety profile have recently been validated. 4wever, in May 2023, the FDA rejected the new drug application of OCA for pre-cirrhotic NASH, concerning safety issues such as hepatotoxicity, cholelithiasis, and pruritus, while its efficacy is modest.Resmetirom is a liver-targeted, thyroid hormone receptor ß (THR-ß)selective agonist.Based on the promising results in the phase 2 clinical trial, 5 phase 3 trials evaluating the efficacy of resmetirom in patients with NASH presenting with compensated cirrhosis (MAESTRO-NASH-Outcomes trial) and stage 2-3 fibrosis (MAESTRO-NASH) are ongoing.In the interim analysis of MAESTRO-NASH trial, which included 955 patients, histological NASH resolution and fibrosis reduction end points were achieved after 52 weeks of treatment. 6Until now resmetirom is the only drug showing both NASH and fibrosis improvement in a phase 3 trial.The antidiabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP), are attractive candidates for the treatment of NASH, considering their beneficial metabolic effects.These are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion.Semaglutide, a GLP-1 RA, showed a significant dose-dependent NASH resolution without worsening of fibrosis in a phase 2 randomized controlled trial (RCT) involving patients with NASH and stage 1-3 fibrosis. 7A phase 3 trial of semaglutide for NASH-related fibrosis