Sagimet Gets FDA Breakthrough Status for Denifanstat in MASH

Sagimet Biosciences Inc., a clinical-stage biopharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to denifanstat. This designation is for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis, specifically stages F2 to F3.

David Happel, CEO of Sagimet, highlighted the significance of this designation, emphasizing the global prevalence of MASH and the need for new therapeutic options. He pointed out that denifanstat is unique as it is the only fat synthesis inhibitor that targets the three primary drivers of MASH: fat accumulation, inflammation, and fibrosis. This makes denifanstat a promising treatment option for MASH patients.

The Breakthrough Therapy designation is granted to drugs that aim to treat serious or life-threatening diseases and have shown preliminary clinical evidence of substantial improvement over existing therapies on one or more significant clinical endpoints. This designation provides benefits such as Fast Track designation privileges, intensive guidance from the FDA on drug development, and organizational involvement from FDA senior managers.

The designation for denifanstat was supported by positive data from the Phase 2b FASCINATE-2 clinical trial, which involved biopsy-confirmed MASH patients with stage 2 or stage 3 fibrosis. The trial results demonstrated that denifanstat achieved statistically significant improvements compared to a placebo on primary endpoints, including MASH resolution without worsening of fibrosis and a reduction in the Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS). Furthermore, patients treated with denifanstat showed a significant improvement in fibrosis by at least one stage without worsening MASH and a higher response rate in MRI-derived proton density fat fraction (MRI-PDFF) reduction by 30% or more compared to placebo.

In the intent to treat (ITT) population, denifanstat achieved significant results on both primary and secondary liver biopsy endpoints. These endpoints were recommended in the FDA draft guidance for accelerated approval in MASH. Additionally, safety data indicated that denifanstat was generally well tolerated by patients. Sagimet plans to initiate a Phase 3 clinical program for denifanstat in MASH by the end of 2024.

Sagimet focuses on developing novel fatty acid synthase (FASN) inhibitors, which target dysfunctional metabolic pathways in diseases caused by the overproduction of the fatty acid, palmitate. Denifanstat is Sagimet’s lead drug candidate, an oral, once-daily pill and selective FASN inhibitor in development for the treatment of MASH. The Phase 2b FASCINATE-2 trial of denifanstat, which used liver biopsy-based primary endpoints, concluded successfully with positive results.

MASH is a severe and progressive liver disease affecting more than 115 million people globally. The United States has recently approved one treatment for MASH, but there are no approved treatments in Europe. In 2023, global liver disease medical societies and patient groups renamed non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) and nonalcoholic steatohepatitis (NASH) to MASH. An overarching term, steatotic liver disease (SLD), was also introduced to encompass various liver diseases associated with fat accumulation. This renaming aimed to provide a more affirmative and non-stigmatizing diagnosis.