Sagimet Biosciences' denifanstat, an oral, selective fatty acid synthase (FASN) inhibitor, has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (stages F2 to F3). This designation aims to expedite the development and review of denifanstat, addressing a critical unmet need in the treatment of MASH, a progressive liver disease affecting millions worldwide. The company plans to initiate a Phase 3 study by the end of 2024.
Clinical Evidence Supporting Breakthrough Therapy Designation
The FDA's decision was supported by positive data from the Phase 2b FASCINATE-2 clinical trial, which evaluated denifanstat in biopsy-confirmed MASH patients with stage 2 or stage 3 fibrosis. The trial demonstrated statistically significant improvements relative to placebo in key endpoints:
- MASH Resolution: A statistically significant proportion of patients treated with denifanstat achieved MASH resolution without worsening of fibrosis, indicated by a ≥2-point reduction in the Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS).
- Fibrosis Improvement: Denifanstat-treated patients also showed statistically significant improvement in fibrosis by ≥1 stage with no worsening of MASH.
- MRI-PDFF Response: A statistically significantly greater proportion of patients achieved ≥30% reduction in MRI-derived proton density fat fraction (MRI-PDFF) compared to placebo.
In the intent-to-treat (ITT) population, denifanstat achieved statistically significant results on primary and secondary liver biopsy endpoints, aligning with FDA draft guidance for accelerated approval in MASH. The safety data indicated that denifanstat was generally well tolerated.
Mechanism of Action and Differentiation
Denifanstat is distinguished as the only fat synthesis inhibitor that directly targets the three main drivers of MASH: fat accumulation, inflammation, and fibrosis. By inhibiting FASN, denifanstat reduces the production of palmitate, a fatty acid implicated in the pathogenesis of MASH. This mechanism differentiates denifanstat from other therapeutics in development for MASH, positioning it as a potential leading treatment option.
Expert Commentary
David Happel, Chief Executive Officer of Sagimet, stated, "The FDA’s Breakthrough Therapy designation for denifanstat underscores the global incidence of MASH and the continuing need for new therapies. As the only fat synthesis inhibitor that directly targets the three main drivers of MASH—fat accumulation, inflammation, and fibrosis—we believe denifanstat is well-positioned to offer a leading treatment option for patients living with MASH."
MASH Disease Burden and Unmet Needs
MASH affects more than 115 million people worldwide and can progress to severe conditions such as cirrhosis, liver failure, or liver cancer, often requiring liver transplantation. As MASH advances to moderate or severe fibrosis (stages F2 and F3), the risk of adverse liver outcomes rises significantly. The vast and diverse MASH market is largely untapped, creating a significant need for novel therapies.
Ongoing and Future Development
Sagimet plans to initiate a Phase 3 clinical program for denifanstat in MASH by the end of 2024. This pivotal study will further evaluate the efficacy and safety of denifanstat in a larger patient population, with the goal of securing regulatory approval and bringing this novel therapy to patients in need.
Current Treatment Landscape
Currently, Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) is the only approved treatment for MASH, indicated for noncirrhotic MASH with moderate-to-advanced liver fibrosis. Several other companies, including Viking Therapeutics, Akero Therapeutics, Eli Lilly, and Novo Nordisk, are also developing treatments for MASH, reflecting the high unmet medical need and significant market opportunity.
