FDA grants breakthrough status to Sagimet’s denifanstat to treat MASH with fibrosis
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The FDA granted breakthrough designation to Sagimet Biosciences’ denifanstat for the treatment of patients with metabolic dysfunction-associated steatohepatitis and moderate to advanced fibrosis, according to a company press release.
Denifanstat, an oral, once-daily fatty acid synthase inhibitor now joins a short list of contenders to become the second FDA approved therapy for MASH, following the approval of Rezdiffra (resmetirom, Madrigal Pharmaceuticals) earlier this year.
“The FDA’s Breakthrough Therapy designation for denifanstat underscores the global incidence of MASH and the continuing need for new therapies,” David Happel, CEO of Sagimet, said in the release. “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.”
The agency based its decision on “positive data” from the phase 2b FASCINATE-2 trial, which assessed the safety and efficacy of denifanstat in patients with biopsy-proven MASH and stage 2 or 3 fibrosis, the release stated.
According to FASCINATE-2 trial results, treatment with denifanstat vs. placebo led to “statistically significant improvements” in MASH resolution without worsening of fibrosis, with an at least 2-point improvement in Nonalcoholic Fatty Liver Disease Activity Score (NAS) and an at least 2-point improvement in NAS without worsening of fibrosis.
In addition, liver fibrosis in those treated with denifanstat significantly improved by at least one stage without worsening of MASH and according to the release, a “statistically significantly greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) 30% responders relative to placebo.”
According to the release, the intention-to-treat analysis showed denifanstat met histology endpoints needed for accelerated FDA approval in MASH and the therapy was “generally well tolerated.”
The company noted that it plans to launch its phase 3 clinical program assessing denifanstat in patients with MASH by the end of this year.
The FDA grants breakthrough designation to expedite development of drugs or devices intended to treat serious conditions and supported by clinical evidence indicating that the product may demonstrate substantial improvement over currently available drugs or devices. Breakthrough designation is intended to accelerate drug/device development, assessment and review for premarket approval, 510(k) clearance and de novo marketing authorization, while still meeting FDA standards for safety and effectiveness.
Perspective
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Jamile’ Wakim-Fleming, MD, FACG, FAASLD
MASH is a serious disease that is rapidly becoming a major cause for liver transplantation and health-related costs in the U.S.
There is an urgency in developing drugs to treat this disease due to its rising prevalence and the risks associated with it, notably cirrhosis, liver cancer and death. The FDA approved the first drug for MASH in March 2024, and many other therapies are being developed, with a few in phase 2 clinical trials.
The FDA grants approval for medications that prove to be safe in clinical trials and effective for their intended use. In addition, drugs intended to treat serious conditions may be granted breakthrough therapy designation to expedite their development and review. In the case of drug approval for MASH, the FDA requires that a drug shows improvement of at least one degree of fibrosis and no worsening of steatohepatitis, or improvement of steatohepatitis and no worsening of fibrosis.
Findings from the phase 2b FASCINATE-2 trial led to breakthrough therapy designation for denifanstat, which will allow drug development and review to be expedited.
The hope is that the drug will meet FDA criteria for approval in phase 3 trials, so that patients with MASH can be treated before any serious complications develop. Other awaited endpoints that need to be further explored are the metabolic features associated with MASH, which incur serious comorbidities.
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