Sagimet Biosciences is advancing its oral therapy candidate, denifanstat, into Phase 3 clinical trials for patients with metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This decision follows what the company described as successful meetings with the U.S. Food and Drug Administration (FDA) regarding the design and scope of the upcoming studies. The trials are expected to commence before the end of the year.
Phase 3 Trial Design and Objectives
The Phase 3 program will consist of two multicenter, placebo-controlled clinical trials. Collectively, these trials are expected to enroll at least 1,800 individuals diagnosed with either MASLD or MASH. Denifanstat is designed to inhibit fatty acid synthase (FASN), an enzyme responsible for synthesizing fat in the liver. By suppressing FASN, the therapy aims to reduce the accumulation of liver fat, a key factor in the progression of both MASLD and MASH.
FASCINATE-3 and FASCINIT Trials
One of the trials, named FASCINATE-3, will focus on MASH patients with moderate to advanced liver fibrosis but without cirrhosis. The primary endpoint of FASCINATE-3 is to evaluate the impact of denifanstat on liver health, as determined by liver biopsy. The trial will also assess the therapy's effects on clinical outcomes over a treatment period exceeding four years.
The second Phase 3 trial, FASCINIT, will enroll a broader population of individuals with suspected or confirmed MASLD or MASH. The primary objective of FASCINIT is to evaluate the safety profile of denifanstat. This trial will utilize non-invasive markers to assess liver health, and participants will not be required to undergo a liver biopsy at the conclusion of the study.
Background and Clinical Significance
MASLD is characterized by the abnormal accumulation of fat in the liver, often associated with metabolic disorders such as diabetes. In severe cases, MASLD can progress to MASH, which involves inflammation and fibrosis (scarring) of the liver. The FDA had previously granted denifanstat breakthrough therapy designation for MASH patients with moderate to advanced liver fibrosis, recognizing its potential to offer a significant improvement over existing treatment options.
Prior Clinical Trial Data
Denifanstat's advancement to Phase 3 is supported by data from the completed FASCINATE-2 Phase 2b clinical trial (NCT04906421). This trial demonstrated that denifanstat was more effective than placebo in resolving MASH without worsening fibrosis in 168 adults with biopsy-confirmed MASH and moderate to severe liver fibrosis.
Expert Commentary
"The agency supports our strategy to conduct two Phase 3 trials to assess the safety and efficacy of denifanstat in [MASH with moderate to advanced fibrosis], a complex disease where treatments with novel/differentiated mechanisms of action that directly target the three main drivers of liver injury: fat accumulation, inflammation, and fibrosis are urgently needed," said Dave Happel, CEO of Sagimet.
