Sagimet Biosciences Shares Phase 2b FASCINATE-2 Trial Data at EASL 2024

Sagimet Biosciences Inc., a clinical-stage biopharmaceutical company focused on developing innovative fatty acid synthase (FASN) inhibitors, has disclosed optimistic outcomes from its FASCINATE-2 Phase 2b clinical trial. The trial, assessing the efficacy of denifanstat against a placebo in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH), was presented at the European Association for the Study of the Liver (EASL) Congress in Milan, Italy.

Denifanstat, an oral, once-daily selective FASN inhibitor, demonstrated significant clinical results in addressing MASH, a progressive liver disease. The drug is specifically designed to mitigate the three primary drivers of MASH: fat accumulation, inflammation, and fibrosis.

Chief Executive Officer of Sagimet, Dave Happel, highlighted the significance of the findings, particularly the improvements in liver fibrosis observed at the 52-week mark. The data revealed substantial enhancements in fibrosis stages ≥ 1 and ≥ 2, especially in patients with stage 3 fibrosis, known as F3. Happel emphasized that these results bolster the company's plans to advance to Phase 3 registrational trials for denifanstat in MASH with fibrosis by the latter half of the year.

The primary endpoint of the trial, a reduction in the NAFLD Activity Score (NAS) by two or more points without worsening fibrosis, was met by 38% of patients treated with denifanstat compared to 16% in the placebo group. Additionally, MASH resolution coupled with a ≥2-point NAS reduction was seen in 26% of treated patients versus 11% in the placebo group. These outcomes underscore the drug's efficacy in the intention-to-treat (ITT) population.

Secondary endpoints were equally promising. Improvement in liver fibrosis by one or more stages without worsening MASH was achieved by 30% of the ITT population treated with denifanstat, as opposed to 14% in the placebo group. In patients with baseline stage 3 fibrosis, this improvement was observed in 49% of the denifanstat group versus 13% in the placebo cohort. For two-stage fibrosis improvement, 20% of the modified intention-to-treat (mITT) population on denifanstat showed positive results, compared to just 2% in the placebo group. Among F3 patients, this figure was 34% for denifanstat versus 4% for placebo.

The trial also reported a significant increase in beneficial polyunsaturated triglycerides in the mITT population over the 52-week treatment period, with denifanstat showing a 42% increase compared to a 4% decrease in the placebo group. Additionally, tripalmitin, a biomarker of denifanstat activity, exhibited an early and sustained reduction in de novo lipogenesis at both the 4-week and 13-week marks.

Safety data indicated that denifanstat was generally well tolerated, with no treatment-related serious adverse events (SAEs) and most adverse events (AEs) being mild or moderate in nature. The incidence of treatment-emergent adverse events (TEAEs) leading to discontinuation was 19.6% for the denifanstat group compared to 5.4% for placebo.

Dr. Rohit Loomba, a professor of medicine and director of the MASLD Research Center at the University of California San Diego, noted the substantial clinical benefits of denifanstat. He emphasized its significant impact on both MASH resolution and fibrosis improvement in patients with moderate to advanced fibrosis due to MASH, supporting its further development.

The Phase 2b FASCINATE-2 trial, a 52-week randomized, double-blind, placebo-controlled study, involved 168 biopsy-confirmed MASH patients with moderate-to-severe fibrosis (F2 or F3) and a NAS of 4 or higher. Participants were randomized to receive either 50 mg of denifanstat or a placebo, taken orally once daily. Histological endpoints were assessed via end-of-trial biopsies reviewed by a central pathologist and AI-based digital pathology methods.

Sagimet Biosciences continues to focus on developing FASN inhibitors to treat diseases associated with metabolic dysfunction, with denifanstat at the forefront for MASH treatment. The company aims to initiate Phase 3 clinical trials later this year, building on the promising findings from the FASCINATE-2 study.