Sagimet Biosciences Publishes Phase 2b FASCINATE-2 Denifanstat Trial Results in The Lancet Gastroenterology & Hepatology

Sagimet Biosciences Inc. has shared promising results from its Phase 2b FASCINATE-2 clinical trial, evaluating the effectiveness of denifanstat, a novel fatty acid synthase (FASN) inhibitor, in treating metabolic-dysfunction associated steatohepatitis (MASH) with moderate-to-severe fibrosis (stage F2/F3). The findings, published in The Lancet Gastroenterology & Hepatology, indicate significant improvements in disease activity, MASH resolution, and fibrosis among patients treated with denifanstat compared to a placebo.

According to the study, denifanstat achieved statistically significant improvements on primary endpoints at week 52. Specifically, 36% of patients receiving denifanstat experienced MASH resolution without fibrosis worsening, compared to 13% in the placebo group. Additionally, 52% of the denifanstat group saw a reduction in NAS by ≥2 points without fibrosis worsening, against 20% for those on placebo. The drug demonstrated its efficacy across both the intention to treat (ITT) and modified intention to treat (mITT) populations.

Rohit Loomba, M.D., M.H.Sc., the primary investigator of the trial and a professor at the University of California San Diego, emphasized the urgent need for treatments that address the core drivers of liver injury in MASH: fat accumulation, inflammation, and fibrosis. Loomba highlighted that denifanstat's mechanism targets these pathways and offers a differentiated approach by inhibiting endogenous FASN activity in hepatocytes, immune cells, and stellate cells.

Dave Happel, CEO of Sagimet, underscored the importance of these findings, noting that they validate denifanstat's potential to improve patient outcomes, particularly as MASH progresses. The results meet the criteria outlined in the FDA draft guidance for Phase 3 MASH trials, encouraging the advancement of denifanstat into Phase 3 development. Happel expressed the company's commitment to addressing the needs of MASH patients and anticipated commencing the Phase 3 program in 2024.

The trial also reported significant outcomes on secondary endpoints. Denifanstat demonstrated a statistically significant fibrosis response rate through both traditional and AI-based digital pathology. Improvements included fibrosis improvement by ≥1 stage without steatohepatitis worsening in 41% of patients versus 18% with placebo and a fibrosis improvement by ≥2 stages in 20% versus 2%, respectively.

Specific patient subsets showed notable responses, such as those with F3 fibrosis (49% improvement with denifanstat vs. 13% with placebo) and type 2 diabetes (40% vs. 19%). Patients on stable glucagon-like peptide 1 receptor agonists also benefited (42% improvement vs. 0% with placebo).

Non-invasive biomarkers indicated improvements in liver and metabolic health, with decreases in liver fat and enzymes. Despite the use of statins in over half of the study participants, LDL-cholesterol levels decreased, particularly in those with baseline levels ≥100mg/dL. Triglyceride levels saw a slight increase, related to changes in fatty acid composition.

Safety data reinforced prior findings, with no treatment-related serious adverse events and the majority being mild or moderate in nature. There were no Grade ≥3 treatment-related adverse events or signs of drug-induced liver injury.

The Phase 2b FASCINATE-2 clinical trial enrolled 168 patients, randomly assigning them in a 2:1 ratio to receive 50 mg of denifanstat or a placebo daily. The 52-week study included end-of-trial biopsies reviewed by a central pathologist and AI-based digital pathology assessments.

Sagimet Biosciences focuses on developing FASN inhibitors to target dysfunctional metabolic and fibrotic pathways, with denifanstat being its lead candidate for MASH treatment. The company's efforts are geared towards offering new therapeutic options for a disease affecting over 115 million people globally, particularly as there are limited approved treatments currently available.