Sagimet Biosciences presents clinical denifanstat, preclinical FASN inhibitor da

Sagimet Biosciences (SGMT) announced the presentation of Phase 2b data demonstrating the anti-fibrotic activity of its fatty acid synthase inhibitor denifanstat, and preclinical data demonstrating potential benefit of FASN inhibition in atherosclerosis, at the American Association for the Study of Liver Disease – The Liver Meeting 2024, November 15-19, 2024 in San Diego, California. A poster titled “Denifanstat significantly improves liver fibrosis in difficult-to-treat MASH patients – Results from conventional and AI-based pathology from the phase 2b FASCINATE-2, a 52-week randomized, double-blind, placebo-controlled trial,” was presented by Rohit Loomba, M.D., M.H.Sc., Professor of Medicine, Chief, Division of Gastroenterology and Hepatology, and Director, MASLD Research Center, University of California San Diego, the primary investigator of the FASCINATE-2 trial. Denifanstat treatment improved fibrosis by greater than or equal to 1 stage without worsening of MASH in the higher-risk patient subgroups described below. Observed improvements by conventional pathology reading included: F3 population: 49% denifanstat vs 13% placebo; GLP1 receptor agonist population: 42% denifanstat vs 0% placebo; Type 2 diabetes population: 40% denifanstat vs 19% placebo; PNPLA3 I148 carrier population: 30% denifanstat vs 6% placebo;Strong consistency in fibrosis improvement was observed between conventional and AI-based pathology in the F3 population. Denifanstat treatment improved fibrosis by greater than or equal to 1 stage in more than 50% of F3 patients as follows: AI-based: 62% denifanstat and 26% placebo; Conventional: 55% denifanstat and 26%; An oral presentation titled “AI-based digital pathology shows that denifanstat improves multiple parameters of fibrosis and reduces progression to cirrhosis in MASH patients with F2/F3 fibrosis – results of the FASCINATE-2 study,” was presented by Mary Rinella, M.D. In this analysis, second harmonic generation microscopy AI-based digital pathology was used to evaluate pre- and post-treatment liver biopsies. Denifanstat showed statistically significant liver fibrosis improvement, particularly in the portal and peri-portal regions. Improvement was observed with AI-based digital pathology not only in patients with greater than1-stage fibrosis improvement but also in patients with “no change” in fibrosis stage by conventional reading, representing important mechanistic insights provided by the AI-based platform. Select fibrosis parameters in the periportal and portal regions are part of AI-based composite score that have been recently linked to liver outcomes and mortality. Overall, both AI and conventional pathology readings demonstrated denifanstat’s strong anti-fibrotic activity in MASH patients, including those with high risk of progression. These data reflect the unique mechanism of action of denifanstat and support the initiation of phase 3 trials. Lastly, a poster titled “Fatty acid synthase inhibitor reduces atherosclerosis development in diet-induced dyslipidaemia LDL receptor knockout mice with MASH,” was presented by Wen-Wei Tsai, Ph.D. In this mouse model, treatment with a FASN inhibitor that is a preclinical surrogate for denifanstat rapidly reduced circulating cholesterol, triglycerides and inflammatory markers associated with atherosclerosis, including CCL4 and CXCL2. The FASN inhibitor also reduced total atherosclerotic lesion area in the aortic root and improved liver steatosis, inflammation and fibrosis. These preclinical results suggest that a FASN inhibitor such as denifanstat could potentially provide benefits in cardiovascular as well as liver health, supporting the clinical evaluation of denifanstat for long term outcomes in MASH patients.