Sagimet's Denifanstat Shows Significant Anti-Fibrotic Benefits in Advanced MASH Patients at AASLD 2025
核心洞察
Denifanstat demonstrated an 85% response rate for fibrosis regression in advanced qF4 MASH (搜索) patients compared to 33% with placebo in a secondary analysis of the FASCINATE-2 trial.
In F3 MASH (搜索) patients, denifanstat achieved a 34% response rate for ≥2-stage fibrosis improvement without MASH worsening versus 4% with placebo (p=0.0065).
AI-based digital pathology and spatial computational histology revealed that denifanstat significantly improved multiple noninvasive biomarkers including FibroScan (-29% vs +26% placebo) and liver fat content (-34% vs +14% placebo).
Sagimet Biosciences presented compelling new data at the American Association for the Study of Liver Disease (AASLD) - The Liver Meeting® 2025 demonstrating denifanstat's robust anti-fibrotic effects in patients with advanced metabolic dysfunction-associated steatohepatitis (搜索) (MASH (搜索)). The presentations, delivered November 7-11 in Washington, DC, revealed significant improvements in liver fibrosis (搜索), inflammation, and steatosis using artificial intelligence-based digital pathology analysis.
Breakthrough Results in Advanced Fibrosis Patients
A secondary analysis of the Phase 2b FASCINATE-2 clinical trial identified a subpopulation of MASH (搜索) patients with advanced fibrosis, defined as qFibrosis stage 4 (qF4), and demonstrated denifanstat's impressive therapeutic potential in this challenging patient group. In qF4 patients, denifanstat treatment improved fibrosis by 1-2 qFibrosis stages with a response rate for ≥1 qFibrosis stage regression of 85% (11/13) compared to 33% (1/3) in placebo-treated patients.
"Our presentations at AASLD this year demonstrate denifanstat's impressive ability to address advanced fibrosis in MASH (搜索) patients," said David Happel, Chief Executive Officer of Sagimet. "A secondary analysis of denifanstat treatment in MASH patients with advanced liver fibrosis (搜索) stage defined as qF4 by AI-based digital pathology reproduced and further detailed denifanstat's anti-fibrotic and anti-inflammatory benefits."
Significant Improvements Across Fibrosis Stages
The data revealed particularly striking results in F3 MASH (搜索) patients using clinical research network (CRN) scoring. The response rate for fibrosis improvement by ≥2 stages without worsening of MASH was 34% (16/47) for denifanstat versus 4% (1/23) in placebo-treated patients, achieving statistical significance with a p-value of 0.0065.
In qF4 MASH (搜索) patients using MASH CRN scoring, the response rate for fibrosis improvement by ≥1 stage was 39% (5/13) for denifanstat, with 4 of the 5 responding patients showing 2 stages of improvement, compared to 0% (0/3) in placebo-treated patients.
Comprehensive Biomarker Improvements
The analysis revealed substantial improvements across multiple noninvasive biomarkers in qF4 patients treated with denifanstat at week 52. FibroScan measurements showed a 29% decrease with denifanstat compared to a 26% increase with placebo. The FAST score, a composite biomarker for MASH (搜索) severity, decreased by 45% with denifanstat versus a 9% increase with placebo.
Liver fat content, as measured by MRI-PDFF, decreased by 34% with denifanstat treatment compared to a 14% increase with placebo. Liver enzyme levels also showed marked improvement, with ALT decreasing by 43% (versus 5% increase with placebo) and AST decreasing by 37% (versus 1% decrease with placebo). The Enhanced Liver Fibrosis (搜索) (ELF) score decreased by 0.3 with denifanstat compared to an increase of 0.02 with placebo.
AI-Driven Precision Medicine Approach
A second presentation by Dr. Vlad Ratziu from Sorbonne Université demonstrated how spatial computational histology could predict treatment response to denifanstat. The analysis revealed that quantitative single-fiber traits and clustering identified specific fibrosis phenotypes that predicted denifanstat response, suggesting computational pathology could be leveraged for patient stratification and personalized treatment approaches.
Addressing Critical Unmet Medical Need
MASH (搜索) represents a significant global health challenge, affecting an estimated 265 million people worldwide. The disease is characterized by fat accumulation in the liver with varying degrees of inflammation and fibrosis, along with systemic metabolic changes including dyslipidemia and insulin resistance. Patients with moderate to severe disease who have advanced fibrosis (F3) or cirrhosis (F4) face the highest risk of liver-related complications including decompensation, hepatocellular carcinoma (搜索), and liver transplantation.
Currently, there are few approved treatments for non-cirrhotic MASH (搜索) (stages F1, F2 and F3 fibrosis) and no approved treatments for MASH cirrhosis (F4), highlighting the critical need for effective therapeutic options like denifanstat.
Regulatory Recognition and Future Development
Denifanstat has received Breakthrough Therapy designation from the FDA for the treatment of non-cirrhotic MASH (搜索) with moderate to advanced liver fibrosis (搜索) (consistent with stages F2 to F3 fibrosis). The company has successfully completed end-of-Phase 2 interactions with the FDA, supporting advancement into further development phases.
Sagimet is also exploring combination approaches, with a Phase 1 pharmacokinetic study of denifanstat combined with resmetirom currently underway, planned for development in cirrhotic patients with F4-stage MASH (搜索). Additionally, the company is developing TVB-3567, a second oral FASN (搜索) inhibitor currently in Phase 1 trials for acne (搜索) treatment.