Summary of Sagimet Biosciences Post EASL Key Opinion Leader Call Company Overview - **Company**: Sagimet Biosciences - **Lead Asset**: Denifenstat, a once-daily oral small molecule targeting fatty acid synthase (FASN) inhibition, primarily focused on treating non-alcoholic steatohepatitis (NASH) and other conditions like acne and certain solid tumors [7][11] Industry Context - **NASH Market**: The NASH market is projected to double in size over the next two decades, with an expected prevalence of at least 3.5 million patients in the U.S. alone [11] - **Combination Therapy**: The company is exploring a combination therapy of Denifenstat and Resmidoram, which is anticipated to improve outcomes for severe NASH patients [8][11] Key Clinical Data - **Phase 2b FASTINate-two Trial**: - Focused on severe NASH patients, showing significant improvements in liver histology and fibrosis. - Primary endpoint: 38% response rate in the Denifenstat group versus 16% in placebo for a two-point improvement in NAFLD activity score without worsening fibrosis [24] - Secondary endpoint: 41% one-stage improvement in fibrosis without worsening NASH in the Denifenstat group versus 18% in placebo [26] - Adverse events were generally well tolerated, with no significant liver injury signals [22] Development Plans - **Future Studies**: - A Phase 1 pharmacokinetic (PK) study of the Denifenstat and Resmidoram combination is planned for the second half of 2025, with top-line data expected in early 2026 [8][46] - A Phase 2 trial targeting F4 NASH patients is anticipated to follow, focusing on liver biopsy as a primary endpoint [47] Mechanism of Action - **Denifenstat**: Inhibits de novo lipogenesis, reducing hepatic steatosis and inflammation, and potentially lowering the risk of hepatocellular carcinoma [15][41] - **Combination Rationale**: The combination of Denifenstat and Resmidoram is hypothesized to have a synergistic effect, enhancing both DNL inhibition and mitochondrial beta-oxidation [40][42] Regulatory Considerations - **Combination Approval Pathway**: The regulatory pathway for the fixed-dose combination is independent of the monotherapy approval, allowing for simultaneous development [88] Market Potential - **Patient Population**: The focus is on advanced NASH patients, particularly those with stage 3 and 4 fibrosis, who are currently underserved by existing treatments [11][41] - **Patent Strategy**: A patent application for the Denifenstat and Resmidoram combination has been filed, potentially extending market exclusivity until 2048 [50] Additional Insights - **Adverse Events**: Hair thinning was noted as a treatment-related adverse event, with a 7% discontinuation rate due to this issue [22] - **Biomarker Development**: Non-invasive biomarkers such as MRI PDFF and ALT/AST slopes will be utilized to assess treatment response in future trials [59] Conclusion Sagimet Biosciences is positioned to make significant advancements in the treatment of NASH through its innovative Denifenstat and Resmidoram combination therapy, with promising clinical data and a clear regulatory strategy. The company aims to address a large and growing patient population with unmet medical needs in the NASH market.