Sagimet Biosciences Inc. - Series A · NASDAQ:SGMT
Sagimet Biosciences Inc. - Series A — Sagimet Biosciences — Technical Presentation (January 2025)
20 slides from Sagimet Biosciences Inc. - Series A's technical presentation, January 2025
Slide 1: The FASN Inhibitor Denifanstat in MASH
The FASN Inhibitor Denifanstat in MASH Marie O’Farrell, PhD
Slide 2: Disclosures
Disclosures Dr. O'Farrell is an employee of Sagimet Biosciences Inc. and holds stock options in the company 2
Slide 3: Outline
Outline • Introduction to FASN and denifanstat • Mechanism of action studies • Phase 2b FASCINATE-2 study results in F2/F3 MASH 3
Slide 4: MASH: A Burgeoning Epidemic
MASH: A Burgeoning Epidemic Estimated Patients in 20301 United States 100.9 million 27.0 million 10.6 million 3.5 million 25 thousand MASH compensated and annual cases among decompensated MASLD population • Complex disease with heterogeneous patient population • SignificantDisease opportunity for ch
Slide 5: FASN is Well Known for its Role in Hepatic De Novo Lipogenesis (DNL)
FASN is Well Known for its Role in Hepatic De Novo Lipogenesis (DNL) DNL pathway Dietary sugar • Hepatic DNL is increased in MASLD/MASH which Acetyl-CoA leads to increased liver fat in hepatocytes ACC • Important initiating event in MASLD/MASH • FASN (fatty acid synthase) is the last committed Malon
Slide 6: FASN Also Plays Key Roles in Two Other Major Cell Types in MASH
FASN Also Plays Key Roles in Two Other Major Cell Types in MASH DNL pathway Dietary sugar Acetyl-CoA ACC Malonyl-CoA FASN Increases Increases Increases Fatty acids Cytokines Fibrogenesis Palmitate Triglycerides Chemokines Cell activation Lipotoxins Cell activation Lipid synthesis 6
Slide 7: FASN Inhibition Directly Blocks Human Liver Stellate Cell Function
FASN Inhibition Directly Blocks Human Liver Stellate Cell Function Stellate cells require DNL for fibrogenesis Primary human stellate cell assay Denifanstat blocks stellate cell activation Denifanstat directly inhibits fibrogenic activity Denifanstat Collagen / total protein (μg/mg) 60 40 * * 20 * *
Slide 8: DNL Inhibition Correlates with Collagen Inhibition Across DNL Inhibitors
DNL Inhibition Correlates with Collagen Inhibition Across DNL Inhibitors Hepatocyte cell line - HepG2 DNL correlates with pro-collagen Stellate cell line - LX2 Stellate cell line - LX2 Adapted from Bates et al., 2020, Hepatology, 20: 30281-6 8
Slide 9: FASN Inhibitor Reversed Hepatic Fibrosis
FASN Inhibitor Reversed Hepatic Fibrosis Collaboration with Dr. Scott Friedman High fat and high sugar diet High fat and high sugar diet CCl4 1x/week CCl4 1x/week Assess liver fibrosis and 3 months 3 months tumor formation +/- FASN inhibitor Quantitated by AI-digital Decreased tumor pathology format
Slide 10: Clinical Development of Denifanstat
Clinical Development of Denifanstat • Subjects with characteristics of MASLD Phase 1 • 10-day denifanstat treatment • Denifanstat decreased hepatic DNL in human1 • MASH patients Phase 2a • 12-week denifanstat treatment FASCINATE-1 • Denifanstat decreased liver fat by MRI-PDFF, decreased inflammation
Slide 11: FASCINATE-2: Biopsy Trial Design Focused on Histological Endpoints
FASCINATE-2: Biopsy Trial Design Focused on Histological Endpoints Denifanstat (50 mg) Primary endpoints Screening Placebo • NAS ≥2 points improvement w/o worsening of fibrosis Study Weeks • MASH resolution + NAS ≥2 improvement w/o 0 52 worsening of fibrosis Baseline Final Selected secondary endpoin
Slide 12: Denifanstat Rapidly Reduced De Novo Lipogenesis and Decreased Liver Fat
Denifanstat Rapidly Reduced De Novo Lipogenesis and Decreased Liver Fat Denifanstat Tripalmitin Liver Fat Change from Baseline Change from Baseline Placebo Denifanstat n=52 n=111 Liver fat by MRI- Placebo Denifanstat LS mean change (ug/mL) PDFF n=38 n=69 -0.4 Relative decrease +5% -23% p=0.0036 Week
Slide 13: Histology Endpoints of MASH Resolution and Liver Fibrosis at Week 52
Histology Endpoints of MASH Resolution and Liver Fibrosis at Week 52 Denifanstat Achieved Statistical Significance (Endpoints per FDA Draft Guidance 2020) Resolution of MASH Improvement in liver fibrosis ≥ 1 stage w/o worsening of fibrosis & No Worsening of MASH 38% 41% p=0.0043 p=0.0051 p=0.0102 %
Slide 14: Additional Fibrosis Analysis by Conventional Pathology
Additional Fibrosis Analysis by Conventional Pathology Denifanstat Achieved Strong Improvement in F3 Population Fibrosis Endpoints Subgroup Placebo Denifanstat p-value All pts 18% 41% 0.0051* >1 stage improvement in fibrosis w/o worsening of MASH F3 only 13% 49% 0.0032** All pts 2% 20% 0.0065** >2 s
Slide 15: Fibrosis Analysis by AI-based Digital Pathology
Fibrosis Analysis by AI-based Digital Pathology Independent Approach Performed Prospectively – Second Harmonic Generation Microscopy Pre-Treatment Pt A qFibrosis Continuous Value NASH-CRN Fibrosis stage F3 with Steatosis Correction All patients Denifanstat Post-Treatment Pt A NASH-CRN Fibrosis stage
Slide 16: qFibrosis by AI-based Digital Pathology Provides Supporting Evidence of Reduced Fibrosis
qFibrosis by AI-based Digital Pathology Provides Supporting Evidence that Denifanstat Significantly Reduced Fibrosis, Notably in F3 Population qFibrosis Continuous Value Morphometric Analysis qFibrosis Continuous Value with Steatosis Correction Septa Area (uM2) with Steatosis Correction F3 only F3 o
Slide 17: qFibrosis Zonal Analysis Improves Parameters Linked to Liver Outcomes
qFibrosis Zonal Analysis Demonstrated that Denifanstat Improves Parameters Previously Linked to Liver Outcomes Portal HA Vein Fibrosis Improvement by Zones BD (Response Rate Ratio) Peri-CV Central Peri-Central Vein Zone 2 Zone 3 Peri-Portal p= 0.028 Zone 2 Portal p= 0.023 Zone 1 -1 0 1 2 3 4 5 6 Cha
Slide 18: Phase 2 Results Are Consistent with Mechanism of Action
Phase 2 Results Are Consistent with Mechanism of Action Denifanstat Denifanstat Denifanstat Hepatic DNL ELF Non-invasive ALT, AST Tripalmitin CK-18 M30, M65 FAST biomarkers Liver fat MRI-PDFF F3 high response rate Histology Steatosis Inflammation Fibrosis Septa favorable changes Ballooning Portal an
Slide 19: Denifanstat Provides a Differentiated Mechanism of Action in MASH
Denifanstat Provides a Differentiated Mechanism of Action in MASH • Denifanstat is not only a liver fat blocker, but acts directly on stellate cells -> tackles both “initiating” (liver fat synthesis) and “progressing” (fibrosis) events • Denifanstat showed significant improvement in MASH resolution
Slide 20: Acknowledgements
Acknowledgements • Sagimet Team • Sagimet Advisors • Investigators, sites and patients involved in FASCINATE studies • HistoIndex Team
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