Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — WCIRDC 2023 (21st Annual Meeting)
18 slides from Fractyl Health's conference presentation, Dec 8, 2023
Slide 1: Single-dose GLP-1-based Pancreatic Gene Therapy Maintains Weight Loss After Semaglutide Withdrawal
Single-dose GLP-1-based Pancreatic Gene Therapy Maintains Weight Loss After Semaglutide Withdrawal in a Murine Model of Obesity Alice Liou Fitzpatrick, Suya Wang, Emily Cozzi, Randy Seeley, Timothy Kieffer, Jay Caplan, Harith Rajagopalan December 8th, 2023
Slide 2: Disclosure Statement
Disclosure Statement Authors Harith Rajagopalan, Alice Liou Fitzpatrick, Suya Wang, Emily Cozzi, Timothy Kieffer and Jay Caplan are employees and shareholders of Fractyl Health, Inc. Randy Seeley is a paid consultant for and received research support from Novo Nordisk, Fractyl Health, Congruence, an
Slide 3: Incretin Therapies: T2D, Obesity, and Beyond
Incretin Therapies: T2D, Obesity, and Beyond Broad-based benefit on surrogate biomarkers and hard endpoints A) Primary Cardiovascular B) Death from Cardiovascular Causes GLP-1RAs can reduce mortality Composite End Point in individuals with obesity and a Placebo Cumulative Incidence (%) Cumulative In
Slide 4: Incretin Therapies: Real-world Discontinuation Rates are High
Incretin Therapies: Real-world Discontinuation Rates are High Majority of patients discontinue therapy within first year Despite proven clinical efficacy in Probability of Treatment Continuation obesity and T2D,1,2 up to 2/3rds of patients discontinue weekly GLP-1RA therapy within 1 year3-6 Patients
Slide 5: Incretin Therapies: Metabolic Rebound Now Well Described
Incretin Therapies: Metabolic Rebound Now Well Described Current GLP-1RAs do not durably alter metabolic setpoint Discontinuation of therapy leads to STEP-1 Trial Extension – Semaglutide 2.4 mg near total loss of metabolic benefit1 Medicine Started Medicine Stopped 68-week treatment phase 52-week of
Slide 6: Pancreatic Gene Therapy (PGTx) to Modify Islet Function
Pancreatic Gene Therapy (PGTx) to Modify Islet Function Potential for durable improvement in metabolic health Islet cells terminally differentiated,1 making adeno-associated virus (AAV) Insulin a suitable means of durable genetic modification Islet β-cell machinery can be leveraged to produce GLP-1R
Slide 7: GLP-1-based PGTx Improves Insulin Production and GSIS in Islets
GLP-1-based PGTx Improves Insulin Production and GSIS in Islets Metabolic improvements in isolated db/db islets 10 weeks after PGTx A) Islet Transduction B) GLP-1RA Protein C) Insulin Content D) Glucose-Stimulated Content Insulin Secretion (GSIS) 400 2000 250 p<0.05 p<0.0001 p<0.001 Vehicle Stimulat
Slide 8: GLP-1-based PGTx Improves GSIS in Human Islets and β-cell Line
GLP-1-based PGTx Improves GSIS in Human Islets and β-cell Line Improved GSIS mediated by GLP-1R activation A) Human Islet B) Human Islet GSIS C) Human β-cell Line GSIS ± Ex9 Transduction (GLP-1R Antagonist) 25 p<0.01 15 p<0.05 Stimulation Index Stimulation Index 20 10 15 10 5 5 0 0 GFP Expression Gl
Slide 9: Proprietary Local Endoscopic Delivery System Extensively Tested
Proprietary Local Endoscopic Delivery System Extensively Tested Dose-dependent transduction throughout porcine splenic lobe A) Extensive GFP in Splenic Lobe B) VG Dose-dependent GFP in Pancreas Duodenal Lobe 5e12 VG 1e13 VG 5e13 VG 1.5e14 VG Connecting Lobe Splenic Lobe WCIRDC 2023 9 21st Annual Mee
Slide 10: Local Endoscopic Delivery Allows High Expression
Local Endoscopic Delivery Allows High Expression Dramatically limits systemic exposure to AAV in porcine model A) Local Delivery (4.2e12 VG/kg) B) I.V. (8.3e12 VG/kg)2 0.005x Pancreas 1000 1000 5.1x 73.29 100 100 33.76 VCN (VG/DG) VCN (VG/DG) 22.67 8.32 10 4.07 10 3.73 2.0 2.91 2.36 0.8 1 1 0.36 0.1
Slide 11: Proof-of-principle Safety with Local Endoscopic Delivery System
Proof-of-principle Safety with Local Endoscopic Delivery System ALT and lipase levels remained within normal range across all timepoints A) 7-day ALT B) 7-day Lipase U/L U/L Normal Range Days Days WCIRDC 2023 Mean ± SEM shown; n=28. 1. Thompson et al. UEGW 2023 poster presentation. Abstract no. AS-U
Slide 12: GLP-1-based PGTx T2D Efficacy Study: Head-to-head vs. Semaglutide
GLP-1-based PGTx T2D Efficacy Study: Head-to-head vs. Semaglutide db/db murine model is de facto standard for T2D development Single I.P. Injection (1e13 or 5e12 VG GLP-1-based PGTx or Vehicle) 35-day-old Mice Days 0 14 28 42 56 70 Daily S.C. Injections Efficacy/MOA (Day 0-70) Sacrifice (Days 58-70)
Slide 13: Glucose-lowering Efficacy in db/db Murine Model
Glucose-lowering Efficacy in db/ db Murine Model GLP-1-based PGTx improves fasting glucose vs. daily semaglutide A) Fasting Blood Glucose B) Fasting Insulin (Week 8, 4-6 Hours Fasted) (Week 8, 4-6 Hours Fasted) p<0.0001 p<0.01 25 1000 p<0.01 Vehicle Control 20 p<0.01 800 Semaglutide (10 nmol/kg) p<0
Slide 14: Body Weight Change in db/db Murine Model
Body Weight Change in db/ db Murine Model GLP-1-based PGTx prevents weight gain vs. daily semaglutide 23% lower total body weight with p<0.0001 PGTx compared to vehicle 55 p<0.0001 20% lower total body weight with Vehicle Control PGTx compared to semaglutide 50 p<0.0001 Semaglutide (Week 4, Grams) (
Slide 15: GLP-1-based PGTx Efficacy Study: DIO Murine Model
GLP-1-based PGTx T2D Efficacy Study: Head-to-head vs. Semaglutide DIO murine model is de facto standard for obesity development Single I.P. Injection (1e13 VG GLP-1-based PGTx or Vehicle) 60% HFD Semaglutide HFD Maintenance Induction Withdrawal & Efficacy (25 Weeks) (Day 29) (Days 1-57) Days 1 8 15
Slide 16: Body Weight and Food Intake Change in DIO Murine Model
Body Weight and Food Intake Change in DIO Murine Model Single-dose GLP-1-based PGTx sustains weight loss after semaglutide withdrawal A) Change in BW Over Time B) End of Study C) Food Intake Over Time BW Change BW Reduction from Day 1 (%) 110 4.5 105 4.0 Food Intake (Grams) 100 3.5 BW Reduction (%)
Slide 17: GLP-1-based PGTx Safety and Feasibility Studies in Model Systems: Conclusions
GLP-1-based PGTx Safety and Feasibility Studies in Model Systems Conclusions to date Early safety and feasibility observations in db/db and DIO mice and Yucatan pigs are encouraging Insulin Compared to chronic semaglutide, single-dose PGTx improves fasting glucose and prevents Islet weight gain in d
Slide 18: Thank You / Acknowledgements
Thank You Acknowledgements Shimyn Slomovic, PhD ERASE Task Force Sr. Director, Head of R&D and Advisors Randy Seeley, PhD Michigan School of Medicine Design and in vitro screening ex vivo and animal studies Device Engineering Lin Quek, PhD Alice Fitzpatrick, DVM, PhD Mike Biasella, BS Alan Cherringt