Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Technical Presentation (May 2024)
21 slides from Fractyl Health's technical presentation, May 2024
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 and Reduces Hepatic Triglycerides in a Murine Model of Obesity Harith Rajagopalan, Alice Liou Fitzpatrick, Suya Wang, Emily Cozzi, Randy Seeley, Timothy Kieffer, Jay Caplan @DDWMeeting | #DDW2024 1
Slide 2: Disclosure Statement
Disclosure Statement We disclose the following financial relationship(s) with a commercial interest: 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 re
Slide 3: Incretin Therapies: Type 2 Diabetes, Obesity, and Beyond
Incretin Therapies: Type 2 Diabetes, Obesity, and Beyond Emerging benefit in MASLD and MASH Clinical studies suggest that Study Year Molecules Treatment Control Odds Ratio Weight GLP-1RAs can improve Yes No Yes No with 95% Cl (%) steatohepatitis, liver function, and fibrosis Armstrong 2016 Liragluti
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 metabolic disease,1,2 up to 2/3 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 STEP-1 Trial Extension – Semaglutide 2.4 mg to near total loss of Medicine Started Medicine Stopped metabolic benefit1 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 are terminally differentiated,1 making adeno-associated virus (AAV) Insulin a suitable means of durable genetic modification Pancreas is readily accessible via endoscopic Islet u
Slide 7: Gene Therapy Route of Administration to Pancreas
Gene Therapy Route of Administration to Pancreas Islets are most easily accessed via endoscopic ultrasound Islets are predominantly in body and tail of pancreas, most easily accessible via Pancreatic Gene Therapy endoscopic ultrasound (EUS)1,2 Upper EUS is routine and straightforward (~300K patients
Slide 8: 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 8 @DDWMeeting | #DDW2024 Raja
Slide 9: Local Endoscopic Delivery Allows High Expression
Local Endoscopic Delivery Allows High Expression Dramatically limits systemic exposure to AAV in porcine model A) Local Delivery1 (4.2e12 VG/kg) B) I.V.2 (8.3e12 VG/kg) 0.005x Pancreas 1000 1000 5.1x 73.3 100 100 33.8 VCN (VG/DG) VCN (VG/DG) 22.7 10 4.1 10 2.0 0.8 1 1 0.4 0.1 0.1 0.1 0.01 0.01 Pancr
Slide 10: Proof-of-principle Safety with Local Endoscopic Delivery System
Proof-of-principle Safety with Local Endoscopic Delivery System Mean 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 10 @DDWMeeting | #DDW2024 Mean shown; n=28. 1. Thompson et al. UEGW 2023 poster presentation. Abst
Slide 11: GLP-1RA PGTx T2D Efficacy Study: Head-to-head vs. Semaglutide
GLP-1RA PGTx T2D Efficacy Study: Head-to-head vs. Semaglutide db/db murine model is de facto standard for T2D development Single I.P. Injection (5e12 VG GLP-1RA PGTx or Vehicle) 8-week-old Mice Days 0 14 28 42 56 62 Daily S.C. Injections Efficacy/MOA (Day 0-62) Sacrifice (Day 62) Semaglutide (10 nmo
Slide 12: Glucose-lowering Efficacy in db/db Murine Model
Glucose-lowering Efficacy in db/db Murine Model GLP-1RA PGTx improves glucose, insulin, and weight vs. daily semaglutide A) Fasting Blood Glucose B) Fasting Plasma Insulin C) Body Weight Change from Baseline (Day 29, 4-6 Hours Fasted) (Day 29, 4-6 Hours Fasted) (Day 29, 4-6 Hours Fasted) Vehicle Con
Slide 13: In Diet-induced Obesity, Compared to Chronic Semaglutide, Can One-time GLP-1-based PGTx Improve Body Weight and MASLD?
In Diet-induced Improve body weight? Obesity, Compared to Improve MASLD? Chronic Semaglutide, Can One-time GLP-1- based PGTx: 13
Slide 14: GLP-1RA PGTx Obesity Efficacy Study: Head-to-head vs. Semaglutide
GLP-1RA PGTx Obesity Efficacy Study: Head-to-head vs. Semaglutide DIO murine model is de facto standard for obesity development Single I.P. Injection (1e13 VG GLP-1RA PGTx or Vehicle) 60% HFD Semaglutide HFD Maintenance Induction Withdrawal & Efficacy (25 Weeks) (Day 29) (Days 1-57) Days 1 8 15 22 2
Slide 15: Body Weight Change in DIO Murine Model
Body Weight Change in DIO Murine Model Single-dose GLP-1RA PGTx sustains weight loss after semaglutide withdrawal A) Change in BW Over Time B) End of Study BW Change 110 105 100 from Day 1 (%) BW Reduction 95 BW Reduction (%) 90 85 80 75 70 65 60 1 8 15 22 29 36 43 50 57 Days Vehicle Control Sema (1
Slide 16: Food Intake Change in DIO Murine Model
Food Intake Change in DIO Murine Model Body weight changes are reflected by alterations in food intake A) Change in BW Over Time B) Food Intake Over Time 110 4.5 105 4.0 100 Food Intake (Grams) 3.5 from Day 1 (%) BW Reduction 95 3.0 90 2.5 85 80 2.0 75 1.5 70 1.0 65 0.5 60 0.0 1 8 15 22 29 36 43 50
Slide 17: Liver Weight and Triglyceride Change in DIO Murine Model
Liver Weight and Triglyceride Change in DIO Murine Model Single-dose GLP-1RA PGTx reduced liver weight and triglycerides 42% lower liver weight with A) Liver Weight B) Liver Triglycerides PGTx compared to vehicle (Day 57) (Day 57) 67% lower liver triglycerides with PGTx compared to vehicle Sema with
Slide 18: Plasma Cholesterol and Triglyceride Change in DIO Murine Model
Plasma Cholesterol and Triglyceride Change in DIO Murine Model Single-dose GLP-1RA PGTx reduced total cholesterol A) Total Cholesterol B) LDL C) HDL D) Triglycerides Vehicle Control Sema Withdrawal + Vehicle GLP-1RA PGTx (1e13 VG) Sema Withdrawal + GLP-1RA PGTx (5e12 VG) 18 @DDWMeeting | #DDW2024 Me
Slide 19: GLP-1RA PGTx Safety and Feasibility Studies in Model Systems: Conclusions to date
GLP-1RA PGTx Safety and Feasibility Studies in Model Systems Conclusions to date Early safety and feasibility observations in db/db Pancreatic and DIO mice and Yucatan pigs are encouraging Gene Therapy Compared to chronic semaglutide, single-dose PGTx improves fasting glucose and prevents weight gai
Slide 20: GLP-1RA PGTx Safety and Feasibility Studies: Next Steps
GLP-1RA PGTx Safety and Feasibility Studies Next Steps First GLP-1 PGTx, RJVA-001, nominated as Pancreatic development candidate Gene Therapy IND-enabling, preclinical studies are underway Anticipate initiating first-in-human trial in type 2 diabetes in the first half of 2025 20 @DDWMeeting | #DDW20
Slide 21: Thank You / Acknowledgements
Thank You Acknowledgements Shimyn Slomovic, PhD Sr. Director, Head of R&D Advisors Chris Thompson, MD Brigham and Women’s Hospital Design and in vitro screening ex vivo and animal studies Device Engineering Lin Quek, PhD Alice Fitzpatrick, DVM, PhD Mike Biasella, BS Linda Lee, MD Assoc. Director Dir