Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — ADA 84th Scientific Sessions 2024
21 slides from Fractyl Health's conference presentation, Jun 23, 2024
Slide 1: Single-Dose GLP-1-Based Pancreatic Gene Therapy Durably Maintains Body Composition and Glycemia
Single-Dose GLP-1-Based Pancreatic Gene Therapy Durably Maintains Body Composition and Glycemia after Semaglutide Withdrawal in a Murine Model of Obesity Harith Rajagopalan, Alice Liou Fitzpatrick, Suya Wang, Rebecca Reese, Nicole Picard, Emily Cozzi, Timothy Kieffer, Jay Caplan June 23rd, 2024
Slide 2: Disclosure Statement
Disclosure Statement Authors Harith Rajagopalan, Alice Liou Fitzpatrick, Suya Wang, Rebecca Reese, Nicole Picard, Emily Cozzi, Timothy Kieffer, and Jay Caplan are employees and shareholders of Fractyl Health, Inc. Harith Rajagopalan is a board member of Fractyl Health, Inc. The Pancreatic Gene Thera
Slide 3: GLP-1 Drugs: Weight Rebound is a Significant Problem
GLP-1 Drugs: Weight Rebound is a Significant Problem Current GLP-1 drugs do not durably alter metabolic setpoint Discontinuation of therapy leads STEP-1 Trial Extension – Semaglutide 2.4 mg to near total loss of metabolic Medicine Started Medicine Stopped benefit1 68-week treatment phase 52-week off
Slide 4: Real-World Evidence Shows High Discontinuation Rates
Real-World Evidence Shows High Discontinuation Rates BCBS data show 50% GLP-1 drug discontinuation within 3 months Overall time to treatment discontinuation in Private insurer survey of ~170K unique GLP-1 GLP-1 drug users for weight management drug users for weight loss from January 2014 to 1.0 Conf
Slide 5: Pancreatic Gene Therapy (PGTx) to Modify Islet Function
Pancreatic Gene Therapy (PGTx) to Modify Islet Function Potential for durable improvement in metabolic health GLP-1 gene therapy, targeted to pancreatic islets, may offer differentiated benefit AAV with GLP-1RA Driven by INS β-cell machinery can be leveraged to Promoter produce nutrient-stimulated h
Slide 6: GLP-1RA PGTx in Human Islets and Human β-Cell Line
GLP-1RA PGTx in Human Islets and Human β-Cell Line Improves glucose-stimulated insulin secretion via GLP-1R A) Human Islet B) Human Islet GSIS C) Human β-cell Line GSIS ± Ex9 Transduction (GLP-1R Antagonist) 25 p<0.01 p<0.05 Stimulation Index Stimulation Index 20 15 10 5 0 Glu Glu Glu + Ex9 GFP Expr
Slide 7: Gene Therapy Route of Administration to Pancreas
Gene Therapy Route of Administration to Pancreas Proprietary, automated, endoscopic delivery device Local delivery enables low viral Pancreatic genome dosing with limited systemic Gene Therapy virus exposure1 Islets are readily accessible2,3 via Stomach already established, routine, upper endoscopic
Slide 8: Dose-Dependent Viral Transduction in Yucatan Pig Model
Dose-Dependent Viral Transduction in Yucatan Pig Model Local delivery effectively and reliably targets islets Yucatan pig model anatomy similar Yucatan Pig Islet Transduction to humans1 80 Splenic Lobe Dose-dependent AAV-GFP Endocrine GFP Expression expression in targeted pancreatic lobe2,3 60 41.2%
Slide 9: 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-1-based PGTx or Vehicle) 8-week-old Mice Days 1 14 28 42 56 62 Daily S.C. Injections Semaglutide (10 nmol/kg/d) or Vehicle ADA 2024 GLP-1=gluca
Slide 10: 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 Vehicle Control Semaglutide (10 nmol/kg/d) GLP-1RA PGTx (5e12) ADA 2024 Mean ± SEM shown; n=
Slide 11: GLP-1RA PGTx Secretion in Isolated db/db Islets
GLP-1RA PGTx Secretion in Isolated db/db Islets Glucose-dependent GLP-1RA release with ample secretory reserve A) GLP-1RA Released B) GLP-1RA Total Content C) GLP-1RA Secretion (% of Total Content) Secretion of Total Content (%) pM nM 2.8G 16.7G 16.7G + IBMX Lysates 2.8G 16.7G 16.7G + IBMX Vehicle C
Slide 12: GLP-1RA PGTx-Induced Insulin Secretion in Isolated db/db Islets
GLP-1RA PGTx-Induced Insulin Secretion in Isolated db/db Islets Increases insulin content and secretion with ample secretory reserve A) Insulin Released B) Insulin Total Content C) Insulin Secretion (% of Total Content) Secretion of Total Content (%) ng/mL ng/mL 2.8G 16.7G 16.7G + IBMX Lysates 2.8G
Slide 13: 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 14: 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 15: 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 Food Intake (Grams) 100 from Day 1 (%) 3.5 BW Reduction 95 3.0 90 2.5 85 2.0 80 1.5 75 70 1.0 65 0.5 60 0.0 1 8 15 22 29 36 43 50
Slide 16: Body Composition Change in DIO Murine Model
Body Composition Change in DIO Murine Model Preservation of lean mass: body weight loss primarily from fat mass A) Body Weight B) Lean Mass C) Fat Mass D) Plasma Leptin BW (%) ng/mL BW (%) Grams Vehicle Control Sema Withdrawal + Vehicle GLP-1RA PGTx (1e13 VG) Sema Withdrawal + GLP-1RA PGTx (5e12 VG)
Slide 17: Fasting Blood Glucose and Insulin Changes in DIO Murine Model (4 weeks)
Fasting Blood Glucose and Insulin Changes in DIO Murine Model Single-dose GLP-1RA PGTx improves FBG and insulin at 4 weeks A) Fasting Blood Glucose B) Fasting Plasma Insulin mmol/L ng/mL AAV Vehicle Control GLP-1RA PGTx (1e13 VG) Sema Vehicle Sema (10 nmol/kg/d) ADA 2024 Mean ± SEM shown; n=5-10 per
Slide 18: Fasting Blood Glucose and Insulin Changes in DIO Murine Model (8 weeks)
Fasting Blood Glucose and Insulin Changes in DIO Murine Model Single-dose GLP-1RA PGTx improves FBG and insulin at 8 weeks A) Fasting Blood Glucose B) Fasting Plasma Insulin mmol/L ng/mL AAV Vehicle Control GLP-1RA PGTx (1e13 VG) Sema Withdrawal + Vehicle Sema Withdrawal + GLP-1RA PGTx (5e12 VG) ADA
Slide 19: Pancreatic Islet Histopathology in DIO Murine Model
Pancreatic Islet Histopathology in DIO Murine Model GLP-1RA PGTx was not associated with inflammation Vehicle Control GLP-1RA PGTx Sema Withdrawal Sema Withdrawal + PGTx Score: 0.25 ± 0.16 0.30 ± 0.15 0.20 ± 0.20 0.20 ± 0.20 Histopathology Scorecard1 0 – No cellular infiltrates 1 – Infiltrates in sm
Slide 20: GLP-1RA PGTx Safety and Feasibility Studies in Model Systems
GLP-1RA PGTx Safety and Feasibility Studies in Model Systems Conclusions to date and next steps Early safety and feasibility observations in db/db Pancreatic and DIO mice and Yucatan pigs are encouraging Gene Therapy First demonstration of nutrient-responsive GLP-1RA secretion in islets PGTx improve
Slide 21: Thank You / Acknowledgments
Thank You Acknowledgments Shimyn Slomovic, PhD Sr. Director, Head of R&D Advisors Design and in vitro screening ex vivo and animal studies Device Engineering Alan Cherrington, PhD Vanderbilt University School Lin Quek, PhD Alice Fitzpatrick, DVM, PhD Mike Biasella, BS of Medicine Assoc. Director Dir