Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — ObesityWeek 2024
20 slides from Fractyl Health's conference presentation, Nov 5, 2024
Slide 1: Islet-Targeted GLP-1 Receptor Agonist Gene Therapy Reduces Fat and Improves Metabolism in Obese Mice
Islet-Targeted GLP-1 Receptor Agonist Gene Therapy Reduces Fat and Improves Metabolism in Obese Mice Harith Rajagopalan, Alice Liou Fitzpatrick, Suya Wang, Nicole Picard, Emily Cozzi, Randy Seeley, Timothy Kieffer, Jay Caplan November 5, 2024
Slide 2: 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 3: 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 Dece
Slide 4: Pancreatic Gene Therapy (PGTx) to Modify Islet Function
Pancreatic Gene Therapy (PGTx) to Modify Islet Function Potential for durable improvement in metabolic health Smart GLP-1TM gene therapy, targeted to pancreatic islets, may offer differentiated benefit AAV with GLP-1 Driven by INS Promoter β-cell machinery can be leveraged to produce nutrient-stimul
Slide 5: 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 15 p<0.05 Stimulation Index 20 Stimulation Index 10 15 10 5 5 0 0 Glu Glu Glu + Ex
Slide 6: 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 7: 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 60 lobe2,3 41.2%
Slide 8: 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 PGTx encoding exendin-4 [PGTx-Ex4] or Vehicle) 8-week-old Mice Days 1 14 28 42 56 62 Daily S.C. Injections Semaglutide (10 nmol/kg/d) or Vehicle Ex
Slide 9: 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) PGTx-Ex4 (5e12) Mean ± SEM shown; n=7-8 per group
Slide 10: 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 PGTx-Ex4 or Vehicle) 60% HFD Semaglutide HFD Maintenance Induction Withdrawal & Efficacy (25 Weeks) (Day 29) (Days 1-57) Days 1 8 15 22 29 36
Slide 11: 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 Change in BW 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
Slide 12: 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 3.5 from Day 1 (%) 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 13: 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 p < 0.001 p < 0.0001 p < 0.05 p < 0.0001 p < 0.05 65 80 p < 0.0001 p < 0.05 50 60 p < 0.0001 p < 0.001 60 50 55 40 60 50 40 BW (%)
Slide 14: Fasting Blood Glucose and Insulin Changes in DIO Murine Model
Fasting Blood Glucose and Insulin Changes in DIO Murine Model Single-dose GLP-1RA PGTx improves FBG, insulin, HOMA-IR at 8 weeks A) Fasting Blood Glucose B) Fasting Plasma Insulin C) HOMA-IR 12 12 80 p < 0.01 p < 0.0001 p < 0.0001 10 10 p < 0.05 60 8 8 Units ng/mL mmol/L 6 6 40 p < 0.05 4 4 20 2 2 0
Slide 15: GLP-1RA PGTx Islet Expression in DIO Model
GLP-1RA PGTx Islet Expression in DIO Model Islet-targeted transduction increases pancreatic expression of GLP-1RA A) Islet PGTx-Ex4 Transduction B) Islet Ex4 Expression 40 30 Islet Area (%) 20 10 0 Vehicle Control Sema (10 nmol/kg/d) Sema Withdrawal + Vehicle PGTx-Ex4 (1e13 VG) Sema Withdrawal + PGT
Slide 16: RJVA-001 PGTx Encoding Human GLP-1 Sequence in DIO
RJVA-001 PGTx Encoding Human GLP-1 Sequence in DIO Single-dose RJVA-001 durably reduces FBG in mice continued on HFD A) Change in FBG Over Time B) FBG (day 95) 250 250 p<0.0001 225 Vehicle 200 AAV.0538 7.5E12 Vehicle Control (mg/dL) FBG (mg/dL) 200 RJVA-001 (7.5e12 VG) FBG (mg/dL) 175 150 FBG 150 10
Slide 17: RJVA-001 PGTx Encoding Human GLP-1 Sequence in DIO
RJVA-001Analysis 2 Individual PGTx Encoding Change_GLP-1 Human only 538 Only GLP-1 Sequence SEM in DIO Single-dose RJVA-001 durably reduces weight in mice continued on HFD 0 -5 BW Reduction (%) Vehicle Adjusted AAV.0538 7.5E12 -10 -15 -20 -25 9 18 27 36 45 54 63 72 81 90 Days After RJVA-001 Dose (7.
Slide 18: GLP-1 PGTx Safety and Feasibility Studies in Model Systems
GLP-1 PGTx Safety and Feasibility Studies in Model Systems Summary and next steps Islet-targeted Smart GLP-1TM PGTx in the DIO model: Pancreatic Gene Therapy Improves fasting glucose, insulin, and HOMA- IR Leads to durable weight loss and weight and body composition maintenance after semaglutide wit
Slide 19: Thank You / Acknowledgments
Thank You Acknowledgments Shimyn Slomovic, PhD Sr. Director, Head of R&D ex vivo and animal studies Device Engineering Alice Fitzpatrick, DVM, PhD Mike Biasella, BS Director Sr. Engineer Manager Advisors Design and in vitro screening Alan Cherrington, PhD Lin Quek, PhD Camila Lubaczeuski, PhD Jake W
Slide 20: ObesityWeek
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