Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Technical Presentation (June 2023)
15 slides from Fractyl Health's technical presentation, Jun 24, 2023
Slide 1: Pancreatic Gene Therapy Durably Improves Glycemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes
Pancreatic Gene Therapy Durably Improves Glycemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes Harith Rajagopalan, Alice Liou, Emily Cozzi, Nidhi Khanna, Jacob Wainer, Rebecca Reese, Jay Caplan, Jason A. West June 24th, 2023
Slide 2: Disclosure Statement
Disclosure Statement Authors Harith Rajagopalan, Alice Liou, Emily Cozzi, Jacob Wainer, Rebecca Reese, and Jay Caplan are employees and shareholders of Fractyl Health, Inc. Nidhi Khanna and Jason A. West are former employees of Fractyl Health, Inc. The Pancreatic Gene Therapy (PGTx) is in early deve
Slide 3: T2D Progression is Driven by Declining Islet Health
T2D Progression is Driven by Declining Islet Health Loss of β-cell function is the sine qua non of T2D Pancreatic Islets Functional β-cell hyperplasia & Secretory β-cell loss hypersecretion dysfunction Disease Progression Normoglycemia Prediabetes Diabetes β-cell function β-cell mass low (β-cell wor
Slide 4: Pancreatic Gene Therapy (PGTx) to Improve Islet Function
Pancreatic Gene Therapy (PGTx) to Improve Islet Function Potential for durable improvement in β-cell function Islet cells terminally differentiated, making adeno-associated virus (AAV) Insulin a suitable means of durable genetic modification1,2 Islet Intra-islet GLP1 signaling is essential for GLP1R
Slide 5: GLP1 PGTx Improves Insulin Production and GSIS in db/db Islets
GLP1 PGTx Improves Insulin Production and GSIS in db/db Islets Metabolic improvements in isolated islets 10 weeks after PGTx A) Islet Transduction B) GLP1RA Protein C) Insulin Content D) Glucose-Stimulated Content Insulin Secretion (GSIS) 400 2000 **** *** Vehicle 250 * GLP1RA (pg/mL) 1500 Stimulati
Slide 6: GLP1 PGTx Improves GSIS in Human Islets and Human β-cell Line
GLP1 PGTx Improves GSIS in Human Islets and Human β-cell Line Improved GSIS mediated by GLP1R activation in human cells A) Human Islet B) Human Islet GSIS C) Human β-cell Line GSIS ± Ex9 Transduction (GLP1R Antagonist) 25 ** 15 * Stimulation Index Stimulation Index 20 10 15 10 5 5 0 0 GFP Expression
Slide 7: Local Delivery of PGTx
Local Delivery of PGTx Proprietary endoscopic ultrasound-guided infusion device Yucatan pig model anatomy similar to humans Yucatan Pig Islet Transduction 80 Splenic Lobe Proprietary device and endoscopic Endocrine GFP Expression procedure previously described1,2 60 >50 animals treated with 100% tec
Slide 8: Compared to Chronic Semaglutide, Can One-Time GLP1 PGTx Improve Glycemia, Delay T2D Progression and Prevent Weight Gain?
Compared to Chronic Semaglutide, Can One-Time GLP1 PGTx: Improve Glycemia Delay T2D Progression and Prevent Weight Gain? ADA 2023 9 83rd Scientific Sessions
Slide 9: GLP1 PGTx Efficacy Proof of Concept
GLP1 PGTx Efficacy Proof of Concept db/db murine model de facto standard for T2D development Single I.P. Injection (AAV-INS-GLP1RA or Vehicle) 35-day-old mice Days 0 14 28 42 56 70 Daily S.C. Injection Efficacy/MOA (day 0-70) Sacrifice (days 58-70) Semaglutide (10 nmol/kg*) or Weekly Fasting Blood G
Slide 10: GLP1 PGTx Expression Restricted to Pancreatic Islets
GLP1 PGTx Expression Restricted to Pancreatic Islets Safety and feasibility in db/db are reassuring thus far High specificity for pancreas Insulin promoter effectively restricts transgene expression to pancreatic islets No detectable expression in off-target tissues (e.g., exocrine pancreas) Favorab
Slide 11: Glucose Lowering Efficacy in db/db Mouse
Glucose Lowering Efficacy in db/db Mouse GLP1 PGTx improves fasting glucose vs. daily semaglutide A) Fasting Blood Glucose B) Fasting Insulin (Week 8, 4–6 hour fasted) (Week 8, 4–6 hours fasted) **** ** 25 ** Vehicle Control 20 ** 800 Semaglutide (10 nmol/kg) * 15 ng/mL mg/dL 600 AAV-INS-GLP1RA 1st
Slide 12: Disease Progression and Durability
Disease Progression and Durability GLP1 PGTx shifts progression of disease vs. daily semaglutide 1.00 % FBG > 250 mg/dL 0.75 Vehicle Control Semaglutide 0.50 (10 nmol/kg) AAV-INS-GLP1RA 0.25 1st Gen (10e12) AAV-INS-GLP1RA 2nd Gen (5e12)† 0.00 1 8 15 22 29 36 43 50 57 64 †Regulatory element Days modi
Slide 13: Body Weight Change
Body Weight Change GLP1 PGTx prevents weight gain vs. daily semaglutide 23% lower total body weight with PGTx compared to vehicle **** 20% lower total body weight with **** 55 PGTx compared to semaglutide Body Weight (week 4, grams) Vehicle Control 50 **** Semaglutide 45 (10 nmol/kg) AAV-INS-GLP1RA
Slide 14: GLP1 PGTx Safety and Pharmacology Studies in Model Systems
GLP1 PGTx Safety and Pharmacology Studies in Model Systems Early feasibility and safety observations in db/db mice and Yucatan pigs are encouraging Insulin Compared to chronic semaglutide, single-dose PGTx improves fasting glucose, delays T2D progression, Islet GLP1R and prevents weight gain in db/d
Slide 15: Thank You Acknowledgements
Thank You Acknowledgements Fractyl Health Advisor Support Cell and Animal Models ERASE Task Force and Advisors Randy Seeley, PhD (Michigan School of Medicine) Alan Cherrington, PhD (Vanderbilt University School of Medicine) Alice Liou Camila Becky Reese Nicole Picard Fitzpatrick Lubaczeuski Dave D’A