Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Technical Presentation (October 2023)
17 slides from Fractyl Health's technical presentation, Oct 4, 2023
Slide 1: Pancreatic Gene Therapy Durably Improves Glycaemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes
Pancreatic Gene Therapy Durably Improves Glycaemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes Harith Rajagopalan, Camila Lubaczeuski, Emily Cozzi, Nicole Picard, Jacob Wainer, Rebecca Reese, Jay Caplan, Alice Liou October 4th, 2023
Slide 2: Disclosure Statement
Disclosure Statement Authors Harith Rajagopalan, Camila Lubaczeuski, Emily Cozzi, Nicole Picard, Jacob Wainer, Rebecca Reese, Jay Caplan, Alice Liou are employees and shareholders of Fractyl Health, Inc. Pancreatic Gene Therapy (PGTx) is a preclinical development program which has yet to be assessed
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 Normoglycaemia Prediabetes Diabetes β-cell function β-cell mass low (β-cell wo
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 can improve GLP1R β-ce
Slide 5: AAV-GLP1RA 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: 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 Glycaemia, Delay T2D Progression and Prevent Weight Gain?
Compared to Chronic Semaglutide, Can One-Time GLP1 PGTx: Improve Glycaemia Delay T2D Progression and Prevent Weight Gain? EASD 2023 8 59th Annual Meeting
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. Injections Efficacy/MOA (day 0-70) Sacrifice (days 58-70) Semaglutide (10 nmol/kg*) or Weekly Fasting Blood
Slide 10: Expression Restricted to Pancreatic Islets
GLP1 PGTx Expression Restricted to Pancreatic Islets Safety and feasibility in db/db murine model 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 panc
Slide 11: Glucose-Lowering Efficacy in db/db Murine Model
Glucose-Lowering Efficacy in db/db Murine Model GLP1 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) **** ** 25 ** Vehicle Control 20 ** 800 Semaglutide (10 nmol/kg) * 15 ng/mL mg/dL 600 AAV-INS-GLP
Slide 12: Disease Progression and Durability in db/db Murine Model
Disease Progression and Durability in db/db Murine Model 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 †Regula
Slide 13: Body Weight Change in db/db Murine Model
Body Weight Change in db/db Murine Model 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 Vehicle Control 50 **** Semaglutide (Week 4, grams) (10 nmol/kg) Body Wei
Slide 14: GLP1 PGTx Efficacy Proof of Concept: DIO Murine Model
GLP1 PGTx Efficacy Proof of Concept DIO murine model de facto standard for obesity development Single I.P. Injection (AAV-INS-GLP1RA or Vehicle) Single-house, Efficacy and HFD-maintenance HFD-induction Baseline and HFD- Day 15: Daily Body Weight, Food Intake maintenance Days -175 -14 -7 1 15 29 Fed
Slide 15: Body Weight Change
Body Weight Change GLP1 PGTx improves weight loss vs. semaglutide in DIO model A) Body Weight B) Food Intake 3.5 0 3.0 Reduction (%) Vehicle Control -5 2.5 Grams -10 2.0 *** Semaglutide *** -15 1.5 (10 nmol/kg) **** -20 1.0 AAV-INS-GLP1RA -25 **** 0.5 2nd Gen (1e13)† ## -30 0.0 0 1 2 3 4 5 6 7 8 9 1
Slide 16: 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 17: 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 Alice Liou Fitzpatrick Camila Lubaczeuski Becky Reese Nicole Picard of Medicine) Virus an
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