Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Technical Presentation (May 2023)
20 slides from Fractyl Health's technical presentation, May 18, 2023
Slide 1: A Pancreatic Gene Therapy Delivery Platform for the Treatment of Type 2 Diabetes
A Pancreatic Gene Therapy Delivery Platform for the Treatment of Type 2 Diabetes Harith Rajagopalan, Jason A. West, Jacob Wainer, Alice Liou, Rebecca Reese, Nidhi Khanna, Suya Wang, Keiko Ishida, Nicole Picard, Camila Lubaczeuski, Christopher C. Thompson, Linda S. Lee, Rob P. Trasolini, Emily Cozzi,
Slide 2: Disclosure Statement
Disclosure Statement Authors: Harith Rajagopalan, Jacob Wainer, Alice Liou, Rebecca Reese, Suya Wang, Keiko Ishida, Nicole Picard, Camila Lubaczeuski, Emily Cozzi, and Jay Caplan are employees and shareholders of Fractyl Health, Inc. Jason A. West and Nidhi Khanna are former employees of Fractyl Hea
Slide 3: Fractyl Health, Inc.: Pioneering new treatment approaches for type 2 diabetes
Fractyl Health, Inc. Pioneering new treatment approaches for type 2 diabetes (T2D) Complementary development programs targeting key organs in T2D Revita® (targeting the duodenum) Endoscopic procedure using hydrothermal ablation in the duodenum Rejuva® (targeting the pancreas) Adeno-associated virus
Slide 4: Rejuva Directly Targets the Pancreas with Gene Therapy
Rejuva Directly Targets the Pancreas with Gene Therapy Key therapeutic elements Endoscopic device AAV Gene Therapy Tissue-Restricted and procedure Delivery Vehicle Transgene Expression 4 Fractyl Health 2023
Slide 5: GLP1RAs for T2D Have Proven Clinical Benefit But Are Limited
GLP1RAs for T2D Have Proven Clinical Benefit But Are Limited Opportunity to advance GLP1RA field with local gene therapy approach Glucagon-like peptide 1 receptor % of Treatment Continuation agonists (GLP1RAs) have proven clinical efficacy Limited by adherence and tolerability of systemic delivery2,
Slide 6: Rationale for AAV-GLP1RA Gene Therapy to Improve Islet Function
Rationale for AAV-GLP1RA Gene Therapy to Improve Islet Function Declining islet health is an early driver of T2D progression T2D islet: β-cell loss of insulin Insulin GLP1RA α-cell excess glucagon Islet GLP1RAs reverse both and improve GLP1R islet cell health1 β-Cell 6 Fractyl Health 2023 Figure ada
Slide 7: Rationale for AAV-GLP1RA Gene Therapy to Improve Islet Function
Rationale for AAV-GLP1RA Gene Therapy to Improve Islet Function Declining islet health is an early driver of T2D progression T2D islet: β-cell loss of insulin Insulin α-cell excess glucagon Islet GLP1RAs reverse both and improve GLP1R islet cell health1 β-Cell AAV-GLP1RA gene therapy may address lim
Slide 8: Rationale for AAV-GLP1RA Route of Administration & Islet Targeting
Rationale for AAV-GLP1RA Route of Administration & Islet Targeting Islets are most easily accessed via endoscopic ultrasound Endoscopic ultrasound (EUS) is Pancreatic routine (~300K cases per year)1 Gene Therapy EUS via stomach provides direct access to pancreatic body and tail Islets are 1-2% of to
Slide 9: EUS-Guided AAV ROA Feasibility in Yucatan Pig
EUS-Guided AAV ROA Feasibility in Yucatan Pig Porcine model approximates human GI tract and pancreas anatomy Days 0 7 14 21 28 EUS-guided Routine Safety Sacrifice (days 21-28) Pancreatic Infusion ALT ALT AAV9-CMV-GFP (Ubiquitous)* Lipase Lipase AAV9-INS-GFP (β-cell Restricted) NF-L NF-L Vector Biodi
Slide 10: EUS-Guided AAV ROA in Yucatan Pig: Serum ALT and lipase in normal range
EUS-Guided AAV ROA in Yucatan Pig Serum ALT and lipase remained in the normal range across most timepoints A) 28-day ALT B) 7-day Lipase C) 28-day Lipase 80 70 70 60 60 60 Normal Range 50 3x ULN 50 3x ULN U/L U/L U/L 40 40 40 30 30 Normal Normal 20 20 Range 20 Range 10 10 0 0 0 0 7 14 21 28 0 0.5 1.
Slide 11: EUS-Guided AAV ROA in Yucatan Pig: Dose-dependent GFP expression
EUS-Guided AAV ROA in Yucatan Pig Dose-dependent expression of GFP throughout targeted splenic lobe A) Extensive GFP in Splenic Lobe B) VG Dose-Dependent GFP in Pancreas Duodenal Lobe 5e12 1e13 5e13 1.5e14 Connecting Lobe Splenic Lobe 11 Fractyl Health 2023 EUS=endoscopic ultrasound, ROA=route of ad
Slide 12: EUS-Guided AAV ROA in Yucatan Pig: ~40% of islet cells express GFP
EUS-Guided AAV ROA in Yucatan Pig ~ 40% of splenic lobe islet cells express GFP transgene at highest dose A) Islet GFP Expression B) On-target VCN 10 100 GFP Expression (% of Cells) 9 8 80 3.5 7 VCN (VG/DG) 3.1 6 60 41.2% 5 1.3 40 4 19.8% 3 20 2 1 2.1% 2.3% 0.0% 0.0 0.0 0 0 Vehicle 5.0e12 1.0e13 5.0
Slide 13: In Vivo and In Vitro AAV-GLP1RA Efficacy Proof of Concept
I n Vivo and I n Vitro AAV-GLP1RA Efficacy Proof of Concept Murine model of T2D progression and islet analyses Days 0 25 50 75 100+ I.P. Injection Efficacy/MOA Sacrifice (days 42-100+) (35-day-old db/db mice) Weekly Fasting Blood Organ Histology AAV9-INS-GLP1RA Glucose Pancreatic GLP1RA Protein Vehi
Slide 14: In Vivo AAV-GLP1RA Efficacy in Db/db Mouse: ~4% of islet cells transduced
I n Vivo AAV-GLP1RA Efficacy Proof of Concept in Db/db Mouse AAV-GLP1RA targets pancreas with ~4% of islet cells transduced A) Pancreatic Islets 10 Weeks B) Islet GLP1RA Protein C) Whole Pancreas GLP1RA Post I.P. Injection Expression Protein Expression **** Vehicle AAV-GLP1RA ** 8 **** 40 % of Islet
Slide 15: AAV-GLP1RA increases fasting insulin and reduces fasting blood glucose
I n Vivo AAV-GLP1RA Efficacy Proof of Concept in Db/db Mouse AAV-GLP1RA increases fasting insulin and reduces fasting blood glucose A) Biweekly Insulin (4–6 hour fasted) B) Weekly FBG (4–6 hour fasted) 20 800 ** 700 * 15 600 ng/mL mg/dL 500 ** 10 400 *** *** * * 300 5 200 *** *** *** 100 ** *** 0 0
Slide 16: In Vitro AAV-GLP1RA Efficacy: Isolated Islets from Treated Mice
I n Vitro AAV-GLP1RA Efficacy – Isolated Islets from Treated Mice AAV-GLP1RA increases db/db islet GLP1RA, insulin, and subsequent GSIS A) VCN within Islets B) Transgene Content C) Insulin Content D) Glucose-Stimulated Insulin Secretion (GSIS) 10 400 2000 * 250 **** *** GLP1RA (pg/ml) 8 200 Stimulat
Slide 17: In Vitro AAV-GLP1RA Efficacy Proof of Concept in Human β-cell Line
I n Vitro AAV-GLP1RA Efficacy Proof of Concept in Human β-cell Line AAV-GLP1RA induces GLP1RA protein secretion and improves β-cell function A) GLP1RA Secretion B) GSIS ± GLP1R Blockade with Ex9 100 15 GLP1RA Secretion (pM) 80 Stimulation Index 10 60 40 5 20 0 0 Glu Glu Glu + Ex9 Untransduced AAV-GL
Slide 18: In Vitro AAV-GLP1RA POC Efficacy in Human Islet
I n Vitro AAV-GLP1RA POC Efficacy in Human Islet AAV-GLP1RA targets up to 30% of human islet β-cells and improves function A) β-cell Transduction B) Transduction Efficiency C) GSIS GFP+ GFP NKX6.1 NKX6.1 25 50 Stimulation Index 40 20 GFP* NKX6.1+/ Untransduced NKX6.1+ (%) 30 15 Low 20 10 Dose AAV-GF
Slide 19: Conclusions
Conclusions EUS-guided ROA is a feasible and novel platform for pancreatic gene therapy AAV9 can dose-dependently target the pancreatic islet and drive transgene expression POC efficacy for GLP1RA-based gene therapy to restore β-cell function and improve glycemic control in rodents and human cells N
Slide 20: Thank You For Your Attention: Acknowledgements
Thank You For Your Attention Acknowledgements Fractyl Health External Support Cell and Animal Models SBH Sciences: Michael Furniss, Beth Griffith, Gerard O’Neil for conducting cell and islet work Joslin Diabetes Center Islet Isolation Core: Alice Liou Camila Becky Reese Nicole Picard Jennifer Hollis