Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Technical Presentation (December 2022)
14 slides from Fractyl Health's technical presentation, Dec 2, 2022
Slide 1: AAV-Mediated Pancreatic Gene Therapy for Type 2 Diabetes
AAV-Mediated Pancreatic Gene Therapy for Type 2 Diabetes Alice Liou Fitzpatrick, Nidhi Khanna, Jacob Wainer, Rebecca Reese, Jason West, Jay Caplan, and Harith Rajagopalan December 2, 2022 Fractyl Health, Inc. 2022
Slide 2: Disclosure Statement
Disclosure Statement Author(s): Alice Liou Fitzpatrick, Nidhi Khanna, Jacob Wainer, Rebecca Reese, Jason West, Jay Caplan, and Harith Rajagopalan are employees and shareholders of Fractyl Health, Inc. 2 Fractyl Health 2022
Slide 3: Fractyl Health's Mission
Fractyl Health’s Mission Target organ-level root causes of metabolic disease Revita System™ for Duodenal Mucosal Resurfacing (DMR) Restore morphology and metabolic function to the duodenum Rejuva® Platform for Pancreatic Gene Therapy Restore metabolic regulation of the pancreas with locally delivere
Slide 4: GLP-1 therapies have proven benefits but are limited by adherence and tolerability
GLP-1 therapies have proven benefits for pancreatic health in T2D but are limited by adherence and tolerability of systemic delivery Real world persistence with systemic GLP-1 • GLP-1 stimulates glucose-dependent insulin therapy remains low1 secretion and improves overall beta-cell health.1 Probabil
Slide 5: Gene therapy approach for improvements in beta-cell health
Gene therapy approach for improvements in beta-cell health Beta-cell specific GLP-1RA transgene GLP-1RA GLP-1RA pA = Polyadenylation 5 Fractyl Health 2022 AAV = Adeno-associated virus ER = Endoplasmic reticulum
Slide 6: Screening a DNA construct library for GLP-1RA producers: secretion
Screening a DNA construct library to identify top functional GLP- 1RA producers in a beta-cell line DNA construct template GLP-1RA secretion 25 mM Glucose stimulation Beta-cell specific GLP-1RA transgene Relative to Tris-EDTA Buffer GLP-1RA Plasmid Library Transfection MIN6 Cells MIN6 = Mouse insuli
Slide 7: Screening a DNA construct library for GLP-1RA producers: cAMP signaling
Screening a DNA construct library to identify top functional GLP- 1RA producers in a beta-cell line DNA construct template cAMP signaling CHO-K1 hGLP-1R Gs cell line Beta-cell specific GLP-1RA transgene Relative to eGFP Control GLP-1RA Plasmid Library Transfection MIN6 Cells MIN6 = Mouse insulinoma
Slide 8: Dose-dependent islet-restricted expression of GLP-1RA via AAV in db/db mouse
Confirmed dose-dependent islet-restricted expression of GLP-1RA via AAV-mediated delivery in the BKS db/db mouse Single IP injection • AAV-GLP-1RA Low • Vehicle Control 5 weeks old • AAV-GLP-1RA High Week 10 post-injection Pancreatic GLP-1RA protein Whole pancreas GLP-1RA GLP-1RA transgene expressio
Slide 9: Dose-dependent reduced glycemia with elevated insulinemia in db/db mouse
Dose-dependent reduced glycemia with elevated insulinemia with AAV-GLP-1RA gene delivery in the BKS db/db mouse Single IP injection • AAV-GLP-1RA Low • Vehicle Control 5 weeks old • AAV-GLP-1RA High • AAV-eGFP Control Weekly FBGs Biweekly insulin 4–6 hour fasted 4–6 hour fasted ng/mL mg/dL Days Days
Slide 10: Improved glucose tolerance and 1st phase insulin secretion
Improved glucose tolerance and 1st phase insulin secretion with AAV-GLP-1RA gene delivery in the BKS db/db mouse Single IP injection • AAV-GLP-1RA Low • Vehicle Control 5 weeks old • AAV-GLP-1RA High • AAV-eGFP Control Week 6 Glucose tolerance test Glucose-stimulated insulin secretion post-injection
Slide 11: GLP-1RA expression and improved insulin secretion from primary db/db islets
GLP-1RA transgene expression and improved insulin secretion from primary BKS db/db islets ex vivo • AAV-eGFP Control • AAV-GLP-1RA Day 4 eGFP expression Total GLP-1RA content Glucose-stimulated insulin secretion (16.8mM Glc + IBMX) / 2.8 mM Glc pg/5 islets AAV-GLP-1RA AAV-GLP-1RA AAV-eGFP AAV-eGFP A
Slide 12: AAV-delivered GLP-1RA enhances insulin secretion in human beta-cell line EndoC-BH5
AAV-mediated delivery of GLP-1RA enhances insulin secretion in a GLP-1R dependent manner in the human beta-cell line EndoC-BH5 AAV = Adeno-associated virus Means ± Std Dev. Two-Way ANOVA, post-hoc Tukey Test ****P<0.0001 12 Fractyl Health 2022 EX9 = Exendin-9, GLP-1R antagonist Glc = Glucose
Slide 13: Summary
Summary 1. Fractyl Health is developing an AAV-mediated gene therapy approach to locally deliver a GLP-1RA to the pancreas to improve beta-cell health and function for T2D. 2. We identified top plasmid constructs yielding functional GLP-1RA production via in vitro screening in a beta-cell line. 3. W
Slide 14: Conclusion
Conclusion • These studies provide proof of concept that a single dose islet-targeted gene therapy durably improves beta-cell function in a diabetic mouse model. GLP-1RA • Targeted gene therapy has the potential to improve glycemic control, modify or reverse disease progression, and reduce therapeut
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