Slide 1: Pancreas-Targeted Dual GIP/GLP-1 Gene Therapy Reduces Body Weight and Hepatic Steatosis
PANCREAS-TARGETED DUAL GIP/GLP-1 GENE THERAPY REDUCES BODY WEIGHT AND HEPATIC STEATOSIS IN A MURINE MODEL OF DIET-INDUCED OBESITY Alice Liou Fitzpatrick, Lin Quek, Junghun Lee, Jessie Von Stetina, Suya Wang, Lindsay Schulman, Nicole Picard, Abdul Alhamood, Zakir Siddiquee, Keiko Ishida, Rebecca Rees
Slide 2: Speaker Disclosure
SPEAKER DISCLOSURE Alice Liou Fitzpatrick I disclose the following financial relationship(s) with a commercial interest: I am an employee and shareholder of Fractyl Health, Inc. Rejuva is an investigational gene therapy program in preclinical development. RJVA-001 is the subject of planned first-in-
Slide 3: GLP-1 and Dual Incretin Agonists Induce Substantial Weight Loss and Metabolic Benefit
GLP-1 and Dual Incretin Agonists Induce Substantial Weight Loss and Metabolic Benefit Chronic Administration Required 11 • GLP-1RAs have transformed management of obesity and type 2 diabetes resulting in: • Significant weight loss3 • Reduction in HbA1c2 • Reduced liver fat4 • Other emerging cardiova
Slide 4: GLP-1 and Dual Incretin Agonists Induce Substantial Weight Loss and Metabolic Benefit
GLP-1 and Dual Incretin Agonists Induce Substantial Weight Loss and Metabolic Benefit Chronic Administration Required 1 • GLP-1RAs have transformed management of obesity and type 2 diabetes resulting in: • Significant weight loss3 • Reduction in HbA1c2 • Reduced liver fat4 • Other emerging cardiovas
Slide 5: Persistence and Durability Limitations Prevent Sustained Metabolic Benefit
Persistence and Durability Limitations Prevent Sustained Metabolic Benefit: A New Strategy is Needed • Low real-world persistence, even with modern incretin therapies1 • Up to 2/3 of patients discontinue within 1 year1 A durable, one-time interventional approach is needed to achieve and maintain wei
Slide 6: Rejuva: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose
REJUVA: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose Novel ROA Novel MOA Targeted administration via purpose-built Incretin(s) under Insulin-derived control for beta cell- endoscopic ultrasound-guided device AAV specific, meal-regulated expression and secretion Payload
Slide 7: Rejuva: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose
REJUVA: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose Novel ROA Novel MOA Targeted administration via purpose-built Incretin(s) under Insulin-derived control for beta cell- endoscopic ultrasound-guided device AAV specific, meal-regulated expression and secretion Payload
Slide 8: Rejuva: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose
REJUVA: An AAV Gene Therapy Platform to Treat Metabolic Disease with a Single Dose Novel ROA Novel MOA Targeted administration via purpose-built Incretin(s) under Insulin-derived control for beta cell- endoscopic ultrasound-guided device AAV specific, meal-regulated expression and secretion Circulat
Slide 9: Rejuva Device Safely Delivers AAV to the Pancreas
Rejuva Device Safely Delivers AAV to the Pancreas Large Animal Safety Model – Yucatan Pig • Rejuva catheter device introduced directly to pancreas parenchyma via standard endoscopic ultrasound techniques that are already part of standard clinical practice • Unique features of Rejuva needle and devic
Slide 10: Rejuva Device Safely Delivers AAV to the Pancreas
Rejuva Device Safely Delivers AAV to the Pancreas Large Animal Safety Model – Yucatan Pig • Rejuva catheter device introduced directly to pancreas parenchyma via standard endoscopic ultrasound techniques that are already part of standard clinical practice • Unique features of Rejuva needle and devic
Slide 11: RJVA-001 Effectively Delivered to Pancreas Via Targeted ROA
RJVA-001 (AAV-INSp-GLP-1) Effectively Delivered to Pancreas Via Targeted ROA Transgene DNA, RNA, and active GLP-1 protein enriched in targeted pancreatic splenic lobe vDNA vRNA Protein 10 3E4 1.0 Infusion site vRNA [copies/10ng RNA] 8 0.8 Active GLP-1 [pg/ug] VCN [VG/DG] 2E4 6 0.6 4 0.4 1E4 2 0.2 0
Slide 12: EUS-Guided Pancreatic AAV Delivery is Safe and Effective
EUS-Guided Pancreatic AAV Delivery is Safe and Effective Constrained Biodistribution and No Safety Signals In Vivo: Treated Yucatan Pigs Pancreatitis Neurotoxicity 50 (lipase) 50 (Nf-L) 3xULN Fasting Lipase [U/L] 40 40 NF-Light [pg/mL] Biodistribution (vDNA) 30 30 15 20 20 ULN VCN [VG/DG] 10 10 10 0
Slide 13: RJVA-001 Improves Glycemia in a Diabetic Mouse Model
RJVA-001 Improves Glycemia in a Diabetic Mouse Model Additional Weight Benefit Observed In Vivo: Treated 8-week-old db/db Mice, 46 days post single IP AAV injection Fasting Blood Glucose Fasting Plasma Insulin Body Weight ✱✱✱ % BW change from baseline Fasting Plasma Insulin [ng/mL] 8 25 Fasting Bloo
Slide 14: Confirmation of MOA from Primary Diabetic Mouse Islets
Confirmation of MOA from Primary Diabetic Mouse Islets Expression and glucose-responsive incretin secretion Ex Vivo: Islets Isolated from treated db/db Mice, 49 days post single IP AAV injection GLP-1 Content GLP-1 Secretion (lysate) (supernatant) ✱✱✱✱ ✱✱✱✱ 8000 80 ✱✱ Total GLP-1 [pM] 60 Vehicle Tot
Slide 15: RJVA-002 Program: Obesity Indication
RJVA-002 program: Obesity Indication A Nutrient-Regulated Dual Incretin Design to Improve Body Weight Loss Dual Incretin transgene construct Confirmed expression and nutrient-regulated Confirmed dual expression of driven by an engineered human secretion in Primary Human Islets GIP/GLP-1 in mouse bet
Slide 16: AAV-GIP/GLP-1 Dual Incretin Gene Therapy Effect on Body Weight in a DIO Mouse Model
AAV-GIP/GLP-1 Dual Incretin Gene Therapy Effect on Body Weight in a DIO Mouse Model Single dose durably reduces body weight and food intake In Vivo: 60% HFD-induced DIO mice 42 days post single IP AAV injection Body Weight Terminal Body Weight 2-week Cumulative 5 ✱✱✱ Food Intake ✱✱✱✱ 0 Body Weight C
Slide 17: AAV-GIP/GLP-1 Dual Incretin Gene Therapy Significantly Attenuates Diet-Induced MASLD
AAV-GIP/GLP-1 Dual Incretin Gene Therapy Significantly Attenuates Diet-Induced MASLD Reduced liver weight, triglycerides, and lipid accumulation Liver Weight Liver Triglycerides Oil Red O ✱ ✱✱ ✱ ✱✱ ✱ 250 60 3.5 3.0 200 %Positive Area 2.5 40 150 Vehicle mg/g grams 2.0 1.5 100 AAV-INSp-GIP/GLP-1 Mid 2
Slide 18: Summary and Conclusions
Summary and Conclusions ▪ Single-dose, pancreas-targeted incretin gene therapy delivers durable, incretin expression and glucose-responsive secretion – eliminating the adherence and persistence limitations of chronic pharmacotherapy ▪ EUS-guided pancreatic delivery leverages an established GI proced
Slide 19: Acknowledgements
Acknowledgements Shimyn Slomovic, PhD in vitro Discovery in/ex vivo Studies Scientific Advisory Board Exec. Director, Head of R&D Lin Quek, PhD Alice Fitzpatrick, DVM, PhD Jacques Bergman, M.D., Ph.D. Director Director Amsterdam UMC Mark Kay, M.D., Ph.D. Stanford University School Medicine Tech Ops