Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — ASGCT 2025
22 slides from Fractyl Health's conference presentation, May 17, 2025
Slide 1: Rejuva: Beta Cell-Targeted “Smart GLP-1” AAV Gene Therapy
Rejuva: Beta Cell-Targeted “Smart GLP-1” AAV Gene Therapy Endoscopic Ultrasound-Guided Delivery of Human Glucagon-like Peptide-1 Pancreatic Gene Therapy: Safety and Feasibility in a Porcine Model Alice Liou Fitzpatrick, Jacob Wainer, Michael Biasella, Lindsay Schulman, Nicole Picard, Jessie Von Stet
Slide 2: Type 2 Diabetes is a Chronic, Progressive Disease Caused by Pancreatic Beta Cell Failure
Type 2 Diabetes is a Chronic, Progressive Disease Caused by Pancreatic Beta Cell Failure • Type 2 diabetes (T2D) affects >30M Americans1 Only 50% of Americans achieve recommended glucose targets6 (blue) • Leading cause of kidney failure, cardiovascular disease, stroke, blindness, amputation2,3 • Ins
Slide 3: Rejuva: A "Smart GLP-1" AAV Gene Therapy for T2D
Rejuva: A "Smart GLP-1TM" AAV Gene Therapy for T2D Single treatment → nutrient-responsive, adaptive, and durable effect Novel ROA Novel MOA Targeted administration via proprietary Human GLP-1 and insulin-derived promoter and secretory endoscopic ultrasound-based needle catheter features for beta cel
Slide 4: The Rejuva Approach is Differentiated from GLP-1 Drugs
The Rejuva Approach is Differentiated from GLP-1 Drugs Intrapancreatic, nutrient-responsive: “Smart GLP-1” gene therapy Feature Rejuva GLP-1 Drugs Exogenous, pharmacologic activation of MOA Simulates endogenous GLP-1 secretion kinetics GLP-1R High pancreas and portal exposure with limited Systemic,
Slide 5: Key Features of the Rejuva Platform
Key Features of the Rejuva Platform Gradient of systems to screen for “smart” and safe GLP-1 gene therapies Platform System Model Utility In Vitro Human Beta Cells – Specificity, Function Ex Vivo Human Pancreas Islets and Slices – Specificity, Function In Vivo Efficacy db/db Diabetic Mice – Performa
Slide 6: Rejuva Expression is Specific to Beta Cells Via an Engineered Human Insulin Promoter-Derived Sequence
Rejuva Expression is Specific to Beta Cells Via an Engineered Human Insulin Promoter-Derived Sequence In Vitro: Transduced Human Cells CMV_GFP hINSp_GFP (ubiquitous) (specific) • Rejuva utilizes an engineered regulatory sequence EndoC-βH5 derived from human insulin promoter (hINSp) (beta cell) MOI 1
Slide 7: Expression is Specific to Beta Cells Via an Engineered Human Insulin Promoter-Derived Sequence (Ex Vivo)
Rejuva Expression is Specific to Beta Cells Via an Engineered Human Insulin Promoter-Derived Sequence Ex Vivo: Transduced Human Pancreas Slices CMV_GFP hINSp_GFP (ubiquitous) (specific) • hINSp drives expression in islets but not Reflectance Insulin DAPI exocrine cells when studied ex vivo in human
Slide 8: Rejuva Expression is Specific to Islets in Relevant Animal Models - db/db Mice and Yucatan Pigs
Rejuva Expression is Specific to Islets in Relevant Animal Models - db/db Mice and Yucatan Pigs In Vivo: Transduced Mice In Vivo: Transduced Pigs CMV_GFP hINSp_GFP Untreated hINSp_GLP-1 • hINSp drives expression in islets but not exocrine cells when studied in vivo in small and large animal models S
Slide 9: Nutrient-Responsive, Dose-Responsive GLP-1 Expression and Secretion in Human Beta Cells
Rejuva Shows Nutrient-Responsive, Dose-Responsive GLP-1 Expression and Secretion in Transduced Human Beta Cells GLP-1 Expression GLP-1 Secretion GLP-1 Bioactivity (lysate) (supernatant) (supernatant) 15000 10000 5000 Rejuva Low MOI Bioactive GLP-1 [pM] Rejuva Mid MOI Total GLP-1 [pM] Total GLP-1 [pM
Slide 10: Rejuva GLP-1 Shows Nutrient-Responsive Expression and Secretion in Transduced Human Islets
Rejuva GLP-1 Shows Nutrient-Responsive, Dose-Responsive Expression and Secretion in Transduced Human Islets GLP-1 Content GLP-1 Expression and Secretion (lysate) (supernatant) 4000 50 Rejuva Low MOI 40 Rejuva Mid MOI 3000 Total GLP-1 [pM] Rejuva High MOI Total GLP-1 [pM] GFP High MOI 30 2000 20 1000
Slide 11: GLP-1 Improves Metabolic Control in db/db Mice
Rejuva GLP-1 Improves Metabolic Control in db/db Mice Dose-responsive improvement in body weight, blood glucose, and insulin levels Body Weight Fasting Blood Glucose Fasting Plasma Insulin 60 800 8 700 Pre-Dose Baseline 6 600 Body Weight [g] 50 FBG [mg/dL] FPI [ng/mL] 500 Vehicle 4 Rejuva Low Dose 4
Slide 12: Rejuva Shows Dose-Responsive GLP-1 Expression and Secretion in Islets from Treated db/db Mice
Rejuva Shows Dose-Responsive, Nutrient-Responsive GLP-1 Expression and Secretion in Islets from Treated db/db Mice GLP-1 Content GLP-1 Expression and Secretion (lysate) (supernatant) 30 6000 Vehicle Rejuva Low Dose Rejuva Mid Dose 5000 Rejuva High Dose Total GLP-1 [pM] Total GLP-1 [pM] 20 4000 3000
Slide 13: Rejuva Shows Safe and Durable Expression
Rejuva Shows Safe and Durable Expression Normal weight and blood glucose observed in healthy mice Body Weight Fasting Blood Glucose Active GLP-1 Active GLP-1 (pancreas) (circulating) 40 300 10 60 Body Weight [grams] Active GLP-1 [pg/mL] Active GLP-1 [pg/ug] 30 8 40 FBG [mg/dL] 200 20 6 20 2.0 100 4
Slide 14: “Smart” GLP-1 Mimics Endogenous Physiology
“Smart” GLP-1 Mimics Endogenous Physiology Potent efficacy and near physiologic circulating levels Rejuva Comparison Chart Active GLP-1 Levels1 • Rejuva GLP-1 levels are significantly lower than pharmacologic GLP-1RA Active GLP-1 Modality Levels Tolerability drug levels (circulating) 20 Physiologica
Slide 15: Rejuva Device Safely Delivers AAV to Pancreas in Large Animal Safety Model – Yucatan Pig
Rejuva Device Safely Delivers AAV to Pancreas in Large Animal Safety Model – Yucatan Pig Rejuva Custom Needle Live Ultrasound Stomach Wall • Rejuva catheter introduced directly to pancreas Needle Custom 27G Needle parenchyma via standard endoscopic ultrasound Conical Tip SA techniques that are alrea
Slide 16: AAV Effectively Delivered to Pancreas Via Targeted ROA
Rejuva AAV Effectively Delivered to Pancreas Via Targeted ROA Transgene DNA, RNA, active GLP-1 protein enriched in targeted pancreatic splenic lobe vDNA vRNA Protein 10 3E4 1.0 vRNA [copies/10ng RNA] Infusion site Active GLP-1 [pg/ug] 8 0.8 VCN [VG/DG] 2E4 6 0.6 4 0.4 1E4 2 0.2 0 0 0.0 Pancreas Key
Slide 17: No Toxicity Observed Following Rejuva Treatment
No Toxicity Observed Following Rejuva Treatment No serum, biodistribution, or histopathologic findings of concern Pancreatitis Neurotoxicity Cardiotoxicity 50 (lipase) 50 (Nf-L) 0.5 (troponin I) 3xULN Troponin I [ng/mL] Fasting Lipase [U/L] NF-Light [pg/mL] 40 40 0.4 Vehicle Rejuva 30 30 0.3 20 20 0
Slide 18: Dose-Bridging Strategy for First-In-Human Dose Selection
Dose-Bridging Strategy for First-In-Human Dose Selection Efficacy Safety Identify minimally Identify safe dose in Define human efficacious dose and pigs with similar measure GLP-1 levels starting dose GLP-1 levels Fasting Blood Glucose Active GLP-1 (pancreas) 800 0.5 700 Minimal Efficacy 0.4 • Dose
Slide 19: Developed a Large-Scale cGMP Manufacturing Process to Support the Projected Patient Population
Developed a Large-Scale cGMP Manufacturing Process to Support the Projected Patient Population • Large-scale AAV production in a suspension HEK293 culture (transient transfection) in 500L bioreactors • Downstream process includes enrichment for filled AAV particles and minimization of product- and p
Slide 20: RJVA-001 FIH Dose Escalation Study Design
RJVA-001 FIH Dose Escalation Study Design Aligned with regulators to assess safety, tolerability, PK, preliminary PD Patient population Endpoints Study design Anticipated timing1 • Adults with T2D and obesity and • Primary: Safety and tolerability • GLP-1 drug therapy • Submit first CTA module: H1 p
Slide 21: Rejuva: Status and Conclusions
Rejuva: Status and Conclusions Compelling Scientific Rationale Encouraging Preclinical Results Favorable Safety Profile in CTA-Enabling Studies Scalable Manufacturing Enabled FIH Clinical Development Risk-Mitigated via Regulator Alignment on Design and Population FIH=first-in-human, CTA=clinical tri
Slide 22: Acknowledgements
Acknowledgements Shimyn Slomovic, PhD in vitro Discovery ex/in vivo Studies Exec. Director, Head of R&D Lin Quek, PhD Assoc. Director Alice Fitzpatrick, DVM, PhD Director Advisors Christopher Thompson, MD Tech Ops and Research Ops JungHun Lee, PhD Jessie von Stetina, PhD Brigham and Women’s Sr. Scie