Fractyl Health, Inc. · NASDAQ:GUTS
Fractyl Health — Meeting on the Mesa 2025
24 slides from Fractyl Health's conference presentation, Oct 7, 2025
Slide 1: Rejuva: Beta Cell-Targeted "Smart GLP-1" AAV Gene Therapy
Rejuva: Beta Cell-Targeted “Smart GLP-1” AAV Gene Therapy Harith Rajagopalan, MD, PhD Co-founder and Chief Executive Officer Fractyl Health, Inc. Meeting on the Mesa| October 7th, 2025 Rejuva is in early development and has not been assessed by any regulatory body for investigational or commercial u
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: Progression and Poor Persistence Limit Effectiveness
Progression and Poor Persistence Limit Effectiveness A durable, tolerable, one-time intervention is urgently needed Progression with current therapies1 Real-world persistence for GLP-1RAs in T2D2 1.GRADE Study 2022 NEJM doi:10.1056/NEJMoa2200433; 2.Polonsky 2022 Diabetes Therapy doi:10.1007/s13300-0
Slide 4: 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 5: 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 GLP-1 High pancreas and portal exposure with limited Syst
Slide 6: Key Features of the Rejuva Development Platform
Key Features of the Rejuva Development 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 Mic
Slide 7: 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 Beta cells DRG Liver Adrenal gland Gastric epithelial CMV_GFP (ubiquitous) hINSp_GFP (specific) • Rejuva utilizes an engineered regulatory sequence derived from huma
Slide 8: 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 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 9: Rejuva Expression is Specific to Islets in Relevant Animal Models
Rejuva Expression is Specific to Islets in Relevant Animal Models - db/db Mice and Yucatan Pigs In Vivo: Transduced Mice In Vivo: Transduced Pigs untreated hINSp_GLP-1 untreated hINSp_GLP-1 DAPI • hINSp drives expression in islets but not Insulin exocrine cells when studied in vivo in GLP-1 small an
Slide 10: 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 11: 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 12: Rejuva 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 13: 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 14: 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 15: "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 16: Rejuva Shows Superior Potency Compared to Semaglutide in db/db Mice
Rejuva Shows Superior Potency Compared to Semaglutide in db/db Mice Fasting Blood Glucose Vehicle 700 Semaglutide 600 Rejuva Mid Dose 500 Rejuva High Dose mg/dL 400 300 200 100 0 1 8 15 22 29 36 43 50 57 Days Data are mean ± SEM, n=8 per mice group. Daily s.c. 10nmol/kg semaglutide injection. s.c.=s
Slide 17: 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 18: 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 19: 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 20: 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 21: 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 22: 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 • First patient dosing: 2026 pr
Slide 23: 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 24: Acknowledgements
Acknowledgements Shimyn Slomovic, PhD in vitro Discovery ex/in vivo Studies Scientific Advisory Board Exec. Director, Head of R&D Lin Quek, PhD Alice Fitzpatrick, DVM, PhD Assoc. Director Director Jacques Bergman, M.D., Ph.D. Amsterdam UMC Tech Ops and Research Ops JungHun Lee, PhD Jessie von Stetin