261-OR: ADA Presidents' Select Abstract: Single-Dose GLP-1-Based Pancreatic Gene Therapy Durably Maintains Body Composition and Glycemia after Semaglutide Withdrawal in a Murine Model of Obesity

Background: Glucagon-like peptide 1 (GLP-1) therapies are effective for metabolic disease, but treatment cessation may lead to rapid weight and glucose rebound. We developed a novel pancreatic gene therapy (PGTx) platform enabling durable islet production of GLP-1-based peptides. Here, we assessed body composition and glycemic parameters of single-dose PGTx versus chronic semaglutide (Sema) in a murine diet-induced obesity model. Methods: Mice fed 60% high-fat diet were randomized to: single-dose intraperitoneal PGTx (1e13 vector genomes VG, n=10), daily subcutaneous Sema (10 nmol/kg/d x 4 weeks, n=10), PGTx vehicle control (VC) (n=8), or Sema VC (n=8). Sema was withdrawn at week (wk) 4, and mice were randomized to PGTx (5e12 VG, n=5) or VC (n=5). Mean body composition and fasting glucose (FG) were assessed. A 0-5-point histopathology score was used to evaluate islet inflammation and integrity. Statistical comparisons were made to cohort baselines. Results: At wk 4, PGTx reduced fat mass by 21% and lean mass by 5% versus 16% fat mass and 5% lean mass with Sema (all, p0.0001). Sema withdrawal led to a fat and lean mass regain to 1% and 2% below baseline, while Sema-withdrawn mice treated with PGTx maintained reductions of 17% (p0.01) and 5% (p0.001) at wk 8. In PGTx and Sema groups, FG reduced by 18% at wk 4 (both, p0.0001). Sema-withdrawal resulted in FG rebound to baseline, while PGTx and PGTx-treated Sema-withdrawn mice maintained 21% (p0.0001) and 22% (p0.001) FG reductions at wk 8. No significant evidence of pancreas inflammation was observed with mean islet histopathology scores of 0.5 in all groups. Conclusions: Single-dose PGTx can durably improve fat mass and glycemia and maintain these metabolic parameters upon Sema withdrawal without causing pancreatic inflammation. The data indicate that PGTx has the potential to advance GLP-1 therapies by offering durable efficacy in type 2 diabetes and obesity. Disclosure A.L. Fitzpatrick: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. S. Wang: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. R. Reese: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. N. Picard: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. E. Cozzi: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. T.J. Kieffer: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. J. Caplan: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. H. Rajagopalan: Board Member; Fractyl Health, Inc. Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc.