Fractyl Health’s AAV-Based Rejuva “Smart GLP-1” Gene Therapy Shows Strong Preclinical Data at ADA 2025

BURLINGTON, Mass. – June 23, 2025 – Fractyl Health, Inc. (Nasdaq: GUTS), a metabolic therapeutics company relentlessly focused on pattern-breaking approaches to treat the root causes of obesity and type 2 diabetes (T2D), today announced compelling new preclinical data from its Rejuva Smart GLP-1 pancreatic gene therapy platform at the American Diabetes Association’s (ADA) 85th Scientific Sessions. The presented abstract, titled “Single-Dose GLP-1-Based Pancreatic Gene Therapy Prevents Obesity and Diabetes in High-Fat Fed Mice,” showcased that a single dose of Rejuva was not only well-tolerated in healthy mice but also remarkably prevented weight gain and hyperglycemia following a switch to a high-fat diet.

These significant findings further validate Rejuva’s potential as a one-time, durable therapy offering potent activity in both obesity and diabetes models, alongside a favorable toxicity profile across multiple preclinical models. A crucial differentiator highlighted by these data is Rejuva’s unique mechanism of action, setting it apart from traditional systemic GLP-1 receptor agonists. The Smart GLP-1 design of Rejuva enables nutrient-responsive GLP-1 secretion, meaning it exerts no physiological effect under healthy metabolic conditions and only activates precisely in the presence of metabolic stress. This targeted activity, which elegantly mimics the body’s endogenous GLP-1 physiology, points to Rejuva’s potential for superior potency and tolerability.

The study rigorously evaluated Rejuva treatment utilizing an AAV vector specifically designed for beta-cell-specific expression of a GLP-1 analog. Key results from the diet-induced obesity (DIO) model showed a 20% reduction in body weight and a 38% decrease in blood glucose by day 21, with these profound effects maintained through day 37 despite continuous high-fat diet exposure. In lean animals, Rejuva completely prevented weight gain and hyperglycemia when later exposed to a high-fat diet.

“These results underscore the transformative potential of Rejuva to offer protection from obesity and diabetes in the setting of modern environmental exposure to unhealthy diets,” stated Harith Rajagopalan, M.D., Ph.D., Co-Founder and Chief Executive Officer of Fractyl Health. He emphasized Rejuva’s localized, pancreas-targeted approach as a fundamental shift from chronic systemic GLP-1 therapies, aiming to “defend humanity from the inevitable metabolic diseases of modernity.”

Fractyl is rapidly advancing towards the clinic, having completed key in vivo studies for RJVA-001, its first clinical candidate from the Rejuva platform targeting T2D. Pending regulatory authorization, Fractyl expects to dose the first patients with RJVA-001 and report preliminary data in 2026, which could lead to a potentially first-in-class, smart, durable gene therapy designed to reprogram the pancreas for natural metabolic control. This scientific validation is further backed by the involvement of renowned metabolic experts like Dr. Timothy Kieffer and Dr. Randy Seeley.