Fractyl Health submits of CTA module in Europe for RJVA-001

Fractyl Health has submitted the first module of its Clinical Trial Application (CTA) in Europe for the company’s gene therapy candidate from its Rejuva platform (RJVA-001). RJVA-001 is designed to express glucagon-like peptide-1 (GLP-1) locally in pancreatic beta cells using nutrient-responsive control, potentially enabling physiologic hormone secretion without the high circulating levels that contribute to side effects seen with systemic GLP-1 drug therapy. Pending regulatory clearance, Fractyl anticipates initiating first-in-human dosing and reporting preliminary data in 2026.

Rejuva platform

RJVA-001 is delivered via a one-time, minimally invasive endoscopic ultrasound-guided infusion directly into the pancreas. The gene therapy construct is designed to harness a proprietary, engineered version of the human insulin promoter and trafficking signals that allow for nutrient-triggered secretion of GLP-1 from transduced pancreatic beta cells—offering a “smart,” physiologic alternative to chronic pharmacotherapy. RJVA-001 is designed to enable the physiologic hormone signalling of GLP-1 through native metabolic circuits in the gut and portal vein rather than relying on high systemic drug levels. This difference from GLP-1 drug pharmacology opens the door to efficacy that matches or exceeds drugs with potentially superior tolerability profiles due to low circulating levels of drug.

“Completing our first CTA module submission for RJVA-001 marks a major step forward in our mission to reimagine treatment for metabolic disease with what we believe can be best-in-class incretin therapies,” said Dr Harith Rajagopalan, Co-Founder and Chief Executive Officer of Fractyl Health. “Our goal is to develop a platform of therapies that offer superior durability, potency, tolerability, and convenience to conventional GLP-1 based drugs. We believe Rejuva can unlock a one-time, durable gene therapy approach to normalize blood glucose and body weight while reducing the burden, side effects, and limitations of lifelong injectable drugs. We believe that our work on developing a potentially superior therapeutic profile with RJVA-001 and our efforts to drive manufacturing scalability and efficiency open the door to a commercially viable path to durable disease remission in T2D and obesity.”

The upcoming Phase 1/2 study is designed to be an open-label, multi-centre, single ascending dose study evaluating the safety, tolerability, and preliminary efficacy of RJVA-001 in adults with inadequately controlled T2D despite use of multiple glucose-lowering agents, including GLP-1 receptor agonists (GLP-1RAs).

“We’ve spent decades managing T2D as a chronic, progressive disease, and this upcoming first-in-human study of RJVA-001 represents the first real attempt to reverse it at the source by targeting the beta cell directly,” said Professor Jacques Bergman, Professor of Gastrointestinal Endoscopy, Deputy Chair, Department of Gastroenterology & Hepatology at Amsterdam UMC. “If successful, RJVA-001 could transform how we think about diabetes from something you manage daily to something you potentially treat once. That’s a fundamentally different future for patients.”

Participants will undergo a standardised medication run-in and GLP-1 washout before receiving RJVA-001 delivered via endoscopic ultrasound-guided intrapancreatic injection. Three escalating dose cohorts (up to 3 participants each) will be followed by an optional expansion cohort of up to 10 additional participants treated at the selected optimal dose. Participants will be monitored for 12 months for safety, glucose control, immune response, and GLP-1 expression, and enrolled in a long-term follow-up study for up to 5 years.

Primary endpoints include safety and tolerability. Secondary endpoints include change in HbA1c, fasting plasma glucose, and time-in-range (by CGM). Exploratory endpoints assess beta-cell function, metabolic biomarkers, cardiovascular risk markers, and transgene expression.