Rejuva Smart GLP-1 pancreatic gene therapy preclinical data highlighting durable potency and safety with limited systemic GLP-1 exposure

New preclinical data from Fractyl Health’s Rejuva smart GLP-1 gene (RJVA-001’s) therapy platform, presented at the American Society of Gene and Cell Therapy (ASGCT) 2025 Annual Meeting, highlight the therapy’s potential to deliver durable, nutrient-responsive GLP-1 secretion from pancreatic beta cells - mimicking natural hormone regulation with low circulating levels of GLP-1 - offering a potentially profound mechanistic advantage over pharmacologic GLP-1 drugs.

 Rejuva smart GLP-1 gene therapy platform

RJVA-001 also showed strong efficacy, targeted delivery, and a favourable safety profile, reinforcing its readiness for first-in-human studies. The data were presented in the abstract, ‘Endoscopic Ultrasound-Guided Delivery of Human Glucagon-like Peptide-1 Pancreatic Gene Therapy: Safety and Feasibility in a Porcine Model’.

The Rejuva platform focuses on developing next-generation adeno-associated virus (AAV)-based, locally delivered gene therapies for the treatment of obesity and T2D. The Rejuva platform is in preclinical development and has not yet been evaluated by regulatory agencies for investigational or commercial use. Rejuva leverages advanced delivery systems and proprietary screening methods to identify and develop metabolically active gene therapy candidates targeting the pancreas. The program aims to transform the management of metabolic diseases by offering novel, disease-modifying therapies that address the underlying root causes of disease.

“RJVA-001 represents a fundamentally different approach to treating metabolic disease - one that delivers the power of GLP-1 in a more natural manner,” said Professor Randy Seeley, Henry King Ransom Professor of Surgery and Director of Michigan Nutrition Obesity Research Center at Michigan School of Medicine. “The ability to drive durable metabolic effects with physiologic hormone levels, from a one-time treatment, would be a scientific breakthrough with huge potential implications for patients. This has the potential to reshape how we think about treating T2D and obesity at scale.”

The data revealed that single-dose RJVA-001 led to durable, dose-dependent metabolic improvements in a well-established diabetic model: In db/db mice, treatment with RJVA-001 led to sustained reductions in blood sugar, improved fasting insulin levels, and improvements in body weight over six weeks - supporting Rejuva’s potential for sustained disease modification on both blood sugar and body weight control. Treatment with RJVA-001 resulted in a >200 mg/dL reduction in fasting blood sugar, a >2-fold increase in fasting insulin levels, and prevention of weight gain, compared to a ~20% increase seen in vehicle-treated controls. These results demonstrate broad-based metabolic improvement in insulin secretion, weight gain, and blood sugar control in this gold-standard model of T2D.

RJVA-001 achieved glycaemic control and prevented weight gain with significantly lower systemic GLP-1 exposure than required by GLP-1 drugs to achieve similar effects: Circulating GLP-1 levels were more than 5-fold lower than those seen with pharmacologic GLP-1 drugs and were comparable to levels observed after gastric bypass surgery - suggesting a substantially lower risk of GLP-1-related side effects such as nausea and vomiting. In db/db mice, circulating levels of active GLP-1 were 10-20 pM with RJVA-001, compared to 50-150 pM typically reported with pharmacologic GLP-1 drugs.

Data show nutrient- and dose-responsive GLP-1 secretion in transduced human beta cells and islets, demonstrating that Rejuva mimics native hormone regulation rather than constant drug-driven stimulation: RJVA-001 activated glucose-dependent expression of GLP-1 in both in vitro and ex vivo models, consistent with physiologic endocrine function. In transduced human beta cells, GLP-1 secretion more than doubled - and GLP-1 bioactivity increased >3-fold - when shifting from low glucose to high glucose conditions. These results demonstrate tight nutrient gating and dose-responsive control of RJVA-001 drug action.

Adaptive expression based on disease state: In db/db mice, RJVA-001 drove higher GLP-1 expression in diabetic animals than in healthy controls at the same dose, demonstrating the platform’s ability to adapt to metabolic need. RJVA-001-treated healthy mice maintained normal weight and blood sugar, reinforcing the potential safety of this nutrient-responsive smart GLP-1. At equal dosing, db/db mice had more than twice the circulating GLP-1 levels of healthy mice, with no effect on weight or blood sugar in the healthy group. These results support the physiologic, selective, and adaptive action of RJVA-001 based on the body’s metabolic state.

Endoscopic ultrasound–guided delivery of RJVA-001 in large animals showed targeted pancreatic expression with no observed toxicity: In Yucatan pigs, device deployment was completed in an average procedure time of <20 minutes using a standard clinical endoscopic ultrasound technique.

RJVA-001 localised to the pancreas with minimal systemic distribution and no adverse safety findings, even at doses exceeding projected clinical levels. Biodistribution studies showed vector copy number of 7 vector genomes/nucleus in the targeted splenic lobe of the pancreas (equivalent to the body and tail of the human pancreas) versus <0.2 vector genomes/nucleus in the liver. These results indicate profound de-targeting of the liver with local administration with the Rejuva catheter and ultrasound-guided route of administration. No acute or longer-term serum or histopathological evidence of toxicity was observed post-procedure. Serum lipase, neurofilament-light, troponin I, and ALT all remained below the upper limit of normal or below detection, indicating the absence of pancreatic, neuronal, cardiac, and liver toxicity, respectively. No on-target or off-target organ inflammation or other histopathological findings were observed in the study.

“We believe RJVA-001 represents a transformative advance in metabolic medicine,” said Dr Harith Rajagopalan, Co-Founder and Chief Executive Officer of Fractyl Health. “These data suggest that a one-time, smart GLP-1 can restore physiologic signalling in the pancreas and achieve durable disease modification in diabetes and obesity - without the high levels of systemic drug exposure that causes side effects with current GLP-1 therapies. RJVA-001 has demonstrated superior potency, durability, and convenience in preclinical models, along with a potentially improved tolerability profile than GLP-1 drugs. We believe the Rejuva platform has the potential to usher in a category-closing modality for T2D and obesity. We look forward to our upcoming CTA submission for RJVA-001 and, pending regulatory authorisation, preliminary human data in 2026.”

The company plans to submit the first Clinical Trial Application (CTA) module for RJVA-001 in type 2 diabetes to regulators by June 2025, and if the CTA is authorised, the company expects to dose the first patients with RJVA-001 and report preliminary data in 2026.