Fractyl Health has presented new data from its preclinical Rejuva Smart GLP-1 pancreatic gene therapy program in a poster titled, ‘Feasibility and Safety of Novel Endoscopic Ultrasound-Guided Delivery of Human GLP-1 Pancreatic Gene Therapy in Pigs’, at the 22nd World Congress Insulin Resistance, Diabetes & Cardiovascular Disease (WCIRDC).
Rejuva is the company’s adeno-associated virus (AAV)-based pancreatic gene therapy program, designed to enable durable production of therapeutic proteins by the pancreas for the treatment of obesity and T2D. The data presented at WCIRDC evaluated the safety and feasibility of infusing RJVA-001, the company’s GLP-1 development candidate for T2D, with an endoscopic ultrasound-guided delivery system into the pancreas of a large animal.
An endoscope with custom delivery needle was used to deliver RJVA-001 into the pancreas of Yucatan pigs. This procedure closely mimics the intended route of administration for the first-in-human studies the company plans to initiate in 2025. An AAV9 vector genome dose of 6e13 vg per pig was administered, approximating a potential human dose of 6e11 vg/kg (for a 100 kg adult with T2D). This dose is more than two orders of magnitude lower than other approved systemic AAV9 therapies, demonstrating the potential of RJVA-001 to be safe and effective at a low total viral dose.
At Day 34 post-procedure pancreatic biopsies showed that active GLP-1 protein expression capacity within pancreatic islets was greatly enhanced. RJVA-001 achieved therapeutically relevant GLP-1 expression levels based on observations in disease models and were five times higher in treated than untreated animals (p<0.02). Pancreatic lipase, a marker of pancreatitis, remained in the normal range in all animals. These results demonstrate the potential of RJVA-001 to dramatically enhance GLP-1 production capacity to therapeutically relevant levels without any observed adverse safety signals.
These data also show that RJVA-001 can be safely delivered endoscopically in a large animal model, allowing for direct pancreatic targeting with a gene therapy, giving the Company confidence in the potential for safe and effective delivery of RJVA-001 in humans.
“RJVA-001 has the potential to be a game changer in the field of obesity and T2D,” said Dr Harith Rajagopalan, Co-Founder and CEO, Fractyl Health. “We have previously shown in mice models that a single dose of Rejuva can help maintain improvements in both weight and blood glucose levels after withdrawing semaglutide - which is a critical unmet need in the management of obesity and T2D. These data presented at WCIRDC help to establish safety and feasibility of targeted delivery in a large animal model - which is one of the last pieces of data we need to have confidence in the successful delivery to the pancreas in humans, as well as to understand the correct dose for our first-in-human studies with our Smart GLP-1 gene therapy, which will be initiated in the first half of 2025. We look forward to reporting additional data from Rejuva Clinical Trial Application (CTA)-enabling studies at upcoming scientific meetings.”
The company intends to initiate its first-in-human study for RJVA-001, its first nominated GLP-1 pancreatic gene therapy candidate designed for the treatment of T2D, in the first half of 2025.
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