Gene Therapy Improves Body Composition in Mice Models of Obesity Alone and After Semaglutide Withdrawal

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Fractyl Health is conducting IND-enabling studies for Rejuva.

Fractyl Health’s adeno-associated virus (AAV) GLP-1 pancreatic gene therapy Rejuva/RJVA-001 reduced weight and improved body composition in murine models of obesity alone and after GLP-1 therapy withdrawal.1

These preclinical data were presented at the American Diabetes Association (ADA) 84th Scientific Sessions Meeting, held June 21-24 in Orlando, Florida, and virtually, by Harith Rajagopalan, MD, PhD, cofounder and Chief Executive Officer, Fractyl.1

“These data demonstrate that Rejuva can durably improve body composition and fasting glucose, compared to or better than semaglutide, by restoring GLP-1 production in a ‘one-and-done’ treatment,” Rajagopalan said in a statement.2 “These data also show Rejuva could help maintain improvements after semaglutide is withdrawn, highlighting our therapy’s potential to fill an emerging and critical need in the management of obesity and T2D: a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines.”

Rejuva is designed to enable durable production of GLP-1 in pancreatic islet cells. It is administered via a proprietary, automated, endoscopic delivery device to the pancreas. Fractyl hopes that the gene therapy may address the issue of weight rebound and high rates of discontinuation with GLP-1 drugs such as semaglutide.

READ MORE: Kadimastem and iTolerance Work to Bring Immunosuppression-Free Diabetes Cell Therapy to Trials

The data presented at ADA are from a study that evaluated Rejuva in mice randomized to a single dose of the gene therapy or daily semaglutide injections for 4 weeks, with a crossover at 4 weeks to evaluate Rejuva in mice after semaglutide withdrawal for another 8 weeks compared to placebo.1

The investigators found that in mouse models of diet-induced obesity, Rejuva improved glucose, insulin, and weight more than daily doses of semaglutide. At week 4, Rejuva reduced fat mass by 21% versus 16% of body weight with semaglutide (both P <.0001 versus placebo, P <.05 Rejuva versus semaglutide) while both Rejuva and semaglutide preserved lean mass with a loss of only 5% of body weight (both, P <.0001 versus placebo).1

In mice after semaglutide withdrawal, Rejuva demonstrated a sustained weight loss. At week 8, fat mass rebounded to 1% below baseline (P >.05) in the semaglutide withdrawal group, and semaglutide-withdrawn mice treated with Rejuva maintained fat reduction of 17% (p<0.01) and weight loss of 22% (P <.0001) at week 8.Looking closer at body composition, treated mice had reduced food intake, primarily fat loss, and improved fasting blood glucose and insulin at 4 and 8 weeks after administration. Rejuva was not associated with any tissue inflammation. The company posits that these data demonstrate feasibility of Rejuva and investigational new drug application (IND)-enabling studies are underway.1

“In addition to the compelling durability of weight loss, body composition, and glucose improvements seen in this model, we are pleased that isolated, genetically modified islets from Rejuva-treated mice show this release of GLP-1 in response to nutrients,” Timothy Kieffer, Chief Scientific Officer, Fractyl Health, added.2 “We believe this clearly demonstrates that Rejuva can mimic the physiologic release of GLP-1 that occurs naturally in the human body.”

REFERENCES
1. Rajagopolan H, Fitzpatrick AL, Wang S, et al. Single-Dose GLP-1-Based Pancreatic Gene Therapy Durably Maintains Body Composition and Glycemia After Semaglutide Withdrawal in a Murine Model of Obesity. Presented at: ADA 84th Scientific Sessions Meeting,June 21-24; Orlando, Florida, and virtually.
2. Fractyl Health Presents New Preclinical Data on Sustained Weight Maintenance and Improved Body Composition from its Rejuva® Single-Administration GLP-1 Pancreatic Gene Therapy in President’s Select Oral Presentation at the American Diabetes Association’s 84th Scientific Sessions. News release. Fractyl Health. June 23, 2024
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