Fractyl's GLP-1 obesity gene therapy outdoes semaglutide for weight loss—in mice

Fractyl Health’s GLP-1-based pancreatic gene therapy has outperformed semaglutide injections for weight loss—at least in mice.

In a presentation Oct. 4 at the annual conference of the European Association for the Study of Diabetes, or EASD, the company presented data showing that a single dose of its GLP-1 PGTx, known by the trade name Rejuva, was able to reduce body fat by about 25% in a mouse model of Type 2 diabetes, compared to roughly 18% in animals that were given daily doses of semaglutide.

Semaglutide is marketed by Novo Nordisk as Ozempic for diabetes and Wegovy for weight loss. The drug has sparked a gold rush in the obesity market with companies trying to improve on the market leader. Fractyl is behind bigger names like Pfizer and Eli Lilly, which has received a diabetes approval for its Mounjaro. Novo, meanwhile, has been stacking its pipeline with next-gen options.  

“We aim to design a better GLP-1 therapy which has the potential for more potency, better tolerability, and more durability,” Fractyl Chief Scientific Officer Timothy Kieffer, Ph.D., said in a press release. “[Rejuva] has the potential to offer these benefits because it targets the pancreas, is designed to mimic human physiology, and may provide durable benefits that persist after the treatment itself.”

Besides losing weight, all of the mice had improved fasting blood glucose and insulin levels at the end of the eight-week study. They continued losing weight for the first 15 days of the study.

Rejuva works by using an inactive adeno-associated virus to deliver a gene that stimulates GLP-1 expression in pancreas cells, leading to insulin release. While semaglutide is given through subcutaneous injections, Rejuva is designed to go directly to the pancreas via an infusion, though the mice in the latest study received intraperitoneal injections. The mode of delivery and the design of the gene therapy restrict it to the pancreas, reducing the potential for off-target effects, according to Fractyl.

So far, researchers haven’t seen any signs of tolerability issues, though “the mouse isn’t a good model for tolerability,” Fractyl's CEO and co-founder, Harith Rajagopalan, M.D., Ph.D., who presented the company’s data at the EASD conference, told Fierce Biotech Research via email. Tissue studies found no evidence of serious adverse effects such as pancreatic cancer.

The research builds on the findings of a proof-of-concept study in pigs, presented earlier this year at the American Society of Gene & Cell Therapy congress. Fractyl is currently working on lead optimization and IND-enabling toxicology studies and is targeting 2024 for its first human studies.