Fractyl’s Single-Dose Obesity Gene Therapy GLP-1 PGTX Outcompetes Chronic Semaglutide in Rodent Study

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The mechanism for weight loss was attributed to reduced food intake observed in both treatment groups.

Fractyl Health’s GLP-1 PGTX, an investigational GLP-1-based pancreatic gene therapy intended to treat obesity, has achieved more efficacious weight loss results than chronic semaglutide in a head-to-head diet-induced obesity (DIO) rodent model study comparing the 2 treatments against each other.1

At the 15-day time point in the study, 10 rodents that had received a single dose of GLP-1 PGTx showed 24.8% lower total body weight; on the other hand, 10 rodents that were being treated with 10 nmol/kg/day of chronic semaglutide showed only 24.8% lower total body weight at the same time point (P < .01). Fractyl noted that plateauing of weight loss was not observed for either treatment group at the 15-day time point. Furthermore, the mechanism for weight loss was attributed to reduced food intake observed in both treatment groups; a phenomena not observed in rodents receiving treatment with a vehicle alone.

“The success of gene therapies in a number of rare diseases may now open the door to sustained benefit from gene therapy for more common diseases, like obesity and type 2 diabetes (T2D),” Mark Kay, MD, PhD, a professor of pediatrics and genetics at Stanford University Medical School and Fractyl Health’s Scientific Advisor. “Results now in 2 efficacy models for GLP1 PGTx and toxicology studies accumulating thus far suggest that local administration of gene therapy to the pancreas may now be feasible for society’s most vexing chronic diseases.”

Fractyl is also evaluating GLP-1 PGTX for the potential treatment of type 2 diabetes (T2D).2 Earlier this year, in June, the company reported results from a separate preclinical study using a db/db rodent model of diabetes. It was found that db/db rodents that received a single dose of GLP-1 PGTX reached 54% lower blood glucose levels and 20% lower total bodyweight than db/db rodents that received 10 nmol/kg/day of chronic semaglutide. Fractyl noted that the gene therapy’s pancreas-directed delivery is driven by the insulin promoter and in the context of T2D is intended to protect the pancreatic islet from failure by improving metabolic control. GLP-1 PGTX utilizes an adeno-associated virus vector and is based on the company’s Rejuva platform, which incorporates delivery systems and proprietary screening methods that are used in the development of pancreas-directed gene therapy products intended to treat metabolic conditions.1

“The power of the GLP-1 mechanism in obesity and T2D is obvious, but we also know we need treatments for T2D and obesity that work even after patients stop taking them,” Harith Rajagopalan, the CEO of Fractyl Health, said in a statement.1 “Our goal with our Rejuva platform is to develop gene therapy candidates that can durably change the trajectory of both obesity and T2D, and today’s results further consolidate preclinical proof-of-concept data for the viability of this approach.”

Recently, CGTLive™ discussed the future of gene therapy research with Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, a clinical research services organization that works with companies developing gene therapies. During the interview, Phippard emphasized that after initial successes in rare lysosomal disorders that result from single-gene mutations, gene therapy companies are now expanding their efforts to therapeutic areas that include more common conditions that may be unexpected targets for gene therapy, such as obesity.

“Something that really fascinated me when was I was talking to a client recently was that you can consider obesity a metabolic disorder or even a central nervous system disorder, thinking about all the hormones that are involved in that disorder,” Phippard said. “Now I see companies are even thinking about obesity as a target for gene therapy.”

REFERENCES
1. Fractyl Health Demonstrated significant improvement in weight loss in head-to-head preclinical obesity studies of its Rejuva® GLP-1- based pancreatic gene therapy candidate (GLP-1 pgtx) compared to chronic semaglutide at EASD's annual meeting. News release. Fractyl Health. October 4, 2023. Accessed October 12, 2023. https://www.fractyl.com/fractyl-health-demonstrated-significant-improvement-in-weight-loss-in-head-to-head-preclinical-obesity-studies-of-its-rejuva-glp-1-based-pancreatic-gene-therapy-candidate-glp-1-pgtx-compared-to-chr/
2.Fractyl Health demonstrates significant improvement in glucose control and obesity in preclinical studies of its Rejuva GLP-1 based pancreatic gene therapy (GLP-1 pgtx) compared to chronic semaglutide at ada’s 83rd scientific sessions. News release. Fractyl Health. June 24, 2023. Accessed October 12, 2023. https://www.fractyl.com/fractyl-health-demonstrates-significant-improvement-in-glucose-control-and-obesity-inpreclinical-studies-of-its-rejuva-glp-1-based-pancreatic-gene-therapy-glp1-pgtxcompared-to-chronic-semaglutide-at/
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