The FDA has approved a pivotal Investigational Device Exemption (IDE) to study the efficacy of Fractyl Health’s Revita system for maintaining weight loss following the discontinuation of GLP-1 receptor agonist (GLP-1RA) drug therapy, addressing a key unmet need in the treatment of obesity. Obesity affects over 40% of the US population and is a critical precursor to various highly morbid and expensive chronic conditions such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease, and cardiovascular disease.
Revita is designed to remodel the duodenal lining via hydrothermal ablation (i.e., duodenal mucosal resurfacing) to edit abnormal intestinal nutrient sensing and signalling mechanisms that are a potential root cause of metabolic disease. It is an outpatient endoscopic procedure that targets the duodenum and is designed to reverse pathology in the duodenal lining that is a root cause of obesity and T2D. In prior clinical studies of Revita conducted in people with T2D in the US and EU, pooled analyses of weight data provided evidence to support the potential for durable weight maintenance after a single Revita procedure.
The IDE approval launches the Remain-1 study, set to begin in the second half of 2024. Remain-1 is a randomised, double-blind trial of Revita versus sham in patients who have lost at least 15% total body weight on tirzepatide therapy. It is designed to be a pivotal study to potentially enable registrational filing for Revita for weight maintenance after GLP-1RA discontinuation. In parallel with the randomised portion of the Remain-1 study, Fractyl Health also announces Reveal-1, an open-label cohort that will follow a similar patient population and management protocol with anticipated open-label data updates as the study progresses.
The rationale for the Remain-1 pivotal study is based on a new need for therapeutic solutions that can offer durable weight maintenance without ongoing medical therapy. Highly potent drugs in the GLP-1RA class, including semaglutide (Wegovy) and tirzepatide (Zepbound), are now approved for the management of obesity and have dramatically altered the treatment landscape.
However, real world studies report high discontinuation rates and clinical trials have indicated the risk of substantial weight rebound after discontinuation in many participants. Strategies to maintain weight loss independent of ongoing medical therapy could provide substantial clinical and economic benefits by extending the value of GLP-1RA drugs even after these medicines are discontinued.
“The unmet need in obesity is shifting from ‘How do we help people lose weight?’ to ‘How do we help people keep the weight off?’” said Dr Christopher Thompson, Director of Endoscopy at Brigham and Women’s Hospital, Co-Director, Center for Weight Management and Wellness at Brigham Health, and Professor of Medicine at Harvard Medical School. “We now need new therapeutic strategies that can offer durable weight maintenance, and I am excited for the prospect of the Remain-1 pivotal study to hopefully address this massive challenge in obesity today.”
The patient population for Remain-1 will consist of obese individuals with a BMI≥30 kg/m2. These GLP-1RA-naïve individuals will initiate tirzepatide therapy, titrated to achieve at least a 15% total body weight loss, followed by discontinuation of tirzepatide and randomisation to either Revita treatment or a sham procedure. At least 315 subjects will be randomised 2:1 to Revita or sham.
The primary objectives of the study are:
To demonstrate that Revita is superior to sham in percent change in body weight from baseline to week 24, and;
To demonstrate that a majority of Revita participants maintain clinically significant weight loss after discontinuing tirzepatide therapy.
"We believe there is substantial clinical and economic value in new approaches to obesity that can enable durable weight maintenance after stopping GLP-1 based drugs," said Dr Harith Rajagopalan, CEO of Fractyl Health. "We were very happy to work collaboratively with key advisors in obesity and gastrointestinal endoscopy by rapidly developing this protocol to address a huge, emergent unmet need in the field."