“Their weight has plateaued, they’ve been on the drug for a while and gotten to a goal of theirs, and now they’re like, ‘What’s next?’”
That’s the question that Harith Rajagopalan, MD, PhD, co-founder and CEO of Fractyl Health, has focused on to prevent the rampant and rapid weight regain after patients stop taking glucagon-like peptide-1 (GLP-1) drugs. The popularity of GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide (Ozempic and Wegovy), has surged recently, with about 1 in 8 (12%) of U.S. adults having tried these diabetes and weight-loss medications despite their high costs, according to a 2024 study. But the benefits aren’t sticking, as 50–75% of users stopped taking GLP-1 RAs within a year, reportedly resulting in participants regaining two-thirds of their prior weight loss.
“This is a massive problem that needs to be solved from a clinical and a medical standpoint,” Rajagopalan told Inside Precision Medicine. “It’s also just a massive problem to be solved from a human health and happiness standpoint because giving someone a medicine suppressing their body weight is great while you’re losing the weight. But when you stop losing weight and are told you have to stay on this medicine to keep it, now it feels like an anchor.”
As global GLP-1 RA adoption accelerates—and discontinuation cases climb—the need for scalable, non-pharmacologic solutions to sustain weight loss presents a significant, underleveraged commercial opportunity. So, at Fractyl Health, Rajagopalan and his team are targeting gut dysfunction, a root cause of obesity, not with a drug but with a 45-minute outpatient procedure.
“We’re in this world now where I can tell you you can take an injectable to get to a lower body weight, and you have to keep staying on that injectable to keep that body weight for the rest of your life,” said Rajagolapan. “What if there were a world where once you got to that body weight, we could tell you now you could throw the injectable away, go through a 40-minute procedure, and then lock in that weight loss indefinitely because we’re fixing the thing that’s going wrong in your brain that was making you obese in the first place.”
Fractyl Health has reported early data from their small REVEAL-1 study showing that their Revita platform—an outpatient endoscopic procedure—has the potential to prevent weight regain after GLP-1 discontinuation. Fractyl’s data from REVEAL-1 demonstrates that at one month after the Revita procedure, seven patients experienced roughly a 40% reduction in average weight regain (1.2%) compared to what’s typically observed at this time after GLP-1 discontinuation (3%) based on prior clinical studies. No safety or tolerability concerns have been reported in the 15 patients treated to date.
“This is the first data set of people who are stopping GLP-1s being followed for at least four weeks, but there are several patients now at three months, and it is showing that people are not gaining back the weight you would expect them to gain back when they stop taking tirzepatide,” Rajagopalan said. “They’ve lost on average nearly a quarter of their body weight… and are stable at that body weight now at one to three months. The tolerability and weight stability look excellent in this early data—it is very promising.”
Resetting the metabolic set point
An ever-increasing body of literature details the effects of stopping GLP-1 medication, including discontinuation rates, metabolic and cardiovascular health effects, and weight rebound information. Put simply, this data demonstrates that discontinuing GLP-1 drug treatment leads to numerous adverse health effects, including changes in body composition and rapid weight regain. Rajagopalan and others theorize that the body’s inability to re-establish a metabolic setpoint following substantial weight loss following GLP-1 medication treatment is the driving force behind weight rebound.
Using the idea of a rubber band being stretched out by the thumb and index finger as a metaphorical vehicle, Rajagopalan, on the other end of the video call, pulled down one side of the rubber band with his other hand and said, “I can pull one side of the rubber band down, but my weight set point is still anchored up high, so if I stopped the diet or the GLP-1 drug, my weight rebounds all the way back because we’re not fixing the weight set point. But what if you pull the rubber band down with the GLP-1 drug and then you lower the weight set point…you can now keep the weight down at that lower level without.”
That’s precisely what Revita is meant to do—to keep the weight loss down by refreshing the “metabolic set point.” But Revita doesn’t target the hypothalamus, let alone any part of the brain directly, which regulates body weight and energy expenditure by maintaining a specific body weight or metabolic set point, similar to a thermostat regulating temperature.
Instead, with Revita, patients undergo a procedure ablating the duodenal mucosa, which triggers the regrowth of a healthy new lining that doesn’t have the abnormal nutrient-sensing signals that people acquire from high-fat, high-sugar diets. The idea is that when the duodenal mucosa is removed, the new nutrient sensing adjusts to the body’s current metabolism, which then changes the connection between the gut and the brain to reset the brain’s metabolism settings.
While not everyone may want to have a tube put in their mouth that then proceeds past the trachea and into the gastrointestinal tract, a significant fraction of patients taking GLP-1 drugs are already required to undergo an upper endoscopy, which requires pausing GLP-1 drug treatment for at least one week.
Rajagolapan stated, “Roughly 10 million individuals are currently using a GLP-1 drug. That number will keep growing, but let’s say 10 million. Of those 10 million people who will try GLP-1 this year, 800,000 will undergo an endoscopy anyway for other reasons… So, there are 800,000 people on a GLP-1 for obesity who are stopping their GLP-1 before their endoscopy this year alone. Suppose Revita gets approved as a durable weight maintenance therapy. How many people will choose Revita as an add-on to the endoscopy that they’re otherwise getting to offer a way not to have to go back on the injectables after the endoscopy?”
All will be REVEALed
To test Revita, Fractyl Health launched the REMAIN-1 study. This study is for patients who have lost at least 15% of their total body weight on GLP-1 drug therapy and wish to discontinue their GLP-1 drug without weight regain. “We have an ongoing pivotal study called REMAIN-1 required for approval of Revita, and the FDA has granted us breakthrough device designation for this indication—weight maintenance after the discontinuation of GLP-1 drugs in people with obesity—through this pivotal study,” said Rajagolapan. “What’s interesting is that the FDA has not given the breakthrough designation to any other broad obesity drugs or devices in development for knowledge. What that means is they are more concerned about the risk of weight regain when stopping these GLP-1 drugs than the risk of the weight in the first place.”
Rajagolapan said that the REMAIN-1 study has generated significant interest. Over 100 patients have been enrolled across the first eight clinical study sites in less than four months since the first site activation, reflecting strong engagement from both patients and physicians. Within the REMAIN-1 study, an open-label cohort is participating in the REVEAL-1 trial.
“People who are enrolling in the studies seem to have gotten where they were aiming, and some of them feel like they’ve been on it for so long that they’re afraid of losing more muscle mass,” said Rajagopalan. “Other people are looking at it and thinking, ‘I don’t like the way [GLP-1 RAs] make me feel every two or three days every week’ or ‘I’m pretty dependent on my insurance covering this, and I’m not sure how long that’s going to happen or the cost.’ So, people are interested in figuring out how to lock in those benefits, and I think that’s what’s driving interest in this study.”
With REVEAL-1, patients who were obese and had a BMI of 30 or higher before beginning GLP-1 are given tirzepatide (Mounjaro for diabetes treatment and Zepbound for weight loss), lose 15% of their body weight, and then stop taking it. They then undergo the Revita procedure, and their weight is monitored over time. Fractyl aims to enroll about 20 patients in this open-label study, with 19 screened so far and 15 already enrolled and treated with Revita. Despite being a small cohort, the baseline demographics of these people are consistent with the general population of people who are on GLP-1 RA therapy today: they are 49 years old, more women than men, their post-GLP-1 body weight is 80 kilograms, their BMI is 29, and they have lost nearly a quarter of their body weight while on the drug.
Of the 15 people treated, most participants haven’t experienced adverse effects from Revita, and those who have experienced any symptoms had anything more than a transient mild or minor grade 1 adverse effect. The safety profile, albeit from a tiny cohort, looks compelling so far. REVEAL-1’s safety data is no surprise and is consistent with what we’ve seen in prior studies and hundreds of patients with type 2 diabetes. One of the major takeaways from the REVEAL-1 study deals with tolerability. People on GLP-1 have 20–40% rates of nausea and vomiting. With Revita, Fractyl Health has reported single-digit percentages of nausea and vomiting, and the symptoms that they experience are indistinguishable from a routine upper endoscopy that millions of people undergo annually.
Regarding the effectiveness of Revita, Fractyl reports that out of the seven people in the REVEAL-1 study, six have not regained the weight that you would have expected them to have regained during their one-month follow-up periods. That means that one patient did gain more weight than anticipated within the first month, of which Rajagolapan said, “Obesity is a heterogeneous disease—there will be some people who are going to respond better than others.”
It may be too early to bet the bank on Revita, as these patients need to be followed for many more months, and more participants are added to the REVEAL-1 cohort. But for now, the data demonstrate a favorable signal of early weight maintenance in a patient population who’ve lost much weight on tirzepatide.
The payer’s calculus
Rajagopalan said that when he talked to the participants, he saw nothing but happy customers, and the demand for an off-ramp as a durable strategy to lock in weight maintenance was screaming. The REVEAL-1 results and Rejuva’s potential may not be suitable for those with GLP-1 drugs on the market, but payers and patients will benefit.
“I think [payer] is desperate for a way to deprescribe these GLP-1s,” said Rajagolapan. “One of the ways to think about the insurance companies is to think about what a GLP-1 costs monthly—somewhere in the range of $500–$1000, depending on whom you ask. For every eight people who start on a GLP-1 drug, only one stays on it after three or four years, and you need to be on the GLP-1 drug for three to four years to see the clinical benefits they report in their Phase III studies. So, when you factor in the cost of all people who start and stop taking a GLP-1 drug, you’re looking at tens of thousands of dollars per patient per year who actually benefit.”
Given the current trends in GLP-1 RAs, Rajagopalan and Fractyl Health are well-positioned to capture a significant market share and potentially achieve substantial financial gains. In some ways, their biggest competition is their Rejuva gene therapy program. Fractyl Health is developing next-generation adeno-associated virus (AAV)-based, locally delivered gene therapies for treating obesity and type 2 diabetes. According to a report earlier this year, Fractyl Health has completed key preclinical in vivo studies with Rejuva. It is on track to initiate first-in-human studies in the first half of 2025. So, it’s possible that in the next couple of months, we will see the first person to be dosed with GLP-1-related gene therapy.
