When Harith Rajagopalan considers the millions of patients who have taken a GLP-1 drug to treat diabetes or obesity, he sees a revolution that is failing to realize its promise. “We are literally lighting tens of billions of dollars on fire,” he said.
Rajagopalan is referring to studies showing that most patients stop taking GLP-1 medications within a year or two, preventing them from reaping the long-term benefits like reducing cardiovascular risk. A cardiologist by training, Rajagopalan believes there’s a better way to harness the benefits of GLP-1 drugs: a gene therapy that, with a single infusion, can program the body to make more of the GLP-1 hormone naturally for years.
Rajagopalan is the co-founder of a small biotech firm making a long-shot bid to disrupt the booming weight-loss industry. His publicly traded company, Fractyl Health, says it is on track to begin a human clinical trial later this year.
There is considerable risk in developing a gene therapy. While Fractyl’s approach promises to be longer lasting, it also comes with a potentially significant downside: What happens if the therapy causes patients’ bodies to produce too much GLP-1?
“The drugs, you can stop,” Giles Yeo, a professor at the University of Cambridge who studies the genetics of obesity, said of people who experience nausea and vomiting after taking GLP-1 medications. “If you genetically modify someone and they can’t stand it, they’re screwed,” he said.
Fractyl, headquartered in Burlington, Massachusetts, also faces financial risk. Since going public in 2024, it has disclosed in regulatory filings that there is “substantial doubt” it can continue as a going concern. Meanwhile, the drugmakers that dominate today’s GLP-1 market, Novo Nordisk and Eli Lilly, are poised to expand even further. They are pursuing next-generation shots that can help people lose even more weight, along with once-a-day pills that offer a convenient and cheaper option.
Rajagopalan is confident that Fractyl can navigate both the safety and commercial risks of its gene therapy. It ended 2025 with enough cash on hand to pay for its money-losing operations for a year, according to a securities filing.
The company has the attention of Wall Street and obesity researchers as it prepares to start its clinical trial for patients with Type 2 diabetes. Closer at hand, Fractyl plans to seek regulatory clearance this year for its other leading product: a procedure to help people maintain weight loss by removing the lining of part of the gut so that healthy tissue can regrow.
So far, investors are more enthusiastic about other, more limited genetic approaches to treating obesity. Wave Life Sciences electrified Wall Street in December when it announced results from a small trial of an injectable drug that dials down the activity of a gene implicated in obesity. A single dose — designed to last at least six months — led participants to lose 9 percent of their visceral fat while increasing lean mass after 12 weeks. The company’s stock jumped almost 150 percent that day.
Arrowhead Pharmaceuticals reported similar results from its own drug targeting the same gene, INHBE, by suppressing a protein that encourages the body to store energy rather than burn it.
For obesity physicians, a major attraction of a gene therapy is that patients wouldn’t have to keep taking a medication over the long haul. Fatima Cody Stanford, who practices obesity medicine at Massachusetts General Hospital and teaches at Harvard Medical School, said about 70 percent of patients at her practice lost coverage for GLP-1 drugs starting this year as a result of insurers pulling back.
“The patients are coming off not because they want to. They’re coming off because they have to, because their financial resources do not allow them to stay on medication,” Stanford said. A long-lasting gene therapy to treat obesity would be a welcome addition, she said, but added that it seems almost too good to be true.
“Would that really happen?” she said. “This sounds almost like a cure, and we’ve never seen that to date.”
Fractyl’s gene therapy, Rejuva, involves injecting a small dose into the pancreas with a proprietary catheter, deploying an innocuous virus to instruct insulin-making cells to produce more of the GLP-1 hormone. By programming the pancreatic cells to boost GLP-1, the hormone circulating throughout the entire body doesn’t surge as it does when taking GLP-1 drugs — which Fractyl says could reduce side effects linked to high concentrations in the blood.
In an ongoing study of Rejuva in mice who received a high-fat diet, Fractyl said in October that a single dose led to as much as 29 percent weight loss after 35 days. The therapy might also have a “self-limiting mechanism,” the company said, noting a separate study showing that lean mice who got Rejuva lost just 6 percent of their body weight over 21 days and didn’t experience low blood sugar.
Lei Cao, a professor at Ohio State University who has worked on gene therapies for obesity, said that Fractyl’s harnessing of the pancreatic cells “is their strength.” She does, however, worry about the long-term effects of producing high levels of GLP-1 in the pancreas, where the hormone isn’t primarily made, such as the potential for cancer. “We don’t know anything about that locally, high-level GLP-1 drug in [the] pancreas,” she said.
Fractyl pointed to evidence that current GLP-1 drugs aren’t associated with increasing the risk of pancreatic cancer and could help protect against it; other research suggests the drugs have little effect on obesity-related cancers.
There’s no perfect formula for calculating the optimal dose of a gene therapy, leaving Fractyl to extrapolate based on their animal studies and start with the low end of the range they expect to have a benefit, said Mark Kay, a gene therapy expert at Stanford University and a member of Fractyl’s scientific advisory board.
“There is always some risk,” he said, adding that there is a drug being developed that could counteract the effects of GLP-1 if patients who get the gene therapy make too much of the hormone.
Fractyl said that it is not relying on an “antidote” to develop its therapy, but that drugs that dial down GLP-1, if approved by regulators, “could provide an additional, external safety mechanism.”
Another question is whether health plans — many of which have balked at the high cost of GLP-1 medications — would be any more willing to pay for a gene therapy with an even higher up-front cost. (Fractyl isn’t disclosing a price but said using a smaller-than-typical dose means “lower cost of goods.” Approved gene therapies range from a cost in the high six figures to low-digit millions). Though some studies show that GLP-1 medications can save health costs in the future by helping patients avoid more serious medical conditions, those benefits are often only realized after many years while the costs have to be borne in the present.
Fractyl said that Rejuva, if successful, would offer “reliable and predictable improvements in glycemic control and metabolic health” rather than “indefinite pharmacy spend” for drugs that patients may ultimately stop taking.
For its initial clinical trial, Fractyl plans to study patients with Type 2 diabetes who have taken GLP-1 medications without serious side effects but still have high blood sugar. A second version of the gene therapy stimulates both GLP-1 and another gut hormone and is being developed to treat obesity.
Rajagopalan says there is no shortage of interest from patients. “We’re getting emails every day from people who are hearing about the Rejuva gene therapy trials who want to be a part of these studies,” he said.
The post The next frontier in weight-loss drugs: one-time gene therapy appeared first on Washington Post.
