The weight loss was surprising, says Rajagopalan. Ozempic and Wegovy are injected into the fatty tissue of the thighs, waist or upper arm. From there it enters the bloodstream, where it somehow communicates with the brain. Since Fractyl’s gene therapy is administered directly to the pancreas, the company’s scientists did not expect significant weight loss.
One explanation is that the gene therapy produces enough GLP-1 in the pancreas that some enters the bloodstream and talks to the brain, says Daniel Drucker, an endocrinologist and professor of medicine at the University of Toronto. Another possibility, he says, is that there’s an unknown signaling mechanism in the pancreas that tells the brain to stop eating.
To deliver the therapy to the pancreas, the company developed an endoscopic procedure that involves inserting a thin needle attached to a catheter that goes down the throat to the gastrointestinal tract. Fractyl scientists tested the procedure for safety in 50 pigs, which have a pancreas anatomically similar to that of humans. The team confirmed that the procedure successfully delivered the gene therapy to pancreatic cells, but did not test whether it led to blood sugar or weight changes in the pigs. No adverse side effects were observed in the animals.
But Drucker is skeptical about injecting a therapy directly into the human pancreas. “The pancreas is a very delicate and important organ,” he says. “If it’s poked or prodded, it can cause inflammation.”
In addition to producing insulin, the pancreas makes digestive enzymes that help break down food. But when it becomes inflamed — a condition called pancreatitis — these enzymes can attack the pancreas instead. Pancreatitis can be short-lived or chronic, the latter causing permanent damage to the organ.
Gene therapy could be an expensive approach to treating diabetes. There are already several gene therapies on the market for other conditions, and they command sky-high prices. One of them, which treats a blood disorder called beta thalassemia, costs $2.8 million. Another, for hemophilia B, costs $3.5 million.
Maria Escobar Vasco, an endocrinologist and diabetes expert at UT Health San Antonio, says the idea of a one-time gene therapy is intriguing, but more testing will be needed. “The question is: how safe is it? I don’t think we know yet,” she says. The company aims to begin a first human trial by the end of 2024, so those answers are still a few years away.
There is already an alternative way to deliver semaglutide: by pill. Novo Nordisk, which produces Ozempic and Wegovy, also makes Rybelsus, a tablet used in the treatment of diabetes, and is now testing a higher-dose version for weight management. Competitor Pfizer is developing its own pill that also mimics GLP-1. Pills can help people stick to a dosing schedule because they are more convenient than injections, but they still come with the risk of gastrointestinal side effects and must also be taken repeatedly.
Whether Fractyl’s gene therapy will cause similar side effects is still unknown. With Ozempic and Wegovy, these effects often occur in the early stages of drug use, when the dose is steadily increased. Usually these go away on their own.
“The effect of the drug to cause nausea actually happens in the brain,” said Randy Seeley, a professor of surgery and obesity specialist at the University of Michigan, who is an advisor to Fractyl. Since Fractyl’s gene therapy is delivered to the pancreas, it can avoid the problem of side effects. But if some GLP-1 does enter the bloodstream, Seeley says there could be side effects similar to those of current drugs.
However, if a one-time gene therapy works — and is safe — it could be a game changer for diabetes and weight management. “Type 2 diabetes is a chronic condition that requires chronic treatment. Obesity is a chronic condition that needs to be treated chronically,” says Seeley. “If you only have to give people access once, instead of every week, the use of this strategy will increase and more patients will benefit from it.”