Could a new drug be 'exercise in a pill'?

Enveda, a biotech startup, is working to develop a new medication that would be able to achieve the same weight loss as GLP-1s, but without the side effects — something that could make it easier for people to stay on the medication in the long term.

Currently, one in eight U.S adults report using GLP-1 medications. However, most people taking these drugs stop them within a year of starting. According to recent meta-analysis from the University of Oxford, many people who stopped taking GLP-1s regained the weight they originally lost and no longer saw improvements to their metabolic health.  

Enveda's experimental pill, which is called ENV-308, is a chemically engineered version of lactate phenylalanine (lac-phe), a small molecule metabolite that was originally discovered by Stanford University scientists in 2022. The body releases lac-phe during intense exercise, as well as after meals, and it has been shown to suppress appetite and reduce obesity in animals.

Both lac-phe and ENV-308 act on the hormone leptin, which drugmakers have been targeting for over 30 years. When fat cells release leptin, it can help control appetite by telling when the body is full. However, in obesity, leptin levels can climb so high that the body becomes insensitive to it, leading to leptin resistance.

"ENV-308 is our attempt to put the chemistry of exercise into a daily tablet, and to offer a sustainable and convenient solution that synergizes with people's daily habits and supports them on the path to long-term health," said Viswa Colluru, founder and CEO of Enveda.

According to Enveda leaders, the biggest difference between ENV-308 and GLP-1 drugs was the lack of gastrointestinal side effects, including nausea and vomiting. Because of this, ENV-308 could potentially help people who had to stop taking GLP-1s due to severe side effects, making it easier to preserve both weight loss and other health improvements.

"We believe the major unmet need now is not in yet another drug that can deliver large rapid weight loss. There's many medicines that can do that now, but the unmet need, as defined by clinicians and by patients, is maintaining that weight and maintaining the metabolic benefits over the long term," Colluru said. "We're going to study the effects of a novel first-in-class mechanism of action to see whether we can lock in the long-term benefits of GLP-1s — not just the weight loss benefits, but the holistic metabolic health benefits."

"There is a need there, of course, for people who cannot tolerate GLP-1s, or who have contraindications for GLP-1s. There are about 40 molecules being investigated right now that somehow relate to GLP-1s," Lopez-Jimenez said. "There is hope on the horizon, and I think that this substance adds to that hope."

Lopez-Jimenez also said he'd like to see a direct assessment of ENV-308's effect on appetite, caloric intake, basal metabolic rate, and insulin or glucose. "The ultimate trial will be: Can people with obesity lose weight?" he said.

However, Lopez-Jimenez also noted that he's not sure if utilizing hormones produced during exercise will lead to weight loss. "It's an interesting thought, but it's an oversimplification because certainly it's not the only thing that is produced with exercise," he said. "Exercise is not necessarily the strategy we use to lose weight. It's caloric restriction, because it's easier not to eat that huge hamburger than going up 100 flights of stairs."

Meanwhile, Long was more optimistic about the potential of the medication. "When I think about exercise, listen, at some point it's going to happen. You're going to be able to therapeutically harness some aspect of biology because at the end of the day, it's just biology," he said. "And then we're going to look at this time as like, well, we were too closed-minded."