An experimental pill could eventually help people maintain their weight and muscle after stopping GLP-1 medications.11

The daily oral pill aims to preserve lean muscle and mimic the effects of a hormone that can suppress appetite. However, clinical trials are still ongoing, and most of the benefits have only been observed in animal studies.

How ENV-308 May Help Control Appetite

Created by the biotechnology company Enveda, ENV-308 is the first drug in human trials to mimic the effects of N-lactoyl-phenylalanine (Lac-Phe), a metabolite induced by intense physical exercise.12 The molecule suppresses appetite and regulates the weight-loss effects of metformin, a medication commonly used to treat type 2 diabetes.3

“Lac-Phe has been implicated in appetite regulation and metabolic effects,” Holly Lofton, MD, the director of the medical weight management program at the NYU Grossman School of Medicine, told Verywell. “But the natural molecule that we make isn’t staying around our bodies long enough to really function conveniently as a drug. So that’s why they’re replicating it in a lab to try to develop this ENV-308.”

The phase 1 trial enrolled 88 healthy adults and evaluated ENV-308’s safety and tolerability. The trial also measured the drug’s impact on leptin, a hormone that normally reduces food intake and increases energy expenditure. However, people with obesity could develop chronically elevated leptin levels, and the brain can stop responding to it, which is known as leptin resistance.1

Phase 1 found that ENV-308 caused rapid reductions in leptin levels, with the greatest decreases occurring in people with the highest leptin levels.4 This suggests that the drug is improving leptin sensitivity, potentially making the hormone more effective at regulating food intake and body mass.

Early Trial Did Not Find Common GI Side Effects

In animal studies, ENV-308 also prevented weight regain and preserved lean muscle mass during weight loss, even after GLP-1 treatment was discontinued.1

“That’s going to be really important for people who can’t actively exercise during weight loss. Do we want everybody to eat less and move more? Absolutely. But what about a bilateral amputee who doesn’t have legs? This could be the start of offering individualized medications based on what the patient needs,” said Catherine Varney, DO, a physician in family medicine and obesity medicine at UVA Health and associate professor of family medicine at the University of Virginia School of Medicine.

It’s unclear whether ENV-308 will preserve muscle and prevent weight regain in humans, but these effects will be examined in the Phase 2 trial.

Enveda, the pharmaceutical company developing ENV-308, said the experimental drug could offer additional benefits, noting that adults who took it did not experience gastrointestinal issues such as nausea or vomiting, which are common side effects of GLP-1.5

Varney noted that more research is needed to confirm whether gastrointestinal side effects could occur with ENV-308.

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ENV-308 Doesn’t Have the Same Weight Loss Effect as GLP-1

ENV-308 may help keep weight off after discontinuing GLP-1 treatment, but it won’t likely have a comparable weight loss effect, says Lofton.

“The fact that you’re getting Lac-Phe with ENV-308 could mean that we have better maintenance for weight that’s been lost than we do right now, when we discontinued GLP-1,” Lofton said.

She said that ENV-308 won’t disrupt the GLP-1 industry and instead praised the idea of developing more than one medication for obesity. Various weight loss drugs are being clinically tested, including retatrutide, which was recently found to help people lose an average of 28.3% of their body weight over a period of 80 weeks in a Phase 3 trial.67

“We still have an obesity issue in America and around the world. So we’re beginning to change the narrative around obesity as a weight loss goal, but a chronic condition that needs long-term disease management,” Lofton said. “We may need multiple therapies for long-term maintenance. ENV-308 is really interesting because it potentially addresses that in a different way.”

ENV-308 Wouldn’t Replace the Benefits of Exercise

Despite ENV-308’s potential to preserve lean mass and prevent weight regain, it would not replace the benefits of exercise, Varney said.

“Exercise is necessary because it’s good for your heart, lungs, circulation, sleep, and weight maintenance,” she added. “When these weight loss medications are studied, they are always studied in combination with a reduced-calorie diet and exercise. So the medications will work best when combined with that.”

ENV-308 is still in the early stages of clinical testing and could take at least three to five years until it can be reviewed and approved by the Food and Drug Administration, Varney said.