New GLP-1 Pill Delivers Up to 12% Weight Loss in 36 Weeks

A groundbreaking oral approach to GLP-1 treatment has been shown to help adults with obesity or overweight lose as much as 12 percent of their body weight over 36 weeks, according to a randomized phase II clinical trial published in Nature Medicine.

The study, led by Robert Kushner, MD, professor emeritus of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, involved 230 adults (average age of 50 years) with obesity or overweight at 38 U.S. medical centers.

Participants were randomly assigned to one of three dose groups: 45, 90, or 120 milligrams. They took the new oral GLP-1 pill, aleniglipron, orally once each day, with doses increased every four weeks, or received placebo. Treatment continued for a total of 36 weeks.

By week 36, average body-weight change from baseline reached −9.0 percent in the 45 milligrams group, -10.7 percent in the 90 milligrams group, and -12.1 percent in the 120 milligrams group. The placebo group had a -0.5 percent change.

According to Dr. Kushner, the results support continued development of aleniglipron as an obesity treatment and further evaluation of its effectiveness in an upcoming phase III trial.

“We didn’t find any concerns; no new safety signals. We found a dose that seems to be effective, and the dose escalation will be slowed down further as we go into phase III trial to increase tolerability,” Dr. Kushner said.

Unlike currently available GLP-1 drugs such as semaglutide, which is sold as Ozempic and Wegovy, aleniglipron is a small-molecule drug taken by mouth. This makes it a more accessible and convenient option for patients, as it eliminates the need for injections.

Small-molecule GLP-1 drugs could address some of the limitations of existing peptide-based GLP-1 medications, which require injections and pose storage challenges. They can also be difficult and costly to manufacture at the scale needed to meet demand.

“The difference with aleniglipron is it’s a small molecule, which means it’s chemically made and could be taken with or without food. Most medications we take, whether it’s aspirin or blood pressure medicine, are small molecules. They’re chemicals that you make structurally, and because of that you can potentially combine them with other medications,” Dr. Kushner explained.

For the placebo-controlled, double-blind clinical trial, researchers evaluated the safety of aleniglipron in participants with obesity or overweight. Gastrointestinal side effects were generally mild to moderate across the treatment groups and became less frequent as the study progressed. Overall, 10.4 percent of participants discontinued treatment, and researchers reported no cases of drug-induced liver injury.

According to Dr. Kushner, the results are promising and support continued development of aleniglipron as an obesity treatment. Further evaluation of its effectiveness in an upcoming phase III trial will provide more insight into its potential as a treatment for obesity.

The study was supported by Structure Therapeutics, and the results were published in Nature Medicine under the title “Oral small molecule GLP-1 receptor agonist aleniglipron in people with overweight or obesity: a randomized, double-blind, placebo-controlled phase 2b trial.”

Researchers reported that aleniglipron was well-tolerated and had a favorable safety profile. The most common side effects were gastrointestinal, and they became less frequent as the study progressed. The researchers also reported that the dose escalation will be slowed down further as they go into phase III trial to increase tolerability.