HMN 2026: How New oral GLP-1 drug delivers up to 12% weight loss in 36 weeks

A new strategy for delivering GLP-1 drugs to patients with obesity or who were overweight resulted in up to a 12% reduction in body weight after 36 weeks, according to a randomized phase II clinical trial published in Nature Medicine.

Robert Kushner, MD, professor emeritus of medicine in the Division of Endocrinology, Metabolism and Molecular Medicine at Northwestern University, was a co-author of the study.

Unlike currently available GLP-1 drugs (glucagon-like peptide 1), including semaglutide, sold as Ozempic and Wegovy, aleniglipron is a small-molecule drug that is taken orally and is currently in development for the treatment of obesity. All GLP-1 drugs mimic the effects of the naturally occurring GLP-1 hormone, stimulating insulin secretion, suppressing appetite and increasing satiety to promote weight loss.

Despite their effectiveness, currently available peptide-based GLP-1 drugs are not widely accessible. Those medications must be injected, which limits patient access because of how the medication is administered, as well as challenges with storing the medication (refrigeration) and scalability issues because of manufacturing and cost.

In contrast, small-molecule GLP-1 drugs can be taken orally and manufactured on a larger scale, addressing gaps in both accessibility and treatment outcomes, Kushner said.

“The difference with aleniglipron is it’s a small molecule, which means it’s chemically made and can 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,” Kushner said.

In the current placebo-controlled, double-blind clinical trial, the investigators evaluated the safety of aleniglipron in 230 adults (average age 50) with obesity or overweight at 38 U.S. medical centers.

Participants were randomized to three dose-level cohorts: 45, 90 or 120 milligrams. Participants were instructed to take aleniglipron orally once daily and then increase their dose every four weeks with aleniglipron or placebo for a total of 36 weeks.

At week 36, body-weight change from baseline was minus 9.0% in the 45-milligram group, minus 10.7% in the 90-milligram group and minus 12.1% in the 120-milligram group, compared with minus 0.5% for the placebo group.

Gastrointestinal side effects were mild to moderate across all patient groups and decreased in frequency over time. Across all groups, 10.4% of patients discontinued treatment, and no events of drug-induced liver injury were reported.

The findings support the development of aleniglipron for the treatment of obesity and further testing of the medication’s efficacy in an upcoming phase III trial, Kushner said.

“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 the phase III trial to increase tolerability,” Kushner said.

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