A new oral approach to GLP-1 treatment helped 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.
Robert Kushner, MD, ’82 GME, professor emeritus of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, was a co-author of the study.
A GLP-1 Drug That Comes as a Pill
Aleniglipron differs from currently available GLP-1 drugs (glucagon-like peptide 1) such as semaglutide, which is sold as Ozempic and Wegovy. Instead of being a peptide-based injectable medication, aleniglipron is a small-molecule drug taken by mouth and is being developed as a treatment for obesity.
GLP-1 drugs work by mimicking the naturally occurring GLP-1 hormone. Their effects include stimulating insulin secretion, reducing appetite and increasing feelings of fullness, which can support weight loss.
Although existing peptide-based GLP-1 medications can be highly effective, access remains limited for many patients. These drugs require injections, creating an additional barrier for some people. They also pose storage challenges (refrigeration) and can be difficult and costly to manufacture at the scale needed to meet demand.
Small-molecule GLP-1 drugs could address some of those limitations because they can be taken orally and may be easier to manufacture in large quantities, Kushner said.
“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,” Kushner said.
Testing Aleniglipron in 230 Adults
For the placebo-controlled, double-blind clinical trial, researchers evaluated the safety of aleniglipron in 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 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.
Side Effects and Next Steps
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.
Kushner said the results support continued development of alenglipron 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,” Kushner said.
This work was supported by Structure Therapeutics.