A new oral approach to GLP-1 treatment helped overweight or obese adults lose up to 12 percent of their body weight in 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 medication that comes in pill form
Aleniglipron differs from currently available GLP-1 (glucagon-like peptide 1) drugs, such as semaglutide, which is sold as Ozempic and Wegovy. Rather than being an injectable peptide-based medication, aleniglipron is a small molecule drug taken orally and is being developed as a treatment for obesity.
GLP-1 medications work by mimicking the naturally occurring hormone GLP-1. Its effects include stimulating insulin secretion, reducing appetite and increasing feelings of satiety, which can promote weight loss.
Although existing peptide-based GLP-1 drugs can be very effective, access remains limited for many patients. These medications require injections, which creates an additional barrier for some people. They also pose storage (refrigeration) challenges and can be difficult and expensive 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 that it is a small molecule, meaning it is produced chemically and can be taken with or without food. Most of the medications we take, whether aspirin or blood pressure medications, are small molecules. They are chemicals that are structurally produced, and because of that, they can potentially be combined with other medications,” Kushner said.
Trial of aleniglipron in 230 adults
For the double-blind, placebo-controlled clinical trial, researchers evaluated the safety of aleniglipron in 230 adults (average age 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 a day, increasing the dose every four weeks, or received a placebo. Treatment continued for a total of 36 weeks.
At week 36, the average change in body weight from baseline reached -9.0 percent in the 45 milligram group, -10.7 percent in the 90 milligram group, and -12.1 percent in the 120 milligram group. The placebo group had a -0.5 percent change.
Side effects and next steps
Gastrointestinal side effects were generally mild to moderate in all treatment groups and became less common as the study progressed. Overall, 10.4 percent of participants stopped 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 found no concerns or new safety signals. We found a dose that appears to be effective, and dose escalation will slow further as we move through the Phase III trial to increase tolerability,” Kushner said.
This work was supported by Structure Therapeutics.