New Oral GLP-1 Treatment Aleniglipron Yields Significant Weight Loss in Clinical Trial

A recent randomized phase II clinical trial published in Nature Medicine demonstrates that an innovative oral treatment for obesity, aleniglipron, enables adults with obesity or overweight to lose as much as 12 percent of their body weight over 36 weeks. Co-authored by Robert Kushner, MD, professor emeritus of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, the study involved 230 participants across 38 U.S. medical centers.

The Oral Approach to GLP-1 Treatment

Aleniglipron is a small-molecule medication that differs from existing GLP-1 drugs, such as semaglutide (marketed as Ozempic and Wegovy), which are peptide-based and administered via injection. Instead, aleniglipron is taken orally, potentially eliminating barriers associated with injectable medications, such as accessibility and storage challenges.

GLP-1 drugs function by mimicking the natural GLP-1 hormone, promoting insulin secretion, reducing appetite, and enhancing sensations of fullness. While peptide-based medications can be effective, their injectable nature limits patient access, prompting the need for oral alternatives like aleniglipron.

Kushner noted, “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.” This formulation could also allow for combinations with other medications.

Results from the Phase II Trial

In the placebo-controlled, double-blind trial, participants were randomly assigned to three dosage groups of aleniglipron at 45, 90, or 120 milligrams, with treatment continuing for 36 weeks. By the end of the study, average weight loss from baseline was reported at -9.0 percent for the 45 milligrams group, -10.7 percent for the 90 milligrams group, and -12.1 percent for the 120 milligrams group. The placebo group exhibited a weight change of -0.5 percent.

Side Effects and Future Directions

While gastrointestinal side effects occurred, they were generally mild to moderate and lessened over time. Approximately 10.4 percent of participants discontinued treatment during the trial, with no instances of drug-induced liver injury reported.

Kushner affirmed the promising nature of aleniglipron for obesity treatment, highlighting the absence of 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,” he added, indicating ongoing development efforts supported by Structure Therapeutics.