5 Late-Breaking Clinical Trials in Obesity to Watch at the ADA 85th Scientific Sessions, June 20-24, 2025

Orforglipron (Lilly) is an investigational, once-daily small molecule oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.

The ADA presentation will announce the full data for the phase 3 ACHIEVE 1 trial, following the positive topline data released in April 2025. Those data suggest the small molecule GLP-1 mimetic could compete with blockbuster weekly injectables for reducing weight, A1c. The reductions in both measures place orforglipron efficacy on par with Novo Nordisk's injectable semaglutide (Ozempic).

Other companies are vying to bring a nonpeptide incretin mimetic to market as well. Novo Nordisk is pursuing late-stage trials of an oral formulation of semaglutide and has begun phase 1 trials of amycretin, a potential first-in-class combination of an amylin and GLP-1 receptor agonist. Viking Therapeutics recently completed enrollment for a phase 2 trial of its oral antiobesity candidate, VK2735, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist.

CagriSema (Novo Nordisk) combines the long-acting amylin analogue cagrilintide and the glucagon like peptide-1 receptor agonist semaglutide, a novel pairing of peptides that share attributes supporting weight reduction that include slowed gastric emptying, reduced secretion of glucagon, and increased satiety.

“This is the next agent in that [dual agent] combination drug story. It will be helpful to see the REDEFINE data in the round and see what’s in store for future therapies in this field," Melanie J. Davies, MB, ChB, MD, said in an ADA news release. Davies, professor of diabetes medicine at the University of Leicester Diabetes Research Centre, United Kingdom, will present efficacy findings in REDEFINE 2, including continuous glucose monitoring, time in range, HbA1c, and other secondary endpoints.

The phase 2 BELIEVE study is investigating an intravenous formulation that combines bimagrumab, a monoclonal antibody that blocks activin type II receptors and stimulates skeletal muscle growth, with the GLP-1 RA semaglutide.

The loss of lean muscle mass can reach as much as 40% of total weight loss among individuals treated with GLP-1 RAs and has become a significant concern that is driving research for solutions. “Semaglutide mainly acts through appetite suppression through the central nervous system and peripheral mechanisms,” Steven B. Heymsfield, MD, professor of medicine at the Pennington Biomedical Research Center, said in an ADA news release. “Bimagrumab was developed for sarcopenia—muscle wasting with age. It binds to activin receptors to stimulate muscle growth. Activin receptors are also present on fat cells.”

Heymsfield will present the efficacy and safety results of BELIEVE. The study builds on earlier data showing a 20.5% decline in fat mass, a 3.6% increase in lean mass, a 9 cm decline in waist circumference, and 6.5% decline in body weight for bimagrumab versus placebo.

Eli Lilly acquired Versanis Bio, which held the rights to bimagrumab, in 2023.

Semaglutide is a GLP1-RA that is administered subcutaneously once weekly. The incretin mimetic has shown positive cardiometabolic effects including glycemic, weight and cardiac benefits in individuals with and without type 2 diabetes. Retrospective data of off-label use has suggested benefits in reducing HbA1c, weight and insulin requirements

ADJUST-T1D is investigating semaglutide as add-on treatment for type 1 diabetes in individuals with overweight or obesity. Study participants are using automated insulin delivery systems for regular treatment and will receive semaglutide or placebo as a weekly injection. Researchers are assessing the ability of semaglutide to improve glycemic control, reduce insulin dosage, and promote weight loss in this population.

MariTide (Amgen) is a bispecific GLP-1 receptor agonist and glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist delivered subcutaneously once a month. Phase 2 findings, presented in 2024 as pooled results from several treatment arms that had been summarized, showed the dual-acting agent led to significant weight loss at 52 weeks.

At the ADA meeting, researchers will present the "unpooled data for each of the treatment arms in people with obesity and details of cardiometabolic measures for people with and without type 2 diabetes,” coauthor Ania M. Jastreboff, MD, PhD, associate professor of endocrinology at Yale University School of Medicine, Director for the Yale Obesity Research Center, and Co-Director of the Yale Center for Weight Management, said in an ADA news release.

Participants in the cohort with type 2 diabetes loss less weight than those with without type 2 diabetes, not an uncommon outcome, according to coauthor Harold Bays, MD, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center. “What we really want to know is how and why the two cohorts stack up the way they did," Bays said in the release.