Eli Lilly’s blockbuster drug in waiting, Mounjaro, hits two targets to treat type 2 diabetes and spark weight loss. The drug still awaits an FDA decision on its use for shedding weight, but Lilly is already following up with a potential successor and the pharmaceutical giant now has clinical data showing this molecule’s approach of addressing three targets leads to an even greater magnitude of weight loss.

The Lilly drug, retatrutide, led to an average 17.5% weight reduction from baseline (41.2 pounds or 18.7 kilograms) across four doses tested over 24 weeks in a Phase 2 study. Weight loss continued with longer treatment. At 48 weeks, the average weight reduction was 24.2% (57.8 pounds or 26.2 kg). These results were presented Monday during the annual meeting of the American Diabetes Association (ADA) and published simultaneously in The New England Journal of Medicine (NEJM).

The first generation of peptide drugs for diabetes and weight loss mimic a hormone called GLP-1, stimulating the body’s production of insulin to regulate blood sugar levels. Lilly markets one such drug, the once-weekly injectable medicine Trulicity. Ozempic, from rival Novo Nordisk is also a GLP-1 agonist. For weight loss, Novo Nordisk sells a different dose of the peptide drug under the brand name Wegovy.

Lilly designed Mounjaro to pair GLP-1 agonism with the activation of another hormone, GIP. Last year, the FDA approved Mounjaro for treating type 2 diabetes. In Phase 3 clinical testing for weight management in patients who have type 2 diabetes, this molecule led to an average 15.7% weight reduction (34.4 pounds or 15.6 kg). Those results were presented last Saturday during the ADA meeting and published in the journal The Lancet. The data are part of the package now under FDA review for chronic weight management.

With retatrutide, Lilly adds one more mechanism, the activation of glucagon receptors. These receptors also play a role in regulating blood sugar. Retatrutide, known in earlier stages of development as LY3437943, was evaluated in a placebo-controlled Phase 2 study that enrolled 388 patients who are obese or overweight and have weight-related conditions (but not type 2 diabetes). Participants were randomly assigned to groups administered different doses of the once-weekly injectable experimental therapy or a placebo for 48 weeks. The main goal was to show the percentage change in weight loss from baseline measured at 24 weeks.

The most common adverse events reported in the study were gastrointestinal problems, which were dose related and classified as mostly mild to moderate in severity, according to the NEJM article. The gastrointestinal effects were mitigated by lowering the starting dose. The article also noted that retatrutide led to dose-dependent increases in heart rate that peaked at 24 weeks and declined after that point.

“We believe that combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed this level of weight reduction,” Dan Skovronsky, Lilly’s chief scientific and medical officer, and president of Lilly Research Laboratories, said in a prepared statement. “These Phase 2 data have given us confidence to further explore the potential of retatrutide in Phase 3 trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively.”

The Phase 3 program will evaluate retatrutide in chronic weight management, obstructive sleep apnea, and knee osteoarthritis in those who are obese and overweight. Lilly plans four Phase 3 studies, each of which could support the submission of an application seeking regulatory approval.

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