Eli Lilly and Company announced encouraging topline results from the ATTAIN-MAINTAIN Phase 3 trial evaluating orforglipron, an investigational once-daily oral small molecule GLP-1 receptor agonist. The study assessed weight maintenance over 52 weeks in participants who had previously completed 72 weeks of treatment with the highest tolerated doses of Wegovy (semaglutide) or Zepbound (tirzepatide) in the SURMOUNT-5 trial. Participants who were eligible were re-randomized to receive either orforglipron or placebo. At the one-year mark, orforglipron met its primary and all key secondary endpoints, demonstrating superior maintenance of weight reduction compared to placebo when combined with a healthy diet and regular physical activity.

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Kenneth Custer, Ph.D., Executive Vice President and President of Lilly Cardiometabolic Health, explained that obesity is a chronic and progressive condition and sustaining weight loss remains a major challenge for many individuals. He highlighted that the ATTAIN-MAINTAIN trial showed participants could maintain their weight loss after switching directly from the highest tolerated doses of injectable therapies to oral orforglipron. Custer emphasized that if approved, orforglipron could provide a convenient oral alternative for millions of people worldwide living with obesity, helping them continue their long-term weight management journey.

The trial showed that participants who switched from Wegovy to orforglipron maintained their previous weight loss with an average difference of 0.9 kg compared to placebo. Those switching from Zepbound maintained their weight loss with an average difference of 5.0 kg. Post-hoc analyses at 24 weeks showed similar trends, with participants switching to orforglipron from Wegovy demonstrating minimal weight change while placebo participants experienced notable weight regain. Likewise, participants switching from Zepbound maintained most of their weight loss compared to significant gains in the placebo group.

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Orforglipron was generally well tolerated, with most adverse events being mild to moderate gastrointestinal issues. Discontinuation rates due to adverse events were low and similar between placebo and treatment groups, with no hepatic safety concerns observed. Lilly plans to present detailed ATTAIN-MAINTAIN results at a future medical meeting and in a peer-reviewed publication next year. The company has also submitted a new drug application to the U.S. FDA for orforglipron as a treatment for adults with obesity or overweight, and the therapy has been granted a Commissioner’s National Priority Review Voucher.

Orforglipron is an oral, once-daily small molecule GLP-1 receptor agonist that can be taken without restrictions on food or water. It was discovered by Chugai Pharmaceutical and licensed by Lilly in 2018. The molecule is under investigation not only for obesity and weight management but also for type 2 diabetes, obstructive sleep apnea, hypertension, knee osteoarthritis in adults with obesity, stress urinary incontinence, and cardiovascular and renal outcomes.

The ATTAIN-MAINTAIN trial was a 52-week, randomized, double-blind, placebo-controlled study enrolling 376 participants in the United States who previously completed the SURMOUNT-5 trial. Participants were assigned to once-daily oral orforglipron or placebo and titrated to a maximum tolerated dose. Participants who regained 50 percent or more of their prior weight loss were eligible for rescue orforglipron therapy. The trial was designed to demonstrate superior maintenance of body weight reduction among participants who had reached a weight plateau in SURMOUNT-5.

SURMOUNT-5 was a 72-week Phase 3b trial comparing Zepbound and Wegovy in adults with obesity or overweight with at least one weight-related comorbidity but without diabetes. Participants followed a reduced-calorie diet and increased physical activity and were randomized to receive maximum tolerated doses of either Zepbound or Wegovy. At 72 weeks, Zepbound achieved an average weight reduction of 20.2 percent, while Wegovy resulted in a 13.7 percent reduction, confirming Zepbound’s superior efficacy.

Overall, Lilly’s ATTAIN-MAINTAIN results highlight that orforglipron can help patients sustain meaningful weight loss when transitioning from injectable GLP-1 therapies, offering the potential for a convenient oral treatment option for long-term obesity management.

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