Lilly Orforglipron Helps Maintain Weight Loss After Injectables

 Topline results from the ATTAIN-MAINTAIN trial show that orforglipron, an investigational oral GLP-1 receptor agonist, helps people maintain weight loss after switching from an injectable, Eli Lilly announced today.

The phase 3 placebo-controlled study evaluated orforglipron for weight maintenance over 52 weeks after initial treatment for 72 weeks with the highest tolerated doses of Wegovy (semaglutide) or Zepbound (tirzepatide), in participants from the SURMOUNT-5 study who were offered the opportunity to be re-randomized to receive orforglipron or placebo. 

SURMOUNT participants had overweight or obesity, but not diabetes, plus at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease.

At 1 year, orforglipron met the primary and all key secondary endpoints compared to placebo, delivering superior weight maintenance as an adjunct to a healthy diet and physical activity in participants who achieved plateau with either Zepbound or Wegovy in SURMOUNT-5. Weight plateau was defined as < 5% body weight change between weeks 60 and 72 in SURMOUNT-5. 

Prespecified analyses at 52 weeks showed that participants who switched to orforglipron from Wegovy maintained their previously achieved weight loss with an average difference of 0.9 kg, whereas those who switched from Zepbound maintained their previously achieved weight loss with an average difference of 5.0 kg.

The ATTAIN-MAINTAIN trial randomized 376 participants in the US in a 3:2 ratio to receive either the maximum tolerated dose (MTD) of orforglipron (24 mg or 36 mg) or placebo, as an adjunct to healthy diet and physical activity.

The primary endpoint was to demonstrate that orforglipron is superior to placebo in maintaining body weight reduction in participants who achieved plateau with either Zepbound or Wegovy in the SURMOUNT-5 trial. 

In ATTAIN-MAINTAIN, participants were randomized to once-daily orforglipron 12 mg (or matching placebo), which was increased every 4 weeks until the randomized maintenance dose of 36 mg or the MTD was reached. Participants who regained 50% or more of their body weight after SURMOUNT-5 were treated with rescue orforglipron MTD.

Post-hoc analyses at 24 weeks, the last time point before placebo participants were eligible for orforglipron as rescue therapy, showed the change in body weight from ATTAIN-MAINTAIN baseline for participants switching to orforglipron from Wegovy was -0.1 kg vs 9.4 kg for placebo. Similarly, for those switching to orforglipron from Zepbound, the change from baseline was 2.6 kg vs 9.1 kg for placebo.

As shown in previous orforglipron phase 3 trials, the most common adverse events were gastrointestinal-related and generally mild-to-moderate in severity. Discontinuation rates due to adverse events for participants randomized to placebo or orforglipron were 4.8% (orforglipron from Wegovy), 7.6% (placebo from Wegovy), 7.2% (orforglipron from Zepbound) and 6.3% (placebo from Zepbound). No hepatic safety signal was observed.

Lilly has submitted a new drug application to the FDA for orforglipron for treating adults with obesity or overweight, and the drug was granted a Commissioner's National Priority Voucher from the FDA. 

Lilly anticipates that orforglipron could receive approval for its first indication as early as next year, a spokesperson told Medscape Medical News. 

https://www.medscape.com/viewarticle/orforglipron-helps-maintain-weight-loss-after-injectables-2025a1000zq2