Oral Orforglipron Maintains Weight Loss After Switch From Injectable Therapies

Topline data were announced from a phase 3 trial evaluating orforglipron, an oral glucagon-like peptide-1 (GLP-1) receptor agonist, for weight maintenance after initial treatment with the highest tolerated doses of Wegovy^® (semaglutide) or Zepbound^® (tirzepatide).

The randomized, double-blind, placebo-controlled ATTAIN-MAINTAIN study (ClinicalTrials.gov Identifier: NCT06584916) compared the safety and efficacy of once daily orforglipron with placebo for the maintenance of body weight reduction in adults with obesity or overweight with weight-related comorbidities who previously completed the SURMOUNT-5 trial.  

Study participants were randomly assigned 3:2 to receive orforglipron at the maximum tolerated dose (24mg or 36mg) or placebo, alongside a healthy diet and physical activity. The primary endpoint was the percent maintenance of body weight reduction in participants who achieved plateau (<5% body weight change between weeks 60 and 72) with either Zepbound or Wegovy in SURMOUNT-5. 

Findings at week 52 showed patients who switched to orforglipron from Wegovy maintained their previously achieved weight loss with an average difference of 0.9kg (from 95.0kg at switch to 95.9kg at 52 weeks). Similarly, patients who switched to orforglipron from Zepbound maintained their previously achieved weight loss with an average difference of 5.0kg (from 90.9kg at switch to 95.9kg at 52 weeks).

Results from post-hoc analyses at week 24 (the last time point before placebo-treated patients were eligible for rescue therapy with orforglipron) showed that the change in baseline body weight for patients switching to orforglipron from Wegovy was -0.1kg vs 9.4kg with placebo. For patients switching to orforglipron from Zepbound, the change from baseline was 2.6kg vs 9.1kg, respectively. 

The safety and tolerability profile was consistent with previous phase 3 studies.The most common adverse events reported were mild to moderate gastrointestinal-related side effects. No hepatic safety signal was identified.

“ATTAIN‑MAINTAIN showed that orforglipron, a once daily oral GLP-1, helped people maintain the weight they worked hard to lose,” said Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health. “Participants in this study were able to switch directly from the highest tolerated doses of available injectable therapies onto oral doses of orforglipron.”

Full results from the ATTAIN-MAINTAIN study will be presented at a future medical meeting and published in a peer-reviewed journal next year. 

According to Lilly, a New Drug Application for orforglipron for the treatment of adults with obesity or overweight has been submitted to the Food and Drug Administration.