What You Should Know:
– Eli Lilly and Company announced positive topline Phase 3 results from ACHIEVE-1, a study evaluating the safety and efficacy of orforglipron compared to placebo in adults with type 2 diabetes whose blood sugar was inadequately controlled through diet and exercise alone.
– Orforglipron stands out as the first oral small molecule glucagon-like peptide-1 (GLP-1) receptor agonist, taken without food and water restrictions, to successfully complete a Phase 3 trial.
– Lilly is confident in its ability to launch orforglipron worldwide without supply constraints, pending regulatory approval. This development aligns with the company’s ongoing mission to reduce the burden of chronic diseases like type 2 diabetes, a condition projected to affect an estimated 760 million adults globally by 2050.
ACHIEVE-1 Trial Results
The ACHIEVE-1 trial met its primary endpoint, demonstrating that orforglipron achieved superior A1C reduction compared to placebo at 40 weeks. Participants receiving orforglipron experienced an average A1C reduction of 1.3% to 1.6% from a baseline of 8.0%, based on the efficacy estimand.
Furthermore, the study met key secondary endpoints with results:
- Glycemic Control: More than 65% of participants on the highest dose (36 mg) of orforglipron achieved an A1C level of less than or equal to 6.5%, which is below the American Diabetes Association’s (ADA) defined threshold for diabetes.
- Weight Reduction: Participants taking the highest dose of orforglipron experienced an average weight loss of 16.0 lbs (7.9%). Notably, the study data suggests that participants had not yet reached a weight plateau at the conclusion of the 40-week period, indicating the potential for further weight reduction with continued treatment.
Analysis based on the treatment-regimen estimand further supported the efficacy of orforglipron, with each tested dose (3 mg, 12 mg, and 36 mg) leading to statistically significant A1C reductions compared to placebo. Similarly, the 12 mg and 36 mg doses demonstrated statistically significant reductions in body weight in the key secondary endpoint.
The observed A1C and weight reductions across the different doses were as follows:
Orforglipron Safety Profile
The overall safety profile of orforglipron in ACHIEVE-1 was consistent with the established GLP-1 receptor agonist class. The most frequently reported adverse events were gastrointestinal-related and generally ranged from mild to moderate in severity. The most common adverse events for participants treated with orforglipron at the 3 mg, 12 mg, and 36 mg doses, respectively, were diarrhea (19%, 21%, and 26% vs. 9% with placebo), nausea (13%, 18%, and 16% vs. 2% with placebo), dyspepsia (10%, 20%, and 15% vs. 7% with placebo), constipation (8%, 17%, and 14% vs. 4% with placebo), and vomiting (5%, 7%, and 14% vs. 1% with placebo). Overall treatment discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg), and 8% (36 mg) for orforglipron compared to 1% with placebo. Notably, no hepatic safety signal was observed during the trial.
Results and Next Steps
The detailed results from the ACHIEVE-1 study will be presented at the ADA’s 85th Scientific Sessions and published in a peer-reviewed journal. Lilly anticipates sharing further results from the broader ACHIEVE Phase 3 clinical trial program later this year and into 2026, alongside findings from the ATTAIN Phase 3 clinical trial program evaluating orforglipron for weight management. The company plans to submit orforglipron for weight management to global regulatory agencies by the end of this year, with the submission for the treatment of type 2 diabetes expected in 2026.
“ACHIEVE-1 is the first of seven Phase 3 studies examining the safety and efficacy of orforglipron across people with diabetes and obesity. We are pleased to see that our latest incretin medicine meets our expectations for safety and tolerability, glucose control and weight loss, and we look forward to additional data readouts later this year,” said David A. Ricks, Lilly chair and CEO, in a statement. “As a convenient once-daily pill, orforglipron may provide a new option and, if approved, could be readily manufactured and launched at scale for use by people around the world.”
