By VETTAPHARMA reporter – Derek Roche: Eli Lilly reported detailed results from three pivotal Phase 3 ACHIEVE studies showing that its oral GLP-1 receptor agonist Foundayo (orforglipron) delivered superior glycemic control and weight loss in adults with type 2 diabetes, including a head-to-head comparison against oral semaglutide. The data were presented at the American Diabetes Association (ADA) 86th Scientific Sessions.
In the 52-week ACHIEVE-3 trial, Foundayo 9 mg and 17.2 mg outperformed oral semaglutide 7 mg and 14 mg across the primary endpoint and all key secondary endpoints. Patients receiving Foundayo achieved mean A1C reductions of 1.9% and 2.2%, respectively, compared with 1.1% and 1.4% for oral semaglutide. At the highest dose comparison, Foundayo produced a 57.1% greater relative reduction in A1C.
Weight-loss outcomes also favored Foundayo. Patients receiving the 17.2 mg dose lost an average of 19.7 pounds (9.2%) versus 11.0 pounds (5.3%) with oral semaglutide 14 mg, representing a 73.6% greater relative weight reduction. Additionally, 76.8% of patients receiving Foundayo 17.2 mg achieved an A1C of 6.5% or lower, compared with 50.9% for oral semaglutide 14 mg, while 37.1% achieved an A1C below 5.7% versus 12.5% with oral semaglutide.
The ACHIEVE-2 study evaluated Foundayo against dapagliflozin in 962 adults with inadequately controlled type 2 diabetes receiving metformin. Foundayo reduced A1C by up to 1.7% from a baseline of 8.1%, compared with 0.8% for dapagliflozin. Up to 68.6% of participants receiving the highest Foundayo dose achieved an A1C of 6.5% or lower, versus 21.6% for dapagliflozin. Average weight reductions ranged from 7.1 to 15.0 pounds across Foundayo dose groups compared with 6.0 pounds for dapagliflozin.
In ACHIEVE-5, which enrolled 546 adults inadequately controlled on insulin glargine, Foundayo demonstrated superior efficacy versus placebo. A1C reductions reached 2.1% from a baseline of 8.5%, compared with 0.8% for placebo. Up to 69.1% of participants receiving Foundayo 9 mg achieved an A1C of 6.5% or lower versus 11.1% for placebo. Patients receiving Foundayo experienced weight reductions of 4.9 to 11.5 pounds, while placebo recipients gained approximately 1.1 pound.
Across all three studies, Foundayo demonstrated clinically meaningful improvements in cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, triglycerides, and systolic blood pressure. The safety profile was consistent with previous studies, with gastrointestinal adverse events such as nausea, diarrhea, vomiting, dyspepsia, and decreased appetite reported most frequently. Treatment discontinuation rates due to adverse events generally increased with higher doses.
Lilly stated that, based on findings from ACHIEVE-1 through ACHIEVE-5, it plans to submit Foundayo for the treatment of type 2 diabetes to the U.S. Food and Drug Administration by the end of the second quarter of 2026 under the Commissioner’s National Priority Review Voucher program.
Quick FAQs
1. What Is Foundayo (Orforglipron)?
Foundayo is a once-daily oral, non-peptide GLP-1 receptor agonist that can be taken without food or water restrictions. It is currently approved in the U.S. for chronic weight management and is being developed for type 2 diabetes and several other indications.
2. What Did Lilly Announce?
Lilly reported detailed Phase 3 ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5 results showing that Foundayo improved blood sugar control and weight loss in adults with type 2 diabetes, including superior performance versus oral semaglutide, dapagliflozin, and placebo.
3. What Are The ACHIEVE Trials?
ACHIEVE-2 was a 40-week active-controlled study versus dapagliflozin (n=962), ACHIEVE-3 was a 52-week head-to-head study versus oral semaglutide (n=1,698), and ACHIEVE-5 was a 40-week placebo-controlled study in patients receiving insulin glargine (n=546).
4. What Is Type 2 Diabetes?
Type 2 diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels resulting from insulin resistance and impaired insulin secretion, often requiring long-term glycemic management to reduce complications.
5. What Were The Key Results?
In ACHIEVE-3, Foundayo reduced A1C by up to 2.2% and weight by up to 19.7 pounds, outperforming oral semaglutide. In ACHIEVE-2 and ACHIEVE-5, A1C reductions reached 1.7% and 2.1%, respectively, with significantly higher proportions of patients achieving A1C goals of 6.5% or lower.
6. Why Is This Important?
The data provide the first Phase 3 head-to-head comparison between two oral GLP-1 therapies and suggest that Foundayo may offer a highly effective oral treatment option for patients with type 2 diabetes. The results support Lilly’s planned regulatory submission for a type 2 diabetes indication in 2026.
