Eli Lilly and Company has reported detailed Phase 3 results from three ACHIEVE trials showing that its oral GLP-1, Foundayo (orforglipron), delivered superior A1C reductions and weight loss in adults with type 2 diabetes. The small molecule oral GLP-1, which can be taken without food or water restrictions, is being evaluated across the ACHIEVE program, and Lilly plans to submit Foundayo for type 2 diabetes to the U.S. Food and Drug Administration by the end of the second quarter under the Commissioner’s National Priority Review Voucher.
In the landmark head-to-head ACHIEVE-3 trial, Foundayo 9 mg and 17.2 mg outperformed oral semaglutide 7 mg and 14 mg on the primary and all key secondary endpoints at 52 weeks. Foundayo lowered A1C by an average of 1.9% (9 mg) and 2.2% (17.2 mg) compared with 1.1% (7 mg) and 1.4% (14 mg) for oral semaglutide, representing a 57.1% greater relative reduction at the highest dose comparison. More patients on the highest dose of Foundayo achieved an A1C below 5.7% (37.1% vs 12.5%), the threshold for normal blood sugar. Foundayo also produced greater weight loss, with mean reductions of 14.6 lbs (6.7%; 9 mg) and 19.7 lbs (9.2%; 17.2 mg) compared with 7.9 lbs (3.7%; 7 mg) and 11.0 lbs (5.3%; 14 mg) on oral semaglutide, a 73.6% greater relative weight loss at the highest dose comparison.
ACHIEVE-2 showed Foundayo achieved superior glycemic control and weight loss versus dapagliflozin over 40 weeks from a mean baseline A1C of 8.1%. Foundayo lowered A1C by up to an average of 1.7% versus 0.8% with dapagliflozin, with up to 68.6% of patients on the highest dose reaching an A1C of 6.5% or less compared with 21.6% on dapagliflozin. Weight loss with Foundayo averaged 7.1 lbs (3.5%; 2.5 mg), 12.8 lbs (6.3%; 9 mg), and 15.0 lbs (7.3%; 17.2 mg) versus 6.0 lbs (3.0%) with dapagliflozin.
In ACHIEVE-5, which evaluated Foundayo added to titrated insulin glargine versus placebo, the drug again delivered significant benefits over 40 weeks from a mean baseline A1C of 8.5%. Foundayo lowered A1C by up to an average of 2.1% versus 0.8% with placebo, and up to 69.1% of participants on Foundayo 9 mg achieved an A1C of 6.5% or less, compared with 11.1% on placebo. Patients treated with Foundayo lost an average of 4.9 lbs (2.7%; 2.5 mg), 11.0 lbs (5.8%; 9 mg), and 11.5 lbs (6.1%; 17.2 mg), whereas those on placebo gained 1.1 lb (0.6%). Across ACHIEVE-3, ACHIEVE-2 and ACHIEVE-5, Foundayo was associated with clinically meaningful improvements in key cardiovascular risk factors, including non-HDL, HDL, VLDL and total cholesterol, systolic blood pressure and triglycerides.
Investigators highlighted the significance of the head-to-head data in ACHIEVE-3 as the first comparison between two oral GLP-1 receptor agonists in type 2 diabetes, with orforglipron demonstrating greater A1C and weight reductions than oral semaglutide at approved diabetes doses. The consistent efficacy across ACHIEVE-2 and ACHIEVE-5 supports the potential for earlier use of oral GLP-1 receptor agonists as a foundation of type 2 diabetes care. Lilly’s cardiometabolic development leadership noted that for the millions of people who prefer an oral therapy that can be taken at any time of day, Foundayo could represent an attractive first-line primary care option.
The overall safety and tolerability profile of Foundayo in the Phase 3 program was consistent with prior studies of GLP-1–based therapies. The most common adverse events were gastrointestinal, including nausea, diarrhea, vomiting, dyspepsia and decreased appetite. Discontinuation rates due to adverse events in ACHIEVE-3 were 8.7% and 9.7% with Foundayo 9 mg and 17.2 mg versus 4.5% and 4.9% with oral semaglutide; in ACHIEVE-2 they were 9.2%, 10.8% and 12.4% with 2.5 mg, 9 mg and 17.2 mg versus 1.2% with dapagliflozin; and in ACHIEVE-5 they were 3.6%, 7.6% and 9.6% with 2.5 mg, 9 mg and 17.2 mg versus 3.6% with placebo. Lilly said its planned FDA submission will also draw on data from the ACHIEVE-1 and ACHIEVE-4 studies.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox!
Sign up now!