Eli Lilly and Company (LLY) published positive topline Phase 3 results from the ACHIEVE-1 study, which compared the safety and efficacy of orforglipron to placebo in persons with type 2 diabetes with inadequate glycemic control with diet and exercise alone. Orforglipron is the first oral small molecule glucagon-like peptide-1 (GLP-1) receptor agonist to effectively complete a Phase 3 study, with no food or water limitations. If approved, the business is confident in its capacity to commercialize orforglipron globally with no supply issues. This would support Lilly’s objective to eliminate chronic diseases like as type 2 diabetes, which is anticipated to affect 760 million individuals by 2050.
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,
David A. Ricks
In the ACHIEVE program’s first Phase 3 trial, orforglipron met the primary goal of greater A1C reduction compared to placebo at 40 weeks, lowering A1C by an average of 1.3% to 1.6% from a baseline of 8.0%, according to the efficacy estimate. In a major secondary objective, more than 65% of people taking the maximum dose of orforglipron had an A1C of less than or equal to 6.5%, which is below the American Diabetes Association’s (ADA) established diabetes threshold.
In another important secondary goal, subjects on orforglipron lost an average of 16.0 pounds (7.9%) at the maximum dose. Given that the subjects had not yet hit a weight plateau when the trial concluded, it seems that full weight loss had not yet occurred.
For the treatment-regimen estimand, each dose of orforglipron resulted in statistically significant A1C decreases. In the primary secondary goal of body weight, dosages of 12 mg and 36 mg resulted in statistically significant decreases.
Orforglipron’s overall safety profile in ACHIEVE-1 was in line with the established GLP-1 class. The most commonly reported adverse effects were gastrointestinal in nature and were mild to moderate in intensity. The most common adverse events for participants treated with orforglipron (3 mg, 12 mg, and 36 mg, 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, 6% (3 mg), 4% (12 mg), and 8% (36 mg) of patients stopped using orforglipron due to adverse events, compared to 1% for placebo. There were no liver safety signals detected.
The ACHIEVE-1 findings will be presented at the ADA’s 85th Scientific Sessions and published in a peer-reviewed journal. More data from the ACHIEVE Phase 3 clinical trial program will be released later this year, as will findings from the ATTAIN Phase 3 clinical trial program, which is investigating orforglipron for weight management. Lilly plans to submit orforglipron for weight management to worldwide regulatory bodies by the end of this year, with a submission for type 2 diabetes treatment expected in 2026.
ACHIEVE-1 and ACHIEVE Clinical Trial Program
A 40-week, randomized, double-blind, placebo-controlled study called ACHIEVE-1 (NCT05971940) compares the safety and effectiveness of orforglipron 3 mg, 12 mg, and 36 mg as monotherapy versus placebo in people with type 2 diabetes whose glycemic control is insufficient with diet and exercise alone. 559 participants from the United States, China, India, Japan, and Mexico were randomized in a 1:1:1:1 ratio to receive either a placebo or 3 mg, 12 mg, or 36 mg of forglipron. The study’s goal was to show that orforglipron (3 mg, 12 mg, and 36 mg) is better than a placebo at lowering the A1C from baseline after 40 weeks in type 2 diabetics who have not taken any anti-diabetic drugs for at least 90 days before visit 1 and are new to insulin therapy. Participants in the study had a BMI of at least 23 kg/m2 and a HbA1c between 7.0 and 9.5%. The study began with a dose of 1 mg of orforglipron once daily for all participants in the orforglipron treatment arms. The dose was then increased gradually at 4-week intervals until the final randomized maintenance dose was 3 mg (via a 1 mg step), 12 mg (via steps at 1 mg, 3 mg, and 6 mg), or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg, and 24 mg). Dosing was not allowed to be flexible.
Orforglipron
Small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist, orforglipron (or-for-GLIP-ron), is an experimental medication that can be given once daily at any time of day without affecting one’s ability to consume food or fluids. 5. Chugai Pharmaceutical Co., Ltd. made the discovery of orforglipron, and Lilly granted a license for it in 2018. Together, Chugai and Lilly released the molecule’s preclinical pharmacology findings. 6. For the treatment of type 2 diabetes and weight control in individuals who are obese or overweight and have at least one weight-related medical condition, Lilly is conducting Phase 3 research on orforglipron. Additionally, it is being researched as a possible treatment for adult obesity-related hypertension and obstructive sleep apnea.
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