Lilly's oral GLP-1 orforglipron consistent with injectable GLP-1 medicines

The topline Phase 3 results from Eli Lilly ACHIEVE-1 study, evaluating the safety and efficacy of orforglipron compared to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone, have revealed that orforglipron met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks.

Orforglipron is 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. If approved, the company is confident in its ability to launch orforglipron worldwide without supply constraints.

In the first Phase 3 trial of the ACHIEVE program, orforglipron lowered A1C by an average of 1.3% to 1.6% from a baseline of 8.0%, using the efficacy estimand. In a key secondary endpoint, more than 65% of participants taking the highest dose of orforglipron achieved an A1C less than or equal to 6.5%, which is below the American Diabetes Association's (ADA) defined threshold for diabetes.

In an additional key secondary endpoint, participants taking orforglipron lost an average of 16.0 lbs (7.9%) at the highest dose. Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction was not yet attained.

For the treatment-regimen estimand, each dose of orforglipron led to statistically significant A1C reductions. In the key secondary endpoint for body weight, 12 mg and 36 mg doses led to statistically significant reductions:

• A1C reduction: 1.2% (3 mg), 1.5% (12 mg), 1.5% (36 mg), 0.4% (placebo)

• Percent weight reduction: 4.5% (3 mg), 5.8% (12 mg), 7.6% (36 mg), 1.7% (placebo)

• Weight reduction: 4.2 kg (9.3 lbs; 3 mg), 5.2 kg (11.5 lbs; 12 mg), 7.2 kg (15.8 lbs; 36 mg), 1.5 kg (3.4 lbs; placebo)

iBody weight secondary endpoints for orforglipron 3 mg were not controlled for type 1 error. iiMean body weight reduction did not reach plateau by 40 weeks.

The overall safety profile of orforglipron in ACHIEVE-1 was consistent with the established GLP-1 class. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity. The most common adverse events for participants treated with orforglipron (3 mg, 12 mg and 36 mg, respectively) were diarrhoea (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 vs. 1% with placebo. No hepatic safety signal was observed.

The ACHIEVE-1 results will be presented at ADA's 85th Scientific Sessions and published in a peer-reviewed journal. More results from the ACHIEVE Phase 3 clinical trial program will be shared later this year, along with findings from the ATTAIN Phase 3 clinical trial program evaluating orforglipron for weight management. Lilly expects 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 anticipated in 2026. 

Orforglipron

Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake. Orforglipron was discovered by Chugai Pharmaceutical and licensed by Lilly in 2018.

The ACHIEVE Phase 3 global clinical development program for orforglipron has enrolled more than 6,000 people with type 2 diabetes across five global registrational trials. The programme began in 2023 with results anticipated later this year and into 2026