Eli Lilly announces Phase 3 ATTAIN-2 trial results for oral GLP-1 agonist orforglipron in obesity and type 2 diabetes

Eli Lilly and Company announced topline results from the Phase 3 ATTAIN-2 trial evaluating orforglipron, an investigational oral GLP-1 receptor agonist, in adults with obesity or overweight and type 2 diabetes.

According to the company, all three doses of orforglipron met the primary and all key secondary endpoints, delivering weight loss, reductions in A1C, and improvements in cardiometabolic risk factors at 72 weeks. For the primary endpoint, orforglipron 36 mg, taken once per day without food and water restrictions, lowered weight by an average of 10.5 per cent (10.4 kg) compared to 2.2 per cent (2.3 kg) with placebo using the efficacy estimand. With the completion of ATTAIN-2, Lilly stated it now has the full clinical data package required to initiate global regulatory submissions for orforglipron.

“Based on my experience leading clinical trials in obesity and diabetes, these data show the potential for orforglipron to offer an efficacy, safety, and tolerability profile consistent with the injectable GLP-1 class,” said Louis J. Aronne, MD, FACP, DABOM, founder and Chair Emeritus of the American Board of Obesity Medicine, former president of The Obesity Society, Fellow of the American College of Physicians, and obesity specialist. “Orforglipron could help health care providers expand treatment options for patients who prefer oral therapies without compromising clinical results.”

In ATTAIN-2, orforglipron met the primary endpoint of superior body weight reduction compared to placebo. Participants taking the highest dose lost an average of 10.4 kg (10.5 per cent) at 72 weeks using the efficacy estimand. A key secondary endpoint showed that orforglipron lowered A1C by 1.3 per cent to 1.8 per cent from a baseline of 8.1 per cent across doses. Additionally, 75 per cent of participants taking the highest dose achieved an A1C ≤ 6.5 per cent, which is at or below the American Diabetes Association’s definition of diabetes. Orforglipron also showed benefits across cardiovascular risk factors including non-HDL cholesterol, systolic blood pressure and triglycerides. A pre-specified exploratory analysis indicated the highest dose reduced high-sensitivity C-reactive protein (hsCRP) levels by 50.6 per cent.

For the treatment-regimen estimand, each dose of orforglipron showed statistically significant improvements across endpoints. Participants on orforglipron achieved body weight reductions of -5.1 per cent (6 mg), -7.0 per cent (12 mg) and -9.6 per cent (36 mg) compared to -2.5 per cent with placebo. Body weight reductions of ≥10 per cent were observed in 22.6 per cent (6 mg), 31.2 per cent (12 mg), 45.6 per cent (36 mg) of participants, versus 9.0 per cent with placebo. Reductions of ≥15 per cent were seen in 6.8 per cent (6 mg), 14.4 per cent (12 mg), and 26.0 per cent (36 mg) compared to 3.0 per cent with placebo.

A1C reductions were -1.2 per cent (6 mg), -1.5 per cent (12 mg), -1.7 per cent (36 mg), and -0.5 per cent with placebo. Percentages of participants achieving A1C <7 per cent were 64.6 per cent (6 mg), 75.9 per cent (12 mg), 75.5 per cent (36 mg), compared to 30.5 per cent with placebo. For A1C ≤6.5 per cent, the results were 52.5 per cent (6 mg), 57.6 per cent (12 mg), 66.6 per cent (36 mg), and 15.4 per cent with placebo.

“The ATTAIN-2 results reinforce the potential for orforglipron, as a once-daily oral, to deliver meaningful weight loss and A1C reduction, consistent with similar landmark trials for injectable GLP-1s,” said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health. “With these positive data in hand, we are moving with urgency toward global regulatory submissions to potentially meet the needs of patients who are waiting. If approved, we are ready to offer a convenient, once-daily pill that can be scaled globally – removing barriers and redefining how obesity is treated around the world.”

Lilly reported that the overall safety profile of orforglipron in ATTAIN-2 was consistent with the established GLP-1 receptor agonist class. The most commonly reported adverse events were gastrointestinal-related and generally mild-to-moderate. The most common adverse events for participants treated with orforglipron (6 mg, 12 mg and 36 mg) were nausea (20.1 per cent, 31.1 per cent and 36.4 per cent) vs. 8.4 per cent with placebo, vomiting (12.8 per cent, 20.2 per cent and 23.1 per cent) vs. 3.8 per cent with placebo, diarrhoea (21.3 per cent, 24.8 per cent and 27.4 per cent) vs. 15.0 per cent with placebo, constipation (17.7 per cent, 21.1 per cent and 22.4 per cent) vs. 7.8 per cent with placebo, and dyspepsia (9.1 per cent, 15.4 per cent and 10.9 per cent) vs. 3.5 per cent with placebo.

Treatment discontinuation rates due to adverse events were 6.1 per cent (6 mg), 10.6 per cent (12 mg) and 10.6 per cent (36 mg) for orforglipron vs. 4.6 per cent with placebo. Overall treatment discontinuation rates were 19.1 per cent (6 mg), 22.3 per cent (12 mg), and 20.5 per cent (36 mg) for orforglipron vs. 20.0 per cent with placebo. No hepatic safety signal was observed.

Lilly stated that detailed ATTAIN-2 results will be presented at a future medical meeting and published in a peer-reviewed journal.

Orforglipron is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken without restrictions on food and water intake. It was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together. Lilly is running Phase 3 studies on orforglipron for type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnoea and hypertension in adults with obesity.

ATTAIN-2 (NCT05872620) is a Phase 3, 72-week, randomised, double-blind, placebo-controlled trial comparing orforglipron 6 mg, 12 mg and 36 mg as monotherapy with placebo in adults with obesity or overweight and type 2 diabetes. The trial randomised over 1,600 participants across the U.S., Argentina, Australia, Brazil, China, Czechia, Germany, Greece, India, South Korea and Puerto Rico. The primary objective was to demonstrate that orforglipron (6 mg, 12 mg, 36 mg) is superior to placebo in mean body weight change from baseline at 72 weeks in people with a BMI ≥27.0 kg/m² and type 2 diabetes who are on stable treatment with diet/exercise or up to three oral antihyperglycaemic medications.

The ATTAIN Phase 3 global clinical development programme for orforglipron has enrolled more than 4,500 people with obesity or overweight across two global registration trials.