Lilly’s oral GLP-1 Orforglipron clears third Phase 3 trial, set for global obesity filings

New Delhi: Eli Lilly and Company has announced positive 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. In the trial, all three doses of orforglipron met the primary and all key secondary endpoints, delivering significant weight loss, meaningful A1C reductions, 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% (10.4 kg) compared to 2.2% (2.3 kg) with placebo using the efficacy estimand.¹ With the completion of ATTAIN-2, Lilly 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 world-renowned obesity specialist. “Orforglipron could help health care providers expand treatment options for patients who prefer oral therapies without compromising clinical results.”

In the ATTAIN-2 trial, orforglipron met the primary endpoint of superior body weight reduction compared to placebo. Participants taking the highest dose of orforglipron lost an average of10.4 kg (10.5%) at 72 weeks using the efficacy estimand. In a key secondary endpoint, orforglipron lowered A1C by 1.3% to 1.8% from a baseline of 8.1% across doses. In another key secondary endpoint, 75% of participants taking the highest dose of orforglipron achieved an A1C ≤ 6.5%, which is at or below the American Diabetes Association’s definition of diabetes.² Additionally, orforglipron showed clinically meaningful benefits across key cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure and triglycerides. In a pre-specified exploratory analysis, the highest dose of orforglipron reduced high-sensitivity C-reactive protein (hsCRP) levels, a marker of inflammation, by 50.6%.

“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., Lilly 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.”

 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 gastrointestinal­related and generally mild-to-moderate in severity. The most common adverse events for participants treated with orforglipron (6 mg, 12 mg and 36 mg, respectively) were nausea (20.1%,31.1% and 36.4%) vs. 8.4% with placebo, vomiting (12.8%, 20.2% and 23.1%) vs. 3.8% with placebo, diarrhea (21.3%, 24.8% and 27.4%) vs. 15.0% with placebo, constipation (17.7%, 21.1%and 22.4%) vs. 7.8% with placebo, and dyspepsia (9.1%, 15.4% and 10.9%) vs. 3.5% with placebo. Treatment discontinuation rates due to adverse events were 6.1% (6 mg), 10.6% (12 mg) and 10.6% (36 mg) for orforglipron vs. 4.6% with placebo. Overall treatment discontinuation rates were balanced across thetreatment groups with 19.1% (6 mg), 22.3% (12 mg) and 20.5% (36 mg) for orforglipron vs. 20.0% with placebo. No hepatic safety signal was observed.

As per company’s statement, the detailed ATTAIN-2 results will be presented at a future medical meeting and published in a peer­ reviewed journal.