On August 26, 2025, Eli Lilly and Company announced that their small molecule GLP-1 receptor agonist, Orforglipron, achieved positive results in the third phase 3 clinical trial, ATTAIN-2. The trial met its primary endpoint and all key secondary endpoints, and Lilly is preparing to submit a marketing application.

Efficacy Results

In the 36mg high-dose group, Orforglipron treatment for 72 weeks resulted in a 10.5% weight reduction, with an 8.3% reduction after placebo adjustment. HbA1c levels decreased by 1.8%, with a 1.7% reduction after placebo adjustment.

Per-Protocol Analysis

In the 36mg high-dose group, Orforglipron treatment for 72 weeks led to a 9.6% weight reduction, with a 7.1% reduction after placebo adjustment. HbA1c levels decreased by 1.7%, with a 1.2% reduction after placebo adjustment.

Percent weight reduction: -5.1% (-5.3 kg; -11.7 lbs; 6 mg), -7.0% (-7.2 kg; -15.9 lbs; 12 mg), -9.6% (-9.6 kg; -21.2 lbs; 36mg), -2.5% (-2.7 kg; -6.0 lbs; placebo)

• Percentage of participants achieving body weight reductions of ≥10%: 22.6% (6 mg), 31.2% (12 mg), 45.6% (36 mg), 9.0%(placebo)

• Percentage of participants achieving body weight reductions of ≥15%: 6.8% (6 mg), 14.4% (12 mg), 26.0% (36 mg), 3.0%(placebo)

• A1C reduction: -1.2% (6 mg), -1.5% (12 mg), -1.7% (36 mg), -0.5% (placebo)

• Percentage of participants achieving A1C <7%: 64.6% (6 mg), 75.9% (12 mg), 75.5% (36 mg), 30.5% (placebo)

• Percentage of participants achieving A1C ≤6.5%: 52.5% (6 mg), 57.6% (12 mg), 66.6% (36 mg), 15.4% (placebo)

Safety data

The overall safety profile of orforglipron in ATTAIN-2 was consistent with the established GLP-1 receptor agonist class. The most commonly reportedadverse events were gastrointestinal-related and generally mild-to-moderate in severity. The most common adverse events for participants treatedwith 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% and23.1%) 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% withplacebo, 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 the treatmentgroups 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.

While the phase 3 clinical data for Orforglipron fell short of expectations, it is unlikely to affect its approval. However, it may have a profound impact on the competitive landscape. In China, several companies have made progress with their small molecule GLP-1 receptor agonists:

• Hengrui's small molecule GLP-1 is being developed overseas through NewCo

• Sincere Biotech's small molecule GLP-1 has been licensed to AstraZeneca

• Hansoh Pharma's small molecule GLP-1 has been licensed to Merck

• Shijiazhuang Pharmaceutical Group's small molecule GLP-1 has been licensed to Madrigal

• Innovent Biologics' small molecule GLP-1 has entered the clinical stage

These latecomers have shown advantages in preclinical studies, but it remains to be seen whether they can surpass Eli Lilly's Orforglipron in clinical trials.

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Reference

https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-successful-third-phase-3-trial