A phase 1 single and multiple ascending dose study of orforglipron in Japanese participants with type 2 diabetes

We aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of orforglipron in Japanese participants with type 2 diabetes.

This was a double-blind, placebo-controlled, randomized, phase 1 study. In Part A, participants received single doses of orforglipron (2 or 3 mg) or placebo. In Part B, participants received multiple ascending doses of daily oral orforglipron (final target doses: 12, 24, and 45 mg) or placebo for 12 weeks.

Parts A and B enrolled 23 and 60 participants, respectively. The most common treatment-emergent adverse events were gastrointestinal events of mild severity. No severe or serious adverse events were reported. At week 12, median t_max was 5.92-8.00 h, and mean terminal half-life was 51.8-76.1 h. Following multiple ascending doses, orforglipron groups had greater mean reductions from baseline to week 12 in glycemic parameters (fasting glucose: orforglipron 12 mg -64.8 mg/dL, 24 mg -61.1 mg/dL, 45 mg -65.6 mg/dL, placebo 7.4 mg/dL; glycated hemoglobin: orforglipron 12 mg -2.16%, 24 mg -2.17%, 45 mg -2.28%, placebo 0.67%) and body weight (orforglipron 12 mg -2.9 kg, 24 mg -6.3 kg, 45 mg -4.8 kg, placebo 0.3 kg) compared with placebo.

In Japanese participants, safety, pharmacokinetic, and pharmacodynamic results were similar to those of previous orforglipron studies. The safety and tolerability of orforglipron were also consistent with those of other glucagon-like peptide-1 receptor agonists. Orforglipron is a potential new treatment option for Japanese patients with type 2 diabetes.