Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA) in healthy participants.
Materials and Method: This was a double-blind, placebo-controlled, Phase 1 study. Overtly healthy adults aged 18–65 years with body mass index of 20–40 kg⁄m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single-dose orforglipron, with 4 cohorts receiving escalating doses (0.3–6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to 4 different final target doses (2–24 mg).
Results: 92 participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract-related. Pharmacokinetics were ~dose proportional, and the mean t1⁄2 was 24.6–35.3 hours after a single dose (0.3–6 mg). On Day 28, the mean t1⁄2 was 48.1–67.5 hours across the dose range (2–24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron-treated participants, compared to a reduction of 2.4 kg with placebo (p < 0.05). Orforglipron decreased fasting glucose levels across Days 1–28, and gastric emptying was delayed on Day 28.
Conclusion: Orforglipron’s long half-life (25–68 hours) allows once-daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP-1RAs, which supports continued clinical development.