Orforglipron (LY3502970), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1a, blinded, placebo‐controlled, randomized, single‐ and multiple‐ascending‐dose study in healthy participants

• DOI: 10.1111/dom.15184
• Publication Date: 2023-06-24T06:06:15Z
• Authors: Edward Pratt; Xiaosu Ma; Rong Liu; Deborah Robins; Axel Haupt; Tamer Coskun; Kyle W. Sloop; Charles Benson
• Keywords: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; 16. Peace & justice; Glucagon-Like Peptide-1 Receptor; Healthy Volunteers; 3. Good health

AbstractAimTo 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 MethodsThis was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 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 four 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 four different final target doses (2‐24 mg).ResultsNinety‐two 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 approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 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 to 28, and gastric emptying was delayed on Day 28.ConclusionsOrforglipron'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.