A First-in-Human Single- and Multiple-Ascending Dose Study Evaluating Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Oral Nonpeptide GLP-1 Receptor Agonist in Healthy Subjects

Background: LY3502970 (LY) is a novel, highly potent, orally bioavailable nonpeptide GLP-1 receptor agonist (RA) , and a potential alternative to injectable therapies or oral peptides whose absorption is affected by food or water intake. Objectives of this study were to evaluate safety, tolerability, pharmacokinetics (PK) , and pharmacodynamics (PD) of single and multiple doses of LY in healthy subjects. Methods: This was a multi-part, randomized, double-blind, phase 1 study (NCT03929744) . In Part A, subjects received placebo or single-dose LY with 5 cohorts receiving escalating doses. In Part B, subjects received 4 weeks of daily placebo or repeated oral LY escalating weekly to 5 different final target doses. Overtly healthy adults 18-65 yrs old with body mass index 20-40 kg/m2 and A1c <6.5% were eligible. Results: Of 133 subjects enrolled, 32 participated in Part A (mean age 43.4 yrs) and 60 participated in Part B (mean age 42.5 yrs) . There were no deaths or serious adverse events. Most common (occurring in ≥3 subjects) treatment-emergent adverse events in Part A were vomiting, nausea, and headache, and in Part B were nausea, headache, and constipation. PK was approximately proportional; mean Cmax in Part A was 1.4-14.9 ng/mL and mean t½ was 24.6-35.3 hrs across the dose range after single dose. In Part B, mean Cmax was 11.1-99.6 ng/mL and mean t½ was 48.1-67.5 hrs on Day 28 across the dose range. Single and repeated doses of LY decreased mean fasting glucose compared to baseline across Days 1-28. In Part B, significant reductions in body weight from baseline were observed after 4 weeks in 4 cohorts (except for the lowest dose) . Gastric emptying was delayed after initial LY dose but was no longer evident at Day 28. Conclusion: This oral nonpeptide had safety and PD marker profiles similar to injectable GLP-1 RAs and PK enabling once daily dosing. These data support further clinical development. Disclosure E.J.Pratt: Employee; Eli Lilly and Company. X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Liu: Employee; Eli Lilly and Company. D.A.Robins: Employee; Eli Lilly and Company. K.Sloop: Employee; Eli Lilly and Company. C.Benson: None.