Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist.

Abstract

We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide1 receptor agonist (GLP-1 RA), in two studies (A and B). StudyA and studyB were phase1, randomized, crossover studies in healthy adults aged 18-65years and 21-70years, respectively. Participants received single (3mg, studyA) or multiple (16mg, studyB) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. StudyA included 12 participants (mean age 45.0years; male 66.7%); studyB included 34 participants (mean age 42.8years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in studyA, and 17.6% and 20.9% in studyB, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type2 diabetes or obesity. ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.