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

Introduction: 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 peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B).

Methods: Study A and study B were phase 1, randomized, crossover studies in healthy adults aged 18-65 years and 21-70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) 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 (C_max), time of C_max (t_max), and half-life (t_1/2) associated with terminal rate constant. AUC and C_max 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.

Results: Study A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and C_max were lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, t_1/2 and median t_max 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.

Conclusion: 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 type 2 diabetes or obesity.

Trial registration: ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

Keywords: Food-effect; GLP-1; Glycemic control; Obesity; Orforglipron; Prandial state; T2D.

Fig. 1

a Study A design. There was a washout period of ≥ 5 days between each dose. In each treatment period, participants remained in the clinical research unit at least until completion of assessments on day 4 and returned for an outpatient visit on day 5. Participants were randomly assigned to one of two treatment sequences. Treatment sequence 1—Period 1: Fasted treatment; Period 2: Food-effect treatment or fed treatment. Treatment sequence 2—Period 1: Food-effect treatment or fed treatment; Period 2: Fasted treatment. OFG orforglipron. b Study B design. PK pharmacokinetic

Fig. 2

a Plasma concentration profile of orforglipron (3 mg) after single oral administration to healthy subjects in the fasted and fed states in study A. b Plasma concentration profile of orforglipron (16 mg) after multiple oral administration to healthy participants in the fasted and fed states in study B. Data in graph are arithmetic mean (+ 1 SD). OFG orforglipron