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

• Published in: Diabetes therapy Vol. 15; no. 4; pp. 819 - 832
• Main Authors: Ma, Xiaosu, Liu, Rong, Pratt, Edward J., Benson, Charles T., Bhattachar, Shobha N., Sloop, Kyle W.
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01.04.2024; Springer; Springer Nature B.V
• Subjects: Analysis; Cardiology; Care and treatment; Complications and side effects; Diabetes; Diagnosis; Diet therapy; Dosage and administration; Endocrinology; Food; Glucagon; Internal Medicine; Medicine; Medicine & Public Health; NCT03929744; NCT05110794; Obesity; Oral administration; Original Research; Peptides; Pharmacokinetics; Risk factors; Type 2 diabetes; United States; Glycemic control; Food-effect; Obesity; GLP-1; Prandial state; Orforglipron; T2D
• ISSN: 1869-6953; 1869-6961
• DOI: 10.1007/s13300-024-01554-1

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.