PE-16: Pharmacokinetics and Pharmacodynamics of Long-Acting GLP-2 Analogue Glepaglutide after Once-weekly Dosing in Adult Healthy Subjects

Introduction: Glepaglutide (ZP1848, glepaglutide1-39, Zealand Pharma) is a potent long-acting glucagon-like peptide-2 (GLP-2) analogue, comprised of 39 L-amino acids, and currently in phase-3 development for the treatment of short bowel syndrome Following subcutaneous (s.c.) injection of glepaglutide, 2 functionally active metabolites are formed (M1: glepaglutide1-34 and M2: glepaglutide1-35). As such, the clinical efficacy should be evaluated as the composite effect of all 3 compounds. A clinical phase-1 trial was conducted to characterize the pharmacokinetic (PK) and pharmacodynamics (PD) profile of glepaglutide in human. Methods: Fifteen healthy subjects (10 males), aged 25-58 years and with BMI of 20-30 kg/m2 received 10 mg glepaglutide s.c. once-weekly for 6 consecutive weeks. Blood samples were collected throughout the 6-week period. PK samples were analyzed for glepaglutide, M1 and M2 using a GLP-validated LC/MS/MS assay. The levels of citrulline, a circulating plasma PD marker for intestinal mucosal cell mass, were monitored. Compound exposure is expressed as area under the curve (AUC) and by the half-life (T1/2, both within the dosing interval). Values were computed for M1 and the constructed analyte “glepaglutide-total” = glepaglutide + M1 + M2, using a non-compartmental approach. As such “glepaglutide-total” represents the combined efficacy of glepaglutide and its 2 main metabolites. Safety and tolerability were assessed. Results: Glepaglutide, M1 and M2 were detected in plasma. All 3 compounds are potent GLP-2 receptor (GLP-2R) agonists. M1 was the main metabolite, accounting for 91% of “glepaglutide-total” based on AUC. The mean effective T1/2 for “glepaglutide-total” was 53±21 hours. Citrulline mean levels increased by 20±16 µM above baseline levels after 6 weeks dosing. Glepaglutide was well tolerated and no serious adverse events were reported. Conclusion: Following once-weekly s.c. dosing of 10 mg glepaglutide, the parent compound and 2 functionally active metabolites were detected. All 3 are potent agonists at the GLP-2R. Thus, the overall efficacy of glepaglutide is a composite of the 3 compounds with a T1/2 of 53 hours. Together data suggest 10 mg glepaglutide once-weekly could be an efficacious intestinotrophic therapy option.