Phase 1 clinical trial of eneboparatide, a novel PTH receptor 1 agonist.

Objective: This study evaluated the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of eneboparatide (AZP-3601), a novel agonist of the PTH receptor 1 developed for the treatment of hypoparathyroidism. Design: This was a randomized, double-blind, placebo-controlled study. One-hundred four healthy volunteers were recruited into seven single ascending dose (SAD) and five multiple ascending dose (MAD) cohorts. Methods: PK parameters were time to peak, Cmax, area under the curve (AUC) and half-life. PD parameters included albumin-adjusted serum calcium (sCa), serum phosphorus (sPh), serum endogenous PTH, 24 hr urinary excretion of calcium (24 h-uCa), fractional excretion of calcium (FECa) and bone turnover markers (s-CTX and P1NP). Results: There were no serious adverse events. All adverse events were of mild-to-moderate intensity. AUC and Cmax of eneboparatide increased with increasing doses. Time to maximum plasma concentration was 5-20 min. SAD showed a dose-dependent increase of sCa and decrease of sPh associated with a reduction of serum endogenous PTH. MAD demonstrated a rapid access to maximal PD effects and maintained levels of sCa throughout the day. Urinary excretion of calcium did not increase as a function of the dose of eneboparatide. P1NP and s-CTX did not change over the treatment period. Conclusion: The PD effects of eneboparatide were prolonged despite the short half-life. These data suggest that eneboparatide may provide sustained control of serum calcium in patients with hypoparathyroidism with once daily dosing. An open-label phase 2 study in patients with hypoparathyroidism has been recently completed and published and a phase 3 study has been initiated. Clinical Trial Registration Number: NCT05239221.