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 being developed for the treatment of hypoparathyroidism.

Design: This was a randomized, double-blind, placebo-controlled study. 104 healthy volunteers were recruited into 7 single ascending dose (SAD) and 5 multiple ascending dose (MAD) cohorts.

Methods: PK parameter 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, 24hr-urinary excretion of calcium (24h-uCa), fractional excretion of calcium (FECa) and bone turnover markers (s-CTX and P1NP).

Results: there were no serious adverse events (SAE). All adverse events (AE) were of mild to moderate intensity. AUC and Cmax of eneboparatide increased with increasing doses. Time to maximum plasma concentration was 5-20 minutes. 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.