Ovize Michel, Allas Soraya, Culler Michael D, Milano Stephane, Ouldrouis Taha, Sumeray Mark, van de Wetering de Rooij Jeroen, Mannstadt Michael
Endocr Connect. 2025 Jun 19;14(6). doi: 10.1530/EC-24-0464. Print 2025 Jun 1.
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.
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.
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).
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.
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.
NCT05239221.
本研究评估了依奈博帕肽（AZP-3601）的安全性、耐受性、药效学（PD）和药代动力学（PK），该药物是一种开发用于治疗甲状旁腺功能减退症的新型甲状旁腺激素受体1激动剂。
这是一项随机、双盲、安慰剂对照研究。104名健康志愿者被招募入7个单剂量递增（SAD）队列和5个多剂量递增（MAD）队列。
PK参数包括达峰时间、Cmax、曲线下面积（AUC）和半衰期。PD参数包括白蛋白校正血清钙（sCa）、血清磷（sPh）、血清内源性甲状旁腺激素、24小时尿钙排泄量（24 h-uCa）、钙分数排泄率（FECa）和骨转换标志物（s-CTX和P1NP）。
未发生严重不良事件。所有不良事件均为轻度至中度。依奈博帕肽的AUC和Cmax随剂量增加而增加。最大血浆浓度达峰时间为5至20分钟。SAD显示sCa剂量依赖性增加，sPh降低，同时血清内源性甲状旁腺激素减少。MAD表明能迅速达到最大PD效应，并在全天维持sCa水平。尿钙排泄量并未随依奈博帕肽剂量增加而增加。治疗期间P1NP和s-CTX未发生变化。
尽管依奈博帕肽半衰期较短，但其PD效应持续时间延长。这些数据表明，依奈博帕肽每日给药一次可能为甲状旁腺功能减退症患者提供血清钙的持续控制。最近已完成并发表了一项针对甲状旁腺功能减退症患者的开放标签2期研究，并已启动3期研究。
NCT05239221。
