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

Abstract

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.

Keywords: bone; calcium; hypoparathyroidism; kidney; parathormone.

Figure 1

Pharmacokinetics of eneboparatide in SAD. Serum concentration of eneboparatide (in pg/mL) is expressed as a function of time after a single subcutaneous administration at doses (n = 6–8/group) ranging from 10 to 120 μg/day. SAD: single ascending dose. Error bars are SEM (standard error of the mean). Eneboparatide was almost undetectable beyond 2 h after administration. The LLOQ was 50 pg/mL.

Figure 2

Pharmacodynamics of albumin-adjusted serum calcium in SAD. Albumin-adjusted serum calcium is expressed as a function of time after a single subcutaneous abdominal administration of placebo or eneboparatide at doses ranging from 20 to 120 μg (n = 6–8/group). Error bars are SEM. There was an early dose-dependent increase of serum calcium, with values remaining significantly higher than baseline at 24 h for doses of eneboparatide above 40 μg/day.

Figure 3

Pharmacodynamics of albumin-adjusted serum calcium in MAD. (A) Mean albumin-adjusted serum calcium during a 14-day treatment period. The mean daily pre-dose albumin-adjusted serum calcium is presented throughout a 14-day treatment period and a subsequent 6 days follow-up phase. Placebo or eneboparatide, at doses ranging from 20 to 120 μg/day, was administered subcutaneously in the abdomen (n = 6–8/group). There was a dose-dependent increase of serum calcium, with values remaining significantly higher than baseline from day 2–3 after the start of the treatment up through the end of treatment on day 14. Return to near baseline levels occurred approximately 2–3 days after the last administration of eneboparatide. Error bars are SEM (standard error of the mean). (B) Variations of the mean albumin-adjusted serum calcium during day 14 (last day of treatment). When compared to placebo, administration of eneboparatide induced a dose-dependent increase in the mean albumin-adjusted serum calcium that remained stable throughout 24 h. Error bars are SEM.

Figure 4

Concomitant effect of increased doses of eneboparatide on serum and urinary calcium. (A) Increasing the dose of eneboparatide resulted in an expected rise in albumin-adjusted serum calcium (ADsCa). Concomitantly, the 24 h urinary excretion of calcium (24 h-uCa) did not significantly increase. Error bars are SEM. (B) FECA was normal (<2%) at baseline. There were no significant changes in FECa whatever the dose of AZP-360. Error bars are SEM.

Figure 5

Effect of eneboparatide on markers of bone formation and resorption. Serum levels of P1NP (A) and CTX (B), markers of bone formation and resorption, respectively, were assessed at baseline after 14 days of daily administration of increasing doses of eneboparatide and 5 days after cessation of this treatment (FU: follow-up). Data are presented as changes from baseline values in milligrammes per decilitre (ng/dL). As compared with placebo, eneboparatide did not significantly change the serum levels of either P1NP or CTX. The moderate rise in P1NP levels after stopping the administration of eneboparatide is likely due to the resumption of endogenous PTH release. Error bars are SEM.