Kidney Week

Abstract: SA-PO0265

Eneboparatide Induces Normalization of Urinary Calcium in Hypoparathyroidism Through Prolonged PTH1R Activation

Session Information

• Pharmacology
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Gaume, Xavier, Discovery Biology, Alexion, AstraZeneca Rare Disease, Écully, France

Xavier Gaume, PhD

• Colman, Ellen, Global Medical Affairs, Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States

Ellen Colman, PharmD

• Aouadi, Myriam, Discovery Biology, Alexion, AstraZeneca Rare Disease, Écully, France

Myriam Aouadi, PhD

• Ravel, Guillaume, Clinical Pharmacology and Safety Sciences, Alexion, AstraZeneca Rare Disease, Écully, France

Guillaume Ravel, PharmD, PhD

• Allas, Soraya, Clinical Development, Alexion, AstraZeneca Rare Disease, Écully, France

Soraya Allas, MD, PhD

Background

In chronic hypoparathyroidism (HypoPT), parathyroid hormone (PTH) deficiency results in a decrease in the renal reabsorption of calcium, contributing to hypocalcemia, hypercalciuria, and subsequent kidney complications in the long term. Eneboparatide is a PTH 1 receptor (PTH1R) agonist in development for the treatment of chronic HypoPT. Despite a short circulating half-life, eneboparatide treatment led to normalization of urinary calcium (uCa) in animal models and in patients with chronic HypoPT in a phase 2 trial. Here, we investigated the mechanism whereby eneboparatide treatment leads to sustained biological effects.

Methods

We used a translational approach combining in vitro and in vivo analyses to compare the binding and activation of the PTH1R by eneboparatide vs PTH(1-34). The potency for the human PTH1R and PTH 2 receptor (PTH2R) was evaluated using a cell-based cyclic adenosine monophosphate (cAMP) assay. Binding affinity to the R⁰ conformation of the PTH1R was measured in vitro. To compare the kinetics of PTH1R activation by PTH(1-34) vs eneboparatide, cAMP was measured for 24 hours in human embryonic kidney (HEK293) cells. The uptake and accumulation of eneboparatide vs PTH(1-34) were examined using quantitative whole-body autoradiography (QWBA) following subcutaneous injection of ³H-labeled eneboparatide and PTH(1-34) in rats.

Results

Like PTH(1-34), eneboparatide activated both the PTH1R and PTH2R. Importantly, eneboparatide had higher affinity for the R⁰ conformation of the PTH1R than PTH(1-34). Eneboparatide treatment resulted in 20-24 hours of cAMP signaling vs 1 hour for PTH(1-34), indicative of sustained PTH1R activation. QWBA analyses showed rapid elimination from the circulation and accumulation of both compounds in tissues expressing PTH1R, with highest levels observed in renal cortex. However, 38.6% of eneboparatide vs 3.7% of PTH(1-34) remained in renal cortex after 6 hours, with 5% vs 0.9% remaining after 24 hours.

Conclusion

The ability of eneboparatide to remain bound to the R⁰ conformation of the PTH1R differentiates it from PTH(1-34) and provides the underlying mechanism whereby eneboparatide maintains sustained normalization of uCa in chronic HypoPT despite its short half-life. A phase 3 study is ongoing to further evaluate the effects of eneboparatide on kidney health in chronic HypoPT.

Funding

• Commercial Support – Alexion, AstraZeneca Rare Disease, Boston, MA, USA.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025k9t5ejgb