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Endocrine Abstracts (2024) 99 OC2.3 | DOI: 10.1530/endoabs.99.OC2.3

ECE2024 Oral Communications Oral Communications 2: Calcium and Bone | Part I (6 abstracts)

A translational approach to investigate the mechanism whereby eneboparatide induces prolonged calcium normalization in patients with chronic hypoparathyroidism

Guillaume Ravel 1 , Rakesh Datta 2 , Stephane Milano 1 , Michel Ovize 1 , Soraya Allas 1 , Myriam Aouadi 1 & Michael Culler 2


1Amolyt Pharma, Écully, France; 2Amolyt Pharma, Cambridge, United States


Maintaining normal serum and urinary calcium in patients with chronic hypoparathyroidism (cHP) remains a therapeutic challenge. Parathyroid hormone (PTH) replacement therapy is not ideal due to its short half-life and transient activation of the PTH 1 receptor (PTH1R). Eneboparatide is a hybrid analog of PTH and PTH-related peptide specifically designed to induce prolonged activation of the PTH1R. Despite a short half-life, eneboparatide is able to normalize serum and urinary calcium levels over a full 24 hours in cHP patients. To gain deeper insight into the mechanism whereby eneboparatide provides sustained calcium normalization, we analyzed tissue distribution and retention of eneboparatide in comparison to natural PTH(1-34) following subcutaneous injection in rats. Quantitative whole-body autoradiography in rats treated with radiolabeled eneboparatide and PTH(1-34) revealed similar rapid elimination from the circulation and accumulation of both compounds in tissues expressing PTH1R, with highest levels observed in renal cortex. However, 6 hours postdose, 38.6% of eneboparatide remained in renal cortex, while only 3.7% of PTH(1-34) was detectable. These results demonstrated a preferential retention of eneboparatide in the renal cortex, where the PTH1R regulates calcium reabsorption. We next assessed whether the eneboparatide tissue retention observed in vivo was due to prolonged binding to the PTH1R. Ligand binding to the PTH1R leads to conformational changes of the receptor from G protein-dependent (RG) to G protein-independent (R0). Using a specific PTH1R binding assay, we confirmed high affinity of eneboparatide for the R0 conformation compared to PTH(1-34) (1.5 nM vs 30.9 nM, respectively). We next investigated whether the strong affinity of eneboparatide for the R0 conformation translated into prolonged receptor activation. To mimic the rapid elimination from the circulation in vivo, we treated HEK293 cells overexpressing the human PTH1R with both ligands for 15 min and, after washing, continued incubation with media alone. As expected, activation of the PTH1R by both PTH(1-34) and eneboparatide led to a rapid and similar increase in cAMP. After removal of PTH(1-34), cAMP production returned to baseline in less than 1 hour. However, following removal of eneboparatide, cAMP production decreased gradually, and residual signal remained strikingly constant and detectable through the last time point measured, 16 hours. Our translational approach demonstrates the potential therapeutic advantage of eneboparatide over PTH(1-34) due to its ability to be retained in renal cortex, to induce a prolonged activation of the PTH1R and to maintain normal serum and urinary calcium over 24 hours in cHP patients.

Volume 99

26th European Congress of Endocrinology

Stockholm, Sweden
11 May 2024 - 14 May 2024

European Society of Endocrinology 

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