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Treatment of autosomal dominant hypocalcemia Type 1 with the calcilytic NPSP795 (SHP635)

Scott Roberts, Mary, Gafni, Rachel I, Brillante, Beth, Guthrie, Lori C, Streit, Jamie, Gash, David, Gelb, Jeff, Krusinska, Eva, Brennan, Sarah C, Schepelmann, Martin, Riccardi, Daniela, Ezuan Bin Khayat, Mohd, Ward, Donald T, Nemeth, Edward F, Rosskamp, Ralf and Collins, Michael T 2019. Treatment of autosomal dominant hypocalcemia Type 1 with the calcilytic NPSP795 (SHP635). Journal of Bone and Mineral Research 34 (9) , pp. 1609-1618. 10.1002/jbmr.3747
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Abstract

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain‐of‐function mutations of the calcium‐sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to 4 distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration‐dependent manner up to 129% above baseline (p=0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol and little calcium supplementation. NPSP795 was generally safe and well‐tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half‐maximally activated (EC50) at lower concentrations of extracellular calcium (Ca2+o) compared to wild type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose‐dependent manner, and thus, serves as proof‐of‐concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype, or the response to calcilytics, suggesting that other parameters impact the response to the drug.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Publisher: American Society for Bone and Mineral Research
ISSN: 0884-0431
Date of First Compliant Deposit: 2 April 2019
Date of Acceptance: 21 March 2019
Last Modified: 19 Oct 2019 22:34
URI: http://orca-mwe.cf.ac.uk/id/eprint/121317

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