Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).

Autor: Roberts MS; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA., Gafni RI; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA., Brillante B; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA., Guthrie LC; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA., Streit J; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA., Gash D; NPS Pharmaceuticals, Inc., Bedminster, NJ, USA., Gelb J; NPS Pharmaceuticals, Inc., Bedminster, NJ, USA., Krusinska E; NPS Pharmaceuticals, Inc., Bedminster, NJ, USA., Brennan SC; School of Biosciences, Cardiff University, Cardiff, UK.; School of Life and Environmental Science, University of Sydney, Sydney, NSW, Australia., Schepelmann M; School of Biosciences, Cardiff University, Cardiff, UK.; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria., Riccardi D; School of Biosciences, Cardiff University, Cardiff, UK., Bin Khayat ME; Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.; Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, Selangor, Malaysia., Ward DT; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria., Nemeth EF; MetisMedica, Toronto, ON, Canada., Rosskamp R; NPS Pharmaceuticals, Inc., Bedminster, NJ, USA., Collins MT; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2019 Sep; Vol. 34 (9), pp. 1609-1618. Date of Electronic Publication: 2019 Jul 26.
DOI: 10.1002/jbmr.3747
Abstrakt: 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 four 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 (Ca 2+ i ), and ERK and p38 MAPK 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 supplementation, 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 (EC 50 ) at lower concentrations of extracellular calcium (Ca 2+ o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC 50 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. © 2019 American Society for Bone and Mineral Research.
(© 2019 American Society for Bone and Mineral Research.)
Databáze: MEDLINE
Externí odkaz: