Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635).Citation formats

Standard

Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635). / Ward, Donald.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2019.

Research output: Contribution to journalArticle

Harvard

Ward, D 2019, 'Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635).', Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. https://doi.org/10.1002/jbmr.3747

APA

Ward, D. (2019). Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. https://doi.org/10.1002/jbmr.3747

Vancouver

Ward D. Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019. https://doi.org/10.1002/jbmr.3747

Author

Ward, Donald. / Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635). In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019.

Bibtex

@article{7c119083254a4840ac565b5cfe3d19ab,
title = "Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635).",
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",
author = "Donald Ward",
year = "2019",
doi = "10.1002/jbmr.3747",
language = "English",
journal = "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
issn = "0884-0431",
publisher = "John Wiley & Sons Ltd",

}

RIS

TY - JOUR

T1 - Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635).

AU - Ward, Donald

PY - 2019

Y1 - 2019

N2 - 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

AB - 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

U2 - 10.1002/jbmr.3747

DO - 10.1002/jbmr.3747

M3 - Article

JO - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

SN - 0884-0431

ER -