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 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 (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 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 (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. © 2019 American Society for Bone and Mineral Research.

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

“…Calcium-Sensing Receptor-Related Genetic Diseases and Therapeutic Interventions). Indeed, the NAM, NPSP795 (SHP635), has recently undergone clinical testing for its therapeutic potential in the treatment of ADH1 (Roberts et al, 2019).…”

“…NPS 2143 reduces the signaling responses of cells expressing gain-of-function ADH2-causing Ga 11 mutants (Babinsky et al, 2016;Gorvin et al, 2017;Roszko et al, 2017) NPS 2143 increases serum calcium and PTH concentrations in mouse models for ADH2 (Gorvin et al, 2017;Roszko et al, 2017) NAM, NPSP795, has been administered to five ADH1 patients in a phase IIa clinical trial and increased plasma PTH concentrations and reduced urinary calcium excretion (Table 3) (Roberts et al, 2019). However, circulating calcium concentrations were not altered in these patients, and the optimal dosing regimen of NPSP795 for ADH remains to be established.…”

Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model

“…(26) NPSP795 was shown to normalize increases in Ca 2+ i and pERK-signaling responses of cells stably expressing the Nuf mutant CaSR, which is in keeping with the reported effects of NPSP795 on ADH1-causing germline gain-of-function CaSR mutations. (23) Our in vivo studies showed that single-bolus administration of NPSP795 significantly increases plasma PTH concentrations in a dose-dependent manner in Nuf mice. However, substantially higher doses of NPSP795 were required to increase PTH secretion in Casr +/Nuf and Casr Nuf/Nuf mice compared with that required for WT mice ( Fig.…”

“…Consistent with this, NPSP795 has been previously shown to improve the gain-of-function caused by mutations located in the extracellular (Glu228Ala, Glu228Lys, and Gln245Arg) and transmembrane (Ala840Val) domains of the CaSR. (23) In conclusion, single-dose administration of NPSP795 has been shown to cause dose-dependent increases in PTH and to ameliorate the hypocalcemia in an ADH1 mouse model. Thus, the NPSP795 calcilytic represents a potential targeted therapy for ADH1.…”

“…administration. (23) However, our study used a markedly higher (25 mg/kg) dose of this calcilytic, and the difference in dosing between the patient and mouse study likely explains the differences observed in circulating calcium responses. The plasma calcium concentrations of Casr +/Nuf mice treated with 25 mg/kg of NPSP795 remained significantly lower than that of untreated WT mice (2.16 AE 0.06 versus 2.50 AE 0.04 mmol/L; p < 0.01).…”