TABLE 3

Summary of key studies assessing effectiveness of PAMs and NAMs for FHH, NSHPT, and ADH

Adapted from Hannan FM, Olesen MK, Thakker RV. Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor–signaling pathway. Br J Pharmacol (2018) 175:4083–4094.

DisorderIn Vitro StudiesIn Vivo Studies
Hypercalcemic disorders
 FHH1/NSHPTNPS R-568 and cinacalcet enhance the signaling responses and cell surface expression of loss-of-function FHH1/NSHPT-causing CaSR mutants (Rus et al., 2008; Leach et al., 2013)Cinacalcet lowers serum calcium and PTH concentrations and improves hypercalcemic symptoms in patients with FHH1 (Alon and VandeVoorde, 2010; Rasmussen et al., 2011; Sethi et al., 2017)
Cinacalcet lowers serum calcium and PTH concentrations in patients with NSHPT harboring a heterozygous Arg185Gln CASR mutation (Reh et al., 2011; Gannon et al., 2014; Fisher et al., 2015) but is less effective for NSHPT caused by biallelic truncating CASR mutations (García Soblechero et al., 2013; Atay et al., 2014)
 FHH2Cinacalcet enhances the signaling responses of cells expressing loss-of-function FHH2-causing Gα11 mutants (Babinsky et al., 2016)Cinacalcet lowers serum calcium and PTH concentrations in a mouse model for FHH2 (Howles et al., 2017) and also normalizes serum calcium concentrations in a patient with FHH2 (Gorvin et al., 2018b)
 FHH3Cinacalcet enhances the signaling responses of cells expressing loss-of-function FHH3-causing Arg15Cys, Arg15His, or Arg15Leu AP2σ mutants (Howles et al., 2016)Cinacalcet lowers serum calcium and PTH concentrations and improves hypercalcemic symptoms in patients with FHH3 with Arg15Cys, Arg15His, or Arg15Leu AP2S1 mutations (Howles et al., 2016)
Hypocalcemic disorders
 ADH1NPS 2143 reduces the signaling responses of cells expressing gain-of-function ADH1-causing CaSR mutants but has limited efficacy for constitutively active CaSR mutants (Letz et al., 2010; Leach et al., 2013)Acute administration of NPS 2143 and JTT-305/MK-5442 increases serum calcium and PTH concentrations in mouse models for ADH1 (Dong et al., 2015; Hannan et al., 2015b)
ATF936 and AXT914 rectify the gain of function caused by constitutively active CaSR mutants (Letz et al., 2014)Administration of JTT-305/MK-5442 over 12 wk reduces urinary calcium excretion and prevents nephrocalcinosis in mouse models for ADH1 (Dong et al., 2015)
Intravenous infusion of NPSP795 increases serum PTH concentrations and reduces urinary calcium excretion in patients with ADH1 (Roberts et al., 2019)
 ADH2NPS 2143 reduces the signaling responses of cells expressing gain-of-function ADH2-causing Gα11 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)