Table 3. Summary of key studies assessing effectiveness of calcimimetics and calcilytics for FHH, NSHPT and ADH.

Disorder	In vitro studies	In vivo studies
Hypercalcemic disorders
FHH1/NSHPT	NPS R-568 and cinacalcet enhance the signaling responses and cell-surface expression of loss-of-function FHH1/NSHPT-causing CaSR mutants (Leach et al., 2013; Rus et al., 2008)	Cinacalcet lowers serum calcium and PTH concentrations, and improves hypercalcemic symptoms in FHH1 patients (Alon and VandeVoorde, 2010; Rasmussen et al., 2011; Sethi et al., 2017) Cinacalcet lowers serum calcium and PTH concentrations in NSHPT patients harboring a heterozygous Arg185Gln CASR mutation (Fisher et al., 2015; Gannon et al., 2014; Reh et al., 2011), but is less effective for NSHPT caused by biallelic truncating CASR mutations (Atay et al., 2014; Garcia Soblechero et al., 2013)
FHH2	Cinacalcet enhances the signaling responses of cells expressing loss-of-function FHH2-causing Ga11 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 an FHH2 patient (Gorvin et al., 2018b)
FHH3	Cinacalcet 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 FHH3 patients with Arg15Cys, Arg15His or Arg15Leu AP2S1 mutations (Howles et al., 2016)
Hypocalcemic disorders
ADH1	NPS 2143 reduces the signaling responses of cells expressing gain-of-function ADH1-causing CaSR mutants, but has limited efficacy for constitutively active CaSR mutants (Leach et al., 2013; Letz et al., 2010)	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 weeks 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 ADH1 patients (Roberts et al., 2019)
ADH2	NPS 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)

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.