Calcilytic administration to patients with postsurgical hypoparathyroidism (PSH) allows investigation of PTH-independent regulation of renal calcium handling by the calcium-sensing receptor (CaSR). We hypothesized that encaleret would decrease fractional excretion of calcium (FECa), lower 24-hour urinary calcium excretion, and raise serum calcium, consistent with the profile of an effective therapeutic for PSH.

Ten participants with PSH received encaleret (NCT05735015). Endpoints were FECa and the proportion of participants achieving both corrected serum calcium (cCa) ≥8.5 mg/dL and normal 24-hour urinary calcium (24h-Uca). Calcitriol was discontinued before encaleret. High-dose encaleret (162 mg) was administered every 12 hours up to 10 doses. All participants received calcium supplementation initially; calcitriol was reinitiated as needed to maintain eucalcemia. Seven participants received 10 doses. Two discontinued after 4 doses, having met both endpoints, to assess post-treatment PK/PD; one discontinued because of hypercalcemia.

FECa decreased by 39 ± 29% (p = 0.002). Nine met the secondary endpoint (95% CI: 55.5% – 99.7%). None met this criterion at baseline. Eight maintained normal 24h-Uca throughout. 24h-Uca decreased from 405 ± 200 to 175 ± 105 mg/day on the final treatment day. Mean cCa increased from 8.5 ± 0.3 to 9.2 ± 0.6 mg/dL at 48 h (p = 0.002). PTH increased transiently from 7.4 (range 4.6–10.1) to 13.0 (4.5–18.1) pg/mL after the first dose, then returned to near baseline. Bone turnover markers were normal and did not change. The only treatment-related adverse events were mild hypercalcemia and headache in one participant. Her cCa continued to be mildly elevated for 60 hours after the last dose of encaleret while 24h-Uca remained <200 mg/day.

Encaleret reduced renal calcium excretion in PSH, supporting a PTH-independent role for CaSR in renal calcium handling. Normalization of urinary and serum calcium supports evaluation of encaleret as a therapy for patients with PSH.