PTH-Independent CaSR Inhibition with the Oral Calcilytic Encaleret Improves Calcium Homeostasis in Post-Surgical...

The calcium-sensing receptor (CaSR) maintains calcium homeostasis by regulating parathyroid hormone (PTH) secretion and directly modulating renal calcium reabsorption. In the kidney, PTH and renal CaSR signaling exert opposing effects on tubular calcium reabsorption and urinary calcium excretion, complicating efforts to define their independent contributions to overall calcium regulation. To examine the PTH-independent effects of CaSR inhibition on renal calcium handling, we administered a calcilytic (CaSR antagonist) to individuals with post-surgical hypoparathyroidism (PSH). In this open-label, phase 2, proof-of-concept study (NCT0573515), ten adults (26-69y) with chronic PSH were orally administered the calcilytic encaleret for up to 5 days. Calcitriol was discontinued one day prior, and calcium and calcitriol were individually titrated based on blood calcium. Mean fractional excretion of calcium (FECa) decreased by 39±29% (p=0.002) by end of treatment. Albumin-corrected serum calcium increased from 8.5±0.3 mg/dL (mean±SD, normal 8.4-10.2) at time 0 to 9.2±0.6 (p=0.002) at 48 hours while urinary calcium decreased from 405±200 mg/day (m:<250; f:<350) to 180±100 (p=0.0005). Although mean intact PTH increased modestly 30 minutes after the first encaleret dose (7.3±3.1 pg/mL to 12.3±7.9 pg/mL; normal 15-65; p=0.008), levels rapidly returned to baseline without further excursions for the remainder of the study. No serious adverse events (AEs) were reported. Transient mild hypercalcemia and headache in 1 participant were the only treatment-related AEs. In PSH, encaleret reduced urinary Ca and increased serum Ca, demonstrating the PTH-independent role of CaSR signaling in renal calcium handling and supporting further study of encaleret as an oral treatment for patients with PSH.