The Effects of Encaleret (CLTX-305) on Mineral Physiology in Autosomal Dominant Hypocalcemia Type 1 (ADH1) Demonstrate Proof-of-Concept: Early Results From an Ongoing Phase 2b Open-Label Dose-Ranging Study

摘要

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene (CASR) encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D, targeting blood calcium at or slightly below the low-normal level to minimize hypocalcemic symptoms. This supplementation typically causes or exacerbates hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. It has been demonstrated in in vitro and in vivo models of ADH1, as well as in a Phase 2b clinical study (Roberts et al, JBMR 2019) that calcilytics (negative allosteric modulators of the CaSR), have the ability to shift the concentration-response relationship between extracellular calcium and the mutant CaSR towards normal.