A Phase 2B, Open-Label, Dose-Ranging Study of Encaleret (CLTX-305) in Autosomal Dominant Hypocalcemia Type 1 (ADH1)

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, with inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D supplementation, which can lead to or exacerbate hypercalciuria. As a result, patients may develop nephrolithiasis and/or nephrocalcinosis, which can progress to renal insufficiency. Calcilytics (antagonists of the CaSR) have demonstrated in in vitro and in vivo models of ADH1, as well as in a small clinical trial (Roberts et al, JBMR 2019), the ability to shift the dose-response relationship between extracellular calcium and the cellular response of cells bearing the mutant CaSR towards normal. This shift has the potential to increase endogenous PTH secretion which in turn may promote skeletal release of calcium into the bloodstream, production of endogenous calcitriol, renal excretion of phosphate, and renal reabsorption of calcium. Additionally, direct effects of calcilytics on renal CaSRs may further reduce renal calcium and magnesium excretion in ADH1. Taken together, this class of drugs has the capacity to restore normal mineral homeostasis, without calcium and activated vitamin D supplements and without attendant risks of iatrogenic hypercalciuria. This Phase 2b, open-label, dose-ranging study will evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of the calcilytic encaleret (CLTX-305) in up to 16 participants with ADH1 (NCT04581629). The study will consist of 3 periods. In periods 1 and 2, participants will undergo a 1-week inpatient evaluation to study the safety and tolerability of daily and twice-daily doses of encaleret. Period 3 will follow participants for up to 24 weeks of continuous outpatient dosing, with periodic inpatient and outpatient assessments. The primary endpoint of period 3 is the change from baseline in albumin-corrected blood calcium concentration. Secondary endpoints of the study include the change in urine calcium (fractional and 24-hour excretion), 1,25-dihydroxy-Vitamin D, phosphate, magnesium, and other blood/urine biomarkers. Enrollment for this study at the National Institutes of Health (NIH) began in September 2020 with topline results expected in 2021. This study is supported by Calcilytix Therapeutics, Inc. and the NIH Intramural Research Program.