Abstract
Introduction: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by gain-of-function variants of the calcium-sensing receptor (CaSR) gene, resulting in receptor proteins with increased sensitivity to extracellular calcium. Individuals with ADH1 exhibit hypocalcemia, hypomagnesemia, hyperphosphatemia, and inappropriately low levels of PTH. Hypocalcemia and hypomagnesemia can slow cardiac repolarization and potentially prolong the QT interval in patients with ADH1. Prolongation of the QT interval can lead to potentially malignant ventricular arrhythmias. Calcilytics are antagonists of the CaSR with the potential to restore normal CaSR sensitivity in ADH1 and thereby normalize blood levels of calcium and magnesium. This study investigated the biochemical and ECG effects of encaleret, an investigational oral calcilytic, in individuals with ADH1. Methods: CLTX-305-201 [NCT04581629] is a 3-period, open-label, dose-ranging study of encaleret in adults with ADH1. In Period 1, supplements were discontinued 1 or 2 days prior to administering sequential, increasing daily doses of encaleret over 5 days with frequent biochemical monitoring. Standard 12-lead surface ECGs were recorded at baseline (BL) and on Day 5 (D5). Results: Data (mean±SD) from the first 6 participants are presented. BL and D5 values were compared as follows: • PTH: BL 3.4±4.5; D5 64.8±49.6 (nl 10-65 pg/mL; p<0.01) • Albumin-corrected total calcium: BL 7.6±0.6; D5 9.0±0.5 (nl 8.4-10.2 mg/dL; p<0.01) • Magnesium: BL 1.6±0.4; D5 2.0±0.5 (nl 1.6-2.6 mg/dL; p<0.01) • Phosphate: BL 4.5±0.7; D5 2.9±0.5 (nl 2.3-4.7 mg/dL; p<0.01) • QT c B: BL 452±9; D5 433±11 (nl <440 msec; p<0.01) There were no important changes or trends in heart rate, blood pressure, or other ECG intervals. Encaleret was well-tolerated and without serious adverse events. Conclusion: Hypocalcemic ADH1 study participants experienced abnormal cardiac repolarization manifested as prolongation of the QT interval at baseline. The consistent responses following encaleret treatment ADH1 participants provide preliminary evidence that encaleret, by raising blood levels of calcium and magnesium, may normalize cardiac repolarization in patients with ADH1. Longer-term evaluation of encaleret in ADH1 is ongoing.
Published Version
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