Endocrine Abstracts

Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR ) variants, is characterized by low parathyroid hormone (PTH) levels, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Conventional therapy (calcium and active vitamin D) can exacerbate hypercalciuria, which may result in renal complications. Calcilytics that act as negative allosteric modulators of the calcium-sensing receptor (CaSR), like encaleret, decrease the sensitivity of hyperactive receptors to extracellular calcium and normalize biochemical abnormalities in ADH1 rodent models. This Phase 2b open-label study of the oral investigational calcilytic encaleret was comprised of 3 periods followed by a long-term extension (LTE). Conventional therapy was discontinued prior to encaleret initiation. Periods 1&2 included dose-finding and safety/tolerability evaluation. Period 3 (P3) optimized dosing and assessed safety and efficacy over 24 outpatient weeks; participants were then allowed to continue in the LTE. Thirteen adults with ADH1 were enrolled and encaleret was individually titrated to normalize albumin-corrected calcium (cCa) and minimize hypercalciuria. Encaleret was well-tolerated with no serious adverse events reported. There were no treatment discontinuations or withdrawals prior to the LTE; one participant withdrew during the LTE for family planning. The mean±SD encaleret sulfate dose at the end of P3, Week 24 (P3W24) was 86±70 mg BID, remaining stable at LTE Month 12 (LTEM12) (n=12) (75±66 mg BID). Mean±SD values taken 4-hours post-dose for P3W24 and LTEM12 compared to baseline (BL) are presented. PTH levels were low at BL (6.3±7.8 pg/ml [nl 10-65]), normal at P3W24 (35.3±10.2 [P<0.01]) and remained consistent through LTEM12 (36.9±15.2 [P<0.01]). Similarly, the hypocalcemia seen at BL (cCa=7.1±0.4 mg/dl [nl 8.4-10.2]) was corrected at P3W24 (9.2±0.5 [P<0.01]); eucalcemia was maintained through LTEM12 (9.2±0.4 [P<0.01]). BL hypercalciuria (395±216 mg/d [nl<250-300]) decreased to 202±83 (P<0.05) at P3W24 and normalization was sustained through LTEM12 (177±94 [P<0.05]). BL blood phosphate (4.5±1.1 mg/dl [nl 2.3-4.7]) decreased by P3W24 (3.4±0.4 [P<0.05]) and was maintained at LTEM12 (3.4±0.5 [P<0.01]). Blood magnesium increased (BL 1.7±0.2 mg/dl [nl 1.6-2.6]); P3W24 2.0±0.2 [P<0.01]; LTEM12 2.1±0.2 [P<0.01]). Bone turnover markers increased from BL (n=7) (CT_X=253±111 pg/ml; P1NP=34±10 mg/l) by P3W24 (n=13) (CT_X=744±565; P1NP=104±87) [P<0.01] and remained elevated at LTEM12 (CT_X=988±652; P1NP=83±49 [P<0.01]). This study represents a molecularly targeted, precision medicine approach to the treatment of ADH1. The consistent and sustained results from over 18 months of outpatient encaleret treatment are clinically meaningful and support Phase 3 evaluation of the efficacy and safety of encaleret as the first potential treatment indicated for ADH1.