OR36-06 Sustained Normalization of Mineral Homeostasis in Autosomal Dominant Hypocalcemia Type 1: Results from a Phase 2 Study Over 42 Months of Encaleret (CLTX-305) Treatment

Abstract Disclosure: R.I. Gafni: Calcilytix Therapeutics. I.R. Hartley: Calcilytix Therapeutics. K.L. Roszko: Calcilytix Therapeutics. E.F. Nemeth: Calcilytix Therapeutics. K. Pozo: Calcilytix Therapeutics. R. Meadows: Calcilytix Therapeutics. E. Ferguson: Calcilytix Therapeutics. A. Mathew: Calcilytix Therapeutics. M. Roberts: Calcilytix Therapeutics. S. Adler: Calcilytix Therapeutics. M.T. Collins: Calcilytix Therapeutics. Autosomal dominant hypocalcemia type 1 (ADH1), due to activating calcium-sensing receptor gene (CASR) variants, manifests as low PTH, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Calcium and active vitamin D treatment worsens hypercalciuria, which may result in renal morbidity. Calcilytics are negative allosteric modulators of the calcium-sensing receptor (CaSR) that decrease the sensitivity of hyperactive receptors to extracellular calcium and normalize biochemical abnormalities in ADH1 mouse models. This Phase 2b open-label study (NCT04581629) of the oral investigational calcilytic encaleret included 2 5d inpatient periods followed by a 24W outpatient period and then a long-term extension (LTE). Conventional therapy was stopped prior to encaleret initiation. After about 18 months in Phase 2b LTE, participants continued encaleret treatment in the CALIBRATE study LTE (NCT05680818). Thirteen adults with ADH1 were enrolled and encaleret was individually titrated to normalize albumin-corrected calcium (cCa). Encaleret was well-tolerated. There were 2 unrelated serious adverse events during the LTE: chest pain and post-surgical pain. There were no treatment discontinuations or withdrawals prior to the LTE; one participant withdrew during the LTE for family planning but subsequently re-enrolled without an intervening pregnancy. Mean±SD values taken pre-dose at P3W24 and LTEM36 compared to baseline (BL) are presented. PTH levels were low at BL (6.3±7.8 pg/mL [nl 10-65]) and normal at P3W24 (35.3±10.2) and LTEM36 (23.7±16.8 [p<0.01]). Similarly, hypocalcemia at BL (cCa=7.1±0.4 mg/dL [nl 8.4-10.2]) had normalized at P3W24 (9.0±0.5) and LTEM36 (9.0±0.3 [p<0.01]). BL hypercalciuria (395±216 mg/d [nl <250-300]) normalized to 202±83 at P3W24 and LTEM36 (162±103 [p<0.01]). BL blood phosphate (4.5±1.1 mg/dL [nl 2.3-4.7]) decreased at P3W24 (3.7±0.5) and LTEM36 (3.7±0.7 [p<0.05]). Blood magnesium rose (BL 1.7±0.2 mg/dL [nl 1.6-2.6]); P3W24 2.0±0.2; LTEM36 2.0±0.2 [p<0.01]). Bone turnover markers, adjusted for age, sex, and menopausal status by dividing by the upper limit of normal for each participant [nl 0-1], were low at BL (CTX=0.4±0.3; P1NP=0.3±0.1) and increased at P3W24 (CTX=1.15±1.0; P1NP=1.22±1.05) and LTEM36 (CTX=0.71±0.53; P1NP=1.37±0.98 [p<0.05; p<0.01]). Compared with screening, DXA Z-scores had decreased at LTEM24 but stabilized at LTEM36 (AP spine Z=2.6±1.5→2.2±1.6→2.2±1.6; Total hip Z=2.2±1.4→1.8±1.1→1.7±1.1; 1/3 radius Z=0.2±0.9→ -0.2±0.4→ -0.1±0.5, n=10-11 [p<0.05]). In patients with ADH1, encaleret corrected biochemical abnormalities and increased bone turnover, with stabilization of bone density by 42 months of continuous treatment. These consistent and sustained results are clinically meaningful and support ongoing efficacy and safety evaluation of encaleret as the first potential treatment for ADH1. Presentation: Monday, July 14, 2025