ECEESPE2025 Oral Communications Oral Communications 7: Bone and Mineral Metabolism (9 abstracts)
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
Rachel Gafni 1 , Iris Hartley 1 , Kelly Roszko 1 , Edward Nemeth 2 , Karen Pozo 1 , Rita Meadows 1 , Elizabeth Ferguson 1 , Arun Mathew 3 , Mary Scott Roberts 3 , Scott Adler 3 & Michael Collins 4
1National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States; 2MetisMedica, Toronto, Canada; 3Calcilytix Therapeutics, Inc., San Francisco, United States; 4Consultant, Washington, DC, United States
JOINT1537
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 induce renal complications. Calcilytics are negative allosteric modulators of the calcium-sensing receptor that decrease its sensitivity to extracellular calcium and normalize biochemical abnormalities in ADH1 mice. 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 a long-term extension (LTE). Conventional therapy was stopped prior to encaleret initiation. After about 18 months in the LTE, participants continued encaleret in the Phase 3 LTE (NCT05680818). Thirteen adults with ADH1 received encaleret 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/withdrawals prior to the LTE. Mean±SD values taken pre-dose at P3W24 and LTEM36 compared to baseline (BL) are presented. PTH was 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 ULN for each participant [nl 0-1], were low at BL and increased at P3W24 and LTEM36 [P<0.05; P<0.01]). Compared with screening, DXA Z-scores had decreased at LTEM24 but then stabilized at LTEM36 (n=10-11). 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.
| Baseline | P3W24 | LTEM12 | LTEM24 | LTEM36 | |
| CTx (value/ULN) | 0.4±0.3 | 1.15±1.0* | 1.45±1.23* | 0.73±0.48* | 0.71±0.53* |
| P1NP (value/ULN) | 0.3±0.1 | 1.22±1.05* | 1.04±0.57* | 1.1±0.68* | 1.37±0.98* |
| AP spine Z-score | 2.6±1.5 | 2.3±1.7 | 2.5±1.7 | 2.2±1.6* | 2.2±1.6* |
| Total Hip Z-score | 2.2±1.4 | 2.0±1.4* | 2.0±1.3* | 1.8±1.1* | 1.7±1.1* |
| 1/3 Radius Z-score | 0.2±0.9 | 0.3±0.9 | 0.5±0.5 | -0.2±0.4* | -0.1±0.5* |
| *P<0.05 compared with Baseline | |||||
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