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Disclosure: P.J. Tebben: Consultancy fees and research funding from Calcilytix. T. Alexander: Steering Committee Member Calcilytix Therapeutics Inc. Honoraria Ultragenyx. S. Mora: Consultancy fees from Calcilytix. R. Padidela: Consultancy fees from Calcilytix. M. Roberts: Employee of BridgeBio and own company stock. D. Li: Employee of BridgeBio and own company stock. S. Adler: Employee of BridgeBio and own company stock. R.I. Gafni: The NIDCR receives research funding from Calcilytix Therapeutics, Steering committee member (unpaid) for adult and pediatric encaleret studies, Medical advisory board (unpaid) of The Hypoparathyroidism Association.
Objectives: Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function variants in the calcium-sensing receptor gene, is characterized by low/inappropriately normal parathyroid hormone (PTH), hypocalcemia, and hypercalciuria. Standard-of-care (SoC) treatment (calcium and active vitamin D) worsens hypercalciuria, increasing renal morbidity. Encaleret, a negative allosteric modulator of the calcium-sensing receptor, is under investigation as a potential ADH1 treatment. In a Phase 2b study [NCT04581629] in 13 adults with ADH1, encaleret led to sustained normalization in PTH, albumin-corrected calcium (cCa), phosphorus, magnesium and 24-hr urine calcium (UCa) excretion over 24 weeks, without serious adverse events reported. A Phase 3 study [NCT05680818, CALIBRATE] in adults with ADH1 is ongoing. CALIBRATE-PEDS is a Phase 2/3 study evaluating pharmacokinetics (PK), efficacy, and safety of encaleret in children with ADH1. Methods: Approximately 28 children (birth-18y) will be enrolled in 4 age cohorts sequentially, starting with the oldest cohort (12-18y). After 3-6 months of stable SoC/PTH treatment, eligible participants will enter Period 1, an inpatient stay lasting up to 6 days, for PK sampling and individualized dose titration. Period 2 follows, during which encaleret doses will be optimized to maintain target cCa while minimizing UCa over 20 outpatient weeks. Period 3 is a 4-week dose maintenance period, when the dose is intended to be fixed. Participants may then continue into a long-term extension period for safety monitoring and continued access to encaleret. PK data from Period 1 will be used to refine population-based PK modeling and inform dosage in younger cohorts. Results: The primary endpoint is the composite endpoint of a) cCa within 8.4 to 10.4 mg/dL in participants aged ≥ 1 year, and within 8.2 to 11.4 mg/dL in participants aged < 1 year and b) UCa <4 mg/kg/d in toilet-trained participants or spot ratio of UCa/UCr within the age-specific reference range in non-toilet-trained participants. Participants meeting both criteria at the end of Period 3 will be considered responders. Key secondary endpoints include safety and tolerability, mineral homeostasis, renal ultrasound, bone density, and self-reported outcomes. The statistical analyses will be descriptive; no statistical testing is planned. Conclusions: CALIBRATE-PEDS is the first pediatric study of encaleret. It is under development and is expected to be initiated globally in 2025.
Presentation: Sunday, July 13, 2025
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1 MD Departments of Internal Medicine and Pediatrics, Section of Endocrinology, Yale University, New Haven, CT, USA
2 MD, PhD Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
3 MD Pediatric Endocrinology, Department of Pediatrics, IRCCS San Raffaele Hospital, Milano, Italy
4 MBBS, MRCPCH, MD Department of Paediatric Endocrinology, Manchester University NHS Foundation Trust Hospital; Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
5 MD Calcilytix Therapeutics, Inc. a company of BridgeBio Pharma, Inc, San Francisco, CA, USA
6 MD, MSc Calcilytix Therapeutics, Inc. a company of BridgeBio Pharma, Inc, San Francisco, CA, USA
7 MD National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA