Endocrine Abstracts

Autosomal dominant hypocalcemia type 1 (ADH1), caused by pathogenic gain-of-function calcium-sensing receptor gene (CASR ) variants, is characterized by low parathyroid hormone (PTH) levels, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Current standard-of-care (SoC) (calcium and active vitamin D) can exacerbate hypercalciuria, which may result in renal complications. Encaleret is an investigational oral calcilytic, functioning as a negative allosteric modulator of the calcium-sensing receptor, that is being studied as a potential treatment for ADH1. A Phase 2b study [NCT04581629] in 13 adults with ADH1 showed that encaleret led to sustained normalization in mean blood levels of intact PTH, albumin-corrected calcium (cCa), phosphorus, magnesium and 24-hr urine calcium (UCa) excretion over 24 weeks compared with baseline. Encaleret was well-tolerated with no serious adverse events reported. CALIBRATE is a global Phase 3 study designed to evaluate the efficacy and safety of encaleret compared to SoC in approximately 60 participants (≥18-years-old in Europe; ≥16-years in other sites) with ADH1. After a screening evaluation, eligible participants will undergo SoC optimization followed by a 4-week SoC maintenance period (Period 1 [P1]). Participants will then be randomized 2:1 (encaleret:SoC) into a 20-week dose titration period (Period 2). Doses of encaleret or SoC will be titrated to achieve target cCa concentrations while minimizing UCa excretion. Participants will then enter a 4-week maintenance period (Period 3 [P3]) where doses of encaleret or SoC are intended to be fixed. The primary efficacy endpoint is a composite endpoint: a) cCa within 8.3-10.7 mg/dl (2.1-2.7 mmol/l) AND b) 24-hr UCa within reference range (men: <300 mg/day [7.5 mmol/day]; women: <250 mg/day [6.25 mmol/day]). Participants who meet both criteria will be considered responders. The primary analysis will be a within-patient comparison of the proportion of responders in the encaleret group at the completion of P3 vs P1 (SoC). Key secondary endpoints include between-treatment arm comparisons (encaleret vs SoC at P3) as well as the evaluation of mineral homeostasis parameters, renal health, bone health, and patient-reported outcomes. Following completion of P3, eligible participants will have the option to enter a long-term extension (LTE) period with all participants having access to encaleret. CALIBRATE is actively recruiting study participants and has sites (active and planned) in 12 countries: USA, Canada, Brazil, Netherlands, Denmark, France, Italy, Czech Republic, Taiwan, Australia, United Kingdom, and Japan.