OC12.4 - LBA_ECE_1141 - The safety and efficacy of eneboparatide, a parathyroid hormone 1 receptor agonist, in adults with chronic hypoparathyroidism: a phase 3, randomized, placebo-controlled study (CALYPSO)

Abstract Background Chronic hypoparathyroidism (cHypoPT) is a rare endocrine disease caused by parathyroid hormone (PTH) deficiency, resulting in hypocalcemia, hypercalciuria, and low bone turnover. Despite conventional therapy (oral active vitamin D and/or calcium) and PTH replacement therapies, there is a need for additional treatments that stabilize calcium and provide control of symptoms and urinary calcium (uCa) excretion with balanced effects on bone. Eneboparatide is a long-acting, novel PTH 1 receptor agonist in development to meet these goals in patients with cHypoPT. Objectives To assess the efficacy and safety of daily subcutaneous (SC) eneboparatide for 24 weeks versus placebo in patients with cHypoPT, followed by a 28-week open-label extension (OLE). Methods Design: Phase 3, multicenter, randomized, double-blind, parallel, placebo-controlled, 24-week treatment, followed by an OLE (NCT05778071). Participants 200 adults (77% women; 154/200) aged 18-80 with cHypoPT were randomized 2:1 to eneboparatide or placebo. All patients who completed the 24-week period enrolled in the OLE (n = 187/200). Intervention After optimization to ensure albumin-adjusted serum calcium (ADsCa) was within 7.8-9 mg/dL (1.95-2.25 mmol/L), participants received a daily SC injection of eneboparatide or placebo. Conventional therapy was progressively reduced, and uptitration of eneboparatide was permitted according to a predefined protocol. Uptitration was not permitted in the last 4 weeks but was allowed again in the OLE. Outcomes The primary efficacy endpoint was the proportion of participants achieving independence from active vitamin D and therapeutic doses of oral calcium (ie, >600 mg/day) and normal ADsCa (8.3-10.6 mg/dL [2.07-2.64 mmol/L]). Key secondary endpoints included normalization of uCa excretion in participants with hypercalciuria at baseline and improvement in symptoms and physical functioning as assessed by disease-specific patient-reported outcomes (PROs). Safety parameters were evaluated, and bone safety measures included serum bone turnover biomarkers and bone mineral density (BMD). Results All primary and key secondary endpoints met statistical significance at week 24. A higher proportion of patients receiving eneboparatide achieved the primary endpoint versus placebo (31% [41/132] vs 6% [4/68] [P < .0001]). 57% (43/76) of hypercalciuric eneboparatide patients normalized uCa excretion versus 20% (9/45) of placebo patients (P = .0001). Through week 52, ADsCa was stable with conventional therapy and eneboparatide titration, and uCa excretion and PRO benefits persisted. Mild-to-moderate hypocalcemia was the most frequently reported adverse event. Changes in bone turnover biomarkers and BMD were consistent with balanced bone turnover. Conclusions Eneboparatide provides prolonged, positive results and clinical benefits for patients with cHypoPT with acceptable safety.