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Bone and Mineral Metabolism

MON-771 - Improvements in Patient-Reported Outcomes With Eneboparatide in Chronic Hypoparathyroidism Over 1 Year: A Phase 3, Randomized, Placebo-Controlled and Open-Label Study Assessing the Efficacy and Safety of Eneboparatide (CALYPSO)

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Disclosure(s):
Michael Mannstadt, MD: Alexion Pharmaceutical: Advisory Board (), Clinical Trial Investigator (); BridgeBio: Advisory Board (), Clinical Trial Investigator (); MBX: Advisory Board (); septerna: Consultant (); Shire Pharmaceuticals/Takeda: Advisory Board (), Clinical Trial Investigator (), Consultant ()


Background: Chronic hypoparathyroidism (cHypoPT) is a rare endocrine disease due to low parathyroid hormone (PTH). Hypocalcemia, hypercalciuria, and low bone turnover are common clinical features. Conventional therapy (oral active vitamin D and calcium) fails to fully correct disordered mineral metabolism and poor patient-reported outcomes (PROs), supporting the need for PTH replacement therapy. Eneboparatide (enebo) is a long-acting, novel PTH 1 receptor agonist in development to meet these goals in adults with cHypoPT.

Objective: Assess the efficacy and safety of daily subcutaneous (SC) enebo for 24 weeks vs placebo in adults 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, funded by Alexion).
Participants: 200 adults (77% women) aged 18-80 with cHypoPT were randomized 2:1 to enebo or placebo. All patients who finished the 24-week trial enrolled in the OLE (n=187/200).
Intervention: After optimization, subjects received a daily SC injection of enebo or placebo. Conventional therapy was progressively reduced, and enebo was titrated at predefined time points. Titration was not permitted in the last 4 weeks but was allowed in the OLE.
Outcome: The primary efficacy endpoint was the proportion of patients achieving independence from conventional therapy and normal adjusted serum calcium (8.3-10.6 mg/dL). Secondary endpoints were normalization of urinary calcium in baseline hypercalciuric patients and change from baseline in symptoms and physical functioning as assessed by validated disease-specific PROs, HPT-DD-SE, HPT-LIQ, and SF-36 Physical Functioning subscale.

Results: All primary and key secondary endpoints met statistical significance at week 24. A higher proportion of patients receiving enebo achieved the primary endpoint vs placebo (31% [41/132] vs 6% [4/68] [P=0.0001]). Compared with placebo, patients receiving enebo showed improvement in PROs, disease-specific core symptoms including muscle pain, muscle cramps, and muscle weakness (−0.97 vs −0.32 [P=0.0169]), disease-specific physical functioning (−1.08 vs −0.23 [P=0.0499]), and the SF-36 Physical Functioning subscale (+8.08 vs +1.76 [P=0.0154]). Through week 52, PRO improvements persisted, and patients from the placebo lead-in phase were comparable to those receiving enebo across all PROs. Mild-to-moderate hypocalcemia was the most frequently reported adverse event during the first 24 weeks in both arms (enebo: 52/132; placebo: 41/68).

Conclusions: Enebo provides improvements in the PROs of symptoms and physical functioning through week 52, consistent with reductions in disease burden, in adults with cHypoPT and shows an acceptable safety profile consistent with previous reports.

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