Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

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) (146689)

Maria Luisa Brandi 1 , Jeremy Turner 2 3 , Steven Ing 4 , Istvan Takacs 5 , Aliya Khan 6 , Lynn Kohlmeier 7 , Andrea Palermo 8 9 , Lars Rejnmark 10 , John Bilezikian 11 , Natasha Appelman-Dijkstra 12 , Lorenz Hofbauer 13 , Manoj Rajadhyaksha 14 , Julien Laffaire 15 , Anna Petryk 16 , Taha Ould Rouis 17 , Soraya Allas 17 , Michael Mannstadt 18
  1. European Institute of Oncology (IEO), Milan, Italy
  2. Norfolk and Norwich University Hospital, Department of Diabetes and Endocrinology, Norwich, United Kingdom
  3. Norwich Medical School, University of East Anglia, Faculty of Medicine and Health Sciences, Norwich, United Kingdom
  4. The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Division of Endocrinology, Diabetes and Metabolism, Columbus, OH, United States
  5. Semmelweis University, Department of Internal Medicine and Oncology, Budapest, Hungary
  6. McMaster University, Division of Endocrinology and Metabolism, Hamilton, ON, Canada
  7. Spokane Osteoporosis and Endocrinology, Arthritis Northwest Research, Spokane, WA, United States
  8. Fondazione Policlinico Universitario Campus Bio-Medico, Unit of Metabolic Bone and Thyroid Disorders, Rome, Italy
  9. Campus Bio-Medico University, Unit of Endocrinology and Diabetes, Rome, Italy
  10. Aarhus University Hospital, Department of Endocrinology and Internal Medicine, Aarhus, Denmark
  11. Vagelos College of Physicians and Surgeons, Columbia University, Department of Medicine, New York, NY, United States
  12. Leiden University Medical Center, Department of Internal Medicine, Section Endocrinology, Leiden, The Netherlands
  13. University Center for Healthy Aging, Technische Universität Dresden, Division of Endocrinology and Bone Diseases, Department of Medicine III, Dresden, Germany
  14. Alexion, AstraZeneca Rare Disease, Immunogenicity Sciences, Boston, MA, United States
  15. Alexion, AstraZeneca Rare Disease, Quantitative Sciences, Barcelona, Spain
  16. Alexion, AstraZeneca Rare Disease, Global Medical Affairs, Boston, MA, United States
  17. Alexion, AstraZeneca Rare Disease, Clinical Development, Ecully, France
  18. Massachusetts General Hospital and Harvard Medical School, Endocrine Unit, Boston, MA, United States

Aims: Chronic hypoparathyroidism (HypoPT), caused by parathyroid hormone (PTH) deficiency, results in hypocalcemia, hypercalciuria, and low bone turnover. Additional treatments are needed to stabilize calcium and urinary calcium (uCa) excretion while preserving bone. We assessed the efficacy and safety of subcutaneous eneboparatide, a long-acting PTH1 receptor agonist, versus placebo for 24weeks, followed by a 28-week open-label extension (OLE).

Methods: In this phase 3, multicenter, randomized, double-blind, parallel, placebo-controlled trial (NCT05778071), 200 adults aged 18–80 with HypoPT (77% women; 154/200) were randomized 2:1 to eneboparatide or placebo for 24weeks. Patients completing 24-week period enrolled in the OLE (n=187/200). After optimization of albumin-adjusted serum calcium (ADsCa) to 7.8–9mg/dL (1.95–2.25mmol/L), participants received a daily subcutaneous eneboparatide or placebo. Conventional therapy was progressively reduced, and eneboparatide was uptitrated per protocol (not permitted in the last 4weeks; permitted again in the OLE).

The primary efficacy endpoint was the proportion of participants achieving independence from active vitamin D and therapeutic oral calcium (>600mg/day) and normal ADsCa (8.3–10.6mg/dL [2.07–2.64mmol/L]). Key secondary endpoints: normalization of uCa excretion in baseline hypercalciuric participants and improvements in symptoms and physical functioning as assessed by disease-specific patient-reported outcomes. Safety, serum bone turnover biomarkers, and bone mineral density (BMD) were assessed.

Results: All primary and key secondary endpoints met statistical significance at 24week. More eneboparatide (31% [41/132]) than placebo (6% [4/68] [P<0.0001]) patients achieved the primary endpoint. uCa excretion normalized in 57% (43/76) of hypercalciuric eneboparatide patients versus 20% (9/45) with placebo (P=0.0001). Through 52week, ADsCa remained stable with conventional therapy and eneboparatide titration; uCa excretion and PRO benefits persisted. Mild-to-moderate hypocalcemia was the most common adverse event. Bone turnover biomarkers and BMD changes were consistent with balanced bone turnover.

Conclusions: Eneboparatide provides prolonged, positive results, and clinical benefits for patients with HypoPT with acceptable safety.