Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial

  • J Bone Miner Res. 2023 Jan;38(1):14-25. doi: 10.1002/jbmr.4726.
Aliya A Khan  1 ,  Mishaela R Rubin  2 ,  Peter Schwarz  3 ,  Tamara Vokes  4 ,  Dolores M Shoback  5 ,  Claudia Gagnon  6 ,  Andrea Palermo  7 ,  Claudio Marcocci  8 ,  Bart L Clarke  9 ,  Lisa G Abbott  10 ,  Lorenz C Hofbauer  11 ,  Lynn Kohlmeier  12 ,  Susanne Pihl  13 ,  Xuebei An  14 ,  Walter Frank Eng  14 ,  Alden R Smith  14 ,  Jenny Ukena  14 ,  Christopher T Sibley  14 ,  Aimee D Shu  14 ,  Lars Rejnmark  15
Affiliations
  • 1. Endocrinology, Metabolism, and Geriatrics, McMaster University, Hamilton, Ontario, Canada.
  • 2. Endocrinology, Columbia University, New York, New York, USA.
  • 3. Internal Medicine and Endocrinology, Rigshospitalet, Copenhagen, Denmark.
  • 4. Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois, USA.
  • 5. Endocrinology, UCSF/VA Medical Center, San Francisco, California, USA.
  • 6. CHU de Québec-Université Laval Research Centre and Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
  • 7. Unit of Metabolic Bone and Thyroid Disorders, Fondazione Policlinico Campus Bio-medico, and Unit of Endocrinology and Diabetes, Campus Bio-medico University, Rome, Italy.
  • 8. Endocrinology, University di Pisa, Pisa, Italy.
  • 9. Endocrinology, Mayo Clinic E18-A, Rochester, Minnesota, USA.
  • 10. Northern Nevada Endocrinology, University of Nevada, Reno, Nevada, USA.
  • 11. Endocrinology, Diabetes, and Metabolic Bone Diseases, Technische Universität Dresden Medical Center, Dresden, Germany.
  • 12. Endocrinology, Endocrinology and Spokane Osteoporosis, Spokane, Washington, USA.
  • 13. Biolanalysis and Pharmacokinetics/Pharmacodynamics, Ascendis Pharma A/S, Hellerup, Denmark.
  • 14. Endocrine Medical Sciences, Ascendis Pharma Inc, Palo Alto, California, USA.
  • 15. Clinical Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
PMID: 36271471 DOI: 10.1002/jbmr.4726
Abstract

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords
CLINICAL TRIALS; DISORDERS OF CALCIUM/PHOSPHATE; HORMONE REPLACEMENT; PARATHYROID-RELATED DISORDERS; PTH/VIT D/FGF23.
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