Efficacy and safety of parathyroid hormone replacement with TransCon PTH in hypoparathyroidism:​ 26-week results from the phase 3 PaTHway trial

Khan, Aliya A.; Rubin, Mishaela R.; Schwarz, Peter; Vokes, Tamara; Shoback, Dolores M.; Gagnon, Claudia; Palermo, Andrea; Marcocci, Claudio; Clarke, Bart L.; Abbott, Lisa G.; Hofbauer, Lorenz C.; Kohlmeier, Lynn; Pihl, Susanne; An, Xuebei; Eng, Walter Frank; Smith, Alden R.; Ukena, Jenny; Sibley, Christopher T.; Shu, Aimee D.; Rejnmark, Lars

Affiliations

¹Endocrinology, Metabolism, and Geriatrics, McMaster University, Hamilton, Ontario, Canada

²Endocrinology, Columbia University, New York, New York, USA

³Internal Medicine and Endocrinology, Rigshospitalet, Copenhagen, Denmark

⁴Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois, USA

⁵Endocrinology, UCSF/VA Medical Center, San Francisco, California, USA

⁶CHU de Québec-Université Laval Research Centre and Department of Medicine, Université Laval, Quebec City, Quebec, Canada

⁷Unit of Metabolic Bone and Thyroid Disorders, Fondazione Policlinico Campus Bio-medico, and Unit of Endocrinology and Diabetes, Campus Bio-medico University, Rome, Italy

⁸Endocrinology, University di Pisa, Pisa, Italy

⁹Endocrinology, Mayo Clinic E18-A, Rochester, Minnesota, USA

¹⁰Northern Nevada Endocrinology, University of Nevada, Reno, Nevada, USA

¹¹Endocrinology, Diabetes, and Metabolic Bone Diseases, Technische Universität Dresden Medical Center, Dresden, Germany

¹²Endocrinology, Endocrinology and Spokane Osteoporosis, Spokane, Washington, USA

¹³Biolanalysis and Pharmacokinetics/Pharmacodynamics, Ascendis Pharma A/S, Hellerup, Denmark

¹⁴Endocrine Medical Sciences, Ascendis Pharma Inc, Palo Alto, California, USA

¹⁵Clinical Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

Abstract and keywords

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.

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

Links

DOI: 10.1002/jbmr.4726

PubMed: 36271471

WoS: 000881940600001

History

Received: 2022-06-23

Revised: 2022-09-22

Accepted: 2022-10-19

Cited Works (1)

Year	Entry
2020	Karpf DB, Pihl S, Mourya S, Mortensen E, Kovoor E, Markova D, Leff JA. A randomized double‐blind placebo‐controlled first‐in‐human phase 1 trial of TransCon PTH in healthy adults. J Bone Miner Res. August 2020;35(8):1430-1440.