用 TransCon PTH 替代甲状旁腺激素治疗甲状旁腺功能减退症的疗效和安全性：3 期 PaTHway 试验的 26 周结果,Journal of Bone and Mineral Research

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用 TransCon PTH 替代甲状旁腺激素治疗甲状旁腺功能减退症的疗效和安全性：3 期 PaTHway 试验的 26 周结果
Journal of Bone and Mineral Research ( IF 5.1 ) Pub Date : 2022-10-21 , 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

Affiliation

Endocrinology, Metabolism, and Geriatrics, McMaster University, Hamilton, Ontario, Canada.
Endocrinology, Columbia University, New York, New York, USA.
Internal Medicine and Endocrinology, Rigshospitalet, Copenhagen, Denmark.
Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois, USA.
Endocrinology, UCSF/VA Medical Center, San Francisco, California, USA.
CHU de Québec-Université Laval Research Centre and Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
Unit of Metabolic Bone and Thyroid Disorders, Fondazione Policlinico Campus Bio-medico, and Unit of Endocrinology and Diabetes, Campus Bio-medico University, Rome, Italy.
Endocrinology, University di Pisa, Pisa, Italy.
Endocrinology, Mayo Clinic E18-A, Rochester, Minnesota, USA.
Northern Nevada Endocrinology, University of Nevada, Reno, Nevada, USA.
Endocrinology, Diabetes, and Metabolic Bone Diseases, Technische Universität Dresden Medical Center, Dresden, Germany.
Endocrinology, Endocrinology and Spokane Osteoporosis, Spokane, Washington, USA.
Biolanalysis and Pharmacokinetics/Pharmacodynamics, Ascendis Pharma A/S, Hellerup, Denmark.
Endocrine Medical Sciences, Ascendis Pharma Inc, Palo Alto, California, USA.
Clinical Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.

由活性维生素 D 和钙组成的甲状旁腺功能减退症的常规疗法旨在缓解低钙血症，但无法恢复正常的甲状旁腺激素 (PTH) 生理机能。PTH 替代疗法是治疗甲状旁腺功能减退症的理想生理疗法。双盲、安慰剂对照、为期 26 周的 3 期 PaTHway 试验评估了使用研究药物 TransCon PTH（palopegteriparatide）对甲状旁腺功能减退症患者进行 PTH 替代疗法的有效性和安全性。参加者（n = 84) 以 3:1 的比例随机分配至每日一次的 TransCon PTH（最初为 18 μg/d）或安慰剂，两者均与常规疗法联合给药。根据血清钙指导的剂量算法滴定研究药物和常规疗法。复合主要疗效终点是在第 26 周达到正常白蛋白调整血清钙水平（8.3–10.6 mg/dL）、独立于常规治疗（不需要活性维生素 D 和≤600 mg/d 钙）的参与者比例，并且在第 26 周之前的 4 周内研究药物没有增加。其他感兴趣的结果包括通过 36 项简短调查 (SF-36) 测量的健康相关生活质量、甲状旁腺功能减退症相关症状、功能和良好-通过甲状旁腺功能减退症患者体验量表 (HPES) 和尿钙排泄进行测量。在第 26 周，p < 0.0001）。与安慰剂相比，TransCon PTH 治疗显示所有关键次要终点 HPES 领域得分（所有p < 0.01）和 SF-36 身体功能分量表得分（p = 0.0347）都有显着改善。此外，93% (57/61) 接受 TransCon PTH 治疗的参与者实现了对常规治疗的独立性。TransCon PTH 治疗使 24 小时尿钙均值正常化。总体而言，接受 TransCon PTH 治疗的 82% (50/61) 和 100% (21/21) wiplacebo 患者出现不良事件；大多数是轻度 (46%) 或中度 (46%)。没有发生研究药物相关的退出。总之，TransCon PTH 维持正常钙血症，同时允许独立于常规治疗，并且在甲状旁腺功能减退症患者中耐受性良好。© 2022 作者。Journal of Bone and Mineral Research由 Wiley Periodicals LLC 代表美国骨骼和矿物研究协会 (ASBMR) 出版。

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

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).

更新日期：2022-10-21

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