A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone-Deficient Adults
A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone-Deficient Adults
复制标题
DOI：
10.1210/jc.2013-1437
复制
发表时间：
2013-06-01
影响因子：
5.8
通讯作者：
Cleland, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Yuen, Kevin C. J.;Conway, Gerard S.;Cleland, Jeffrey L.
背景：每日施用重组人 GH (rhGH) 对患者依从性提出了相当大的挑战。减少给药频率可能会改善治疗依从性和潜在的整体治疗结果。 目的：本研究评估了 GH 缺乏症成人单剂量长效 rhGH 类似物 VRS-317 后的安全性和耐受性以及达到目标范围内 IGF-I 水平的潜力。设计：这是一项随机、双盲、安慰剂对照、单次剂量递增研究。患者：50 名生长激素缺乏症成年人（平均年龄 45 岁）在 5 个治疗组中进行研究，每个治疗组有 10 名受试者（8 名活性药物和 2 名安慰剂）。背景：该研究在北美和欧洲的 17 个成人内分泌中心进行。主要结果指标：不良事件、实验室安全性评估以及 VRS-317 药代动力学和药效学（IGF-I 和 IGF 结合蛋白-3）分析。结果：在 0.80 mg/kg 浓度下，VRS-317 的平均终末消除半衰期为 131 小时。单次 VRS-317 剂量 0.05、0.10、0.20、0.40 和 0.80 mg/kg（大约相当于 30 天内每日 rhGH 剂量 0.3-5.0 μg/kg）以剂量依赖性方式安全地增加了 IGF-I 反应的幅度和持续时间。单次 0.80 mg/kg 剂量后，血清 IGF-I 平均 3 周内维持在 -1.5 至 1.5 SD 值之间的正常范围。没有观察到意外或严重的不良事件。结论：VRS-317 的消除半衰期比之前研究的 rhGH 产品长 30 至 60 倍，并且刺激更持久的 IGF-I 反应。延长 IGF-I 反应不会以过度暴露于高 IGF-I 水平为代价。药代动力学和药效学与观察到的安全性相结合表明了安全有效的每月给药的潜力。
Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes.Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317.Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study.Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe.Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed.Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3-5.0 mu g/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed.Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.