Single-and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody Against Sclerostin, in Healthy Postmenopausal Women
Single-and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody Against Sclerostin, in Healthy Postmenopausal Women
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DOI：
10.1002/jbmr.2092
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发表时间：
2014-04-01
影响因子：
6.2
通讯作者：
Chiang, Alan Y.
中科院分区：
文献类型：
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作者：
McColm, Juliet;Hu, Leijun;Chiang, Alan Y.
进行了两项临床研究，以评估绝经后女性（包括既往/当前双膦酸盐（BP）使用者）单次和多次给药（静脉[iv]和皮下[sc]）blosozumab的安全性、耐受性、药代动力学（PK）和药效学（PD）。在这些I期、随机化、受试者和研究者设盲、安慰剂对照研究中，受试者接受递增剂量的blosozumab：单次静脉给药高达750 mg，单次皮下给药150 mg，多次静脉给药高达750 mg每2周一次（Q2 W），持续8周，多次皮下给药高达270 mg Q2 W，持续8周，或安慰剂。在单次给药研究中，6例受试者被随机分配至每个剂量组（安慰剂组12例），在多次给药研究中，每组最多12例受试者。Blosozumab耐受性良好，单次或多次给药高达750 mg后未发现安全性问题。单次和多次（最多5次）给予blosozumab后，在硬化蛋白、1型前胶原N末端前肽、骨特异性碱性磷酸酶、骨钙素、1型胶原C末端片段和骨矿物质密度（BMD）中观察到剂量依赖性反应。在单次或多次给予blosozumab后第85天，腰椎BMD相对于基线的变化分别高达3.41%（p= 0.002）和7.71%（p< 0.001）。当考虑骨生物标志物和BMD反应时，既往BP使用似乎对单次给药blosozumab的作用没有明显影响。通过筛选试验检测到blosozumab抗体，但未发现剂量或给药途径的模式，也未发现对blosozumab暴露或PD应答的明显影响。总之，blosozumab耐受性良好，对骨具有合成代谢作用。这些发现支持进一步研究blosozumab作为骨质疏松症的潜在合成代谢疗法。© 2014美国骨与矿物质研究学会。
Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject‐ and investigator‐blind, placebo‐controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single‐dose study (12 to placebo) and up to 12 subjects to each arm in the multiple‐dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose‐dependent responses were observed in sclerostin, N‐terminal propeptide of procollagen type 1, bone‐specific alkaline phosphatase, osteocalcin, C‐terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p= 0.002) and up to a 7.71% (p< 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.