BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial
BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial
复制标题
DOI：
10.1002/jbmr.3143
复制
发表时间：
2017-07-01
影响因子：
6.2
通讯作者：
Winkle, Peter J.
中科院分区：
文献类型：
--
作者：
Glorieux, Francis H.;Devogelaer, Jean-Pierre;Winkle, Peter J.
这项为期 21 周的开放标签 2a 期试验旨在评估 BPS804（一种中和性抗硬化素抗体）在成人中度成骨不全 (OI) 患者中多次、逐步输注的药效学和安全性。患者接受 BPS804（三个递增剂量，每个剂量间隔 2 周 [5、10 和 20 mg/kg]）或不接受治疗（参考组）。主要疗效终点是从基线到第 43 天的平均变化：1 型原胶原 N 端前肽 (P1NP)、1 型原胶原 C 端前肽 (P1CP)、骨特异性碱性磷酸酶 (BSAP)、骨钙素 (OC) 和 1 型胶原交联 C 端肽 (CTX-1)。还评估了腰椎面积骨矿物质密度 (aBMD) 从基线到第 141 天的平均变化。每两周评估一次 BPS804 的安全性和耐受性。总体而言，共有 14 名成年人入组（BPS804 组：n = 9，平均年龄 30.7 岁，平均 aBMD Z 得分 -2.6；参考组，n = 5，平均年龄 27.4 岁，平均 aBMD Z 得分 -2.2）。在 BPS804 组中，与基线相比，P1NP、P1CP、BSAP 和 OC 分别增加 84% (p< 0.001)、53% (p = 0.003)、59% (p< 0.001) 和 44% (p = 0.012)（参考：P1NP，+6% [p = 0.651]；P1CP， +5% [p = 0.600]；BSAP，-13% [p = 0.582]；OC，-19% [p = 0.436]）。 BPS804 治疗使 CTX-1 较基线下调 44%（参考：-7%；未测试该生物标志物的显着性），并使 aBMD 增加 4%（p = 0.038；参考组：+1%；p = 0.138）。 BPS804 总体耐受性良好。 9 名患者报告了 32 起不良事件；没有人怀疑与治疗相关。没有发生与治疗相关的骨折。 BPS804 可刺激中度成骨不全成人的骨形成、减少骨吸收并增加腰椎 aBMD。这为进一步研究 BPS804 在 OI 患者中的疗效、安全性和耐受性的长期 3 期试验铺平了道路。 (C) 2017 年美国骨与矿物质研究学会。
This 21-week, open-label, phase 2a trial aimed to evaluate the pharmacodynamics and safety of multiple, escalating infusions of BPS804, a neutralizing, anti-sclerostin antibody, in adults with moderate osteogenesis imperfecta (OI). Patients received BPS804 (three escalating doses each separated by 2 weeks [5, 10, and 20 mg/kg]) or no treatment (reference group). The primary efficacy endpoints were mean changes from baseline to day 43 in: procollagen type 1 N-terminal propeptide (P1NP), procollagen type 1 C-terminal propeptide (P1CP), bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and type 1 collagen cross-linked C-telopeptide (CTX-1). Mean change from baseline to day 141 in lumbar spine areal bone mineral density (aBMD) was also assessed. BPS804 safety and tolerability were assessed every 2 weeks. Overall, 14 adults were enrolled (BPS804 group: n = 9, mean age 30.7 years, mean aBMD Z-score -2.6; reference group, n = 5, mean age 27.4 years, mean aBMD Z-score -2.2). In the BPS804 group, P1NP, P1CP, BSAP, and OC were increased by 84% (p< 0.001), 53% (p = 0.003), 59% (p< 0.001), and 44% (p = 0.012), respectively, versus baseline (reference: P1NP, +6% [p = 0.651]; P1CP, +5% [p = 0.600]; BSAP, -13% [p = 0.582]; OC, -19% [p = 0.436]). BPS804 treatment downregulated CTX-1 by 44% from baseline (reference: -7%; significance was not tested for this biomarker), and increased aBMD by 4% (p = 0.038; reference group: +1%; p = 0.138). BPS804 was generally well tolerated. There were 32 adverse events reported in nine patients; none was suspected to be treatment-related. There were no treatment-related fractures. BPS804 stimulates bone formation, reduces bone resorption, and increases lumbar spine aBMD in adults with moderate OI. This paves the way for a longerterm, phase 3 trial into the efficacy, safety, and tolerability of BPS804 in patients with OI. (C) 2017 American Society for Bone and Mineral Research.