Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial
Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial
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DOI：
10.1016/s1474-4422(20)30489-0
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发表时间：
2021-03-01
期刊：
影响因子：
48
通讯作者：
Florian, Hana
中科院分区：
文献类型：
--
作者：
Hoeglinger, Guenter U.;Litvan, Irene;Florian, Hana
背景进行性核上性麻痹是一种与tau蛋白聚集相关的神经退行性疾病。Tilavonemab(ABBV-8E12)是一种与人tau蛋白N末端结合的单抗。方法我们在澳大利亚、加拿大、法国、德国、意大利、日本、西班牙和美国的66家医院和诊所进行了一项第二阶段的多中心、随机、安慰剂对照、双盲研究。被诊断为可能或可能的进行性核上性麻痹的参与者(年龄=40岁)，症状出现时间不到5年，有可靠的研究伙伴，能够在最小限度的帮助下走五步，通过互动反应技术被随机分配(1：1：1)，在第1、15和29天静脉注射替拉蒙单抗2000 mg、替拉蒙单抗4000 mg或匹配的安慰剂，然后每28天一次，直到52周治疗结束。随机化是由研究赞助商的随机化专家完成的，他没有参加过这项研究。赞助商、研究人员和参与者并不知道治疗分配。主要终点是意向治疗人群中进行性核上性瘫痪评定量表(PSPRS)总分从基线到第52周的变化。对接受至少一剂研究药物的参与者的不良事件进行了监测。预先指定的临时无效标准是基于模型效应大小，当60名参与者完成52周的治疗时，其效果大小为0或更低，而当120名参与者完成52周的治疗时，其效果大小为0.12或更低。这项研究在ClinicalTrials.gov上注册，编号NCT02985879。研究结果在2016年12月12日至2018年12月31日期间，466名参与者接受了筛查，378人被随机分配。在第二次中期分析满足预先指定的无效性标准后，该研究于2019年7月3日终止。共有377名参与者接受了至少一剂研究药物，并被纳入疗效和安全性分析(2000毫克，n=126；4000毫克，n=125；安慰剂，n=126)。从基线到第52周，所有组的PSPRS的最小二乘平均变化都是相似的(组间差异：2000 mg，0.0[95%CI-2.6to2.6]，效应大小0.000，p>；0.99；4000 mg，1.01.0[-1.6to3.6]，-0.105，p=0.46)。大多数参与者报告了至少一次不良事件(2000毫克，111[88%]；4000毫克，111[89%]；安慰剂，108[86%])。跌倒是最常见的不良反应(2000毫克，42[33%]；4000毫克，54[43%]；安慰剂，49[39%])。发生严重不良事件的患者比例在各组间相似(2000毫克，29例[23%]；4000毫克，34例[27%]；安慰剂33例[26%])。跌倒是最常见的治疗紧急严重不良事件(2000毫克，5[4%1；4000毫克，6[5%]；安慰剂，6[5%])。在研究期间发生了26例死亡(2000毫克，9例[7%]；4000毫克，9例[7%]；安慰剂，8例[6%])，但没有一例与药物有关。未记录到有益的治疗效果。虽然这项研究没有提供进行性核上性麻痹有效的证据，但这些发现为未来使用tau抗体进行被动免疫治疗进行性核上性瘫痪提供了潜在的有用信息。版权所有(C)2021爱思唯尔有限公司。保留所有权利。
Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy.Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged >= 40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0.12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879.Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received a t least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0.0 [95% CI -2.6 to 2.6], effect size 0.000, p>0.99; 4000 mg, 1.0 [-1.6 to 3.6], -0.105, p=0.46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%1; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related.Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Copyright (C) 2021 Elsevier Ltd. All rights reserved.