Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis The MIRROR study
Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis The MIRROR study
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DOI：
10.1212/wnl.0000000000005516
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发表时间：
2018-05-15
期刊：
影响因子：
9.9
通讯作者：
Sorensen, Per S.
中科院分区：
文献类型：
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作者：
Bar-Or, Amit;Grove, Richard A.;Sorensen, Per S.
目的在2b期复发性多发性硬化(RMS)双盲研究中，评价抗CD20单抗对多发性硬化(RMS)疗效和安全性的量效关系。方法将232例患者随机分为单抗3 mg、30 mg、60 mg每12周一次，单抗60 mg每4周一次，或安慰剂24周，主要终点为12周时新出现的Gd强化病变的累积数量(每例脑MRI)。评估复发和安全性/耐受性，并测定CD19+外周血B淋巴细胞计数。安全性监测持续24到48周，随后的个体化随访评估B细胞的回收。结果与安慰剂相比，所有阿托单抗剂量组的累积新病变数量减少了65%(p<；0.001)。专案后分析(不包括第1-4周)估计，在所有累积的阿托单抗剂量=30毫克/12wk的情况下，与安慰剂(第12周)相比，皮损减少了90%。CD19B细胞呈剂量依赖性耗竭。值得注意的是，完全耗尽并不是强大的治疗效果所必需的。最常见的不良反应是注射相关反应(52%的阿托单抗，15%的安慰剂)，97%的不良反应为轻至中度，最常见的是与第一次注射有关，并随着后续剂量的减少而减少。结论影像显示所有阿托单抗皮下注射都显示出疗效(最稳健：累积剂量=30 mg/12wk)，安全性与现有的阿托单抗数据一致。这种治疗效果也发生在仅部分耗尽循环B细胞的剂量方案中。证据分类这项研究提供了I类证据，证明对于RMS患者，在开始治疗12周后，Of atumab减少了新的MRI Gd增强病变的数量。
ObjectiveTo assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).MethodsPatients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.ResultsThe cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a >= 90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses >= 30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.ConclusionImaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses >= 30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.Classification of evidenceThis study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.