那他珠单抗 6 周给药与持续 4 周给药治疗复发缓解型多发性硬化症的药代动力学和药效学。
Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis.
机构信息
From the Rocky Mountain MS Clinic (J.F.F.), Salt Lake City, UT; Department of Neurology (G.D.), Centre Hospitalier Universitaire de Caen, France; Hackensack Meridian Medical Group - Neurology (L.Z.R.), Jersey Shore University Medical Center, Neptune City, NJ; Mellen MS Center (J.A.C.), Neurological Institute, Cleveland Clinic, OH; Montréal Neurological Institute (D.L.A.), McGill University; NeuroRx Research (D.L.A.), Montréal, Quebec, Canada; Department of Neuroscience (H.B.), Central Clinical School, Monash University, Melbourne, Victoria, Australia; University of Alabama at Birmingham (G.R.C.), School of Public Health; Blizard Institute (G.G.), Barts and The London School of Medicine and Dentistry; Queen Mary University of London (G.G.), United Kingdom; Department of Neurology (J.K.), Amsterdam University Medical Centers, Vrije Universiteit, Netherlands; Department of Neurology with Institute of Translational Neurology (H.W.), University of Münster, Germany; Biogen (K.L., L.D., M.T., K.F., J.S., T.L.), Cambridge, MA; and Ashfield MedComms (H.E.), Middletown, CT.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2024 Dec;11(6):e200321. doi: 10.1212/NXI.0000000000200321. Epub 2024 Oct 11.
BACKGROUND AND OBJECTIVES
Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA.
METHODS
In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity.
RESULTS
In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%.
DISCUSSION
Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice.
TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.
背景与目的
纳武利尤单抗是一种有效的治疗复发性多发性硬化症（RRMS）的药物，与进行性多灶性白质脑病（PML）的风险增加有关。与每 4 周（Q4W）给药相比，纳武利尤单抗的延长间隔给药与 PML 风险降低相关。在第 3b 期 NOVA 临床试验中，大多数转换为每 6 周（Q6W）给药的患者保持了临床疗效。在本文中，我们报告了 NOVA 中 Q6W 与 Q4W 给药的药代动力学（PK）和药效学（PD）。
方法
在 NOVA 研究第 1 部分中，RRMS 患者（年龄 18-60 岁，扩展残疾状况量表评分<5.5），接受 IV 纳武利尤单抗 Q4W 治疗≥12 个月，随机继续 IV Q4W 纳武利尤单抗治疗或转换为 IV Q6W 纳武利尤单抗治疗，并随访 72 周。探索性结果是测量血清纳武利尤单抗浓度、α4-整合素饱和度和可溶性血管细胞黏附分子-1（sVCAM-1）浓度的低谷值。使用重复测量的混合模型来估计组间的平均治疗差异。在有复发或影像学疾病活动的患者中检查了个体水平的 PK 和 PD 数据。
结果
在 NOVA 中，486 名（Q6W，n=245；Q4W，n=241）和 487 名（Q6W，n=246；Q4W，n=241）参与者分别纳入 PK 和 PD 人群。纳武利尤单抗的平均谷浓度范围为 10-21μg/mL（Q6W）和 33-38μg/mL（Q4W），α4-整合素饱和度平均保持在 65.5%（Q6W）以上和 77.9%（Q4W）以上。在 Q6W 组中，sVCAM-1 水平在第 24 周增加了 23.6%，并在整个研究期间保持升高，而 Q4W 组的 sVCAM-1 水平基本保持稳定。在任一治疗组中，大多数有 T2 病变活动或复发活动的患者，均保持纳武利尤单抗谷浓度>10μg/mL和谷α4-整合素饱和度>50%。
讨论
与 Q4W 给药相比，Q6W 给药使平均纳武利尤单抗谷浓度降低 60%-70%，平均α4-整合素饱和度降低 9%-16%。在个体水平上，纳武利尤单抗浓度和α4-整合素饱和度均不能一致地预测病变或复发活动，这表明在临床实践中应谨慎解读纳武利尤单抗和α4-整合素饱和度的测量结果。
临床试验注册信息
ClinicalTrials.gov，NCT03689972；EudraCT，2018-002145-11。2018 年 9 月 27 日提交。首次入组患者：2018 年 12 月 26 日。https://clinicaltrials.gov/study/NCT03689972。
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