克拉屈滨治疗复发型多发性硬化症的临床及机制效应：MAGNIFY-MS研究的2年结果

Clinical and mechanistic effects of cladribine in relapsing multiple sclerosis: 2-year results from the MAGNIFY-MS Study.

作者信息

Schmierer Klaus, Wiendl Heinz, Barkhof Frederik, Montalban Xavier, Achiron Anat, Derfuss Tobias, Chan Andrew, Hodgkinson Suzanne, Prat Alexandre, Leocani Letizia, Sellebjerg Finn, Vermersch Patrick, Jin Hulin, Sponton Laura, Chudecka Anita, Gardner Lidia, De Stefano Nicola

机构信息

The Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Faculty of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.

Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.

出版信息

Ther Adv Neurol Disord. 2025 Jul 31;18:17562864251351760. doi: 10.1177/17562864251351760. eCollection 2025.

DOI:10.1177/17562864251351760

PMID:40756532

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12317234/

Abstract

BACKGROUND

Cladribine, an oral prodrug, penetrates the blood-brain barrier, impacting biomarkers of disease progression within the central nervous system.

OBJECTIVES

Describe disease activity in cladribine tablets (CladT)-treated people with highly active relapsing multiple sclerosis (pwRMS) using clinical outcomes and biomarkers.

DESIGN

MAGNIFY-MS was an open-label, single-arm, phase IV trial with four sub-studies. Participants were grouped by previous treatment (Tx); Tx-naïve versus Tx-experienced; those with previous exposure to second-line therapies were excluded. This analysis describes cerebrospinal fluid (CSF) and optical coherence tomography (OCT) sub-studies. CSF sub-study participants were stratified by the number of oligoclonal bands (OCBs) at baseline (≥2/≥4).

METHODS

Logistic regression analysis is reported for no evidence of disease activity (NEDA)-3 and no evidence of progression or active disease (NEPAD) at Year (Y)1 and Y2, and annualized relapse rate (ARR) at Y2. Changes in intrathecal (OCBs, kappa free light chain [KFLC], immunoglobulin [Ig]G and IgM indices), OCT measures, and neuroaxonal degeneration (neurofilament light chain [NfL]) biomarkers are reported at baseline, month (M)12, and M24.

RESULTS

MAGNIFY-MS included 270 pwRMS; 28 and 36 were included in the CSF and OCT sub-studies, respectively. In Y2, estimated rates of NEDA-3 were 64.1% overall and 69.1% in the Tx-naïve group. The estimated rate of NEPAD overall was 60.2% in Y2. The estimated ARR was 0.09 from baseline to M24 (Tx-naïve participants, 0.04). In participants with ≥2 OCBs at baseline ( = 17), 76.5% had OCB reduction or disappearance at least once in the study. KFLC and IgG indices were reduced at M24 versus baseline. Sustained reductions were observed in median NfL, while IgG and IgM remained within normal ranges for most participants. Mean OCT measurements showed no retinal nerve fiber thinning.

CONCLUSION

For CladT-treated pwRMS, disease activity and biomarkers of intrathecal inflammation and neuroaxonal damage were reduced versus baseline.

TRIAL REGISTRATION

ClinicalTrials.gov identifier, NCT03364036. Date registered: June 12, 2017. Date first patient enrolled: May 28, 2018. https://clinicaltrials.gov/study/NCT03364036. Extension study ClinicalTrials.gov Identifier: NCT04783935. Date registered: March 05, 2021. Date first patient enrolled: March 10, 2021. https://clinicaltrials.gov/study/NCT04783935.

摘要

背景

克拉屈滨是一种口服前体药物，可穿透血脑屏障，影响中枢神经系统内疾病进展的生物标志物。

目的

使用临床结局和生物标志物描述接受克拉屈滨片（CladT）治疗的高度活动性复发型多发性硬化症（pwRMS）患者的疾病活动情况。

设计

MAGNIFY-MS是一项开放标签、单臂、IV期试验，包含四项子研究。参与者按既往治疗情况分组；初治患者与经治患者；既往接受过二线治疗的患者被排除。本分析描述脑脊液（CSF）和光学相干断层扫描（OCT）子研究。CSF子研究参与者按基线时寡克隆带（OCB）数量分层（≥2/≥4）。

方法

报告了第1年（Y1）和第2年（Y2）无疾病活动证据（NEDA）-3和无进展或活动性疾病证据（NEPAD）的逻辑回归分析，以及Y2时的年化复发率（ARR）。报告了基线、第12个月（M12）和第24个月时鞘内（OCB、游离κ轻链[KFLC]、免疫球蛋白[Ig]G和IgM指数）、OCT测量值以及神经轴索变性（神经丝轻链[NfL]）生物标志物的变化。

结果

MAGNIFY-MS纳入了270例pwRMS患者；CSF和OCT子研究分别纳入了28例和36例。在Y2时，总体NEDA-3估计率为64.1%，初治组为69.1%。Y2时总体NEPAD估计率为60.2%。从基线到M24的估计ARR为0.09（初治参与者为0.04）。在基线时OCB≥2的参与者（n = 17）中，76.5%在研究中至少有一次OCB减少或消失。与基线相比，M24时KFLC和IgG指数降低。观察到NfL中位数持续降低，而大多数参与者的IgG和IgM仍在正常范围内。平均OCT测量显示视网膜神经纤维无变薄。