Hartung Hans-Peter, Derfuss Tobias, Cree Bruce Ac, Sormani Maria Pia, Selmaj Krzysztof, Stutters Jonathan, Prados Ferran, MacManus David, Schneble Hans-Martin, Lambert Estelle, Porchet Hervé, Glanzman Robert, Warne David, Curtin Francois, Kornmann Gabrielle, Buffet Bénédicte, Kremer David, Küry Patrick, Leppert David, Rückle Thomas, Barkhof Frederik
Department of Neurology, Universitätsklinikum Düsseldorf (UKD) and Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany/Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany/Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia/Department of Neurology, Medical University of Vienna, Vienna, Austria.
Department of Neurology, Universitätsspital Basel, Basel, Switzerland.
Mult Scler. 2022 Mar;28(3):429-440. doi: 10.1177/13524585211024997. Epub 2021 Jul 9.
The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions.
This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups.
The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions ( = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged.
Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS.
CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18.
人类内源性逆转录病毒W（HERV-W-Env）的包膜蛋白由巨噬细胞和小胶质细胞表达，介导慢性活动性多发性硬化症（MS）病变中的轴突损伤。
这项针对复发缓解型MS的2期双盲、为期48周并延长48周的试验评估了替美立单抗的疗效和安全性；替美立单抗是一种中和HERV-W-Env的单克隆抗体。主要终点是在第24周时脑磁共振成像（MRI）扫描中钆增强T1病变累积数的减少。其他终点包括T2和T1低信号病变的数量、磁化传递率和脑萎缩。总共270名参与者被随机分组，接受每月一次静脉注射替美立单抗（6、12或18mg/kg）或安慰剂，为期24周；在第24周时，接受安慰剂治疗的参与者被重新随机分组至各治疗组。
未达到主要终点。在第48周时，与安慰剂/对照治疗组相比，接受18mg/kg替美立单抗治疗的参与者出现的新T1低信号病变较少（P = 0.014），并且脑萎缩和磁化传递率降低呈现出持续但无统计学意义的下降趋势。后两种趋势在96周内持续存在。未出现安全性问题。
替美立单抗未能显示出对急性炎症特征的作用，但表现出可能的抗神经退行性作用的初步影像学迹象。当前数据支持替美立单抗用于进展型MS的研发。
CHANGE-MS：ClinicalTrials.gov：NCT02782858，EudraCT：2015-004059-29；ANGEL-MS：ClinicalTrials.gov：NCT03239860，EudraCT：2016-004935-18。
