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反义寡核苷酸tofersen治疗SOD1突变所致肌萎缩侧索硬化的1~2期试验
Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS


Timothy Miller ... 其他 • 2020.07.09
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摘要


背景

tofersen是一种反义寡核苷酸,介导超氧化物歧化酶1(SOD1)信使RNA的降解,从而减少SOD1蛋白的合成。目前正在研究tofersen鞘内给药治疗SOD1突变所致的肌萎缩侧索硬化(ALS)。

 

方法

我们开展了一项1~2期剂量递增试验,目的是评估tofersen在SOD1突变所致ALS成人患者中的作用。在各剂量组(20 mg、40mg、60 mg或100 mg)中,我们以3∶1的比例将参与者随机分组,分别接受为期12周的5剂tofersen或安慰剂鞘内给药。主要结局是安全性和药代动力学。次要结局是第85日的脑脊液(CSF)SOD1浓度相对于基线的变化。我们还测定了临床功能和肺活量。

 

结果

共计50例参与者被随机分组,并被纳入分析;48例参与者接受了计划的全部5剂治疗。大多数参与者发生了与腰椎穿刺相关的不良事件。在接受tofersen治疗的参与者中,分别有4例和5例报告了不良事件CSF白细胞计数增加和蛋白质升高。在接受tofersen治疗的参与者中,1例于第137日死于肺栓塞,1例于第152日死于呼吸衰竭;安慰剂组1例参与者于第52日死于呼吸衰竭。对于20 mg剂量、40 mg剂量、60 mg剂量和100 mg剂量,在tofersen组和安慰剂组之间,第85日的CSF SOD1浓度相对于基线的变化的差异分别为2个百分点(95%置信区间[CI],-18~27)、-25个百分点(95% CI,-40~-5)、-19个百分点(95% CI,-35~2)和-33个百分点(95% CI,-47~-16)。

 

结论

SOD1突变所致的ALS成人患者中,在12周期间,最高浓度tofersen鞘内给药后,CSF SOD1浓度降低。一些接受tofersen治疗的参与者出现了CSF脑脊液细胞增多。大多数参与者发生了与腰椎穿刺相关的不良事件(由渤健公司资助,在ClinicalTrials.gov注册号为NCT02623699;在EudraCT注册号为2015-004098-33)。





作者信息

Timothy Miller, M.D., Ph.D., Merit Cudkowicz, M.D., Pamela J. Shaw, M.D., M.B., B.S., Peter M. Andersen, M.D., Ph.D., Nazem Atassi, M.D., M.M.Sc., Robert C. Bucelli, M.D., Ph.D., Angela Genge, M.D., Jonathan Glass, M.D., Shafeeq Ladha, M.D., Albert L. Ludolph, M.D., Nicholas J. Maragakis, M.D., Christopher J. McDermott, M.D., Ph.D., Alan Pestronk, M.D., John Ravits, M.D., François Salachas, M.D., Randall Trudell, M.D., Philip Van Damme, M.D., Ph.D., Lorne Zinman, M.D., C. Frank Bennett, Ph.D., Roger Lane, M.D., Alfred Sandrock, M.D., Ph.D., Heiko Runz, M.D., Ph.D., Danielle Graham, Ph.D., Hani Houshyar, Ph.D., Alexander McCampbell, Ph.D., Ivan Nestorov, Ph.D., Ih Chang, Ph.D., Manjit McNeill, M.Sc., Laura Fanning, M.D., Stephanie Fradette, Pharm.D., and Toby A. Ferguson, M.D., Ph.D.
From the Washington University School of Medicine, St. Louis (T.M., R.C.B., A.P.); the Healey Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.C., N.A.), and Biogen, Cambridge (A.S., H.R., D.G., H.H., A.M., I.N., I.C., L.F., S.F., T.A.F.) — both in Massachusetts; the Sheffield Institute for Translational Neuroscience, University of Sheffield, and NIHR Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (P.J.S., C.J.M.), and Biogen, Maidenhead (M.M.) — both in the United Kingdom; the Department of Clinical Science, Neurosciences, Umeå University, Umea, Sweden (P.M.A.); Montreal Neurological Institute and Hospital, Montreal (A.G.), and Sunnybrook Research Institute, Toronto (L.Z.); Emory University, Atlanta (J.G.); Barrow Neurological Institute, Phoenix, AZ (S.L.); the University of Ulm, Ulm, Germany (A.L.L.); Johns Hopkins University School of Medicine, Baltimore (N.J.M.); the University of California San Diego, La Jolla (J.R.), and Ionis Pharmaceuticals, Carlsbad (C.F.B., R.L.) — both in California; Paris ALS Centre, Hôpital de la Salpêtrière, Paris (F.S.); the University of Tennessee Medical Center, Knoxville (R.T.); and KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.). Address reprint requests to Dr. Miller at the Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, or at miller.t@wustl.edu; or to Dr. Ferguson at Biogen, 225 Binney St., Cambridge, MA 02142, or at toby.ferguson@biogen.com.

 

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