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.).
N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to mutations.
We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.
A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.
In adults with ALS due to mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
Tofersen 是一种反义寡核苷酸，可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。由于 突变，鞘内给予 tofersen 正在研究用于治疗肌萎缩侧索硬化症（ALS）。
我们进行了一项 1-2 期递增剂量试验，评估了鞘内给予 tofersen 治疗 突变引起的 ALS 成人患者的安全性和药代动力学。在每个剂量队列（20、40、60 或 100mg）中，参与者按 3:1 的比例随机分配接受 5 次 tofersen 或安慰剂鞘内注射，持续 12 周。主要结局是安全性和药代动力学。次要结局是第 85 天脑脊液（CSF）SOD1 浓度与基线相比的变化。测量临床功能和肺活量。
共有 50 名参与者接受了随机分组并纳入分析；48 名参与者接受了所有 5 个计划剂量。大多数参与者出现了腰椎穿刺相关的不良事件。在接受 tofersen 的 4 名和 5 名参与者中，分别有 1 名报告 CSF 白细胞计数和蛋白升高为不良事件。在接受 tofersen 的参与者中，1 名患者在第 137 天死于肺栓塞，1 名患者在第 152 天死于呼吸衰竭；1 名安慰剂组患者在第 52 天死于呼吸衰竭。在第 85 天，鞘内给予 tofersen 组与安慰剂组 CSF SOD1 浓度与基线相比的变化差值分别为：20mg 剂量组为 2 个百分点（95%置信区间[CI]，-18 至 27），40mg 剂量组为 25 个百分点（95%CI，-40 至-5），60mg 剂量组为 19 个百分点（95%CI，-35 至 2），100mg 剂量组为 33 个百分点（95%CI，-47 至-16）。
在因 突变而患有 ALS 的成年人中，在 12 周的时间内，鞘内给予最高浓度的 tofersen 导致 CSF SOD1 浓度下降。一些接受 tofersen 的患者出现 CSF 白细胞增多。大多数参与者出现与腰椎穿刺相关的不良事件。（由 Biogen 资助；临床试验.gov 编号，NCT02623699；EudraCT 编号，2015-004098-33.）。
