美国华盛顿大学医学院Timothy Miller团队研究了反义寡核苷酸Tofersen治疗SOD1 ALS的疗效。该成果发表在2020年7月9日出版的《新英格兰医学杂志》上。

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。目前鞘内注射tofersen来治疗因SOD1突变而引起的肌萎缩侧索硬化症（ALS）正在研究中。

研究组进行了临床1-2期的递增剂量试验，以评估tofersen治疗因SOD1突变而患有ALS的成年人的疗效。在每个剂量组（20、40、60或100 mg）中，以3：1的比例随机分配参与者，分别接受5剂tofersen或安慰剂鞘内给药，为期12周。主要结果是安全性和药代动力学。次要结果为第85天时脑脊液（CSF）中SOD1浓度相对于基线的变化。

共有50名参与者接受了随机分组，并纳入了分析； 48名参与者接受了所有五种剂量。大多数参与者都观察到腰椎穿刺相关的不良事件。接受tofersen的参与者中有4名发生CSF白细胞计数升高，5名发生蛋白质升高等不良事件。在接受tofersen治疗的参与者中，有1例在第137天死于肺栓塞，另1例在第152天死于呼吸衰竭。安慰剂组中有1例参与者在第52天死于呼吸衰竭。治疗第85天，Tofersen 20 mg组和安慰剂组参与者的CSF SOD1浓度比基线高2个百分点，40 mg组比基线低25个百分点，60 mg组低19个百分点，100 mg组低33个百分点。

总之，在由SOD1突变引起ALS的成人中，在鞘内注射最高浓度的Tofersen，CSF SOD1浓度降低，持续12周，但一些患者出现脑脊液多细胞增多。

附：英文原文

Title: Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author: 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.,, Franois 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.

Issue&Volume: 2020-07-08

Abstract: Abstract

Background

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 SOD1 mutations.

Methods

We conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 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.

Results

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.

Conclusions

In adults with ALS due to SOD1 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.

DOI: 10.1056/NEJMoa2003715

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2003715