Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
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- 9 July 2020
- journal article
- research article
- Published by Massachusetts Medical Society in New England Journal of Medicine
- Vol. 383 (2), 109-119
- https://doi.org/10.1056/NEJMoa2003715
Abstract
BackgroundTofersen 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. MethodsWe 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. ResultsA 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. ConclusionsIn 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. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.) In a phase 1-2 dose-escalation trial involving adults with ALS due to SOD1 mutations who received intrathecal tofersen (an antisense oligonucleotide) or placebo, the levels of mutant SOD1 in the CSF were 33 percentage points lower in the highest-dose tofersen group than in the placebo group.This publication has 18 references indexed in Scilit:
- Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS modelsJCI Insight, 2018
- Comprehensive analysis of the mutation spectrum in 301 German ALS familiesJournal of Neurology, Neurosurgery & Psychiatry, 2018
- Increase in DNA methylation in patients with amyotrophic lateral sclerosis carriers of not fully penetrant SOD1 mutationsAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2018
- Defining SOD1 ALS natural history to guide therapeutic clinical trial designJournal of Neurology, Neurosurgery & Psychiatry, 2016
- SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALSAdvances in Biological Regulation, 2015
- SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis PathologyThe Neuroscientist, 2014
- Is SOD1 loss of function involved in amyotrophic lateral sclerosis?Brain, 2013
- ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis geneticsHuman Mutation, 2012
- Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyondThe Journal of cell biology, 2009
- Mutation of SOD1 in ALS: a gain of a loss of functionHuman Molecular Genetics, 2007