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Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Open accessAbstract
BACKGROUND: mutations. METHODS: 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: 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.).
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“ASO injection is a current standard of care for the fatal childhood disease spinal muscular atrophy15 and is in five ongoing Phase I trials in ALS, Parkinson’s, and Alzheimer’s diseases and in Phase III trials for inherited ALS from a mutation in superoxide dismutase16,17 and for Huntington’s disease18.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [17]
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“Experience from Alzheimer’s disease (AD), spinal muscular atrophy (SMA),5 and amyotrophic lateral sclerosis (ALS)6 suggests treating FTD will be most successful if treatment is initiated early in the disease course, ideally prior to the onset of symptoms.”
From Temporal order of clinical and biomarker changes in familial frontotemporal dementia (2022) · cites this paper as [6]
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Metadata
- Authors
- Miller, T., Cudkowicz, M., Shaw, P. J., Andersen, P. M., Atassi, N., Bucelli, R. C., Genge, A., Glass, J., Ladha, S., Ludolph, A. L., Maragakis, N. J., McDermott, C. J., Pestronk, A., Ravits, J., Salachas, F., Trudell, R., Van Damme, P., Zinman, L., Bennett, C. F., Lane, R., Sandrock, A., Runz, H., Graham, D., Houshyar, H., McCampbell, A., Nestorov, I., Chang, I., McNeill, M., Fanning, L., Fradette, S., & Ferguson, T. A.
- Affiliations
- 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...
- Harvard University (US)
- Montreal Neurological Institute and Hospital (CA)
- Barrow Neurological Institute (US)
- Biogen (United States) (US)
- ORCID
- Cudkowicz, Merit
- Shaw, Pamela J.
- Andersen, Peter M.
- Atassi, Nazem
- Bucelli, Robert C.
- Genge, Angela
- Glass, Jonathan
- Ladha, Shafeeq
- Maragakis, Nicholas J.
- McDermott, Christopher J.
- Pestronk, Alan
- Ravits, John
- Trudell, Randall
- Zinman, Lorne
- Bennett, C. Frank
- Lane, Roger
- Runz, Heiko
- Graham, Danielle
- McCampbell, Alexander
- Nestorov, Ivan
- Chang, Ih
- Fradette, Stephanie
- Ferguson, Toby A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-07-09
- Volume
- 383
- Issue
- 2
- Pages
- 109-119
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3040840440
- Cited by
- 565
- References
- 27
- Citations by year
- 2026: 64 · 2025: 73 · 2024: 87 · 2023: 90 · 2022: 130 · 2021: 83 · 2020: 36
- FWCI
- 36.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0617-10077)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- tofersen, antisense oligonucleotides, amyotrophic lateral sclerosis, SOD1, intrathecal administration, pleocytosis, dose escalation
- MeSH terms
- Superoxide Dismutase-1, Adult, Amyotrophic Lateral Sclerosis, Dose-Response Relationship, Drug, Double-Blind Method, Female, Headache, Humans, Injections, Spinal, Intermediate Filaments, Leukocytosis, Male, Middle Aged, Mutation, Oligonucleotides, Vital Capacity, Oligonucleotides, Antisense, Disease Progression
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