Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Open accessAbstract
BACKGROUND: ALS). METHODS: ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).
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The most common therapeutic route for CSF drug delivery is intrathecal administration into the lumbar cistern.
“The CSF has several access points for drug delivery, the most common therapeutic route being intrathecal administration into the lumbar cistern.”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [43]
The Trial Design section says tofersen was delivered by intrathecal injection through a lumbar puncture, supporting this route as an example of therapeutic CSF drug delivery. It does not say that this is the most common route, identify the lumbar cistern specifically, or compare CSF access points. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeveral ASO therapies targeting genes in the spinal cord provide clinical benefit after intrathecal administration; Spinraza and Tofersen have extended survival for patients with spinal muscular atrophy and amyotrophic lateral sclerosis, respectively.
“Notably, several ASO therapies targeting genes in the spinal cord provide clinical benefit after intrathecal administration; Spinraza and Tofersen have extended survival for patients with spinal muscular atrophy and amyotrophic lateral sclerosis, respectively [43,51].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [43]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSeveral ASO therapies targeting genes in the spinal cord provide clinical benefit after intrathecal administration, with Spinraza and Tofersen extending survival in SMA and ALS patients.
“Notably, several ASO therapies targeting genes in the spinal cord provide clinical benefit after intrathecal administration; Spinraza and Tofersen have extended survival for patients with Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis, respectively.5,6”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [6]
The trial description (p. 1100) confirms that tofersen is an intrathecally administered ASO studied in adults with SOD1 ALS. The combined VALOR and open-label extension analysis (p. 1104) reports a lower hazard of death for early-start than delayed-start participants, but says median survival could not be estimated because there were few events; this does not establish that tofersen extended survival for ALS patients generally. This paper does not address Spinraza or SMA. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- Authors
- Miller, T. M., Cudkowicz, M. E., Genge, A., Shaw, P. J., Sobue, G., Bucelli, R. C., Chiò, A., Van Damme, P., Ludolph, A. C., Glass, J. D., Andrews, J. A., Babu, S., Benatar, M., McDermott, C. J., Cochrane, T., Chary, S., Chew, S., Zhu, H., Wu, F., Nestorov, I., Graham, D., Sun, P., McNeill, M., Fanning, L., Ferguson, T. A., & Fradette, S.
- Affiliations
- From the Washington University School of Medicine, St. Louis (T.M.M., R.C.B.); the Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.E.C., S.B.), and Biogen, Cambridge (T.C., S. Chary, S. Chew, H.Z., F.W., I.N., D.G., P.S., L.F., T.A.F., S.F.) — both in Massachusetts; Montreal Neurological Institute and Hospital, Montreal (A.G.); the Sheffield Institute for Translational Neuroscience, University of Sheffield, and the National Institute for Health and Care Research 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; Aichi Medical University, Aichi, Japan (G.S.); the University of Turin, Turin, Italy (A.C.); KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.); the University of Ulm, Ulm, and Deutsches Zentrum für Neuro...
- Montreal Neurological Institute and Hospital (CA)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2022-09-22
- Volume
- 387
- Issue
- 12
- Pages
- 1099-1110
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4296698991
- Cited by
- 966
- References
- 2
- Citations by year
- 2026: 257 · 2025: 269 · 2024: 269 · 2023: 151 · 2022: 18 · 2019: 1
- FWCI
- 93.20
- 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)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Lirias (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Biogen
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- tofersen, antisense oligonucleotides, amyotrophic lateral sclerosis, SOD1, neurofilament light chain, ALSFRS-R, disease progression, neurological adverse events, open-label extension, muscle strength, vital capacity, biomarkers
- MeSH terms
- Superoxide Dismutase-1, Adult, Amyotrophic Lateral Sclerosis, Double-Blind Method, Humans, Injections, Spinal, Oligonucleotides, Biomarkers, Oligonucleotides, Antisense, Neurofilament Proteins, Recovery of Function
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