Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS | NEJM



The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).


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In this phase 3 trial, we randomly assigned adults with SOD1 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).


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.


In persons with SOD1 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 numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.)

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Tofersen for SOD1 ALS


Funding and Disclosures

Supported by Biogen.

Disclosure forms provided by the authors are available with the full text of this article at

A data sharing statement provided by the authors is available with the full text of this article at

We thank the participants in VALOR and the open-label extension and their families and caregivers, without whom this trial would not have been possible; members of global patient advocacy organizations; site staff (see the Supplementary Appendix); Christine Nelson, Pharm.D. (Biogen), and Yien Liu, Ph.D. (Excel Scientific Solutions), for medical writing assistance with earlier versions of the manuscript; and Cara Dickinson, B.A. (Excel Scientific Solutions), for assistance with copyediting and styling of an earlier version of the manuscript in accordance with Journal requirements.

Author 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 Neurodegenerative Erkrankungen, Bonn — both in Germany (A.C.L.); Emory University, Atlanta (J.D.G.); the Neurological Institute, Columbia University Irving Medical Center, New York (J.A.A.); and the Department of Neurology, University of Miami, Miami (M.B.).

Dr. Miller can be contacted at [email protected] or at the Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110. Dr. Fradette can be contacted at [email protected] or at Biogen, 225 Binney St., Cambridge, MA 02142.

The members of the VALOR and OLE Working Group are listed in the Supplementary Appendix, available at

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