First ever targeted treatment for SOD1-ALS: FDA approve tofersen

On April 25th, 2023, the U.S. Food and Drug Administration (FDA) approved tofersen (BIIB067) for the treatment of amyotrophic lateral sclerosis (ALS) associated with a superoxide dismutase 1 (SOD1) mutation, making it is the fourth drug available for patients with ALS and the first approved specifically for use in SOD1-ALS.1

ALS is a rare and fatal neurodegenerative disease that results from the loss of motor neurons involved in controlling voluntary muscle movement. It is characterized by progressive muscle weakness and atrophy, which leads to a loss of independence as the ability to move, speak, eat, and ultimately breathe diminishes. Once symptoms present, the life expectancy is 3-5 years, which can be even lower in patients with SOD1-ALS.2 Around 2% of ALS cases are SOD1-ALS and over 200 mutations have been described, which are associated with highly variable rates of progression and disease severity.3 It remains unclear whether all ALS-related SOD1 mutations are causative in nature or if some are only modifying or accompanying variants. It is believed that the neuronal degeneration seen in SOD1-ALS is caused by a toxic gain of function mutation within the SOD1 gene, which causes structural destabilization and subsequent protein aggregation.3 However, the exact set of causes of neuronal loss is an ongoing debate, and some argue that detrimental loss of activity of SOD1 may also contribute to pathogenesis. Before now, there had been no approved targeted treatment for SOD1-ALS.

Tofersen (also known as BIIB067) is an antisense oligonucleotide (ASO) that is intrathecally administered³. It is believed to reduce the synthesis of SOD1 protein by inducing RNase H-mediated degradation of SOD1 messenger RNA³. Steady progress has been made in this space, with several other ASO-based strategies approved in recent years, including in Duchenne muscular dystrophy and spinal muscular atrophy.

The approval of tofersen comes following the placebo-controlled, double-blinded, randomized (2:1 ratio), Phase III VALOR trial (NCT02623699). A total of 108 participants were involved in this study across 32 sites in 10 countries, which ran from 2016-2021.4 Initially, there was a 4-week screening period, followed by 24 weeks of treatment and long-term follow-up in an ongoing open-label extension (OLE) study. Over the treatment period, participants received 8 doses of tofersen (n=72) or placebo (n=36) (100mg) by intrathecal bolus injection.4 There were three doses every 2 weeks, followed by 5 doses once every four weeks. The primary endpoint was the change from baseline to week 28 in total score on the ALS Functional Rating Scale-Revised (ALSFRS-R) with secondary endpoints such as change in concentration of SOD1 protein in cerebrospinal fluid (CSF) and concentration of neurofilament light chain (NfL) in plasma.3

Despite VALOR not reaching statistical significance in its primary endpoint, there were certainly trends toward reduced disease progression in the treatment arm across the secondary and exploratory endpoints. The primary endpoint showed the change at week 28 in ALSFRF-R score was -6.98 for tofersen and -8.14 for placebo (p=0.97).3 Tofersen use led to greater reductions in the concentration of SOD1 in the CSF and in plasma NfL when compared to placebo. Given the close associations between SOD1 and NfL and the presumed disease processes, these findings were taken as a sign of the potential therapeutic effect of tofersen. Most of the adverse events in the VALOR trial were mild to moderate in severity and did not cause withdrawal or discontinuation of the trial agent.3

‘There is a substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process’ – Timothy Miller, MD, PhD, Principal Investigator of VALOR and Co-Director of the ALS Center at Washington University School of Medicine, St. Louis.2

The approval of tofersen was based on the NfL findings, with treatment leading to a 55% reduction in plasma NfL, compared to a 12% increase in those treated with placebo.1 The FDA Advisory Committee unanimously agreed that the reduction in plasma NfL seen with tofersen treatment was reasonably likely to predict clinical benefit in SOD1-ALS.5

Following on from VALOR, the OLE (NCT03070119) recruited 95 participants and will last 236 weeks.³  A prespecified combined analysis of VALOR and its OLE took place at 52 weeks, which witnessed a smaller decline in the ALSFRS-R score, respiratory strength, and muscle strength for the patients who had started with tofersen early, compared to delayed initiation six months later (not statistically significant).³ These findings supported the decision by the FDA to approve tofersen.

An additional Phase III trial is ongoing (ATLAS; NCT04856982), which is investigating tofersen use in presymptomatic adult carriers of a SOD1 mutation with elevated NfL levels and if this can delay clinical onset.3 It has recruited 150 individuals since May 2021, and is expected to finish in August 2027. The continued approval of tofersen may rely on verification of its clinical benefit in this confirmatory trial.

The approval of tofersen is a huge step in tackling SOD1-ALS and, as the first genetically targeted treatment of ALS, paves the way for new precision treatments.

Written by Ashely Ellison

Reviewed by Juliet Lawrence


  1. FDA. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. [Press Release]. 25 Apr 2023. Accessed 25 Apr 2023.
  2. Biogen. The New England Journal of Medicine Publishes Pivotal Tofersen Data that Show Benefits in Rare, Genetic Form of ALS. [Press Release]. 21 Sep 2022. Accessed 25 Apr 2023.
  3. Miller T, Cudkowicz M, Genge A, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. Sep 2022;387(12):1099-110.
  4. An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS) (VALOR (Part C)). Accessed 25 Apr 2023.
  5. Biogen. Biogen Provides Update on FDA Advisory Committee Meeting on Tofersen for SOD1-ALS. [Press Release] 22 Mar 2023. Accessed 25 Apr 2023.