Lay summary by Matthew Chakraverty, reviewed by Dr Naomi Hartopp and an MND lay panel
Background
Mutations in the gene which code for the protein SOD1 are one of the most common genetic causes of motor neuron disease (MND). In healthy people, SOD1 (superoxide dismutase) protects cells from reactive molecules, but the mutation damages this function and can even cause harm instead.
Tofersen is a potential treatment to slow MND marketed under the brand name ‘Qalsody’. It is a type of medication called ‘antisense oligonucleotides’ which aims to stop cells from producing unhealthy SOD1. In motor neurons (the cells most affected by MND) this could limit damage and thus the symptoms of MND. Tofersen has been effective in short term clinical trials but whether it will continue to work effectively and safely over a period of months or years was unknown.
Why is the study important?
Current therapies for MND only extend a patient’s life for a few months. There is a huge unmet need for therapies that tackle the disease. Approximately 2% of MND cases are caused by SOD1 and could be treated by Tofersen. A previous international study of 108 MND SOD1 patients found Tofersen to be safe and effective in the short term. This previous study came to this conclusion by giving half the patients the drug and comparing the outcomes with the other half who received standard treatment. To be approved for longer term use it needed to be tested further so a longer clinical trial was organised.
What did the authors do and how did they do it?
In this study patients from the original Tofersen study could continue to participate; 95 of the MND patients decided to continue. Patients were separated into 2 groups: those who had started treatment during the first study and were said to have an ‘early start’ and those who started treatment during the second study were said to have a ‘delayed start’.
The authors measured changes in SOD1 levels, damage to neurons, ability to breathe, muscle strength and the time before either dying or needing machinery to breathe. Importantly they also measured the patient’s ‘quality of life’ as the aim of new medication is not just to extend someone’s life but to make them more comfortable for longer. These changes in total were measured for a total of 3 years from the beginning of the original study.
What are the results?
In both groups there was a decrease in SOD1 levels after eight weeks from starting treatment, so Tofersen was working on the unhealthy SOD1 gene. Levels of neurofilament light chain, which is a protein often used to measure the damage to neurons, also dropped suggesting Tofersen was reducing damage to neurons and remained effective over time.
Both groups experienced a worsening of their condition and quality of life, but the disease progressed slower than what would be expected without medication and was slowest in those who started earlier. Those starting early were on average able to go significantly longer without needing machinery to breathe or dying.
The most common side effects volunteers reported included headaches, pains, and falls. Many of these were likely caused by MND, as well as other conditions. Many of the risks were associated with the method of giving Tofersen, as a lumbar puncture, rather than the drug itself. Nine participants experienced more serious neurological effects which could have possibly been brought on by the drug, such as inflammation of the spinal cord, but these were treated effectively. Overall, the drug is safe for most people, but patients should still be monitored for side effects.
What do the findings mean going forward for people with the disease?
Should Tofersen be approved for use as a treatment, then it will only be useful for those with unhealthy mutated SOD1. For those people it will not completely prevent the disease but should reduce the symptoms experienced and slow the disease, meaning they should experience a longer more comfortable life.
The findings also show the drug does not seem to lose effectiveness over time so can be given long-term and can be given safely. Importantly it also supports starting medication as soon as possible to get the most benefit and demonstrates it is possible to slow down at least one form of MND. Future research may give us treatments to slow down other forms of MND as well.
This study can be found at https://jamanetwork.com/journals/jamaneurology/fullarticle/2843130
Paper title
Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis
Lead author
Timothy M. Miller, Stephanie Fradette
Publication details including date of publication
JAMA Neurol. 2026;83(2):115–125. doi:10.1001/jamaneurol.2025.4946