Tofersen: What have we learned about using it to treat MND so far?

Motor Neuron Disease (MND) is a term that includes a wide range of diseases with shared characteristics affecting the central nervous system (CNS). In MND, loss of specific nerve cells (the motor neurons) interrupts communication between the CNS and muscles in the body, leading to muscle weakness and wasting. The most common and devastating form of MND is Amyotrophic Lateral Sclerosis (ALS), which dramatically reduces life expectancy to between 2 and 5 years after diagnosis. ALS is a complex disease that can be triggered by multiple factors, including environmental factors as well as known changes in genes, called mutations. Importantly, people at risk of inheriting a faulty gene that causes ALS from a parent can be identified through genetic testing. This kind of disease received the name of familial ALS (fALS). However, spontaneous forms of the disease have been identified when parents are not involved. Furthermore, the first gene shown to be mutated in ALS was the SOD1 gene in 1993.

Developing effective treatments for ALS has been challenging. This is because the disease interferes with multiple processes in nerve cells, thereby necessitating drugs that act on several processes to treat the disease. However, in cases caused by faulty genes (which account for approximately one-fifth of all cases, known as fALS), directly interfering with the faulty gene can correct these processes, as they are a direct result of that genetic defect. Therefore, if doctors can directly correct this gene, they are fixing the root cause.

Tofersen, also known as Qalsody, is a medication administered via spinal injection by experienced healthcare professionals that interferes with the SOD1 gene. It was approved for treatment of SOD1 ALS in the United States in April 2023, in Europe in May 2024, and in the UK in July 2025.

Why is the study important?

The initial approval of Tofersen was based on a 28-week study evaluating its effectiveness in 147 patients with SOD1-ALS. This study did not actually show a statistically significant positive effect on the patients in the trial. It was only when they were treated for longer that benefit was seen, so the initial approval was subject to certain conditions and restrictions that allowed it to be used, so that whether it truly benefits patients could be determined. Several groups have since published their findings from treating patients with Tofersen. A meta-analysis takes results from several studies to form a single conclusion, so this meta-study aimed to evaluate how well Tofersen works, as well as confirmed that it is safe to use by combining the results from studies published before and after its approval for use.

What did the authors do and how did they do it?

The authors of this study searched the PubMed, Web of Science, and Scopus databases. The search identified studies on individual patients, larger groups of people, and the effects of the new treatments. The primary focus was on the safety and efficacy (how well it works) of Tofersen in patients with SOD1-ALS. The review ultimately included results from randomized controlled trials (RCTs) where some patients received Tofersen and others a placebo, and cohort studies where all patients received Tofersen.

The initial search identified 218 articles, of which 12 met the inclusion criteria and were included in the final analysis. Across these studies, 195 participants received Tofersen. The authors looked for evidence that Tofersen interferes with the production of the SOD1 protein from the SOD1 gene. They also looked for evidence that it prevented nerve damage by measuring levels of a substance called Neurofilament, which is released by dying nerves and can be measured in cerebrospinal fluid (CSF) taken from around the spinal cord or in plasma prepared from blood. Patients treated with Tofersen showed lower levels of the harmful SOD1 protein in CSF and lower levels of Neurofilament in plasma, signs which confirming that Tofersen interferes with SOD1 production and reduces nerve damage in patients.

In terms of clinical results, the meta-analysis of RCTs showed a significant reduction in the decline of a measure of breathing ability. In these studies, a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores was also found in people using Tofersen compared to people given a placebo. Many patients maintained their muscle strength and respiratory function for longer, and some even experienced improvements in their symptoms. Meta-analysis of five studies showed a significant decrease in ALS progression rate. Most side effects were mild (e.g., headache, back pain), although a few individuals experienced serious neurological events like inflammation of the spinal cord. In summary, Tofersen appeared to slow disease progression and was generally well-tolerated.

What do the findings mean going forward for people with the disease?

Overall, the meta-analysis confirmed that Tofersen is an effective treatment for slowing the progression of SOD1 ALS and improving quality of life. These findings also show the importance of genetic testing for individuals with or at risk of developing ALS due to a family history of the disease. Testing allows neurologists to assess the disease from a therapeutic point of view and determine if a targeted treatment like Tofersen is appropriate. In the future, we can expect to see targeted treatments for ALS cases caused by other faulty genes.

Longer-term studies are needed to determine the full extent to which Tofersen can delay the decline in breathing, a critical aspect of ALS progression. Future research should also focus on whether the preservation of essential motor skills and daily autonomy translates to a delayed need for specialized medical assistance. However, despite these generally positive results, close monitoring of patients is essential. This is due to the risk of serious neurologic events reported in a few patients during the studies, such as inflammation of the spinal cord and high pressure in the brain, which led to headaches.

Additionally, future studies should include patients outside of the US and Europe to evaluate responses among patients with different characteristics, such as age, ethnicity, and the presence or absence of other medical conditions. Importantly, the overall take-home message is positive in that interfering with SOD1 production in SOD1 ALS is beneficial. Scientists are developing other ways of targeting SOD1 that work differently to Tofersen that could prove to be even better.

This study can be found at
Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis – PubMed

Paper title
Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta- analysis.

Lead author
Abdullah Ashraf Hamad

Publication details including date of publication
Neurological Sciences, 17 January 2025, Volume 46, pages 1977–1985, (2025), DOI: 10.1007/s10072-025-07994-2