This systematic review and meta-analysis aimed to summarize the current evidence on efficacy and safety of tofersen for SOD1 ALS. In terms of efficacy outcomes, Tofersen treatment resulted in a reduction in SOD1 concentrations in CSF compared to placebo in the included RCTs. This decrease in CSF SOD1 levels can be attributed to the drug’s mechanism of action in suppressing the SOD1 gene [27]. ALS patients typically show increased levels of NfL due to axonal damage. However, treatment with tofersen led to a significant decrease in plasma NfL concentrations across all the studies, indicating a potential slowing of disease progression.

Functional outcomes were also assessed, and significant improvements were observed in ALSFRS-R decline rate scores after tofersen therapy compared to the pre-therapy period. ALSFRS-R scores were even stopped or increased in some treated patients [4, 24]. This improvement can enhance the quality of life for ALS patients and reduce their need for assistance. Additionally, a significant difference was noted in the decline of the percentage of SVC between tofersen and placebo, which may delay respiratory failure, a common cause of death in ALS [28]. The VALOR and its Open Label Extension, as well as multiple case studies, have shown a significant slowdown in disease progression, as measured by ALSFRS-R scores, and a less rapid decline or stabilization of respiratory function.

The quality of the studies evaluating tofersen’s efficacy in ALS treatment were fair. While the studies provided valuable insights, it is important to note that the sample size in these trials was relatively small, which might limit the generalizability of the findings. However, despite these limitations, the observed effect sizes in the treated groups were notable, suggesting a potential therapeutic benefit of tofersen in ALS patients.

In recent research, the utilization of neurofilaments as biomarkers has gained attention in ALS studies. Neurofilaments are structural proteins found in neurons, and their levels in CSF or blood can reflect neuronal damage and disease progression [29]. Incorporating neurofilament measurements as biomarkers in ALS studies has provided valuable information on the disease’s pathophysiology and response to treatment [30]. By monitoring neurofilament levels, researchers can better understand disease progression and gauge the effectiveness of therapeutic interventions, as appeared in most of the included studies [23, 24].

Compared to prior ALS drugs such as riluzole and edaravone, tofersen has shown promising results in terms of disease progression and functional outcomes. While riluzole primarily targets glutamate release and Edaravone acts as a free radical scavenger [28], tofersen’s mechanism of action involves targeting the SOD1 gene, which plays a role in protein production. This personalized approach based on genetic mutations offers a potentially more tailored treatment strategy for ALS. This personalized, mutation-based approach represents a significant step toward precision medicine in ALS therapies [31]. Furthermore, the use of biomarkers, including neurofilaments, and the consideration of disease progression in the study design have helped in assessing the efficacy of tofersen and monitoring its effects on patients with ALS.

Regarding safety outcomes, the most frequently reported side effects were related to disease progression or tofersen use. Common adverse effects included headache, injection site pain, fatigue, joint pain, pleocytosis (increased white blood cells in CSF), and muscle pain [11, 20]. In the VALOR study, a small percentage of patients receiving tofersen reported severe neurological adverse events, such as myelitis, meningitis, increased intracranial pressure, and papilledema. However, most of these events resolved without discontinuing the medication, although some required additional treatments such as glucocorticoids and plasma exchange. Other cases of myelitis and weakness were also reported, but the exact mechanism behind these neurological symptoms remains unclear [4, 25]. It is suggested to monitor CSF cell counts and total protein levels as a potential cause of transient weakness [25]. Another study reported two cases of autoimmune myeloradiculitis and lower limb weakness, both of which resolved clinically [4].

Our study represents the first systematic review and meta-analysis on tofersen in patients with ALS, providing a comprehensive summary of the available evidence on this topic. We strictly followed preferred guidelines for conducting systematic reviews and meta-analyses, ensuring the reliability and validity of our findings. However, a limitation of our study is that all the reported studies included in our analysis were conducted in Europe or the USA, which highlights the need for further research in different geographical regions to examine the generalizability of the findings to other racial and ethnic groups. Another limitation is the small sample sizes in most of the included studies, which may limit the statistical power and generalizability of the results. Also, pre post meta-analysis is not considered a highly reliable analysis, with a chance of the effect of confounding factors [32]. Further observational studies on patients receiving tofersen will strengthen the current literature and deepen our understanding of tofersen’s effects. Additionally, ongoing monitoring of post-marketing adverse events associated with tofersen remains crucial.