Safety profile of tofersen in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

OBJECTIVE

To evaluate the safety profile of tofersen in patients with SOD1-associated amyotrophic lateral sclerosis (ALS) through a systematic review and meta-analysis of randomized controlled trials and observational cohorts.

METHODS

A comprehensive search was conducted up to August 2025. Eligible studies included adults with SOD1-associated ALS treated with intrathecal tofersen. Outcomes were treatment-emergent adverse events (AEs), serious adverse events (SAEs), cerebrospinal fluid (CSF) abnormalities, and procedure-related complications. Pooled incidence rates with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models depending on heterogeneity. Risk of bias was assessed with MINORS, and certainty of evidence was graded using GRADE.

RESULTS

Six studies (2 RCTs, 4 cohorts) comprising 179 patients receiving tofersen and 48 placebo controls were included. The pooled incidence of any AE was 98.0% (95% CI: 95.6–100), while SAEs occurred in 10.0% (95% CI: 0–22.1). Common adverse events included procedural pain (56.2%), headache (54.1%), back pain (38.4%), and extremity pain (35.9%). CSF pleocytosis was reported in 44.1% of patients, with high heterogeneity across studies. Gastrointestinal and constitutional events such as nausea (17.0%) and fatigue (21.6%) were usually mild. Respiratory failure occurred in 9.2% of cases. Most adverse events were manageable, though rare severe complications (e.g., meningitis, myelitis, intracranial hypertension) were described in individual reports.

CONCLUSION

Tofersen is associated with frequent adverse events, predominantly mild to moderate, while serious complications are less common but clinically relevant. The overall safety profile supports its continued clinical use in SOD1-associated ALS, although long-term surveillance is warranted to better characterize rare outcomes.