#VisualAbstract: Intrathecal tofersen for amyotrophic lateral sclerosis

1. A 100mg treatment of tofersen was shown to decrease cerebrospinal fluid (CSF) superoxide dismutase 1 (SOD1) concentration in adults with amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.

2. Lumbar puncture-related adverse events were shown to be present in most participants.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Amyotrophic lateral sclerosis, resulting from superoxide dismutase 1 (SOD1) mutations consist of approximately 2% of all cases with over 180 disease-causing mutations identified within the gene. Tofersen is an antisense oligonucleotide (ASO) which mediates SOD1 mRNA degradation, thereby, reducing the synthesis of SOD1 protein. However, the effect of tofersen dosing on patients diagnosed with ALS is unknown. As such, this study evaluated the safety, pharmacokinetics, and pharmacodynamics of tofersen in adults with SOD1 mutation mediated ALS. Intrathecal administration of tofersen was shown to significant reduce CSF SOD1 concentrations. While, this study was adequately powered to test the reduction of SOD1 concentration in the CSF, the study was not able to conclusively determine other clinical or biological measures due to its low power. Nonetheless, this study was strengthened by its extensive follow-up period and the additional analyses conducted on the exploratory nature of the efficacy outcomes.

Click to read the study, published today in NEJM

Relevant reading: Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models

In-Depth [randomized controlled trial]: This randomized control trial enrolled 50 patients across 18 sites in the United States, Canada, and Western Europe. Patients enrolled in the study were adults over the age of 18 years with muscle weakness attributed to ALS, documented SOD1 mutation, and normal coagulation variables. The exclusion criteria for the study included participants currently taking or scheduled to start edaravone treatment. Patients were randomized in a 3:1 ratio to receive 20, 40, 60, or 100 mg tofersen doses or a placebo regimen. A single dose of the treatment was administered on days 1, 15, 29, 57, and 85. The primary outcome was treatment safety. The most common adverse events included headache (16 participants, 32%), procedural pain (16 participants, 32%), and post-lumbar puncture syndrome (13 participants, 26%). The difference in ratio of CSF SOD1 concentration between baseline and day 85 for the 20-mg group was 2 percentage points (95% confidence interval [CI], -18 to 27) compared to the placebo group. The difference in ratio of CSF SOD1 concentration for the 40-mg group was -25 percentage points (95% CI, -40 to -5) compared to the placebo group. The difference in ratio of CSF SOD1 concentration for the 60-mg group was -19 percentage points (95% CI, -35 to 2) compared to the placebo group. The difference in ratio of CSF SOD1 concentration for the 100-mg group was -33 percentage points (95% CI, -47 to -16) compared to the placebo group. Taken together, the 100-mg tofersen treatment was shown to decrease SOD1 concentration in adults with ALS with associated procedural-related adverse events.

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