The U.S. Food and Drug Administration (FDA) has approved tofersen (Qalsody) to treat individuals with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS). Tofersen is an antisense oligonucleotide that targets SOD1 mRNA to reduce the synthesis of the SOD1 protein.

In the United States, it is estimated that about 500 people have SOD1-ALS and accounts for about 2% of all ALS cases. SOD1-ALS is a progressive neurodegenerative disease that attacks and kills neurons that control voluntary muscles. Much like sporadic ALS, the end results is muscle weakness that leads to paralysis.

The approval was largely based on a 28-week, randomized, double-blind, placebo-controlled clinical study in patients with SOD1-ALS received  tofersen 100 mg (n = 72) or placebo (n = 36) for 24 weeks (three loading doses followed by five maintenance doses).

The participants were approximately 43% female; 57% male; 64% White; and 8% Asian. The average age was 49.8 years (range from 23 to 78 years).

The primary endpoint was a reduction in plasma neurofilament light (NfL), a blood-based biomarker of axonal injury and neurodegeneration. Patients receiving tofersen had nominally significant reductions in plasma NfL concentration at Week 28 compared to the placebo arm. The findings were determined to be reasonably likely to predict a clinical benefit. The observed reduction in NfL was consistent across all subgroups based on sex, disease duration since symptom onset, site of onset, and use of other medications for ALS treatment. Results from this trial were recently published in the New England Journal of Medicine.

The most common side effects were pain, fatigue, arthralgia (joint pain), increased cerebrospinal (brain and spinal cord) fluid white blood cells, and myalgia (muscle pain).

The drug was approved under the accelerated approval pathway. A Phase 3 pivotal trial is currently underway to confirm the clinical benefit of tofersen.

Interestingly, a FDA Peripheral and Central Nervous System Drugs Advisory Committee reviewed the date for tofensen earlier this year. The panel voted unanimously in favor that reductions in NfL are reasonably likely to predict clinical benefit but were mixed on whether tofenersen was effective based on the current data.

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