How tofersen works
ALS is a progressive neurodegenerative disorder where damage to and death of motor neurons (the nerve cells that control the movement of muscles) leads to a loss of muscle control and paralysis. The exact cause of the disease is unknown, but some inherited forms of ALS are caused by a mutation in the superoxide dismutase 1 (SOD1) gene. SOD1 encodes for a protein, which neutralizes harmful radical oxygen molecules. Mutations in SOD1 can cause the enzyme to misfold as it is being made, which may lead to a toxic buildup of misfolded protein.
Tofersen is a type of antisense therapy. It is an artificially created piece of DNA that is designed to specifically bind to SOD1 mRNA (mRNA is a temporary copy of a gene that is used by the machinery of the cell to make protein). By binding to the SOD1 mRNA, tofersen targets it for degradation and prevents it from being read, thereby stopping SOD1 protein production. By reducing levels of SOD1 protein, tofersen may be able to slow the progression of this form of ALS.
Tofersen in clinical trials
A Phase 1 clinical trial (NCT01041222) assessing the safety, tolerability, and activity of tofersen in SOD1-related familial ALS patients has been completed. The randomized, double-blind, placebo-controlled trial tested four different doses of tofersen in 33 patients. Participants received 0.15 mg, 0.5 mg, 1.5 mg, or 3 mg of the treatment over a 12-hour period. They were then assessed for 28 days following treatment. No serious adverse effects were observed in response to tofersen treatment, and the most common side effects were post-lumbar puncture syndrome, also known as spinal headache, back pain from the injection, and nausea. The results are published in the medical journal The Lancet Neurology.
Subsequently, a second and larger Phase 3 trial (NCT02623699) was initiated. The trial aims to enroll 72 patients and is currently recruiting participants in the U.S. Canada, Europe, and the U.K. The aim of the randomized, placebo-controlled trial is to confirm the safety and tolerability of tofersen. It will also evaluate the effects of tofersen on levels of SOD1 protein in the spinal fluid of patients. Patients who complete this trial will be invited to participate in another study (NCT03070119) evaluating the long-term safety and tolerability of tofersen.
Tofersen received orphan drug designation from the European Medicines Agency on Aug. 29, 2016.
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