“The positive CHMP opinion represents a turning point that demonstrates the value of tofersen for the treatment of Sod1 ALS and Biogen's commitment to addressing the unmet needs of people with ALS. We are proud to have helped pioneer the role of neurofilaments in Sod1 ALS clinical trials. And we are deeply grateful to the people with this disease, their loved ones, and the clinicians who collaborated on the study for their dedication to advancing research for the ALS community.” Thus Priya Singhal, Head of Development at Biogen, comments on the green light from the Technical Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency EMA for the first therapy for the treatment of adults with amyotrophic lateral sclerosis who have a mutation in the superoxide dismutase 1 (Sod1) gene.
“The approval of tofersen” by the EMA “offers new hope to the ALS community in Europe – underlines Philip Van Damme, professor of neurology and director of the Neuromuscular Reference Center at the University Hospital of Leuven in Belgium – It is a milestone for the entire ALS community: for the first time we have a treatment that has led to significant reductions in neurofilaments, which are a marker of axonal damage and neurodegeneration. The tofersen development plan has also provided fundamental new knowledge with respect to clinical trial design and the use of surrogate biomarkers such as neurofilament. These are useful advances for the entire field.”
The European approval – explains a note – is based on all the evidence collected, which includes the targeted mechanism of action, biomarkers and clinical data. In the 28-week phase 3 Valor study, a 60% reduction in plasma light chain neurofilament (NFL) concentration was observed in participants receiving tofersen compared to the placebo group, thus suggesting a reduction in neuronal damage. Furthermore, in treated patients, a tendency to reduce the decline in clinical function measured by the Als Functional Ratings Scale-Revised (Alsrs-R), in respiratory function (percentage of predicted slow vital capacity) and in muscle strength ( through manual dynamometry), compared to the placebo group.
EU decision expected in the second quarter of 2024
The most common side effects include: pain, fatigue, fever, joint pain, muscle pain, and increased levels of white blood cells and proteins in the cerebrospinal fluid. Serious neurological events have also been reported, including myelitis and/or radiculitis, papilledema and elevated intracranial pressure, aseptic meningitis.
Marketing authorization in exceptional circumstances is recommended when the benefit/risk assessment is considered positive but, due to the rarity of the disease, it is unlikely that complete data can be obtained as in normal circumstances of use. The CHMP recommendation for tofersen will now be reviewed by the European Commission for a decision on marketing authorization in the European Union, with an expected outcome in the second quarter of 2024.
Tofersen – concludes the note – is an antisense oligonucleotide (Aso) designed to bind to the mRNA of the Sod1 gene, with the aim of reducing the production of Sod1 protein levels. The US Food and Drug Administration granted accelerated approval based on the reduction in plasma NFL levels observed in patients treated with tofersen. Approval for this indication may be subject to verification of clinical benefit during one or more confirmatory studies.
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