Drug silences motor neurone disease mutation

Tofersen was effective in slowing the progression of a rare form of motor neurone disease when taken over a period of 12 months.

Researchers at the Washington School of Medicine led a phase 3 clinical trial to test the effectiveness of tofersen at six- and 12-months. The trial was conducted at 32 sites in ten countries and included 108 motor neurone disease patients with SOD1 mutations. After six months of tofersen treatment patients had a reduction in the biomarkers of motor neurone disease, but did not show a physical improvement. However, at 12 months some patients did exhibit  stabilisation in their mobility, muscle strength and lung function, indicating that it may take prolonged treatment before physical benefits are seen.

Dr Timothy Miller, lead researcher of the study, said: 'those that started on tofersen early and were on the drug for about six months longer had greater preservation of function, higher scores on breathing, and greater strength'.

Motor neurone disease, also known as amyotrophic lateral sclerosis or ALS, leads to the degeneration of nerve cells in the brain and spinal cord, resulting in progressive paralysis and eventual death. Participants in this study had an inherited form of motor neurone disease, responsible for around two percent of all cases, caused by a faulty form of the SOD1 gene. This faulty gene leads to an accumulation of a mutant SOD1 protein, triggering the progressive breakdown of nerve cells.

Antisense oligonucleotides, such as tofersen, are small sections of DNA or RNA which can bind to specific genes to block the production of target proteins. Through this mechanism, the administration of tofersen prevents the production of the faulty SOD1 protein.

Initially, the trial was designed to end after six months but, despite the promising results, the trial had missed its key target. At this point, researchers offered all participants the opportunity to receive the drug.

Publishing their results in the New England Journal of Medicine, the researchers found that patients who had received tofersen for a full year exhibited a slower disease progression, as evidenced by the stabilisation in their muscle strength and control.

'… this treatment has the potential to deliver a significant benefit in modifying the disease course.' said Dr Brian Dickie, director of research development at the Motor Neurone Disease Association in Northampton, who was not involved in the study. 'The other encouraging point is the biomarker-based evidence, which provided investigators with early encouraging data that the drug was both hitting its intended target and also reducing nerve cell damage, in advance of notable clinical changes in motor function.'

The clinical trial, which remains ongoing, is funded by the biotechnology company Biogen Inc, who have submitted a new drug application to the US Food and Drug Administration for tofersen to be used as a treatment for SOD1-linked motor neurone disease.