Results from the ground-breaking phase 1-2 clinical study published in the New England Journal of Medicine show University of Sheffield researchers demonstrate the safety and efficacy of a new precision therapy drug, Tofersen, in patients with motor neurone disease (MND). 
Scientists from the University of Sheffield’s Institute for Translational Neuroscience (SITraN) worked with the Sheffield Teaching Hospitals NHS Foundation Trust on a ground-breaking international clinical trial sponsored by Biogen. The only site in the UK to participate, the researchers contributed to findings that the investigational molecule, Tofersen, reduces toxic levels of the disease-causing SOD-1 enzyme in patients with MND, also known as amyotrophic lateral sclerosis (ALS). 
MND is a neurodegenerative disease affecting around 5,000 individuals in the UK. Damaged neurones in the brain and spinal cord progressively worsen the patient’s ability to speak, walk, swallow, and breathe. The cause of the disease is not fully understood, but up to 1 in 10 cases are inherited, with mutations in the SOD1 gene resulting in 2% of all cases. 
Professor Chris McDermott from SITRaN and principal investigator for the Sheffield trial said: ”Superoxide dismutase 1, known as SOD1 was the first gene found to cause MND…The primary objective of the study was to evaluate the safety and tolerability of tofersen which shows signs of potential efficacy in lowering the levels of the toxic SOD1 protein in the nervous system, something which will reduce damage in the nerve cells and help to slow the progression of symptoms.” 
Safety and efficacy of Tofersen was evaluated in 50 participants with SOD1-MND. The results show an improvement in the levels of SOD1 in the Tofersen group compared to placebo, alongside a slower reduction in lung function, muscle strength, and ALS Functional Rating Scale-Revised Score (a scale used in monitoring the disease’s progression). These positive findings provide promising prospects for patients worldwide, and key stakeholders will be keenly awaiting the results from the next phase of the trial. 
Most adverse events recorded during the trial were directly related to the lumbar puncture procedure of drug administration, with five Tofersen and two placebo-treated participants experiencing serious adverse events. One death occurred in the placebo group due to MND-related respiratory failure. Two deaths occurred in the Tofersen group during a follow-up period as a result of pulmonary embolism and respiratory failure. 
Helen Wollff, a Research Nurse on the study, said: “It is a testimony to the research conducted at SITraN that Sheffield was the only UK site for the initial phases of the clinical trial. We look forward to the next stage of this clinical study sponsored by Biogen Inc. which will further evaluate the safety and efficacy of Tofersen.”
While this phase was successful, it is still early days for Tofersen. It now must undergo rigorous testing in the international phase 3 trial before it is released to the market. Phase 3 is already underway and will test the efficacy of the drug alongside its long-term safety and should be completed in July 2021.


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