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Scientists believe a new genetically-targeted therapy to treat motor neurone disease (MND) could be a turning point for patient care, after the results of a Phase 3 clinical trial showed significant physical benefits for patients after 12 months.

Researchers from the Sheffield Institute for Translational Neuroscience (SITraN) found that patients with a faulty SOD1 gene - responsible for two per cent of MND cases - noticed that the progression of their symptoms slowed down 12 months after taking the investigational drug tofersen.

Sheffield was the only UK site involved in the research, which took place at the Royal Hallamshire Hospital’s NIHR Sheffield Clinical Research Facility.

108 MND patients known to have the faulty SOD1 gene took part in the pioneering Phase 3 clinical trial funded by biotechnology company Biogen Inc. Although a significant clinical improvement was not found at the primary endpoint of the study at 28 weeks, when the trial was extended to 52 weeks, notable changes in patients’ motor function and lung function were reported.

Results of the trial, published in the New England Journal of Medicine, show that biomarkers in patients' spinal fluid showed a reduction in the SOD1 and neurofilament protein levels after taking tofersen for six months, suggesting that the treatment successfully hits the therapeutic target and reduces loss of motor neurones which may allow them to start regenerating connections with muscles in the body. However, it took longer for patients to experience reported physical improvements.

Professor Dame Pamela Shaw, Professor of Neurology and Director of SITraN at the University of Sheffield and Honorary Consultant at Sheffield Teaching Hospitals, said: “I have conducted more than 25 MND clinical trials and the tofersen trial is the first trial in which patients have reported an improvement in their motor function. Never before have I heard patients say ‘I am doing things today that I couldn’t do a few months ago - walking in the house without my sticks, walking up the garden steps, writing Christmas cards’. For me this is an important treatment milestone.”

Dame Pam added: “What we have found is that we can reduce or slow damage from happening biologically, but it takes more time for the motor neurones to heal and regenerate their connections with the muscles. So, the motor system needs time to heal before we see a physical and clinical change.

“Patients with SOD1 mutations are relatively rare, but this trial is going to change the future of MND trials for patients. Not only can we look at other genes which also cause MND, but we now have a biomarker which we can measure to see if a treatment is working. This is going to make trials much more efficient. In future we may be able to tell in three to six months if an experimental therapy is having a positive effect.”

Professor Chris McDermott, Professor of Translational Neurology at SITraN University of Sheffield, Consultant Neurologist at Sheffield Teaching Hospitals and Co-Author of the study, said: “This is the first time I have been involved in a clinical trial for people living with MND where I have seen real benefits to participants. Although tofersen is a treatment for only two per cent of those living with MND, we have learned much in doing this clinical trial that will help us do smarter and faster clinical trials in the future. The approach used, of reducing proteins harmful in MND, is likely to have wider applications for more common types of MND.”

In the trial, two-thirds (72) of the participants were randomly assigned to receive eight doses of tofersen over a 24-week period, while the remaining 36 people received eight doses of a placebo.

All participants were assessed at 28 weeks to measure motor function across four areas: swallowing and speaking, breathing, fine motor skills, and gross motor skills.

They also gave samples of spinal fluid so the researchers could measure levels of proteins associated with MND. Results showed that the drug did not improve motor control and muscle strength after six months but patients reported better patient mobility and lung function after 12 months.

MND, also known as amyotrophic lateral sclerosis (ALS) is a disorder that affects the nerves - or motor neurones - in the brain and spinal cord that form the connection between the nervous system and muscles to enable movement of the body. The messages from these nerves gradually stop reaching the muscles, leading them to weaken, stiffen and eventually waste. The progressive disease affects a patient’s ability to walk, talk, use their arms and hands, eat and breathe.

SOD1 is the known cause for triggering MND in two per cent of all patients with ALS, and up to 20 per cent of patients who have a family history of the disease.

Dr Brian Dickie, Director of Research at the MND Association said: “These latest results provide mounting confidence that tofersen is having both a biological and a beneficial clinical effect in people living with SOD1 MND. They also provide important ‘proof of concept’ that similar gene therapy-based approaches may be helpful for other forms of the disease. We are closely following the recent news that tofersen will be reviewed by the U.S. drug regulatory authorities and are in contact with Biogen to discuss what the regulatory approval process will look like elsewhere.”

Clinicians and scientists hope that this is a first step towards a licensed therapy for MND patients.

ENDS