Promising motor neuron disease drug helps slow disease progression and benefits patients physically

• A Phase 3 clinical trial of the investigational drug tofersen in patients with motor neuron disease caused by the faulty SOD1 gene, has shown it can slow and reduce progression of the disease.
• Patients on the trial reported better patient mobility and lung function after 12 months.
• Researchers from the University of Sheffield Institute for Translational Neuroscience (SITraN) and the Sheffield NIHR Biomedical Research Centre found that, though biomarkers in patients' cerebrospinal fluid showed improvement at 6 months, it took 12 months for identification of physical benefits.
• 108 patients took part in the clinical trial, funded by the biotechnology company Biogen Inc. Sheffield was the major trial site in the United Kingdom.
• Around 5,000 people in the United Kingdom have motor neuron disease – also known as amyotrophic lateral sclerosis (ALS), with 2% developing motor neuron disease due to a faulty gene called SOD1.

Scientists believe a new genetically-targeted therapy to treat motor neuron disease 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 2% of motor neuron disease cases - noticed that the progression of their symptoms slowed down 12 months after taking the investigational drug tofersen.

108 patients with motor neuron disease and known 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 6 months, suggesting that the treatment successfully hits the therapeutic target and reduces loss of motor neurons, 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, said: “I have conducted more than 25 motor neuron disease 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 neurons 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 motor neuron disease trials for patients. Not only can we look at other genes which also cause motor neuron disease, but we now have a biomarker that we can measure to see if a treatment is working. This is going to make trials much more efficient. In the future, we may be able to tell in 3 to 6 months if an experimental therapy is having a positive effect.”

Professor Chris McDermott, Professor of Translational Neurology at SITraN University of Sheffield and Co-Author of the study, said: “This is the first time I have been involved in a clinical trial for people living with motor neuron disease where I have seen real benefits to participants. Although tofersen is a treatment for only 2% of those living with motor neuron disease, 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 motor neuron disease, is likely to have wider applications for more common types of motor neuron disease.”

Motor neuron disease, also known as amyotrophic lateral sclerosis is a disorder that affects the nerves--or motor neurons--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 motor neuron disease in 2% of all patients with amyotrophic lateral sclerosis, and up to 20% of patients who have a family history of the disease.

Dr Brian Dickie, Director of Research at the Motor Neuron Disease 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 motor neuron disease. 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 United States 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 motor neuron disease patients.

Source: News Release
University of Sheffield
September 21, 2022