Scientists believe a new genetically-targeted therapy to treat motor neuron disease (MND) could be a turning point for patient care as 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.
A total of 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 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.
“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,” said Professor Dame Pamela Shaw, Professor of Neurology and Director of SITraN at the University of Sheffield.
“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,” Shaw said.
She said 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 the future we may be able to tell in three to six months if an experimental therapy is having a positive effect,” Shaw 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,” said Chris McDermott, Professor of Translational Neurology at SITraN University of Sheffield and co-author of the study.
The approach used, of reducing proteins harmful in MND, is likely to have wider applications for more common types of MND, McDermott said.
MND, also known as amyotrophic lateral sclerosis (ALS) 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 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.
Les Wood, 68, from Thorne, South Yorkshire, was diagnosed with MND 10 years ago and first took part in the Phase 3 trial in 2016. After the first 12 months of taking the drug, Les reported physical benefits which allowed him to return to enjoying holidays in Spain with his wife Val “After 12 months of taking the drug, I could actually walk in the house without sticks, I was able to come off some of my painkillers and I felt a lot better in myself. MND is a progressive disease so although my symptoms have continued to worsen, I would not be without the drug and the difference I know it has made to my quality of life,” he said.
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,” Dickie said.
Clinicians and scientists hope that this is the first step towards a licensed therapy for MND patients.