A new drug to treat motor neuron disease has given thousands new hope after it helped a man walk again.
An advanced clinical trial produced unprecedented results, slowing the progression of the disease in some patients and even reversing it in others.
The drug, known as tofersen and manufactured by the American health company Biogen, can be administered through a wood puncture injection in the lower back.
It works by dampening the effect of a faulty gene so that it produces less harmful proteins that damage motor neurons — cells in the brain and spinal cord that allow us to move, speak, swallow and breathe — and cause the disease.
That gene, known as SOD1, is responsible for 2 percent, or about 100, of the 5,000 cases of the disease in the UK.
But scientists are hopeful that, after showing that gene therapy can work in the disease, similar techniques could be used to target the 30 or so genetic mutations that cause about 10 percent of MND.
They also believe the techniques could be used to help patients whose disease was not caused by the faulty genes, as they could also be affected by some of the same toxic proteins that the body has not properly regulated. There is hope that the majority of MND patients may eventually benefit from gene therapy treatments like this one.
However, researchers stressed that while this is an exciting breakthrough, it’s too early to know how many people could benefit from it.
The drug has just entered a Phase III clinical trial led by Sheffield University’s Institute for Translational Neuroscience, a leading center for research into the disease.
What’s clear is that the treatment has shown unprecedented results, improving symptoms for the first time in some patients, researchers said.
“I’ve never heard patients say, ‘I’m doing things today that I couldn’t do a few months ago: walking around the house without my sticks, walking up the garden stairs, writing Christmas cards’. For me, this is an important milestone in treatment,” said Dame Pamela Shaw, professor of neurology at the University of Sheffield.
“I have conducted more than 25 clinical studies in motor neuron disease, and the Tofersen trial is the first in which patients have reported an improvement in their motor function.
“Patients we cared for reported stabilization or even improvements and the first patient who was in a wheelchair at the beginning is now walking around without their canes – so we’ve seen some pretty striking stories of improvements in individual patients.
“These studies have shown that if you get the right treatment, motor neuron degeneration is treatable.”
Les Wood, 68, from Thorne, South Yorkshire, can now walk. He was diagnosed with MND 10 years ago and first entered the Phase 3 trial in 2016.
After 12 months of taking the drug, Les reported physical benefits that allowed him to enjoy vacations in Spain with his wife Val again.
He said: “After taking 12 months of the drug, I could really walk around 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 wouldn’t be without the drug and the difference I know it has made to my quality of life.
“Not only does it give us hope, it gives you hope for the future for many people, including my own family, because motor neuron disease in my case is familial, I think well, maybe my own family will benefit from this in the long run.”
Co-investigator Professor Chris McDermott, also from Sheffield University, said: “This is the first time I’ve been involved in a clinical trial for people with MND where I’ve seen real benefits for participants. Although tofersen is a treatment for only two percent of people with MND, we learned a lot from conducting this clinical trial. The approach used, reducing proteins that are harmful to MND, will likely have broader applications for more common types of MND.”
“If we use gene therapy not only to correct defective genes, but to influence the broader pathway that goes wrong in motor nerve degeneration, no matter what the trigger is, then it could potentially be the majority.”
dr. Brian Dickie, director of research at the Motor Neuron Disease Association said: “These latest results provide growing confidence that Tofersen has both a biological and a beneficial clinical effect in people living with SOD1 MND.
“They also provide an important proof of concept that similar gene therapy-based approaches could be useful for other forms of the disease. We are closely following the recent news that Tofersen will be under review by US drug regulatory authorities and are in contact with Biogen to discuss what the regulatory approval process will look like elsewhere.”
Biogen will also approach the UK regulatory agency, the Medicines and Healthcare products Regulatory Agency (MHRA), for approval to use the drug in the country.
However, according to Professor McDermott, some patients may already be taking the drug in the UK.
“Biogen has launched an early access program in the UK for anyone with an SOD1 mutation and motor neuron disease as complex regulatory discussions are underway,” he said.
“We have a number of patients in Sheffield on the early access program and there are other centers across the country.”
Treatment involves a monthly injection into the lower back to supplement therapy that researchers say is no more uncomfortable than a blood test.
“If this becomes a licensed treatment within the NHS, I think there will be more patient-friendly ways to deliver the therapy,” said Professor Shaw.
“There may be a way to deliver the monthly treatment without having to have a lumbar puncture every time, so there are implantable devices that can be in the spinal fluid where you can get the [treatment] in a reservoir that could be buried under the skin.”
Professor Michael Swash, Professor Emeritus of Neurology and Hon Consultant Neurologist, Barts Health NHS Trust, who was not involved in the study, said it was “a big step forward” but warned that more work needs to be done.
dr. Paul Wright, chief scientist at LifeArc, the medical research charity, said: “This is promising and potentially exciting news for people with MND whose condition is caused by a defective SOD1 protein. Although defective SOD1 causes a small part of MND, it is the first evidence that reducing SOD1 protein production could work and will provide more insight into how SOD1 causes MND.”
“Overall, it’s an interesting study, but it needs follow-up,” added Dr. Adolfo López de Munain, clinical chief of the University Hospital of Donostia in Spain.
MND, also known as amyotrophic lateral sclerosis (ALS), is a condition that affects the nerves — or motor neurons — in the brain and spinal cord that connect the nervous system and muscles to allow movement of the body. The messages from these nerves gradually stop reaching the muscles, causing 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 of MND triggering in two percent of all patients with ALS and up to 20 percent of patients with a family history of the disease.
108 MND patients known to have the defective SOD1 gene participated in the groundbreaking Phase 3 clinical trial funded by biotechnology company Biogen Inc. Although no significant clinical improvement was found at the primary endpoint of the study at 28 weeks, when the study was extended to 52 weeks, notable changes in the patient’s motor function and lung function were reported.
The causes of most MNDs are unknown. In sporadic or non-hereditary MNDs, environmental, toxic, and viral factors are thought to play a role in disease development.
HOW THE TREATMENT WORKS:
The drug, given as a wood prick injection in the lower back, works by dampening the effect of the SOD1 gene so that it produces fewer harmful proteins that damage motor neurons in the spinal cord and brain.
When they work properly, SOD1 proteins remove free radicals — particles in our bodies that can damage our cells and cause disease and aging.
But when the genes that make SOD1 proteins are defective, a whole host of things go wrong in the motor neurons, causing motor neuron disease.
Injecting a drug into the fluid at the bottom of the spine can safely dampen the activity of these genes, as injected fragments bind to the genes and dampen their activity.
Professor Shaw said: “SOD1 was the first gene to cause familial MND in 1993. It is very abundant in the nervous system and it removes those potentially harmful free radicals.
“We can lower the level of the SOD1 gene and protein with relative impunity.
“We know that when a tiny amino acid building block of the SOD1 protein is damaged, a whole host of things go wrong in the motor neurons themselves and in the surrounding cells nearby.”
Using molecules known as ‘Antisense oligonucleotides’ or ASOs, the genes’ ability to make a protein can be blocked.
“We’re going upstream and lowering the level of SOD1 protein that triggers a toxic function,” said Professor Shaw.
“The ASO is given through a wood puncture – a needle in fluid at the bottom of the spine. It binds to the messenger RNA from the SOD1 gene that is the blueprint for the SOD1 protein and causes it to be broken down.”
The study is published in the New England Journal of Medicine.