An experimental therapy developed to address the genetic cause of a Amyotrophic lateral sclerosis (ALS), rare form of motor neurone disease (MND) has shown encouraging results in early research supported by the NIHR.

The phase 1-2 study, supported by the National Institute for Health Research and published in the New England Journal of Medicine, has shown tofersen is safe and well tolerated in people with a genetic form of MND.

Around 5,000 people in the UK have MND, a disorder that affects the nerves in the brain and spinal cord that form the connection between the nervous system and muscles, enabling movement of the body.

In people with the disease, the messages from these nerves gradually stop reaching the muscles, leading them to weaken, stiffen and eventually waste, affecting a patient’s ability to walk, talk, use their arms and hands, eat and breathe.

Superoxide dismutase 1, known as SOD1, is the first gene found to cause ALS, in around 2% of all patients and around 20% of those who have a family history of MND.

In the trial, which was sponsored by Biogen, tofersen was shown to have the potential to reduce the levels of the toxic protein generated by the faulty SOD1 gene, which would reduce damage in the nerve cells and help slow the progression of symptoms.

The most commonly reported adverse events in people who received one or more doses of tofersen (n=38) were headache, procedural pain, post-lumbar puncture syndrome and falls.

Five tofersen- and two placebo-treated people experienced serious adverse events. One death occurred in the placebo group during the trial due to respiratory failure secondary to ALS and two deaths occurred in the tofersen group during a follow up period due to pulmonary embolism and respiratory failure (20mg and 60mg group, respectively).

The secondary outcome was the change from baseline in cerebrospinal fluid (CSF) SOD1 protein concentration. Treatment with tofersen 100mg (n=10) over a three-month period resulted in a 36% reduction of SOD1 concentration compared to 3% in the placebo group (n=12).

Exploratory measures demonstrated numerical trends towards slowing of clinical decline as measured by the ALS Functional Rating Scale Revised (ALSFRS-R) as well as slow vital capacity and muscle strength measured by handheld dynamometer (HHD) compared to placebo.

The mean change in ALSFRS-R score from baseline to day 85 was -1.19 in the tofersen 100mg group compared to -5.63 in the placebo group on a 48-point scale. Across exploratory clinical measures, separation from the placebo group was primarily driven by the fast-progressing subgroup.

Professor Dame Pamela Shaw, director of SITraN, European chief trial investigator and director of the NIHR Sheffield Biomedical Research Centre, the only site in the UK to participate in the major international clinical trial, said: “The rise of genetic screening in our clinic means that we can now identify the different genetic subtypes of MND, which is helping to enhance the research effort.

“It’s a step forward that the published results warrant additional study in a larger patient group.”