A drug, still under investigation and developed to treat a rare and inherited form of amyotrophic lateral sclerosis (ALS), has reduced the molecular signs of this fatal and paralyzing disease and has slowed neurodegeneration; however, at six months the drug did not improve motor control or muscle strength, according to results from a phase 3 clinical trial of 108 patients led by researchers at Washington University School of Medicine in St. Louis (USA.).
On the positive side, the researchers found evidence that long-term use of the drug could help stabilize muscle strength and control, a finding they called encouraging. The data has been published in “The New England Journal of Medicine”.
Participants in the trial carry mutations in a gene called SOD1 that creates a misfolded version of a protein of the same name, which causes ALS.
The trial showed that the drug -tofersen- reduces the levels of SOD1 and also of a neurofilament protein, a molecular marker of neurological damage.
At the end of the placebo-controlled study period, participants were offered the option of receiving tofersen as part of an open-label extension lasting up to another 4½ years.
In this open-label extension, there were two groups of participants: those who had taken tofersen from the start and those who had received a placebo for six months before starting tofersen.
An interim analysis six months after the extension revealed a significant difference in motor function between those who started taking the drug before and after. After a year on the drug, some participants showed a plateau in muscle strength and control, a finding relevant to a disease characterized by relentless decline.
Last July, the US health authorities (FDA) accepted Biogen’s new drug application as a treatment for ALS related to SOD1 mutations.“This is an exciting and hopeful step towards finding a therapy for SOD1-related ALS,” acknowledges principal investigator Timothy M. Miller, of the University of Washington.
“We have seen clear evidence that the drug slows down the initiating factor – a SOD1 mutation – as well as the neurodegenerative disease process. We did not see substantial clinical improvement at six months, but stabilization of function and strength over longer timeframes suggests that people may take time to heal from the damage already done. The vast majority of people living with ALS experience a relentlessly progressive downward course, so the stabilization of function during open-label extension is truly remarkable.”
In Spain there are more than 3,000 people with ALS. This deadly disease kills the nerve cells that control walking, eating, and breathing. Few people survive more than five years after diagnosis.
Mutations in the SOD1 gene
About 2% of ALS cases are caused by mutations in SOD1. Tofersen is an antisense oligonucleotide, a DNA-based molecule that interferes with genetic instructions for building proteins. The molecule is designed to block the production of the SOD1 protein.
The phase 3 trial was conducted at 32 centers in 10 countries and included 108 ALS patients with SOD1 mutations. “The published data is encouraging for the ALS community because there are currently no treatments that can slow or stop the progression of the disease,” says co-investigator Merit Cudkowicz.
“The drug has the potential to improve quality of life for people living with SOD1-ALS by stabilizing muscle function with long-term use, which is an extremely promising development,” he adds.
“Most of the course participants at our center have regained and/or maintained several of their activities of daily living, and our strength tests and measurements corroborate their history of improvement, stabilization, or both,” notes Robert Bucelli, whose center from the University of Washington, attended 10 participants. “As a neuromuscular clinician, the privilege of witnessing this firsthand has changed the way I think about this and other related and devastating neurodegenerative disorders.”
Although the results of this trial only apply to people with ALS caused by mutations in SOD1, they could provide information that could benefit people with other forms of the disease. “I have always believed that ALS is a treatable disease,” adds Miller. .