An experimental treatment for the rapidly progressive disease ALS, or amyotrophic lateral sclerosis, has been called potentially “game-changing.”
The treatment, called tofersen, was found to slow the decline of muscular function associated with a genetic form of ALS in a study to be presented next week at the annual meeting of the American Academy of Neurology.
“ALS is a devastating and fatal disease that has no effective treatment options, so there is an opportunity to pioneer innovative treatments,” said Dr. Timothy Miller, professor of neurology at Washington University in St. Louis and first author of the study, which has not been published.
Tofersen is still in its developmental stages, and how much it could cost is not yet known.
Specifically, the experimental treatment contains antisense oligonucleotide, which targets a type of ALS, also known as Lou Gehrig’s disease, caused by mutations on the SOD1 gene. Worldwide, SOD1 gene mutations cause 15% to 20% of familial ALS or ALS that runs in families, according to the US National Library of Medicine.
The study noted that about 2% of all ALS cases are linked to SOD1 mutations.
“This particular mutation, called SOD1, was the first mutation that was shown to cause ALS. That was back in 1993,” said Dr. Jonathan Glass, a professor and director of the Emory ALS Center at the Emory University School of Medicine, which participated in the antisense oligonucleotide trial.
“We think that this abnormal protein, this mutant protein, somehow causes toxicity to the nervous system and kills neurons and causes ALS,” Glass said.
“What antisense oligonucleotides can do is reduce the production of the mutant SOD1 protein by binding to and shutting down the genetic machinery that produces the mutant protein,” he said. “This potentially could be game-changing, at least for this subgroup of patients.”
He added that the treatment is administered as a spinal tap, during which antisense oligonucleotide is injected into spinal fluid.
The study involved 50 participants with ALS caused by the SOD1 mutation. The patients were randomly assigned to receive either 20, 40, 60 or 100 milligrams of the tofersen treatment or a placebo for 12 weeks.
During that time, the researchers assessed the safety and efficacy of the treatment. Overall, they found that the treatment was effective in reducing muscular decline in the patients assigned to receive doses of tofersen.
Among the participants who received 100 milligrams of the treatment, the researchers found a 37% reduction of the SOD1 protein in their spinal fluid compared with those who received the placebo. Participants who got smaller doses showed less of a reduction.
That reduction of SOD1 led to reductions in how the ALS disease affected the body.
“Reducing the level of the SOD1 protein would be a good thing for people with SOD1 mutations causing ALS,” Washington University’s Miller said. “The SOD1 protein with the mutation is what’s causing the toxicity. It’s what’s causing ALS in people with a genetic change in SOD1.”
The researchers also found that the majority of side effects were mild or moderate, such as pain at the injection site and headaches, Miller said.
Two drugs are approved by the US Food and Drug Administration for the treatment of ALS: riluzole and edaravone.
“Neither of them are a panacea in terms of slowing this disease down. It’s a very modest effect, if any,” Glass said.
As for the new treatment approach targeting a specific gene mutation, “we’re in a new era of therapeutics for neurological disease,” he said. “These diseases that were universally fatal may be treatable in the near future, and that’s going to be pretty exciting. That’s a huge leap forward.”
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Dr. Catherine Lomen-Hoerth, neurologist and director of the ALS Center at the University of California, San Francisco Medical Center, called the new study impressive in terms of its findings and the number of patients recruited to participate.
“We currently do not have any treatments specific for the genetic forms of ALS, and what is unique about genetic forms of ALS is the ability to identify patients prior to their symptoms starting,” said Lomen-Hoerth, who was not involved in the study.
“Treatments work best when given prior to symptoms starting or at the very start of symptom onset. This is something not possible with sporadic ALS because it takes time to establish a diagnosis, and by then, the symptoms can be quite advanced,” she said. “While this treatment would only affect 2% of ALS patients, it may be much more impactful than other treatments for ALS, since it can be administered much earlier in the disease process – perhaps even before a patient develops symptoms.”