An experimental drug has shown promising results in treating a rare inherited form of amyotrophic lateral sclerosis (ALS), according to findings from a phase 1/phase 2 clinical trial. The drug, tofersen, demonstrated safety and biological activity in patients with ALS caused by mutations in the SOD1 gene.
The trial, conducted at Washington University School of Medicine in St. Louis, Massachusetts General Hospital in Boston, and other global sites, was sponsored by Biogen Inc. Results published in The New England Journal of Medicine on July 9 have led to the initiation of a phase 3 clinical trial to further evaluate the drug's safety and efficacy.
"ALS is a devastating, incurable illness," said principal investigator Timothy M. Miller, MD, PhD, the David Clayson Professor of Neurology at Washington University and director of the ALS Center at the School of Medicine. "While this investigational drug is aimed at only a small percentage of people with ALS, the same approach – blocking the production of specific proteins at the root of the illness – may help people with other forms of the illness."
Understanding SOD1-Related ALS
ALS affects approximately 20,000 people in the United States, progressively killing nerve cells that control walking, eating, and breathing. The prognosis is poor, with few patients surviving beyond five years after diagnosis. Current treatments offer only modest benefits in slowing disease progression.
About 10% of ALS cases are inherited, and one-fifth of those inherited cases (approximately 2% of all ALS cases) are caused by mutations in the SOD1 gene. These mutations cause the SOD1 protein to become hyperactive, suggesting that reducing protein levels could benefit patients with this specific genetic mutation.
Tofersen's Mechanism and Trial Design
Tofersen is an antisense oligonucleotide, a DNA-based molecule designed to interfere with the genetic instructions for building proteins. Specifically, it blocks production of the SOD1 protein. Previous studies in mice and rats with SOD1 mutations showed promising results, with treated animals living longer and exhibiting fewer signs of neuromuscular damage.
To assess the drug's safety and biological activity in humans, researchers recruited 50 people with SOD1 ALS for the clinical trial. Participants were randomly assigned to receive either tofersen or a placebo, administered via injection into the cerebrospinal fluid. The treatment ratio was 3:1, with three participants receiving tofersen for every one receiving placebo.
Each participant received five doses over a 12-week period. The study included four dosage groups, with participants receiving 20 mg, 40 mg, 60 mg, or 100 mg per dose.
Promising Results
The researchers found that tofersen was generally well-tolerated. Most adverse events were related to the administration method – spinal tap – and included headaches and pain at the injection site. Five patients in the tofersen group and two in the placebo group experienced serious adverse events, including two deaths in the tofersen group and one in the placebo group.
Importantly, the study provided evidence that the drug effectively lowered SOD1 protein levels in the cerebrospinal fluid. Protein concentrations decreased by an average of 2% in the low-dose group and 33% in the high-dose group.
"This trial indicated that tofersen shows evidence of safety that warrants further investigation and that the dose we used lowers clinical markers of disease," Miller noted. "There are even some signs that it slowed clinical progression of ALS, although the study was not designed to evaluate effectiveness at treating the disease, so we can't say anything definitive."
Moving Forward
Biogen is continuing to provide tofersen to participants in the phase 1/phase 2 trial under an open-label extension until further evaluation is complete. A separate phase 3 trial is now enrolling additional participants to further assess safety and determine whether the drug helps preserve muscle strength and function and extends survival.
While tofersen would directly benefit only a small fraction of ALS patients if proven effective, the approach could pave the way for other oligonucleotide-based drugs targeting different forms of ALS and other neurodegenerative conditions.
"Sometimes patients say, 'Why is all this work being done in the 2% who have SOD1 ALS? What about the 98%?'" said co-principal investigator Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital. "But the same technology that can turn off the SOD1 gene can be used to turn off other targets, and in fact, there are many companies working on other targets. Everything we have learned with SOD1 ALS could end up aiding new approaches to fighting other forms of ALS or other neurological conditions."
The early work on oligonucleotides received support from the Muscular Dystrophy Association, the ALS Association, and the National Institute of Neurological Disease and Stroke at the National Institutes of Health (NIH), recognizing the potential these compounds hold for treating neurodegenerative conditions linked to abnormal protein levels or structures.
As the phase 3 trial progresses, researchers and patients alike are cautiously optimistic that this approach may not only help those with SOD1 mutations but also establish a platform for addressing other forms of this devastating disease.
