Long-term data suggest newly approved therapy can change trajectory of a rare inherited form of ALS, with sustained gains in some patients.
Amyotrophic lateral sclerosis (ALS) has followed a grim and predictable path for decades. Muscle weakness worsens, movement becomes harder and vital functions like breathing and swallowing eventually fail. Treatments have focused mainly on slowing the inevitable.
New long-term data suggest that the path may no longer be fixed, at least for a small group of patients.
A trajectory shift, not a cure
Researchers report that tofersen, a drug approved by the US Food and Drug Administration (FDA) in 2023 for a rare genetic form of ALS, can slow disease progression, extend survival, and in about one-quarter of patients, stabilize or even improve strength and function [1].
The findings were published December 22 in JAMA Neurology and are based on follow-up data spanning up to five years [2].
“Stopping disease progression and making improvements over three to five years is unheard of in this type of ALS. These results provide hope that we can change the trajectory of this devastating disease,” said Timothy M Miller, MD, PhD, a neurologist at Washington University School of Medicine in St Louis and lead author of the study.
Tofersen targets ALS caused by mutations in the SOD1 gene, which account for roughly 2% of all ALS cases. While that makes the drug relevant to a small patient population, its impact is outsized. People with SOD1-related ALS typically live just two to three years after symptoms begin.
Small population, big implications
For a therapy aimed at a tiny slice of ALS, tofersen is oddly big news. It validates a precision strategy that neurodegeneration has needed for years: hit the causal biology early, confirm target engagement, and track a biomarker that actually behaves like a compass, not a weather vane.
And the story doesn’t stop at treatment. A presymptomatic trial is now testing whether tofersen can delay or prevent disease in mutation carriers who haven’t developed ALS. Prevention, not triage. That’s a longevity mindset in its purest form: intervene upstream, long before the system tips into irreversible decline.
Antisense meets a known target
Tofersen works by blocking the production of the faulty SOD1 protein that damages motor neurons. Earlier trial results showed that tofersen reduced markers of nerve injury, leading to accelerated FDA approval. The new analysis looks at what happens when patients stay on the drug long term.
Over about three years of continuous treatment, roughly one in four participants experienced stabilization or improvement in grip strength and breathing capacity. Across the full group, disease progression was significantly slower than what doctors expect to see in untreated ALS.
What it looks like in real life
For Rickey Malloy, the change has been tangible. Diagnosed with SOD1-ALS at age 41 after more than a year of medical uncertainty, the former plumber began tofersen shortly after its approval.
“I’ve been on the drug two years now, and I feel pretty good,” Malloy said. “I have far less muscle spasming and cramping in my legs – it’s helped tremendously.”
Instead of steadily losing strength, Malloy has been able to increase the intensity of physical therapy, walk more and even tackle stairs. He recently qualified for knee replacement surgery, which he had previously been denied because his ALS was considered too advanced.
“My goal is to be able to stand on my tiptoes again,” he said. “I’m now building strength rather than just maintaining it.”
His wife, Jenny Malloy, described the drug as more than a medical intervention. “This medication represents more than just treatment,” she said. “It offers hope, progress and a renewed belief that a cure is possible.”
Survival is the signal
The phase 3 VALOR trial initially compared tofersen with a placebo over six months. After that period, all participants were allowed to receive the drug in an open-label extension. This design means nearly everyone eventually received tofersen, making long-term comparisons more nuanced.
Even so, the trends were clear. Patients who started tofersen earlier showed less decline in physical function, breathing ability, muscle strength, quality of life and risk of death than those who started later. While some differences did not reach statistical significance, researchers note this was likely due to the short delay before placebo participants switched to the drug.
What stands out most is survival. Historically, most people with SOD1-ALS die within a few years. In this study, at least half of the participants were still alive nearly five years after the trial began.
“There’s variability in patient response – it’s not a panacea,” said Robert Bucelli, MD, PhD, a study co-author. “But for those who do respond, maintaining independence is nothing short of a miracle.”
Tofersen is administered monthly via injection into the fluid surrounding the spinal cord. The most common side effects include headache, back pain and discomfort related to the procedure. About 9% of participants experienced more serious neurological side effects, mostly inflammatory, which were successfully treated.
A new trial is now underway to test whether tofersen can delay or prevent symptoms in people who carry SOD1 mutations but have not yet developed ALS – a shift from treatment to prevention [3].
For investors and longevity researchers, tofersen represents more than a single drug success. It validates a precision-medicine approach to neurodegenerative disease and strengthens confidence in antisense therapies targeting specific genetic drivers.
For patients like Malloy, the impact is simpler and far more personal. ALS may still be relentless, but for the first time, it no longer looks unstoppable.
[1] https://medicine.washu.edu/news/drug-for-rare-form-of-als-based-in-part-on-washu-research-approved-by-fda/
[2] https://jamanetwork.com/journals/jamaneurology/fullarticle/2843130
[3] https://www.clinicaltrials.gov/study/NCT04856982
