Tofersen Slows ALS Progression in Genetic Subtype, Offering New Hope for Patients
A groundbreaking new treatment is offering a beacon of hope for individuals battling amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. Long-term use of tofersen, recently approved by the Food and Drug Administration (FDA), has been shown to slow disease progression in patients with a specific genetic form of ALS, and researchers are optimistic about its potential application to other subtypes of the illness.
Historically, ALS has been a relentlessly progressive disease, gradually stripping individuals of their ability to move, speak, eat, and ultimately, breathe. However, recent findings published in JAMA Neurology demonstrate a significant shift in this trajectory for those with a specific genetic mutation.
Researchers from Washington University School of Medicine in St. Louis and their collaborators report that tofersen not only delays the worsening of symptoms but, remarkably, leads to stabilization or even improvement in approximately one-quarter of participants. “Stopping disease progression and making improvements over three to five years is unheard of in this type of ALS,” explained a senior author of the study. “Tofersen shows benefits compared with what we expect to see for these participants, with about 25% of participants experiencing improvement. These results provide hope that we can change the trajectory of this devastating disease, and we are optimistic we can do the same for other forms of ALS.”
Tofersen is specifically designed to address ALS caused by variants in the SOD1 gene, accounting for roughly 2% of all ALS cases. The drug functions by blocking the production of the mutated SOD1 protein, which is believed to contribute to neurodegeneration. Initial phase 3 trial results prompted the FDA to grant accelerated approval in 2023, and these new long-term data further solidify its efficacy.
Over a three-year treatment period, data indicates that around one-quarter of participants experienced stabilization of their symptoms, with some even demonstrating functional improvements in grip strength and respiratory function. This positive outcome is particularly poignant for patients like Rickey Malloy, a 41-year-old plumber diagnosed with SOD1-ALS in 2023.
“I’ve been on the drug two years now, and I feel pretty good,” Malloy shared. “I have far less muscle spasming and cramping in my legs—it’s helped tremendously. My physical therapy team has added more exercises and walking, and even stairs are getting easier. My goal is to be able to stand on my tiptoes again. I’m now building strength rather than just maintaining it.” Tofersen is administered monthly via injection directly into the fluid surrounding the spinal cord.
Approximately 20,000 people in the United States live with ALS, also known as Lou Gehrig’s disease. The disease attacks nerve cells responsible for controlling muscle function, leading to progressive paralysis. The average life expectancy for individuals with SOD1-ALS is typically two to three years from the onset of symptoms. However, the improvements observed in patients receiving tofersen represent a significant departure from this grim prognosis.
According to a co-author of the study, “There’s variability in patient response to tofersen—it’s not a panacea for everyone,” but “for those patients who do have a substantial response, the fact that they’re able to maintain the independence they had when they went on the drug is a miracle.” Malloy’s case exemplifies this, as he recently qualified for and underwent a total knee replacement surgery that was previously deemed impossible due to the severity of his condition.
The positive impact extends beyond the clinical data. Jenny Malloy, Rickey’s wife, emphasized the emotional toll of the diagnosis and the transformative effect of finding care at Washington University. “Connecting with the team at WashU Medicine became the turning point we so desperately needed,” she stated. “We are incredibly grateful to the physicians and researchers who have dedicated their careers to finding a cure for ALS. Their relentless pursuit of answers has brought light to what once felt like a dark and uncertain path.”
Tofersen belongs to a class of drugs called antisense oligonucleotides, which work by interfering with the activity of specific proteins. Researchers pioneered this approach, initially focusing on SOD1-ALS, but are now exploring its potential for targeting other damaging proteins involved in various forms of ALS and other neurodegenerative diseases.
The development of tofersen, also known by the brand name Qalsody, was a collaborative effort between Biogen, Ionis Pharmaceuticals, and the research team led by Timothy Miller. Biogen funded the clinical trials, which involved a six-month phase 3 trial comparing tofersen to a placebo, followed by an open-label extension where all participants were given access to the drug. Forty-six of the original 108 participants completed the study after 3.5 to 5.5 years of follow-up.
The study revealed that participants treated with tofersen experienced slower disease progression overall compared to the typical course of ALS, and the drug prolonged survival. Notably, at least half of the trial participants were still alive nearly five years after the study began, significantly exceeding the typical two-to-three-year life expectancy for SOD1-ALS patients.
While the study design—allowing all participants to eventually receive tofersen—limited the ability to demonstrate statistically significant differences between early and late starters at the three-year mark, the numerical trends consistently favored those who began treatment sooner. The authors suggest that even a relatively small difference in treatment duration can be difficult to detect over several years, but the overall evidence supports tofersen’s efficacy.
The most common side effects reported included headache, procedural pain, falls, back pain, and pain in the extremities. A small percentage of participants (9%) experienced more serious neurological side effects, which were successfully managed with additional therapies.
Currently, a new multisite clinical trial is underway to investigate whether tofersen can prevent or delay the onset of SOD1-ALS in individuals known to carry the gene variant but who have not yet developed symptoms. Robert Bucelli is leading the trial at the Washington University site.
“We are grateful to the many people who have helped make tofersen a successful, available treatment for SOD1-ALS: the funders, scientific colleagues, clinical trial investigators, other partners and especially the study participants who dedicated so much time and effort to this study,” Miller concluded.
It is important to note that Miller has received consulting fees from Biogen and previously served on the company’s advisory board, while Bucelli has served on advisory boards for Biogen and is a paid consultant and member of the ATLAS steering committee for Biogen. Washington University has no financial interest in tofersen.
