Long-term use of tofersen slows amyotrophic lateral sclerosis progression in patients with a genetic SOD1 variant, according to a phase 3 study published Dec. 22 in JAMA Neurology. Researchers at WashU Medicine report that the drug delays symptom progression and leads to stabilization or functional improvement in roughly one-quarter of participants.
Amyotrophic lateral sclerosis is a fatal neurodegenerative condition that attacks nerve cells controlling muscles required for movement, speech, swallowing, and breathing. Most patients experience a relentless neurological decline. For patients with SOD1-ALS, life expectancy is typically two to three years from the onset of symptoms. While the rare genetic form linked to variants in the SOD1 gene accounts for approximately 2% of all cases, researchers have searched for targeted interventions to alter its devastating course.
Long-Term Follow-Up Data Show Stabilization in a Subset of Patients
Data from an open-label extension of the phase 3 trial indicate that prolonged administration of tofersen can alter disease trajectories. The treatment works by blocking the production of the mutated SOD1 protein. Investigators observed that over roughly three years of therapy, about 25% of trial participants experienced stabilization of symptoms, alongside functional gains in grip strength and respiratory function.
“Stopping disease progression and making improvements over three to five years is unheard of in this type of ALS.”
Timothy M. Miller, MD, PhD, David Clayson Professor of Neurology at WashU Medicine and co-director of the WashU Medicine ALS Center
The drug gained initial Food and Drug Administration approval in 2023 through an accelerated pathway after early trial results demonstrated reductions in neurodegeneration. The FDA-approved treatment is administered monthly via an injection directly into the fluid surrounding the spinal cord. WashU Medicine researchers and their collaborators co-led both the pivotal trial and the subsequent long-term evaluation published in JAMA Neurology.
Patient Experiences and Clinical Variability Under Treatment
Clinical responses to tofersen vary significantly among individuals. Clinicians emphasize that while the therapy is not effective for every patient, those who respond substantially can maintain their independence.
“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.”
Robert Bucelli, MD, PhD, professor of neurology and co-director of the WashU Medicine ALS Center
For patients such as Rickey Malloy, who was diagnosed with SOD1-ALS at age 41, the treatment has yielded functional gains. After two years of monthly spinal injections, Malloy reported reduced muscle spasms and cramping in his legs, allowing his physical therapy team to incorporate more walking and stair climbing. The functional recovery enabled Malloy to undergo a total knee replacement surgery that doctors previously deemed him ineligible for due to advanced disease severity.
The search for effective ALS therapies extends across multiple experimental approaches, though not all trials have succeeded. A randomized controlled trial known as RespiStimALS evaluated whether electrical stimulation of the diaphragm, termed diaphragm pacing, could delay the need for ventilation support or prolong survival. Data from that trial and a parallel UK study called DiPALS revealed higher mortality rates and an earlier requirement for non-invasive ventilation among patients receiving diaphragm pacing compared to control groups, leading to the termination of the trial and clinical consensus that diaphragm pacing should not be used at any stage of ALS.
Meanwhile, investigations into other therapeutic modalities continue. Researchers tested bone marrow-derived stem cells stimulated to secrete neurotrophic factors in trials involving 26 patients with disease of less than two years’ duration. While injection into muscle or spinal tissue proved safe—with patients experiencing mild, temporary side effects such as headache and fever—further follow-on studies remain necessary to assess clinical benefits.
Future Outlook and Therapeutic Implications
The long-term findings on tofersen provide hope for treating other forms of ALS. Investigators remain optimistic that targeting specific genetic variants and neurodegenerative pathways will yield similar disease-modifying therapies for a wider population of patients living with the condition.
