It looks like the holiday wishes for many ALS patients might have been answered this year. Researchers have announced evidence that early, sustained treatment can meaningfully slow the disease and extend survival in a rare genetic form of amyotrophic lateral sclerosis.
In a new long-term analysis appearing in JAMA Neurology, researchers report that adults with ALS caused by mutations in the SOD1 gene experienced slower functional decline and lived longer. The benefits, the authors explain, cropped up when patients received early treatment with tofersen, an antisense therapy designed to reduce production of the SOD1 protein.
The research team relied on up to three-and-a-half years of follow-up from the phase 3 VALOR trial and its open-label extension, which paints the clearest picture yet of tofersen’s potential long-term clinical impact.
“Stopping disease progression and making improvements over three to five years is unheard of in this type of ALS,” WashU Medicine professor and first author Timothy M. Miller, MD, PhD, said in a statement. “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.”
Methodology (and a Little Background)
About 2% of ALS cases can be traced back to pathogenic variants in SOD1. Tofersen, delivered via multiple lumbar punctures, targets this subgroup by silencing SOD1messenger RNA and slashing levels of the harmful protein. It’s the only approved therapy specifically for SOD1-related ALS on the market today.
The VALOR trial originally randomized 108 adults with SOD1-ALS to receive tofersen or placebo for 28 weeks. All participants could then enter an open-label extension, in which everyone received tofersen. This design allowed researchers to compare people who started the drug early with those who began treatment roughly six months later.
By the end of follow-up, participants had accumulated 42 to 60 months of observation time. Over that period, those who received tofersen earlier consistently fared better across multiple measures of disease progression. At 148 weeks, early-start patients showed less decline in daily function, respiratory capacity, muscle strength, and quality of life than those who started off with the placebo.
Exceeding Expectations
The differences – admittedly modest in absolute terms – stood out against the frustrating history of ALS. Untreated patients typically lose 22 to 34 points on the ALS Functional Rating Scale over a comparable timeframe. In stark contrast, patients in the early-start group fell by about 10 points. Delayed-start patients declined by roughly 14 points.
Treated patients showed an even more unusual pattern: marked stabilization. And in some more dramatic examples, patients showed actual improvement. Roughly a quarter of early-start participants enjoyed measurable gains in muscle strength over three years. Statistical modeling suggested almost no chance of finding this kind of improvement.
Biomarker data reinforced the clinical findings. Tofersen produced sustained reductions of more than 60% in plasma neurofilament light chain (NfL). The drop occurred early in treatment and persisted for years, supporting the idea that tofersen slows the underlying neurodegenerative process rather than simply treating the symptoms.
Survival analyses also favored early treatment. Among patients with high baseline NfL levels – and expected to progress fastest – early treatment extended event-free survival by more than three years vs. delayed treatment.
The Fine Print
The safety findings echoed earlier reports. And most adverse events reflected either ALS progression or complications of lumbar puncture (such as headache and back pain).
Serious neurological events, including inflammation of the spinal cord or meninges, were uncommon and nearly always reversible. Few patients discontinued treatment because of side effects.
The authors, however, did concede a few caveats, including a small sample size, disease heterogeneity, and the fact that all participants eventually received the drug, which complicates direct comparisons.
Even so, the authors insist that the long-term data strengthen the case for treating SOD1-ALS as early as possible – maybe even before symptoms appear.
“There’s variability in patient response to tofersen — it’s not a panacea for everyone,” WashU Medicine ALS Center co-director and co-author Robert Bucelli, MD, PhD, added. “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.”
Researchers are now in the midst of ongoing trials to test tofersen in presymptomatic carriers of SOD1 mutations, guided by rising neurofilament levels. If successful, they could shift ALS care toward earlier detection and intervention. It’s an approach that’s transformed outcomes in other genetic neurologic diseases.
For a field long overshadowed by repeated disappointments, the tofersen data suggest something new – and uncharacteristically promising. Maybe targeting the root molecular cause of ALS, early and relentlessly, can shar the disease’s trajectory in a meaningful way.
Further Reading
Researchers Discover Abnormal Proteins in ALS Patients
ALS Patients Lose Another Treatment Option
Suicide Attempts in Patients With Amyotrophic Lateral Sclerosis
