ALS Drug Yields Meaningful Clinical Benefit, Phase 3 Data Show

Megan Brooks

September 27, 2022

Longer-term data show that the antisense oligonucleotide tofersen (Biogen) slows functional decline in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

Combined 1-year data from the phase 3 VALOR study and open-label extension study show sustained reductions in SOD1 protein and neurofilament, a marker of neurodegeneration, and slowed decline in clinical function, respiratory function, strength, and quality of life with earlier initiation of tofersen.

The 1-year results show a deceleration in functional decline that is similar, but more pronounced, than the previously reported 6-month results, which were not statistically significant.

"There is a meaningful clinical benefit when looking at the later time points in the open-label extension," said Timothy Miller, MD, PhD, principal investigator of VALOR and co-director of the ALS Center at Washington University School of Medicine, St. Louis, said in a Biogen news release.

Data from the combined analysis were presented in June at the European Network to Cure ALS (ENCALS) annual meeting, reported by Medscape Medical News at that time.

The study was published online September 22 in the New England Journal of Medicine. 

Under FDA Priority Review

VALOR was a 6-month phase 3, randomized, double-blind, placebo-controlled study testing the effects of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks) versus placebo in 108 adults with SOD1 ALS.

In the open-label extension, 32 placebo-treated patients switched to tofersen (delayed-start group) and were compared with 63 patients originally assigned to tofersen (early start group) up to 1 year.

At 52-weeks, the change in ALS Functional Rating Scale-Revised (ALSFRS-R) total score from the VALOR baseline was –6.0 points for early start participants versus –9.5 points for delayed-start participants, a statistically significant difference of 3.5 points favoring early start tofersen.

There was also a benefit associated with early start tofersen for several secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration, plasma neurofilament light chain levels, and respiratory function.

The most common adverse events in participants receiving tofersen were procedural pain, headache, pain in the arms or legs, falls, and back pain.

Most adverse events were mild to moderate in severity. Serious neurologic events including myelitis, chemical or aseptic meningitis, radiculitis, increased intracranial pressure, and papilledema were reported in 6.7% of participants receiving tofersen in VALOR and the open-label extension study.

The US Food and Drug Administration (FDA) has accepted Biogen's new drug application for tofersen for priority review, with a targeted action date of January 25, 2023.

Promising, Exciting Results

This study is "promising and potentially exciting news" for people with motor neurone disease (MND) whose condition is caused by a faulty SOD1 protein," Paul Wright, PhD, principal scientist, LifeArc, London, UK, told the nonprofit UK Science Media Centre.

"Although faulty SOD1 causes a small proportion of MND, it's the first evidence that reducing SOD1 protein production could work and will provide further insight into how SOD1 causes MND. The SOD1 protein is known to aggregate, and it would be interesting to see if this approach could offer hope to other neurodegenerative diseases where protein aggregation is also seen," Wright said.

Because the study shows the benefits are seen after a longer period, it also highlights the need to have "better tests to spot the disease earlier, to identify the exact type of disease a person has, and to monitor how it progresses. It's likely the disease is easier to treat, and people will respond better if personalized treatments are given before more nerve damage occurs," Wright added.

Brian Dickie, PhD, director of research development, Motor Neurone Disease Association, said he shares the "positive view of neurologists that this treatment has the potential to deliver a significant benefit in modifying the disease course."

"It is, of course, limited to a small, relatively rare subset of people with ALS, but given that treatments to date have been modest in slowing the disease, a genuinely positive impact will deliver new insight that should hopefully help open the door to novel treatments for other forms of the disease," Dickie told the UK Science Media Centre.

"The other encouraging point is the biomarker-based evidence, which provided investigators with early encouraging data that the drug was both hitting its intended target and also reducing nerve cell damage, in advance of notable clinical changes in motor function," he added.

"These latest trial results raise the important issue of whether earlier treatment in the disease course may be even more effective or, indeed, whether this strategy can delay or even prevent the onset of disease in asymptomatic mutant SOD1 gene carriers — a question that is currently being addressed by Biogen through their ATLAS study," Dickie added. 

This research was supported by Biogen. Disclosures for the authors are listed with the article. Disclosures for Wright and Dickie were unavailable by press time.

N Engl J Med. Published online September 22, 2022. Abstract

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