FDA Panel Supports Tofersen for Rare Genetic ALS

A panel of FDA advisors voted unanimously that plasma neurofilament light chain (NfL), a biomarker of neurodegeneration, is a reasonable surrogate endpoint in amyotrophic lateral sclerosis (ALS) associated with a mutation in the SOD1 gene (SOD1-ALS).

In a 9-0 vote on Wednesday, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee said the available evidence was sufficient to conclude that reducing plasma NfL was reasonably likely to predict clinical benefit of the investigational antisense drug tofersen in Ω-ALS.

The vote occurred in the context of a potential accelerated approval, an expedited FDA pathway for drugs that fill an unmet medical need.

“My conclusion is that yes, we do have sufficient data to conclude there is a reasonable likelihood of NfL predicting clinical benefit and, as such, supporting accelerated approval,” stated committee member Tanya Simuni, MD, of Northwestern University in Chicago.

The committee did not agree, however, that tofersen was ready for traditional FDA approval. In a 3-5 vote (with one abstention), the FDA advisory panel said the clinical data from tofersen’s pivotal VALOR trial and its open-label extension did not provide convincing evidence of the drug’s effectiveness.

Tofersen mediates the degradation of SOD1 messenger RNA to reduce SOD1 protein synthesis. Around 2% of ALS cases are caused by mutations in SOD1.

In VALOR, tofersen led to greater reductions in SOD1 protein in cerebrospinal fluid and plasma NfL but missed the study’s primary endpoint, failing to slow neurologic and functional decline on the ALS Functional Rating Scale-Revised (ALSFRS-R) at 28 weeks compared with placebo.

Data from the open-label extension, however, suggested long-term use of tofersen may have benefits. At 12 months, participants who had started tofersen earlier appeared to have a slower rate of functional decline.

On Wednesday, the advisory committee and FDA staffers tried to balance uncertain clinical data about tofersen’s efficacy against the life-threatening effects of ALS.

No statistically significant effects on any prespecified clinical outcomes were seen in the double-blind VALOR study, observed Tristan Massie, PhD, of the FDA’s office of biostatistics. Additional post hoc analyses are difficult to interpret due to their exploratory nature, and conclusions about the relationship between NfL and the ALSFRS-R are limited, Massie argued.

“The data doesn’t meet the standard of convincing evidence of efficacy,” acknowledged advisory panelist Robert Alexander, MD, of the University of Arizona in Phoenix.

“You can speculate that maybe if the duration of the double-blind period had been longer, or if NfL had been used as a covariate, you might have seen a clear signal,” Alexander added. “But that wasn’t done.”

Certain situations — like when a disease is rare, life‐threatening, or severely debilitating with an unmet medical need — may warrant additional flexibility, noted Teresa Buracchio, MD, acting director of the FDA’s neuroscience office.

Agency guidance indicates that in certain settings, a somewhat greater risk of false positive conclusions and less certainty about effectiveness “may be acceptable, when balanced against the risk of rejecting or delaying the marketing of an effective therapy for an unmet medical need,” Buracchio pointed out.

Based on the evidence presented at the meeting, the committee reached an overall consensus that the benefit-risk assessment for tofersen in SOD1-ALS was favorable, but emphasized that more research is needed.

The FDA is scheduled to make its final decision about tofersen by April 25. The agency often follows the advice of its advisory committees, but isn’t required to do so. If approved, tofersen will be the first treatment to target a genetic cause of ALS.

Tofersen currently is being studied in the ATLAS trial, which is assessing whether the drug can delay clinical onset of ALS in presymptomatic patients with a SOD1 genetic mutation and biomarker evidence of disease activity. ATLAS is scheduled to be completed in 2027.