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FDA Advisory Committee Backs Accelerated Approval of Tofersen for SOD1-ALS
A US Food and Drug Administration (FDA) advisory committee supported accelerated approval of tofersen for a rare genetic form of amyotrophic lateral sclerosis (ALS). Members of the committee agreed 9-0 that a demonstrated reduction in plasma neurofilament light chain (NfL) concentration in patients with SOD1-ALS is reasonably likely to predict clinical benefit. The FDA Peripheral and Central Nervous System Drugs Advisory Committee, however, did not agree that the investigational antisense drug was ready for traditional FDA approval.
The New Drug Application for tofersen, an investigational antisense medicine for patients with SOD1-ALS, was submitted to the FDA for consideration under accelerated approval. The FDA is expected to announce its final decision by April 25, 2023.
At the advisory committee’s March 22, 2023, meeting, the panel unanimously voted that evidence was sufficient to conclude a reduction in plasma Nfl is reasonably likely to predict tofersen’s clinical benefit.
On another question — “Does the clinical data from the placebo-controlled study and available long-term extension study results, with additional supporting results from the effects on relevant biomarkers (ie, changes in plasma NfL concentration and/or reductions in SOD1), provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?” — the committee voted 3-5, with 1 member abstaining, against consideration of a potential traditional approval.
According to a recent report, the phase 3 VALOR trial showed greater reductions in SOD1 protein in cerebrospinal fluid and plasma NfL with tofersen, but the treatment did not slow neurologic and functional decline on the ALS Functional Rating Scale-Revised (ALSFRS-R) at 28 weeks, which was the study’s primary endpoint. Nevertheless, the open-label extension suggested benefit: patients treated earlier with tofersen appeared to have slower functional decline at 12 months.
“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. But that wasn’t done,” remarked committee member Robert Alexander, MD, of the University of Arizona in Phoenix.
In addition to the ongoing open-label extension of VALOR, tofersen is being studied in the phase 3 ATLAS trial. The study is designed to evaluate whether tofersen can delay clinical onset when initiated in presymptomatic individuals with a SOD1 genetic mutation and biomarker evidence of disease activity.
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