FDA panel votes in favor of tofersen biomarker data
However, opinions are mixed about toferson's effectiveness in SOD1-ALS patients
Changes in neurofilament light chain (NfL) levels — a biomarker of nerve cell damage — were deemed by an advisory committee reasonably likely to predict clinical efficacy from tofersen in people with amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations.
The unanimous vote from the Peripheral and Central Nervous System Drugs Advisory Committee, part of the U.S. Food and Drug Administration (FDA), indicates that NfL levels alone may be considered as a good surrogate marker of the experimental therapy’s effectiveness.
However, the committee narrowly voted “no” when asked if currently available data gives substantial evidence that tofersen is effective in SOD1-ALS patients.
The FDA will consider these recommendations from the committee’s March 22 meeting in its ongoing review of tofersen, with a decision expected by April 25. The agency usually aligns with the decisions of its expert committees, but is not obligated to do so.
“We thank the FDA for convening this important discussion,” Priya Singhal, MD, executive vice president and head of development, and interim head of research and global safety and regulatory sciences at Biogen, said in a press release.
Biogen is developing tofersen after licensing the therapy from prior developer Ionis Pharmaceuticals.
“We are encouraged by the outcome of today’s advisory committee meeting,” C. Frank Bennett, PhD, executive vice president and chief scientific officer at Ionis, said in a press release from the company. “If approved, tofersen would be the first medicine targeting a known cause of familial ALS.”
Mutations in the SOD1Â gene are found in up to 20% of people with familial ALS, and up to 2% of sporadic ALS cases. These mutations lead to the production of an abnormal version of the SOD1 protein that forms clumps in nerve cells, which are thought to be toxic and drive disease progression.
Tofersen is an RNA-based therapy designed to disrupt the production of the SOD1 protein, thereby reducing the formation of these toxic protein clumps. It’s administered via an injection into the spinal canal, called an intrathecal injection.
VALOR clinical trial
Biogen’s application for accelerated approval of tofersen is supported by data from the Phase 1/2/3 clinical trial VALOR (NCT02623699). The Phase 1 and 2 portions of the study provided proof-of-concept that tofersen could lower SOD1 protein levels as designed, and also indicated the treatment was generally well tolerated.
In the Phase 3 part of VALOR, 108 adults with ALS were assigned randomly to receive eight injections of tofersen (100 mg) or a placebo over the course of 28 weeks, or about six months. The study’s main goal was to assess the impact of treatment on disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R).
Top-line results from VALOR showed it failed to meet that goal; changes in ALSFRS-R scores were not significantly different between patients given tofersen or a placebo.
However, newer data from an open-label extension study (NCT03070119), in which 95 patients from VALOR are being treated with tofersen for up to seven years, indicated that disease progression was slower among patients given tofersen in the initial study, compared with those who got placebo for six months in the original trial.
Data from VALOR and its extension study also indicated that treatment with tofersen markedly reduced levels of NfL, a structural protein in nerve fibers. When nerve cells are injured or die, NfL gets released into bodily fluids, so it often is used as a marker of nerve damage.
Analyses from VALOR suggested that tofersen-treated patients with a sharper NfL reduction in the first months after initiating treatment tended to experience slower disease progression.
In its meeting, the FDA voted unanimously “yes” in answer to the question, “Is the available evidence sufficient to conclude that a reduction in plasma neurofilament light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS?”
 Seeking accelerated approval
Biogen is seeking approval of tofersen under the FDA’s accelerated approval pathway, which allows the agency to give conditional marketing authorization for therapies where early biomarker data suggest a likely benefit. Developers of therapies given accelerated approval are mandated to conduct additional testing to confirm a clinical benefit.
According to Biogen and Ionis, the unanimous vote from the committee likely favors accelerated approval.
“After hearing the moving experiences of the ALS community and reviewing the totality of data, the Committee voted that reductions of neurofilament are reasonably likely to predict clinical benefit of tofersen,” Singhal said. “If approved, tofersen would potentially represent a major advance for people living with SOD1-ALS.”
Considering NfL as a good surrogate biomarker of efficacy may have implications beyond ALS, as NfL is a common marker of nerve damage and is elevated in numerous neurological disorders. However, it still remains to be seen whether the FDA itself will deem the NfL data sufficient to support an accelerated approval.
The second question
The committee was mixed, however, in its vote on the 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 (i.e., 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?”
In answer, five committee members voted no, three voted yes, and one abstained. This represents a narrow vote against a traditional approval of tofersen at this time, according to the therapy’s developers.
Biogen is running a Phase 3 trial, ATLAS (NCT04856982), to learn more about the efficacy of tofersen. The study is testing tofersen against placebo in people who have SOD1 mutations and elevated NfL levels, but have not yet developed any symptoms of ALS. The study is recruiting participants at locations worldwide.
“We are grateful to all the people with SOD1-ALS who participated in our tofersen studies, and their caregivers, families, study investigators and the entire community, without whom this scientific progress could not have been made,” Singhal said.
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