At a session on March 22, a panel of external advisors to the US Food and Drug Administration (FDA) gave Biogen’s amyotrophic lateral sclerosis (ALS) treatment, tofersen, full support for accelerated approval. The recommendations, which the FDA does not have to follow, came despite a failed Phase 3 trial and are instead based on biomarker data.
Copper zinc superoxide dismutase 1 (SOD1) mutation is the second most common genetic mutation that causes familial ALS. Though the mutation affects only about 330 people in the US, those impacted have heartbreaking stories to tell: During the hearing, one patient shared that her family has recorded 33 deaths from ALS across seven generations and counting.
The first drug candidate for SOD1-ALS, Biogen’s tofersen, is an antisense oligonucleotide that binds to messenger RNA to silence the expression of the faulty SOD1 protein. But a reduced protein level doesn’t necessarily translate to outward improvement among patients.
In a six-month double-blinded Phase 3 trial among 108 participants, tofersen failed to meet its primary endpoints—individuals that took the drug showed similar declines in physical function to those that were on the placebo. However, the open-label extension of the clinical trial gave an upturn in the results. After a total of 52 weeks, the study showed a more significant slowing in disease progression among the participants who started the regimen six months earlier than their delayed counterparts.
During the clinical trial, tofersen also successfully lowered the concentration of neurofilaments (NFL) in the blood plasma. These neurofilaments, the proteinaceous flotsam of injured neurons, are broadly suggestive of neurodegeneration.
Neurofilaments have never been used as a surrogate biomarker for a drug’s approval, but Biogen argued that, at least for the case of SOD1-ALS, the data showed that it is likely one. The vote at last week’s hearing indicated that the advisory panel agreed unequivocally—that a reduction in neurofilament levels signifies potential clinical benefit, despite the failed Phase 3 study.
“My conclusion is yes, we do have sufficient entirety of the data to conclude that there is reasonable likelihood of NFL predicting clinical benefit,” Tanya Simuni, a neurologist at Northwestern University and temporary voting member on the committee, said at the hearing. Her logic was later echoed by her fellow panelists to justify their voting decisions.
Many ALS researchers and physicians hailed the opinion. Every inch of patient improvement that any drug can bring is worth fighting for, says Hande Ozdinler, a neurologist at the Les Turner ALS Center of Northwestern University. The heterogeneity of ALS means that no drug can cure all patients, and patients need as many drug options as possible. “I don’t think that we should disregard the fact that a small population has improved,” she says, even if this clinical result were statistically insignificant. “Reducing people to numbers is not what we are aiming for.” While the FDA is not obligated to follow the recommendation of the advisory panel, the regulatory body will likely abide by their votes, says Pamela Spicer, a principal analyst at Citeline. The FDA will officially decide on tofersen by April 25.
In 2020, Biogen applied for accelerated approval for a different drug that also showed mixed results in the clinic: aducanumab, a monoclonal antibody for Alzheimer’s disease. Citing its conflicting clinical data, an expert panel voted against its fast-track approval, but the FDA defied its recommendation to green-light the drug in 2021.
The FDA advisory panel voted differently for tofersen for several reasons, Spicer says, despite the fact that it too flunked clinical trials. SOD1-ALS affects a much smaller population compared with Alzheimer’s, so a repeat trial or achieving statistically significant outcomes for any SOD1-ALS drug are unlikely with a small participant groups. The open-label period of tofersen’s Phase 3 study, which showed marginal clinical benefit, was also compelling enough to elicit a unanimously favorable vote for the drug. Moreover, SOD1-ALS progresses much more rapidly: people diagnosed with the disease have an average survival of less than 3 years. “The unmet need could be arguably greater in ALS than Alzheimer’s,” she adds.
At the session, the advisors recommended conditional approval in a 9-0 vote, but tofersen failed to secure a recommendation for full approval. The panel voted 3-5, with one advisor abstaining. The sentiment was that while the clinical data suggested that potential clinical benefit, it did not meet the standards for convincing evidence for efficacy. A confirmatory trial involving 150 presymptomatic people with the SOD1 mutation is underway, one that Biogen estimates to complete in 2027.