The Food and Drug Administration appears inclined to clear an unproven, but closely watched, medicine being developed by the biotechnology company Biogen for amyotrophic lateral sclerosis.
In documents made public Monday, agency staff cited the need for applying “regulatory flexibility” when considering treatments for serious, life-threatening diseases like ALS, even in cases of limited clinical trial evidence.
Yet the FDA reviewers seem to also hold doubts over Biogen's ability to conduct adequate follow-up testing to confirm the drug works. The uncertainty raises questions about whether the company could meet regulatory requirements in a timely fashion should the FDA decide in the coming weeks to grant the drug a conditional approval.
Known as tofersen, the medicine was developed by Biogen for patients with a genetic form of ALS. Specifically, these patients have mutations in a gene called SOD1, which researchers first linked to the disease three decades ago.
While SOD1 has become a prominent target among ALS drug developers, very few patients actually have this form of the disease. SOD1 mutations are responsible for less than 500 of the roughly 30,000 ALS cases in the U.S., according to estimates cited by the FDA.
That limited population sets up a challenge for the FDA, as the agency is deciding whether to grant tofersen a so-called accelerated approval that would require Biogen to conduct additional clinical testing to confirm the purported benefits of its drug.
Torn, the FDA has asked a group of external advisors to convene Wednesday and weigh in on tofersen’s merits.
“Given the extremely rare nature of SOD1-ALS, and the very small pool of patients available for enrollment into a clinical study,” conducting a second adequate trial of tofersen in symptomatic patients with this form of the disease “does not appear to be feasible at this time,” FDA staff wrote in the briefing documents released Monday.
Biogen does have another study of tofersen ongoing in people with SOD1 mutations who don’t yet have symptoms of ALS. It is proposing to use results from that trial as confirmatory evidence of the drug’s benefit, but it’s only about 50% enrolled and results are not expected until 2027.
Additional data from “open-label” testing, where patients know they’re receiving the drug, could also be used. Still, the FDA views that kind of data as “limited in interpretability.”
Further complicating the tofersen review is the drug’s failure in the main study Biogen is using to support its approval application. In that study, which evaluated 108 adults with SOD1-ALS over the course of half a year, tofersen wasn’t significantly better than a placebo at slowing the functional decline associated with the disease.
Tofersen did, however, appear to have a substantial effect on SOD1. Researchers found that the protein the gene produces decreased significantly in the cerebrospinal fluid — the liquid surrounding the brain and spinal cord — among patients in the trial’s drug arm versus the control group.
Tofersen-treated patients also experienced sizable reductions in a protein called neurofilament light chain, which signals neurological damage when levels are elevated in the blood and cerebrospinal fluid.
After learning of tofersen’s failure, Biogen officials met with FDA staff in September and December 2021 to discuss possible next steps for its drug, including “the appropriateness of the traditional approval pathway,” a company spokesperson confirmed in an email. According to the briefing documents, the agency said during its December meeting that a full approval would be “challenging to support” based on a single, failed trial.
Biogen ultimately chose to pursue an accelerated approval, which hinges on the FDA’s belief that a drug’s effect on a marker of disease is likely to provide some level of benefit to patients. In this case, Biogen built its argument around the neurofilament light chain data.
The advisory committee meeting Wednesday will be tasked with debating and voting on the reliability of neurofilament light chain as a disease marker, and whether it’s “reasonably likely” to be predictive of clinical benefit.
A positive vote on that question could help support the FDA in granting an accelerated approval, even if questions remain about Biogen’s ability to later obtain confirmatory results. (The company anticipates finishing enrollment of the key part of its ongoing study by late 2025, the spokesperson said.)
The FDA is also considering another scenario, in which the available data from Biogen could be seen as sufficient enough to grant full approval of tofersen. A second voting question for the committee appears worded as to gauge the group’s views on this approach.
Michael Yee, an analyst at the investment bank Jefferies, expects the committee to vote favorably on the first question but to be split on the second, according to a note he sent to clients Monday.
Analysts at RBC Capital Markets and Mizuho Securities also described the documents as supportive of an approval decision in client notes.
The meeting, and the FDA’s subsequent decision, could be another litmus test of how the agency navigates the competing priorities of upholding approval standards while being flexible to meet patient demands for new treatments. ALS has become one of several battlegrounds for this debate, which played out during the FDA’s review of Amylyx Pharmaceuticals’ recently approved medicine Relyvrio.
Editor’s note: This story has been updated with comment from Biogen.