A FDA advisory committee has boosted Biogen and Ionis’ prospects of winning accelerated approval for their amyotrophic lateral sclerosis (ALS) drug. The experts unanimously voted that biomarker evidence supports conditional approval—but a failed clinical trial proved a barrier to support for a full approval.
Late in 2021, Biogen reported that its Ionis-partnered antisense drug prospect tofersen failed to improve the functional status of a genetic subset of ALS patients in a placebo-controlled clinical trial. Despite the primary endpoint failure, Biogen outlined plans to talk to regulators about the next steps, pointing to changes in a potential biomarker of neuronal degeneration to make the case for the drug candidate.
The advisory committee found Biogen’s evidence on the biomarker, plasma neurofilament light chain (NfL), compelling. Asked whether a reduction in NfL concentration is reasonably likely to predict the clinical benefit of tofersen, all nine experts on the advisory committee voted yes.
In explaining his vote, David Weisman, M.D., director of Abington Neurological Associates' Clinical Trial Center, said: “It appears that Nfl is bad for neurons and is tied with neuronal death. So, if it's lower, then neuronal death should be lower.”
Liana Apostolova, M.D., a professor at the Indiana University School of Medicine, expanded on the implications of establishing Nfl as an ALS biomarker.
“As an [Alzheimer’s] specialist, I must admit that I'm envious of my ALS colleagues for having such a promising prognostic biomarker, Nfl, that seems to be linked to clinical and functional outcomes, at least among the patients with this rare causal mutation, but also hopefully more generally across the entirety of the ALS population,” Apostolova said. “I was convinced by the data and voted yes.”
Apostolova and four other members of the committee were less convinced by other aspects of the data, however. The panel voted five to three against when asked whether the clinical data from the placebo-controlled study and long-term extension study results provide substantial evidence of the effectiveness of tofersen in the treatment of patients with mutations in the SOD1 gene. One expert abstained on that question.
The second question gauged the experts’ position on whether Biogen has the evidence to support a full, traditional approval despite the failure of the placebo-controlled trial. Richard Kryscio, Ph.D., professor of statistics and biostatistics at the University of Kentucky, set out his reasons for voting no.
“The trial did not meet its goals. We heard from the sponsor that they didn't know a whole lot about the natural history of the disease,” Kryscio said. “We're going to have data that's based on the open-label extension, we will have more events to find out if the positive results on the biomarker, the neurofilament light, actually translates into a true clinical benefit, which I don't see right now.”
Other committee members who voted no confirmed that they felt the submission meets the standards for accelerated approval but not for full approval. People on both sides of the vote said it was a difficult choice, with Weisman saying he “agonized” over the decision before ultimately voting yes.
“I think that the odds are extremely high that this drug works,” Weisman said. “I guess I really worry about the consequences of an accelerated approval, maybe as a neurologist, where payers will not cover this drug and consider it experimental, which I think would be a big problem clinically.”
The FDA is scheduled to make a decision on whether to approve tofersen by April 25.