The fate of what was poised to be the first drug approved to treat the underlying cause of Alzheimer's disease is now less certain, following a contentious Friday meeting of an expert committee convened by the Food and Drug Administration to debate the experimental medicine.
Advisers on the panel were sharply critical of the evidence supporting the drug, rejecting arguments made by its developer, Biogen, and the FDA in an overwhelmingly negative vote. Ten panelists voted against the drug, known as aducanumab, while one voted "uncertain." None were convinced the clinical trial results presented were proof of effectiveness.
The vote punctuated a seven-hour meeting that put both aducanumab, and the FDA's seeming support of it, under intense scrutiny. While the regulator could still choose to approve Biogen's drug, the panel's negative view likely makes that decision harder.
"Alzheimer's treatment is a huge, urgent, unmet need. But I also think that if we approved something where the data is not strong, that we have a risk of delaying an effective treatment for more than a couple of years," said one of the panelists, Joel Perlmutter, a professor of radiology and neuroscience at the Washington University School of Medicine.
"I think there's a huge danger in approving something that turns out not to be effective," he added.
The back-and-forth could have been expected, given aducanumab has divided the Alzheimer's research community for quite some time. After completing an early study, Biogen designed two much larger trials meant to show once and for all whether it could slow cognitive decline for patients who were in the earliest stages of the disease.
Biogen cut both trials short in March 2019, however, once an independent team of researchers determined neither was likely to succeed. Aducanumab, it seemed, would join a long list of similar drugs which had failed as Alzheimer's treatments.
That was until October 2019, when Biogen announced that further analysis showed patients in one of the trials who received high doses of aducanumab actually fared significantly better than those who got placebo. Though the other large trial was still negative, Biogen discussed the breadth of results with the FDA and concluded they were positive enough to ask for approval. The agency is supposed to give its verdict by March 2021.
Due to the unprecedented circumstances surrounding aducanumab, the agency requested feedback from the outside panel of advisors who met virtually on Friday.
While the FDA was surprisingly supportive of aducanumab, the committee experts proved to be in stark opposition. Over a series of discussions and votes leading up to the meeting's Friday evening conclusion, advisers pushed back several times on the agency's interpretation of Biogen's data and its eagerness to accept it.
When asked whether the results from EMERGE — the large, successful trial — were strong enough evidence on their own to say aducanumab is effective, just one panelist voted yes. Eight others voted no, while two abstained.
"There were, I think, six or seven reasons I voted no," said Aaron Kesselheim, an associate professor of medicine at Harvard Medical School.
By contrast, the FDA's own reviewer had described EMERGE as "exceptionally persuasive" in briefing documents made public earlier this week.
While the FDA isn't bound to follow the lead of its advisory committees, it usually does. Biogen, therefore, may now have a much slimmer chance at securing approval.
In that respect, the meeting was a major blow to Biogen, which has staked billions of dollars in research and the future of its business on aducanumab.
The FDA's review of aducanumab featured unusually close collaboration between the agency's neuroscience division and Biogen that saw the FDA overlook its usual benchmark for what constitutes a successful trial.
The failure of Biogen's second study, however, did not go unnoticed by committee members who repeatedly pressed agency staff about their willingness to discount it.
"It is abundantly clear that whatever relationship FDA Director Dr. Billy Dunn has with aducanumab, his objectivity is completely lost," wrote Baird analyst Brian Skorney, referring to the agency's director of the Office of Neuroscience in a note to clients following the meeting.
The panelists, Skorney added, "were able to make extraordinarily quick work of taking apart the conclusions."
While Friday's meeting may push the FDA to reject Biogen's drug, there's also immense pressure to approve it, as there are no disease-modifying treatments for a disease which affects millions of people.
More than a dozen patients, advocates and physicians spoke at the meeting, too, delivering emotional testimony to the devastating impacts Alzheimer's has on health and quality of life.
Nearly all 16 of the speakers argued in favor of approval for aducanumab, many describing painful experiences with the disease, for which there are no treatments that can stop or slow its course.
Others suggested approval with a requirement Biogen run another study, so patients could access the medicine sooner. "A four-year delay is too long for too many," said Joanne Pike, chief strategy officer at the Alzheimer's Association.
Steven Salloway, a professor of neurology at Brown and a dementia specialist, compared aducanumab to AZT, the first therapy approved for HIV/AIDS, saying an approval would be a foundation upon which better drugs could be added.
Only two speakers expressed skepticism about approving aducanumab. One, Michael Carome of the advocacy group Public Citizen, argued Biogen's data was more likely a false positive than proof of benefit.
For the time being, patients, researchers and Biogen are left wondering what the FDA will ultimately decide. As its done for years, aducanumab left Friday's meeting with more questions than answers.
Editor's note: A previous version of this article mis-characterized a vote for "uncertain" as an abstention.