Biogen, the large, Cambridge, Massachusetts-based biotech, has for the past year tried to make a case that one of its experimental drugs can slow the course of Alzheimer's disease.
Yet, hopes that the first true Alzheimer's treatment is within reach dimmed on Friday, when a committee of experts tasked with evaluating the drug came back with a blistering rebuke that there was far from enough evidence to confidently say it worked.
The committee of mostly professors of neuroscience, medicine or statistics voted almost unanimously against the drug, known as aducanumab. The vote proved to be a gut punch not only for Biogen, which saw its share price drop nearly 30% Monday morning, but also — and perhaps more so — the Food and Drug Administration.
The FDA had worked closely with Biogen on how to analyze the clinical data meant to support aducanumab's approval. By the time of Friday's meeting, clinical reviewers at the agency and, importantly, the director of its neuroscience division appeared in full support of the drug.
That support looks to have backfired, however, as committee members criticized agency staff for being "very biased" in the questions they posed, which asked the committee to look past the negative results aducanumab had accrued and focus solely on positive data.
But the FDA remains under great pressure to give the millions of Alzheimer's patients with few options a chance at an effective treatment. A rejection for aducanumab could mean the drug's end, or at least a multi-year wait while Biogen runs another trial.
Here are five takeaways from a meeting that could change how the FDA views aducanumab and, quite possibly, the drug's future.
A tough decision for the FDA just got much harder
Ever since Biogen decided to push aducanumab forward late last year, researchers and analysts have questioned whether the FDA would buy into the company's pitch that its drug works in spite of conflicting results.
In the days leading up to Friday's meeting, agency staff appeared torn. On one side were its statisticians, who asserted that the aducanumab studies showed "no compelling substantial evidence" of the drug slowing Alzheimer's progression. On the other side were its clinical reviewers, who claimed the opposite.
The clinical reviewers set the prevailing tone, though, creating what several Wall Street analysts called a "best case" scenario for Biogen. Investors reacted appropriately, sending the company's share price soaring Wednesday and lifting its market value more than $15 billion.
However, after resoundingly negative feedback from the advisory committee, the FDA is in a tougher spot.
While the agency doesn't have to follow what the committee recommends, it typically does. An approval, therefore, would be an eyebrow-raising departure, and would likely be met with confusion and criticism.
"Honestly, the panel was a disaster for aducanumab. And it is completely justified," wrote Steven Seedhouse, an analyst at Raymond James, in a Nov. 6 note to clients.
Seedhouse added that an aducanumab approval would signal that futility analyses, statistics, advisory committee votes and the FDA's own guidance and statutes "don't matter, and we're left wondering what actually matters in determining what drugs make it to market."
An approval could have consequences for the FDA's reputation
Four years ago, the FDA weighed the needs of a desperate patient community against study results that didn't clearly show the drug they were fighting for, a Duchenne muscular dystrophy treatment called eteplirsen, would help. The agency looked to an expert panel for advice, and after a tense meeting, saw a majority of them weren't weren't convinced eteplirsen had met the agency's standards.
But the FDA approved the drug, now known as Exondys 51, anyway, in part due to input from a powerful champion within the agency, top drug evaluator Janet Woodcock.
With aducanumab, the FDA is in a similar position, only magnified by the broader burden of Alzheimer's disease. There are an estimated 5 million American's with Alzheimer's, exponentially many more than with Duchenne. No drug meant to slow Alzheimer's progression has ever gone under FDA review, and if aducanumab is rejected, it could be years before another one does.
And unlike with eteplirsen, the FDA's hand-picked experts — many of whom served on the advisory panel in 2016 — unequivocally panned aducanumab. On the critical question of whether aducanumab was effective, not a single member voted yes.
The vote sets FDA drug reviewer Billy Dunn, who clearly voiced support for Biogen's drug during the meeting, against the panel. If the FDA bucks the opinions of its advisers, its reputation for data-driven decision-making could be damaged at a time in which the agency's credibility with the public is as important as ever: Critical regulatory decisions for experimental coronavirus vaccines and treatments are likely to come soon.
The experts had mixed feelings about the amyloid hypothesis
Aducanumab works by binding to clumps of a protein known as amyloid-beta. Viewed by many as a "hallmark" of Alzheimer's disease, these plaques have been the target of dozens of would-be medicines, every one of which has failed until now.
The steady drumbeat of failures for one promising drug after another had sapped enthusiasm for the so-called amyloid hypothesis of treating Alzheimer's disease, making the FDA's treatment of aducanumab consequential for the research field as well as Biogen.
As far as the regulator is concerned, the long list of setbacks for amyloid-targeting drugs has little bearing on aducanumab. In documents released ahead of Friday's meeting, agency staff wrote that past disappointments don't indicate a "class failure" nor are they "particularly informative for the assessment of the effectiveness of aducanumab."
While committee experts panned Biogen's clinical data, they were more supportive of the idea that aducanumab was working as intended. Asked whether the company had presented "strong evidence" on the drug's effect on Alzheimer's disease pathology, five panelists voted yes while six answered "uncertain."
Madhav Thambisetty, a National Institute on Aging laboratory head and professor at Johns Hopkins University, found Biogen's study results as "clear evidence" aducanumab removed amyloid plaques.
But on the larger question of whether that would translate into clinical benefit, he was less sure, calling the data "far less compelling."
Panelists had issues with Biogen's data. But they had even more problems with the FDA's handling of the data
The FDA worked unusually closely with Biogen to reinterpret the results from the two originally negative studies of aducanumab.
Soon after the drugmaker's March 2019 announcement that the trials failed, for example, FDA reviewers told Biogen executives the decision to stop further study was "flawed," and indicated results from one test could be interpreted as "supportive." The agency pushed for further analysis and proposed to work with Biogen as part of a "bilateral effort."
That cooperation extended through to Friday's meeting, in advance of which the FDA released a highly favorable review of Biogen's data that largely sidelined issues raised by the agency's own statisticians. Questions posed by the FDA to the committee were similarly positively phrased, suggestive of a regulator eager to approve aducanumab.
Committee experts, however, weren't happy with the FDA's framing, repeatedly criticizing the agency's presentation of aducanumab's results.
"I have not been super impressed with how the briefing book and presentations have gone from the FDA for this study," said Scott Emerson, a biostatistician at the University of Washington.
"I feel, to a certain extent, the clock has been run out. We haven't been able to ask questions because mainly the FDA just gave us conclusions and not results."
Other advisers took issue with the FDA's requests to analyze the one positive study in isolation, and sought to hear more from the agency's lead statistician, who recommended against approval.
Biogen will almost certainly have to run another large, expensive trial
More often than not, approved drugs are backed by positive results from at least two large studies.
Aducanumab, though, doesn't have such a track record. Instead, Biogen had hoped that data from the large study it claimed to be successful, coupled with results from a much smaller, earlier trial, would be enough evidence to show the committee its drug works.
And, to Biogen's credit, the FDA appeared in support of this strategy. The director of the agency's neuroscience division on Friday called the large, successful trial a "shining example" of a single study meant to illustrate aducanumab's effect.
The committee wasn't sold, however.
"In no sense would I regard that [smaller study as taking] the place of another confirmatory study," said University of Washington's Emerson.
Having received such pointed feedback from the committee, Biogen may ultimately need to run a third large study to support aducanumab's approval — a daunting task even for the most powerful of drug companies.
"It'll be a bit of a setback," said Howard Fillit, chief science officer of the Alzheimer's Drug Discovery Foundation, who noted that such a study would be quite expensive, likely costing Biogen hundreds of millions of dollars if not more.
That's money Biogen "may or may not have at this point," according to Fillit. (The company recorded $2.2 billion in cash and cash equivalents at the end of September.)
Requiring another trial before approval could weigh heavily on patients, too. "The problem with needing a third trial is that patients will have to wait probably three or four more years before there's access to the drug," Fillit said.
At the meeting, several patients and advocates highlighted this, asking the FDA to give them a chance at treatment sooner.
"A four-year delay is too long for too many," said Joanne Pike, chief strategy officer at the Alzheimer's Association.