The announcement came as a shock. Late in 2019, Biogen revealed it would ask the Food and Drug Administration to approve an experimental Alzheimer's disease drug that, just seven months earlier, the biotech had said was unlikely to work.

Biogen's surprising reversal, and the data used to support it, have divided Alzheimer's researchers, doctors and biotech investors since.

By June 7, Biogen's bet-the-company decision will either pay off in spectacular fashion with a landmark clearance or go bust with a rejection that would carry heavy consequences for the drugmaker and the scientific hypothesis that birthed its drug. For the FDA, which has already extended its review once, the choice could reshape its reputation and that of its leaders.

An approval would mean the most, however, to the millions of Americans who have Alzheimer's and no effective therapy to treat their underlying disease.

"This is a hugely consequential decision for the FDA and it will send an enormous signal to patients, clinicians and the market," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health and an adviser to the agency.

The path Biogen's drug took to reach the FDA's door is among the most unusual in regulatory history, and one of the most highly scrutinized. Strikingly, the regulator played a direct role in encouraging Biogen's reassessment of its negative clinical trial results — support that has little, if any, precedent.

Their collaboration has drawn considerable criticism, particularly at a contentious advisory meeting last November when a panel of independent experts voted overwhelmingly against the drug.

The committee's rebuke injected significant doubt into an already controversial review that will soon deliver a verdict on biotech's most closely watched drug.

Reversing course

Called aducanumab, Biogen's medicine is the latest in a long line of would-be treatments that bind to a type of plaque found in the brains of people with Alzheimer's. Over the past two decades, drugmakers have advanced more than 20 drugs aimed, in various fashion, at these "amyloid" plaques, only for every one to fail in clinical trials.

Each time, developers responded by inventing more precisely targeted molecules and refining their clinical trials to enroll patients earlier and earlier in the course of their disease, when treatment might be more likely to produce a benefit.

Shaped by those lessons, aducanumab was viewed as having the best chance to succeed. In 2015, early study results showed the drug dramatically cleared plaques from the brain and, in a first, suggested treatment slowed patient's cognitive decline. Biogen and its development partner Eisai proceeded to invest more than $1 billion in testing over the next five years.

But in March 2019, aducanumab looked to be yet another disappointment. Biogen, consulting with researchers overseeing two near-identical Phase 3 trials of aducanumab, determined the drug was likely to be ineffective. Accordingly, the drugmaker shut down both studies, an announcement that erased $18 billion from the company's market value.

In October, however, Biogen reversed course. Further data, the company said, had shown one of the two trials actually succeeded — the first positive result from a large, randomized and placebo-controlled study of a Alzheimer's drug meant to do more than just ease symptoms. The other trial remained negative, Biogen concluded.

Biogen's case for aducanumab is disputed and, by the rules of how clinical trials are typically analyzed, highly unorthodox. The benefit it claims for the drug is small even if taken at face value, which many experts aren't.

"How do you get from a drug that's about to not be developed any further because of futility to all of a sudden being a drug that could be approved?" said Constantine Lyketsos, a professor of psychiatry and Alzheimer's specialist at Johns Hopkins University.

"Exceptionally persuasive"

The FDA's support appears to have been one important factor in Biogen's reinterpretation. Following the March announcement that the trials failed, company scientists pored over the initial findings, as well as new results collected through the date the trials were halted. They discovered the trial outcomes changed with the additional data, diverging to show patients in one study benefiting versus placebo.

Several months later, in June, the company sat down with the FDA to go over the trials and potential next steps. At that meeting, the FDA told Biogen some of the now positive-seeming data could be considered "exceptionally persuasive" in support of aducanumab's efficacy. The agency agreed to collaborate with Biogen on further evaluation of the studies.

The principal explanation Biogen came up with for why the trials yielded conflicting results involves differences in exposure to a higher drug dose between participants in the positive and negative studies. Due to differences in patient enrollment, the drugmaker found that more patients in the successful trial were given the ostensibly more effective, high dose for longer.

In a second meeting, held on Oct. 21, the FDA appeared convinced by Biogen's hypothesis. A summary of the meeting states the agency agreed Biogen's after-the-fact analysis was interpretable and, furthermore, potentially supportive of considering the positive trial alone as "evidence adequate to establish the effectiveness of aducanumab for the treatment of Alzheimer's disease."

The next day, Biogen announced it would submit an application to the FDA, which typically requires two well-controlled, positive studies for approval of a new drug.

Biogen would meet two more times with the regulator before officially submitting aducanumab the following July.

A contentious meeting

The extent of Biogen and the FDA's collaboration wasn't known publicly until November 2020, when the agency published review documents ahead of a meeting it convened with outside advisers.

Unusually, the regulator presented its views alongside Biogen's, a departure from its normal practice of preparing a separate, often more critical rundown of a drug company's data.

"In our experience in attending and testifying at advisory committees for decades, we had never seen such a joint briefing document before," said Michael Carome, director of the health research group at Public Citizen. "That resulted, in our view, in a review document for the meeting that was heavily biased, heavily weighted in favor of Biogen."

Carome's view was shared by some of the FDA advisers, too.

"I feel that, to a certain extent, the clock has been run out and we haven't been able to ask questions because mainly the FDA just gave us conclusions and not results," said Scott Emerson, a panelist and professor emeritus of biostatistics at the University of Washington, at the November meeting.

One FDA reviewer, a statistician named Tristan Massie, notably dissented from the rest of the regulatory team that reviewed aducanumab. His analysis was sharply critical, judging there to be "no compelling substantial evidence" supporting a benefit to aducanumab.

But advisers hardly heard from Massie at the meeting, despite several direct questions. Ultimately, ten of them voted that the one trial considered positive by Biogen and the FDA was not enough to prove aducanumab's effectiveness. The eleventh voted "uncertain."

Advisers appeared particularly concerned the FDA and Biogen were too narrowly focused on explaining why the negative trial failed, rather than more carefully scrutinizing the one judged positive.

"There was this emphasis on showing that the trial that didn't work was a false negative," said Johns Hopkins' Alexander, "at the expense of properly considering [whether] the trial that did work was a false positive."

Alexander argues the question is best solved by Biogen running a third study of aducanumab, as a tie-breaker of sorts. Others, including some of Alexander's fellow panelists as well as Alzheimer's experts not involved on the panel, agree.

Biogen has not committed to another trial, choosing to focus resources on preparing for a commercial launch. "We stand by our data," company CEO Michael Vounatsos said at a conference hosted in March by investment bank Cowen.

"We will assess based on what will be the ultimate decision from the FDA, but we continue the pre-launch activities," the executive added.

High stakes

Whether the FDA approves or rejects aducanumab, its decision will have far-reaching consequences.

For patients, a number of whom spoke strongly in favor of approval at the November meeting, aducanumab represents a potentially better option than the few available drugs that can temporarily ease symptoms. Advocacy groups, most notably the Alzheimer's Association, have lobbied hard for an approval.

"The community of patients and families is rather desperate," said Lyketsos, the Alzheimer's expert at Johns Hopkins. "I think there will be a substantial number of patients that will ask for and in some instances look for the doctor who will give them this drug."

Yet physicians worry about offering false hope for a treatment that, at best, modestly slows patients' decline and comes with notable side effects for some. Aducanumab is also likely to be costly, with some Wall Street analysts predicting a price tag in the tens of thousands of dollars per year.

Some experts are concerned that approving aducanumab — without clear proof of it benefit — could hamper research into other, potentially more effective therapies by drying up enthusiasm for participating in clinical trials.

"The stakes for offering genuine benefit for our current patients, for future health economics, and for future clinical trials in [Alzheimer's], could not be higher," wrote David Knopman, a neurologist and Alzheimer's specialist at the Mayo Clinic, in a November paper published in the journal Alzheimer's & Dementia. In the paper, Knopman and two coauthors argued Biogen's data was insufficient to prove a benefit.

The FDA's decision on aducanumab will likely be viewed as a verdict on the broader amyloid hypothesis, too, although the agency has said it doesn't view anti-amyloid drugs as a single class.

Another amyloid drug, from Eli Lilly, recently showed promise in a mid-stage study and expectations for it will likely swing on how the FDA treats aducanumab.

"I think that a little bit of success might buoy the advocacy community and perhaps some of the other competitors of Biogen, that their drug might get through the process and that it's feasible to see a benefit," said Knopman, in an interview. "On the other hand, I've never known people in pharma to be passive and afraid of taking risks so will that really make a difference?"