Biogen is planning to file for FDA approval of its failed Alzheimer’s disease drug aducanumab. The drug flunked a futility analysis in March, but Biogen resurrected it after factoring in data generated after the cutoff for the interim assessment.

In making the case for aducanumab, Biogen argued that the futility analysis was based on a smaller data set that featured fewer patients who received high-dose aducanumab. Adding in the additional data showed aducanumab reduced clinical decline, Biogen said, leading the company to make an unequivocal statement about the evidence in support of the anti-amyloid beta antibody.

“The result of the futility analysis was incorrect,” Biogen wrote in a presentation about aducanumab.

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That confident conclusion is likely to face pushback, potentially from regulators. But after talking to its external advisers and the FDA, Biogen thinks it has enough evidence in support of aducanumab to file for approval in the U.S. early next year.

Biogen shared some of that evidence in the aducanumab presentation. In the expanded data set for one of the phase 3 trials, EMERGE, Biogen associated the high dose of aducanumab with statistically significant changes on a clinical dementia scale, recording p-values of 0.010 or 0.031 depending on when the data cutoff date is set. The high dose also hit several secondary endpoints.

The data from the second phase 3 trial, ENGAGE, are far less encouraging. In that trial, the high dose of aducanumab performed worse than placebo on the clinical dementia scale—the primary endpoint of the study—and on a test of cognitive function.

Biogen saw a divergence between the data generated in the two studies at the time of the futility analysis but was unable to explain the finding. Now, Biogen thinks the greater exposure to the high dose in EMERGE is the primary driver of the divergence, leading it to argue the totality of evidence supports approval of aducanumab. Biogen pointed to the better results seen in a subset of ENGAGE patients it said were exposed to sufficient high-dose aducanumab to make its case.

As the trials were identically designed, Biogen needs a way to explain why patients in EMERGE had greater exposure to high-dose aducanumab. Biogen’s explanation centers on amendments it made to the protocol. The hypothesis is that the timing of enrollment in the trials meant the amendments had different effects in each study. Biogen knew that was possible but not that it could warp the data to the extent it now claims.

The big question now is what the FDA will make of Biogen’s case. The FDA has shown a willingness to approve medicines on the basis of evidence that falls short of its historical standards in recent years, particularly if they target major unmet medical needs. Biogen’s filing will provide a test of where the FDA will set the bar for a filing that will, at best, be somewhat unconventional.

Biogen saw its shares rocket up more than 40% premarket on the news this morning. Analysts at Jefferies said in a note to clients that "key question is EMERGE looks good on "completers" but ENGAGE looks a lot weaker on patients who completed." In fact, they say it's actually a reverse, potential negative trend on CDR-sb. But, Biogen argues that of those patients, "the ones who got most "exposure" to high dose had a trend in benefit and support the overall picture (we see no p-values on that though).”

Meanwhile, J.P. Morgan analysts were a lot more colorful: “Does this mean the mother of all FOMO trades is back on?! We’re left somewhat speechless by news this morning that Biogen’s Alzheimer’s drug candidate aducanumab is back from the dead.”

In their note to clients, the JPM analysts said there are, naturally enough, “some major questions about the data” and approvability, but added that “it’s also hard to look past the unmet medical need and the FDA simply saying there’s a chance.”