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In major surprise, Biogen will ask FDA to approve Alzheimer’s drug aducanumab

Biogen is filing its closely watched Alzheimer’s disease drug aducanumab for approval in a major pivot from earlier this year, when the biotech halted two large studies of the drug because interim analyses signaled they were unlikely to succeed.

Those analyses were incorrect, CEO Michel Vounatsos said Tuesday. As data from more than 1,500 additional patients became available, the EMERGE trial ended up hitting its main goal of significantly reducing clinical decline. While the other trial, ENGAGE, still didn’t meet that endpoint, Biogen said results from a subset of participants support the findings from EMERGE.

Biogen said it has consulted with the Food and Drug Administration about the new analysis and intends to submit a Biologics License Application for aducanumab in early 2020. If approved, it would be the first ever disease-modifying Alzheimer’s drug to come to market, although it’s not at all certain the FDA will agree with Biogen’s new analysis.

Investors appeared bullish on aducanumab’s revival, sending Biogen’s share price up 35% Tuesday — worth $14 billion in added market value for the biotech. Wall Street analysts had a more measured take, however, acknowledging there are still many unanswered questions about the studies.

A major point of confusion is the inconsistency between EMERGE and ENGAGE, which Biogen emphasized were identically designed.

ENGAGE participants who received the higher dose of aducanumab, the dose on which Biogen is hanging its approval application, performed worse than placebo-treated patients on the study’s main cognitive test.

That’s opposite to what happened in EMERGE, in which aducanumab-treated patients experienced a 23% reduction in cognitive decline compared to those on placebo.

Additionally, Brian Abrahams of RBC Capital Markets highlighted how a subset of ENGAGE patients whom Biogen posed as supportive to the EMERGE findings was “relatively small” — totaling less than 100, with each receiving at least 10 uninterrupted treatments of high-dose aducanumab.

“Though FDA apparently provided some endorsement for the idea of filing, which could maintain some probability of approvability, we believe the new details suggest the data may be more mixed than initially perceived, and we believe the ENGAGE failure will be a point of controversy as investors debate adu[canumab]’s prospects,” Abrahams wrote in a note to clients.

How supportive the FDA was in discussions with Biogen is perhaps the greatest uncertainty, as the agency doesn’t comment on the feedback it gives drugmakers.

“This could range from ‘the agency has reviewed all the data with us and has guaranteed approval’ to ‘you can file whatever you want and we’ll review it,'” wrote Geoffrey Porges of SVB Leerink in an Oct. 22 investor note.

“Regardless, this filing will now come down to a torturous discussion of data, statistics, endpoints, exposure, treatment effects and safety liabilities,” he added, while noting it probably won’t “include a discussion of the massive societal and economic cost of going further down this rabbit-hole of marginal treatment effects in such a widespread and catastrophic disease.”

Biogen, unsurprisingly, is more confident in its chances.

Chief Medical Officer Al Sandrock, who is also handling R&D operations since the recent departure of Michael Ehlers, noted on a Tuesday call that, as Biogen understands it, any treatment that can provide at least a 20% improvement on cognitive decline would be clinically meaningful.

Whether or not aducanumab becomes available for patients, Tuesday’s update is likely to further complicate views surrounding the amyloid hypothesis, a theory in Alzheimer’s research that the disease is caused by amyloid proteins that, when misfolded, can create sticky plaques which poison brain cells.

No amyloid-targeting drug, including Eli Lilly’s solanezumab, Roche’s crenezumab and Pfizer’s bapineuzumab, has ever succeeded in Phase 3 testing, and the futility analyses announced in March all but solidified that aducanumab would join the list. Yet the EMERGE study’s results could reenergize debates about whether these drugs have a beneficial effect and, if so, in which patients.

“In this particular case, their study was in what we call early AD, but these individuals are already symptomatic. I think we need to go even earlier than that, in the presymptomatic stage,” said Eliezer Masliah, director of the National Institute of Aging’s neuroscience division. “Maybe the reason why we’re seeing these mixed results is because of that.”

Richard Isaacson, who serves as director of the Alzheimer’s Prevention Clinic at Weill Cornell Medical College/NewYork-Presbyterian Hospital, has been skeptical of the amyloid hypothesis. Still, he says he saw one of his patients who was enrolled in an earlier trial of aducanumab respond to the highest available dose.

“There will be continued regulatory hurdles to navigate, but based on this initial report, there is certainly hope,” he wrote in an email to BioPharma Dive.

Vounatsos said Biogen also has hope that “we may be in the position to offer Alzheimer’s patients the first therapy to reduce clinical decline in this devastating disease.”