In a test for Hahn's FDA, Biogen submits controversial Alzheimer's drug aducanumab

It took a little longer than expected, but Biogen’s done it—along with partner Eisai, the Big Biotech has completed an FDA filing for aducanumab, the once-failed Alzheimer’s drug it resurrected just in time for Halloween.

After letting analysts speculate in January that a filing could come “within weeks” with a potential nod arriving by the end of the year, Biogen announced in April it had started submitting modules for a Biologics License Application to the FDA with eyes on finishing the filing in the third quarter. The company has met that deadline, and it’s asked the agency for priority review to boot.

Aducanumab’s fate will be a test of how far the FDA and its commissioner, Stephen Hahn, M.D., are willing to diverge from its established approval standards. Under U.S. law, companies need to show “substantial” evidence of effectiveness to win approval. Biogen will arrive at the FDA with results from one trial that suggest aducanumab is no better than placebo and data from another that link it to improved scores on a dementia scale.

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The data underpinning the filing come from two phase 3 studies dubbed EMERGE and ENGAGE that tested aducanumab in patients with early-stage and mild Alzheimer’s, as well as from a phase 1b study. There was a discrepancy between the phase 3 studies—patients in the EMERGE trial who got the highest dose of aducanumab had a statistically significant improvement on a clinical dementia scale, but the same patient group in the ENGAGE study did worse than patients taking placebo on that same measure, as well as on a test of cognitive function.

What's more, the phase 3 program flunked a futility analysis in March 2019, leading Biogen to pull the plug on the studies, but the company about-faced eight months later, saying the analysis was “incorrect.” Biogen argued 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, the company said.

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Jefferies analyst Michael Yee chalked the delay up to “the FDA wanting more analyses and information in the filing.”

He noted the filing came at the early end of the third quarter, which he said could be linked to a shake-up at the FDA: “We continue to attribute the new development in part perhaps based on new FDA re-org that completed in December 2019 which split the CNS division into two categories and importantly—with new group review heads—and which the Alzheimer's and other neurodegenerative diseases, were split away from migraine and other areas,” he wrote in an investor note Wednesday.

Yee and Cantor Fitzgerald’s Alethia Young sketched out a timeline for aducanumab, which could see the FDA accepting the BLA in early September with a PDUFA date in early March 2021 if Biogen gets its speedy review.

Young is “reasonably confident” that the agency will accept the application, but wrote in an investor note that aducanumab is by no means a shoo-in. Young and her colleagues “don’t view this approval as certain,” thanks to “the complicated issues around the statistical analysis and the inconsistent outcomes from both pivotal trials” upon which the BLA rests. And Brian Abrahams of RBC Capital Markets sees a 30% chance that the FDA OKs aducanumab “despite the mixed ph.III data.”

For its part, Biogen is bullish on the drug’s prospects.

“The aducanumab BLA is the first filing for FDA approval of a treatment that addresses the clinical decline associated with this devastating condition, as well as the pathology of the disease. We are committed to driving progress for the Alzheimer’s disease community and look forward to the FDA’s review of our filing,” said Biogen CEO Michel Vounatsos in a statement.

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But Baird analyst Brian Skorney has dismissed aducanumab’s chances, saying the bulk of the data shows aducanumab doesn’t provide a clinical benefit.

“If Biogen said based on this data it was running another study, the stock would be down because the data doesn’t justify investing in another study. The regulatory threshold is higher than that,” Skorney wrote in December. “The bottom line is, the FDA standard of approval is substantial evidence of efficacy and the cumulative data for aducanumab falls really far of this standard.”