The decision by the FDA on the drug application was expected on March 7, but is now delayed until June 7, 2021.
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The U.S. Food and Drug Administration (FDA) extended the review period for Biogen and Eisai’s Biologic License Application (BLA) for aducanumab for Alzheimer’s disease. The drug has been fraught with controversy—and unexpected hopes. The decision by the FDA on the drug application was expected on March 7, but is now delayed until June 7, 2021.
In March 2019, Biogen and Tokyo-based Eisai announced they were discontinuing the global Phase III clinical trials ENGAGE and EMERGE of aducanumab in patients with mild cognitive impairment for Alzheimer’s and mild Alzheimer’s dementia. They were also discontinuing the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial. An independent data monitoring committee indicated they were unlikely to hit their primary endpoint.
It appeared to be the final nail in the amyloid theory of Alzheimer’s disease. Aducanumab is an antibody targeting beta-amyloid, one of the proteins that accumulates in the brains of Alzheimer’s patients.
But in October 2019, the two companies announced plans to pursue regulatory approval for the drug. It turned out, the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen presented the findings in the final data analysis in a December conference, and although there was still some skepticism about the overall data, it did appear to be enough to file for a BLA, and the company planned to do so in the second quarter of 2020.
What they presented was that the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen said the data from a subset of patients that received a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation and language, as well as benefits on activities of daily living.
Although many had issues with some of the data, which was very complex, the companies felt they had a strong enough case to submit it to the FDA and were expected to do so this spring.
Then, in April 2020, they announced that although the company had begun to submit parts of the BLA, they did not expect to complete it until the third quarter of this year.
The submission was completed in August 2020 with ongoing collaboration with the FDA and include data from the Phase III EMERGE and ENGAGE trials, as well as the Phase Ib PRIME study. Biogen has also requested Priority Review.
“Alzheimer’s disease remains one of the greatest public health challenges of our time,” Michel Vounatsos, chief executive officer at Biogen, said at the time. “It robs memories, independence and eventually the ability to perform basic tasks from the people we love. 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.”
In November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee slammed the drug submission, voting 1 yes, 8 no and 2 uncertain on the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?” It also voted 0 yes, 7 no and 4 uncertain on whether Study 103 (PRIME) supported the effectiveness of the drug. Again and again, the committee voted against the drug.
Although the FDA isn’t obligated to follow the recommendation of their advisory committees, they usually do.
Not everyone is as skeptical.
“There were clear cognitive benefits on a number of end point measures, which [is] unprecedented in a Phase III Alzheimer disease trial, and furthermore, there was a very clear indication of target engagements, as measured by a dose-dependent reduction in amyloid plaques on amyloid PET,” said Thomas Wisniewski, professor of neurology, and director, Pearl I. Barlow Center for Memory Evaluation and Treatment, who was not associated with the studies, told NeurologyLive. He added that the potential of the drug was “game-changing” and even though the effect size was not large, “it does look like it’s disease-modifying and of cognitive benefit.”
To add insult to injury, the consumer’s group Public Citizen demanded the Office of the Inspector General (OIG) for the U.S. Department of Health and Human (HHS) conduct an investigation into “inappropriate collaboration” between the FDA and Biogen over the company’s submission for Alzheimer’s drug aducanumab.
It is unlikely aducanumab would have made it this far if there were any effective treatments for Alzheimer’s disease, which is a disease with an increasingly growing older population and a largely unmet medical need. But Alzheimer’s drug development has been a wasteland of failed mid- and late-stage clinical trials, and there is a feeling of increasing desperation for any drug that might prove to be even a little effective.
Apparently the newest delay is related to the FDA requesting additional analyses and clinical data. Biogen complied, and the FDA considered it a Major Amendment to the application, thus requiring additional review time.
“We are committed to working with the FDA as it completes its review of the aducanumab application,” Vounatsos said. “We want to thank the FDA for its continued diligence during the review.”
