The controversial Alzheimer's treatment aducanumab (Aduhelm) won FDA approval Monday using the accelerated approval pathway.
Under this pathway, approval can be based on the drug's effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that benefit.
The FDA's decision was based on the surrogate endpoint of reduction of amyloid beta plaque in the brain.
"We are well-aware of the attention surrounding this approval," the FDA wrote in a statement explaining the decision. "We understand that Aduhelm has garnered the attention of the press, the Alzheimer's patient community, our elected officials, and other interested stakeholders. With a treatment for a serious, life-threatening disease in the balance, it makes sense that so many people were following the outcome of this review."
"At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward," the agency added.
Aducanumab, a monoclonal antibody that selectively binds to aggregated forms of amyloid beta, raised considerable controversy in the wake of findings from two identical phase III studies, EMERGE and ENGAGE. The trials were terminated in March 2019 when a futility analysis determined aducanumab was unlikely to outperform placebo at completion. In October 2019, Biogen reversed its position, saying a review of previously unavailable data showed the drug actually reduced cognitive decline in EMERGE, but not in ENGAGE.
In November 2020, an FDA advisory committee voted overwhelmingly against the data presented about the Alzheimer's drug candidate, saying the positive results seen in one of the two trials could not be considered alone, but must be taken together with its twin, which clearly was negative.
In the FDA advisory committee meeting, Biogen's senior vice president Samantha Budd Haeberlein, PhD, attempted to account for the differences between EMERGE and ENGAGE, suggesting that failure in one trial did not detract from the findings of the other. Billy Dunn, MD, director of the office of neuroscience in the FDA's Center for Drug Evaluation and Research, agreed at the time, echoing what was presented in the FDA's briefing documents and emphasizing the urgent need for Alzheimer's treatment.
EMBARK, Biogen's ongoing phase IIIb re-dosing trial, currently is studying Alzheimer's patients who were actively enrolled in aducanumab trials when they were halted in March 2019, including participants in EMERGE, ENGAGE, the long-term extension of the phase Ib PRIME study, and the EVOLVE safety study.
Prescribing information for aducanumab includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain and often resolves over time. Another warning is for a risk of hypersensitivity reactions including angioedema and urticaria. The most common side effects of aducanumab were ARIA, headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.
The FDA will continue to monitor aducanumab and is requiring Biogen to conduct a post-approval clinical trial to verify the drug's clinical benefit. "If the drug does not work as intended, we can take steps to remove it from the market," the agency wrote.