Aducanumab (Aduhelm; Biogen) is the first approved novel treatment for Alzheimer disease since 2003.
The FDA has granted accelerated approval aducanumab (Aduhelm; Biogen) for the treatment of Alzheimer disease (AD), despite complex trial data with respect to clinical benefits.1
Aducanumab represents a first-of-its-kind therapy that targets the fundamental pathophysiology of the disease, aiming to slow disease progression. It is the first novel treatment approved for AD since 2003.1
“Our current treatments for things like [AD] and some of these degenerative dementias are symptomatic medications…they all try to help the symptoms but none of them that are available right now get to what a lot of people think are the core issues to modify the disease,” Douglas Scharre, MD, neurologist, director of the division of Cognitive Neurology at Ohio State Wexner Medical Center, said in a commentary about the FDA’s decision.2
The approval was supported by the surrogate end point of reduction of amyloid beta plaque in the brain, which is a hallmark of AD. However, there has been considerable public debate on whether aducanumab should be approved as a result of uncertainties surrounding its clinical benefit, with differing perspectives offered by the expert community. Of 2 pivotal phase 3 clinical trials, 1 met its primary end point of a reduction in clinical decline, whereas the second trial failed to demonstrate efficacy. In November 2020, the Peripheral and Central Nervous System Drugs Advisory Committee convened to review clinical trial data for aducanumab and did not agree that it was reasonable to consider the clinical benefit of 1 successful trial as the primary evidence supporting approval.1,3
As part of the ongoing review, Biogen submitted additional analyses and clinical trial data to the FDA. In January, the agency extended the prescription drug user fee act date from March to June 7 to provide additional review.
“In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Patrizia Cavazzoni, MD, director of the FDA Center for Drug Evaluation and Research, wrote in an agency blog post.3 “It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.”
In 3 separate studies, investigators evaluated the efficacy of aducanumab in a total of 3482 patients with AD, who participated in double-blinded, randomized, placebo-controlled dose-ranging studies. According to the results, patients who received treatment with aducanumab demonstrated significant dose-and-time dependent reduction of amyloid beta plaque, whereas patients who did not receive aducanumab had no reduction in amyloid beta plaque.1
“Although the data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefit to patients,” Cavazzoni wrote.3 “As a result of FDA’s approval of Aduhelm, patients with Alzheimer’s disease have an important and critical new treatment to help combat this disease.”
The prescribing information for aducanumab includes a warning for amyloid-related imaging abnormalities (ARIA), which commonly presents as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms. However, some patients have experienced symptoms of headache, confusion, dizziness, vision changes, or nausea. Aducanumab also carries a warning for the risk of hypersensitivity reactions. The most common adverse effects associated with aducanumab were ARIA, headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.1
As part of the accelerated approval provisions, Biogen is required to conduct a post-approval trial. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw its approval.1