FDA Approves Aducanumab for Alzheimer Disease

The FDA has approved a monoclonal antibody targeting amyloid ß (Aß) aggregates, aducanumab, (Aduhelm; Biogen, Cambridge, MA) for the treatment of Alzheimer disease (AD). The approval is based on data from 2 randomized double-blind placebo-controlled clinical trials: EMERGE (NCT02484547), and ENGAGE (NCT02477800) as well as the PRIME (NCT01677572) phase 1 dose-finding study. In all 3 of these trials, aducanumab provided dose- and time-dependent reductions in Aß in the brains of people with AD, which was not seen in participants treated with placebo. 

Aducanumab is the first disease-modifying treatment to be approved for AD and the first to target Aß, which is one of the earliest causative steps in the pathophysiology of AD. Because symptoms of AD do not occur until decades after Aß pathology begins to occur, evidence of long-term benefits on cognition may take several more years. Additionally, treatment may need to begin in presymptomatic stages of AD for long-term cognitive benefit to be achieved because Aß deposition occurs primarily in those stages. 

Jeffrey Cummings, MD, ScD, Joy Chambers-Grundy Professor of Brain Science Director, Chambers-Grundy Center for Transformative Neuroscience Department of Brain Health School of Integrated Health Sciences University of Nevada Las Vegas (UNLV) commented on the news, “This is good for patients and for the field. There are lingering questions, but the data are sufficient to warrant approval and I am very happy that the FDA courageously took this pathway in spite of some vocal objections." Dr. Cummings is also a member of the Practical Neurology Editorial Board.

There has been controversy around aducanumab because of a history of starts and stops during the clinical development of the drug. Although Aß plaque was significantly reduced by aducanumab in all trials, the long-term clinical benefit remains unclear. In the EMERGE clinical trial aducanumab also reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score by 22% for participants given the higher of 2 aducanumab doses after 78 weeks of treatment (n= 547) compared with those given placebo (n=548) (P=.01). Statistically significant improvement was also seen on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; P=.01), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; P=.001). However, improvements seen in other cognitive measures in EMERGE or ENGAGE did not reach statistical significance. An advisory panel recommended against approval. 

The FDA, however, approved aducanumab via the accelerated pathway, in which people with a disease that has unmet medical needs can be treated while additional studies are ongoing. In the case of aducanumab, the FDA is requiring a new trial a new randomized, controlled clinical trial to verify clinical benefits of aducanumab. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug. 

The first AD drug to be approved in almost 2 decades will surely change the field of cognitive neurology, making screening and diagnostic testing for AD biomarkers essential. 

The Alzheimer's Disease Association sent an e-mail to their research community regarding this news that states, "This is the beginning of a completely new future for treatments in Alzheimer’s and other dementia. It is important to acknowledge that this FDA-approved treatment slows progression (in a limited population) of mild cognitive impairment (MCI) due to AD and early AD dementia. It may not stop decline or improve cognition. But, it represents an important step and progress in Alzheimer's science. The Alzheimer’s Association will do everything in its power to ensure access to the drug and requisite tests for all who will benefit. One of our highest priorities will be eliminating barriers to access." 

The prescribing information includes warnings for hypersensitivity reactions and amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain that is often asymptomatic and usually resolves.