On June 7, 2021, the United States Food and Drug Administration (FDA) controversially approved aducanumab (Aduhelm; Biogen) for the treatment of Alzheimer disease (note: I am a consultant to Biogen). Although this approval offers hope, considerable controversy surrounds it. The American Neurological Association told its members it should not have been approved, and my institution, The Cleveland Clinic, will not administer the drug to patients.

Biogen stopped the 2 pivotal phase 3 trials of the drug in March 2019 when an interim analysis showed it was not likely to improve cognition in mild Alzheimer disease. A post-hoc analysis of the data revealed a subset of patients in the high-dose group of 1 trial in which the drug worked (0.39 benefit on an 18-point scale), but no benefit in any other group, the other trial, or in the low-dose group. The Advisory Committee (AdCom) questioned the drug’s effectiveness and safety benefit, and it voted unanimously not to approve the drug (10-0; there were no “yes” votes). Having presented to 3 AdComs, I knew that the FDA usually follows the AdCom’s vote.

However, the FDA approved the drug, using its “accelerated approval pathway” based on Aduhelm’s ability to lower levels of beta amyloid, which lead to amyloid plaques in the brain. This means it is “reasonably likely” to benefit patients but may not. The surrogate marker was used instead of cognition. In addition, the label given was much broader than expected and included all patients, when it only seemed to benefit early patients with mild disease. The reason the AdCom and many neurologists are concerned by this approval is that other drugs have lowered amyloid but had no effect on cognition and were not approved. In this case, the clinical benefit was also very limited. Moreover, the drug is not without significant side effects, including brain swelling or bleeding seen in 40% of the high-dose group. The statistical FDA reviewers reported that the data did not support approval and recommended an additional study; however, the clinical reviewers felt it did. Interestingly, there was extensive cooperation between Biogen and the FDA to the point of making combined presentations of the trial data at scientific meetings and at the AdCom (usually the FDA and the company make separate presentations). The FDA is requiring an additional randomized phase 4 study to verify the clinical benefit to be completed by 2029 and can rescind the approval if the data are not supportive. This study will be very difficult to recruit in the United States, because it needs to contain a control group and patients can get the drug outside a trial.

In this issue, we explore the remarkable similarities of the pathology in Alzheimer disease and age-related macular degeneration. Toxic soluble beta amyloid oligomers have been found in drusen. Several companies have tried their failed Alzheimer drugs in dry AMD trials with little success, but the question remains: was the failure due to the drug, or the target? In Alzheimer, the plaques were not the correct target. Is beta amyloid the correct target? Now, we have several companies working in the beta amyloid space for the treatment of dry AMD with pills and drops. This is very exciting, but our excitement must be tempered given the difficult road in Alzheimer disease. Hopefully, this approval will spur research into other neurodegenerative diseases, such as the ones we face daily in retina. It certainly has increased investment into Alzheimer drugs in clinical trials. RP