The Problem of Aducanumab for the Treatment of Alzheimer Disease

Abstract

REVERBERATING PROBLEMS WITH DRUG APPROVAL AND RESEARCH Aducanumab was approved despite the concerns of scientists and regulatory experts about its efficacy. Notably, an FDA statistician and an advisory committee on which one of us served (G.C.A.) reviewed the product at a November 2020 hearing and concluded that it should not be approved on the basis of the evidence to date (1). Nevertheless, the FDA approved it, using an “accelerated approval” pathway that the advisory committee had been informed was not being considered. Under accelerated approval, a drug is approved on the basis of its effect on a surrogate marker of a disease—in this instance, brain b -amyloid levels—rather than clinical outcomes, such as signs or symptoms of Alzheimer disease. As Biogen sells Aduhelm, it is required to conduct a randomized controlled clinical trial to confirm its clinical benefits. Biogen s chief executive officer, Michel Vounatsos, has stated that the study will be completed by 2030 (2).With the stakes so high, 9 years is an unacceptably long time to wait. Moreover, such confirmatory studies, even when completed,may fail to identify true clinical benefit (3). Accelerated approval is intended for products expected to provide a meaningful advantage over available therapies for a serious disease but for which there is uncertainty about clinical benefit. Howdo these conditions alignwith aducanumab? Alzheimer disease is a serious disease, and there are no proven therapies to treat it. Elevated measures of b-amyloid, together with t protein, are diagnostic of pathologic Alzheimer disease. Aducanumab s phase 1 study indicates the drug reduces b-amyloid levels (4). Whether b-amyloid alone is a valid surrogate for treatment of Alzheimer disease is unclear and was, until the morning of 7 June 2021, a topic of ongoing and important study (5). Now, treatment of an amyloid level is suddenly clinical practice. However, evidence from aducanumab s phase 3 trials shows an unclear relationship between b-amyloid reductions and cognitive improvements (6), and more than 2 dozen failed studies of other experimental treatments have tested the “amyloid cascade hypothesis,” including some that have convincingly demonstrated reductions in b-amyloid levels in the brain without clinical improvements and, in some cases, with clinical worsening (7). Aducanumab s approval will have notable impacts on drug development and regulation. The FDA s willingness to accept amyloid as a surrogate may prompt Biogen and other companies to seek approval for other drugs that reduce levels of amyloid or other biomarkers but have unclear clinical benefits. Persons living with Alzheimer disease may choose to drop out of or not enroll in clinical trials and instead take Aduhelm. This decision is of course their ethical privilege, and if aducanumab were effective, their collective action could revolutionize Alzheimer disease trials (8). Imagine, for example, head-to-head comparison studies to show which of 2 treatments is safer and more effective. We can only imagine—aducanumab s clinical benefits have not been validated. In reality, as desperate patients understandably take it and possibly other amyloid-reducing drugs, the pace and progress of demonstrating safe and effective treatments for Alzheimer disease will slow.