In early June, the Food and Drug Administration will decide whether to approve a treatment for Alzheimer’s disease, which today affects more than five million Americans, with millions more at risk over the next decade. The decision will be consequential, because it will set the bar for market entry and define standards of care against which future drug candidates will be tested.
That’s why the agency should reject it, despite support from patient advocacy groups and pressure from the manufacturer. It hasn’t yet been shown to work.
Alzheimer’s is a progressive brain disorder that gradually robs patients of their ability to remember, plan, speak and, ultimately, move. It is a fatal condition and we have no medications that can slow its relentless progression. It also has a profound impact on families; they commonly suffer physically, mentally and financially while providing years of caregiving support.
It should come as no surprise, then, that substantial human and financial resources have been marshaled to slow or stop the disease. This momentum has galvanized clinical and scientific communities across federal agencies, industry and academia to identify cures. But we worry that federal regulators may feel pressure to approve experimental therapies even when it’s not clear they work.
As physicians who care for patients with Alzheimer’s, we are concerned such pressure is building around the F.D.A.’s pending action on a new product, aducanumab, made by Biogen, a biotech company focused on neurological diseases, and codeveloped with Eisai, a global pharmaceutical company. Indeed, two advocacy groups for patients, the Alzheimer’s Association and Us Against Alzheimer’s, support the drug’s approval.
What appears to be an unusually close collaboration between the F.D.A. and Biogen before and during the agency’s review only adds to our concern. The group Public Citizen has asked the Department of Health and Human Services’ inspector general to investigate, arguing that the collaboration “dangerously compromised the independence and objectivity” of the F.D.A.’s “senior staff and clinical reviewers.”
Aducanumab is seen as a potential medication for the roughly two million Americans with mild Alzheimer’s-related cognitive decline. It is one in a series of experimental treatments that involve injecting patients with an antibody meant to remove fragments of brain beta amyloid, a protein considered critical to the development of Alzheimer’s. Several of these possible treatments have been shown to reduce brain levels of amyloid.
However, none of these antibodies, including aducanumab, have demonstrated a convincing effect on slowing progression of the disease. More than 25 clinical trials have tested the unproven “amyloid cascade” hypothesis and not one has been successful.
To assess the efficacy of aducanumab, two large studies of the drug versus placebo were performed. The trials were stopped in March 2019 because the drug didn’t appear to be effective. But analysis of additional data showed that in the first, there was a small slowing of decline in a group of patients receiving a high dose of the treatment. Another group received a low dose of the antibody and continued to decline at a rate that was not statistically different from that in patients receiving a placebo. In the second study, patients receiving aducanumab, whether at a high or low dose, declined at the same rate as patients on placebo.
While there is precedent for the F.D.A. approving a treatment based on substantial evidence generated from a single trial, the limited evidence provided by the first of the two large aducanumab trials, the outright failure of the second and many other inconsistencies hardly meet this threshold. An F.D.A. advisory committee, on which one of us served, agreed and expressed with near unanimity serious concerns with the evidence to date.
Despite this, Biogen has done everything it can in news releases and investor reports, and at scientific conference presentations to explain away the uncomfortable and disappointing fact that this product has not been proved to work.
Biogen says that the results from the failed trial would have been positive had investigators followed the patients longer and that analysis of a subset of patients with longer exposure to the high dose in the second trial supports the positive findings of the first trial.
But this post-hoc justification simply cannot replace additional, well-designed, blinded, placebo-controlled randomized trials.
Given our lack of effective treatments, some may argue that aducanumab is better than nothing. We strongly disagree. In the aducanumab trials, three out of 10 patients exposed to a high dose had brain swelling as a complication, and although this was usually asymptomatic, in some patients, it led to confusion, disorientation and falls. The swelling was detected with the use of rigorous safety screening, including routine M.R.I. scans. Such regular screening is unlikely to occur outside of the clinical trials, and because similar symptoms can be seen in progressive Alzheimer’s, distinguishing these adverse effects from disease progression would be especially difficult.
Approval of aducanumab will also, inevitably, slow progress in finding a new drug that is clearly safe and effective. A lot of continuing and forthcoming drug trials require regular infusions of the drugs being tested and safety M.R.I. scans. Conducting these trials will be more challenging in a setting where many patients are already on monthly infusions of an F.D.A.-approved drug that frequently causes brain swelling. Some patients and caregivers may be reluctant to enroll in a study if they are taking a newly approved drug they presume works. Others, while taking aducanumab, might be ineligible for new trials, since it would be hard to know whether adverse effects such as confusion or brain swelling were from aducanumab or any new investigational drug.
As millions of Americans know all too well, there is an urgent need to identify new treatments for Alzheimer’s. But there is no fundamental conflict between that challenge and maintaining the standards that have earned the F.D.A. the respect of regulatory agencies around the world. Our patients and their families deserve nothing less, and approving aducanumab without persuasive evidence that it actually works will only slow the discovery of what we need most — treatments that we can be confident actually work.
Dr. Michael Greicius is a professor of neurology at Stanford, where he directs the Stanford Center for Memory Disorders. He is also a co-founder of SBGneuro, a company that analyzes M.R.I. data in clinical trials. Dr. G. Caleb Alexander is an internist and professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. He served on an F.D.A. advisory committee evaluating aducanumab.
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