The fate of an experimental dementia drug will be decided within days. On Monday, the U.S. Food and Drug Administration is set to announce whether it will approve Biogen’s antibody-based therapy aducanumab as a treatment for Alzheimer’s disease — the first intended to slow down the progression of the incurable ailment. But either way, the history of aducanumab’s development is likely to make it a controversial and fiercely debated verdict.
As Gizmodo has detailed before, aducanumab is a lab-made antibody designed to go after amyloid beta (or beta-amyloid), a protein found in the brain thought to be crucial to the development of Alzheimer’s. In those with Alzheimer’s, a fatal disease in which victims lose their memory and other cognitive functions, deposits of misfolded amyloid and another protein called tau build up over time. These amyloid plaques and tau tangles, as they’re known, are then thought to help trigger or cause the brain’s gradual destruction that leads to symptoms of dementia and eventual death. Because aducanumab has been shown to break down plaque in the lab, scientists hoped that it could slow or reverse the decline of a patient’s brain beset by Alzheimer’s.
Massachusetts-based Biogen licensed the drug from its creators, the Swiss company Neurimmune, and began putting it through the clinical trial process in 2012. Data from the earliest human trials seemed to show that it was safe and well-tolerated and suggested that it could be benefiting patients. But these trials were not intended to see whether it was effective at treating Alzheimer’s. So, by 2015, Biogen began two Phase III trials, each involving over 1,300 patients with early Alzheimer’s or mild cognitive impairment suspected to eventually lead to Alzheimer’s.
In March 2019, Biogen abruptly announced that it would immediately suspend all research into aducanumab. An independent panel of experts monitoring the trials (a common research practice) had looked at the Phase III data collected up until then and determined that the drug likely wouldn’t meet the pre-established goals of the trials in noticeably slowing down patients’ loss of cognitive function. It was at the time the latest failure of the amyloid hypothesis: the theory that amyloid is the main driver of Alzheimer’s and that tackling its accumulation in the brain would stop the disease.
A little more than six months later, though, Biogen had a sudden about-face. In October, it announced that a reanalysis of both trials actually had found enough evidence for aducanumab’s therapeutic potential. According to the new analysis of updated data, one trial did show a statistically significant effect of the drug, particularly for those given the largest doses (10 milligrams or more). The other trial overall failed to show an effect, but one was similarly found in the subset of high-dose patients. With that, the company said it would conduct follow-up trials of these patients (set to conclude in 2023) and that it would petition the FDA to weigh the drug’s approval after all.
By August 2020, Biogen had secured a priority review of the drug, meaning that the FDA had to conclude its process within six months. The FDA delayed this decision before the original March deadline, but it’s now set to decide right at the last second, on June 7.
Patient advocates and some doctors have long voiced their support for the drug, arguing that just a small benefit in slowing down the disease would be worth its approval. But other experts have been reluctant to endorse it, countering that the data is just too murky to know that it’s capable of providing even that much at this point. And even if it does “work,” they add, it’s unlikely to be anywhere near effective enough to justify its possible risks, such as small bleeding in the brain, and its expected high costs of $US50,000 ($64,130) a year.
In November 2020, an outside advisory committee of experts was assembled by the FDA to evaluate the evidence, as is standard for a new drug approval. Though some did agree that aducanumab demonstrated potential in affecting the pathology of the disease, they largely ruled against approval. In the most important question posed to them, 10 of 11 votes agreed that the EMERGE trial (the Phase III trial that seemingly found a statistically significant effect), along with other data, had failed to show “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease” — the 11th person voted “uncertain.”
The recommendations of these committees are non-binding, but the FDA rarely disagrees with them. Given the real pressure to find something, anything to treat Alzheimer’s, though, it’s not certain just how the FDA will sway. There are of course many potential Alzheimer’s treatments in the research pipeline, but aducanumab and other anti-plaque drugs like it are the closest to fruition. So it’s likely this decision will carry serious ramifications down the line.
If this drug is approved, for instance, it will renew the hope that anti-plaque drugs are a viable strategy for Alzheimer’s. But if it then turns out to be largely ineffective, as many experts fear, then it may delay for years the development of other, more promising drugs, since many patients could decide to avoid enrolling in new trials and just stick to aducanumab. And time is unfortunately not on our side — experts have argued that an ever-growing and likely more unhealthy ageing population than past generations will lead to a continued surge in Alzheimer’s in the years to come. It’s a dreadful situation to be in, even in the already bleak world of Alzheimer’s research.