In an unusual move, the FDA went against its advisory committee this week to approve the first Alzheimer’s drug in nearly 20 years.
On Wednesday, the FDA approved aducanumab, sold by Biogen under the brand name Aduhelm, despite the objections of its advisory Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee. In response, at least one member of the committee has resigned, with reports of a second following suit.
The controversy is essentially a tale of two studies. Starting in 2015, aducanumab enrolled two large Phase III clinical trials, comprising a total of 3,285 Alzheimer’s patients. Both trials were stopped prematurely in 2019 by Biogen. At the time, one trial was trending positive, while the other was showing the ineffectiveness of aducanumab.
Upon re-analyzing the data, however, Biogen concluded that some patients—in both trials—who received high doses of aducanumab demonstrated a slower rate of cognitive decline.
At a meeting in November 2020 to review this evidence, the FDA advisory committee ultimately concluded that the drug is ineffective at slowing Alzheimer’s disease. Typically, the FDA and its advisory committees require two major studies with the same positive outcome to approve a drug. Since that was not the case here, the committee dissented.
However, this week, the FDA concluded the “benefits of Aduhelm for patients with Alzheimer's disease outweigh the risks of the therapy,” granting the drug Fast Track designation.
"I resigned from the PCNS committee because if I ever were asked to serve on a future panel, I wouldn't have wanted to be treated in the disrespectful way that the aducanumab external advisers were treated," Mayo Clinic neurologist David Knopman told CNN.
Knopman is the lead author of a November 2020 analysis published in the journal Alzheimer’s and Dementia that concluded the two clinical trials of aducanumab failed to demonstrate efficacy.
“Our analysis supports the conduct of a third, Phase 3 trial with high-dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes,” the researchers wrote.
That third trial will happen, but aducanumab will be available to Alzheimer’s patients in the meantime. As a condition of the FDA’s Fast Track designation, aducanumab must undergo a new randomized, controlled clinical trial.
The trial, which could take years to complete, will provide Aduhelm on a monthly basis via infusion—with all patients required to undergo regular brain scans to detect/prevent possible deadly side effects. Previous trials indicated bleeding or swelling in the brain is a rare but serious side effect of Aduhelm.
Overall, the two clinical trials did seem to prove that, for some patients, high doses of aducanumab resulted in a reduction of amyloid beta plaque, whose accumulation is the fundamental pathophysiology of Alzheimer’s. But, does that reduction actually slow the progress of Alzheimer’s disease?
The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee says no. The FDA says yes.
Photo: An example of a transaxial slice of the brain of a 56-year-old patient (male) taken with positron emission tomography (PET). Not affiliated with the clinical trials.