The FDA has approved the controversial Alzheimer's drug after all - against the recommendation of its own advisory committee. Three members have since left the expert committee. You can check part II of the blog article on this story here.
Aducanumab, a monoclonal antibody that binds to soluble and insoluble beta-amyloid, has repeatedly made headlines since 2019. The manufacturer, Biogen, initially stopped its two large phase-III clinical trials early in 2019 prematurely after interim analyses showed that the primary endpoint (reduction in clinical worsening) was unlikely to be met. The case seemed settled. And then again it wasn't: in the three months between dataset fixing for the futility analyses and the announcement of the results, more data arrived. A little later, Biogen announced that a post hoc analysis of this larger data set in treated patient subgroups had now shown a positive signal after all, and and an approval application was submitted.
The decision was supposed to be made in March 2021, but the US Food and Drug Administration (FDA) postponed it until June for unclear reasons. Surprisingly for many, approval was actually announced on 7 June 2021. The FDA thus overrode the recommendation of its own scientific expert committee, which after reviewing the data had voted 8 to 1 against approval (two other members said they were uncertain about the efficacy). Three members have already resigned from the Peripheral and Central Nervous System Drugs Advisory Committee in connection with this approval process.1
The first to do so was Dr. David Knopman, a clinical neurologist at the renowned Mayo Clinic in Rochester, Minnesota, who was excluded from the FDA's scheduled meeting of external advisors on aducanumab last November because he was involved in clinical trials of the drug.2 In a paper published last autumn in the journal Alzheimer's & Dementia, a group of authors he led recommended further studies and initially concluded as follows:
"The efficacy of aducanumab for the treatment of cognitive dysfunction in Alzheimer's disease is not supportable by clinical trials with divergent results."3
Medscape headlined at the time, that "FDA excludes critics from review panel for controversial Alzheimer's drug".2 "I don't want to be part of an advisory committee [either] in the future and be treated like my colleagues who were on the advisory committee for aducanumab," Dr. Knopman recently told Medscape Medical News.1
Following the announcement of the fast-track approval, two other members have now resigned from the committee: Prof. Aaron Kesselheim, from the Harvard Medical School in Boston, and Prof. Joel Perlmutter, from the Washington University School of Medicine in St Louis.1 Prof. Kesselheim and two other colleagues still serving on the committee justified their no vote in a "viewpoint" published in the Journal of the American Medical Association.4 "There is no reason to favour the trial with the positive signal in one of two treatment groups over the trial with the negative outcome in both treatment groups", he argued on the available data.
The meagre evidence for efficacy was not the only concern. Concerns about possible side effects, the huge costs, and possible delays in the development of other therapies that this approval could cause, also played a role. "For these reasons, I resigned my membership of this committee," Perlmutter explained.
The removal of amyloid in the brain can lead to leaky vessels, resulting in brain oedema and microhaemorrhages. Aducanumab also caused abnormal, small, scattered lesions in the brain (so-called ARIA for amyloid-related imaging abnormalities) in many study participants. It is currently unclear whether these also lead to neurological changes.1 The monthly infusion is said to cost $56,000 per year and patient (not including the costs of the necessary monitoring for therapy success and side effects).
The one study (Study 302) with the supposedly positive otucomes also failed to convince the committee members due to possible methodological flaws. These included the change in the study protocol, the fact that not all participants completed the study, and the possible unblinding of patients with ARIA (the most common side effect), as ARIA requires additional imaging. Some also questioned the validity of the statistical conclusions and the consistency of the evidence, according to a Medscape report.5
Normally, two large studies reaching the same conclusion are needed for a drug to be approved. "But at this meeting, the FDA stopped its experts from focusing only on the positive study, and it also presented a data analysis that was really very favourable to the drug. None of that went down well with these advisers," the news service NPR reported.6
What do other experts think of these events? Read more next week in Part 2 on this blog on the issue.
References:
1. Two FDA Panel Members Resign Over Alzheimer’s Drug Approval. Medscape http://www.medscape.com/viewarticle/952802.
2. FDA Bars Critic From Review Panel of Biogen’s Controversial Alzheimer’s Drug. Medscape http://www.medscape.com/viewarticle/940175.
3. Knopman, D. S., Jones, D. T. & Greicius, M. D. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s & Dementia 17, 696–701 (2021).
4. Alexander, G. C., Emerson, S. & Kesselheim, A. S. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA 325, 1717–1718 (2021).
5. Aducanumab’s Road to Approval Blocked. Medscape http://www.medscape.com/viewarticle/940572.
6. The FDA Has Approved A New Alzheimer’s Drug — Here’s Why That’s Controversial. NPR.org https://www.npr.org/2021/06/07/1003964235/fda-approves-controversial-alzheimers-drug-aducanumab.