This week we review the current status of a previously tested investigational treatment for Alzheimer’s disease (AD) reflecting the clinical trial approval process. In March of 2019 two phase III clinical trials of Biogen’s Aducanumab, a monoclonal amyloid-clearing antibody, terminated due to lack of efficacy after an interim futility analysis. As disappointing as these initial results were, the Aducanumab story most likely won’t stop here.
Biogen, has appealed the FDA to receive approval for the drug after sub-group analyses showed possible efficacy. These analyses were required because, of two parallel phase III trials (301 and 302), only one showed efficacy while the other failed to meet its endpoints. The FDA review board, and the academic community at large, are divided as to whether approving this drug would be a progression in AD treatment or a roadblock to future progression. Approving an ineffective drug “will slow down finding something that does work” says Michael Greicius, a professor of Neurology at Stanford. Let’s look at both sides of the issue.
Biogen, having had one phase III trial that showed efficacy and one that did not, explained that these differential results may be due to variance in the study sample as the 301 trial had changed dosing directions mid-study and also had a large sample of “rapid progressors”. This left the review board to ponder whether the single successful 301 trial, if viewed on its own, provided sufficient evidence that the drug worked as intended. Only one member voted that the 302 trial supported approval of the therapy. Five members agreed that the treatment reduced amyloid-beta plaques in the brain, however, they were not convinced that the reduction of amyloid correlated to clinical improvements in cognition.
One review board member, Joel Perlmutter, stated he “recognized the urgent, unmet need for treatment […] However, approving a treatment that ultimately does not work can be harmful” due to the fact that approval of this drug would “substantially slow recruitment into ongoing and future studies” and could reduce “enthusiasm and support for testing other potentially more effective treatments”. With this in mind, it seems reasonable to maintain skepticism when it comes to inconsistent results like those in the Aducanumab trials.
Furthermore, Perlmutter explains an even larger concern, being that if it were approved “we may be required to test any new treatment not against placebo but against this drug”. In other words, if this drug is not effective in treating AD but is approved, all future treatments simply have to show more improvement than Aducanumab, meaning that other less effective drugs could continue to be approved and administered to patients simply because they are less ineffective. However, if Aducanumab really does work, we could be setting ourselves back years while we wait for another effective treatment to successfully complete phase III in the clinical trial process. As you can see, the research and clinical review processes are quite complicated and must proceed with caution. Making an incorrect decision at one stage has the potential to fully derail a field of study such as AD treatment. We hope the FDA requires a new Phase III trial for Biogen’s Aducanumab to prospectively test its effectiveness.