Dr Atri discusses aducanumab, first FDA approved anti-amyloid-beta antibody for treatment of Alzheimer’s disease.
Marwan Sabbagh, MD: That brings us to the discussion, Dr Atri, of our first approved monoclonal antibody, aducanumab. Can you give us an overview on how we got to the other monoclonals and talk about aducanumab in terms of its approval, and start that with that?
Alireza Atri, MD, PhD: Aducanumab received for the first time accelerated approval, not based on showing definitive clinical effect, but based on the biomarker effect, as Dr McDade was saying, on lowering amyloid plaques. There is a link that there may be a likelihood that this could translate to clinical effect. It goes back to our understanding that is evolving of, in what patients, for how long, and when in the disease course do you have to lower amyloid, and by how much, before there’s a temporal delay before, potentially, you may get a clinical benefit. And clinical benefit, it’s important to understand for our colleagues that we aren’t talking about turning the clock back 5 years clinically. We’re talking about, not a cure, but something that is meaningful that can slow the course of the disease, and by doing that potentially also for some individuals—and we have to determine with our biomarkers who can benefit more—slow this clinical decline.
With aducanumab, unfortunately the studies were stopped early because of an interim analysis that didn’t go as planned. So there was always an asterisk next to those studies in some ways, where one showed benefit and the other one was clearly negative. But in totality, when you take the aducanumab data along with phase 2 data from donanemab, another monoclonal, and also with lecanemab, there was a suggestion that if for a group you can lower amyloid sufficiently, then you may get a group difference of about 20% to 40% relative slowing over 18 months in global severity, like on the CDR [Clinical Dementia Rating], on measures of cognition or function. That’s where we are now. We’re in that spot, but even in those studies, at the end, not everybody is amyloid negative. It could be only half or two-thirds of individuals.
What was promising also was that there were consistent effects on some biomarkers downstream, suggesting that not only is this affecting the biology of the disease on the amyloid part, but also affecting things like p-tau or tangle pathology, which again, are closer to neurodegeneration and clinical benefit. Along with that there are always safety signals. These are manageable in the context of a clinical trial, often related to amyloid-related imaging abnormalities, and that’s something that requires both a careful patient population selection, but also monitoring during the trials.
Transcript edited for clarity