Aducanumab’s FDA Approval to Treat AD

EP: 1.The Pathophysiology of Alzheimer’s Disease

EP: 2.Common Screening Tools for AD and Their Importance

EP: 3.Biomarker Testing and its Role in an AD Diagnosis

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EP: 4.Aducanumab’s FDA Approval to Treat AD

EP: 5.Diagnostic Evaluation for Using Aducanumab in Patients With AD

EP: 6.Diagnostic Evaluations Continued

EP: 7.The Importance of Different Tests When Caring For Patients With AD

Alireza Atri, MD, PhD: We’re in a new era of accurate molecular diagnosis for Alzheimer’s disease, classifying individuals as A-positive, T-positive, and N-positive, or some combination thereof. Remember that we’ve taken these categories and dichotomized them. We’ve made amyloid positivity a yes or no question. But of course, very few things in life are binary. There’s a continuum here. Just as we’re in this new era of diagnostics, which are going to help us iterate and improve our approaches to treatment, we’re in a new era of treatments with lots of opportunities and some challenges ahead of us with monoclonal antibodies [mAbs].

There are several monoclonal antibodies. The only one that has accelerated approval at this moment is aducanumab [Aduhelm]. I won’t get into the whole process of approval, but the pathway that the FDA [Food and Drug Administration] uses has been used for a very long time, going back to HIV drugs. It allows approval based on a biomarker, something that’s thought to be important in the disease mechanism and that some effect on it is going to have a reasonable likelihood that there would be benefits down the line.

With that being said, clinically, we have these opportunities. But we also have challenges because there are some adverse effects that we can talk about that need to be monitored, managed, and detected. There has to be strict inclusion/exclusion criteria based on both the FDA label and the appropriate use criteria that a panel of experts published over the summer.

I happen to be on the panel that was published in the Journal of Prevention of Alzheimer Disease. It’s freely downloadable. It’s aducanumab appropriate use criteria, our recommendations. It’s important to think about where we have the most evidence from clinical trials—most of the evidence for aducanumab comes from the 2 phase 3 trials, ENGAGE and EMERGE—and try to reasonably translate that into clinical practice so that the right type of patient is selected. The patients go through an important patient-centered engagement process for them to decide whether this is the right approach and drug for them. For this to be implemented in clinical practice, this has to be done by a team that’s proficient to give infusions and do the monitoring.

Aducanumab is a second-generation mAb in the sense that some of the initial attempts of the mAbs years ago, like bapineuzumab and others, were studied in later stages in populations where there wasn’t biomarker validation that individuals had amyloid in their brain. Now we have this second generation of mAbs coming in for a very selective population. With it, there’s consistent evidence not just from aducanumab but also from lecanemab and donanemab and other drugs, like gantenerumab, that can be lowering and removal of amyloid plaques in the brain.

With some of the published data, there’s also a suggestion that along with that, we’re not going to reverse cognitive impairment on average and make somebody the way they were a year ago. But for a group, there seems to be somewhere between a 20% to 25% slowing of cognitive decline that can be shown on some of these instruments at 18 months. It’s around a 30% to 40% relative slowing compared with placebo functional decline. In some cases, there may be larger benefits with behavior.

The opportunities here are great. I want to give a parallel to multiple sclerosis that I think will resonate with my colleagues. I went to medical school when the interferons came out for multiple sclerosis in the early 1990s. The approval at that point was also based on biomarker. I remember hearing, “The benefits on reducing disability haven’t been shown. These drugs have some adverse effects. Is it really worth it?” When people look back now with hindsight 28 years later, you can see that the first-generation drugs that were approved for multiple sclerosis led to 20 or more other approvals. It also benefited clinical practice in learning how to do these medicines in real life and how to manage complications and adverse effects. And now, many forms of multiple sclerosis have become incredibly manageable, and data have been shown that it reduces disability.

These are our aspirations and hopes. There’s a rational basis for this hope because we’re seeing the signals from the clinical trials. We don’t know for who and how much the benefit will be in reducing cognitive function and behavior decline. We have to monitor and manage some adverse events. But it’s an exciting story because we also have biomarkers to inform us. For that reason, it’s a really hopeful time for us. But at the same time, we need guardrails for these medications because there are adverse effects, including amyloid-related imaging abnormalities [ARIA] that need to be detected, monitored, and managed.

This transcript has been edited for clarity.