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AAN 2022 | Important developments in dementia: biomarkers & clinical trials
Philip Tipton, MD, Mayo Clinic, Jacksonville, FL, outlines the most important developments in dementia from the past years. The development of biomarkers has been one of the most significant advances in the dementia field. Since most of the diseases causing dementia are neurodegenerative, it is critical to have biomarkers to inform on disease progression and severity. The second biggest advance in recent years has been the development and approval of novel drugs. In June 2021, the FDA granted accelerated approval to aducanumab – a monoclonal antibody with a high affinity for neurotoxic oligomeric amyloid-beta – for the treatment of early Alzheimer’s disease. Although the approval of aducanumab was controversial, it was also a landmark moment as it was the first time that a treatment that may provide disease-modifying effects was available for patients with Alzheimer’s disease. Three other monoclonal antibodies are currently being evaluated in clinical trials: donanemab, gantenerumab, and lecanemab. Data from those clinical trials are expected in the following months and will provide more insights into anti-amyloid antibodies in Alzheimer’s disease and potentially change the treatment landscape. This interview took place at the American Academy of Neurology 2022 Congress in Seattle, WA.
Transcript (edited for clarity)
The past year has been really exciting in the field of dementia. I feel a little guilty. This is the first time I’ve given this talk and there’s so much to talk about. Whereas in previous, probably, decades, there hasn’t been a ton to talk about. But really over the past year or so, the highlights focus on biomarker development. And so we’ve come a long way in terms of our ability to detect biomarkers as surrogates for disease progression...
The past year has been really exciting in the field of dementia. I feel a little guilty. This is the first time I’ve given this talk and there’s so much to talk about. Whereas in previous, probably, decades, there hasn’t been a ton to talk about. But really over the past year or so, the highlights focus on biomarker development. And so we’ve come a long way in terms of our ability to detect biomarkers as surrogates for disease progression. And in the field of dementia, since most of the diseases we’re talking about are neurodegenerative diseases i.e., slowly progressive, it makes a lot of sense to have a biomarker to give us some idea of the clinical trajectory or how severe disease is.
And that dovetails nicely into the other major advance in dementia, which are clinical trials. And I think everyone’s probably aware at this point of the recent FDA approval of aducanumab or Aduhelm is the brand name. And regardless of how you feel about that medication, that’s the first of several anti-amyloid monoclonal antibodies that target against amyloid and so potential treatments for Alzheimer’s disease. Biomarkers are being used heavily in those trials and then also in other trials moving forward. So we’re excited to see what plays out with aducanumab as well as three of the other monoclonal antibodies that being donanemab, gantenerumab, and lecanemab.
Well, I think it remains to be seen what’s going to happen with the monoclonal antibodies against amyloid. Just in the time I think since last summer, when aducanumab was approved, we’ve already seen just a ton of drama but also excitement around the field in Alzheimer’s disease. And so to be able to offer these patients a treatment that may provide some disease modifying effect is a game changer that we’ve never had. The medications for Alzheimer’s disease up to this point aren’t disease modifying, the cholinesterase inhibitors to name one.
But the other monoclonal antibodies, donanemab, gantenerumab, and lecanemab, those have data that are expected to be coming out within the next six to 12 months. And so we’ll know more about whether or not they work in Alzheimer’s disease. And when we start to put that into play in the disease, I mean, we’re really talking about changing the landscape of the field in a major way. Because most of the trials now are geared towards prodromal or early, mild Alzheimer’s disease. And so this is a time in the disease where we can really change the trajectory, even if you could slow the progression of the disease, rather than halting the progression of disease. We’re talking about a drastic change in what Alzheimer’s looks like in the world.
And then off of that, the biomarkers are a major tool that are being used in these trials. I’ll go back to the aducanumab approval. One of the main reasons why the FDA felt it was appropriate to approve that drug was because there was good evidence of biomarker engagement. There was good evidence of amyloid PET scans, showing reduction in amyloid, CSF amyloid being reduced as well. And so they felt like those surrogates were important to explain that this medication was doing what it intended to do. Now there’s the two trials EMERGE and ENGAGE had differing results. One was a positive and one was a negative, and there’s a third confirmatory Phase IV trial that’s scheduled to begin next month, actually, to understand what the truth really is. But I think it illustrates nicely how important the biomarkers are.
And now just moving outside of the realm of Alzheimer’s disease. We’re seeing biomarkers in the form of tau, total tau in the spinal fluid, neurofilament light chain. And even RT-QuIC based assays for the detection of alpha-synuclein not only in the spinal fluid, but even in the skin. So we’re talking about diseases that for years have been nebulous and a little bit difficult to differentiate. And that’s been a major problem in clinical trials. If we go back to some of the earlier clinical trials of say Alzheimer’s disease, we’ve learned that some patients that we thought had Alzheimer’s disease actually had other diseases. And so now to have biomarkers where we’re really confirming that you’ve got a disease, that’s going to go a long way in terms of helping the field move forward.