Early Diagnosis, Testing, and Treatment of Dementia - Episode 16

Monoclonal Antibodies to Treat Alzheimer Disease

October 30, 2019

Alireza Atri, MD, PhD: We’ve covered a lot, as far as management goes, so let’s talk about precision medicine and targets and hope for the future. I’ll turn to you, Brad. Brad, you had mentioned what Alzheimer disease is caused by or defined by. What are the conceptual approaches and experimental therapeutics that are targeting amyloid right now?

Bradford C. Dickerson, MD: Sure. So I talked a little about the process of the pathogenic, pathologic form of amyloid that is generated. There are these soluble stages, and there are monomers, oligomers, and then protofibrils. Something about that process interferes with synaptic function. And then, as the amyloid becomes insoluble and deposited as fibrillar plaques that have a neuritic component that includes tau—hyperphosphorylated tau—they interfere with the structure of the brain, including the axons and dendritic structure between neurons, and are thought to possibly have a variety of toxicities at the synaptic level and at the cellular level. And so from the perspective of the amyloid cascade hypothesis, there are various points of intervention—some of which have been tried pretty vigorously and have not worked very well, and some of which have not really been tried—and I think we’re refining our thinking about what the different mechanisms of action are.

There have been a couple of recent trials that I think are worth talking about, in terms of where the field is going despite the failures that we’ve had. I just want to mention BAN2401, which is a monoclonal antibody that is really targeting the soluble protofibrils of amyloid beta. I think excitement at the AAIC [Alzheimer’s Association International Conference] meeting a couple of years ago was based on the reporting of the multidose 18-month study of about 800 patients with MCI [mild cognitive impairment] or dementia due to Alzheimer disease. The highest-dose group that got 10 mg/kg twice monthly showed reduced brain and amyloid on PET [positron emission tomography], and there was some evidence of clinical efficacy on a couple of outcome measures representing cognition that wasn’t seen in the group that got the less frequent dosing—once a month.

I think we’re all watching the phase 3 trial of this compound that is maybe a slightly different mechanism of action than some of the other approaches, which haven’t done so well in the recent past.

Alireza Atri, MD, PhD: This is a trial that’s ongoing and is focusing mostly on protofibrils. What are some other amyloid monoclonal antibodies that are also currently being tested and have kind of withstood earlier-phase testing?

Bradford C. Dickerson, MD: Gantenerumab is 1, and that’s really targeting the fibrillar stage of amyloid plaques with the idea that we should also be trying to remove the plaques from the brain. The early studies of gantenerumab did not meet primary clinical outcomes. But like all trials, we try to learn from those. One way we learn is with open-label continued follow-up of patients to see if maybe there might be longer-term clinical efficacy, even if the primary a priori—specified outcomes were not met.

The other thing is that in the higher-dose arm of 1 of the early trials of gantenerumab, there was evidence of reduced amyloid in the brain even though the clinical outcomes weren’t met. I think that’s always exciting. There are always these exploratory analyses of clinical subgroups that can teach us better ways to hopefully target treatments in the future. And so 1 of the things that was done with that data set was looking at faster progressors.

I think 1 of the challenges that we have in all Alzheimer-related drug trials is that some people naturally don’t progress very fast. If you happen to have a group like that in your treated arm, you’re potentially going to be fooled into thinking that the drug is doing something. If you happen to have those people in your control arm, you’re going to be potentially fooled into thinking the drug is doing something. That’s why it’s always important to examine whether the different groups in the trials are representative of what we think the placebo arm should be, for example.

So the subanalysis that was purely exploratory after the fact of the faster explorers suggested that not only did they have the reduced brain amyloid, but maybe they also would have met some beneficial clinic outcomes if that had been the group that was the sole group in the study.

These all lead us to feel that there might still be some signal, both in terms of the target engagement, which is reducing the amyloid plaque, and in terms of possible clinical efficacy, which is why these cohorts are being followed in open-label trials. And whether new studies of this compound, both in the dominantly inherited Alzheimer network of people with autosomal dominant AD [Alzheimer disease], and also in sporadic AD with ongoing clinical trials that are recruiting new patients with prodromal and dementia stage AD.

Alireza Atri, MD, PhD: Right. That’s actually an important point. One of the exciting things, as you mentioned for BAN2401, is that the earlier-phase data had suggested that you can actually remove amyloid from the brain. Some of the studies in the past were in the later stages of patients who didn’t have amyloid in the brain. They were included years ago before we had PET scans and CSF [cerebrospinal fluid], or there were more severe stages. What are plans for things like BAN2401 to go even earlier in the disease process for people without symptoms? I think you alluded to that.

Bradford C. Dickerson, MD: Right. So there is the DIAN study—and there are other studies ongoing of so-called preclinical Alzheimer disease, which we haven’t talked about today. I think this is a very hot area in the field that’s not yet ready for clinical practice. We don’t want to talk about it as if people should be looking for their primary care doctor to perform molecular biomarker studies on them, but they’re normal. I don’t think we’re there yet. I hope we will get there. Because if we get there, that’s going to mean we’re able to do something about it. I think the field is saying that we know that amyloid gets deposited in the brain, maybe as long as 20 years prior to when people develop substantial symptoms. And there’s the tau pathology that also precedes the symptomatic stage of the illness. There is dysfunction of brain networks, and even atrophy if you measure it carefully in the brain with MRI [magnetic resonance imaging] that can be detected prior to symptoms.

There’s this fairly long preclinical stage that is now the subject of a number of ongoing studies in genetic forms of AD and sporadic forms of AD where, primarily, the amyloid-based strategies, including the use of gantenerumab, are being evaluated with regard to whether it can delay the onset of symptoms, whether it can reduce brain amyloid, hopefully do both of those things together, and hopefully have a meaningful impact on when people develop symptoms, even if they have the beginnings of the Alzheimer pathologic process happening in their brain.

Alireza Atri, MD, PhD: Right. It kind of goes back to what you were saying, Mary, about the value of a timely diagnosis and allowing people to be at the highest point to make their decisions, including whether they want to become involved in research. We’re also hearing that there are studies that are either launched or being launched that can look at people who may have amyloid in their brain but don’t have symptoms. One of the ones that recently has been brought up is, again, BAN2401 being put in early. Again, this is a hope for the future—that people can participate.

Transcript edited for clarity.