Repurposing Dabigatran for the Vascular Activation Process in Alzheimer Disease

Paula Grammas, PhD

In Alzheimer disease, one of the hallmarks of research has become the attempt to repurpose therapies which are already available for other conditions to explore their potential use in dementia.

Paula Grammas, PhD, the executive director of the University of Rhode Island’s George & Anne Ryan Institute for Neuroscience, is part of the university’s team seeking to do just that with dabigatran, a direct thrombin inhibitor approved for the treatment and prevention of deep venous thrombosis and pulmonary embolism, among other indications.

Recently, with funding from the Alzheimer’s Drug Discovery Foundation, Grammas and her colleagues announced that they’ll be conducting a phase 1, proof-of-concept trial with the treatment to explore its effects on the vasculature in Alzheimer.

To find out more about the trial and the decision to repurpose dabigatran, as well as the research that led to this clinical assessment, NeurologyLive spoke with Grammas in an interview.

NeurologyLive: What led you and your colleagues to undertake this study?

Paula Grammas, PhD: We’ve been interested in the cerebral microcirculation and the vasculature for a really long time, and we started with the very simple premise that, in Alzheimer disease, the neurons die, so why is that? Over the years, we felt like enough attention wasn’t paid to the vasculature because, really, it’s the vasculature that creates the environment in which the neurons sit. So, we developed a technique many years ago for isolating blood vessels from the brain to look at how those vessels might be altered biochemically in Alzheimer disease. We started with human post-mortem material and, again, over probably 30 years we looked at the vasculature and we determined that the vessels in Alzheimer disease are what we call very highly activated—they overproduce a lot of noxious proteins, they make a lot of inflammatory proteins, a lot of proteases, a lot of different things. We said that all these vascular-derived neurotoxic factors may contribute directly to neuronal cell death, or indirectly via activation of astrocytes and microglia, which then contribute to neuronal cell death. The idea being that, if you could turn the switch down that leads to the production of all these neurotoxic factors, that that would be some benefit in Alzheimer, so how exactly do we do that?

The production of all these factors, we believe, is part of the process that we call vascular activation where the endothelial cell changes its phenotype from a quiescent, sort of neurotrophic supportive cell, to a very activated, highly metabolic cell producing all these noxious factors. If we could use a drug that damps that process down, there could be a benefit in Alzheimer. Then, we began to look at animal models in Alzheimer to test this hypothesis, and we tried a couple of drugs.

We ended up settling on dabigatran as the gateway to eventual human study because it has a good safety profile, it’s been in use for a long time, it’s been in use in a population whose age range is pretty close to the population in Alzheimer. Over the years, we’ve developed this idea that in the vascular activation process, one of the key mediators that turns the whole process on and keeps it going is thrombin. We think thrombin is a key mediator in this process, so therefore, if we use a drug that inhibits thrombin, we believe that we can make some inroads into this neurodegenerative process in the brain.

What makes dabigatran a viable agent for repurposing in Alzheimer?

We originally began with a different drug which is not a thrombin inhibitor, but we believe also impacts the process of vascular activation a Pfizer drug, sunitinib, which was developed for renal cell carcinoma. It is a VEGF receptor inhibitor and we believe that, again, part of the vascular activation process could be damped down through that. But we’ve found over the years that thrombin is really a key driver and so we started to switch gears and think about really looking at the thrombin inhibitors.

Dabigatran was our choice mostly because it’s orally available—there are a few other thrombin inhibitors that require injection—and again, there’s significant clinical history with dabigatran and a good safety profile.

We’ve said for a really long time that if we can look at a repurposed drug, then yay us. That would cut down the remaining time to develop one. Starting from a great idea in the lab to bedside to human clinical trial, that’s a lot of years. Even with an expedited review, you’re looking at a very long time for safety testing and lab testing et cetera, and so beginning with a repurposed drug—we’ve thought this for a long time—would probably be the way to go. Which is not to say that down the road there couldn’t be other, better drugs.

Part of the issue with any of the thrombin inhibitors is that thrombin does a lot of things. We’re interested in thrombin through what we’re targeting, this vascular activation, vascular inflammatory pathway, but obviously, thrombin is also involved in the coagulation cascade. One of the concerns, and why it’s taken us a while to dot all the I’s and cross all the T’s in our trial, was to make sure that we had the safety profile as well as we could manage it because there’s obviously the potential for some bleeding. In the future, an ideal drug would be one that inhibits thrombin inflammatory activity but doesn’t affect its clotting or affects its clotting activities less. We’re trying to develop those kinds of compounds, I know other people are also looking at that as a therapeutic strategy, but meanwhile, we still have to have proof-of-concept and work with the drugs available, so I think dabigatran is a good candidate. Is it the perfect candidate? I don’t know, but it’s the perfect candidate for where we are right now.

What’s the main goal of the study? Do you anticipate follow-up research?

The plan is, if we see a positive result, if we see positive trends, the hope would be that we would be able to perform this in a larger format study. What funding we have with Alzheimer’s Drug Discovery Foundation will allow us to run what we consider a pilot clinical trial, proof-of-concept. But really before this were to go into widespread therapeutic use, we would need a trial with much larger patient enrollment—either through the Alzheimer’s Disease Cooperative Study or some other larger component. I think that would be worth looking at. So that’s the hope, show proof-of-concept here and take it to a large trial. Then, if in fact that works, and then along the way, if we learn more—anytime we do any study like this you learn things as you go along—there may be opportunities in a larger study to tweak something and look at the things we didn’t appreciate in this study. But we won’t know that until we are actually in it.

Are there secondary end points of interest in the trial?

The hope would be that we might see some sort of cognitive benefit. That’s the ultimate gold standard. But again, small sample size, not that long of a study. We’re hoping to see changes in plasma biomarkers, but that’s still an evolving field, the inflammatory biomarkers in the periphery and what they may or may not tell us about the brain. So, we’re actually really interested in seeing how those change over the course, first of all, in the Alzheimer patient population that we’re going to look at, and how they might change in treatment. Which, again, might give us some insights into what’s going on in the disease and might also make some suggestions down the road for other types of therapies.

What should the clinician community know about this trial?

They should know that it’s basically an entirely new premise. It’s a new target. It’s not based on what’s been the focus of Alzheimer research for so long, which is essentially amyloid lowering. It’s focused on a different pathological mechanism which amyloid may or may not be involved in, in some capacity down the road at some point. But the target here is a target that’s never been looked at before. We’re specifically targeting the vasculature.

Transcript edited for clarity.

REFERENCES

1. Ryan Institute for Neuroscience at URI Receives Approval for Groundbreaking Clinical Trial Targeting the Blood Vessels in Alzheimer’s Disease [press release]. Kingston, RI: URI; Published January 14, 2019. today.uri.edu/news/ryan-institute-for-neuroscience-at-uri-receives-approval-for-groundbreaking-clinical-trial-targeting-the-blood-vessels-in-alzheimers-disease. Accessed January 14, 2019.