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Welcome to the Quick Consult podcast brought to you by Medall. Before starting this podcast, please review the faculty information, disclosure statements and learning objectives using the link in the episode description. To claim your CME credit, complete the evaluation using the link in the episode description. This podcast is a continuing education activity managed and accredited by Current Concepts Institute in collaboration with META. This activity is supported by independent medical education grant from Johnson and Johnson and Bristol-Myers Squibb. Welcome back to Voices and Thrombosis, a meal education series. I'm your host, Phil McElnay, and today we continue our conversation with Doctor Christian Ruff from Brigham and Women's Hospital and Harvard Medical School. In our last episode, we discussed the current best practices for thrombosis management, including the use of DA. Today we're looking to the future. Uh, Doctor Ruff, while DAs are a huge improvement over warfarin, bleeding seems to remain a significant concern that leads to many high-risk patients being undertreated or not treated at all. This has led to the search for an even safer anticoagulant. Could you introduce the concept of factor 11, 11A inhibitors, and why they're generating so much excitement? Oh, it's a great question, Phil. Thank you for having me. Obviously we have effective anticoagulants, warfarin and the Doax. They are very effective in reducing ischemic events, particularly stroke and atrial fibrillation. The problem is that where they block the clotting cascade, you end up interfering not only with preventing dangerous clots or bad clots that cause heart attacks or strokes, but they also impair the body's ability to repair injured blood vessels, which is kind of the good clotting. So evolutionarily we've developed good clotting. Say you're running around and you get bit by a tiger and you're bleeding. You want to prevent a clot or you cut yourself shaving or you nick yourself walking by a tree. Uh, you want to have that type of clotting where you have an injured blood vessel So you don't want to sort of bleed out from an injury, but you don't want to have a heart attack or stroke. And the problem with our current anticoagulants, including the Doax, is the way they act in the clotting cascade. You end up impairing both. You prevent the bad clots, which is great, but you still prevent the good clots, so you get a lot of bleeding, and we know that bleeding leads to significant undertreatment of patients and the promise of factor 11 inhibition. Is that where factor 11 sort of operates in the body's ability to clot seems to be very unique and that it's essential for bad clotting. We call that pathological thrombosis. So when you form a clot, it propagates and it explodes and it blocks the brain artery, just stroke, blocks the heart artery, it's a heart attack. Factor 11 is essential in that process. And so if you block factor 11, you would prevent potentially that bad clotting. But factor 11 really doesn't participate at all. In fact, it's not really needed in the good clotting in the normal mestasis, the ability of the body to repair blood vessels. And so that led to the idea of this uncoupling. Hemostasis from thrombosis. So by using a factor 11 inhibitor, maybe we can block the bad clotting but still allow the normal injury, uh, healing of the blood vessel. And there's a lot of data from patients who are or individuals who are born with low levels. A factor 11 that support this, there are people walking around there with almost no factor 11, and they appear to have very low rates of ischemic events, heart attacks, stroke, venous thromboembolism, and they don't appear to bleed very frequently, at least not spontaneously and not even with major surgeries. And so that observation then led to a lot of interest like, well, what about if we develop a drug that blocks that pathway, maybe we can recapitulate that effect, preventing the bad clotting while protecting the body's ability to preserve the normal healing of blood vessels. So the theory is we can target the bad clotting while leaving the good, good clotting relatively intact. That's exactly right. What, what clinical evidence do we have to support this idea? It's a great question. As I mentioned that there are populations where genetically they, it's more common to have factor 11 deficiency, and it's very, it's much more common in the Nazi Jewish population. So there are a lot of studies out of Israel looking at people with very low levels of factor 11 or almost no factor 11. Uh, and they appear to have these very low rates of stroke, heart attacks, etc. and they don't have any bleeding. And when we've looked, then, you know, factor 11 levels vary like anything height or weight in populations. When we've looked at factor 11 levels in other populations. They've been done in the US and Europe. We see that people with high factor 11 levels tend to have more ischemic events, more heart attacks or strokes. Patients with low levels appear to have less. And so there's a lot of evidence that factor 11 levels are important. If you have low levels, you seem protected from cardiovascular events. If you have high levels, you're at increased risk. And so again, lots of support just epidemiologically and genetically that factor 11 is an important factor whether you have a high or low risk of ischemic events. And again, having low levels of factor 11 don't appear to increase your risk of bleeding or at least not serious bleeding. And so there was a lot of kind of evidence out there already in the human community in our neighborhoods. That suggested that targeting factor 11 pathway pharmacologically may be an effective strategy to uncouple this process where we want to prevent the bad clotting, but we don't want to cause a lot of bleeding. And as I mentioned with our current anticoagulants, we do both. We prevent clotting, but we cause a lot of bleeding and this may be an opportunity for us to be more selective, more precise in how we block clotting. The evolution of discovery in medicine is really fascinating, isn't it? Uh, it is. Uh, you've been a researcher in this space, and, and I want to dive into some of the trials that are ongoing here. Could you walk us through the key findings, for instance, from the Azalea Timmy 71 trial which studied the factor allay 11-11 inhibitor, um, bilsilumab. Yeah, it's, it's a great question, and we were really excited about the Azalea to me 71 results. It really cemented this, the safety hypothesis of factor 11 pathway inhibitors. Abilizumab is a very potent monoclonal antibody to factor 11, factor 11A. In fact, it reduces factor 11 levels by 99%, so almost eliminates it. And despite being that potent compared to standard of care rivaroxaban in patients with moderate to high risk atrial fibrillation, it decreased bleeding by 60 to 70%. And in fact it almost eliminated gastrointestinal bleeding. So it kind of proved the concept that you can have a very potent factor 11 pathway inhibitor, and it's remarkably safer compared to even our most advanced. And so I think that it really supports that the factor 11 hypothesis is true with respect to safety that bleeding is remarkably low and if proven effective, these drugs would be transformational because it would allow us to treat even our most vulnerable patients and of course then you know that is the phase 3 studies that are obviously required and they're ongoing for many of these agents to sort of cement the efficacy of these agents. A reduction in bleeding is a game changer in this space, however, another trial with a different factor 11 inhibitor, oceanic AF and uh asindexion, was stopped early for lack of efficacy. What do you think that tells us about this class of drugs? Yeah, first of all, that's why it's very important to do clinical trials, right, because you, you need the evidence, and I think, You know that was a phase 3 study, so an efficacy trial against standard of care ixaban for stroke prevention atrial fibrillation, and as you mentioned, the small molecule as indexin, which is a factor 11A or activated factor 11 inhibitor, was stopped. And I think what we've learned, which has been true for drug development for decades and decades, is getting the dose of these drugs right is really essential. And one of the things that's challenging about the factor 11. A inhibitors is there's not a great test, a blood test to determine the efficacy for factor 11, there's a standard factor 11 clotting assay that's been used for many decades, but for just a drug that inhibits activated factor 11, there's not a great activated factor 11 test. And so the dose of that agent was picked by a proprietary assay by the company, but it wasn't really ever validated with respect to clinical endpoints. It's like that level reduce strokes or reduce clots. And so it was selected based on a test that that wasn't clinically validated and in retrospect, it looks like that drug was likely significantly underdosed. Uh, and we know dosing is important. We know that from the DA if you use an inappropriately low dose, they're not nearly effective. And so I think many of us in the field believe that the more potent factor 11 pathway inhibitors that are still in in late stage development for atrial fibrillation are likely going to be a lot more effective than oscidexium. Um, so it doesn't diminish my enthusiasm for the factor 11 pathway hypothesis, but it does.