And, you know, I want to get into a couple questions around this, this idea of phase two trials and why they're important to set us up for the big phase three. And of course, the phase three are the ones that really help us determine if a drug gets approved. Gene, maybe I'll start with you. Can you talk to us maybe for a minute about why it's so important that we do these knee arthroplasty studies on an anticoagulant? What is it that we're learning in a phase two study of a knee arthroplasty that then helps us make a decision about AFib or acute coronary syndrome or something like that? Well, that's a great question. And thanks, Jeff. No, so the knee arthroplasty model is a very slick model. And when you review these papers for the New England Journal, which I've done, you can't find much fault with them. They really are well done, well written. But one of the benefits is you're taking relatively healthy population that can undergo surgery and you know that there's a high risk of thrombosis in a specific location. But most importantly, you can also get results within two weeks, right? So that you can rapidly do multiple dose findings or dose escalation studies and dose determination and compare to a true gold standard comparator for which we really know what the rates are for preventing thrombosis. And so that's huge. Well-defined, relatively healthy population with a known VTE risk and known pathophysiology for that VTE. So there's not a lot of confounding. And again, the rapid turnaround time. I mean, where else do you get results, you know, a readout in individual patients in two weeks, right? So that's really why those studies, we think, are so important for dose finding and dose range. You know, another sort of lesson I think we are learning in the phase two, and as we're moving into phase three, is this question about how to measure the impact or the amount of drug, you know, that's inhibiting factor XI. It makes me think of the transition we made from vitamin K antagonists to the DOACs, right? Where we went from something that was very easily measured with an INR to something that we didn't have any measure of when we got to Dabigatran, Apixaban, Rivaroxaban, and Adoxaban. Mark, you hinted at this a little bit. I'm wondering if maybe you can offer us some more insights. Do we have a uniform way of measuring how these factor XI drugs are taking impact? I mean, what do we know about these different activities or free factor XI levels? Are they all the same? Is it unclear? Is this all mud, or is there some clarity you can offer? I'm going to have to phone a friend in a moment next to Gene, but I'll say I don't think we do. I mean, you know, one thing people look at across the trials is the PTT. They all go up. I'm not sure that that's an appropriate measure of the relative efficacy of them. You know, is it free factor XI, factor XI activity? I don't know. I think someday we will. We'll be able to tie these biomarkers to efficacy. I just don't think we're there yet, because what the drugs are doing is different. So whether you prolong the PTT by using an antibody and blocking factor XI in an inactive state and activated, that may be different than a small molecule effect. So I don't think we're there, but Gene's smarter than I am. So let me ask her. Not smarter. Just different field. Now, I actually deleted a slide on this, because I decided it was an area that's very controversial, right? As Mark alluded to, the APTT goes up with factor XI deficiency. And for those with congenital absence of factor XI to varying degree, there is some linearity between amount of factor XI activity and PTT. But those two things don't correlate with risk of bleeding. So we can have patients who have no detectable XI activity and have no bleeding, and we can have people who have detectable XI activity of 30%, you know, and have major bleeding with invasive procedures. So that correlation is missing, right? And so we do, you've heard a lot, like we use the PTT when in the U.S. the only available XI replacement is FFP, or frozen plasma. And we can use the PTT to guide when somebody with no XI activity reaches 20 to 30%, which is sufficient for neuroaxial anesthesia and all of that. So you can say, oh yeah, their PTT dropped from 80 to 30, you know. So we're happy. It's in the normal range. The issue with an assay that's out there with the Bayer Company is that it's more like the chromogenic anti-10A assay. So we're looking at how much color is developed by factor XI within the patient's plasma, and how much the test drug inhibits that color development. And that is very different than XI activity. And every patient has a wide range, you know, normal range of XI activity is 50 to 150%. So we need better ways to do this. So what I'm hearing you say, which is I actually think a bit of a familiar story, is we have different ways of measuring. They don't correlate one-to-one, and we don't even know if those ways of measuring have direct relationships to the clinical outcomes we care about, which in many ways reminds me of what happened with the factor XAs when they first came out. We wanted something we could measure, just like we had with an INR, and we had to get used to the idea that we can just prescribe a drug with a fixed dose and not necessarily rely on a measure. I mean, is that... Yeah, no, and it's even worse than that, actually, because if you're trying to measure unfractionated happen, right, you know, to use the anti-XA or the PTT. But you're right. The XAs go in there and the anti-XAs don't affect the PTT or in most assays the PT. So what's it doing and how can it have activity, right? So we're relying. Yeah. Bob, thoughts? Yeah. This is why when Jean described the DVT studies, they're so important. Because what you're trying to make sure that you understand is that whatever dose you're at, do you prevent human thrombus? There was the animal models that certainly showed that you could, but you needed really to have the human model, which is really what the arthroplasty model is, is it really demonstrates in an area where we literally have tens of thousands of experiences where we know how enoxaparin behaves in preventing thrombosis. And so you need... That's why that piece is so critical to demonstrate that you prevent clot. But as Mark also indicated, well, you know, it may not be that venous clot is the same as arterial clot and that's what the phase three clinical trials are really critical for. Well, I think that is a great sort of transition here to some of the questions we've been getting from folks online. And so thank you for submitting those. I'll tell you the highest voted question right now is where do we get those amazing socks, Dr. Harrington? Those are really special. So if you have a plug for anyone and they want to figure out how to get them, we'll let you connect. I have so many red and heart socks that I'm happy to share my store choices with you. So one of the questions we are getting is about the clearance of these drugs. And we highlighted, actually, I think Christy was in your presentation, how there's really not any renal clearance and that's a potential real advantage for this class. Couple people have asked a really great question. What about liver clearance? Do we need to worry about liver function with these drugs? I don't know. Does anyone want to maybe take a stab at that one? We have a PharmD with us. I think, you know, a lot of times with the monoclonal antibodies and things like that, we don't see a lot of liver clearance. So it, you know, it is definitely also promising. I mean, I'll comment first on Melvexian because this is what we're studying now. We know that it goes through the cytochrome P450 system. So drugs that interfere with that system, you have to be aware of. And we're looking at all of that in the clinical trials. But we're not yet sure of what the effect on liver clearance will be. We'll get a better sense of it at the end of the clinical trials. Another question that's come in, I think gets at this concern about, well, what do you do if you're using one of these really long half-life drugs? I'm thinking about the drugs that maybe you're using once a week or once a month. And Mark, you showed an interesting slide in there. This was from the Abolacemab data where they looked at who was undergoing surgical procedures and whether or not they had any bleeding. Could you maybe talk a little bit about how should we be thinking about a drug that has a long half-life and what are the implications of that for bleeding procedures? What do we know and what do we still need to know? That's a great question. I mean, this even goes back to the Vorapaxar days, because that had a long half-life. And there's two sides to that coin, right? I mean, these drugs, if they increase bleeding, at least Vorapaxar did, a long half-life is a real liability. What do you do if somebody's bleeding and this thing's on board? On the other hand, the short half-life of antithrombotics, in fact, I think the oral 2B3As were an example of short half-life. But even drugs we use today, the DOACs, people miss a few doses and they're at risk. So I think in this context, it really depends on what's shown in the phase three trials. But if these drugs are safe, having a long half-life could be a real advantage where you don't have to worry about a daily pill. You don't have to worry about daily adherence. Even for the small molecules, I'd say if they could be given without interruption for a lot of routine procedures, low bleeding risk procedures, that's a real advantage. It's not only an advantage in terms of risk, because I think these on-offs are risky. It's also an advantage for the headache we get when we continue to get inbox messages and things about how do you want to manage this around whatever procedure. I think if these drugs really prove to be safe in the periprocedural setting for lower intermediate risk procedures, it's going to be a huge advantage. I want to build off of that, and Kristen, maybe I'll come to you. For so long, we had Warfarin. It was our only oral anticoagulant. I know many of us as physicians relied on our nursing and pharmacist colleagues to help us manage that better. Then come the direct oral anticoagulants, and there's sort of this question of can we just go it alone as prescribers, or do we need the support of a pharmacist? As I think about this next class of agents, the Factor XI's, it feels to me like there's going to be even more complexity. I'm wondering what role do you see our CV team, and in particular, the pharmacists having in supporting patients, supporting prescribers to make sure that the right drug is prescribed initially, the periprocedural issues are done. Somebody who says, oh yeah, I take a pill as my blood thinner. Well, how is that going to impact things? What role does the pharmacist have in sort of making sure this is all being done appropriately and safely? Yeah. I think it's critical, and the devil's in the details, right, of which medication are they on, what is the risk level of bleeding during that procedure, and I agree with you completely that if we got some data that for certain procedures, colonoscopies, tooth extractions, how much that would minimize the burden in our inboxes, and also the sense of comfort for those providers, the dentists and you know that kind of thing to know that it would make it more straightforward but you I think the role of the pharmacist in that of delineating it all out and helping to characterize it for each medication and as we get more data for each of these new drugs is going to be very critical. You know Jean I want to come to you next. Mark showed sort of the three different drugs that are in our phase three trials and one of them is abalasumab and it's interesting they've got two studies looking at that cancer-associated VTE. Why is that a particularly interesting population to be looking at for a factor 11 or 11a inhibitor? Well it's it's high risk for both recurrent thrombosis and bleeding right so we're talking venous thrombosis that there about seven times greater venous thrombotic events than arterial but but we know that in the patient the cancer patient population their risk of recurrence is so high their risk of bleeding is so high and that's where it could be a big win for patients if we really can dissociate necessary hemostasis from pathologic thrombosis. I mean that would be huge. You know the other place that I think as cardiovascular specialists we think about anticoagulation a lot obviously is atrial fibrillation. You know we've done that with warfarin, we do that with the doax, now we're testing it with these factor 11 inhibitors and Mark maybe I'll ask you to comment a little bit on this. It's interesting that all three of the drugs and in the phase 3 trials have have looked at some different types of AFib populations. Where do you think a factor 11 may have a role in stroke prevention for an AFib patient? Is this something that is going to be kind of the first line we use for everyone? Is this going to be niche? Do we not know? Where are you thinking the tea leaves are starting to kind of lay out here? It's a great question. It's a big population. I mean I guess the first comment is that a lot of patients AFib aren't anticoagulated. That's a big problem. There's probably multiple reasons for that. You know safety is one, maybe more importantly tolerability. I mean the kinds of bleeds that I think you know Bob you mentioned the bleeding we used to tolerate in trials. You know certainly bruising never really raised the sort of you know main slide deck in the LBCT. But I think for a lot of people that they find that troubling. I had a patient in clinic who admitted to me that they you know they get bruising they don't like it then they take their apixaban once a day for a week and it goes away and they go back. I mean you know it's this is what's really happening out there. So you know when it comes to AFib it's going to be complicated. We've got great drugs and apixaban is a great drug. You know these are going to go generic. They're going to be accessible and they've they're highly efficacious. That being said I think there's going to be a lot of movement towards a safer alternative. Not only if the let's say there's not the same reduction intracranial hemorrhage we saw with the DOACs versus warfarin but if they're just better tolerated you don't have to interrupt for procedures. I mean I just think that this is a very patient centered conversation and you know that may cause some friction with payers and in others and it may require some way to navigate. I mean in the way that we've had to for lipid lowering you know do they tolerate a stat and other things. It's probably gonna be a lot of work to figure out how to navigate this and and you know I wonder if we're going back to the Coumadin Clinic for a pharmacist to help us sort of navigate the pathway of how we get there. But I I think there are great drugs the 10As are great drugs but if these are better tolerated I think patients are going to embrace them. Well and and that really makes me think about this question of what is it we're trying to improve and when I put myself in that patient perspective yes they're aware or they might be aware that there's an intracranial hemorrhage risk but that's such a rare event. Kristen I mean I'm sure you hear about this all the time it's the bruising it's the little bleeding it's those things that are a real nuisance and they're a concern and there's this movement I think to talking about patient relevant bleeding right it's not minor bleeding it's not nuisance but no this is patient relevant stuff that often leads to them stopping their anticoagulant. Is that going to be important for us to really understand how these factor 11s differ from the factor 10 inhibitors? Absolutely I mean it is it is not uncommon I find if you really question a patient the right way that they have come up with a creative way of dosing their DOAC or you know to get around that that bruising it's the bruising they it just really bothers them you know that if I they say if I look at something wrong I bruise you know and if if we can find a niche there that's gonna be huge. Bob I want to ask you a question when I think about oral anticoagulants my brain immediately goes to venous found blemblism and atrial fibrillation and that's sort of where I tend to anchor a lot but I find it really interesting that these factor 11 drugs are also being tested in a couple other populations and I'm wondering if you could talk to us a little bit about the rationale for why it may be a good fit I'm thinking about the acute coronary syndrome patient and that secondary stroke sort of the person who had that stroke it's not a fib related how do we prevent the next one why might a factor 11 be a particularly good approach for those populations? Yeah maybe I'll walk through the sort of the three scenarios because I think that's something both Kristen and Mark said is really important to understand the framework. Apixaban is a great drug particularly in atrial fibrillation I mean if you look at it relative to warfarin and don't forget how good warfarin is relative to placebo I mean we're talking a 67% stroke reduction in the combined trial so to beat that was really tough so Apixaban is a great drug if you're going to be the replacement if you will for Apixaban you need to demonstrate that you're at least as good as Apixaban but that you offer something else and yet what you have to offer something you have to have less bleeding and that's the way that's the only way that it's going to be considered to be better and and we'll see I mean we've I was telling Jeff before we started we've already crossed the 20,000 patient mark and and the AF trial will finish enrollment soon so we'll know the answer with a large population of patients. In secondary prevention of stroke I mean I know it's mostly cardiologists here but if you think about it from the neurology community perspective this is a huge clinical problem and there has been very very little progress made in the secondary prevention of stroke particularly early strokes but also later strokes and the addition of you know dual antiplatelet therapy is added a little bit but not a lot other anticoagulants have not really shown to be be able to offer a reduction in stroke with a tolerable bleeding risk and in that case it isn't a cranial hemorrhage and secondary into expansion of strokes etc so in the stroke trial we're really going against placebo and the dose is a lot less as Mark pointed out it's a hundred BID of milvexian in the AF trial because it has to work. In the stroke trial it's against placebo it's 25 milligrams BID against placebo and then in ACS again I like to take the long view here the historical perspective if you go back to the Warfarin days Warfarin had an effect in post myoclone infarction if you go back to the Warris trials but it was so messy to use I mean you know I hadn't heard the phrase Coumadin clinic in a long time but it was like it was this cottage industry to manage this one drug and that's why that you know people switched to antiplatelet therapy just because it was easier. I think that this is an opportunity to say we've certainly gotten what we've gotten out of dual antiplatelet therapy and now can you add a little bit of anticoagulation it's also 25 milligram BID make it tolerable and add it on to either single antiplatelet therapy or dual antiplatelet therapy. Well and it's so interesting because in both of those populations you're adding an anticoagulant to antiplatelet therapy I think something a lot of us have been trying to go away from you know we've been saying if you're on an anticoagulant for something like AFib can we stop the antiplatelet it's interesting here you're saying no the antiplatelet is still there because we have clear reasons in an ACS population in a secondary stroke population to use antiplatelet therapy can we get more by adding this unique anticoagulant that doesn't increase bleeding because of this ability to separate out thrombosis and hemostasis. And that's the key thing right it has it can't add bleeding it it has it has to be safe. And so Mark you showed that one slide that looked at the risk of bleeding for folks using one of the factor 11 inhibitors with and without antiplatelets and I actually found that to be really striking data because anywhere else you look at an anticoagulant as soon as you add an antiplatelet agent to it boy that bleeding risk really goes up and so does this give you a lot of hope that this may be something that can be really safe and hopefully efficacious for these populations that need antiplatelet therapy? Yeah I think it does I mean both the Abl-Asimab data and their AFib population with with and without antiplatelet therapy is very reassuring but also Pacific AMI the phase two with asyndexia I mean that was all on DAPT and the bleeding risk really looked quite you know it didn't seem to be increased at all and so I think these both give us support that perhaps we can change that paradigm of either or and we can tolerate some antiplatelet therapy in the background and maybe maybe that is you know we don't know what is the right cocktail of agents I mean maybe you should do a little bit of factor 10a and a little bit of factor 11 a little anti but I mean we don't know right that's gonna have to be investigated in future trials but I think for the arterial disease as Bob said that you don't want to get rid of the antiplatelets completely and so I think the combination is a nice nice option opportunity. Well you know as we come to the end of our session here I think there are several points that I'm really reflecting on and the first is that there's been this amazing evolution in our approach to anticoagulant therapy I mean we had the vitamin K antagonists right and that had a lot of challenges we were able to get a lot of advances when we went to the direct oral anticoagulants and now this question is can we decouple thrombosis and hemostasis can we prevent that bad clot while still allowing that hemostatic plug to occur so we don't get the bleeding we don't get the bruising and when we look at some of that phase 2 data there's a lot of promising data behind it to tell us yeah we may be able to achieve that the question now is in these large well-powered well-designed phase 3 studies what's going to be the right drug what's the right dose what's the right population can we see efficacy and if we can achieve that I think there's going to be a lot of opportunity for us to really advance the care for our patients to figure out who needs these therapies that offer protection with maybe some less bleeding risk and how's that going to fit into our armamentarium and I'm pretty sure that once we get to that point I'm going to be calling my pharmacist even more than I was before to help me figure it all out because it's it's going to be challenging but it's exciting that we have this sort of coming down the pike any other thoughts that folks want to share as we sort of wrap things up here yeah we should find out who won I think that's a perfect so why don't we go ahead and pull up on the screen do we know which of our our teams won the big battle who's gonna take home this wonderful this wonderful the Evander Holyfield group hey congratulations if you're in the Evander Holyfield table raise your hand where's our Holyfield group there we go I see some in the back over there perfect well congratulations thank you guys again for coming and being with us tonight I want to thank all of the panelists the presentations were just so informative this was great discussion we had a lot of fun you'll all be receiving an email be sure you fill that out to get your credit thanks again for joining and have a wonderful rest of your ACC meeting

phase two trials

anticoagulants

knee arthroplasty

factor XI inhibitors

direct oral anticoagulants

patient-centered outcomes