So, to kick us off, we're going to have three different rounds of this, and I want to invite Dr. Kristen Campbell to the podium. She's going to start us off, really helping us think through, you know, what's new in the ring, what are we doing, where did we come from, talking a little bit about anticoagulation in general. So, Kristen, I'll turn it over to you. Thank you. Hit that start. Sorry. Okay, it's getting done. Okay. Okay. All right. So, disclosures. So, I am going to start things off with a quick discussion of the available anticoagulants, a review for all of us, and then an introduction to the Factor XI inhibitors. And I don't want to steal Dr. Conner's thunder, so I'm just going to briefly orient you to the coagulation cascade. So we have the contact or intrinsic pathway, which is activated when blood is exposed to an inflamed or damaged tissue surface. And then we also have the tissue factor or extrinsic pathway, which is activated in response to trauma to stop bleeding. These merge into the common pathway where thrombin is activated. We have platelet aggregation, all of those things. And looking at our current agents, we have a lot of different mechanisms. We have the thrombin inhibitors, the Factor X inhibitors, we have warfarin. Most of the agents that are available now work on those active forms of thrombin or Factor X or a combination of those and are all part of the common pathway. So they play a critical role in both the formation of pathologic thrombi and also the body's ability to form a clot in response to bleeding at the same time. Our holy grail in balancing the prevention of formation of a pathologic thrombus or bad clot with those hemostatic efforts remaining uninhibited, which is good clot, that's what we're looking for. And the target for that seems to appear to be potentially the contact pathway. So this is just a quick summary of the agents that are available, the anticoagulants. So we have warfarin, obviously vitamin K antagonist, inhibits liver's production of clotting factors 2, 7, 9, and 10, works on all three pathways. Thrombin inhibitors, mainly dabigatran and argatraban are byvalerudin. They use both direct and indirect methods to prevent thrombin from catalyzing the conversion of fibrinogen to fibrin. Heparin has activity inhibiting Factor Xa along with other anticoagulant factors. And then our Factor Xa inhibitors, rivaroxaban, apixaban, doxaban, fondoparanox, bind to circulating Factor Xa to prevent it from catalyzing in the conversion from prothrombin to thrombin in, again, the common pathway. And fondoparanox also binds to antithrombin 3 with high infinity and increases antithrombin's ability to neutralize Factor Xa. So we have these agents, they're oral, IV, fondoparanox being sub-Q. They have relatively quick onset, warfarin being the slowest of them. Half-life, that necessitates at least daily dosing, sometimes more frequent than that. These medications can have a decent amount of renal elimination, limiting our populations that we may be able to use these medications in. And then we also have drug interactions to consider and, you know, I highlighted a few of those there for you. So again, this idea of Factor XI being a potential target, it is, Factor XIa is essential for thrombus growth, but it only plays a minor role in stabilizing hemostasis. So modification of that could prevent that pathologic thrombi from forming, but still allow that tissue factor pathway to remain functional and minimize bleeding risks that we always have had a concern with, with the current anticoagulants available. And in fact, we've seen that patients with genetic Factor XIa deficiency have substantially lower rates of venous thromboembolism, stroke, and possibly MI than the general population, making this a, you know, ideal target potentially to look at. So just as an introduction of these agents that are being studied, we had an introduction to them in the pre-test questions. We have three classes. The first class is the antisense oligonucleotides. They promote the degradation of Factor XI messenger RNA in the liver, and thus they reduce Factor XI production. These agents most closely resemble that inherited Factor XI deficiency. They do have a relatively quick onset of action, but they have a persistent effect with a long half-life, which makes it appealing in terms of frequency of dosing necessitated. However, you know, they also have limited to no renal elimination and really no drug interactions. The next class are the monoclonal antibodies, and they bind to the catalytic domain of Factor XI or Factor XIa. And so some prevent Factor XIa from performing its catalytic activity on Factor XI, and then others prevent the activation to Factor XIa. So those agents are mainly parenteral. They're subcure IV. They also have a relatively quick onset of action and relatively long duration of action. So they persist in the body for quite some time. Again, really appealing is lack of renal elimination and lack of drug interactions. And then the last class are the small molecules, and these bind and inhibit to the catalytic site of Factor XIa. Both of these agents that are in study are oral, which is certainly appealing. They have a rapid time to onset and a relatively short half-life. So these agents most closely resemble the DOACs from our clinical application, and that can be appealing. There are some drug interactions with Melvexian to consider, but that's really the first time that that has come up with any of these three classes. And again, limited renal elimination. So to get things started for us tonight, I just wanted to introduce these agents. And we'll go through lots of study data and practical advice for them. But their impact on the contact pathway makes them unique from our other available agents. And they offer unique kinetic and pharmacodynamic properties in that long duration of action. Minimal renal elimination, minimal drug interactions. And one of the things that is quite exciting is looking at them in clinical roles that we talked about in the pretest questions, as well as thromboprophylaxis of foreign material implantation, and specifically in populations that we really don't have many options in, like LVAD patients where we really only have data using warfarin in those patients. And these are very appealing for those special populations. So that will get us started. And then we go to our first question. Which of the following investigational agents inhibits both the Zymogen Factor 11 and the Coagulative Coagulation Protease Factor 11A, Ablysumab, Ascindexan, Fesumersan, Milvexan, or Osisumab? »» So everyone go ahead and use your phones to enter in your answers. So which of these inhibits both Factor 11 and Factor 11A? Go ahead and choose your answer there. I know we got more than 26 people in the room. So let's get all those answers in. Earn those points for your team. »» There we go. »» There. Okay. Great. Okay. So we got the answer? »» Yep. »» Let's see how many points we got for each of the teams. Okay. Muhammad Ali got a lot of points there. I'm worried none of the other teams earned any points. So we're going to figure out the scoring system in the back while we move on to this. I know I saw some people entering other answers. So I'm sure we've got some other points going on. Do you want to give us the correct answer? »» Yes. So the correct answer is Ablysumab. That's the monoclonal antibody that inhibits Factor 11 and the Factor 11A. All the other agents either work on just Factor 11A or Factor 11. »» Awesome. You know, I want to have a little discussion about this gene. Maybe I'll start with you as our hematologist. This idea of inhibiting Factor 11 versus 11A, do we think it matters? Why might this be important? Or what's different about having the activated versus the non-activated form of a clotting factor? Could you give us maybe a little bit of insight into that? »» Sure. Well, thanks, Jeff. So this needs to be proved, right? We need to determine which of these molecules is going to be best at inhibiting coagulation of rhombus formation. And they all have different mechanisms of action. Factor 11A clearly is what drives the next activation, right? Factor 10A, sorry, Factor 9, you know, 11, 9, right? And if you shut off 11A, you're not going to make that next step in the clotting cascade. However, we know from some situations where we look at, say, the 10A inhibitors only, that there may be so much overwhelming activation of 10A that we may not be able to shut off enough 10A, right, alone. And so by knocking out 11, you even prevent the ability to generate 11A. And that may be a better mechanism. The devil is in the details. And we're all anxiously awaiting and hopefully awaiting the results of the clinical trial. »» So it sounds like it's a little bit to be learned. There's more for us. »» Very to be learned, right? I mean, you know, and there's also the different drug advantages, right? Like if you use an antisense, you know, and knock out 11 production, that's great, right? You have no 11 there. You're not going to generate 11A. But onset of action, you know, other, you know, variables in taking the drug may make it more difficult than a small oral molecule inhibitor. »» Mark, I'm wondering if I could ask you a question. One of the things I noticed on Kristen's table that she highlighted is essentially there's no renal clearance from any of these factor XI drugs. And I'm wondering, you know, as a clinician, is that important? Does that give you any advantage as you think about how these drugs might be used for anticoagulants? How important is that renal clearance? »» Yeah, I think that it's actually very important in the clinic, you know, the comorbidities or the indications that are being explored. We'll talk about this acute coronary syndrome, atrial fibrillation and others. The alias for older populations, we see a lot of renal dysfunction. And, you know, we always have to think about the safety of dosing when we have impaired renal function, impaired renal clearance. That's particularly the case when we worry about safety for anticoagulants. And, you know, there's good data now for the DOACs, but we, I think, routinely see underdosing of DOACs where people are concerned about clearance, concerned about the bleeding risk associated with renal dysfunction. And so I think this is a huge advantage of these compounds. »» Bob, I'll turn to you maybe for the last question. The other thing that really stuck out to me on one of Kristen's slides was the variation we have in these sort of properties of the drugs, meaning some of them are very rapid onset, others take a while. Some of them, you know, we're going to need to dose them once or twice a day, whereas others are going to be once a week or once a month. Does that level of variation give you concern or does it maybe offer some opportunities to test these in different patient populations? How are you looking at sort of that heterogeneity across these different drugs? »» I think your latter comment really nails it in that the drugs work differently. As Gene has already indicated, we're going to find out in the clinical trials is it factor XI, is it factor XIA. But for me, the exciting part piece is we may have the opportunity to use different drugs at different times in a patient's disease course. So you might imagine in the acute care setting that you're looking for more rapid onset, more rapid treatment, such stuff that you can take off pretty quickly. In the more chronic setting, you might say, huh, something I can give infrequently might be best. »» Especially if you have a patient in whom you're concerned about adherence, maybe taking something once a week or once a month would make that a little easier. »» So we're going to have to do all the trials. But I think at the end of the day, giving clinicians choice and patients choice will be the best way to go. »» I love that.

Factor XI inhibitors

anticoagulation

antisense oligonucleotides

monoclonal antibodies

thrombus growth