Okay, I think we're ready now for round three. So Mark, I'm going to have you come on up here and let's jump into some of the clinical data, that phase two and phase three data. What is it telling us about these factor 11 inhibitors? I'll turn it over to you. Well, thank you. It's great to be part of this important session. And yeah, I want to begin with the unmet need, which is thrombosis remains core to most of the events or many of the events that we find most troubling in our patients. The acute coronary syndrome, acute limb ischemia, stroke, and so on. And I do believe that we have an unmet need, despite what we may do with weight loss drugs or cholesterol lowering, thrombosis is still core to the path of biology of what we need to prevent. And that's why I think this topic is so exciting. As you've heard, you know, there are a number of observations that really give us a lot of hope here. There are knockout mice from factor 11 and in vivo animal models that show that we can reduce thrombotic risk with protecting from bleeding. We have inherited factor 11 deficiency, as you've heard about, and we know that in patients who have elevated factor 11 levels, they have higher risk of some thrombotic events of VTE. And so the title of my talk was, is this going to be a knockout or a split decision? And so all of what I'm showing you on this slide gives us a lot of excitement and exuberance, but it may not be that every agent works in every setting, that we have to learn from our clinical trials of where these agents really work. And this is a spectrum of things, and I didn't have room for the brain for the secondary stroke prevention, but a lot of areas where people said, wow, contact pathway, thrombosis is a risk, let's examine these. And there are studies that have been done in end-stage renal disease. There are trials ongoing in atrial fibrillation, acute coronary syndrome, venous thromboembolism, and I think we'll eventually get to mechanical heart valves, although that's a high-risk situation where we learned some tough lessons with the DOACs. So will this be unanimous or a split decision? And I guess the question is, what are we going to split by? Is it mechanism and dose? I think for the DOACs, we thought all are pretty good. We've gotten pretty comfortable with what we have, although there are DNAs and DTIs in different doses. But really, in the market, I think there are some small differences in safety that have driven a lot of adoption of certain agents versus others, and that may happen here. And as we talked about, I think for Factor XI, it may depend heavily on what we're actually doing with Factor XI. Are we preventing its generation? Are we chasing activated Factor XI? I also think it may be split by indication. We see data that the lifetime risk or protective risk in Factor XI deficiency is pretty compelling for VT and stroke, maybe not as clear for myocardial infarction. And there could be other implications in terms of thrombosis and different disease states like acute coronary syndrome where you have background antiplatelet therapy. So it's been a busy and evolving landscape. This is one slide, and I'm going to show you updates to it. But I think the flavor of the clinical data are that we have small molecules, and there are two that are out there in trials. There's Milvexian, and they had their phase two trials. I'll show you some data in phase three called Librexia, and Dr. Harrington is leading that program. There's Ascindexion, which had phase two programs called Pacific. I'll review some data. Phase three in Oceanic, and then Ablacemab. There are other agents out there, and I'll touch on those as well. This is a coagulation cascade I could understand because it's only got like four or five boxes on it. But to me, the factor XI story is really like, what are we actually doing? And we've gotten to this, but I think we need to understand when we look at individual agents, are we inhibiting generation? That may take time, but it may mimic factor XI deficiency. Are we inhibiting factor XI activation by factor XIIa or by thrombin? Are we chasing activated factor XI? And all of these agents and their mechanisms differ, and it may be that they don't all work for the same disease states. And so the question that the clinical trials need to answer is, what's the right dose of the specific drug? That's really phase two. And what is the right patient and right background therapy? And then we need phase three to provide definitive proof. Now, dose finding is hard. We don't have great surrogates for thrombosis, at least for this. We don't know what it means to block factor XI measuring a specific assay and what that translates to for outcome. So probably the best way to understand what to do in dosing is actually to see if the drug at the doses applied prevents clots. That's total knee studies where people get total knee replacement. You look with venograms at whether they develop clot. And there have been at least four trials that have shown that if you give factor XI inhibitors in the upper left in oligonucleotide, two antibodies here, and then Melvexine, a small molecule, all have shown that at certain doses, they are at least as good or better than low molecular weight heparin at preventing clot. I think that's a pretty good reassurance that you're doing something with your dose. Here's an example of one of those trials. This is the ablacemab antibody. And this is a total knee study. You can see on the left, bleeding looks pretty good across the doses. Not a lot of bleeding for major or clinically relevant non-major bleeding. And then you can see the composite outcome of thrombotic disease. And a lot of these are asymptomatic, but this is proof of concept. And at the higher doses, you see significantly lower rates of DVT relative to inoxaparin, which is a pretty good anticoagulant. I think that gives us a lot of hope, and it does help establish dosing for proof of concept. One caveat is just because I showed you those four studies, that doesn't apply to every agent or mechanism in every dose. We know factor XI for these agents work, but I'd be cautious as you look at other agents for extrapolating, because I still think we're in the early days of understanding how the biomarkers we measure relate to true outcomes. Now to show you some of the more clinical data, I showed you ablacemab for the total knee study. This was carried forward in a large phase two program. This is a program that compared ablacemab at two doses to rivaroxaban, a very good anticoagulant. And this is in AFib patients. You can see they measured free factor XI, percent reduction free factor XI, and by that measure these were both very potent doses. And you can see that there were significantly lower rates of bleeding. And Christian Ruff published these data in the New England Journal, I think really landmark trial results. So the hypothesis that you can reduce bleeding has been shown. There aren't enough strokes here to know whether there's actually efficacy. We know from the total knee data we're supportive, but we don't know relative to rivaroxaban really what the benefit might be in terms of efficacy. That's phase three. We did learn a couple things. One is background antiplatelet use. And here you can see that relative to rivaroxaban, the bleeding liability of ablacemab or factor XI inhibition on top of antiplatelet therapy actually looks quite reassuring. We do see an increase in the riva bleeding dose. We know that from other trials at DOACs when added to dual antiplatelet therapy increased bleeding risk significantly, and we don't see that here. So maybe this is not only safer, but safe to use with dual antiplatelet therapy or other antiplatelet regimens. We also have some idea about procedures. You can see on this slide that there were a lot of procedures done during the trial. Most of these were low procedural bleeding risks, some were higher, and most of these were elective. And when you look at when they were done, at least half or more were done within the sort of half-life of the drug, meaning they were done on drug. And what do we know about the procedural bleeding safety? We can see overall, even though these drugs with antibodies have very long half-life, that the bleeding liability looks quite modest. And I think this is also reassuring for telling us maybe these are drugs we don't have to interrupt all the time when people are having procedures, because there's not only risk of bleeding, but thrombotic risk around these interruptions. So that's data for the antibody ibulosimab. If I turn to the small molecules, Ascindexion had a large phase II program. Rather than a total knee study, these were explored in the diseased populations, AF stroke and acute myocardial infarction. And I'll show you some of the key data. This is factor XI A activity. And what you're seeing on this slide is the ratio to baseline. This is an assay measuring that. Now what this biomarker means in terms of thrombosis hasn't been well validated. But at least by this measure, the doses studied, 20 and 50, appeared to be pretty potent in terms of reducing this measure. Certainly in the AFib trial, there were not enough thrombotic events to really know what was happening here. In fact, for ischemic stroke or systemic embolism, there were a total of three events amongst the doses. So not big enough or long enough to really know if there was efficacy. But we do know that there was less bleeding. And so here you can see amongst the various bleeding measures that Ascindexion appeared to be safer than Apixaban. So this was in atrial fibrillation in acute coronary syndrome. The bleeding liability on DAPT looked pretty reassuring. Not much signal for efficacy, although underpowered for that. Certainly did not appear to support a big benefit here for AMI in that phase three program actually did not move forward. And then the last phase two that was shown was secondary stroke prevention. This is a big trial. It's complicated, including lacunar strokes. And I'm kind of showing you the take-home message here was that in patients who had large artery strokes or had atherosclerosis, so the true artery embolism we think is atherothrombotic, there appeared to be a benefit here. And this has been carried forward into a phase three program. So the two phase three trials for Ascindexion were in secondary stroke and in AFib. And the reason we do trials is because we need to know what these drugs do in patients. And sometimes we get surprised unpleasantly. And this was the phase three oceanic trial. This was led by Jonathan Pacini and Manish Patel. A really well-conducted trial, but in a surprising result. Terminated early for a lack of efficacy, in fact harm. And you can see very early divergence in the curves. And so this is a cautionary tale, I think, for dosing. We don't see a lot of bleeding there, but we don't see bleeding with placebo either. And so this begged a lot of questions. Does this invalidate the Factor XI hypothesis? And I think there's various reasons for the result. Maybe Factor XI doesn't work. Well, that doesn't seem to be as plausible. We know the epi. We know that the total knee studies worked. We've got other studies ongoing that haven't been terminated. Maybe it's the mechanism, chasing Factor XI versus locking the Factor XI in an inactive state as the antibodies do. There's another small molecule out there that still has ongoing studies. Maybe it was the dose study. Maybe the proof of concept or the lack thereof in a total knee study just meant that the dose was too low and that the assay used wasn't well-validated. Maybe it was the population, taking people off an effective anticoagulant and moving them into a new trial is different than VK or anticoagulant naive. And maybe it was the comparator. You know, Pixaban's a pretty good drug, which was the comparator, and it's hard to beat. So I think there's a lot of question there, but I don't think this invalidates at all the Factor XI hypothesis. Probably supports that we need to know what we're doing with our dosing for the mechanisms that we have. In terms of Melvexian, Dr. Herring can tell us more. There was a nice stroke trial, which looked at bleeding here with the various doses, and I'll show you efficacy on the next slide, supported the doses chosen. I believe 100 milligrams BID for atrial fibrillation and for stroke. And these are the data for the stroke prevention, which look quite supportive. This is placebo-controlled. It's not an active comparator, but you can see at the 50 and 100 milligram dose, lower rates of stroke, which are supportive. So these have been the Phase II data. I'll talk a little bit more about the ongoing Phase III programs, but I just want to make a comment that we always get surprised. We've seen beautiful biology. And when the Factor XAs or the DOACs were studied, I don't think that anyone really understood how important a tissue factor was for intracranial hemorrhage. It wasn't until these enormous studies were done for this rare event that we saw a 50% reduction. So I think we are going to have probably surprises as these big trials are done, and hopefully in a positive way like we saw with the XAs. So what's out there for Phase III? Well you can see there's the Abl-Asimab trial. So there's Lilac that's against placebo in patients unsuitable for oral anticoagulation. And there are two, and I'm going to talk about this in a moment, VTE cancer studies ongoing, which are really, I think, interesting. For Asyndexion, there's the Oceanic Stroke Trial, which is ongoing. And then there are three really large, well-conducted trials with Malvexian, natrial fibrillation, secondary stroke prevention, and acute coronary syndrome. And I do want to say that these trials really give me a lot of hope. I don't think there's any place where we see more prothrombotic milieu than in cancer patients who've had a venous thromboembolism. And these are head-to-head trials with, you know, very potent agents, apiximen and daltapirin, and they're ongoing with DMCs, overseeing, and everything else. And so this really tells me that there likely is a potent anticoagulant effect if you're using the right agent at the right dose. So in summary, we've got strong observational genetic and animal data. This gives us hope. Phase two, proof of concept and total knee studies have proved that for those agents at those doses, there's proof of concept. The Asyndexion experience is a cautionary tale, that we need to know what we're doing with these agents in the right population at the right dose. I do think that the ablacemab data clearly show a bleeding advantage for Factor XI. That's quite clear. I think the ongoing trials in phase three for atrial fibrillation with Melvexian and cancer with ablacemab, they're ongoing against highly effective comparators, and that's reassuring that there's got to be some beneficial effect going on. And there are other agents out there that are coming. This is a busy field. I've just shown you the top line, but there are other antibodies that are looking at new indications, and it's going to be an exciting time. All right. So now we have an audience response. So we've got our final question. So everyone get those phones out and let's get ready. Let's see if you guys can earn those last points here for round three. Mark, I'll have you go ahead and maybe read the question for us. Okay. So in the completed phase two studies, which of the following is true regarding Factor XI or Factor XIa inhibitors for stroke prevention in atrial fibrillation? Is it that ablacemab demonstrated a reduction in stroke and systemic embolism compared to rivaroxaban? Is it, number two, ascindexion demonstrated a decreased risk of bleeding compared to apixaban? Is it that Melvexian demonstrated a decreased risk of bleeding as compared to dabigatrin? Or is it that isosumab demonstrated similar rates of stroke and systemic embolism as compared to adoxaban? Okay. Great. So think about this. This is the phase two in AFib. And Mark, I actually remember a slide you specifically put up that gave the correct answer to this. So everyone's got to think back to that slide that Mark showed a couple minutes ago. Which is true about phase two of a Factor XI or XIa inhibitor in stroke prevention in AFib? Let's go ahead and get all those answers in. Okay good. We got above 30. Great. So our answer here is ascindexion demonstrated a decreased risk of bleeding as compared to apixaban. I remember you showed a slide about that. You want to tell us about that real quick? So that's the Pacific AF trial. Around 800 patients. They were randomized to multiple doses of, or different doses of ascindexion or apixaban. There were a few ischemic events. But as you correctly note, there was clearly a reduction in bleeding relative to apixaban. Yeah. No, that's great. I'm told that we're going to hold off on giving the championship answer away until after we have our discussion. Because we want to make sure you guys get all of the education. So I'm going to hold that for a second. Mark, maybe I'll have you come over here.

Factor XI inhibitors

thrombosis management

clinical trials

stroke prevention

anticoagulation