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Thank you so much, Phil for that kind introduction. It's a pleasure to be here with everyone tonight. Um So these are my disclosures of importance to this presentation. Um And buyer is a sponsor of the Oceanic stroke trial that I lead. Important to note that factor 11 inhibitors are not approved for any indication at this time and trials to evaluating their utility are underway. But this is the landscape of antithrombotics for secondary stroke prevention. Currently, we have dual antiplatelet uh therapy for short term use after minor stroke and TI A and this has been in advance, but it leaves aspirin as a single agent for most stroke subtypes. For long term use, we have made major advances in major risk cardiac sources, principally atrial fibrillation with direct acting anticoagulants like the factor 10 inhibitors. And there is some evidence to support the use of aspirin and low dose rivaroxaban in patients with atherosclerosis. Now, aspirin for secondary pre uh prevention is effective but not very powerful. These are the odds ratios of risk reductions for acute stroke and long term in patients who had tia and stroke comparing to placebo. And as you can see, the risk reductions are uh a relatively modest when compared to what we're getting with anticoagulants for atrial fibrillation. For instance, where that risk reduction is about 70%. We did try using dual anti plates platelets for the long term in patients uh after a stroke and, and other conditions in the match trial. And unfortunately, this was unsuccessful. As you see in the left hand panel, really no significant benefit for using aspirin and clopidogrel uh uh compared to clopidogrel alone. And on the right hand side, there is a risk for intracranial hemorrhage being increased with long term use of these agents. Now, our approach to reducing secondary stroke really has been focused on the stroke, cell type. We have different approaches to large artery atherosclerotic disease, especially intracranial disease where we use endarterectomy or stenting cardioembolic strokes where anticoagulants have proven effective lacunar strokes and and other types of strokes have been somewhat harder, including the cryptogenic group in this group. Uh There's a realization that the majority of cryptogenic strokes are embolic in nature. Although the em uh source of the embolism may not be known, there was a trial looking at dual antiplatelet therapy in uh lacunar stroke. This was the SPS three trial. And in this trial, patients who had MRI proven lacunar stroke, about 3000 of them were randomized, either an antiplatelet therapy, dual or aspirin. And then in a two by two factorial fashion to do 222 different levels of BP. The usual level with targets between 1 31 49 or an intensive level was a BP target below 130. Now, looking at the antithrombotic uh comparison, there really wasn't a difference in stroke between aspirin by itself and aspirin with clopidogrel. Those rates were just over 2.5% per year. There was however, a difference in mortality uh with more mortality in the dual antiplatelet therapy group and more intracranial hemorrhage as well. On the right hand side or the rates of intracranial hemorrhage, um or actually the absolute numbers of intracranial hemorrhage in the combination therapy arm and on the left hand side in those burs with aspirin by itself. And you'll really see that for CN hemorrhage for intracranial hemorrhage. Uh there is an increased risk when uh uh when dac platelet therapy is used in patients who have a tumor stroke for the cryptogenic group. And in particular, the subgroup that's embolic the ESIs group, embolic stroke of uncertain sort. Uh We did uh attempt to compare Rapam with aspirin uh for this group of patients in the navigate trial here, patients who had recent ischemic stroke which appeared to be embolic, that is to say nonlacunar and who didn't have other recognized sources were randomized, either the Raban 15 mg a day or aspirin 100 mg per day. And unfortunately, here we did not see a benefit, the rates of recurrent stroke with oxen and aspirin were virtually the same. Uh those two curves are superimposed and the trial was stopped early due a lack of efficacy. We did see a difference in the risk of hemorrhage with a higher risk of hemorrhage from ri and than aspirin. Now, in this particular trial, for reasons that are not clear the risk of hemorrhage and aspirin was really extremely low. Uh Hence this difference in the two arms. Now, you know, as we step back and think about it, we've differentiated our use of antithrombotics based on what we perceive to be co to be the composition of the thrombus. On the one side. On the left hand side, you have thrombi that are made mainly off platelets and so called white thrombi, which occur in arterial disease, mainly in the coronary arteries. On the right side, there are venous thrombi which have more fibrin and red cells, the so-called red clots. And for these, we use anticoagulants and for the former antiplatelet agents. Well, the honest truth is that every thrombus that you and I treat is composed of both platelets and fibrin uh in different come in different proportions. And we don't always know particularly in stroke, the composition of the thrombus and subsequent embolus. And the story gets a little more complicated when you appreciate that uh activated platelets can turn on the production of thrombin and vice versa. Thrombin also activates platelets. So these two systems, the platelet system and the fiber and thrombin system are not independent. Uh they actually interact with each other and result in that and thrombus. So there have been uh a number of trials uh looking at combining antiplatelet agents with anticoagulants in the proper proportion to reduce thrombosis. And indeed, MRI, one of the more interesting of these for us was the compass trial. In this trial, we randomized 27,395 patients who had coronary artery or peripheral artery disease. And I must say for this trial, peripheral arteries included the carotid vessels. So a number of these patients had carotid disease. Primary outcome was stroke, MRI or cardiovascular death. And patients were randomized into one of three groups, aspirin by itself, Rivaroxaban by itself or the combination of low dose rivaroxaban, 2.5 mg B ID and aspirin combined. Now, that dose of rivaroxaban came from dose finding studies in uh the coronary disease population. So this was a combination which was found to be effective in coronary artery disease and uh with acceptable rates of hemorrhage, this was a result of the compass trial for ischemic stroke and we included uncertain stroke with that. Although there were a small number of those Rx plus aspirin had a hazard ratio, 0.51 cutting. The risk of recurrent stroke almost in half. If you look to the curves at the right to the blue curve is a combination of oximin and aspirin. While the red curve is aspirin alone. Those curves start to separate early and that separation continues throughout the study period. If you looked at patients who had a previous history of stroke in uh compass, there was an even more striking effect. So on the right hand side, in about two years, patients with a previous history of stroke had a stroke rate of 6% on aspirin by itself. And this was reduced by 58% down to 2.6% with a combination of low dose rim and and aspirin. So the lesson we learned from compass was if you had the correct dose of an anticoagulant combined with aspirin, it could achieve a much greater effect than with either a alone. And we set out really to find a way of using this paradigm of the dual pathway approach for stroke. One of the issues with most of the anticoagulants we use is a high risk for hemorrhage and in particular for Raban. In that trial, we had not used it within one month of stroke. So we're looking for safer agents and one of the thoughts was to look at factory 11 inhibitors. Now, this slide shows a coagulation cascade on the right hand side, under the extrinsic pathway, we have what's required for hemostasis. So this begins with vessel injury which exposes tissue factor activates factor seven and factor 10. Prothrombin is converted to thrombin and fibrin uh generated the anticoagulants. We currently use affect this extrinsic pathway. So, warfarin on the right hand side blocks a 7910 and two. the factor 10 inhibitors of course inhibit activated factor 10 and the betatron inhibits thrombin. It's not surprising then that current anticoagulants result in an increased risk of hemorrhage. On the left hand side is the intrinsic pathway and one of the major triggers for activation of factor 11 is the presence of thrombin. So once a thrombus is generated and thrombus exists, it feeds back turns on factor 11 to the activated form. And then there's an amplification loop which which feeds on itself through factor 11. There are two small molecule factor 11 inhibitors currently under uh uh uh under trial conditions for stroke prevention, asy vexin and malvasia. Now, that's all very nice in terms of the theoretical structure of the coagulation cascade. But what evidence do we have that? It actually works that way reduces a pathologic thrombi without increasing hemorrhage. Well, there's preclinical evidence. So when you uh inhibit factor 11 in vitro, it stops that amplification of thrombin by the cascade. Exactly as we predict in mice who don't have the factor 11 gene thrombosis in a number of models is reduced. And interestingly, there's no decrease in in uh their ability to stop bleeding. So the tail bleeding time was unaffected in factor of 11 null mice. Compared to wild type mice, the Throid that they produce are smaller, have less fibrin and platelet deposition as you might expect based on the on the theoretical foundation. Now, there is a human model of this as well, which is factor 11 deficiency. Now, that deficiency in most people in the world has an incidence of about one in 11. But it's concentrated in Middle Eastern populations, uh affects both men and women and their number of mutations described which can result in different levels of factory 11. Now, interestingly, people who have this, unlike other types of hemophilia have a very mild bleeding, phenotype, spontaneous bleeding generally doesn't occur and really bleeding is seen sometimes when there is surgery or trauma in particular tissues with high fibrinolytic activity such as the nasopharynx and the G tract. This was first described in the fifties in New York City in a family that had excess bleeding from the nose and after tonsil extraction. Now, what's the impact of Factor 11 deficiency on cardiovascular events? This is a cohort study that comes to us from Israel where factor 11 levels were categorized as normal if they're more than 50% mild between 30 50% and more severe deficiency, less than 30%. What you see is once you get below 50% you have a significant reduction in recurrence of cardiovascular events by over 40%. But there is also the converts. So people who have genetically higher than normal levels of factor 11 do show an increased risk of ischemic stroke. This is true for large artery atherosclerosis, cardioembolism and strokes which fall in that cryptogenic uh um uh category as well. Not so much for those with small vessel occlusion. On the left hand. Now, what you see is for those who have uh genetically lower factor 11 levels, decreased risk of ischemic stroke, as well as venous thromboembolism and more of an equivocal effect on MRI. So just to summarize with factor 11 deficiency, you have a low risk of bleeding, generally clinically well tolerated. Often these people go through life not knowing they have it and bleeding which is spontaneous is really quite rare. It's associated with a low risk for ischemic stroke and venous thrombosis. Whereas elevated factor 11 levels increase the risk of stroke and venous thrombosis. This led to the design of a few phase two trials. I'm gonna talk about one here and uh uh Doctor Savior will cover the other one which is of great relevance to us. And in a subsequent talk, the first trial is the oxy SSP trial. And this was a dose finding trial for the oral factor 11, a dermal vexin. We took patients who had an acute stroke or transient ischemic attack and randomized them within 48 hours of symptom onset to one of five doses of MVA or placebo. All patients were treated with dual antiplatelets for the 1st 21 days and then subsequently monotherapy up to day 90. Now, the primary outcome in this trial was a combination of symptomatic stroke and MRI defined infarcts. So we did a baseline infarcts on all patients and then a 90 day MRI and used a comparison of the two to deter determine if there had been an incident infarct. And given what we knew to date, we excluded lacunar stroke and everyone in this trial had to have visible atherosclerosis on their imaging. These were the primary uh results. We did not find a difference for the primary endpoint. However, the primary endpoint actually hit what was actu what was happening. There was no effect on covert infarcts on MRI. However, for all doses of milvexian tested, apart from 200 mg, there was a reduction in the risk of symptomatic stroke compared to placebo. And if you look at the doses tested, there does seem to be somewhat of a dose response curve. The highest dose 200 mg B ID is a bit of an anomalous finding inconsistent with other data and likely spurious um bleeding wasn't significantly increased in this trial with the limitations of a phase two trial where your numbers are relatively small, there was a numeric increase. Once you got past the dose of 50 mg B ID, there was as well another trial involving milvexian and total total knee replacement. In this trial. Patients who are undergoing joint replacement surgery were randomized either to enoxaparin or milvexian at B ID or once daily dosing on the left hand side, you see the rates of VT E in the blue bar and major bleeding, uh and clinically relevant nonmajor bleeding in the red part with enoxaparin. And you compare those with Malvo. So doses of 50 mg twice a day or higher, you saw a significant reduction in the risk of VT E without really an increase in bleeding compared to enoxaparin. So, more efficacy without higher bleeding, which is what the theoretical construct would suggest based on what we understand of the role of factor 11 in the coagulation cascade. Now, um Asy dein, which is the other small molecule has been tested as well in three phase two trials, which give us a lot of evidence to go forward to phase three. These were in atrial fibrillation, acute M I and then the Pacific stroke trial and noncardioembolic ischemic stroke. In the AF trial, we randomized patients who had Af either Apixaban or two doses of AEX in 2050 mg. Now, it was a short term study. So this was not designed to show a difference in stroke or rather safety and pharmacodynamics. What we found in the studies was a dose of 50 mg. Once a day, there was a reduction in factor 11 activity more than 90% at peak and trough levels. Compared to Apixaban. There was significantly lower risk of hemorrhage on the right hand side uh um with both doses of Asy deum. So the green burs on the right panel depict the bleeding risk with Apixaban and the other burs the two doses of mild uh or rather a vexin as well as the combined effect. And you see, you know, for all bleeding, 10.4% with Apixaban versus 4.8% for combi uh for the combination of the two doses of ayin. Um There was a similar study in a myocardial infarction in here because patients were on dual antiplatelet therapy. There was an even higher bar in terms of safety. Uh in this setting, patients who had acute M I were randomized, either placebo or three different doses of avaxim ranging from 10 to 50 mg once a day. And what we saw was significant bleeding compared to placebo was about the same even at the highest dose of axin. Likewise with all bleeding factor 11 inhibition at four weeks. Once again, with a 20 mg and particularly 90 mg dose was quite significant over 90% at peak and trough just as was seen in the phase two atrial fibrillation trial. Now, the last trial in in the phase two program with ASEX in stroke patients uh will be subject of of a more detailed talk by doctor saver shortly. Now, this was an important trial which really give us a sense of safety and potential efficacy. Um in patients who've had ischemic stroke. On the basis of these phase two trials, there are currently two phase three trials undergoing uh the oceanic stroke trial which takes patients who've had acute non cardiomelic ischemic stroke or high-risk TI A and randomizes them to asym dein or placebo. It's an event driven trial. Um It's gonna last at least 31 months in terms of followup. And I should add that the sample size have been increased to 12,300 patients in oceanic stroke. Uh The other trial which is going on is labrea stroke. Similarly, patients with acute ischemic stroke or high risk ti a randomized in this case to Malex B ID or placebo and in both cases, uh added to antiplatelet therapy um going on for 41 months. So the results of both of these trials are keenly awaited. Thank you very much for your attention.