Hello, good morning, and good afternoon, everybody, and welcome to our investor webinar on the results of the OCEANIC-STROKE phase III trial directly live from ISC 2026 in New Orleans. So my name is Alexander Seidler. I'm with the Bayer Investor Relations Department, and I'm joined by three fine young men with me today, so very much looking forward to being with you for the next hour. The gentlemen are Christoph Koenen, our head of clinical development and operations at Bayer. He will give a brief overview of the remaining unmet medical need in the secondary stroke prevention setting. Then, very happy to have you with us, Ashkan Shoamanesh, a professor of neurology at McMaster University in Canada, and importantly, one of the two principal investigators of the OCEANIC-STROKE trial. He will obviously go through the data with us and later on address any remaining questions that you may have, if you have any, because the data are pretty good. Finally, we have Jan Voss with us, who is the global head for asundexian at Bayer as well. He will, you know, take you through some health economic challenges which remain in the secondary stroke setting and maybe highlight how asundexian could be a potential option to address these in the future. We will then obviously go into Q&A. You should receive the instructions for the Q&A in your chat, so please follow these, but we can go through that again when we get there. Very briefly, I do want to bring your attention to our cautionary statements from our Safe Harbor statement. With that, Christoph, I would hand it over to you. Thank you, Alex, and welcome everyone to this call. Stroke is affecting a lot of people. There are more than 100 million people living in the world that survived a stroke, and each year another 12 million people will be affected by stroke. Stroke is not only the third leading cause of death, probably even more importantly, the second leading cause of disability. The problem with stroke is that a lot of survivors of a first stroke will experience a second stroke. One in five will experience a second stroke within five years. One in ten will even experience the second stroke within one year. Overall, up to 30% of all strokes that are experienced are what we call recurrent stroke. And what is extremely important is that these second strokes in general are more deadly. These second strokes create a higher degree of disability, so they're much more detrimental on the quality of life of the survivor, as well as, and that is a little bit underrated, can actually increase the chance of dementia as well. So overall, the second stroke is much more severe, usually, than the first stroke, and it creates a lot of fear in these patients. So you hear things like, "I'm afraid to wake up in the morning because I'm afraid that I have a second stroke during the night." The treatment of stroke has not really advanced over the last two decades. Currently, patients have the options to take antiplatelet therapy, monotherapy, or dual antiplatelet therapy, but that was introduced more than 20 years ago, and nothing has happened. That is actually the reason why the occurrence rate has not really changed. We in Bayer have a long legacy of advancing treatment in coagulation as well as in overall cardiovascular disease. We started out with the discovery of aspirin more than 125 years ago, but actually looked at the effect that aspirin can have on cardiovascular risk factors such as stroke, in the 1980s. We broadened this expertise with more antithrombotic research, and of course, the most prominent brand that came out of that is Xarelto. We are now building on this expertise, on this legacy, and all the knowledge that we have accumulated over the time, and now advancing antithrombotic treatment further with asundexian. So asundexian is unique because it's the first oral, once daily, Factor XIa inhibitor that successfully completed a phase III trial in secondary stroke prevention. As you will see in a minute, we chose to design a pragmatic study that represents a broad stroke population and fits very well within the standard of care in current clinical practice. As you will see, the effect we will demonstrate is generalizable across different subtypes of stroke. We are, of course, very, very proud that we met both our safety as well as our efficacy endpoint. We are currently in an active dialogue with health authorities around the world in order to make sure that approval of asundexian in secondary stroke prevention happens as fast as possible. We do think that asundexian has the potential to become the new standard of care in secondary stroke prevention, and based on that, we do believe it has blockbuster potential. With this, over to you, Ashkan. Thank you very much, Christoph. Well, hello everyone. It is an absolute pleasure, and really a privilege given how the turn-out, the data has turned out, to be presenting the results of OCEANIC-STROKE with you today on behalf of the steering committee and some investigators and my colleague Mike Sharma. As we've seen and, and we've discussed on prior calls, genetic Factor XI deficiency is associated with reduced risk of ischemic stroke without an increased risk of ICH. And this really boils down, in a simplistic term, due to Factor XI's strategic positioning within the coagulation cascade that leads it to be very important for clot propagation, leading to pathologic thrombus formation, but only having a very minor subsidiary role in hemostasis. By blocking Factor XI, you're able to inhibit pathologic thrombus formation while maintaining hemostasis, uncoupling these two physiologic processes that up to this point with other anticoagulants were tied together at the hip. asundexian is a direct oral inhibitor of Factor XIa. Its advantages are that it's once-daily dosing. In animal models, there was no effect on bleeding time with using asundexian, either alone or in association with dual antiplatelet therapy. Across a robust, large phase II program of over 4,000 participants, it was shown that asundexian at its currently tested dosing of 50 milligrams daily leads to over 90% inhibition of Factor XIa at peak and trough without any significant increase in major bleeding over placebo, either when it's used with or without antiplatelet agents. It is on this background that we designed the OCEANIC-STROKE trial as a placebo-controlled, double-blinded, event-driven phase III randomized study comparing asundexian 50 milligrams once daily and placebo in patients with non-cardiomyopathic ischemic stroke or high-risk TIA who were planned to receive either single or dual antiplatelet therapy. As you can see, this was a massive global initiative led at 702 sites across 37 countries, which really speaks to the generalizability of our results to a global population. The efficacy and safety endpoints are demonstrated on this slide. Our primary efficacy endpoint was time to first occurrence of ischemic stroke, whereas our primary safety endpoint was time to first occurrence of ICH major bleeding. Our secondary endpoints on the efficacy side included all stroke, the three-point MACE outcome, which was a composite of cardiovascular death, non-fatal MI or non-fatal stroke, the composite of all-cause mortality, MI or stroke, ischemic stroke in the first 90 days, and then, importantly, disabling stroke, MRS, basically strokes that result in disability or death. Our secondary safety endpoints include the composite of ICH major bleeding or clinically relevant non-major bleeding, ISTH clinically relevant non-major bleeding in isolation, symptomatic intracranial hemorrhage, hemorrhagic stroke, fatal bleeding, and also minor bleeding. The key eligibility criteria are shown in this slide. To be eligible, participants need to be 18 years of age or older and presenting within 72 hours of symptom onset with a non-cardiomyopathic ischemic stroke up to a stroke severity scale of 15. So this would be mild or moderate ischemic strokes and even kind of inching towards higher severity or more severe strokes. And patients with high-risk TIA were also eligible if they were quantified as being at high risk for stroke on the ABCD2 score, and the cutoffs for that were either having a six or seven. In addition, we had some enrichment criteria in our study in that, to keep it simple, you either had to have a non-lacunar stroke to get into the study. If there was a lacunar stroke as part of the qualifying event, you needed to have some evidence of atherosclerosis as well. And that included even the slightest little plaque in the blood vessels in the chest, the neck, or the brain that did not need to be proximal to the stroke. That could have been in a small vessel or a large vessel, and it didn't have to be a significant stenosis. It could have just been a little bit of plaque protruding into the vessel lumen. Or that patients with lacunar stroke required to have a history of atherosclerosis such as peripheral artery disease or coronary artery disease. And in addition, patients required to be planned to be treated with antiplatelet therapy, either single or dual. Our key exclusion criteria are also listed here, and those included a history of atrial fibrillation or other cardiomyopathic sources requiring anticoagulation, an ischemic stroke within 7 days prior to enrollment, strokes following the procedures or other specific causes, end-stage renal disease requiring dialysis, active non-trivial bleeding, whereas more trivial bleedings that are sometimes seen in the acute stroke period were eligible, and then history of non-traumatic ICH or significant GI bleeding within the past 6 months. This is the randomization schema showing that patients were randomized 1:1 to receive either asundexian 50 mg daily or matching placebo, and that randomization was stratified according to planned antiplatelet therapy, either dual antiplatelet therapy or single antiplatelet therapy. The treatment period was a minimum of 3 months to a maximum of 31 months for a cohort with a common termination date for our participants in this event-driven study. As you can see, of 12,578 participants or potential participants or patients that were screened for eligibility, 12,327 were randomized. Of those who were randomized, the vast majority received allocated intervention, with less than 100 participants not receiving the allocated treatment, arm that was intended for them, in a 12,000-participant trial, which is quite remarkable. An equally large number of participants completed this study, with only about 80 participants not completing the study either due to being lost to follow-up, or having withdrawn consent, which, again, is very impressive from a data quality standpoint. Ultimately, all 12,327 contributed to our intention to treat primary efficacy analysis, and only a smaller group did not make it to the primary safety endpoint analysis, which was an on-treatment analysis, where there was about 80 participants that were removed from that 12,327, again, speaking to the high-quality metrics during the conduct of the trial. Here you're seeing baseline demographics, according to treatment arm. What you'll see is that, one, these are evenly distributed between the two treatments in that the randomization worked very well in such a large trial, and that the baseline demographics represent what you would expect in this population. The mean age was about 68. Females accounted for a third of the population. This is less than what we would expect, but is quite consistent with what we see in secondary prevention trials across cardiovascular medicine that, unfortunately, despite our best efforts, and we did have a lot of efforts and even had a specific committee to improve representation of females in underrepresented populations, we still didn't reach our intended targets there. But still, in a 12,300-participant trial, you have 4,000 females that were tested, so we have confidence in our subgroup analyses as a result. And I'll show that to you later in this presentation. In terms of prior history, medical history, about 20% of participants had a prior history of stroke or TIA other than the qualifying event, speaking to the importance of recurrent stroke in the natural history of this population that Christoph showed you earlier. 15% had coronary artery disease, 80% had hypertension, a third were diabetic, and a quarter were smokers. Race is shown here, where you see that two-thirds of the population was white. However, a large proportion of Asian populations as well were represented. Black participants accounted for 2% of the population, about 300 participants in total. This is reflective of the lack of recruiting sites in Sub-Saharan Africa. We are, however, pleased to indicate that in countries where there is a large Black demographic, such as the United States, the proportion of Blacks recruited was commensurate with the expected proportion in that population. In terms of qualifying events, the vast majority were ischemic stroke at 95%, and 5% were high-risk TIA. I think for stroke neurologists, the next categorization is going to be very important in trying to see whether there's adequate representation of the different ischemic stroke subtypes that contribute to the umbrella of non-cardiomyopathic ischemic stroke. And indeed, here we have large representation of the subgroups of in or ischemic stroke subtypes of interest. 43% had large artery atherosclerosis, 30% had stroke of undetermined etiology, and 20% had small vessel occlusive disease. Post-randomization, there were also some patients that were, in retrospect, identified to have stroke of other etiology as well as cardiomyopathic stroke, even though at the time of randomization, these would have been exclusion criteria. In terms of stroke severity, the NIHSS at randomization had a median of 2, with an interquartile range of 1-4. You'll see that, in contrast to other early antithrombotic stroke prevention trials that tested dual antiplatelet therapy, a third of our population had moderate or greater severity of stroke, with the NIH cutoff of 4 or greater. Ultimately, two-thirds of the population was planned to receive dual antiplatelet therapy. The majority of our data is in comparison to placebo on top of dual antiplatelet therapy. Keep that in mind when we're looking at the efficacy and safety results. Now, when we're looking at acute treatments for our patients, a large number of individuals received intravenous thrombolysis or endovascular thrombectomy. That's about a quarter of the population, which increases our confidence in the safety signal early that we're seeing in this population. This is actually a very large proportion. I think some of the best centers in the world will reach levels of 20%-25% acute revascularization treatment for patients with hyperacute ischemic stroke. Without further ado, these are the primary, efficacy results of time to first occurrence of ischemic stroke, where asundexian was shown to reduce the hazard of this outcome by 26%. You see over the Aalen-Johansen curves depicted here, that the separation is occurring early, but that, importantly, you're also seeing continued separation of these curves throughout the entire duration of follow-up. When looking at our other secondary endpoints, efficacy endpoints, excuse me, you'll see reductions in all stroke, a 26% reduction in hazard for all stroke. When you add hemorrhagic stroke to ischemic stroke, you could consider that, in and of itself, a net benefit endpoint for stroke. When you're looking at cardiovascular death, MI, or stroke, the three-point MACE, you see statistical reductions, significant reductions in that endpoint, as well as when you're looking at all-cause mortality, MI, or stroke. When looking at ischemic stroke in the first 90 days, you see that the point estimate or the cause-specific hazard ratio is very consistent with what we're seeing in terms of effect sizes, across the other endpoints. However, as there was a lower number of events within the first 90 days, we did not have power to reach significance here, with the upper bound of the confidence interval just crossing the null barely at 1.02. When looking at an important endpoint of disabling or fatal stroke, here we're even seeing a larger 31% reduction in the cause-specific hazard of having this with asundexian versus placebo. When looking at the primary safety endpoint of ISTH major bleeding, what is remarkable is that we're seeing these consistent benefits across our efficacy endpoints without any offsetting harm. This is true across all our secondary safety endpoints, including ISTH major or clinically relevant non-major bleeding, clinically relevant non-major bleeding, symptomatic intracranial hemorrhage, and hemorrhagic stroke, which is of greatest concern to us in stroke neurology. We also see no significant excess in fatal bleeding or impressively minor bleeding, where actually even numerically, there's less minor bleeding, but, of course, with the point-effect estimate and the confidence interval really making this a neutral finding. I think when you combine what we've seen with efficacy and what we're seeing here with safety, and here we're showing the cumulative incidence of the primary safety endpoint over time, where there's really no separation and the majority of excess risk in both arms is occurring early, which is quite consistent with what we've seen with other antithrombotics, is that this is really a historic, revolutionary finding that we have never seen previously in cardiovascular medicine with any antithrombotic to date. It gets better. Here we're seeing subgroup interactions and forest plots looking at whether there was any heterogeneity in the treatment effect according to different subgroups of interest. Sometimes in these trials, you find that the devil is in the details, but we're very grateful and happy to say that irrespective of any of the prespecified subgroups, which included age, sex, geographic region globally, race, prior history of risk factors such as hypertension, diabetes, prior history of stroke or TIA, medical history of atherosclerosis, whether there was any atherosclerosis at all on vascular imaging, yes or no, there was no difference with all point-effect estimates favoring asundexian versus placebo. In addition, when we're looking at whether the stroke presentation was a non-lacunar infarct or a lacunar infarct, whether the qualifying event was an ischemic stroke or a TIA, importantly, according to the stroke subtype, and we'll get into some of the details of that in a few slides as well, time from symptom onset to randomization, thank you, whether someone got revascularization treatment, stroke severity at onset, or intention to receive, importantly, either dual antiplatelet therapy or single antiplatelet therapy, we find, again, consistency in the results in favor of asundexian. It's important to note that we will be publishing the subgroup analyses for a primary safety endpoint, hopefully soon, in a major journal, where you'll also see that there were no treatment interactions across the board, irrespective of subgroup for our primary safety endpoint of ISTH major bleeding. Now, as I mentioned, the subgroups of greatest interest to stroke neurologists would be how did patients fare according to their qualifying ischemic stroke subtype. The three large eligible subgroups were strokes through large artery atherosclerosis, small vessel occlusive disease, or strokes of undetermined etiology. It's important to note, just on the sheer scale and size of OCEANIC-STROKE, that each one of these subgroups, the numbers allow them to be informative. For instance, we have over 5,000 participants with large artery atherosclerosis. If this was a single standing study of just large artery atherosclerosis, it would be the largest trial ever conducted in this subgroup of patients. When we think about small vessel occlusive disease, to put things in perspective, we have about 2,500 participants with small vessel occlusive disease, actually 2,600 participants. The largest trial of small vessel occlusive disease was the SPS3 trial, and that had just over 3,000 participants. When we think about stroke of undetermined etiology, a subgroup, the major subgroup of which is embolic strokes of undetermined source, the second largest trial that was conducted, that was 5,000 participants, we have 3,500 participants with strokes of undetermined etiology. The third largest study ever conducted was 1,000 participants. So really, a large number of patients in each subgroup. Then that is reflected in the point-effect estimates and confidence intervals that you're seeing here that are showing consistent reductions in ischemic stroke with asundexian versus placebo, irrespective of the stroke subtype, with the point-effect estimate of the cause-specific hazard ratio ranging from 0.61-0.82. So you see significant confidence intervals across the board. However, the p-value for the interaction indicates that the best way to interpret the results is that there was a consistent efficacy across ischemic stroke subtypes, not that a specific stroke subtype is outperforming another one. And we're seeing similar results for all stroke and as well, importantly again, in disabling or fatal stroke. These are the Aalen-Johansen curves of patients who entered the study with large artery atherosclerosis, again, consistent with the overall trial findings. We're seeing early separation in favor of asundexian and continued separation throughout the duration of follow-up. We're seeing similar curves in patients with small vessel occlusive disease. And again, consistency in those with stroke of undetermined etiology. When looking at the primary safety endpoint, again, there's no suggestion of excess harm across these, different ischemic stroke subtypes, demonstrating consistency in the overall results, irrespective of stroke etiology. This also holds true for the secondary safety endpoints of symptomatic intracranial hemorrhage and hemorrhagic stroke. It is worth noting that actually numerically, this bleeding event that is of greatest concern to stroke neurologists, hemorrhagic stroke, is actually less with asundexian versus placebo, irrespective of stroke subtype, including in patients with small vessel occlusive disease who are at greatest risk for this endpoint. Lastly, on the heels of four randomized trials to date that have thus far been unsuccessful in improving stroke prevention in patients with embolic stroke of undetermined source with either Factor Xa inhibitors or with direct thrombin inhibitors, what we see here is that with Factor XI inhibition with asundexian compared to placebo, we're seeing a large treatment effect for reducing recurrent strokes in patients with this disease and with a 47% risk reduction, a confidence interval that's statistically significant. Here, there is an interaction p-value of 0.07. Again, statistically insignificant. So overall, this subgroup, we have to interpret as behaving similarly and benefiting similarly as the overall population. But the p-value is approaching 0.05 in an exploratory fashion. This could be a hypothesis generating of even perhaps a greater treatment effect. I'll point that in this subgroup, the absolute risk reduction was 4% at one year, with a number needed to treat of 25. For the overall study, the number needed to treat was 50 at one year for benefit, with an absolute reduction of 2%, which is quite outstanding when you're thinking about the incremental gain we're getting here on top of blood pressure reduction, lipid lowering therapy, two-thirds of the population receiving DAPT, the best possible existing secondary stroke preventions. And we're seeing such large relative and absolute benefits. We're extremely pleased with these results and for what it means for our patients. And lastly, the safety endpoint was also consistently not increased in patients with ESUS. So to conclude, OCEANIC-STROKE enrolled a large representative sample of non-cardiovascular ischemic stroke subtypes. asundexian reduced ischemic and disabling stroke without increasing ISTH major bleeding or intracranial hemorrhage across all qualifying ischemic strokes. These findings were consistent in patients with qualifying ESUS, expanding this new paradigm to this one stubborn subgroup where we've had no success or lack of success to date. And overall, asundexian now provides a novel, efficacious, and safe secondary stroke prevention treatment for patients with non-cardiovascular ischemic stroke, irrespective of underlying etiology. Thank you. I'll pass the mic now over to Jan to take us through kind of potential for how this is impacting the market as well as our patients. Yeah, thank you very much, Ashkan. It was really stunning when I was attending yesterday, here at the ISC, several sessions conducted by the AHA. It was very, very clear that they were stating that stroke really presents a global public health crisis. Why is that? I mean, you have heard already by Christoph the number of patients that suffer from stroke each year and the more than 100 million patients that suffer actually from the long-term consequences of stroke. When you look at the humanistic burden, that translates very fast into the economic burden. The most recent numbers from the World Stroke Organization show that the global financial impact of stroke has reached already close to $900 billion, and it's projected not to decline, actually to increase to over $1 trillion by 2030. And when you look at all the things like direct cost, treatment, rehab, social care, informal caregiving, et cetera, it really accounts for a significant proportion of that. And also, not to forget the productivity loss of the caregivers. Because if you take the number of patients that are affected by stroke, you can double, triple, quadruple this number to really estimate the total impact of stroke to society based on the countless wives and husbands and the sons and daughters that are equally affected by it. So this is, I think, one of the points why preventing recurrent strokes, and Ashkan, you have alluded to the fact that second strokes, and you have done this as well, second strokes are actually more disabling, even more detrimental, more deadly. That, of course, has also a much greater effect than, of course, than also on the healthcare systems, worldwide. Preventing recurrent strokes could really alleviate the economic burden and free up healthcare resources, and then, of course, allow for more stroke survivors to remain productive. There is actually staggering evidence that shows that stroke in patients below 65 is actually increasing quite drastically in most of the top eight markets. So having said that and having also had a look at the data that we've just seen, I really concur with what has been said, not only by you, Ashkan, but also by the many other thought leaders that I have had the chance to talk to over the last couple of days. This is truly a groundbreaking moment. It's a groundbreaking moment for secondary stroke prevention, as there has been no innovation for the past two decades. But it's also really groundbreaking for patients and, of course, for Bayer. In summary, I am firmly believing that those results will enable us to rewrite the future of stroke survivors and their families. As you alluded to, Christoph, we are already in contact with health authorities worldwide and really try to make this drug available now as fast as we possibly can to as many patients as we possibly can. I am personally very much looking forward to then see the results of the label, and then, of course, also go into the respective negotiations with payers worldwide, so that they can really understand on the one side what I've described now, what the total cost of stroke really means to their respective societies, but also what we could do together to lower the impact of secondary stroke by also making asundexian available. So with that, I would like to thank you everyone very much and then open up for Q&A. Fantastic. So thanks, gentlemen. This was very insightful and fun to listen to you. I hope this is true for the rest of the audience as well. So we're going into the Q&A now. And I would ask everybody to please limit their questions to one to two at max. You should have received the instructions for the Q&A in your chat. And here my iPad tells me that first we have Sachin Jain from Bank of America, followed by James Quigley from Goldman Sachs. And I will then call up others, as they line up. So Sachin, please go ahead with your questions. Hi team, thanks for taking my questions. The first one is for Ashkan, if I may, just a couple of factors that made it take commercial. So if you could comment on how you think about duration of therapy, relative to antiplatelets, which is typically short term, and then how broad you could initiate therapy in terms of timing versus the index event. The question's driven by, on duration, efficacy curves diverging, safety seen up front. And then on the initiation, there's a forest plot that shows it sort of is almost better, more than 72 hours. It's a very small end. But are you doing any post-hoc data that would allow you to access a prevalent population versus just initiation acute? So that's for Ashkan. The question for Jan. So it's the data's been described by, the lead investigator, historically revolutionary, never seen with any anti-thrombotic. You've described, this as a large opportunity, same number of patients, a swath. So what do you need to see to change your peak sales, which I think is currently sitting at EUR 1 billion? Thank you. Okay, thanks. Yeah, so I believe there are two questions there for myself. One was the duration of treatment. As you've seen in the Aalen-Johansen curves, the treatment arms were diverging throughout the entire duration of follow-up. There wasn't a point where there was a plateau in the treatment effect that we saw. As a result, we expect this to be a lifelong treatment. In terms of duration from time of onset to initiation, the protocol allowed anything up to 72 hours. But I think you rightly point out that based on what we see within the curves, it is quite tempting to go beyond that. Obviously, as a purist and a trialist, we can only say that up to 72 hours is what our eligibility criteria mandated. Having said that, speaking with many colleagues and thought leaders at this Congress, many of us looking at those curves will feel comfortable treating these patients, even if they were outside of that 72-hour window, on the basis of the continued lifelong benefit that we expect from this treatment. Yeah, and Sachin, I think it's a very valid question. I can tell you, of course, we are continuing to believe in the blockbuster potential that asundexian has. Based on those groundbreaking results, I have to say I am very confident to fulfill this promise. It is a little bit too early at this present time to give any specific comment on any specific number on peak sales. I think it's on the one side, of course, depending on the label that we are ultimately going to get from the FDA, from other health authorities worldwide, EMA. That is very much defining, of course, on the one side the commercial potential. The second one is that we are currently in an environment that is, from a global pricing landscape, pretty volatile. We have to, first of all, focus on making sure that payers worldwide truly understand the total holistic impact that stroke has on their respective nation, and then also make sure that health economic arguments are then also taken into account much more than they potentially have before. So let me allude to things like bleeding is a cost driver. We should not forget that this is not just about preventing strokes. It also really ensures that based on the data that we've seen, there's no increase versus placebo. That is, of course, also a value driver in itself. And so from those perspectives, this is what we are trying now to work out very hard to understand the total impact of stroke from a cost perspective on the respective nations and make that transparent to governments so that we ultimately get a proper recognition of the value that asundexian may then bring to the respective markets. And that defines, of course, then the pricing levels. So label pricing levels based on the impact of the value that we are delivering, that's ultimately going to determine our peak sales. But you see me smile. And of course, when you think about the blockbuster potential that we have commented on before, I'm more than confident that we are very surely deliver against this. But how much more? Yet to be seen. Cool. Thank you, Jan. So James, James Quigley from Goldman Sachs, please your one or two questions. And after that, I would call up Richard Vosser from J.P. Morgan just so that you can prepare. But James, over to you now. Excellent. Thank you, Alex. So just to follow up with Ashkan on the dose intensity. So in the study, how many patients were on therapy for the duration of the study? So the whole study, the whole sort of time they're on treatment versus those that may have discontinued earlier. And is there any data or correlation between the length of time on therapy and the benefit that was seen in the trial? And then second one. So. And sorry, go for that. I'll follow up. You go. Let's have Ashkan answer. And James, you ask your second question then. Let's do that. Yeah, makes sense. Yeah. Cool. Okay. So, there was actually a 20% discontinuation throughout the duration of this study for non-protocol mandated discontinuations. What I mean in that is that if patients were detected, for instance, to have newly identified a cardiomyopathic source like A-fib, and there was actually mandates within the protocol for them to be taken off-study drug and started on the appropriate anticoagulation therapy. But when you remove deaths and you remove some of these other indications that are required to get off-study drug, but there was about 20% discontinuation. But what's important to note is that it was the same in either arm of the study. So there was no suggestion of excess discontinuation with asundexian versus placebo. And this really gets to some of the consistency that we saw in the other adverse events and that there was, when looking, forget bleeding and our safety endpoints. But even when we look at just any potential off-target effects or any potential adverse events systemically, there was really no suggestion of anything standing out with asundexian versus placebo in this large global study. And I would say that that 20% discontinuation, although it's much higher than we would have wanted, is more reflective of the proportions we would expect in the real world. It actually makes our results a bit more generalizable to the real world. And it actually builds our confidence that despite 20% discontinuation, which would typically attenuate treatment effects, we're seeing these large benefits. Then for your second question, regarding if you can remind me, Alex. We didn't have the second question yet. Oh, sorry. No, no, but there was a second clinical question there. The second part was the correlation between if patients stayed on therapy, so they're on asundexian for longer. So we actually saw, and you kind of get an impression of it in the curves that I showed, that actually the longer patients were on treatment, the greater the benefit that they had from intervention. And there is going to be a landmark analysis. And then and I didn't mention this when Sachin asked a similar question earlier, that we're going to present at ESOC, or the European Stroke Organization Congress, in May, where we will be asked you to show you that data based on different time points of follow-up. Fantastic. So then your 1.5 question, James. This is the second question. So, maybe more for the Bayer team. So how are you thinking about potential competition in the space? We have Milvexian on the horizon. Is there anything in the PKPD data or the phase II data that could potentially show differentiation? Also, some KOLs have talked about some investigator trials looking at low doses of Factor XIa inhibitors plus antiplatelets. Is this a risk in terms of the long-term follow-up or the long-term potential for asundexian? So maybe I'll start answering. I mean, obviously, you know, it's kind of difficult to speculate about differences. When, you know, with asundexian, we, of course, have a clear-cut result both on efficacy and safety. I think let me start with, I mean, that is actually clinically, I think, important is the fact that asundexian is a once-daily treatment. It's a once-daily oral treatment, which we know is a preferred way of administration by patients. A once-daily is obviously a more convenient way of taking a pill rather than having to take it twice a day. Yeah, I think that is actually a very important differentiator. Yeah, I think everything else, I think the data will speak for itself. Obviously, you know, at some point we will have the second study in with a with an XIa reading out. I think then we can have another conversation about that. Regarding the low-dose Factor Xa, I mean, there has been a lot of discussion for a long, long time about trying to, you know, reduce the risk of bleeding by administering lower doses of Factor Xa. I think in secondary stroke prevention, based on the COMPASS data that we have and is now, what, more than five years old, it's very clear that even a low-dose DOAC has a remaining bleeding risk that we have not seen here. So there's no reason to believe that, you know, it's somehow attractive to dose a patient with a low-dose DOAC. I think the data speaks for itself. We have an effective and we have a very safe treatment here. Great. Thank you very much. Cool. Thanks, James. So then Richard, you'd be next. Richard Vosser from J.P. Morgan, and he'll be followed by Charles Pitman-King from Barclays. So Richard, over to you. Thanks very much. Two questions, please. First question, just, the bleeding was obviously identical, even in minor bleeding. So, you alluded to this dose during the presentation. So is there a thought that you could have maybe got even better data by raising the dose even higher to inhibit the Factor XI even more? Any thoughts there that you're about pushing the dose or thinking about that? And second question is on the path forward in potential other indications. We obviously know these products probably don't work in ACS. But what about other areas of stroke or intolerance to Factor XAs in AF? Just some thoughts there would be great. Thank you very much. Yeah. So to the first question, when we looked at peak and trough degrees of Factor XI inhibition, it was between 92% inhibition at trough and kind of 96% inhibition at peak. And that narrow difference really implies that there isn't much else to gain by going to higher doses. And this is why in the dose finding studies, such as the phase II PACIFIC-STROKE study, 50 milligrams was selected as the highest dose in that dose escalation paradigm. So on that basis, it was felt that going higher than 50 milligrams would not provide additional benefit. Yeah. So I think, again, a 26% relative risk reduction in this study, it's going to be hard to beat. And there's no pharmacological reason to believe that a higher dose would have yielded more efficacy. When it comes to the additional indications, obviously we are actively thinking about, you know, new trials with asundexian. Part of that is, of course, you know, looking at generating more data in secondary stroke prevention. But on the other hand, looking at other indications as well. You know, as we have always said, we are currently still looking at the potential of asundexian in preventing stroke in patients with atrial fibrillation as well. But there's nothing right now that we can disclose. There's actually just maybe one more comment on the minor bleeds. Because when you think about, it sounds minor, but it is actually having a pretty profound impact on patients because it's visible, it's recognizable, and it is very often one of those drivers to stop treatment. And this is why I am personally very happy that we are not seeing any difference in minor bleedings versus placebo because of the increased compliance and persistence of those patients long term. So from that perspective, on top of what you have just alluded to, Ashkan, with regards to the efficacy and that higher doses would not really gain anything further beyond the 26%, I think it is also very, very good that we have hit here the absolute right dose for the patients, in order to ensure that they are staying on that treatment as long as they possibly can to gain the biggest benefit from this drug as possible. Fantastic. So thanks, Richard. With that, we'll move over to Charles Pitman-King from Barclays, who will then be followed by Alek Ebbeling form UBS. Hi, guys. Thanks very much for taking my questions. Two from me. Just on the first point that you mentioned that a third of the patients were deemed severe on NIHSS at the baseline. That differs to the other trials in the space. I'm just wondering how that compares to your kind of intent to treat population and whether or not you think that's going to help at all in your kind of pair discussions. And then just secondly, on the fatal bleed rate, I mean, 14 versus 8 sounds large, but 0.2% versus 0.1% does not, especially given the all-cause mortality reduction. Just wondering if you can kind of directly address that slightly larger rate of death scores by bleeds. Thanks. Yeah, 100%. So, for the second part regarding the excess and fatal bleeding, as you've indicated yourself, very small numbers, right? And so that could just easily be a chance finding in the same and the most deadly bleeds that we see in stroke patients and actually in with the use of antithrombotics are hemorrhagic strokes, right? What do we see with hemorrhagic strokes? We actually see numerically a 30% reduction in hemorrhagic stroke. But again, due to the small numbers, that's just a chance finding. And in the same way, we're not going to claim that we're reducing hemorrhagic stroke with asundexian by 30%-40%. We're not going to claim that there's any concerns about fatal bleeding here because the numbers are so small. And I think it's just a chance numerical finding, as you've alluded to yourself. And sorry, remind me of the first question again. Charles, do you just want to repeat that? Sorry. Sure. It was just, the rate of severe patients at baseline, and how you expect that. Yeah, so that's a great question. So, there is this perception, even amongst stroke neurologists, and it's a misperception that patients with non-cardiomyopathic stroke, generally, would have higher NIH stroke scales as an average. Actually, that is not the case. We see this in hospital registries, as well as in population studies and also in trials of patients with non-cardiomyopathic ischemic stroke where the agent wouldn't be one that would make physicians hesitant from using it in more severe strokes, that the average has generally turned out to be somewhere between an NIH stroke scale of 2-3, which is where we've landed. You'll see in the accompanying publication that will be hopefully published soon that we do include in a supplement, existing literature estimates of what you would expect in this population outside of a randomized trial and that we're really generalizable to the target population in this regard. Fantastic. Okay. Thank you very much, Charles. So we're moving over to Alek Ebbeling from UBS, who will then be followed by Rajesh Kumar from HSBC. Hi. Thanks for taking my questions too, please. The first is on efficacy in small vessel occlusion. So after the phase II study, the investigators suggested there may be reasons to believe factor XI would be less effective in the stroke subtype. But in the study, the efficacy was actually better in small vessel occlusion versus large artery atherosclerosis. So just wondering why you believe that's the case. And then kind of second along those lines, the competitive positioning. So you obviously enriched your phase III trial for patients with atherosclerosis or a non-lacunar infarct and therefore had more patients with the large artery atherosclerosis subtype. Meanwhile, your competitor didn't do this in their phase III inclusion criteria. But the efficacy was better in small vessel occlusion versus large artery atherosclerosis. So do you think this could potentially create concern for a cross-trial comparison? Yeah. So good questions. So what we did see in phase II, which was PACIFIC-STROKE, as you've indicated, was that patients that had any degree of atherosclerosis, not large artery, so large artery atherosclerosis, certainly there was a greater treatment effect. But also really the greatest treatment effect was in patients that had any degree of atherosclerosis, irrespective of the vascular bed that we were looking at, just somewhere under CT angiogram of the arch to the top of the brain. We dove into the data in PACIFIC-STROKE to see whether a lacunar stroke patient that had some degree of atherosclerosis would benefit. Indeed, in that subgroup, and we never published this, but it informed the design of the phase III, that once you had some degree of atherosclerosis somewhere in the body, it didn't really matter what the stroke looked like anymore. It would, and this is why in this one subgroup, you had to have atherosclerosis. But I want to clarify that, that was only in patients with lacunar stroke. If you had a non-lacunar infarct, you didn't need atherosclerosis to get into this study. And really the overall message that's emerging from the phase III trial data right now is that it doesn't really matter, right? what what the stroke subtype is. Now, you indicate that the competitor does not have enrichment criteria. Well, they do in a way because they cap their enrollment to 20% of lacunar stroke. So, because usually you would expect about 40% of this population to be lacunar stroke, they've capped it to 20%. And by just our enrichment criteria, we've landed at around 22% of the population being lacunar stroke. And the reason we're seeing a treatment effect with lacunar stroke patients that's consistent with the overall treatment effect, again, the p-value of the interaction term, does not allow us to say that one subgroup is outperforming another. We have to say that it's consistent across the board, maybe because of our enrichment criteria, right? So it would be a leap of faith to say that at this point, that all lacunar strokes are going to benefit similarly. It may be the fact that we have this enrichment criteria, that we're seeing this consistent treatment effect in lacunar stroke. But however, we'll have further insights once we see the subgroup analysis of LIBREXIA-STROKE. But I think that would be informative for the class, right? I don't think the community is going to think that it's going to be a drug-specific effect if the lacunar stroke population that's not enriched in LIBREXIA-STROKE benefits as well, that there is a there's a drug effect there, but rather a class effect. And it'll be generalizable in the community, for the overall class effect of factor XI inhibition. Wonderful. Okay. Thanks. So then Rajesh Kumar from HSBC, you're up. And I think that would then probably be the last question that we can take, in the time. But Rajesh, over to you. Hi. Thank you very much. Just in terms of - Rajesh, sorry, we can't hear you. You're extremely quiet. Any better? It's getting better now. Yes. Yeah. Sorry about that. So, just in terms of, you know, you see in OCEANIC-STROKE now, OCEANIC-AF data, you know, given the differences in the outcomes, what did we learn or what can we speculate about the mechanism? You know, or was there a particular patient selection or design difference that sort of mattered here? I noticed you increased the trial size for stroke. And, you know, that could have helped. And would you probably wait for the MRI substudy to come before you could, you know, speculate on the mechanism a bit more? That would help. And the second one is a commercial question. Any thoughts on what sort of labeling you might be targeting, whether it would be, you know, secondary prevention in patients with non-cardiomyopathic stroke or, you know, slightly, FDA might go for a slightly smaller universe. And then looking at the data, what do you think the labeling could be? And could you actually target a longer duration use of this medicine? So any thoughts on the price point would be very helpful. So let me let me start with the question about what have we learned. I think what we have learned is that thromboembolic strokes and atrial fibrillation, the etiology is different than strokes in stroke that had that experience in patients that experience ischemic stroke. Yeah. It's a different etiology. It's probably a substantially different pathophysiology that leads to the formation of these thromboembolic clots. And therefore, XIa might not be as efficacious as it is in secondary stroke prevention. Yeah. As I said before, we actually currently still looking at that because we do want to understand that this a little bit more in detail in order to then make a determination whether there is actually a role for asundexian to play in stroke prevention in patients with atrial fibrillation. Yeah. I think there's other aspects, of course, the fact that here we have a patient population that is routinely treated with antiplatelet therapy. So asundexian is administered on top of antiplatelet therapy, whereas obviously, usually in atrial fibrillation, antithrombotic treatment is given as a single therapy to prevent thromboembolic clots. Regarding maybe I'll start a little bit with the label and then I'll hand over to you. I mean, obviously, you know, a label is something that we, you know, negotiate with health authorities around the world. It's very much based on the evidence that we have produced. And of course, the evidence we have produced is the patient population that you have just seen. But the evidence as well includes, of course, the fact that the treatment effect is something that has been seen over the entire duration of the trial. So one of the exciting aspects that we see here is that the effect is not limited to a short treatment duration, but the effect is actually something that continues. When you look at the curves, obviously it seems to continue even beyond the duration of the trial. Based on that, we do think there's a benefit for patients to take this long term. And this is, of course, something that we will negotiate with the authorities in order to make sure that this is appropriately reflected in the label. Perfect. Nothing to add. Wonderful. So then we're actually at the top of the hour. Perfect timing. I would like to thank our speakers, obviously all of our participants for joining us on a Friday afternoon for most of you in Europe, and also want to make sure to thank the colleagues who've helped in supporting to set all this up and prepare us for this activity. And with that, I'd like to wish everybody a good weekend, safe travels home for some of us, and, yeah, be well. And we'll conclude the call with that. Thanks, everyone. Thanks, everyone. Thank you. Bye. Thank you. Thank you.