I hear we're good to go. Good morning, good afternoon, and good evening to everyone. Thank you for joining Sanofi's Hemophilia Investor Event, either here in London or online. As always, the slides can be found on sanofi.com. If we could go to the next one. The next one, please. Yes. As always, I would like to remind you that information presented here contains forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. I refer you to our Form 20-F document on file with the SEC and also our Document d'enregistrement universel for a description of these risk factors. Next slide, please. For today, we've put together a two-hour event to show Sanofi's commitment and ambition to improve people's lives living with hemophilia, or other rare blood diseases. I mean, you're gonna see that there is a broader portfolio that we're building here. In the context of ISTH that has just concluded, we want to focus today on fitusiran and efanesoctocog alfa. We're very privileged to be joined today by two investigators, by Dr. Young and Dr. Weyand, who will present the data to us. We will also take a closer look at the hemophilia market and how we see it evolving. In the end, there will be time for questions. You can participate either in the room or online. I'm gonna talk later again about the modalities. I just wanted to mention for those who are online, you have the possibility to ask questions through the Q&A box. You can send them in in writing, and we already invite you to send some of the questions during the presentation. As said, we wanna first run through our agenda, and then we will certainly have enough time for questions. With this, I hand to Dietmar. Thank you, Eva. I don't think I need this one. Welcome also from my side. My name is Dietmar Berger. I'm the Head of Development and the Chief Medical Officer for Sanofi, and it's great to see you all here. As a hematologist oncologist myself, it's actually my pleasure to speak about Sanofi's ambition in rare blood disorders, in hematology, and our commitment to patients and our commitment to the hematology community here. Next slide, please. We are focused, we are committed to transforming the lives of people with hematologic disorders, with rare blood disorders. We have a marketed product portfolio on the left here with first-in-class products in hemophilia, extended half-life factors like Eloctate or Alprolix. With a first-in-class therapy in CAD, in cold agglutinin disease and Enjaymo, and with Cablivi in acquired thrombotic thrombocytopenic purpura, where no other treatments basically existed before we came with that drug to the market. On the right, we are building a portfolio of molecules in hematology, with a focus both on hemophilia and also on immune-mediated blood disorders. In hemophilia, we have efanesoctocog alfa and fitusiran. Both were featured prominently here at the meeting, and obviously we'll focus a lot on these two molecules. We have really four molecules in broader settings of immune-mediated blood disorders and rilzabrutinib in ITP, an immune thrombocytopenic purpura, is actually already in a phase III trial. Next slide. Let's focus a bit more on that portfolio in hematology, which is really a broad set of innovative pipeline assets addressing unmet medical needs in the area. Just briefly focusing on these unmet medical needs, patients in hemophilia still suffer from breakthrough bleeds and joint bleeds, which then over time lead to joint deterioration and really to an impact on quality of life, severe impact on quality of life of patients. We also have to try and reduce the treatment burden of these patients. We cannot go with IV infusion therapies every other day in many of these patients when we think about factor therapy. We also need to improve access to treatment, really on a global level. Talking about immune thrombocytopenia, ITP, where rilzabrutinib is in a phase III trial. We know that ITP is a disorder of platelet destruction and also impaired platelet production, but what patients feel actually goes beyond that. It's not only the bleeding we have to talk about, it's also the fatigue, the quality of life impairment, that these patients suffer from. When we think about cold agglutinin disease, we're really aiming with our SAR445088 molecule, we're aiming to address complement C1s, activated complement-mediated hemolysis. Talking about warm autoimmune hemolytic anemia or wAIHA, this is an acute disorder with currently no approved treatment. We have two different molecules in clinical trials and earlier clinical trials. Next slide. Just stepping back for a moment and speaking about rilzabrutinib in immune thrombocytopenia. The remainder of the meeting is on hemophilia, so we just wanna take a second here and talk about our oral reversible BTK inhibitor, which is potentially a first-in-class treatment approach here to immune thrombocytopenia. Again, thinking about the unmet need, patients need really treatment beyond the platelet counts. We really need to impact fatigue and quality of life. How do we do that? It's the realization that inflammatory processes play an important role in these patients and eventually lead from pathophysiologic perspective to those symptoms. Consequences of the disorder, more generally, like microbleeds, could potentially lead to irreversible damage and need to be addressed. Just talking about the opportunity, more than 25,000 adults currently in the U.S. suffer from chronic ITP and are really eligible for a second-line plus treatment beyond steroids, after steroids. Rilzabrutinib has the potential to address these issues because BTK inhibition of Bruton's tyrosine kinase, has the potential to reduce both the Fc gamma receptor-mediated macrophage function and also the autoantibody production. That's the realization that ITP is not only an autoantibody-driven disease, but also a macrophage-driven disease, and we're targeting these two mechanisms with a BTK inhibitor, thus really targeting the underlying cause of disease via addressing multiple cell types and also addressing the inflammatory effect. Next slide. We were also able to show that in phase I, II studies. These studies have been published by Dave Kuter and colleagues in the New England Journal of Medicine early this year. We saw a strong effect around 40% response rate across all analyzed subgroups here in this study. This is a graph from the paper looking at the different subgroups of patients. You will see that effect size is maintained, even in the more severe patients. All of these were heavily pre-treated, highly refractory patients. When you look, for example, at patients with a prior splenectomy, you look at patients with four and more prior therapies, you again get this around 40% response rate. Rilzabrutinib was well-tolerated in these studies, and the effects were durable. We saw clinically significant platelet responses that were also maintained in the long-term extension of the study. Next slide. Going back to the main topic, hemophilia. Sanofi has a unique portfolio, in my view, in hemophilia. We're really well-positioned to define new standards for different patient populations, right? New standards when it comes to efficacy on one side and when it comes to reduction in treatment burden on the other side. On the left, we have efanesoctocog alfa, or Efa, how we call it, for hemophilia A, in development for hemophilia A. This is a uniquely designed molecule because what you have is you have the factor VIII molecule, but then we have these XTEN side chains that were fused to the molecule. You also have parts of the von Willebrand factor engineered into the molecule, all with the intention to increase the half-life of the molecule. You get to an unprecedented half-life of close to two days, and that then allows us to give the drug IV once a week. It not only helps us with the dosing frequency, it also helps us to maintain factor VIII levels really high for the majority of the week. On the right, you have fitusiran, which is an entirely different approach, which is a first-in-class small interfering RNA or a siRNA molecule targeting antithrombin III. Balancing coagulation, rebalancing coagulation, and eventually leading to an increase in thrombin formation, which is the final goal of the coagulation cascade. That also allows us to develop fitusiran for hemophilia A or B, with or without inhibitors, so with a really broad applicability. Next slide. Just a little more detail on efanesoctocog alfa, and this gives you factor levels over a week, right? Remember, with Efa, we only need once a week therapy, and you see that factor levels stay at normal or near normal levels for the majority of the week, which is really unprecedented. We believe that that will also translate into improved efficacy. For example, when it comes to joint bleeds, avoiding joint bleeds in patients and really maintaining a normal lifestyle in patients. We've had positive phase III data from the XTEND study. Primary and key secondary endpoints were met. The study was presented here, and we're really privileged to have Dr. Weyand with us, who will talk about the data and about her experience with the drug later. I'm pleased to inform you that the FDA submission has gone in. The BLA has been submitted. We have received breakthrough designation and fast track designation, and we're planning to file in Japan in the second half of this year. Next slide. Fitusiran has the potential for consistent efficacy, but with a much reduced treatment burden. We have completed three phase III studies in adults and adolescents with the 80 milligrams monthly dose. The third study has been presented here at the meeting. Again, we're privileged to have Dr. Young here, who will talk more about his experience with fitusiran in a second. The program is now continuing with an amended protocol with two lower doses, but also with a lower dosing frequency to optimize the benefit risk profile. That would put us, hopefully, into a position to dose fitusiran for the majority of patients only 6 times a year. Six times a year subcutaneous injection in order to control bleeding to protect patients in hemophilia A or B with or without inhibitors. The data with those lower doses are expected in the second half of 2023, and the first filing here is planned for 2024. There's also a pediatric study that is ongoing, and the first filing for that study is planned in 2026. With that, next slide, please. It's my pleasure to hand over to Guy Young, the director of the Hemostasis and Thrombosis Center at Children's Hospital Los Angeles. Guy. All right. Thank you. I forgot. I came up here looking for the clicker, and I forgot that there isn't one. Anyway. Thank you for being here, and it's my pleasure to talk about fitusiran. Let's go ahead and roll with the next slide. This is kinda my vision of the unmet needs in hemophilia. For non-inhibitor patients, we have pretty good treatments, to be honest. We need to reduce the treatment burden. In fact, Dr. Weyand and I were just having a discussion about you know, non-adherent patients. It's a huge problem with patients not giving their factor on a regular schedule. We need to somehow reduce the treatment burden while still maintaining really good efficacy. For the inhibitor patients, there's still a lot of work to be done to improve outcomes. We definitely need better treatments to prevent bleeding in inhibitor patients. We do have emicizumab now that's available, but, you know, we don't just want one product, and the other thing is emicizumab doesn't work in hemophilia B in any case. Ultimately, you know, the ultimate unmet need per se is obviously to cure a disease. There is work being done, as you know, and you've seen in this meeting on gene therapy. It still seems like we've got a ways to go, particularly in hemophilia A gene therapy, before we're really at a truly curative kind of situation. Next slide. I'm gonna talk about three studies. The first two were presented at ASH. The first one is the ATLAS-INH or inhibitor study. This was a study for patients receiving monthly fitusiran 80 milligrams compared to another group randomized receiving bypassing agents on demand. Right? The comparison was on-demand versus fitusiran prophylaxis. The second study was also presented at ASH at the late breaker session. This is the similar study, in fact, really very similar design, except this is for patients without inhibitors. Again, the comparison group was patients receiving on-demand therapy, so only therapy as needed for bleeding. The third one was presented here at this meeting in the late breaker session, which we call ATLAS-PPX. This was a study comparing patients. This is patients with and without inhibitors, and the comparison group is patients on prophylaxis, either with bypassing agents if they have inhibitors or factor products if they don't have inhibitors. Go to the next slide. These are all, by the way, for patients older than 12. As you saw, there is a pediatric study that is ongoing for patients less than 12 for those different groups. This slide is looking at the two studies where the comparator group was on-demand treatment. You can see that on the left side is the ATLAS-INH study, where the median annualized bleeding rate for on-demand patients was 16.8, which is not surprising. If you're on on-demand therapy, you do bleed more frequently. With fitusiran, the median was 0. The reduction in bleeding was about 90%. On the right panel, that figure is from the ATLAS-A/B study. That is the study I mentioned where it's patients without inhibitors, and you're comparing again to on-demand, and you see essentially a similar reduction in the bleeding. Again, you see with fitusiran that the median ABR was zero. The next slide, this is looking at the study that was presented here. This is comparing again to prophylaxis. This is patients with and without inhibitors, and the patients on the standard of care arm were receiving either bypassing agents for prophylaxis or factor products for prophylaxis. You see that the annualized bleeding rate in that group is lower because they're already on a prophylactic regimen. It's 4.4. Again, with fitusiran, the median was zero, and that represents a reduction of 61%. You see it's statistically significant, but really more importantly, that is a clinically significant reduction. We don't want patients, regardless of what prophylaxis they're on, four bleeds a year is not acceptable. Next slide. We're gonna take a look now at percentage of patients with zero bleeds. Now, we put all three of those studies. Again, the same studies, ATLAS-INH on your left, ATLAS-A/B in the middle. Those are the two comparing to on-demand and ATLAS-PPX on the right. We're looking at the percent of patients with zero bleeds. You can see that it's somewhere about 50%-65% between the different studies. When you compare the on-demand studies, you see only 5% of the patients in the on-demand arms had zero bleeds during the efficacy period. For the prophylaxis, it was a little higher, 17%. Obviously, that means the majority of patients were still having at least one bleed. Next slide. Let's take a look at some quality of life measures. This is the Haem-A-QoL. The important thing to understand here is negative or the results going lower is actually a better outcome. There's some quality of life tools where you want the numbers to go up. There's some where you want the numbers to go down. This whole area needs a little bit of a cleanup in terms of how we look at things. Be that as it may, in this case, going down is good. This is the physical health domain from a hemophilia-specific quality of life tool called Haem-A-QoL. You have the three studies across, and you can see very significant reductions, particularly on the left side, for the patients with inhibitors. If you are not bleeding and if you're only having to dose once a month with a subcutaneous drug, obviously that's going to improve your quality of life. In this case, in the physical health score, the fact that you're not bleeding is obviously helping your physical health. In the middle panel, you see also a reduction of 23. With this score, this is not, you know, this is more of a gestalt, but any drop that's 10 or more is really affecting your quality of life in a very positive way. You see 30 and 23 is, to be honest, really quite remarkable. In the last one, you see that the reduction is a bit different. You see it's the difference is minus 3.6. Again, that's because patients on the other arm were on prophylaxis. They were already getting some form of prophylactic therapy. Next slide. This is a total score. We looked at the physical health score. This is the total score. This will incorporate things like, you know, the frequency of infusions and things like that. Again, you see very big differences between the fitusiran arm in green and the other arm, either bypassing agents on demand, factor on demand, or factor bypassing agent prophylaxis in the black. Next slide. Let's talk about safety. Here we're gonna do each study one by one. This is the ATLAS-INH study, again, the inhibitor study. You see the bypassing on-demand group is in the middle column. The fitusiran group is on the right column. The box is highlighting the treatment emergent adverse events of special interest. You see there were 11. On the bottom panel, we break that down. You see there were 11 patients that had either elevations in their hepatic enzymes and one patient who had cholestasis. I will tell you that for those 11 patients, none of those discontinued the drug. For most of them, the transaminases went back down to normal or at least were, you know, stable and not, high range. None of those patients discontinued the drug as a result of those elevations in transaminases. They were not, you know, really that clinically significant. Now, there were two thrombotic events. It looks like four, but the first three, notice the bracket is the same patient. The investigator put, like, three names for the thrombotic event. He called it deep vein thrombosis, subclavian vein thrombosis, thrombophlebitis superficial. I guess it involved a few different veins. That's one thrombotic event. Then the second one was a suspected thrombotic event. I think the verbatim was suspected spinal vessel thrombosis. The second one was a suspected one. You see a total of two patients on this trial that had thrombotic events. A thrombotic event and one suspected thrombotic event. Next slide. This is gonna be the ATLAS-AB study. In this case, you see 15 treatment-emergent events of adverse events of special interest. These were all elevations in the hepatic enzymes and none of the patients discont. There were two patients who discontinued because of that. One was related to the elevation. They were both one was cholecystitis, and one was elevation of ALT. Those two patients discontinued based on the investigator decision. Again, the rest of those did continue on the drug, these transaminase elevations either normalized or remained stable and at a relatively low level of increase. The final study. Next slide, I guess, is it? Yeah. This is the prophylaxis study. You see the two columns as we showed you, and let's focus on the in the middle there first. We've got two patients who discontinued fitusiran. One was due to a cerebrovascular accident, so I'm gonna talk about that in a little more detail in a moment. The second was due to abdominal discomfort, and that patient just chose to discontinue the drug. Below, we have the treatment, the adverse events of special interest, and so you see two thrombotic events. Again, one was this cerebrovascular accident. The other one was a suspected event which involved a thrombosis. I think it was written as the suspected thrombosis on the papilla of the left eye. If you wanna ask me more details about that, I don't really have that. That's what the investigator put. So that's the two thrombotic events. We have the other adverse events of special interest, which is again, the liver-related events. You see elevations in transaminases and five patients with cholelithiasis, five with cholecystitis. The numbers don't add up because some of the patients have more than one event. Trying to think if there was one other point I wanted to make here. Yeah, as far as the discontinuations, again, one was a cerebrovascular accident and one was abdominal discomfort. Okay. Yeah, next slide. This is a slide that's looking at a summary of the thrombotic events that have been so far published since the start of the fitusiran program. This includes the four on the top or from the two trials I just mentioned. The one on the bottom is from an older phase I trial. You can read the details there. It's not that those are not important. I just don't have time to get into all the detail. The key point here is the last column, which is when this was analyzed in depth, the category of the antithrombin level for these five thrombotic events was that the first three, they had antithrombin levels less than 10%, and the other two were between 10% and 20%. Moving forward, it was determined or decided that based on these thrombotic events, that we should not be lowering antithrombin levels below 10%. Because of this risk. It's decided to make the lower threshold 15%, partly to account for variability between patients, with respect to, you know, when there might be a thrombosis and also for some margin of protection or margin of error. An upper limit was set. In other words, we wanna keep the antithrombin levels between two points. Of course, after all, the point of the drug is to lower antithrombin levels. After a deep dive of the data with patients with antithrombin levels that were in all various areas of this category, 35% was chosen because patients even up to in that range still had really good efficacy. That's why it was chosen to say, "Let's aim for 15%-35%," because we can improve, hopefully improve, we'll see as the data emerges, but hopefully improve upon the safety margin without compromising efficacy. That leads to a new dosing schema, which is going forward in the phase III trials now, which I'll show you on the next slide. All patients in the ongoing phase III studies are now going to start on, first of all, a lower dose, 50 milligrams, not 80 milligrams. And second of all, it's going to be every other month. Fifty milligrams every two months, that's how you start. Then antithrombin levels will be measured. If you are greater than 35%, you will increase your frequency to every month because we want the levels below 35%. If you're below 15%, we don't want anybody there, your dose is going to go down. You're gonna stay in every other month, but you're gonna go down to 20 milligrams every other month. If you're in the right range, you're just gonna stay on 50 milligrams, every other month. The sense is that most patients, nearly all the patients will require either no dose changes or maybe just one dose change to get them in the range. We expect 80% of the patients to remain on an every other month schedule, which means 6 subcutaneous injections per year. You have there on the right, the target levels and sort of the rules that are being followed in the phase III trial. Next slide, I think is my last slide. The conclusions based on these three completed phase III studies, 80 mg of monthly fitusiran prophylaxis resulted in sustained lower antithrombin levels and increased thrombin generation. There was some data presented at this meeting, specifically looking at that thrombin generation, so you can find that abstract if you're interested in that. The present findings and low ABR, the 80 mg monthly, suggest that fitusiran reduces rebalances hemostasis and provides really a continuous and sustained bleed protection. We do need to optimize the dosing, as I just showed you in the last couple of slides, and that's being worked on right now. With that, I will stop and I'm gonna pass the baton to Dr. Weyand. Dr. Weyand, I would like to say she's a rising star in our field, but that would be selling her short because she's already very well-known in our field, nationally and internationally. It gives me great pleasure to have her come up and talk to you about Efa. Thanks. Oh, be careful right there. Thank you, Dr. Young. It's a tough act to follow. My name is Angela Weyand, as Dr. Young mentioned, and I'm excited to have the opportunity to talk today about efanesoctocog, which I'm gonna shorten for your sake and mine to Efa for the presentation, and the clinical experience with that. Next slide. Efa has had and continues to have a comprehensive clinical development program. There have been phase I and II PK studies that have been completed, as well as the pivotal phase III XTEND-1 study in adolescents and adults greater than or equal to 12 years of age. That is gonna be the focus of this presentation. There are ongoing trials in pediatric patients less than 12 years of age, as well as the extension study, where the XTEND-1 patients rolled over into that. Additionally, there are other trials ongoing that will be looking at other special populations. Next slide. The XTEND-1 study that will be the focus of this presentation was an open-label, multicenter phase III study in previously treated patients. Inclusion criteria were adults and adolescent patients at least 12 years of age who had a diagnosis of severe hemophilia A and who had had prior treatment with at least 150 exposure days of factor VIII, whether that be through factor VIII products or cryoprecipitate. The study was composed of two arms. Arm A was for patients who had previously been on a stable prophylaxis regimen, and those patients, when enrolled, transitioned to weekly Efa at a dose of 50 international units per kg. Arm B was for patients who had not previously been on prophylaxis and had been on an on-demand regimen. Those patients on enrollment were started on on-demand Efa at that same dose of 50 international units per kilo, which they continued for 26 weeks, at which time they transitioned to a prophylaxis regimen of that same weekly dose of 50 international units per kilo. Patients were also able to participate in a prospective observational pre-study, prior to enrollment, in the bigger study, during which time their prior treatment regimen and bleeding was collected. The primary and key secondary endpoints focused on one of our favorite measurements in hemophilia, the annualized bleed rate. Secondary outcomes also included things such as pain, physical health, including wearable digital technology, and joint health, including things such as joint ultrasound. Next slide. Looking first at the primary and key secondary endpoint, the primary endpoint was met as the median ABR was zero with an interquartile range of 0-1.04. Using a model-based mean, the ABR was 0.71. I don't think this information was surprising to any of the investigators. I think we expected this to be an efficacious treatment, and I really think that the bigger focus in my mind is should be on the key secondary endpoint, which compared the intrapatient ABR between prior factor VIII prophylaxis and EFA prophylaxis. As you can see here, the mean ABR for the prior factor VIII prophylaxis in the patients that participated in the pre-study was 2.96. EFA prophylaxis, the mean ABR was 0.69, a 77% decrease. That's impressive on its own, but I think it's important to appreciate the context in which this happened. Our patients who are on standard of care factor VIII prophylaxis are infusing themselves intravenously a minimum of two times a week, some three times a week, some even every other day. We saw with EFA prophylaxis, a 77% decrease in the mean ABR in the setting of patients doing fewer than half of the number of infusions that they were doing on their prior prophylaxis. A significant decrease in their treatment burden was still very strong levels of protection with that lower mean ABR. Next slide, please. We also have started focusing more and more on hemophilia on the proportion of patients with zero bleeds. I think as our treatment options get better, we are able to aim for higher, better goals such as patients not bleeding at all. In the study, the number of patients in arm A, so these were patients who'd previously been on prophylaxis, 64.7% of them had no bleeds over the course of the study. This is in comparison to arm B, where 76.9% of patients had no bleeds, which would seem to be a bit shocking with a higher number in the patients that had previously been on on-demand, but this number is higher as they were on prophylaxis for a shorter amount of time. That 26 weeks versus the full year that arm A received prophylaxis. The figure on the right is similar to the figure we talked about on the last slide, but looking at arm B. Prior to enrolling in the EFA trial, patients in arm B had a mean ABR of 21.42. This is horrible. This is almost two bleeds a month and is really not what we should be looking to achieve in these patients. Once these patients were put on EFA prophylaxis, the mean ABR decreased to 0.69, a 98% decrease, and I think this is even more remarkable when we think about the patients that were enrolled in this arm. Patients in on-demand treatment bleed a lot, as you can see, almost two times a month. We know that each time patients bleed into a joint, it puts joint at risk for more bleeding. The joint is not normal and just kind of gets into a vicious cycle of bleeding and bleeding and bleeding some more. The fact that we were able to decrease the mean ABR in this patient population to 0.69 is quite remarkable. Next slide. Every time I see this figure, I continue to be amazed. I've seen it so many times, and it still is a little shocking to me. I think that's really because ever since I started in hemophilia, and Dr. Young has been doing this much longer than I have, but this is what we've been aiming for. Every factor company has been trying to extend the half-life of factor VIII. We made some small progress with the EHLs, but this is really the next level. As you can see here, patients who were on EFA prophylaxis at that 50 international unit per kilo dose were able to achieve normal or near normal factor levels for the majority of the week, so out to four days. Additionally, even out to one week when these patients would be redosed, their trough levels were at 15%. This is not something that we have been able to achieve with other factor products outside of making our patients infuse every day or every other day. Additionally, in addition to these higher levels than what we've been able to accomplish, there was minimal accumulation of the drug and very low variability between patients, which is really nice for healthcare providers because we really can use this one-size-fits-all dose, 50 international units per kilo once a week, and really be able to provide our patients a lot of guidance about where their factor levels are, without having to poke them a million times to do their own PK studies. Next slide. What does this mean clinically for our patients? As I mentioned, the secondary endpoints looked at a number of different things, including quality of life with the Haemo-A-QoL, which has already been mentioned in other presentations today. As Dr. Young stated, lower numbers are better, and you can see that the Haemo-A-QoL over the course of the study, there was a sharp decrease or improvement in the score in the first 26 weeks, and that continued out over the course of the year. Similarly, the PROMIS pain intensity score, although pain is a negative, this scale also a decrease is an improvement, and you can see steady improvements over the course of the study. Additionally, patients really reiterated this as well. Twenty-nine patients had exit interviews performed, and 100% of those patients stated that they would prefer EFA to their prior factor VIII prophylaxis. Next slide. In hemophilia, we obviously often look at joints, as this is a lot of the morbidity that we see in our patients. In multiple different metrics, we saw significant improvements in joint health in the patients on EFA prophylaxis. In arm A, 72% of patients did not have any joint bleeds over the course of the study. There were 14 patients in Arm A that had target joints. These are those joints that are abnormal and continue to have frequent bleeds. Of the 45 target joints in that group of patients, all of them resolved over the 12 months of treatment. Arm B patients did not receive a full 12 months of prophylaxis, so we weren't able to make a similar comparison in those patients, but there was a 96% decrease in the rate of bleeds in target joints in those patients. HJHS is a commonly used joint health score in hemophilia and really is designed to detect very small changes in joint health. This was done on patients within the study as well. In as short a time as 52 weeks, there were statistically significant improvements in this outcome, which again, is designed to detect very minor changes in joint health. I think this is exciting to see in such a short time period, especially when you think about pediatric patients like Dr. Young and myself. We meet these patients as infants, and they will be on treatment for decades, right? This isn't something like cancer, where you get treated for a year or two, and then you're done. These are treatments that will be ongoing for long, long periods of time. The fact that we are seeing clinically significant changes as little as 52 weeks, I think is really promising for what we might see over the longer term. Next slide. Clearly, we don't want our patients to bleed, but sometimes they do, and sometimes they need surgery. We also need to know that in addition to preventing bleeds, that the factor is effective in treating the bleeds. They did look at the bleeds that occurred in the study, and 96.7% of those bleeds were able to resolve with just one infusion of Efa, at that same dose of 50 international units per kilo. I mentioned that there weren't very many bleeds in the study, and 362 may seem like a lot. It is a lot, but most of the bleeds, in that group actually occurred in Arm B when those patients were on that 26 weeks of on-demand treatment. You know, we're not surprised that they occurred as unfortunately, bleeds happen when patients are on on-demand regimens. Additionally, there was a subset of patients that did require procedures or surgeries, but their hemostatic response, 100% of them were deemed excellent by the investigator or surgeon involved in the procedure. Next slide. Clearly, we need to know that the products that we prescribe are safe, and I think that the safety data from Efa is very reassuring. Efa was well-tolerated. There was no detection of inhibitors in any of the patients that were treated, and there were no allergic, anaphylactic, or thrombotic events. There were two patients that discontinued treatment, one because they received another factor treatment, so became ineligible to continue, and another who had a decrease in their CD4 count that was an HIV patient. Next slide. I think in conclusion, clearly Efa once-weekly prophylaxis really provides superior bleed protection, and in, you know, as short of a time period as 52 weeks really has shown clinically meaningful improvements in our patients', outcomes. We're seeing very high sustained factor activity levels with normal to near normal factor levels out to four days or over half of the week, and really just falling to 15%, which is still solidly in that mild hemophilia range, right at the time of redosing. This was superior to other factor VIII prophylaxis and showed, you know, substantial improvements in patients' quality of life, pain, as well as joint health. This treatment was clearly shown to be well-tolerated and safe, with all of the adverse events being expected within a study, in this population. Next slide. I think it's important to put all of this in the context of what this really means for our patients. These are just a few quotations from study participants. I won't read them myself. You can read them. I think they are striking. I enrolled several patients in the study, and they had overwhelmingly positive things to say and positive experiences. I think one of the patients I enrolled was an older patient who has very bad joints, who has target joints, and who really prior to the study, organized her life around the disease. She, you know, didn't participate in activities that she wanted to participate in. She oftentimes had to say no to invitations. She was constantly worried about, you know, when her pain would start, how much she could do before it was too painful to continue. I think, once, you know, she started on Efa, not only was she quite pleased with the once-weekly dosing, but she really started to change her overall mindset and the way she was approaching life. She started, you know, having days where she wasn't having pain and started having, you know, the opportunity and the ability to do more activities for longer periods of time without having that pain. Instead of saying no immediately to all of her invitations, was saying yes to all of her invitations. Also having, you know, these thoughts in the back of her head of, "My doctor says I should exercise more, but I previously had so much pain, I can't exercise. But maybe now I can exercise, and I'm gonna join a gym, or I'm gonna, you know, try to train for a 5K," which sounds crazy to her because that's nothing she would have ever really anticipated being able to do. My other patient was younger and you know, I think, had a very similar experience where, part of the reason he came on the study was that, his parents were going through a divorce, and his mom wanted to get divorced. It was very tumultuous at home. The whole family was affected. Their parents weren't getting along. The mom was terrified that if they got divorced, he wouldn't be able to get his infusions. Dad's not good at infusions. Dad doesn't remember infusions. How does this work if he's with dad half the week and he doesn't get his infusions? She's seen the, you know, older hemophilia patients at these conferences that can't walk because they've bled into their joints, and she doesn't want her child to have that future. When she heard about Efa, turns out mom can infuse once a week. Doesn't matter if dad forgets to infuse, doesn't matter if dad can't infuse, right? The whole family was affected by this ability to really change, you know, their weekly schedule. Parents got divorced. Everyone's happier. Parents aren't arguing all the time, right? It's like, who knew that a drug could totally change the course of this entire family's life? But I think it's been a really positive experience for them. Mom doesn't have to worry that the fact that her marriage didn't work out is gonna doom her child to a life of disability. It's been, you know, really fantastic for both of them. I personally am very excited to have this available for more of my patients. With that, I will hand it over to Bill Sibold. Well, thank you, Dr. Weyand and Dr. Young. Just to be clear, that will not be a promotional part of Efa when it's ultimately approved. We cannot guarantee that type of outcome with that patient and their marital life. At any rate, it's a real pleasure to be here. Thanks. Really welcome to everyone that's here. It's so nice to see so many familiar faces in the crowd today. I have to say, being at ISTH, there's a lot of energy here at the meeting this week. I think that there was, as I said, energy for people being face-to-face and getting to talk to colleagues which they hadn't seen over the many years, I guess, since we've had a live meeting. Also there was a lot of energy around the data that was presented and acknowledgment of what we as a company, Sanofi, are providing to this important community. Let's go to the next slide, and let's start there and talk about Sanofi and rare blood disorders. As I said, there is great appreciation for what we have been doing in rare blood disorders. Really, if you look, we've generated a lot of firsts. Dietmar pointed this out in the first slide. With Enjaymo, the first treatment for CAD, which we recently launched. Cablivi, first treatment for aTTP. Then, our current hemophilia products, Alprolix and Eloctate, which were the first EHLs launched in hemophilia A and hemophilia B. They represent about EUR 1 billion of the EUR 1.2 billion in sales that we have in this therapeutic area. Next slide, please. Let's look at the hemophilia A market and pick up where Dr. Weyand left off about the exciting opportunity with Efa. Specifically here, we're looking at the hemophilia A non-inhibitor segment, which is the largest opportunity. As you can see, it's about EUR 7.4 billion. If you look further at the factor portion of that, the opportunity is significant. About 70% is factor, and that represents EUR 5 billion in sales worldwide. Now, if you also look at the right column here, this is a highly fragmented category. There are almost 20 different factor products across the world that are used in this segment. They're relatively undifferentiated, and there hasn't been any real innovation in the segment since the launch of Eloctate, which is almost 10 years ago now. This segment, we think, is ripe for innovation. Based on the data that you've seen with Efa, we fundamentally believe Efa will be the winner in this segment. Let's go to the next slide. This is looking at, so really, where is this market going? Evaluate Pharma expects this EUR 7.4 billion to grow by almost 40% over the next five years, exceeding EUR 10 billion. That's really gonna be driven by the introduction of new and innovative products, which will drive further adoption of prophylaxis. We know the market is gonna grow, and based on our recent market research, that the market is going to be dynamic. Here you can see six out of 10 hemophilia A patients are open to or likely to switch treatments within two years. You know, we know that there's been switching in the past when innovation comes in, and we fully expect that's going to happen again with the new innovation, that we have. How will that EUR 10 billion be split out? In that survey of patients that we did, we asked the question, "What would you prioritize in terms of your treatment?" Here you see 40% said they wanted the highest efficacy levels, and 44% said they'd rather have efficacy with the lowest treatment burden. We feel extremely well-positioned. When you see this is what patients are stating they want, that is their new expectation. With our portfolio, we're extremely well-positioned. Let's go to the next slide, please. Here, we map out the market on these two dimensions of efficacy and treatment burden. You can see where the current classes fall, where the open space exists, and the opportunity for Efa and fitusiran in that future. Maybe we'll start with fitusiran. While all patients want efficacy, as we said, treatment burden is a very important consideration for many patients. Based on the expected product profile for fitusiran, we see it offering both better efficacy and a lower treatment burden than current therapy. We're calling this the extended efficacy class. Now for Efa. Based on the data you've seen today, we see it really creating a new class. This is a high efficacy class offering superior efficacy above any product that there has been in hemophilia A and anything that we see. Near normal factor levels for the majority of the week and true once-weekly dosing. This new standard of possibility, I would call it, is just starting to be appreciated, and I think for those of you who were at ISTH this week, I think the community is trying to understand a new level of efficacy which hasn't been seen when you're near normal for almost a week. That's gonna be what takes some time for people to understand. As we get closer and closer to launch, I think that one of the things that we're gonna be working on is making sure that the community does understand this and see the possibility that exists now for patients living with hemophilia A. We're very excited about the future. We think that we have the portfolio. We think that we have credibility in the space based on all the firsts that we have. What you're seeing here today are two new firsts that we're going to have in the space. There is more to come. As you know, Dietmar said, we filed, we expect to launch next year with Efa, and we have full efforts on making that an incredibly successful launch and bringing a game changer to the market. With that, I will turn it back to Dietmar for some closing remarks before we move to Q&A. Thank you very much. Great. Thank you, Bill. I hope what you took away is really, yes, we are committed to the space, both to patients with hematologic disorders, but also to the hematology community, to the hemophilia community as well. We've also spoken about the market, how that is gonna develop, especially in hemophilia, and we are really well-positioned to participate there and have a bigger stake in that. That's really based on the understanding that you have different patient populations who have different needs and we have products that can address those needs in a way that we have not been able to address them before. With that, I would ask all the presenters to come back. Basically, what's gonna happen is, Eva is gonna structure the questions for us because there's also questions coming online. We have quite a number of people also dialing in online. We will take a seat here on these very comfortable-looking barstools, and then we're gonna answer your questions. Thank you. Just need to arrange myself here. Yes. We're gonna start with questions. We would like to ask you, certainly for the first round, if you could keep your questions to one or two. We're gonna start in this room momentarily. I think we have two mics ready, so we would like to ask you to wait for the mic so the people on the webcast can follow you. Just a quick word to those that are following online, you will be able to ask questions. I can see there are already some hands raised. We will get to you shortly. If we call out your name, please make sure to unmute your microphone so we can hear you. I can also see the questions that are in the box, so if you have more questions to submit, please go ahead. We probably gonna start on this first. If we do Jo first. Thank you. Jo Walton, Credit Suisse. Thank you very much, doctors, for your presentations. I wonder if I could ask you where you feel that these new products might fit in with your practice. I think we've understood from Dr. Young it's with everybody who's on their factors, but what about fitusiran? And if I could ask just when you're thinking of that, if you have any idea of the mechanism of action that gets you this cholecystitis and cholelithiasis, whether that's a concern to you, whether it appeared just at the beginning of the study or it might coming later. And if you have any issues of patients who might need surgery. you know, if you're concerned if you put them on fitusiran and then they need surgery, do you have enough experience of all of those sorts of things to look for what's really a fundamentally very different type of product? Thanks for your question. Different questions. Let's start with the cholecystitis, cholelithiasis. The mechanism of action is not known. I know that Sanofi is very interested to understand what that might be, and they're working on that. How concerned am I about that? Well, speaking personally, I had a cholecystectomy last summer, and I went into the hospital in the morning, and I went home later in the afternoon. I was gonna say I had hamburgers and french fries, but my doctor would get mad at me. I mean, I think that it's some area of concern because we don't understand what is causing it. I also think that, you know, cholelithiasis and cholecystitis is really quite common. I'm a good example of that. I think for a patient for whom fitusiran is going to be really beneficial to treat their hemophilia, that's not really too big a concern for me. I obviously- You know, we'll tell them that it's a possibility, but I don't think that would stop me from using it in a patient who's gonna, you know, potentially significantly benefit from it. As we've seen from the studies that, you know, really any patient with hemophilia A or B, with or without inhibitors, could potentially significantly benefit from it. That was the cholelithiasis one. Surgery. It hasn't been presented. There's been surgeries, you know, during the trial. I can't get into the details of it because, for one thing, it's not published. For another thing is I don't remember all of it in any case. You know, with all of these products, we sometimes, you know, patients need to have surgery, and we have always figured out, both in inhibitor patients and non-inhibitor patients, how to manage patients through elective surgeries or even surgeries related to their, you know, hemophilia, whether it's joint disease or things like that. I'm not concerned that we won't know how to manage those surgeries. Some have already been done in the trial. Yeah, that is something that as we accumulate more evidence and more surgeries, we will have a good idea as to how to best manage that, fairly simply. Your first question, I think, related to, you know, which patients, you know, would be most interested in fitusiran. I think one thing that I can tell you we deal with all the time is venous access issues. I mean, it's a huge problem. I take care of children and adults. In younger children it's a tremendous problem. We often have to put central venous catheters in patients, which is never something we want to do. If we don't do that, it's practically an impossible task for parents to keep repeatedly finding veins to poke their children, not to mention having to hold them down and have one parent hold the kid down while the other one's jabbing a needle in their veins. Nobody really wants to do that. In older patients who have accessed their veins for years, that becomes a problem too. Some of them only use one vein or two veins. I remember touching one guy's vein. It literally felt like, you know, like a copper cord or something. I was like, "That's where you poke it through?" He's like, "Yeah." I was like, "That's gotta hurt." He goes, "Yeah, it hurts a lot." You know, so then we talked to him about, you know, the potential options and future options. Venous access remains a big problem. For those patients in whom venous access is a big problem, fitusiran could be a great solution. You know, for those who don't, who prefer factor and venous access is not an issue, and I have plenty of adult patients who they rotate their veins and they can manage with that. You know, that's where fitusiran is still an option, but that's where, you know, Efa could be an option. I hope I don't wanna take too much time answering every question, but I hope I answered the ones you had. Thanks. If I can just briefly chime in and add, right? We're obviously changing the dosing paradigm for fitusiran with the objective to really also improve further the benefit risk. We're confident that will impact really the risk of thromboembolic events. It will also impact the risk of any, for example, liver transaminase elevations or also cholelithiasis. It's our expectations. We're obviously going to follow up on that, right, with the amended studies. There may be more to learn about really the frequency of these events and how does that impact benefit risk eventually. Okay, thank you. Go to the middle, if we have Vimal, and then we just wanna continue that table. Thanks, everybody. I'm Vimal Kapadia from Bernstein. Two questions, please. First, just on efanesoctocog alfa. I'm just curious, for one dose, you know, if you were just to have one dose, how long would it take to get to a factor level similar to one of the existing factor VIII? Is it nine days, 10 days, 14 days? I'm just curious. The reason I ask is, in the real world, could we see patients really using this drug for longer than every week? Because the area under the curve is quite, you know, quite robust. That's the first question. Then my second question is just I appreciate the change in the dosing for fitusiran. Given hemophilia patients are quite conservative, you know, if you are on fitusiran and, for example, you feel pain in your arm, you think you might have a bleed. You know, when you're on factor in that situation, you can dose up to 100% without the risk of thrombosis. I appreciate in the clinical trial setting, but in the real world, how practical is the drug when you always have this concern at the back of your mind that if you feel like you might have a bleed, you have to be very controlled about the amount of factor you have to give. Thank you. Yeah. Why don't you do the Efa question? You know, currently or longer term, historically, we have aimed to keep the factor level above 1%, and I don't know the exact number of days for Efa where that is. I think, you know, the thought is that it's more of a one-size-fits-all 50 international units per kilo once a week. I think definitely, there will be patients and healthcare providers that personalize that more, whether that be, doing it more frequently to try to keep people normal for longer or extending the interval for people who may not need as high a level of coverage. I think that, definitely, in my mind, will likely happen once the product is approved. I think it is nice that there is not very much variability, so people can stick to that kind of one-size-fits-all if they want to. I just want to add, I mean, obviously, the intention with Efa is to increase efficacy, right? To really have patients avoid, for example, their joint bleeds, and to really have them lead a normal life. The intention for us for Efa is not to extend kinda the treatment intervals much more and then to not be differentiated versus standard factor, right? Obviously, it's harder for us to predict what will happen in the real world, but that's clearly the intention, and we don't wanna give up on that advantage because that's what we really feel is moving the field forward. Yeah. As to your other question, it's a really good point. First of all, no matter what type of hemophilia you have or what treatment you're on, at some point, you're likely to have a bleed. I mean, it's hard to prevent 100% of bleeds 100% of the time and 100% of the patients. I mean, most patients at some point are going to have something that may be a bleed. What you're relating to is something that feels like a bleed but not sure it's a bleed and, you know, in those circumstances in the past, we always said, "Well, if you think it's a bleed, just treat." I think we're learning actually that, you know, regular aches and pains happen in hemophilia. The experience that I've had, you know, with emicizumab over the past bunch of years is we have patients who feel like a little ache, and actually even during the trial, they actually started to say, "Well, I'm not sure it's a bleed, and I'm just gonna wait." Many times, it didn't turn out to be a bleed, and they didn't have to give factor. Then if the symptoms got worse, then they would treat. I don't think it's an issue. I mean, it's gonna end up being a, you know, the way that the physicians and the healthcare team interacts with the patient. Some may say, "Well, you know, yeah, if you're feeling some pain, I would like you to give a dose of factor." You know, the doses to, you know, use factor for management of bleeds or potential bleeds on fitusiran, there is a guide on how to do that. It's lower doses than we traditionally use because you get this added effect. I think for some patients, the conversation might be, "Look, if you feel a little bit of pain and you don't think it's a bleed, maybe wait it out a few hours and then see what happens." This is something we're trying to figure out with these newer products. I don't think it's an issue in terms of, you know, for those patients that we do prescribe, whether it's factor or Hemlibra or in the future, you know, fitusiran or frankly, even Efa, there's gonna be those situations where you're not sure something is a bleed. And then it's, you know, it becomes, like I said, it's a discussion that you have with each individual patient, and some may just, you know, they're more anxious, so they want to dose. So that's fine. They can dose. Whether it's a bleed or not, they can dose and feel better about it. If it was starting to be a bleed, they stop it. If it wasn't, you know, generally speaking, no harm done. If they wanna wait to see if there's further symptoms, then some patients will say, "Yeah, I think I'd rather just wait it out. If my symptoms worsen, then I'll give a dose." Not really too concerned about that, but it is something we're seeing more, is these sort of subtle kind of pains and should we really react right away, or should we take a little bit of a wait and see approach? We're starting to do a little bit more of this wait and see approach. Okay. If we just move over to Laura. Thank you. Laura Sutcliffe, UBS. I have a question on fitusiran please for both Dr. Young and Dr. Weyand, 'cause it's about how it might be used. If you have a patient on emicizumab, the likelihood is they've already had a pretty radical change in what their treatment burden looks like. Fitusiran comes along. Can you get those patients, like, back from Hemlibra in inverted commas? Or what is it the case that once a patient has made a really big step change like that, they're gone and they're not accessible for something like fitusiran? Why don't you go ahead first? I think personally, my experience has been in the clinic that, you know, we've had this huge increase in the number of products being studied and available in trials for hemophilia. I think there's been a little bit less of that like, "Okay, now, like, this is my product forever." Because I think people are hearing more and more like, "Okay, well, now there's maybe another new bispecific antibody, and now there's gonna be fitusiran, and now there's." You know, it's just like always something new. I think patients are more open to, "Well, if there's something better, why would I not try that?" And I think the, you know, every other month versus monthly is halving your treatment for the year, right? It's getting to so few treatments. Dr. Young and I were talking about right before this started that, you know, we have not been super impressed with hemophilia A gene therapy. You know, we're not there yet. That having a treatment you could do six times a year or a gene therapy that gets you a decade or less, it becomes a lot. You know, I think we're getting to this point where the treatments are amazing and the treatment burden is so low. I think that patients still, you know, will identify even if it's just, you know, my quality of life is really, really good now, but it would be just a little bit better. I think they're more open to that now because there's so many options. Yeah. My comment on that is that if you look at real world data, about 70% of patients on Hemlibra are on every two weeks, so that's 26 injections per year. And I will say, you know, they, these are they're single-dose vials. You have to draw up the dose every single time. And depending on your size, the volume can be, you know, one ml, two ml, actually even three mls. It can be fairly large. And what I'll say that I've learned from, you know, talking to my patients about it is that, you know, the injection, the needle doesn't hurt at all. Actually, I've had patients like, "Turn your head." They don't even feel the needle going in when they're giving the Hemlibra. Once you start pushing the plunger, it does burn a little bit. Now, look, I am a fan of emicizumab. I was involved in the HAVEN trials. I have a lot of patients on it, and it is a great drug. If you're asking me and you ask who's gonna potentially switch over, well, 26 infusions a year versus six, larger volume of infusion versus smaller, painful infusion versus what is really not a painful infusion at all. You know, I do see situations where parents are like, "Yes, the Hemlibra is great and Boy, it's really tough, you know, when we have to do the infusion." Even going from 26 to six and having them be less painful, you know, certainly for some patients who are adults and for some parents of children, that added value and keeping everything else the same, like it's gonna be equally effective, it's gonna be otherwise, you know, equally safe. If we keep all that the same, which I think we've shown pretty much is, I certainly think there'll be patients who will consider switching just on the basis of this less frequent, less painful and less voluminous infusions. Okay. Simon? Hmm? That's Simon Baker from Redburn. Two questions, please. On ATLAS-PPX, I noticed there was a case of Hy's Law. I wonder if you could just go into the details around that. Also, presumably or hopefully, when you move to a lower dose, the level of liver enzyme elevation will decline. I just wonder if you have any data to support that. Then a broader question, which Dr. Weyand was starting to allude to, really where we stand in terms of gene therapy in this space. Much has been promised. We've seen a few advances. We've seen a few setbacks. Doesn't look like anything's really set the world on fire yet. Really just getting a clinician perspective from both of you would be great on where gene therapy stands and the future PROMIS. Thanks so much. I mean, on the Hy's Law thing, I mean, we're seeing clearly there is an increased evidence of hepatic enzyme and cholestasis. That's being looked at and investigated. The thing I like is that, you know, from the data, is that most of the patients that did not lead to any discontinuation of their medication. You know, it's something that, you know, as was mentioned already. You know, Sanofi is continuously looking at this, trying to understand it. Will the lower and less frequent doses impact on that is something that we'll see. It is only one case out of, you know, many over the course since phase I and phase II that have added up to the, you know, several hundred patients who've been on it. So, you know, are the liver issues something that need to be investigated, understood, try to, you know, eliminate? Yeah, of course. Is it something that seemingly is going to, I think, derail this in the future? I don't think so. I mean, there's you know, if every drug that elevated transaminases, you know, was not approved by the FDA, we'd lose about 50% of the drugs that are on the market, I mean, in all honesty, if you take a look. So I don't think that is too concerning, but I. You know, I certainly, as a clinician, wanna know more from the company as they investigate this, if they can explain things a little bit better, particularly, you know, like I said, the cholestasis. I'll let Angela start on the gene therapy. Yeah. I think everyone is excited about curing hemophilia. Gene therapy right now does not cure hemophilia. I think the rate of decline with factor eight is a huge question. There was a session at ISTH this week, where the levels at five and six years are in the single digits. You're risking whatever long-term, you know, risks there are associated with gene therapy, which we don't really understand, and being exposed to AAV, which we know is gonna probably preclude you from other AAV gene therapy. In my mind, it's difficult for me to identify patients that I would recommend that for anytime in the near future, just given that it is a very finite amount of time. Dr. Young and I were talking on this right before the session started, so I think he has, you know, kind of a subset of very unique patients that it might be a good option for. I think it's a difficult thing to think of who in my practice those patients would be. In addition to the fact that pediatric patients are obviously not going to be treated with it. Inhibitor patients obviously are not gonna be treated with it. I will let you talk about- Yeah. kind of that subset. Well, yeah, I'll bring up that subset in a minute. I think you have to think about it as hem A and hem B differently. I think with hem A, what we've seen is, as Angela said, you know, we're seeing declining levels. We're seeing patients already some on the BioMarin phase III study who are already back on prophylaxis even at two years. The other issue that really troubles me a little bit is the steroids. You know, the average duration of steroids is like nine months. The last thing you know, one thing we get taught early on in our careers in medicine is when you're treating something, don't treat one thing and then cause other problem. You don't wanna trade one problem for another. I mean, the last thing I wanna do is give somebody gene therapy and then they're on steroids for, you know, up to a year, which we've seen even longer. Now I've caused them, you know, some permanent like avascular necrosis of their hip, which is a problem you can't even fix without a hip replacement is the only way. I mean, is that really a success? Hey, your hemophilia is cured, but, you know, I destroyed your hip. We have to be cautious about that. I think that what makes me a little bit cautious with the BioMarin data that I've seen. You know, the other products are a little further behind and, you know, maybe they'll be different or maybe they won't. For hem B gene therapy, I'm definitely more optimistic, to be honest. You know, with the CSL product, we've seen you know, really quite good data. We've seen patients who are not on prophylactic steroids and only about 20% end up needing any steroids. I think there's definitely some optimism there. It's still gonna be a brand-new platform. Somebody mentioned the hemophilia community is a little bit conservative, so I don't see that all of a sudden all hem B patients are gonna be clamoring for this. I definitely think there'll be some who would. In terms of the subset of patients, I have some young adults, they're you know, 18-24. Obviously, these are pretty much all males. I remember when I was in. I don't have hemophilia, but as an 18- to 24-year-old male, I didn't really do things the right way very often myself either. It's partly a miracle I'm still here, but no, that's a different story. In any case, the point I'm making is that I've got these young men who, you know, mommy and daddy did all their infusions and made sure they did their infusions when they were in high school, and now they're either going off to university or they're starting jobs and, you know, they're just not doing their factor. They just aren't doing it. Even some I put on Hemlibra, they're not doing that either. For that group of hem A patients who are starting to get joint disease after 18 years of their parents making sure they didn't have joint disease. If I can Even if it only lasts two years, four years, five years, especially, you know, for most patients, you're getting decent levels at least four or five years, it seems like from the phase I data. If I can buy them those five years where they don't need factor, where they'll have a good enough factor level to get them to, you know, some level of maturity. Oftentimes, you know, then they're not as transient as they were, transient moving around. You know, they may wanna start a family or have a partner and, you know, they'll probably wanna take better care of themselves. I see for some of these patients that this could be a great product to sort of bridge them when they're just not gonna do any sort of treatment and destroy their joints. I think I have some patients for whom I think clearly that product is gonna be great for them, and as soon as I can get it, I will prescribe it for them. For the sort of massive, you know, hemophilia A adult patients, you know, those who really want it, sure, I will discuss the risks and the benefits and we'll see how it goes. There's a small subset that I think really can benefit from it. If we finish the table with Keyur and then we move over to the other side. Hi. Keyur Parekh from Goldman Sachs. Two questions, please. The first for you, Dr. Weyand. You said 354 of the 362 bleeds in that study were resolved with a single dose of Efa. Can you kinda give us some details for the other 12? If my memory is correct, there was also a patient death on that study. Any kind of details around the patient death on the study would be useful. Then separately, question for both of you. I think Dr. Young, a lot of us were in the room when you presented HAVEN 2 a few years back, and there was kind of silence in the room until it broke out into an applause. I think it was just the sheer notion of how much of a move forward emicizumab was compared to the standard of care at that point of time. As you think about fitusiran, do you see it as a similar move in kind of providing new options? Linked to that, kind of the space is gonna get increasingly crowded, be it concizumab, be it MIM8, be it kind of few other bispecifics over the next few years. What do you think kind of the treatment protocol or standard of care looks like in five years from now? I believe the death in the study was completely unrelated and was a type of cancer in a patient. And the 12 bleeds that were not resolved with one, I believe, were resolved with two infusions, but I don't have the exact details on all of that. But I think, you know, just even having the resolution of the bleeds with just one infusion, I think opens up a whole another segment of the population in terms of we have a lot of mild to moderate patients that are not on prophylaxis. They may be interested in being on prophylaxis now that we have better products, but even if they aren't, those are patients that don't typically self-infuse. I think knowing that we can resolve bleeds with one infusion, these are patients that typically would come to the ER to be infused. Saving them additional ER trips or additional time, I think, would be very valuable. Yeah. Yes. Yeah, I just wanted to respond to the question from Sanofi, Craig Benson. Those 12 bleeds, I think they all resolved with one or two doses of follow-up factor, but we'll confirm that after the conference. Yeah. Craig Benson is the head of the program at Sanofi. Oh, thank you for reminding me about the HAVEN 2 presentation. That was my Sergio Agüero moment, for those of you who know what I'm talking about. I probably should have retired right after that. Yeah, it was for those of you who weren't there, as I presented the HAVEN 2 study for the first time and, yeah, there was sort of some silence, and then, you know, the applause just went on and on and on, and really never seen that in any sort of meeting before. It was a great moment for me. Yes, it was because it really was a huge step. I mean, you know, particularly kids with inhibitors, I mean, gosh, there's just suffering. I mean, this is. We don't like to see adults suffer, but it even hurts even more to see children just suffering. You know, before that drug came along, you kinda knew what their future was 'cause we saw the adults with inhibitors. Like, your future is you're gonna be in a wheelchair and you're gonna have a lot of pain. Yes, it, I mean, just, you know, it has revolutionized the treatment of patients, especially with inhibitors. And it's absolutely made a massive step forward in their life. However, you know, there's always room for improvement. If we just wanna, you know, rest on our laurels, then, you know, we'll never make more advances and more progress. For, you know, patients with inhibitors, there was no obvious comparison to Hemlibra. You know, does fitusiran offer something that Hemlibra does not? We talked a little bit about these convenience factors, so there's clearly something there to be said. You know, what about, you know, sort of efficacy? I mean, you're not gonna show in a clinical trial better efficacy than what you see with Hemlibra. It's already so low. There's no way even statistically to show it even clinically meaningful differences. Is there something about fitusiran? We've seen data on thrombin generation at this meeting. Is there something about that it gives you better thrombin generation than emicizumab? I think it's a definite possibility. I really would like to see sort of more work being done in that area. Because what we do see with Hemlibra is patients are starting to get more and more active, and they wanna do more sports. We do start to see trauma-related bleeds. We know Hemlibra is converting patients to more or less a mild hemophilia phenotype. You know, maybe it's 10%, 15%, 20%. There's different studies that have estimated in that area. It's definitely not giving people normal hemostasis. The question is, can fitusiran offer something better than that? I think there's more to learn about that. I think what we see in the thrombin generation data, if you just flatly compare one to the other, it does seem like it looks better. I think we need to do more work to really suss out those differences. If it does, then there may be patients for whom in particular who are more active, that if you do have a product that gives you know, sort of better protection and you wanna be really active, but you don't wanna do IV therapies. I mean, we have Efa for patients like that, possibly. You really, you know, venous access issues. I think there could be some potential advantages there. Then you mentioned a few other products. Yeah, I think it's always, you know, one thing I really respect about, you know, all the drug companies involved here is that they're just kinda pushing the envelope more. We used to think like, oh, 1% trough level and, you know, you do IV three times a week and things are great. Well, that was the case in 2000 and 2005. But then we got to the extended half-life factor. You saw some of that evolution. We wanna keep getting better and better and better, and we wanna keep doing more and more. I would love to get to a point where, you know, all my patients can do anything they want and not really worry about bleeding and hardly ever have to infuse anything. But there's a long way to go for that. You know, the competition between companies to further innovate and further do better, I mean, it's fantastic for patients. I know we'll have more options. The more options we have, the better off the patients will be. Okay. I think if we have a mic on this side or we have one. I do wanna bring up that you did skip this young man here. He had his hand up a while ago. Oh, I You moved away from the table. He- I've been in that position before, so we'll circle back to you. Sorry. No, no, that's okay. Well, it's not your fault. Actually, I think. He came to me. Sorry. I think I skipped. There was, I think, a last question. Sorry. Will there be a change in treatment protocols going forward, right? Wasn't that sort of the last bit when we have more treatment? I think the answer to that is the more options we have for patients, the more we can offer different things. Some patients, you know, the values of different patients, you kinda saw a little bit about treatment burden versus efficacy. There's other things too. You know, the more options we have, the better. I kinda jokingly say that, you know, with hemophilia, for the most part, it was like going to have lunch at Subway. You're leaving with a sub. I mean, you may have some different flavors, but that's what you're leaving with. Well, we're gonna have a much broader menu. I don't think you guys have The Cheesecake Factory around here, not that I'm a big fan of it, but some restaurant that has Caffè Concerto. I think you have those, right? You can go in there and get a salad, get fish, get a sandwich, get a hamburger. Yeah, we wanna have more on the menu because not everybody likes salad and not everybody likes a hamburger. Emily. Emily Field, and I love The Cheesecake Factory. But just kinda building on the last question, more, I guess, kind of where we're at today, and kind of also in where we're going. In terms of across your practices, what's the share of patients that are on-demand and not getting any prophylaxis at all? Of the patients that are getting factor prophylaxis, what's the share that are on the extended half-life therapies? And kind of the broader question is sort of who are gonna be the initial candidates for EFA? Are they the ones that are maybe already on the extended treatments that are more motivated to reduce the treatment burden? Or is this something that is extended enough that maybe those not on any prophy at all could pick up treatment? Yeah. I think of the patients that we currently have on any factor, we actually have a very small number still on standard half-life factor products, more on extended half-life. I think there's no medical reason why they wouldn't all switch to EFA, ones that are already on factor, and I think it will open up a segment of the population, women, mild, moderate patients, all that, you know, may be more likely to use prophylaxis with the longer half-life. I think there's also, you know, patients that we currently have on non-factor products that would also be interested in switching, whether it's. pain with the subcutaneous injections that prefer intravenous, which I have a handful of patients in that situation, or patients that, you know, want to be able to do activities that they aren't necessarily able to do without those higher factor level equivalents. Yeah. I guess I can add just briefly that it's interesting as we're thinking about moving forward. There was a presentation this morning about differences between hemophilia A and B in mild and moderate hemophilia, which got me thinking about that. You know, as we push the envelope and as we get the severe patients. My answer, all my severe patients are on prophylaxis. Maybe about 25-30% of my moderate patients are on prophylaxis. But what about those moderate patients that are not on prophylaxis and some of the milds that are, you know, not 30%, but 5-6%? I mean, if we're gonna give all the severes a treatment that their lowest level is gonna be 12 or 15%, well, then we're doing a disservice to the moderates that are 3 or 4% and the milds. I think we're going to start getting more and more patients that we're just gonna push, try to push everybody to a better place. Because why should somebody walk around with 5% or 6% where, you know, one bad fall on a hike, or one car accident, which happens, could be, you know, really like life-threatening when I can have their level higher? We're just gonna have to get, you know, the payers to understand that, you know, this is a severe disease. It's a life-threatening disease, even for those that have higher levels. It just takes that one wrong accident. I think as we're pushing things, you know, we can't treat all the severes and have them be 12% or higher or on fitusiran or on emicizumab, and then have these moderates at 3% or 4% and milds at 5% and say, "No, you're fine the way you are." That's not fair. Maybe just to comment on the level of prophylaxis. It varies by country. In the U.S., it's around 70%. In Japan, it's closer to 80%. We expect fully over this time, this next five years, where it gets above that 80% number. Okay. The next question from Harry. Brilliant. Thank you very much. It's Harry Sephton from Credit Suisse. I just wanted to touch on, in the EFA data, I think you saw 0 inhibitors during the study. Is there a structural reason that you see as to why EFA might not develop inhibitors versus what you see from Eloctate? Is that something that you're excited about in the data that that might be something differentiated for your factor eight patients? I don't think there's anything in my mind structurally that makes it different from a Eloctate, for example, like in terms of inhibitor formation. I think it's difficult because these were all previously treated patients who are at a lower risk of inhibitors. I personally would like to see some PUPs treated with it, so that we can see those numbers, because I think that still is a question. We'll just kind of have to see. Anything to add, Dr. Young? We're obviously following that really closely right. There has been a hypothesis that, you know, the side chain, the extended side chain, which uncover the immunogenic epitopes. Obviously those side chains come off at one point. I really think we need to see in the clinical trials. To me, it's quite encouraging there that we haven't seen anything so far, but we'll follow that. Brilliant. Thank you very much. Okay. I would then go to the webcast, and the first question would be from Graham Parry. Graham, if you could unmute yourself and go ahead. Great. Thanks for taking my question and apologies for not being there in person. Just want to follow up actually on that issue about inhibitors. I think the patients in XTEND-1 have been on factor VIII for more than 150 exposure days. Does that pre-select patients who are unlikely to develop inhibitors? Do you think we will see a higher rate of inhibitors in real world? Second question was just on fitusiran. Just given the safety issues that have been seen, both thrombosis and liver at the monthly dosing, you seem to be fairly dismissive of those. Just if that was an approved product today and you had exactly the profile you've seen in those monthly dose phase IIIs, how comfortable would you be in using it and what sort of proportion of your patients do you think you'd actually use it in, given that we have something or we'll by the time it gets to the market, I guess, have something like Efa on market with high efficacy and extended dosing. Yes, choosing patients that have had at least 150 days of exposure does make you more likely to not have inhibitors. Absolutely. I think that when we look at the general population, the more patients you treat, the more, you know, issues you're going to see. The fact that we saw zero inhibitors, I think at some point a patient on Efa will have an inhibitor, right? I don't think we've had any factor products that no one ever got an inhibitor using. I think at some point we will. I think I'm also encouraged by the fact that we haven't seen any so far. Thanks for your question. I didn't mean to be so dismissive of the liver issues and I, you know, and if I was, I apologize. I mean, it definitely needs to be investigated. I mean, we wanna know what is causing it. We wanna try to understand if there's a way to mitigate against it, even maybe prevent it entirely. I think just in the grand context of things, as I think about, you know, hemophilia A and B patients, particularly those with inhibitors, but also those without inhibitors, you know, we always look at every drug with the benefits versus the risks. In a given situation, you know, if the benefits outweigh the risks then obviously you're going to go for that. What if there's a patient who's, you know, struggling with IV infusions or doesn't have good IV access? Maybe they have hemophilia B, for example, so they can't have emicizumab. You know, a situation where they're having more bleeds and joint bleeds and, you know, we need to get that under control. What would their options be? Maybe gene therapy would be an option, but that obviously has risks that are potentially long-term and even some short-term that that we're still learning about with the new platform. Then there might be fitusiran. Then with fitusiran, there is the issue of, you know, some percentage of patients that are having elevated transaminases. As I said, with elevated transaminases, almost all those patients stayed on the drug and the transaminase levels either normalized or kinda stayed stable. Then some did get cholelithiasis and had cholecystectomies. Those were treated and then they went on. Like with every drug, we have to look at the individual patient. What are the benefits of this drug? What are the benefits for fitusiran for this patient? What are the potential risks weighed all together? Yeah, there may be some patients who, you know, maybe already have some liver disease or who knows, maybe they had an ultrasound, they already have some cholelithiasis. I might not, you know, wanna use fitusiran in them. It's again just a balance of everything. I think, you know, in medicine, there's almost never, you know, a free lunch. There's always gonna be some side effects that you have to weigh against the potential benefits of the drug. So yeah, I didn't mean to be entirely dismissive. I think it's there in a, you know, minority of the patients, but not a small minority. It's just something that needs to be weighed when you're making those decisions. Got it. Thanks. Thank you, Graham. The next question is from Richard Vosser. Richard, can you unmute your line? Yes. Thanks. Thanks, Eva. Two questions, please. Firstly, on the Efa intrapatient comparison, was that done on all bleeds or treated bleeds? And could you put the data into context with Hemlibra's data in HAVEN 3? Because that's the only other one where I think we've seen this intrapatient comparison. That would be helpful. And then secondly, just maybe slightly off topic, but just going on to rilzabrutinib. We've seen quite a lot of BTKs having liver enzyme monitoring. Question is rilzabrutinib having liver enzyme monitoring now in the ITP trials? And would you see this as a problem for the use in ITP, given there are plenty of other treatment options, including generic TPO-RAs by the time this comes to market? Just thoughts there. Thanks very much. For the Efa, all of the bleed data were treated bleeds. Specifically comparing it to emicizumab, you might have a better idea. Well, I think actually what's remarkable, if you look at the HAVEN 3 data, the intra-patient comparison, when you look at pre factor prophylaxis before, if you look at the ABR, I think it was actually 4.4. It was almost exactly the same. That struck me when I saw that. I was like, "Yeah, that's kind of exactly." Which tells you that in the real world, that's kind of the ABRs you get with factor, is really somewhere around 4. That's, and I think it's a favorable comparison. With regards to Rilza, that's obviously going to the BTK inhibitor question. We are monitoring liver enzymes in all of our clinical trials, right? But for Rilza specifically in our studies, we have not seen any elevations of liver enzymes at this point. Remember that rilzabrutinib is differentiated in a sense where we have this tailored covalency concept. We were hoping from the beginning that there would be differentiation also on the safety side due to that difference in binding to the BTK. At least so far, we have not seen anything in our studies. We're maintaining our standard monitoring in those studies. Thank you. We would move on to Seamus. Seamus Fernandez. Great. Thanks. Just a couple of quick questions. Excuse me. First question is, you know, for the physicians, as you think about pediatric patient populations, you know, we've had some Hemlibra evangelists that we've spoken to, sort of suggest that there really isn't a reason for a pediatric patient to go on to factor VIII therapy, largely because of the risk of developing inhibitors. You know, what are your thoughts along those lines? You know, what really is it that drives the patient community, and the physician community towards the use of factor VIII therapy, too, I think a preference to some degree, and correct me if I'm wrong there, a preference in of use of factor VIII in the pediatric patient population. Then, separately, as we just think about the broader opportunity, I was just hoping, Sanofi, if you could clarify for us, you know, what the breakdown is in the United States versus international markets, you know, in terms of where the concentration of the revenue that you showed for factor VIII therapy is. Just seems like the physicians that we've talked to in the hemophilia space are really driving a huge number of their patients to Hemlibra therapy, regardless of inhibitor status. Thanks. With the evangelist perspective, I don't agree with that. I think that it's important to remember that even if you're treated with emicizumab, you're still going to need factor VIII, right? They did a procedural study on minor surgeries thinking that patients on emicizumab would not need factor for procedures. That didn't go the way that it was expected, right? Patients are still going to need it for procedures and surgeries. They're still going to use factor for treatment of bleeds. We don't know what that means for inhibitor development if you have factor VIII, you know, exposure over a more extended period of time, so you don't get to 150 exposure dates until you're much older. We don't really know. These are things that we'll hopefully be learning as people are on emicizumab. We do treat a lot of young children with emicizumab at my center, not because it's not factor VIII, but because of the access issue where you can start an infant on subcutaneous injections much easier than doing intravenous access. My mentor, a wise man that Dr. Young knows very well, you know, has said over and over, like, "If you have a deficiency of factor VIII, you treat that with factor VIII." I think that's the simplest thing that, in my mind, covers all of your bases and is most safe. I think that to think that you wouldn't use factor in children because of a risk of inhibitor does not make sense to me. I've been accused of being a Hemlibra evangelist, but of course, I was involved in the clinical trials. What I'll say is that I'm a patient outcomes evangelist. That's the only evangelism, by the way, I ascribe to. In my practice now, 60% of my prophylaxis patients are pediatric patients on Hemlibra, 40% are on factor. You might ask yourself, why is that? Hemlibra obviously has a lot of advantages in terms of ease of use and things like that, and that's why the majority have opted for Hemlibra. I think that, you know, to think that a huge number of those patients, when Efa is available, say, "Oh, now I'm willing to go back to IV once a week from sub-Q every two weeks," you know, I think that's unlikely. What about those 40% that have chosen factor? Why? Well, as Angela said, and her mentor, a good friend of mine, Steven Pipe, you know, he says it right, which is that, you know, one way we think about hemophilia A is it's a deficiency of factor VIII, so isn't the best way to correct it to replace it with factor VIII? Well, yes, except that that has to be done IV, the adherence issues, the multiple times a week issue, something that Efa is trying to address. But still, some patients really, really stick to that. They say, "I don't wanna try something new or different. I don't wanna try something that isn't factor." That's why 40% of my pediatric patients still use factor VIII replacement, as difficult as it might be. That's fine. That is a patient choice, a parent choice, and having more choices is better. How do I see my patients going forward? Those 60% that have already declared, "I want the easiest, I want sub-Q, I don't wanna deal with IVs." I don't really see hardly any of those going to EFA, but I do see those as an opportunity for fitusiran, as we talked about at some point, when that becomes available. For those 40% who are still on factor, I honestly can't imagine why anyone wouldn't want EFA. If you can have your cake and eat it too. What do I mean by that? Well, you saw the data. You can infuse less often and have higher levels. I don't really know why a patient wouldn't want that. Now, we know there's conservatism as one of you mentioned earlier. Some patients, yeah, are gonna stick to that. Even though we've had recombinant factor rates in the U.S. for 30 years, I just got my last patient off plasma, like 2 years ago. He was, like, clinging to it, like people clung to the BlackBerry, right? You know, so I think that there's always gonna be some who are just gonna stick with what they've been on. I think the majority of factor patients in my practice, I imagine once EFA's available, will switch. I think the Hemlibra patients, the vast majority of them probably won't switch. Maybe to the question about the market split. If you look in that non-inhibitor hema market, about 40% is U.S., it's about 50% when you include Japan. With this, we would move on to Emmanuel. Emmanuel Papadakis, if you could unmute your line. Thank you very much for taking the questions. Emmanuel Papadakis, Deutsche Bank, and also apologies for not being there in person. Perhaps a question on fitusiran. I'm assuming if it's approved, patients that go on to the 50-milligram would need to regularly monitor for antithrombin levels. So how frequent would that need to be, and to what extent is monitoring antithrombin and then indeed titrating dosing accordingly going to be a practical handicap in the real world? And then just, I guess, you Doctors Young and Weyand, you've given us some very helpful data points, but perhaps I could ask a slightly more direct follow-up. If you could just give us two numbers each, approximately what percentage of your total patients are still on factor therapies? For example, Dr. Young, I know you just mentioned the pediatric group, but the total group would be very helpful. Approximately what proportion of those do you anticipate within a couple of years could be moved on to efanesoctocog? Thank you very much. Um, so the, um- Antithrombin monitoring. Antithrombin monitoring. Yeah, sorry. First of all, antithrombin monitoring is not difficult because, you know, most hospitals, certainly hospitals that have hemophilia treatment centers, typically have antithrombin testing on-site in their own lab. Even if they don't, the turnaround is a couple of days. It's not like, I mean, with a drug that's given every two months, it's not like you need the result right away, right? 'Cause you're not gonna make the dose change for a while. The monitoring of antithrombin levels is not, it's really not difficult. It's readily available. There may be some nuances to this that I won't get into, but other than to say that, you know, there's nothing that can't be overcome. Antithrombin levels, getting antithrombin levels is easy. All labs have it. These are approved tests. Even if you don't have it on-site, you can get it back, you know, quick enough within two months to make a dose adjustment. Now, how important or how necessary will that be? You know, we clearly are gonna have to do that at the beginning, right? We're gonna start patients on a dose. We're gonna have to see what their level is. If they have a dose adjustment, they can have a dose adjustment. I think if we make a dose adjustment, I would wanna check again. If I don't have to make a dose adjustment, we know that the levels stay really steady. I certainly is not gonna be doing it on a regular basis. You know, we see patients every six months, every year. Probably at the beginning, I will wanna see what the levels are. You know, it's not like it's difficult to do, as I said. It's not like it would be that often. When patients come to clinic, I might monitor them. It's simple to do and I think it's reasonable to do, certainly in the first phases of commercialization of this drug as we're learning about it. That's my answer about the antithrombin monitoring. Maybe it's getting late, but I forgot the other question. It was something about EFA or something. What percentage of your patients are on factor and how many of them would switch to Efa? Thanks. In the first period after it was approved? Angela pointed out that I'm older than her before, and I think it's showing. I mentioned in pediatrics it's a 60/40 split right now with emicizumab versus factor. The adult patients are at, as we pointed out multiple times, they're a little bit more conservative. That split is, it's just about the opposite. It's like a 40/60 split. Still 40% have switched to emicizumab, 60% remain on factor. That's obviously just the hemophilia A patients, clearly. Obviously, hemophilia B, everybody's on factor. Would any of them switch to EFA? Well, you can answer that. Oh, my patients. I already answered that. What I said about the EFA is I honestly, after seeing the data that I saw here, and I'm part of the trial as well, so I've got four patients on EFA now, three 12 and olders, and one who started recently as a pediatric patient. I've had patients on EFA now for I think more than a year. Three of them were close to that. Again, I you know, from the data I've seen and what I've seen in my patients, I don't really know why a patient wouldn't switch from whatever factor product they're on to EFA. I mean, like I said, you have less frequent dosing and higher levels. It's just really intuitive that that makes sense to do that. Our pediatrics are probably 50/50 with non-factor and factor. I agree with Dr. Young. I can't think of one reason, medical reason why we wouldn't switch all of the factor patients to EFA when it was approved. I actually differ a little bit from Dr. Young in that I've had a handful of emicizumab patients that have expressed interest in switching to EFA once it's approved as well. Extremely helpful. Thank you. We move to the last question. The last question is from John Murphy. If you can unmute your line. We cannot hear you. Okay, in that case, I see also Graham has raised his hand. We do the last question with Graham. Graham, can you unmute? Yep. Can you hear me? Yes. Great. Yeah, actually, you've mentioned a number of times that you can't see a reason why a patient wouldn't switch to Efa if they're on factor already. But do you think payers will have the last say on this? And just in your experience with dealing with payers in hemophilia, you know, how much of a barrier can they be? How much do you expect them to be able to recognize the benefits of efanesoctocog versus the current factor therapies? What's your expectation for coverage and how problematic it could be? Well, I mean, obviously, I can't comment on what the cost will be, and I'm not gonna go there. What I will say is every time we've had a new product in hemophilia, and I'll go back even to I was around, 'cause I am older. When Advate came out, which was in 2005, it was, you know, hailed as, you know, the purest product. Back then, we're still, you know, living in the, you know, waning days of the HIV hepatitis, I mean, which was still very heavily on our minds back then. It was, you know, the quote-unquote "purest product" 'cause it didn't have albumin or any human proteins in the processing or in the final product. That was its big thing. It was, as a result, you know, it was priced more expensively. You know, payers paid for it. It became the leader of the market. Then we had extended half-life factors come out, and they were priced higher. Eloctate came out a year or 10 years ago, and we started prescribing it, and payers paid for it. You know, when Hemlibra came out, also payers paid for it. I've never had a situation where a new product came out. I wanted to prescribe it to a patient, obviously, you know, within the realm of normal indications or normal doses, not doing something that's absurd, that hasn't been paid. Now, I think, you know, in the United States, for those of you who are from the U.S., you know, we have a very fractured healthcare system. I'm from California, which is a little bit one of the progressive states, thankfully. You know, I have a colleague, Miguel Escobar. Some of you may have heard of him or know him, who's in Texas. You know, it's a little bit different, you know, down in some of the other states where the payers can be a little bit more restrictive. I think at the end of the day, when all these new drugs have come out incrementally in hemophilia, if a patient wanted it, the payers paid for it. I don't see that not being an issue, you know, as long as, you know, Efa isn't, you know, priced at some, you know, insane point where the payer's like, "Well, we're not gonna pay twenty times more for something like that." I'm being a little facetious. I mean, you know, there is. I'm sure for the payers that there's some level at which they probably would say, "No, that's. We're not going there." I still don't see that that's gonna happen because, like I said, every time we had a new drug, we've been able to prescribe it. Maybe just to comment, we still see that innovation is recognized. I mean, if we talk about, for instance, Dupixent around the world has been recognized for the innovation it brought, and we think that with Efa, innovation will be recognized. I would agree. I think when we started switching patients to extended half-life, we actually left a lot of patients on the same interval to try to provide additional protection, which clearly was not, you know, what was in the product insert or, and still really didn't have an issue with payers. I think we're lucky to work in multidisciplinary hemophilia treatment centers where we have dedicated social workers and nurses that oftentimes help us navigate this when it is a problem, so that it doesn't become a problem. Okay. I think I have to go to the last one because I think I have to really, at some point, release these people from this uncomfortable chair so that next time when I invite for event, not having trouble. We're to the very last question from Keyur, and then we go to some closing remarks to Dietmar. Thank you. Just kind of picking up on a couple of statistics you guys have mentioned. You said there were roughly two kind of bleeds per month in the non-prophylaxis arms, the arm B kind of getting into the study. Then kind of you guys have mentioned 70% of patients are on prophylaxis treatment in the U.S., 30% are not. I guess my question is what's stopping the other 30%? If you, if you're gonna inject yourself twice a month because of a bleed in any case, what's been the bar to that 70% not being 90% or 100%? Because if I remember data from four or five years back, that was closer to 50% prophylaxis, 50% on demand. It's obviously moved in the right direction, but kind of why isn't it much higher? At our center, similar to Dr. Young, 100% of our severe pediatric patients are on prophylaxis. The patients at our center that are not, that are continuing to be on demand tend to be older adult patients who grew up prior to prophylaxis and so just have not necessarily, you know, have an attitude of, "I've not done that my entire life. Why would I start to do that now?" I do think that there is a rationale now that we have things that are not as frequent. If you are gonna have to treat twice a month for your bleed anyway, why would you not treat a little bit more and have much better outcomes likely? I would assume that that will continue to go up, especially as these new products are available. I mean, I'll just add that unfortunately in the United States, again, with our fractured healthcare system, unlike the UK, where every patient is assigned to a hemophilia treatment center, that's not the case in the U.S. Roughly, there was a study a few years ago. It's hard to get good numbers, but it estimated roughly 30% of hemophilia patients in the U.S. do not get care at a hemophilia treatment center. They go to their local, literally oncology program, and some oncologist who mostly does lymphoma and leukemia, who I'm sure is excellent at doing that, doesn't really know much about hemophilia. It's kind of an afterthought for them. I mean, we do. You know, that number where we see that you know should be 100% of severe patients is not the case. That's a result in the U.S. of just a bad healthcare system, to be honest with you. I mean, in other countries, developing countries, we know that economic issues play an impact, but there's no reason why every severe hemophilia patient in the U.S. shouldn't be on prophylaxis. It's true that that's not the case, and it's a kind of sad fact. Do we have to close on a sad note? Anyway. Say something uplifting now. Yeah. No. Look, I wanna go back to a question that was asked early on, which was, Efa being used, less frequently than once per week. Since that you asked the question, I've been sitting here thinking about that. All I can think of, that would be very sad and that would be a real shame because you have the opportunity now to offer efficacy that frankly has never been seen in hemophilia A. It hasn't. You know, if you compare to some of the non-factors, Efa is finishing the week where others are starting the week. This is an example, or this is the reason why we have to define this high efficacy space and set the bar higher for the expectations of the community and of the patients. That's something that, you know, as I say, it will be a shame if that happens because now there is this opportunity to offer something that hasn't been able to be offered before. Could it also be a positive that a lot of mild, moderate patients who maybe shouldn't be on prophylaxis, but actually if you've got something that you can use once every 10-12 days, they may be more inclined to be on prophylaxis? Could you think of it that way? Well, that's like gonna be a completely different scenario anyway, right? Because these are patients that are normal for four out of seven days, starting at zero. If you're starting at 10%, then clearly that's like a different curve than what we're seeing in these patients. I think that's a whole different scenario when you're talking about mild and moderate patients, and definitely I think is great as well, right? If you could dose, you know, have a longer interval for those patients because you're still providing very high level protection, then that would be great. Just to be clear as well, where we're going, right? I think that going after factor, no brainer, right? I mean, I think that, you know, I say I believe we will win, but we're not going to restrict ourselves from going to every heme patient and putting that as the bar saying, "Here's the efficacy that can be offered with this innovation, and that's something you should at least be considered." That I consider a more positive note in which I will. Very good. Hand over to- Very good. Dear colleague and friend, Dietmar. I was gonna close on the positive note as those peanut butter brownies were fabulous. Are there any more? Yeah, I was hoping there was some left. I think we will get all of us out of here quickly. I will pick up on what Guy said before, which is the patient outcomes evangelist. I really like that term. I think that's what we hope we have shown to you that, you know, we have new options for patients with hemophilia. We think there are better options when it comes to efficacy, also when it comes to reduction in treatment burden. Actually, I believe also when it comes to covering the global need, right? Because, for example, fitusiran once every two months, subcutaneous, no cold chain required. That's just another drug that you can use globally much better. I think we have these new options. We have the strong commitment to the community and to the patients. You know, thank you all for coming. Thank you for all your questions and for the discussion. Thank you also to Dr. Weyand and Dr. Young, really for really giving us great insights also into the clinical practice questions here. I think that that's just so much more tangible what the benefit of these drugs can be. Thanks very much. Nice work. I need a massage after this chair. I know, right.