Sanofi (SAN) Earnings Call Transcript & Summary

So I hear we are 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 and the next one, please. Yes. So 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. So next slide, please. So for today, we've put together around [ 2-hours ] 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 going to see that there is a broader portfolio that we're building here. And 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 2 investigators by Dr. Young and Dr. Weyand, who will present the data to us, and we will also take a closer look at the hemophilia market and how we see it evolving. And in the end, there will be time for questions. You can participate either in the room or online. I'm going to 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 writing, and we already invite you to send some of the questions during the presentation. But as I said, we want to first run through our agenda and then we will certainly have enough time for questions. And with that, I hand to Dietmar.

Thank you, Eva. I don't think I need this one. So 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 really 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. So we are focused. We are committed to transforming the lives of people with hematologic disorders with rare blood disorders. You know we have a marketed product portfolio on the left here with first-in-class products in hemophilia, elongated half-life factors like Eloctate, Alprolix, then with a first-in-class therapy in CAD and called cold agglutinin disease and Enjaymo, and with Cablivi in acute 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 2 molecules. And then we have really 4 molecules in broader settings of immune-mediated blood disorders and rilzabrutinib in ITP and 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. And 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. And 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 reduction. 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 you think about cold agglutinin disease, we're really aiming with our SAR-088 molecule. We're aiming to address complement 1S activated complement-mediated hemolysis. And then talking about warm autoimmune hemolytic anemia or wAIHA. This is an acute disorder with currently no approved treatment. So we have 2 different molecules in clinical trials than 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 want to 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 micro bleeds could potentially lead to irreversible damage and need to be addressed. And just talking about the opportunity, more than 25,000 adults currently in the U.S. suffer from chronic ITP and are really eligible for second line plus treatment beyond steroids, after steroids. And rilzabrutinib has the potential to address these issues because BTK inhibition, inhibition of Bruton's Tyrosine Kinase has the potential to reduce both the Fc gamma receptor-mediated macrophage function and also the autoantibody production. So that's the realization that ITP is not only an autoantibody-driven disease but also macrophage-driven disease and we're targeting these 2 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 earlier 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 also the different subgroups of patients. You will see that, that effect size is maintained even in the more severe patients. All of these were heavily pretreated, highly refractory patients. But when you look, for example, at patients with a prior splenectomy, you look at patients with 4 and more prior therapies, you can get this around 40% response rate. Rilzabrutinib was well tolerated in these studies and the effects were durable. So 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. And Sanofi has a unique portfolio in my view, in hemophilia. And 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 extend side chains that refuse to the molecule. And 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 2 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 3, 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? And 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, and 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. And then fitusiran has the potential for consistent efficacy, but with a much reduced treatment burden. We have completed 3 Phase III studies in adults and adolescents with the 80 milligrams monthly dose. The third study has been presented here at the meeting. And 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 2 lower doses, but also with the 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 6x a year, 6x 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 planned on that study is 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 in 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, yes, so thank you for being here and it's my pleasure to talk about the fitusiran so let's go ahead and roll with the next slide. So this is kind of my vision of the unmet needs in hemophilia. And for non-inhibitor patients, we have pretty good treatments, to be honest, but we need to reduce the treatment burden. In fact, Dr. Weyand and I were just having a discussion about nonadherent patients. And it's a huge problem with patients not giving their factor on a regular schedule. So 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 we don't just want 1 product and the other thing is emicizumab doesn't work in hemophilia B in any case. And then ultimately, the ultimate unmet need per se is obviously to cure a disease. And there is work being done, as you know, and you've seen in this meeting on gene therapy. But 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. So I'm going to talk about 3 studies. The first 2 were presented at ASH. The first 1 is the ATLAS-INH inhibitor study. This was a study for patients receiving monthly fitusiran 80 milligrams compared to another group randomized, receiving bypassing agents on-demand, right? So 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. And the third 1 was presented here at this meeting in the late breaker session which we call ATLAS prophylaxis. And this was a study comparing patients. So 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. So 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. So this slide is looking at the 2 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, just not surprising, your on-demand therapy do bleed more frequently with fitusiran, the median was 0. And then for the -- so 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. And again, you see with fitusiran that the median ABR was 0. The next slide, this is looking at the study that was presented here. This is comparing again to prophylaxis. So this is patients with and without inhibitors and the patients on the standard of care arm we're receiving either bypassing agents for prophylaxis or factor products for prophylaxis. So you see that the annualized bleeding rate in that group is lower because they're already on a prophylactic regimen, it's 4.4. But again, with fitusiran, the median was 0, and that represents a reduction of 61%. You see it statistically significant, but really more importantly, that is a clinically significant reduction. We don't want patients regardless of what prophylaxis. There are on 4 bleeds a year is not acceptable. Next slide. So we're going to take a look now at a percentage of patients with 0 bleeds. Now we put all 3 of those studies. Again, the same study is Atlas INH on your left, ATLAS-A/B in the middle, those are the 2 comparing to on-demand and ATLAS prophylaxis on the right. And we're looking at the percent of patients with 0 bleeds. You can see that it's somewhere about 50% to 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 0 bleeds during the efficacy period. For the prophylaxis, it was a little higher, 17%. But obviously, that means the majority of patients were still having at least 1 bleed. Next slide. So 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 somewhere 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, but be that as it may, in this case, going down is good. So this is the physical health domain from a hemophilia specific quality of life tool called Haem-A-QoL. You have the 3 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. And 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. And these -- with this score, this is not -- this is more of a gestalt, but anything less than -- any drop that's 10 or more is really affecting your quality of life in a very positive way. So you see 30 and 23 is -- to be honest, it's really quite remarkable. And then the last one, you see that the reduction is a bit different. You see it's -- the difference is minus 3.6. And again, that's because patients on the other arm were on prophylaxis. So they're already getting some form of prophylactic therapy. Next slide. And this is a total score. So we looked at the physical health score, this is the total score. This will incorporate things like the frequency of infusions and things like that. And 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. So here is -- so we're going to do each study one by one. So this is the ATLAS-INH study, again, the inhibitor study. And you see the bypassing on-demand group is in the middle column, the fitusiran group is on the right column. And the box is highlighting the treatment emergent adverse events of special interest. You see there were 11. And on the bottom panel, we break that down. So you see there are 11 patients that had either elevations in their hepatic enzymes and 1 patient who had cholestasis. I will tell you that for those 11 patients, none of those discontinued the drug. And for most of them, the transaminases went back down to normal or at least were stable and not high range. So none of those patients discontinued the drug as a result of those elevations in transaminases. So they were not really that clinically significant. Now there were 2 thrombotic events. It looks like 4, but the first 3 notice the bracket is the same patient, the investigator put like 3 names for the thrombotic event. He called it Deep vein thrombosis, Subclavian vein thrombosis, Thrombophlebitis superficial. I guess it involves a few different veins. So that's 1 thrombotic event. And then the second 1 was a suspected thrombotic event. I think the verbatim was suspected spinal vessel thrombosis. So the second 1 was a suspected one. So you see a total of 2 patients on this trial that had thrombotic events. Well, a thrombotic event in 1 suspected thrombotic event. Next slide. This is going to be the ATLAS-A/B study. In this case, you see 15 treatment-emergent events, adverse events of special interest. These were all elevations in the hepatic enzymes and none of the patients discontinue -- I'm sorry, there was 2 patients who discontinued because of that. One was related to the elevation. They are both -- but 1 was cholecystitis and 1 was elevation of ALT. So those 2 patients discontinued based on the investigator decision. Again, the rest of those did continue on the drug and these transaminase elevations, either normalize or remain stable at a relatively low level of increase. And then the final study. Next slide, I guess, is it. Yes. So this is the prophylaxis study. Again, you see the 2 columns as we showed you, and let's focus on the -- in the middle there first, we've got 2 patients who discontinued fitusiran. One was due to cerebrovascular accident. So I'm going to 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 2 thrombotic events. Again, 1 was this cerebrovascular accident. The other 1 was a suspected event, which involved a thrombosis. I think it was written as a suspected thrombosis on the papilla of the left eye. If you want to ask me more details about that, I don't really have that. That's what the investigator put. So that's the 2 thrombotic events. And then we have the other adverse events of special interest, which is, again, the liver-related events. You see elevations in transaminases and 5 patients with cholelithiasis 5 with cholecystitis. The numbers don't add up because some of the patients have more than event. Trying to think if there's 1 other point I wanted to make here. Yes. As far as the discontinuations, again, 1 was the cerebrovascular accident and 1 was abdominal discomfort. Okay. Yes, next slide. So this is a slide that looking at a summary of the thrombotic events that have been so far published since the start of the fitusiran program. So this includes the 4 on the top or from the 2 trials I just mentioned, the 1 on the bottom is from an older Phase I trial. And so 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 5 thrombotic events, so was that the first 3, they had antithrombin levels less than 10%. And the other 2 were between 10% and 20%. And so 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. And so he's decided to make the lower threshold 15%, partly to account for variability between patients with respect to when there might be a thrombosis and also for some margin of protection or margin of error. And then an upper limit with sent another was set. In other words, we want to keep the antithrombin levels between 2 points. Of course, after all the point of the drug is to lower antithrombin levels. And so 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. So that's why it was chosen to say, let's aim for 15% to 35% because we can improve -- hopefully improve, and we'll see as the data emerges, but hopefully improve upon the safety margin without compromising efficacy. So 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. So 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. So 50 milligrams every 2 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 going to stay in every other month, but you're going to go down to 20 milligrams every other month. And if you're in the right range, you're just going to 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 1 dose change to get them in the range. And we expect 80% of the patients to remain on every other month schedule, which means 6 subcutaneous injections per year. So you have there on the right, the target levels and sort of the rules that are being followed in the Phase III trial. So next slide, I think is my last slide. So the conclusions based on these 3 completed Phase III studies, 80 milligrams of monthly fitusiran and 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. And the present findings and low ABR, the 80 milligrams monthly suggests that fitusiran reduces -- rebalances hemostasis and provides really a continuous and sustained bleed protection. But 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. So with that, I will stop, and I'm going to pass the baton to Dr. Weyand. Dr. Weyand, I would like to say she's a rising star in our field, but that will be selling her short because she's already very well known in our field nationally and internationally. So it gives me great pleasure to have it come up and talk to you about Efa.

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 going to shorten for your sake in mind to Efa for the presentation and the clinical experience with that. Next slide. So 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 going to 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 we'll be looking at other special populations. Next slide. So 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 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 2 arms. Arm A was for patients who had previously been on a stable prophylaxis regimen. And those patients when enrolled transition to weekly Efa at a dose of 50 international units per kilo. 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 Efa on-demand at the same dose of 50 international units per kilo which they continued for 26 weeks, at which time they transition 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 prestudy prior to enrollment in the bigger study, at which during which time their prior treatment regimen and bleeding was collected. The primary and key secondary endpoints focused on 1 of our favorite measurements in hemophilia, the annualized bleed rate. And secondary outcomes also include things such as pain, physical health, including wearable digital technology and joint health, including things such as joint ultrasound. Next slide. So looking first at the primary and key secondary endpoints. The primary endpoint was met as the median ABR was 0 with an interquartile range of 0 to 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, it should be on the key secondary endpoint, which compared the intrapatient ABR between prior Factor VIII prophylaxis and Efa prophylaxis. So 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, that mean ABR was 0.69, a 77% decrease. And that's impressive on its own, but I think it's important to appreciate the context in which this happened. So our patients who are on standard of care Factor VIII prophylaxis are infusing themselves intravenously a minimum of 2 times a week, some 3 times a week, some even every other day. So we saw with Efa prophylaxis, a 77% decrease in mean ABR in the setting of patients doing fewer than half of the number of infusions that they were doing on their prior prophylaxis. So a significant decrease in their treatment burden with 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 0 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 have 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, but this number is higher as they were on prophylaxis for a shorter amount of time. So at 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. So prior to enrolling in the Efa trial, patients in Arm B had a mean ABR of 21.42. This is horrible. This is almost 2 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 and 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 2x a month. And we know that each time patients bleed into a joint, it puts that 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. So 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. But 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. And we've made some small progress with the EHLs, but this is really the next level. So as you can see here, patients who were on Efa prophylaxis at that 50 international unit per kilo dose we're able to achieve normal or near normal factor levels for the majority of the week, so out to 4 days. Additionally, even out to 1 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 infused 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 our health care 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. So 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 Haem-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 Haem-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. So 29 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. So 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. So these are those joints that are abnormal and continue to have frequent bleeds. And 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 and 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, and this was done on patients within the study as well. And in a shorter 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 2 and then you're done, these are treatments that will be ongoing for long, long periods of time. And so the fact that we are seeing clinically significant changes and as less as 52 weeks, I think, is really promising for what we might see over the longer term. Next slide. So clearly, we don't want our patients to bleed, but sometimes they do and sometimes they need surgery. And we also need to know that in addition to preventing bleeds that the factor is effective in treating the bleeds. So they did look at the bleeds that occurred in the study and 96.7% of those bleeds were able to resolve with just 1 infusion of Efa and 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. So we're not surprising that they occurred as unfortunately, bleeds happen when patients are on 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. So 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. So Efa was well tolerated. And 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 2 patients that discontinue treatment, 1 because they received another factor treatment, so it became ineligible to continue and another who had a decrease in their CD4 count that was an HIV patient. Next slide. So I think in conclusion, clearly, Efa once-weekly prophylaxis really provides superior bleed protection. And as short of a time period is 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 4 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 substantial improvements in patients' quality of life, pain as well as joint health. And this treatment was clearly shown to be well tolerated and safe with all of the adverse events being expected within study in this population. Next slide. And I think it's important to put all of this in the context of what this really means for our patients. So 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 1 of the patients I enrolled was an older patient who has very bad joints who has target joints and really prior to the study, organized her life around the disease. So she didn't participate in activities that she wanted to participate in. She oftentimes had to say no to invitations. She was constantly worried about when her pain would start, how much you could do before it was too painful to continue. And I think once she started on Efa, not only was she quite pleased with the once-weekly dosing, but she really started to change her overall mindset in the way she was approaching life and started having days where she wasn't having pain and started having the opportunity and the ability to do more activities for longer periods of time without having that pain. And so instead of saying no immediately to all of her invitations, was saying yes to all of her imputations and also having the thoughts in the back of our 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 going to join a gym, I'm going to 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 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 divorce. It was very tumultuous at home. The whole family was affected, but the parents weren't getting along. But the mom was terrified that if they got divorced, he wouldn't be able to get his infusions, dad's not got his infusions, dad is remember infusions. How does this work, if they with dad half the week and he doesn't get infusions and she's seeing the older hemophilia patients at these conferences that can't walk because they bled into their joints, and she doesn't want her child to have that future. But 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? And so the whole family was affected by this ability to really change their weekly schedule, parents got divorce, everyone's happier. Parents 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 and mom doesn't have to worry that the fact that her marriage didn't work out is going to doom her child to a life of debility. So it's been really fantastic for both of them, and I personally am very excited to have this available for more of my patients. And with that, I will hand it over to Bill Sibold.

Well, thank you, Dr. Weyand and Dr. Young. Just to be clear, that it 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, and really welcome to everyone that's here. It's so nice to see so many familiar faces in the crowd today. And 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. But 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. So let's go to the next slide. And let's start there. and talk about Sanofi and rare blood disorders. And as I said, there is great appreciation for what we have been doing in rare blood disorders. And really, if you look, we've generated a lot of first and deep mark pointed this out in the first slide, but within Enjaymo, the first treatment for CAD, which we recently launched. Cablivi, first treatment for aTTP. And then our current hemophilia products, Alprolix and Eloctate, which were the first EHLs launched in heme A and heme B, and they represent about EUR 1 billion of the EUR 1.2 billion in sales that we have in this therapeutic area. Next slide, please. So let's look at the hemophilia A market and pick up where Dr. Weyand left off about the exciting opportunity with Efa. So specifically here, we're looking at the non -- pardon me, the hemophilia A noninhibitor segment, which is the largest opportunity. As you can see, it's about EUR 7.4 billion. And if you look further at the factor portion of that, the opportunity is significant. About 70% is a 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. So this segment, we think, is ripe for innovation. And based on the data that you've seen with Efa, we fundamentally believe Efa will be the winner in this segment. So let's go to the next slide. And this is looking at -- so really, where is this market going and Evaluate Pharma expects this EUR 7.4 billion to grow by almost 40% over the next 5 years, exceeding EUR 10 billion. And that's really going to be driven by the introduction of new and innovative products, which will drive further adoption of prophylaxis. So we know the market is going to grow. And based on our recent market research that the market is going to be dynamic. Here you can see 6 out of 10 hemophilia A patients are open to or likely to switch treatments within 2 years. 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. So how will that EUR 10 billion be split out? And in that survey of patients that we did, we asked the question, what would you prioritize in terms of your treatment? And here you see 40% said they wanted the highest efficacy levels and 44% said they'd rather have efficacy with the lowest treatment burden. So we feel extremely well positioned. When you see this is what patients are stating they want that, that is their new expectation with our portfolio, we're extremely well positioned. So let's go to the next slide, please. So here, we map out the market on these 2 dimensions of efficacy and treatment burden. And you can see where the current classes fall, where the open space exists, and the opportunity for Efa and fitusiran in that future. So maybe we'll start with fitusiran. While all patients want efficacy, as we said, treatment burden is a very important consideration for many patients. And 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. So 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 or for almost a week. And that's going to be what takes some time for people to understand and as we get closer and closer to launch, I think that 1 of the things that we're going to 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. So 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 first that we have. What you're seeing here today are 2 new first that we're going to have in the space. And there is more to come. As you know, we Dietmar said, we filed, we expect to launch next year with Efa and we have full efforts on making that an incredibly successful launch in bringing a game changer to the market. So 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. And 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 going to develop, especially in hemophilia, and we are really well positioned to participate in and have a bigger stake in that. And 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. So with that, I would ask all the presenters to come back. Basically, what's going to happen is Efa is going to structure the questions for us because there's also questions coming online. We have quite a number of people also dialing-in online. And we will take a seat here on this very comfortable looking bar stools, and then we're going to answer your questions.

Thank you. So I just need to arrange myself here. Yes. So we're going to start with questions. We would like to ask you certainly for the first one, if you could keep your questions to 1 or 2, we're going to start in this room momentarily. I think we have 2 mics ready. So we would like to ask you to wait for the mics, so the people on the webcast can follow you. [Operator Instructions] So we're probably going to 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 come in later? And if you have any issues of patients who might need surgery, 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 fundamentally very different type of product?

Okay. Yes. Thanks for your question. I guess, let's see if I can -- well, 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. And I was going to say I had hamburgers and French fries, but my doctor would be getting mad at me. But so I mean, I think that it's some area of concern because we don't understand what is causing it. But I also think that cholelithiasis and cholecystitis is really quite common. I'm a good example of that. And 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. And obviously, we'll tell them that it's a possibility, but I don't think that, that would stop me from using it in a patient who's going to potentially significantly benefit from it. And as we've seen from the studies that really any patient with hemophilia A or B with or without inhibitors could potentially significantly benefit from it. So that was the cholelithiasis one. Surgery, so it hasn't been presented. There's been surgeries during the trial. I can't get into the details of it because for one thing, it's not published for another things, I don't remember all of it in any case. With all of these products, we sometimes -- 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 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. And 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 which patients would be most interested in fitusiran. I think 1 thing that I can tell you, we deal with all the time as venous access issues. I mean it's a huge problem. It's -- 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 in finding veins to poke their children, not to mention having to hold them down and have 1 parent hold the kid down, while they are the one's jabbing a needle in their veins. So 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 1 vein or 2 veins. I remember touching 1 guy's vein. It literally felt like a copper cord or something. And I was like, that's where you poke it through. He's like, "yes." I was like, "that's got a hurt." He goes, "Yes, it hurts a lot." And so then we talk to him about the potential options and future options. So venous access remains a big problem. And for those patients in whom venous access is a big problem, fitusiran could be a great solution. For those who don't, who prefer factor and venous access is not an issue, not plenty of adult patients who -- they rotate their veins. and they can manage with that. That's where fitusiran is still an option, but that's where Efa could be an option. So I hope -- I don't want to take too much time to answer every question, but I hope I answered the ones you had.

But 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, that will impact really the risk of thromboembolic events. It will also impact the risk of any, for example, liver transaminase elevations or also cholecystitis. It's our expectation. So we're obviously going to follow up on that, right, with the amended studies, but there may be more to learn about really the frequency of these events and how does that impact benefit risk eventually.

Okay. Thank you. So go to the middle, if we have Wimal and then we're just going to continue that table.

Wimal Kapadia from Bernstein. So two questions, please. So first, just on Efa. I'm just curious for 1 dose, if you would just have 1 dose, how long would it take to get to a factor level similar to 1 of the existing Factor VIII. Is it 9 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 robust. So that's the first question. And then my second question is just I appreciate the change in the dosing for fitusiran. But given hemophilia patients are quite conservative, if you are on fitusiran and for example, you feel pain in your arm, you think you might have a bleed when you're in fact in that situation, you can dose up to 100% without the risk of thrombosis. So 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 fact that you have to give?

Yes, why don't you do that -- the Efa question.

Okay. I will defer the actual time to -- so 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 the thought is that it's more of a one-size-fits-all 50 international units per kilo once a week. But I think definitely, there will be patients or in health care 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. But I think it is nice that there is not very much variability, so people can't stick to that kind of once-size-fits-all fit one.

And 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 the kind of 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 want to give up on that advantage because that's what we really feel is bringing -- is moving the field forward.

Yes. As to your other question, it's a really good point. So first of all, no matter what type of hemophilia 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. And what you're relating to is something that feels like a bleed, but not sure it's a bleed. 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 regular aches and pains happen in hemophilia. And the experience that I've had with emicizumab over the last 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 going to wait." And many times, it didn't turn out to be a bleed and they didn't have to get factor. And then if the symptoms got worse than they would treat. I don't think it's really -- it's an issue. I mean it's going to end up being the way that the physicians and the health care team interacts with the patient. Some may say, well, you have -- you're feeling some pain, I would like you to give a dose of factor. And the doses to 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 additive 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. And this is something we're trying to figure out with these newer products. But I don't think it's an issue in terms of for those patients that we do prescribe, whether it's Factor or Hemlibra or in the future, fitusiran or frankly, even Efa, there's going to be those situations where you're not sure something is a bleed. And then it becomes -- like I said, it's a discussion that you have with each individual patient and some may just -- they're more anxious so they want a dose. So that's fine. They can dose, whether it's a bleed or not, they can dose and feel better about it if they were starting to be a bleed, they stop it if it wasn't, generally speaking, no harm done. And if they want to wait to see if there's further symptoms, then some patients will say, yes, I think I'd rather just wait it out and my symptoms worsen then I'll give a dose. So not really too concerned about that, but it is something we're seeing more as 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. And we're starting to do a little bit more of this wait-and-see approach.

If we just move over to Laura.

Laura Sutcliffe of UBS. I have a question on fitusiran, please, for both Dr. Young and Dr. Weyand because 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 back from Hemlibra and [ inverter comers ] Or is it the case that 1 patient has made a really big step change like that, they're gone, and they're not accessible for something like fitusiran?

I think personally, my experience has been in the clinic that we've had this huge increase in the number of products being studied and available in trials for hemophilia. And so 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 going to be fitusiran and now there's -- it's just like always something new. And so I think patients are more open to, well, if there's something better, why would I not try that. And I think the -- every other month versus monthly is having your treatment for the year, right? It's getting to so few treatments. Dr. Young and I were talking about right before this start is that we have not been super impressed with hemophilia A gene therapy. We're not there yet. And that having a treatment you could do 6x a year or gene therapy that gets you a decade or less, it becomes a lot -- I think we're getting to this point where the treatments are amazing and the treatment burden is so low, but I think that patients still will identify even if it's just 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 are so many options.

Yes. My comment on that is that, so if you look at real-world data, about 70% of patients on Hemlibra are on every 2 weeks. So that's 26 injections per year. And I will say -- and they're single-dose vials. They have to drop at the dose every single time. And depending on your size, the volume is -- can be 1 ml, 2 ml, actually even 3 mls. It can be fairly large. And what I'll say that I've learned from talking to my patients about it, is that 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. But 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. But if you're asking me, and you ask who's going to potentially switch over? Well, 26 infusions a year versus 6, larger volume of infusion versus smaller, painful infusion versus what is really not a painful infusion at all. And so I do see situations where parents like, yes, Hemlibra is great. And -- but boy, it's really tough when we have to do the infusion. And so even going from 26 to 6 and having them be less painful, 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 going to be equally effective. It's going to be otherwise 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?

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. And 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. And 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. It doesn't look like I think to really set the world on fire. So really just getting a clinician perspective from both of you would be great on where gene therapy in the future promise.

Yes. I mean on the Hy's law, I mean, we're seeing, clearly, there is an increased evidence of hepatic enzyme and cholelithiasis and cholecystitis. And again, that's being looked at and investigated. The thing I like is that from the data is that most of the patients that did not lead to any discontinuation of their medication. But it's something that, as was mentioned already, 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. But it's only 1 case out of many, many over the course since the Phase I and the Phase II that have added up to the several hundred patients who've been on it. So are the liver issues, something that need to be investigated, understood, try to eliminate? Yes, 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 -- if every drug that elevated transaminases 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 certainly, as a clinician, want to know more from the company as they investigate this, if they can explain things a little bit better, particularly, like I said, the cholecystitis, cholelithiasis. And I'll let Angela start on the gene therapy.

Yes. I think everyone is excited about curing hemophilia. Gene therapy right now does not cure hemophilia. I think the rate of decline with Factor VIII is a huge question. There was a session at ISTH this week where the levels that 5 and 6 years are in the single digits. You're risking whatever long-term risks there are associated with gene therapy, which we don't really understand and being exposed to AAV, which we know is going to probably preclude you from other AAV gene therapy. So in my mind, it's difficult for me to identify patients that I would recommend that for any time in the near future, just given that it is a very finite amount of time. Dr. Young and I were talking about this right before the session started. So I think he has kind of a subset of very unique patients that it might be a good option for, but 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 an inhibitor patients obviously are not going to be treated with that, but I will let you talk about kind of that subset.

Well, yes, I'll bring up that subset in a minute. I think I have to think about it as heme A and heme B differently. I think with heme A, what we've seen as Angela said, 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 2 years. And then the other issue that really troubles me a little bit is the steroids. The average duration of steroids is like 9 months. And the last thing, 1 thing we get taught early on in our careers in medicine is when you're treating something, don't treat 1 thing and then cause other problems. You don't want to trade 1 problem for another. I mean, the last thing I want to do is give somebody gene therapy and then they're on steroids for up to a year, which we've seen even longer. And now have caused them 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. So I mean, do I -- is that really a success? -- hey, your hemophilia is cured, but I destroyed your hip. So we have to be cautious about that. And I think that what makes me a little bit cautious with the BioMarin data that I've seen. The other products are a little further behind, and maybe they'll be different or maybe they won't. For heme B gene therapy, I'm definitely more optimistic, to be honest, with the CSL product. We've seen 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 going to be a brand-new platform. Somebody mentioned the hemophilia community is a little bit conservative. So I don't see but all of a sudden, all heme B patients are going to be clamoring for this. But I definitely think there'll be some who would. In terms of the subset of patients, I have some young adults, they're 18 to 24. Obviously, these are pretty much all males. And 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. Partly miracle, I'm still here, but that's a different story. In any case, the point I'm making is that I've got these young men who mommy and daddy did all their infusions and made sure they did their infusions and they're in high school now. They're either going off to university or they're starting jobs. And they're just not doing their factor. They just aren't doing it. And even some I put on Hemlibra, they're not doing that either. And so for that group of heme 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 2 years, 4 years, 5 years, especially -- for most patients, you're getting decent levels at least 4, 5 years, it seems like from the Phase I data. If I can buy them those 5 years where they don't need factor, where they'll have a good enough factor level to get them to some level of maturity. And oftentimes, then they're not as transient as they were transitory moving around. They may want to start a family or have a partner and they'll probably want to take better care of themselves. So I see for some of these patients that this could be a great product to sort of bridge them when they're just not going to do any sort of treatment and destroy their joints. So I think I have some patients for whom I think clearly, that product is going to be great for them. And as soon as I can get it, I will prescribe it for them. But for the sort of massive hemophilia A adult patients, those who really want it, sure, I will discuss the risks and the benefits and we'll see how it goes. But there is a small subset that I think really can benefit from it.

So if we finish the table with Keyur, and then you move over to the other side.

Keyur Parekh from Goldman Sachs. Two questions, please. The first for you, Dr. Young. So you said 350 of the 362 bleeds in that study were resolved with a single dose of Efa. Can you kind of give us some details for the other 12? And if my memory is correct, there's also a patient death on that study. So any kind of details around the patient death on the study would be useful? And then separately, a 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 applause. And I think it was just the sheer notion of how much of a move forward emicizumab was compared to 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 -- and then linked to that, kind of the space is going to get increasingly crowded, be it concizumab, be it heme A, be it kind of few other bispecifics over the next few years. How do you -- what do you think kind of the treatment protocol or standard of care looks like in 5 years from now?

So I believe the death in the study was completely unrelated and was the type of cancer in a patient. And the 12 bleeds that were not resolved with 1, I believe were resolved with 2 infusions, but I don't have the exact details on all of that. But I think just even having the resolve resolution of the bleeds with just 1 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. And so I think knowing that we can resolve bleeds with 1 infusion, these are patients that typically would come to the ER to be infused, so saving them additional ER trips or additional time, I think, would be very valuable.

Yes, I just wanted to respond to the question from Sanofi, Craig Benson. Those 12 bleeds, I think they all resolve those 1 or 2 doses of follow-up factor, but we'll confirm that after the conference. Craig Benson is the head of the program at Sanofi.

And thank you for reminding me about the HAVEN 2 presentation. That was my -- I called it -- that was my Sergio Aguero moment for those of you who know what I'm talking about. And I probably should have retired right after that. Yes. It was -- for those of you who weren't there, as I presented the HAVEN 2 study for the first time, and there was sort of some silence and then the applause just went on and on and on, and really never seen that in any sort of meeting before. So it was a great moment for me. And yes, it was because it really was a huge step. I mean, particularly kids with inhibitors, I mean, gosh, there was just suffering. I mean this is -- and we don't like to see adults suffer, but it even hurts even more to see children just suffering. And you know before that drug came along, you kind of knew what their future was because we saw the adults with inhibitors. Like your future, you're going to be in a wheelchair and you're going to have a lot of pain. So yes, it has revolutionized the treatment of patients, especially with inhibitors. And it's absolutely made a massive step forward in their life. However, there's always room for improvement. If we just want to just rest on our laurels, then we'll never make more advances and more progress. And so for patients with inhibitors, there was no obviously comparison to Hemlibra. 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. What about sort of efficacy? I mean you're not going to 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. But is there something about fitusiran and we've seen data on thrombin generation at this meeting? Is there something about that it gives you better thrombin generation than emicizumab. And 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 want to do more sports. And so we do start to see trauma-related bleeds. And we know Hemlibra converting patients to more or less a mild hemophilia phenotype maybe it's 10%, 15%, 20%, there's different studies that have estimated in that area, but it's definitely not giving people normal hemostasis. And so the question is can fitusiran offer something better than that? And I think there's more to learn about that. I think what we see in the thrombin generation data, if you just flatly compare 1 to the other, it does seem like it looks better. But I think we need to do more work to really suss out really those differences. And 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 sort of better protection and you want to be really active, but you don't want to do IV therapies. I mean we have effort for patients like that possibly, but you're really veinous access issues. I think there could be some potential advantages there. And then you mentioned a few other products. And yes, I think it's always -- 1 thing I really respect about all the drug companies involved here is that they're just kind of pushing the envelope more. We used to think like, oh, 1% trough level and you do IV 3 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. And we want to keep getting better and better and better, and we want to keep doing more and more. I would love to get to a point where 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. And so the competition between companies to further innovate and further do better. I mean, it's fantastic for patients, and I know we'll have more options. And the more options we have, the better options for the patients to be.

Okay. I think if we have a mic also on this side, we have...

I do want to bring up that you did skip this young man here. He had his hand out a while ago and you moved away from the table. And I've been in that position before. So we'll circle back to you.

Sorry. Actually, I -- Sorry, I think I skipped -- so 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?

I mean I would -- I think the answer to that is the more options we have for patients the more we can offer different things. Some patients -- the values of different patients, you kind of saw a little bit about treatment burden versus efficacy. There's other things, too. And the more options we have, the better. I kind of jokingly say that 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 going to have a much broader menu. I don't think guys have Cheesecake Factory around here, not that I'm a big fan of it, but some restaurant that has Caffè Concerto, think you got those, right? You can go in there and get a salad, get fish, get a sandwich, get a hamburger. Yes, we want to have more on the menu because not everybody likes salad and not everybody likes a hamburger.

Emily Field, Barclays, and I love the Cheesecake Factory. But just kind of 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 going to 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 going to 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 appropriate at all could pick up treatment?

Yes. So 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 and moderate patients, all that may be more likely to use prophylaxis with the longer half life. I think there's also patients that we currently have on nonfactor 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 want to be able to do activities that they aren't necessarily able to do without those higher factor level equivalents.

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 heme A and B and mild and moderate hemophilia, which got me thinking about that. As we push the envelope and as we get the severe patients. So 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 not 30%, but 5%, 6%? I mean if we're going to give all the severes of treatment that their lowest level is going to be 12% or 15%. Well, then we're doing a disservice to the moderates that are 3% or 4% and the milds. And I think we're going to start getting more and more patients that we're just going to push -- try to push everybody to a better place because why should somebody walk around with 5% or 6% where 1 bad fall on a hike or 1 car accident, which happens, could be really like life-threatening when I can have their level higher. And we're just going to have to get the payers to understand that this is a severe disease. It's a life-threatening disease, even for those that have higher levels. It just takes that 1 wrong accident. And I think as we're pushing things, we can't treat all the severes and have them be 12% or higher or on fitusiran or on emicizumab and then have these moderate to 3% or 4% and mild at 5% and say, "No, you're fine the way you are. That's not fair.

Maybe just a 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%, and we expect fully over this time, this next 5 years where it gets above that 80% number.

Okay. Then the next question from Harry.

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? And is that something that you're excited about in the data that, that might be something differentiated for your Factor VII patients?

I don't think there's anything in my mind structurally that makes it different from Eloctate, for example, like in terms of inhibitor formation. I think it's difficult because these were all previously treated patients who are at lower risk of inhibitors. I personally would like to see some pops treated with it's -- so that we can see those numbers because I think that still is a question, but we'll just kind of have to see. Anything to add, Dr. Young?

And we're obviously following that really closely, right? There has been a hypothesis that the site change, the extend site change, which will cover the immunogenic epitopes. Obviously, those side chains come off at 1 point. So I really think we need to see in the clinical trials. But to me, it's quite encouraging there that we haven't seen anything so far, but we'll follow that.

Okay. I would then go to the webcast. And the first question would be from Graham Parry.

Apologies for not being there in person. So I just want to follow up a on that issue about inhibitors. So I think the patients in XTEND-1 had been on factor at for more than 150 exposure days. So does that preselect patients who are unlikely to develop inhibitors? And so could 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 seeing both thrombosis and liver at the monthly dosing. You seem to be fairly dismissive though. So just if that was an approved product today, you had exactly the profile you've seen in those monthly dose Phase IIIs. How comfortable would you be 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 will by the time it gets to the market, I guess, have something like Efa on market with high efficacy and extended dosing?

So yes, choosing patients that have had at least 150 days of exposure does make you more likely to not have inhibitors. So absolutely. And I think that when we look at the general population, the more patients you treat, the more issues you're going to see. So -- and the fact that we saw 0 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. So I think at some point, we will, but 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 if I was, I apologize. I mean it definitely needs to be investigated. I mean, we want to know what is causing it we want to try to understand if there's a way to mitigate against it even maybe prevented entirely. I think just in the grand context of things, as I think about hemophilia A and B patients, particularly those with inhibitors, but also those without inhibitors is we always look at every drug with the benefits versus the risks. And in a given situation, the benefits outweigh the risks, then obviously, you're going to go for that. So what if there's a patient who is struggling with IV infusions or doesn't have good IV access, maybe they have hemophilia B, for example, so they can't have emicizumab. And a situation where they're having more bleeds and joint bleeds, and we need to get that under control. Well, what would their options be maybe gene therapy be an option, but that obviously has risks that are potentially long term and even some short term that we're still learning about with the new platform, and then there might be fitusiran. And then with fitusiran, there is the issue of some percentage of patients that having elevated transaminases. I said with elevated transaminases, almost all those patients stayed on the drug and the transaminase levels either normalized or kind of stayed stable. And then some did get cholelithiasis and had cholecystectomies. And so those were treated and then they went on. So 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. And yes, there may be some patients who maybe already have some liver disease or who knows, maybe that in ultrasound, they already have cholelithiasis. I might not want to use fitusiran in them. But -- it's again, it's just -- it's a balance of everything. And I think in medicine, there's almost never a free lunch. There's always going to be some side effects that you have to weigh against the potential benefits of the drug. So yes, I didn't mean to be entirely dismissive. I think it's there in a minority of the patients, but not a small minority, and it's just something that needs to be weighed when you're making those decisions.

So the next question is from Richard Vosser.

Two questions, please. Firstly, on the Efa interpatient comparison. Was that done on all bleeds or treated bleeds? And could you put the data into context with Hemlibra data in Haven 3 because that's the only other 1 where I think we've seen this interpatient comparison. So 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. So the question is, 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 GPOs by the time it comes to market? So just thoughts there.

So for the Efa, all of the bleed data were treated bleeds, specifically comparing it to heme A. You might have a better idea?

Well, I think actually, what it's remarkable. If you look at the HAVEN 3 data, the intrapatient comparison when you look at pre factor prophylaxis before, if you look at the ABR, I think it was actually 4.4 or -- it was almost exactly the same. So that struck me when I saw that, I was like, yes, 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. So that's -- and I think it's a favorable comparison.

And 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? And -- 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 an sense where we have this tailored covalency concept. So we were hoping from the beginning that there would be differentiation also on the safety side due to that due to that difference in binding to the BTK -- and at least so far, we have not seen anything in our study. So we're maintaining our standard monitoring in those studies.

Then we would move on to Seamus, Seamus Fernandez.

Great. So just a couple of quick questions. First question is for the physicians. As you think about pediatric patient populations, 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. What are your thoughts along those lines? And what really is it that drives the patient community and the physician community towards the use of Factor VIII therapy to -- I think, a preference to some degree. And correct me if I'm wrong, their preference of use of Factor VIII in the pediatric patient population. And then separately, as we just think about the broader opportunity, I was just hoping, Sanofi, if you could clarify for us what the breakdown is in the United States versus international markets 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.

So with the evangelist's 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? We -- they did a procedural study on minor surgeries, thinking that patients with on emicizumab would not need factor for procedures that didn't go the way that it was expected, right? So 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 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 more 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. But my mentor, a wise man that Dr. Young knows very well, has said over and over, like if you have a deficiency of Factor VIII, you treat that with Factor VIII. And I think that's the simplest thing that in my mind covers all of your bases and is most safe, but 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.

So I've been accused of being a Hemlibra evangelist, but of course, I was involved in the clinical trials. And what I'll say is that I'm a patient outcomes evangelist. That's the only evangelism by the way, I ascribe to. So in my practice, now 60% of my prophylaxis patients are pediatric patients are on Hemlibra, 40% are on factor. So you might ask yourself, why is that? Well, 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 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 subcu every 2 weeks," I think that's unlikely. But what about those 40% that have chosen Factor, why? Well, as Angela said and her mentor, a good friend of mine, Steve Pipe, he says it right, which is that 1 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 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 stick to that. They say, "I don't want to try something new or different. I don't want to try something that isn't factor." And that's why 40% of my pediatric patients still use Factor VIII replacement as difficult as it might be. And that's fine. That is a patient choice, a parent choice and having more choices is better. So how do I see my patients going forward? Those 60% that have already declared, I want the easiest I want subcu. I don't want to 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 Efa becomes available. For those who -- 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 1 of you mentioned earlier. Some patients, yes, are going to stick to that. Even though we've had recombinant Factor VIII in the U.S. for 30 years, I just got my last patient off plasma like 2 years ago. It was like clinging to it like people clung to the BlackBerry, right? But -- so I think that there's always going to be some who are just going to stick with what they've been on. I think the majority of factor patients in my practice, I imagine once Efa is available, will switch. I think the Hemlibra patients, the vast majority of them probably won't switch.

And maybe to the question about the market split. So if you look in that non-inhibitor heme A market, about is U.S. It's about 50% when you include Japan.

So with this, we would move on to Emmanuel, Emmanuel Papadakis.

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, Drs. Young and Weyand, you've given us a very helpful data points. But perhaps I could ask slightly more direct follow-up. If you could just give us 2 numbers each approximately what percentage of your total patients still on factor therapies, for example, I know you just mentioned the pediatric group -- but the total group would be very helpful. And then approximately what proportion of those do you anticipate within a couple of years could be moved on to efanesoctocog.

So the antithrombin monitor, yes, sorry. So first of all, antithrombin monitoring is not difficult because most hospitals, certainly hospitals that have hemophilia treatment centers, typically have antithrombin testing on-site in their own lab. And even if they don't, the turnaround is a couple of days. It's not like -- I mean, with the drug that's given every 2 months, it's not like you need the result right away, right? Because you're not going to make the dose change for a while. So 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 there's nothing that can't be overcome. But antithrombin level -- getting antithrombin levels is easy. I mean you all labs have it. These are approved tests. And even if you don't have it on site, you can get it back quick enough within 2 months to make a dose adjustment. Now how important or how necessary will that be? We clearly are going to have to do that at the beginning, right? We're going to start patients on a dose. We're going to 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 want to check again. If I don't have to make a dose adjustment, we know that the levels stay really steady. I certainly is not going to be doing it on a regular basis, but we see patients every 6 months, every year. Probably at the beginning, I will want to see what the levels are. It's not like it's difficult to do, as I said, it's not like it would be that often. But when patients come to clinic, I might monitor them. So -- 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. So that's my answer about the antithrombin monitoring. And maybe it's getting late, but I forgot the other question. Some of that...

What percentage of your patients are on Factor and how many of them would switch to Efa in the first period after it was.

Angela pointed out that I'm older than her before, and I think it's showing. So I mentioned in pediatrics, it's a 60-40 split right now with heme versus factor. The adult patients are -- as we pointed out multiple times, we're a little bit more conservative. So that split, it's just about the opposite. It's like a 40-60 split. So still 40% have switched emicizumab, 60% remain on factor. That's obviously just the hemophilia A patients, clearly. Obviously, hemophilia B, everybody is at Factor.

And 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 4 patients on Efa. Now 3, 12 and olders and 1 who started recently as a pediatric patients. But I've had patients on Efa now for, I think, more than a year, 3 of them were close to that. And again, I -- 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 nonfactor and factor. And I agree with Dr. Young. I can't think of 1 reason, medical reason, why we wouldn't switch all of the factor patients to Efa when it was approved. And 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.

So then we move to the last question. The last question is from John Murphy. And in that case, I see also Graham has raised to send, and we do the last question with Graham.

Great. Yes, actually, so 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 of dealing with payers in hemophilia, 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 going to go there. What I will say is every time we've had a new product in hemophilia, and I'll go back even to an Advate. I was around because I am older -- when Advate came out, which was in 2005, it was hailed as the purest product. Back then, we're still living in the waiting days of the HIV, hepatitis, I mean, which was still very heavily on our minds back then. So it was the purest product because it didn't have albumin or any human proteins in the processing or in the final product. So that was its big thing. And it was -- as a result, it was priced more expensively and 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. A lot they came out of your 10 years ago, and we started prescribing it and payers paid for it. And when Hemlibra came out, also payers paid for it. So I've never had a situation where a new product came out, I wanted to prescribe it to a patient. Obviously, within the realm of normal indications and normal doses, not doing something that's absurd, that hasn't been paid. Now I think in the United States, for those of you from the U.S., we have a very fractured health care system, and I'm from California, which is a little bit 1 of the progressive states, thankfully. But others say, I have a colleague, [indiscernible], Miguel Escobar, some of you may have heard of him or know him, who is in Texas. And it's a little bit different down in some of the other states where the payers can be a little bit more restrictive. But 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. So I don't see that not being an issue. As long as Efa isn't priced at some -- in same point where the payers, we're not going to pay 20x more or something like that, just I'm being a little facetious. But I mean 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. But I don't -- I still don't see that that's going to happen because, like I said, every time we had a new drug, we've been able to prescribe it.

So maybe just a 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 at broad and we think that with Efa, innovation will be recognized.

And 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 what was in the product inserter and still really didn't have an issue with payers. And 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 was -- so 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 chairs so that next time when I invite for event, not having trouble. So we do the very last question from Keyur, and then we go to some closing remarks to Dietmar.

Just picking up on a couple of statistics you guys have mentioned. So you said there were roughly 2 kind of bleeds per month in the non-prophylaxis arms, the Arm B kind of getting into the study. And then kind of you guys have mentioned 70% of patients are on prophylaxis treatment in the U.S., 30% are not. That is my question is what's stopping the other 30%? If you're going to 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 4 or 5 years back, that was closer to 50% prophylaxis, 50% on-demand. It's obviously moved to the right direction. But kind of why isn't it much higher?

So at our center, similar to Dr. Young, 100% of our severe patients -- severe pediatric patients are on prophylaxis. The patients that are 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 have an attitude of, I've not done that in 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 going to 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. But 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 health care system, unlike the U.K., 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 oncologists 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. So I mean we do -- so that number where we see that should be a 100% of severe patients, it's not the case. And that's a result in the U.S. of just a bad health care 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 patients in the U.S. shouldn't be on prophylaxis, but it's true that that's not the case, and it's a kind of a sad fact. We have to close on a sad note? Anyway.

See something uplifting now?

Yes. So look, I want to go back to a question that was asked early on, which was Efa being used less frequently than once per week. And I've been since that you asked the question, I've been sitting here thinking about that. And 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. If you compare to some of the nonfactors, Efa is finishing the week where others are starting a week. And 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. And that's something that, 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 patient to maybe shouldn't be on prophylaxis. But actually, if you've got something that you can use once every 12 -- 10 to 12 days, they may be more inclined to be on prophylaxis. Could you think about that right?

And that's like going to be a completely different scenario anyway, right? Because these are patients that are normal for 4 out of 7 days starting at 0, but if you're starting at 10%, then clearly, that's like a different curve than what we're seeing in these patients. So 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 have a longer interval for those patients because you're still providing very high-level protection, then that would be great.

And 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 I say I believe we will win. But we're not going to restrict ourselves from going to every heme A 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. So that, I consider a more positive note in which I will there.

Hand over your colleague and friend Dietmar.

I was going to close on the positive note as those peanut butter brownies were fabulous.

Are there any left?

I think we will get out of us out of here quickly. But I will pick up on what Guy said before, which is the patient outcomes evangelist. I really like that term. I think that's we hope we have shown to you that 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 2 months, subcutaneous, no cool chain required. That's just another drug that you can use globally much better. So I think we have these new options. We have the strong commitment to the community and to the patients. And thank you all for coming. Thank you for all your questions and for the discussion. And 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's just so much more tangible what the benefit of these drugs can be. So thanks very much.