Ladies and gentlemen, welcome to the Advancing the Standards of Care in Hemophilia conference call and live webcast. I am Alice, the conference call operator. I would like to remind you that all participants will be in listen-only mode, and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for questions at any time by pressing star and one on your telephone. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to Guido Oelkers, Chief Executive Officer. Please go ahead, sir. Yeah, thank you so much, and good afternoon, respectively, good morning for some of to this event of Sobi. And that it's really a great pleasure, you know, to, to have you all with you. You know, and it's a sequence of events after our last event on my elofibrosis. Very excited about it. And, you know, maybe move to the next slide, you know, which is a forward-looking statement as per usual. So today, you know, I'm joined by Lydia Abad-Franch, who is our acting Chief Medical Officer, and who will review clinical efficacy and safety of efanesoctocog alfa. But I'm really, really delighted also to have to welcome Dr. Robert Klamroth, who is Head of Internal Medicine at the Hemophilia Comprehensive Care Center, Vivantes in Berlin, Germany. He's not only one of the foremost clinicians in hemophilia, probably also one of the foremost thought leaders. He will give us some insights on raising the bar for hemophilia treatment. With this said, you know, I just wanted to provide you with some context with regard to Sobi. So when you think about Sobi as a company, I mean, we are obviously supremely proud, as you will see, about our hemophilia franchise, in particular, our latest addition, ALTUVIIIO. But we have dived beyond into hematology and, namely into Doptelet, our latest TPO-RA, that makes significant progress as C3 inhibitor, and we are really excited about the progress we are making in the area of PNH. That we launched in DLBCL and making now strides, at least in some European countries and in the Middle East. And with Vonjo, obviously, our product, our JAK2 sparing inhibitor, JAK1 sparing inhibitor, and JAK2 inhibitor now in the US. Next slide. So when you come to hemophilia, and I don't want to, you know, go into the old history, I just wanted to tell you that, you know, we have a long history in hemophilia, relating to, you know, preceding entities of Sobi like Kabi, KabiVitrum, you know, dating back, you know, a long time, as you can see here. And I think, you know, then obviously moving over to moving on with certain partnerships, latest by Vitrum now with Sanofi. But I think important to note for you is that this hemophilia competence is not there since yesterday. And, you know, our scientists have done very important steps with regard to inventive steps in Fc fusion, which is part of Elocta and Alprolix, but also of efanesoctocog alfa. So long history and long-lasting competence. Next slide, please. And when you come to our hemophilia products, you know, they made obviously quite a bit of progress over the years, and we are very grateful for this and you may feel that this is a sense of obligation as well. But we have diversified, as you can see here, beyond hemophilia quite significantly, and this is at the example of our 2022 data. Next slide. But for us, you know, hemophilia is not just an area, you know, of where we obviously are excited, you know, to penetrate and, and, you know, provide market shares, that are important for investors. But it's also, let's say, a sense of obligation. And, you know, with our partner then, Biovitrum, we have inaugurated the Humanitarian Aid program with the WFH. And, you know, over 32 kids have been treated since, and, you know, 22,000 people are on therapy. So that's, you know, compares very favorable, even with the number of patients we currently have on commercial treatment, and it's a blessing, and, but also a sense of duty, to take care of these patients in developing countries where we are never intending. So that's basically coming back to our portfolio. So we are very excited about, obviously, our legacy portfolio with Elocta and Alprolix, that you are very well aware of. Today, it's all about efanesoctocog alfa. We believe it's a new class in the factor VIII replacement therapy, and, you know, the reason why we are so excited, you know, will become clearer when Lydia now shows you a little bit more on the clinical profile and insights, and then obviously, Robert will take it from there. Thank you so much. And Lydia, maybe you take it from here. Thanks, Guido... So So in the next few minutes, I will give you an overview of the efanesoctocog alfa molecule, review the clinical data that makes us very confident and truly excited, and then I will briefly show you a bit of the clinical program that we have ahead of us. So here, first, the introduction to the molecule and how it was designed. So all currently approved factor VIII therapies circulate as a complex with von Willebrand factor, and the half-life is determined by the VWF clearance. This puts a ceiling on factor VIII's half-life of 14-19 hours, imposed by the endogenous VWF. So efanesoctocog alfa represents a new class of factor VIII replacement therapy, purposely designed to decouple from endogenous, to decouple factor VIII from endogenous von Willebrand factor to overcome the imposed half-life ceiling and to increase the factor VIII levels to the non-hemophilia range for most of the week, and what is really important, with once-weekly dosing. Efaneseoctocog alfa is a fusion protein of human single-chain recombinant factor VIII, the Fc domain of a human IgG1, the factor VIII binding D'D3 domain of von Willebrand factor, and two extended polypeptides, as depicted on the slide. So if we look now at the sequential PK data, if you can click. In the sequential PK1 study in adults, a single dose of EFA, 50 units per kilogram, resulted in a three- to fourfold longer half-life than the competitors. In the graph, you can see on the right side, you see a red recombinant standard half-life factor VIII product. In blue, the extended half-life factor VIII product, and in green, the PK profile of EFA, with a terminal half-life of 43 hours, one week after the infusion. The mean factor VIII levels were maintained above 40% during the first four days after the administration and were at 10% on day seven. So from the clinical data, we know that efanesoctocog alfa is an effective monotherapy for all clinical settings. It's well-tolerated and effective in adults and children for routine prophylaxis, bleed prevention with once-weekly dosing, for on-demand treatment to control the bleeding episode, and for the management of surgeries. So let's have a look through the studies. On these slides, we present the design of our two completed pivotal trials, XTEND and XTEND-Kids, that have demonstrated the safety and efficacy profile of EFA in adults and children with severe hemophilia A. XTEND-1 included previously treated adults and adolescents. 133 patients previously on prophylaxis enter arm A and receive EFA 50 units per kilo weekly prophylaxis for 12 months. Important to mention that 82 of these 133 patients roll over from the observational and prospective pre-study. Additionally, 26 patients previously on-demand entered the arm B and received EFA on-demand for the first six months, followed by EFA prophylaxis during additional six months. The primary endpoint of the study, the annualized bleeding rate in the prophylaxis arm, was successfully met, and I will come back to that in the next slide. But in the pediatric XTEND-Kids study, for previously treated patients younger than 12 years of age, all patients received EFA weekly prophylaxis, 50 units per kilogram, and were followed up for 12 months to assess the occurrence of inhibitor development, which was the primary endpoint. In the XTEND-1, the primary endpoint was met, as mentioned, as I just mentioned, with a mean annualized bleeding rate of 4.71, demonstrated that EFA is highly effective in bleed protection. The key secondary endpoint was based on the intra-patient comparison of ABR during the prophylaxis arm versus the ABR during the pre-study prophylaxis. And we demonstrated that switching from pre-study factor VIII prophylaxis to EFA prophylaxis decreased the mean annualized bleeding rate from 2.96 to 4.69. This is a reduction of 77%, clearly demonstrating superior bleed protection over prior prophylaxis with EFA. So if what we now look at the PK results from the adults and adolescents in the XTEND-1 study, they confirmed the PK profile previously depicted, with mean factor VIII levels in the non-hemophilia range, above 40% for the first four days after administration of EFA, and above 10% during the remaining days of the week. In addition, the data from 17 patients reassessed at week 26 showed no or minimal accumulation, as represented with these two similar PK profiles in the graph. Turning over to our attention to the children, the high efficacy of EFA has been confirmed in the pediatric population, with all analyzed bleeding rates below 1 and very low joint and spontaneous ABR, as you can see in the table on the left-hand side. We analyzed joint bleeding rate of 4.59 and annual spontaneous bleeding rate of 4.16. These results are reflected in the high proportion of children without any joint bleeds, 82%, and any spontaneous bleed, 88%. If we focus now on the treatment of bleeds and surgeries, the efficacy of EFA is clearly demonstrated in the phase 3 studies across all ages and clinical settings. For on-demand treatment, almost 100% of the bleeds were resolved with a single EFA dose. And for surgeries, for surgeries, the hemostatic response was always rated as excellent or good. And this includes 12 major surgeries in XTEND-1, with six major orthopedic surgeries, and then two major surgeries in the XTEND-Kids trial. Turning over to safety, efanesoctocog alfa has proved to be safe and well-tolerated in patients of all age. No development of inhibitors has been observed in previously treated patients, and no serious allergic reactions, anaphylaxis, or thrombotic events occur in XTEND and XTEND-Kids. There was one patient, unfortunately, who passed away due to a metastatic pancreatic carcinoma that was assessed by the investigator as not related to efanesoctocog alfa, and two patients were discontinued. One, due to a decrease in CD4 lymphocyte count in a patient with a previous history of HIV infection, and another patient due to a traumatic combined tibia fibula fracture, in a patient who had to receive an emergency surgery that was performed with another factor product that was prohibited during the study. We also have data indirectly comparing the efficacy of EFA with emicizumab. This compares the corresponding pivotal studies, XTEND-1 with HAVEN3. On the left-hand side of the slide, you see the comparison of the annualized bleeding rates in patients with prior prophylaxis. It compares XTEND-1 arm A, so the patients who went through with prophylaxis, with emicizumab arm B, which was the once-weekly dosing. Efanesoctocog alfa prophylaxis was associated with significantly lower rates of bleeding than emicizumab prophylaxis. The annualized bleeding rates for any bleed, any treated bleed, and treated joint bleeds were significantly lower with EFA prophylaxis than with emicizumab. The ABR for treated spontaneous bleeds was also lower with EFA versus EMI, although the result was not statistically significant. On the right-hand side, you see the comparison of the HJHS, the Hemophilia Joint Health Score, between EFA prophylaxis and emicizumab prophylaxis. EFA was associated with significantly greater change from baseline in both Hemophilia Joint Health Score joint score and the total score compared with emicizumab. So in summary, the XTEND program demonstrated efficacy and safety of efanesoctocog alfa with factor VIII activity levels within the normal to near normal range for a significant part of the week. Patients experienced superior bleed protection compared to prior factor prophylaxis and significant improvements in joint health, physical health, and pain. There was no inhibitor development. Now that the clinical development program for efanesoctocog alfa has been successfully completed, we have a comprehensive program in place to generate additional data. Here on the slide, you can see the XTEND-ed study, which is an extension study ongoing to provide long-term data, to further support safety and efficacy. The FREEDOM trial, a new phase 3b study sponsored by Sobi that has recently started in the EU. It aims at providing data on the impact of EFA prophylaxis in supporting physically active lifestyles, maintaining joint health in patients with severe hemophilia A. With that, I would like to hand over to Dr. Klamroth for his presentation. Thank you, Lydia. So now it's my task to give some clinical perspective on efanesoctocog alfa. Next slide, please. So you all know hemophilia patients are missing factor VIII, and due to this, they bleed. And replacing the factor VIII to treat bleeds and to prevent bleeding is our main goal. But of course, over the years, throughout the life, the tasks and challenges changes. So at birth and diagnosis, a lot of parents are surprised that they have a child with hemophilia because more than 50% are spontaneous mutations, and they have to make a treatment choice. And mostly, and which is most logical, is the treatment of choice is to replace the missing factor VIII to avoid any bleeding. Of course, there's worry still when the child starts to run. They are really afraid that they fall and get bleeding. They have to learn and cope with the injections intravenously, which is quite difficult in a young child. But normally, I think over this time, we are able to teach the parents, later on, the kids, to do the intravenous injections by themselves. They have increasing activities. They learn how to replace the missing clotting factor, that they can participate in sports activities. They got an increasing responsibility about treatment. They can judge risks and benefits to have hemophilia. But still, there might be joint damage. There might be other comorbidities later in life. And if you are old, there might be decreasing activity. And of course, over the years, in the next slide, there are still unmet needs in hemophilia treatment. So depending on which country you live, there are still recurrent bleeds despite prophylaxis, because it's not effective enough. That leads to joint bleeds and later to joint deterioration. Hemophilia patients, especially older hemophilia patients with joint disease, have a lot of pain. Due to this pain, a reduced health-related quality of life and physical functioning. And of course, if they need surgery, and that's still in most patients, orthopedic surgery, there's a challenging preoperative management. Next slide.... Over the years, there was some development, and, Inga Marie Nilsson was the first one who thought, "Okay, we convert severe hemophilia A to moderate hemophilia A to due to regular Factor VIII infusions." And this initial goal, to convert severe to moderate, or at least to have a trough level above 1%, resulted in a reduction in bleeds, but not that there were no bleeds at all, and patients still developed joint disease. To achieve higher levels with standard half-life factor VIII was quite difficult and only with daily injections possible. In 2010, with the advance of extended half-life factor VIII and the non-factor mimetic therapy, we were able to achieve higher trough levels and more protection. And the new target levels recommended by WFH and by the German guidelines, are now to convert a patient to a moderate, mild patient with levels of 3%-5%. And in the future, we hope we can do even better with new classes of factor VIII therapy, like efanesoctocog alfa, and the non-factor mimetic and rebalance therapies and gene therapies, to go for higher levels and a better protection in patients with hemophilia, and that they are comparable with to mild hemophilia patients or even be hemophilia-free individuals. Next slide. If you look more in the future, I think if we want to achieve this goal with health equity and full participation in physical activity and social functioning, we have to go for a near normal hemostasis. So in the future, our goal will be to normalize hemostasis in patients with hemophilia, to have a full protection and full participation. Next slide. Next slide. So here I can show you, is it possible already with the existing products on, on the market? And I like this slide very much because you can see with standard half-life factor VIII, the half-life around 8-10 hours. You have to infuse very frequently to get high levels, and you have a lot of peaks and troughs. That improves a little bit with extended half-life factor VIII, but only with efanesoctocog alfa, we have now the possibility, with once-weekly injections, to normalize hemostasis for the first four days of the week and be in the mild range, above 50%, for the second half of the week. With non-factor therapies, like emicizumab, which is licensed already, we can achieve a constant level in the mild range, but we cannot normalize hemostasis. With gene therapy, where the factor VIII is produced in the liver of the patient after gene therapy, you know, the results are very, very heterogeneous, and I think 20% of patients have a normalized hemostasis after gene therapy, but another 20% have no or a very small effect. So it's not very predictable at the moment. Next slide. I want to give a short spotlight now, how efanesoctocog alfa can fix or can be an improvement in unmet needs like recurrent bleeds despite prophylaxis, in joint deterioration, in hemophilia-related pain, in reduced health-related quality of life, and in the challenging perioperative management. For this, I will pick a little bit out of data from the studies Lydia already presented. Next slide. So you can see here, prophylaxis, and if you look at the rollover population, that there was a significant reduction in patients who were prior to treatment with efanesoctocog alfa on standard half-life factor VIII. You see here, the mean ABR was 3.2 in patients with standard half-life factor VIII and 0.4 to 0.79 with efanesoctocog alfa. And if you look at the patients with extended half-life factor VIII prophylaxis before entering the study, was a bit lower than the standard factor VIII, but still 2.6, and this went down to 0.55. So overall, in the rollover population, there was a reduction from an ABR, a mean ABR of 3 to 0.69. So from my point of view as a clinician, with prophylaxis, with efanesoctocog alfa, and I can reduce ABR significantly in my patients, and as a consequence, I will have later reduced joint disease and less bleeding. Next slide. This reduced ABR and better protection results in significant improvements in joint health. If you here look, especially in the older population, where you already have destroyed joints or at least affected joints after bleeding, you can see that there is a reduction or a change in the Hemophilia Joint Health Score. The Hemophilia Joint Health Score is a score where we can look at the six major joints, ankles, knees, and elbows, and to see the impact of bleeding and joint disease. If you are able to lower the score, you have an improvement in your patients. I think, of course, if the joint is more destroyed and there's more joint destruction in HA, and we saw there is a greater improvement in older patients, if you have a good prophylactic regimen. This is the case with efanesoctocog alfa in the study. Next slide. Usually, this relates in pain, and if you look at the PROMIS pain intensity score in these patients, you can see that there's a statistically significant reduction, which is clinically meaningful in pain intensity. Of course, if your joints are destroyed, one year of improved prophylaxis cannot make you a new joint. But normally, we would assume that with ongoing age and with patients getting older, there's more joint destruction. To reverse that, at least a bit, to have less pain, I think is a great success in these patients. Next slide. This has impact on quality of life. There are different domains, and this health-related quality of life questionnaire, it's a hemophilia-specific tool called Haem-A-QoL. And if you here look in at the patients before and after the study, you can see that there is a reduction, and reduction means better health-related quality of life, especially concerning the physical health, the treatment with less injections, the view of patients themselves. So 71.4% of participants maintained or improved their physical health score from baseline to week 52, which I think is a sign that with once-weekly effective prophylaxis, you can reach a better quality of life for your patients. Next slide. In surgery, it's especially in countries where clotting factor concentrates are not available, it's quite difficult to maintain painlessness during surgery, especially if you need high factor VIII levels. And with this drug, surgery is quite easy, with one injection before, one injection during the week, and then injection the next week. The 12 major surgeries in this trial went very well, and you see in the median number of injections until day 14 were exactly 4 in most patients. In my center, we did three surgeries in the study and exactly using only 1 or 2 additional injections additional to the regular prophylactic regimen, which makes surgery much easier in this kind of setting. Next slide. So after the XTEND-1 study, 100% of participants reported efanesoctocog alfa as their preferred hemophilia therapy, compared to previous factor VIII prophylaxis. I had 4 patients in the study. All patients are in the extended study, and they are waiting for the approval of the drug. They are doing very well with this weekly prophylactic treatment. In Germany, a lot of patients still want to remain on Factor VIII because replacing the missing Factor VIII is logical to treat this disease. With this drug, with efanesoctocog alfa, for the first time, with once-weekly injection, there is a possibility to have a really effective prophylaxis and be protected against all bleeds. Now I hand over back to Guido. Yeah, thank you so much, Robert, very much appreciated. And, you know, you, you can sense, you know, when, when we had interactions with you, and we talked about unmet medical needs and hemophilia and also the excitement around the product profile, why we were so excited, you know, after these, very important, presentation. Back to thank Robert, obviously, and, and also Lydia. And I think now is the time for, for Q&A, and, maybe we can, have the first, you know, question, and, and then we can refer them whoever, whoever is the most relevant for the question. Operator, maybe, are we having any questions? Yes, we'll now begin the question and answer session. Anyone who wishes to ask a question may press star and one on their touch-tone telephone. You will hear a tone to confirm that you have entered the queue. If you wish to remove yourself from the question queue, you may press star and two. Questioners on the phone are requested to choose only answers and eventually turn off the volume from the webcast. Anyone who has a question may press star and one at this time. Our first question comes from the line of Charlie Mabbutt with Morgan Stanley. Please go ahead. Hi, it's Charlie Mabbutt from Morgan Stanley. Thanks for taking my questions. So I guess firstly, factor therapies still account for around 60% of the prophylactic market. So I guess how do you see that trending over time with Hemlibra continuing to take share, other bispecifics coming to market, and gene therapy now entering the space? And then- Yeah. - secondly- Mm-hmm. Secondly, many patients have obviously remained on factor therapies despite the stronger product profiles of products like Hemlibra. So I guess what gives you the confidence that these patients will now switch to ALTUVIIIO? Thanks very much. Thank you. I mean, Robert, if you don't mind, I take this maybe. Yeah, as this is more commercially driven. I mean, you know, basically, you know, when you look at the market, I mean, I think in Europe, probably the share of factor treatment is even higher, let's say, than the 60%. And yes, Hemlibra has made some significant inroads, but, you know, as you rightfully said, you know, the market is not, is still, you know, mainly driven by factor, and this is related to, obviously, to customer. You know, as Robert pointed out, there are many patients who prefer factor over other therapies. And, you know, but, you know, now the big question is why now? Why the shift now and not earlier? Well, first of all, I think you have to say that in, you know, Hemlibra did, you know, taking significant share relatively rapidly. And, we think that, but, you know, not able to address all needs, you know, and this is what we always said, you know, there is no panacea, it's always a trade-off. We think that this trade-off of a product with the efficacy of efanesoctocog alfa or efmoroctocog alfa, helping patients to be, you know, normal for days a week, is quite an important, you know, winning argument. And, you know, and also, if you're an active patient, let's see, you know, this area where you basically could see factor equivalent levels of Hemlibra, you know, that will not enable an active life alone. So, you know, we think that there will be a large group of patients that may want to benefit. And, you know, we also believe that there is a positive momentum. You know, there's a lot of, you know, patient reported stories from, you know, the clinical trials, and this will excite patients to try. And, you know, we couldn't have not asked for, you know, a better patient feedback, obviously, from the trial. It can't be better than 100%. And, you know, we think that this will make its way into the community, and then, you know, So we think that we will take, you know... You have seen the latest report from Sanofi, who think that they are taking 10% of the Hemlibra patients, or 10% of their patients are from Hemlibra, and then, you know, quite a few from Elocta, but also mostly from other factors. We think that we could probably take more from Hemlibra, given our relative position and given the fact that, you know, our share with Elocta is larger than in the US. And, you know, we think that this also speaks to the relative strengths of our organization. So we believe that, you know, we can take the material share from new therapies. We don't believe that gene therapy, with the very significant costs and the that are associated with this and the ones, in the setting, will be an easy sell. And you can see this from, you know, the number of patients that are published, you know, and related to, you know, gene therapy. You know, there will be some, but, you know, right now it's, you know, it's a really small number. And I think, you know, the trade-off decision, you know, gene therapy versus a factor treatment that allows you to be normal four days a week, is, if there is a one. So we think, and therefore, our opinion hasn't changed. We believe that this is gonna be a leading therapy. We will not be a leading therapy, and this is probably north of 30%-40%. Yeah. Great. Thank you very much. Thank you, Christian. Yeah, that's great. Thank you. Maybe next question. The next question comes from the line of Neil Alexander from Deutsche Bank. Please go ahead. Hi, everyone. It's Neil Alexander from Deutsche Bank. One, if you can give any color on the pricing outlook for factor products and margin implications of launching ALTUVIIIO in 2024. Thanks. Yeah. Yeah, no, I mean, I think, you know, when, when you look at pricing, I mean, we, we believe that we will peg the price, on a treatment basis versus the net price of, Hemlibra and, and, EHLs. And, in some cases, we will be able to get a premium, and, some cases, you know, we just have to accept the cost per treatment are the same and, and basically make then the economic case, as we reported previously, via market share expansion. And in terms of margin, you know, obviously, you know, the, the margins will be very comparable for us overall in hemophilia versus the past, simply because, you know, there will be some, obviously, a price erosion. But, you know, we don't think to the, this, this dramatic shift as we have seen historically, because, you know, prices are now adjusted across Europe. But, you know, this is not a prediction, this is our assumption. And, and if this is the case, so it's more of a gradual, economization, then, you know, we, we should be with the, with the change of, production side and the improvement there and the, and also the fact that, you know, obviously, you take it only once a week, the once a week setting, we should be all right. And, you know, and obviously, we'll get bolstered from the, the overall hemophilia profit from the royalties that we are receiving from, from Sanofi. I think in terms of profitability of the overall hemophilia franchise, we have a more stable outlook, but, you know, with increase of revenues. Thank you very much. Thank you. Thank- Another question. I mean, we have Robert here. I mean, he, you know, this is your, the opportunity to ask some really tricky questions, yeah. ...The next question comes- Any other Chris? Yes, sorry. The next question comes from the line of Alistair Campbell with Royal Bank of Canada. Please go ahead. Thanks very much. Thanks for taking the question. Yeah, one for Dr. Klamroth, please. Basically, I'd love to understand of the patients you're currently treating with factor what percentage are on prophylaxis versus on demand? And do you think actually the availability of EFA could change that dynamic, and you could see more patients moving from on-demand towards prophylaxis? And then I'd also just like to get a sense of how important you think the lack of inhibitor data are so far in terms of profile you've seen with EFA. Thank you. Yeah. So I think in Germany, it's a long tradition of prophylaxis, but started in the early 1970s by Hans-Hermann Brackmann in the Bonn Center. And so in Germany, all patients with a severe bleeding phenotype are on prophylaxis. So that includes all patients with severe hemophilia A and patients with moderate severe hemophilia A, who have a severe bleeding. So, depending on that if that all patients who bleed are on prophylaxis, then there are certain trade-offs, I would see not a big amount of patients who will go for prophylaxis with this product. But Germany is conservative, doctors are conservative, patients are conservative, and so still Factor VIII is the most widely used product for prophylaxis in our patients. And I see some potential, at least for these patients who refuse so far to switch. You know, from your analysis, perhaps that in Germany, still a lot of adults are on plasma-derived Factor VIII because they didn't want to switch, and this is from my point of view, there's a huge potential because they clearly want to stay on Factor VIII and didn't see a big improvement with the first-generation extended half-life products. But now with this product, I guess there will be a lot of patients who will switch now to this product to have a more effective prophylactic treatment in Germany. Okay, maybe you also would go on. Sorry, yeah. Yeah, well, of course, follow up and try and understand why so many patients who've stayed on plasma-derived, what's led them to stay on plasma-derived and whether that could change now with EFA. Thank you. That's always difficult, but I told you already that patients were conservative, and doctors in Germany are usually conservative, too. So the Hemlibra uptake is in Germany, I think it's one of the countries which can afford it, but the uptake was very low due to this, from my point of view, due to this reason. For the non-inhibitor population, there was a very low uptake because patients and doctors perceive Factor VIII as a logical, replacement treatment for hemophilia patients. And the older patients, and it depends, they say, "Okay, it worked for me. It worked for me for a long time now, for 20 years, for 25 years, and I don't know if you do if you switch a treatment" and ask yourself for that. If you switch something, there's always a risk, that it might be worse afterwards and not better. Now I think with these data, all hemophilia treaters in Germany are confident to say, "Okay, it will be better." There's no change that it could be, could be worse due to the better pharmacokinetic and the higher efficacy. That would be my guess about this in Germany. Okay, thank you. Sorry, Robert, I think he also asked before about your opinion on the inhibitor, the absence of inhibitors in the XTEND and XTEND-Kids. Yeah, of course, so far, we have no inhibitors. Of the, the EMA doesn't require any more PUP data, so we will see in the real world. As always, with this, this is modified drugs, it could go in both directions. I personally think because the molecule is shielded and fused, there are less epitopes for inhibitor development, and it might be even less immunogenic than the existing Factor VIII. But that's all speculation. We will just see it in reality, if the first patients are treated with no Factor VIII before. Our next question comes from the line of Mattias Häggblom with Handelsbanken. Please go ahead. Mm-hmm. Yeah, thank you so much, Mattias Häggblom, Handelsbanken. Two questions, please. Firstly, for Dr. Klamroth, the 10% of patients that is said to switch from emicizumab to Altuviiio in early feedback from the US launch reported by Sanofi. So, help me think of the profile of such patient that you think is willing to switch from a weekly subcutaneous therapy back to weekly IV infusion. And then secondly, for Guido, when I look at the first generation of extended half-life Factor VIII, ELOCTA and ELOCTATE, sales generated by Sobi and Sanofi in each of your regions last year was broadly the same, roughly EUR 500 million. If we leave differences in pace of getting reimbursement for US and Europe aside, is it reasonable to think about two of you also ending up commercially equal in size for the two regions over time? Or what would be the difference here? Thanks so much. Now, first, my part, so I think, I think there's a clear population, and this is a population who are using Hemlibra and has still breakthrough bleeds. And we are, of course, we are using in my center because it's the second biggest center in Germany, we are using Hemlibra in the non-inhibitor population. But there's a percentage of 20%-30% who have regular breakthrough bleeds every one or two months, where they need Factor VIII, additional Factor VIII. So they need two drugs for treatment, Hemlibra and Factor VIII in the case of a breakthrough bleed, because you all know Hemlibra doesn't normalize hemostasis. You are still in the mild range, and you can have bleeds. And this is from my point of view, the population, because they are able to infuse, because they have to infuse regularly with breakthrough bleeds. From my point of view, that will be the population who will switch to one drug again, where we can treat everything, and that would be from efanesoctocog alfa, from my point of view. Yeah, Matthias, with regard to the regions, I mean, we would think that our region, in comparison to the, because, you know, Sanofi has obviously global rights except our region. So our region would probably represent, you know, 30%-35% of the total potential. Now, historically, we have been able to achieve a better performance than this, yeah, relatively speaking. You know, we would have to, you know, I don't want to speculate, but, you know, the US obviously is having a very different price level. So even though we have many more patients, you know, that does not necessarily mean that we have, you know, in real life, not right now, does not translate 100% into economics. So but, you know, we will—we are very happy with our region. You know, we know this region very well. We're making good progress, as you said, you know, and, and I can tell you, the team is super excited to launch this product. And, and, so, you know, we will make a very significant... We think that we can push, you know, the, you know, above our, our, our, our, our potential. Yeah, so that's clear. But, you know, beyond that, I, I would not like to make estimates, but it will be—You know, we think that anyway, efanesoctocog alfa will be together with Vonjo, our key product for the future. So quick follow-up, maybe for Dr. Klamroth. There was correspondence in American Journal of Hematology last week with regards to a real-world retrospective multi-institutional cohort using emicizumab. So I think the message from the correspondence was that more patients than shown in the clinical program backing emicizumab is in severe muscle bleeds. So although anecdotal, I'm curious to hear how, what you see in your practice. You obviously referenced some of that in your earlier response, but any thoughts on the observations shared? Yeah, I thought- Yeah. The problem is always if you go anecdotal and you have some experience. I think, so the first, what I truly believe is that with efanesoctocog, we have a better protection compared to emicizumab. Right? Concerning what we see in the studies and concerning the factor VIII levels. And we have patients, too, and in my center, personally, I have to switch already three patients back from emicizumab to factor concentrate because they used as much factor concentrate as additional treatment as a prophylaxis before. And usually, they were patients who were very active and had severe muscle bleeds, or they had very severe joint disease before and had the protection was not enough. I think there's a huge difference in individual patients, how much protection emicizumab can offer, and I truly believe that better protection will be achieved with efanesoctocog alfa. Thank you so much. Thank you. Thank you for the question. Maybe another question? The next question comes from Christopher Uhde with SEB. Please go ahead. Hi there. Thank you for taking my questions. I guess I have a few that are kind of all related to each other for Dr. Klamroth. And then one for Guido, and I'll just shoot that one across quickly first, because it's short. Do you think that you can get faster launches across Sobi territories than you did with Elocta? And then for Dr. Klamroth, I'm just thinking about the profile of efanesoctocog alfa that came out of the trial where it's the first to show improved joint health in a prospective pivotal trial. And also, I guess we have some encouraging quality of life outcomes data from that as well, right? So, what to what extent—And we also know that mild hemophilia patients will ultimately experience joint damage over the course of their lifetimes. So, to what extent do you think that joint health is appreciated, or sort of the impact of therapies on joint health is appreciated today? Were you surprised to see the improvements in pain and joint health in the clinical program here? And I guess, you know, thinking about the results in the surgical setting, you know, does that kind of freedom or greater freedom to have surgery with fewer complications, treatment issues make it more attractive for the elderly patients that are on other older therapies? Thanks very much. So, shall I just start quickly, Robert, because, you know, we have quite a bit of questions, or you want to start? Otherwise, you know, I just kick it off, yeah? Christopher, I mean, are we faster than with the Elocta answer is very likely and because we think, you know, that the market is now there's more noise level on therapies and yeah, Robert is now dialing in, so it was back in. Hi, Robert. Connecting more. No problem. I just finished off my, the first part, and then, you know, you can pick it up from there. And, and basically, you know, so we think that we will be faster than with the Elocta. Will obviously depend on the reimbursement, but, you know, as we, we do not have too high expectations with regard to cost of therapy in comparison to what is already approved. Hopefully, this will help. Yeah, so and then obviously it will depend on whether we do a good job. But, you know, the, the team is in place. We think that, you know, that we can make a significant impact with a very good product, as, as, as pointed out. Maybe back to Robert now for the other questions. Yeah, I think this point of view is very important, that what I heard from you, how this will be appreciated. And I think in Germany, most of us, we believe that chronic synovitis is the main trigger of joint disease in age. And in our experience, it's one bleed enough to trigger chronic synovitis, which is very difficult to detect clinically. So you have to do an MRI or an ultrasound. And in Germany, the most popular treatment to treat chronic synovitis is to go for higher factor VIII levels, above 15%-30%. And with this prophylaxis, you have already the levels we normally use to treat chronic synovitis. That is, from my point of view, the reason that we had such a success or for the first time in a pivotal study over a quite short period, because in hemophilia, one year is quite a short period concerning the assessment of joints, that there was an improvement. And my personal hypothesis is that patients came in the study, and some of them, despite prophylaxis before, had a certain chronic synovitis in one or more joints, and with this high-intensity prophylaxis, with efanesoctocog alfa and the full protection against new bleeds, this chronic synovitis disappeared over time. And that was the improvement, because you cannot change the joint structure with prophylaxis. If the bone is destroyed or if there's some deterioration, then prophylaxis will not cure it. Then you need other means, like joint surgery. Chronic synovitis is susceptible to high levels of factor VIII, and that, from my point of view, is my hypothesis, why this drug is more successful than other drugs. Thanks. And then there was just also in terms of the surgical advantages. I mean, is that something that could help to convince elderly people on older products that, you know, it's worth the risk to change or maybe not such a strong factor? And yeah. Yeah, I think it's already done more often that during surgery or in the hospital, the cost to reimbursement is yet to, yet that you switch products. And I guess that will convince a lot of patients who go for surgery, because it's so much easier for the work, for the patient. You don't need to measure Factor VIII so often that we will use this product for surgery. Right. And, I guess one last kind of follow-up related question. We've heard some, a number of people, experts mulling the idea of biweekly dosing rather than the once weekly. But I guess, you know, yeah, we've, we haven't—we don't know whether or not the... Is that something that makes sense to you, or given the chronic synovitis, is that, synovitis, is that, something that would need to be pre-tested prospectively? What, what are your thoughts around that? We have no studies for this, but I can tell you that a lot of German treaters lobbied exactly for this, to have full protection over the time. I, it's not clear if this will add a lot of value, but from a theoretical point of view, to have a factor VIII in the normal range all the time might be more beneficial. But you always have to weigh the benefits, and from my personal point of view, for patients, and that is what I see in the hemophilia B population. Because there is once weekly injections, we already have this kind of treatment, which we will have in the future with efanesoctocog alfa in the hemophilia A market. I can tell you, in Germany, and for sure in my center, but in most bigger centers, all hemophilia B patients who are on prophylaxis switched to this, to extended half-life products, exactly with this prospect to have the once weekly prophylactic regimen. So I think it's always from a theoretical point of view, yes, but from a patient point of view, I think that it's very appealing to inject only once weekly. Thanks very much. Thank you. Maybe we go to the next caller. Thank you. Yes, sir. The next question comes from the line of Luisa Hector with Berenberg. Please go ahead. Oh, hello, thank you for taking my questions. I'm sorry if this has been addressed, the line was not very clear, but I just want to explore a little bit more with Dr. Klamroth about the first patients that are likely to use Efa, just to kind of profile as a patient. I know we've touched on various parameters, but you know, I'm just trying to get a sense of very much this will be a switch. Will it be switch from the short acting, and severity, age, I get it. Just the kind of color, who you think is literally sitting there ready to be the first patients that use Efa? And how will this be decided? How often are you seeing your patients each year? Is this going to be you recommending the switch? Do you expect some of them to be informed, and to be requesting that? And then maybe a quick follow-up on, you talked about the Hemlibra patients using backup factor VIII. I didn't hear, sorry, but I don't know if you quantified what percentage that might be, and whether that is just simply linked to their levels of activity that they would require the backup. Thank you. So for the last question, I can tell it only for Germany and for my center, that about 20%-30% of Hemlibra patients need backup Factor VIII, and it's related to high activity, so then mainly muscle bleeds, or if they have already very destroyed joints and they have joint bleeds, and then it might be not enough. The other question now about, which are the patients I would like to switch. So normally, in daily practice, we see patients with hemophilia, with severe hemophilia, on prophylaxis at least two times a year. Most of the patients we see up to four times a year. And switching is normally. There are two main reasons. The first reason is the doctor is not satisfied with the treatment because there's too much bleed, and second is the patient is not satisfied with the treatment because too many infusions, too many bleeds, too many pain. And then there's a discussion, what we can improve? Can we raise the dose? Can we use a different product? And then there will, then we will recommend the switch. So the first patients who will be switched soon after the launch of this product will be the patients where the doctor or the patient or both are not satisfied with the current treatment. From patient side, it's mostly regular intravenous injections, and if they skip one injections, they get a bleed. So and from my side, it's mainly protection, because in Germany, all patients keep diaries, so most electronic diaries. So I can exactly see when do they inject, is there a bleed, and is there nothing. And it was a lot of work to make patients comply with this approach, to document everything, and with this electronic tools now we have to capture infusions and bleeding, we can discuss goals of treatment and efficacy and protection, of course. And that will be the first, first patient, but of course, regularly, we make an update to our patients about new treatment options. Yeah. And now with gene therapy, we have a lot of, just as an example, a lot of informative discussions with every patient who might be suitable for gene therapy, for instance. Thank you. Mm-hmm. Can I, could I just follow up and say, so that sort of patient who, they're not controlled, that you're maybe saying there's too many bleeds and they, they have certain issues. I don't know what proportion that might be, or maybe the question would be: what, what proportion of your patients come in at each visit and they're perfectly happy, everything's going well, they're complying, and you have no concerns? What, what proportion that would be? So unfortunately, the majority of patients come into my office, said: "Everything is fine. Give me my factor. I want to go away. I don't want to lose too much time," because they are doing well. Now, they're doing well, they have their jobs, they have no or less bleeding with prophylaxis. And it's always my task to dig a little bit deeper, to get really out if it's satisfied. I think it's, for the future, it's very interesting. It's not so much ABR, it's more and more joint health. And we do, we monitor the joints of our patients, we do some ultrasound and see if we have to improve our prophylaxis and go for a better protection. Yeah. So it's, it's difficult to say how many people, but I think there is still room for improvement in about 30% of my patients, at least. At least. And it depends always on the goals, because the younger patients are more and more ambitious. They travel around the world, they want to do all sports, and they need a higher protection level than my older patients, who are more inactive, sitting more at home. But always on an, on an individual level. But I can tell you now, I'm in hemophilia now for more than 25 years, and the activity level of patients changed so much due to the better prophylaxis and will change in the future due to more participation, that we need a better protection in the future to ensure this to our- and, and make this possible for our patients. Thank you. Maybe we have the last question, given the time we set for this call. The last question. Any more... Yeah. The last question comes from Line of Viktor Sundberg with Nordea. Please go ahead. Yes, hi. Hi, and thanks for taking my question. So I have two here for, for Dr. Klamroth. I actually also had a question around the, the biweekly dosing that was, discussed among experts. But maybe if I turn that question around also, could you dose longer than one week as well for patients seeking convenience, that are, you know, non-active office workers, given how robust the pharmacokinetic profile looks like, after seven days? Was my first question. And, secondly, I also wondered, in, in your practice, what is the most common treatment regimen for Hemlibra? When we have talked to clinicians, you know, in, in Europe, it seems like most are treating, patients with the, once every other week. I just wonder, for example, how many are Hemlibra once weekly patients, for example, in your practice in Germany, or in the German market in general as well? That would be very interesting. Thank you. Yeah. So first, the Hemlibra question. So, I think 50% of my patients are treating every week, then 30% every two weeks, and the rest every four weeks. So to give an estimate, and we are of course treating all inhibitor patients with the Hemlibra for prophylaxis. The other question is, again, with the two weekly, of course, it depends. And when I look back, we never dosed factor VIII according to the SmPC or due to the prescription. We dosed factor VIII mostly according to levels and according to the needs of the patient. And depending on in which country you are using Hemlibra, of course not Hemlibra, you are using efanesoctocog alfa or efmoroctocog alfa, you can go for higher doses or for lower doses. In India, for instance, they use Hemlibra in a much lower dose for prophylaxis. And I can imagine that this drug can do a lot of good in low-resource countries, even if you give it on a lower dose once weekly. But from the German perspective, where we want to offer better protection and better joints for our patients, I think we will start in most centers, this is 50 units per kilogram body weight per week. And then depending how the patient reacts, we will adapt this treatment. That would be my strategy. Okay, thanks. Just a very quick follow-up. You said that 50% of Hemlibra patients were once weekly. Is that the same for non-inhibitor patients as well? Just wanted to confirm that. Thanks. Yes. In my center, yes. But in other centers, I heard there are more every two weeks or every four weeks. But it depends, again, I cannot speak for other doctors in detail. Okay. Thank you very much. Thank you. I mean, we had one very last question, I think, from Yoon from Jefferies, and then we close in reality. Yoon, please. Well, thank you very much. Thank you. Thank you for taking my question. So, you know, Efa is not yet approved in your territories. So in Europe, approval is expected in early 2024, but do you expect an earlier approval potentially this year? And second question is, given that this is a superior product than other products on the market, so how fast do you expect the pricing negotiation to go? And if I can squeeze in one more question there. Sometimes, you know, in rare disease areas, some patients are quite reluctant to switch when they are doing well with the kind of a brand loyalty. So what percentage do you think, patients in your territory would be in that category? What do you think you would need to convince them to switch? Thank you. Yeah, thank you, Yoon. I mean, so I start with the, with the easy ones, the regulatory part. Yeah, in 2023, we will enable, you know, the usage of patients in end of 2023 in some of the Middle Eastern countries. And as you, and you're right, you know, that mid of 2024, we will start—we will get, I mean, in Q2, we, we expecting approval, and then subsequently, we would launch in, in anyone. It wouldn't surprise you if Germany would be the first, and then, you know, we will roll it out according to the traditional sequence. I mean, we think that the product profile is should make it, you know, a good proposition for payers. You know, if they cannot—if, if basically, you know, you get better protection but, you know, similar costs should be a winning proposition given the broad support of the product. And, you know, we'll, we'll go through some assessments, also with the, you know, in some countries to, to further get... Because we are very convinced that this is a very cost-effective treatment from a, from a payer perspective. So, you know, we, we think that, you know, that the, we have maybe, I mean, maybe in the—maybe a little bit faster than what we had with, with Elocta. And obviously, we had some learnings, you know, you, so you would, you would expect this. And when, with regard to the brand loyalty, I mean, as Robert has alluded to, you know, and obviously, this is a very diverse picture. There are, you know, patients who are quite, you know, loyal to their brand and have not seen enough, let's say, reason to move. And, you know, while, you know, obviously, Robert sees his patients very frequently, but there are patients who see their physicians only once, you know, in a year. Yeah, I mean, as we know from some surveys, but good care looks very different, as Robert pointed out. And so the for us, the key is going to be that we mobilize patients and basically show them the opportunity as we show physicians. And... I think, you know, we will start clearly from where the product has its largest benefit, and this is with the, you know, those who are seeking an active lifestyle. We are building upon, obviously, our platform, you know, with our digital platform Florio to make sure, you know, that people understand that they can monitor the success and foster the dialogue between the patient and their treating physician. We hope that this will be a strong that we will break in. But, you know, we think that those patients who, you know, who are now reticent to new therapies may consider, many of them may consider if... But, you know, time will tell. But, you know, we, you know, again, we, we don't think this is now one model fits all. I think, you know, we—but we think that we can make major inroads into this clearly against other short-acting and long-acting, but also take share back from Hemlibra for the reasons that were pointed out. And so I think, you know, we at this stage, you know, I, it's, I don't think I'm in a position here to say how many of those will stay brand loyal. I think, you know, I, I think we—it would be nicer to delight you that we have been able to switch a large portion of those than, you know, make too many prognosis on the playout. But, you know, we have already said, you know, we think it's going to be a leading therapy. And with this, we have basically set the mark of what the management team believes. And, you know, at the end, it will be in the eyes of the beholder, meaning the physicians and the patients, whether they think that this therapy is creating enough advantages for them. Yeah, but I think this gives you an indication. I think we should be, the portion of patients that basically today is not willing to move, for instance, on from their existing therapy, whether short-acting or even plasma, should shrink more rapidly. Yeah, that's our assumption. Thank you. Yes. Thank you very much. Thank you. Thank you, Yoon, thank you for asking. So I think we have come to the end of this session, and I just want to be respectful of everybody's time. And, you know, I'd like to end this session with a quotation from the New England Journal of Medicine, Dr. Leissinger, who was obviously very fond of our data and said, "You know, in a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner, a major therapeutic advantage." Well, with this, you know, I hope we—you know, this is a bold ambition. We have now to live up to it. But, you know, I think it signifies what we believe we have in our hands, you know, and I hope you found this discussion interesting. I'd like to thank Dr. Klamroth, obviously, for his contribution and also Lydia. So on this note, thank you so much for a delightful afternoon to staying on. If you had questions beyond that we weren't able to address, please refer to Jennifer and Tobias, and we will refer the questions to the respective expert. Thank you and wish you a great day. Thank you. Ladies and gentlemen, the conference is now over. Thank you for choosing Chorus Call, and thank you for participating in the conference. You may now disconnect your lines. Goodbye.