Swedish Orphan Biovitrum AB (publ) (SOBI) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to the Advancing the Standard of Care in Haemophilia Conference Call and Live Webcast. I am Alice, the Chorus Call operator. [Operator Instructions] At this time, it's my pleasure to hand over to Guido Oelkers, Chief Executive Officer. Please go ahead, sir.

Thank you so much, and good afternoon, respectively, good morning to this event. Let's say, it's really a great pleasure to have you all with you the sequence of events after our last event on [indiscernible] very excited about it. And maybe move to the next slide, which is a forward-looking statement as per usual. Today, I'm joined by Lydia Adad who is our acting Chief Medical Officer and who will be clinical efficacy and safety of efanesoctocog alfa. I'm 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. And he is not only one of the foremost clinicians in hemophilia, probably also one of the foremost top leaders. And he will give us some insights on raising the bar for hemophilia treatment. With this fact, I just wanted to provide you with some context with regard to Sobi. So when you think about Sobi as a company, we're obviously supremely proud as you will see about our hemophilia asset in particular, our latest addition, efanesoctocog alfa. But we have defied beyond into hematology and namely into the 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 our strides at least in some European countries and in the Middle East. And with Guangzhou obviously, our product, our JAK1 sparing inhibitor and JAK2 inhibitor in now in the U.S. Next slide. So when you come to hemophilia, and I don't want to go into the old history, I just wanted to tell you that we have a long history in hemophilia relating to proceeding entities of Sobi like Kabi Vitro dating back a long time, as you can see here, and I think then we'll probably moving over to -- moving on with certain partnerships latest Biovitrum now with Sanofi. But I think important to note for you is that this hemophilia competence is not there since yesterday. And our scientists have done very important steps with regard to innovative steps in FC fusion, which is part of Elocta and Alprolix, but also efanesoctocog alfa, so a long history and long lasting competence. Next slide, please. And when you come to our hemophilia products, 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 the example of our 2022 data. Next slide. For us, hemophilia is not just an area of where we obviously are excited to penetrate and provide market shares that are important for investors. But it's also, let's say, a sense of obligation and with our partners and Biovitrum, we have inaugurated the humanitarian aid program with the WFH and over 32 [Technical Difficulty] have been treated since and 22,000 people are on therapy. So that compares very favorable even with the number of patients we currently have on commercial treatment and it's lasting 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 tens efanesoctocog alfa. We believe it's a new class in the Factor VIII placement therapy. And the reason why we are so excited 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 in the next few minutes, I will give you an overview of the efanesoctocog alfa molecules, 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 factory therapies circulates a complex with [indiscernible] brand factor. And the half-life is determined by the BWS clearance. This puts a ceiling on factories half-life of 14 to 19 hours imposed by the endogenous BWS. So efanesoctocog alfa represents a new class of Factor VIII replacement therapy purposely designed to decouple from endogenous to the apple factories from endogenous [indiscernible] factor to overcome the impose house ceiling and to increase the factor levels to the non-hemophilia range for most of the week and what it's really important with once-weekly dosing. Efanesoctocog alfa is a fusion protein of human single chain recombinant Factor VIII, the FC domain of a human IgG1, factor [indiscernible] factor and to extent polypeptides as depicted on the slide. So if we look now at the sequential PK data, if you can treat, in the sequential TK1 study in adults, a single dose of EFA 50 units per kilogram resulted in a 3 to 4 for longer house life than the comparators. In the graph, you can see on the right side, you see a red recombinant standard has life factory product in blue, the extended house-line Factor VIII product and ingrain the PK profile of EFA with a terminal half-life of 43 hours 1 week after the infusion. The main factory levels were maintained 40% during the first 4 days after the administration, and we're at 10% on day 7. So from the clinical data, we know that an efanesoctocog alfa is an effective monotherapy for all clinical settings. It was tolerated and effective in adults and children for routine prophylaxis with prevention with once weekly dosing for demand treatment to control the bleeding episodes and for the management of surgeries. So let's have a look through the studies. On this slide, we present the design of our 2 completed pivotal trial, 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 an A and received F50 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 RMB and received EFA on demand for the first 6 months, followed by EFA prophylaxis during additional 6 months. The primary endpoint of the study, the annualized bidding rate in the prophylaxis bond was successfully met, and I will come back to that in the next slide. But in the pediatric XTEN study for previously treated patients younger than 12 years of age, all patients receive EFA weekly prophylaxis 50 units per kilogram and will follow 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 I just mentioned, with a mean annualized leading rate of 0.71, demonstrated that EFA is highly effective in bit protection. The key secondary endpoint was based on the intrapatient 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 0.69. This is a reduction of 77%, clearly demonstrating superior bleed protection over private prophylaxis with EFA. So if we now look at the PK results from the adult and adolescents in the XTEND-1 study, they confirm the PK profile previously depicted with main Factor VIII levels in the non-hemophilia range above 40% for the first 4 days after administration of F1 and above 10% during the remaining days of the week. In addition, the data from 17 patients reassessed at week 26 show no or minimal accumulation as represented with these 2 similar PK profiles in the graph. Forward our attention to the children, the high efficacy of ESA has been confirmed in the pediatric population with all annualized bleeding rates below 1 and very long joint and spontaneous ABR, as you can see in the table on the left-hand side. We analyzed joint bleeding rate of 0.59 and any spontaneous bleeding rate of 0.16. These results are reflected in the high proportion of children without any joint bleed, 82% and any spontaneous bleed, 88%. If we focus now on the treatment of laser surgeries, the efficacy of oversight clearly demonstrated in the Phase III studies across all ages and clinical settings. For demand treatment, almost 100% of the bleeds were resolved with a single EFA dose. And for surgeries, the hemostatic response was always rated as excellent or good. And this includes 12 major surgeries in XTEND-1 with 6 major orthopedic surgeries and then 2 major searches 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 have been observed in previously treated patients and no serious allergic reactions anaphylaxis or traumatic events occurred 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 2 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 VIII product that was provided during the study. We also have data indirectly comparing the efficacy of EFA with emicizumab. This compares the corresponding pivotal studies XTEND-1, with HAVEN 3. 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, [indiscernible] So the patients who went with prophylaxis with emicizumab RD, which was the once-weekly dosing. Efanesoctocog alfa prophylaxis was associated with significantly lower rates of bleeding than in emicizumab prophylaxis. The annualized bleeding rate for any bleed, any treated bleed and treated joint bleeds were significantly lower with alfa prophylaxis than with emicizumab. Behavior for treated spontaneous lease 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 JHS, the hemophilia and Joint Health Score between alfa prophylaxis and emicizumab prophylaxis. EFA prophylaxis was associated with significant greater change from baseline in both Hemophilia Joint Health Score joined the score and the total score compared with emicizumab. In summary, the XTEN 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 VIII prophylaxis and significant improvements in joint health, physical health and pain, and 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. And here on this slide, you can see the extended study, which is an extension study ongoing to provide long-term data to further support safety and efficacy and the freedom trial, a new Phase IIIb study sponsored by Sobi that has recently started in the EU. It ends up providing data on the impact of alfa prophylaxis in supporting physically active lifestyles, maintaining joint health in patients with severe hemophilia A. And with that, I would like to hand over to Dr. Klamroth his presentation.

Thank you, Lydia. So now it's my task to give some clinical perspective on efanesoctocog alfa. Next slide, please. So our 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. Of course, over the years throughout the life, the tasks and challenges changes. So from our present diagnosis, a lot of parents are surprised that they have tried this hemophilia because more than 50% are spontaneous mutations. It's going to have to make a treatment short. And lastly, and which is most logical is the treatment of choices to replace missing Factor VIII to avoid any bleeding. Of course, there's worry still the child starts to run, they are really afraid that they fall and get bleeding. They have to learn and come with injections intravenously, which is quite difficult in the young child. But normally, I think over this time, we are able to treat the parents later on the kids to do the intravenous injections by themselves. They have been treating activities. They learn how to replace the mitigating factor that they can participate in sport activities. They got an increasing responsibility about treatment, they conduct risks and benefits to help hemophilia. But still, there might be joint damage, there might be other comorbidities later in life. And if you are, they 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 recurring bleeds despite prophylaxis because it's not effective enough that leads to joint please and later to join 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 perioperative management. Next slide. Over the years, there was some development. And [indiscernible] first one we thought, okay, we convert severe hemophilia A to moderate hemophilia due to regular Factor VIII infusions. In this initial goal to convert severe to moderate or at least to have a tough level above 1% resided in a reduction in bleeds, but not to that were now be at all and patients still developed joint bleeds. To achieve higher levels with standard heart factor VIII was for difficult and only with daily injections possible. In 2010, with the advance of extended half-life Factor VII and the non-factor related therapy, we were able to achieve higher trough levels and more protection in the new target levels recommended by WFH and by the German guidelines are now to convert a patient to a moderate mild patients with levels of 3% to 5%. And in the future, we hope we can do even better with new classes of Factor VIII therapy like efanesoctocog alfa and the nonfactor mimetic and rebalance therapies and gene therapies to go for higher levels and better protection in patients with hemophilia and that they are comparable with mild hemophilia patients or even the hemophilia-free individuals. Next slide. And 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 near normal hemostasis. So in the future, our goal will be to normalize hemostats in patients with hemophilia to have a full protection and full participation. Next slide. So here, I can show you, is it possible already with the existing products on the market. And I like the slide very much because you can see with standard Factor VIII, we have like around 8 to 10 hours. You have to infuse very frequently to get high levels and you have a lot of peaks stress. Let us move a little bit with extended half-life Factor VIII. But only if efanesoctocog alfa we no the possibility with once weekly injections to normalize hemostasis for the first 4 days of the week and be in the mild range above 15% for the second half of the week, with no factor therapies like emicizumab, which is license 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 and other results are 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 if one efanesoctocog alfa can fix or can be an improvement in unmet needs like recurrent bleeds despite prophylaxis, in joint deterioration in hemophilia-related pain and reduced health related quality of life and in the challenging preoperative management. And for this, I will peak a little bit out of data from the studies Lydia already presented. Next slide. So I can here see key 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 4 to 0.79 with efanesoctocog alfa. And if we 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 billion. So overall, in the remote 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 locations. 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. And if you here look especially in the wider population, where you already have destroyed joins or at least affected joints after bleeding. You can see that there is a reduction or a change in the hemophilia joint health score. Hemophilia joint health score as a score where we can look at the 6 major joints, ankles, knees and elbows and to see the impact of bleeding and joint disease. And if you are able to lower the score, you have an improvement in your patients. And I think, of course, if the joint is more destroyed and there's more joint destruction in age. And so there is a greater improvement in older patients, if you have a good prophylactic regimen. And this is the case with efanesoctocog alfa in the study. Next slide. Usually this relates in pain. And if you look at this from pain intensity score in these patients, you can see that there's a statistically significant reduction, which is clinically meaningful in pay intensity. Of course, if your joints are destroyed 1 year of improved prophylaxis cannot make you a new join. But normally, we would assume that this ongoing age and if patients getting older, have a joint destruction and to reverse that at least a bit to have less pain, I think it's a great success in these patients. Next slide. This has impact on quality of life. There are different domains in this age-related quality of life. Personal hemophilia-specific tool called TMA core. And if you look 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, a view of patients in health. And so 71.4% of participants maintained or improved their physical health score or baseline to B52, 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 Factor VII concentrates are not available. It's quite difficult to maintain stable during surgery, especially if you need high Factor VIII levels. And with this drug, surgery is quite easy with one injection before, 1 injection during the week and then inject in the last week and the 5 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. And in my center, we did 3 surgeries in the study and exactly using only 1 or 2 additional injections, additional to the regular prophylactic regimen, which makes serving much easier in this kind of setting. Next slide. So after the XTEND-1 study, 100% of participants reported efanesoctocog alfa is 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 new kit prophylactic treatment. And in Germany, a lot of patients still want to remain on factor VIII because replacement in Factor VIII is logical to treat this disease. And with this 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. And now I hand over back to Guido.

Yes. Robert, I very much appreciate it. And you can sense when the he 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 after these very important presentation back to thank Robert, obviously, and also Lydia I think now is the time for Q&A. And maybe we can have the first question, and then we can refer them whoever was most relevant for the question. Operator, maybe are we having any questions?

[Operator Instructions] Our first question comes from the line of Charlie Mabbutt with Morgan Stanley.

It's Charlie Mabbutt from Morgan Stanley. So I guess, firstly, factor therapy still account for around 60% of the prophylactic market. So I guess, how do you see that trending over time with Hemli continuing to take share, other base specifics coming to market and gene therapy now entering the space? And then secondly, many patients have obviously remained on factor therapies despite the stronger product profiles of products like Hemlibra. [Technical Difficulty] So I guess what gives you the confidence that these patients [Technical Difficulty].

We think that we will take -- 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 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 given the fact that our share with Elocta is larger than in the U.S. And we think that this also speaks to the relative strength of our organization. So we believe that we can take material share from new therapies. We don't believe that gene therapy with the very significant costs and that are associated with this and the ones in the setting will be an easy sell, and you can see this from the number of patients that are published related to migratory therapy. There will be some. But right now, it's a really small number. And I think the trade-off decision gene therapy versus a factor treatment that allows you to be normal 4 days a week is if there is a want of these things. And therefore, our opinion have been change, we believe that this is going to be a leading therapy. We will not be the leading therapy and this is probably north of 30% to 40%.

The next question comes from the line of Niall Alexander from Deutsche Bank.

It's Niall Alexander, from Deutsche Bank. I wonder if you can give any color on the pricing outlook for Factor VIII products and margin implications of launching ALTUVIIO in '24?

I think when you look at pricing, we believe that we will fix the price on a treatment basis versus a net price of Hemlibra and EHLs. And in some cases, we will be able to get a premium. In some cases, we just have to accept that cost per treatment are the same and basically make them the economic case, as we reported previously via market share expansion. And in terms of margin, obviously, the margins will be very comparable for us overall in hemophilia, but to surpass simply because there will be some, obviously, price erosion, but we don't think to this dramatic shift as we have seen historically because prices are now adjusted across Europe. But this is not a prediction. This is our assumption. And if this is the case, so it's more of a gradual economization then we should be with the change of production side and the improvement there and the -- and also the fact that obviously, we take it only once a week, the once a week setting, we should be all right. And obviously, we'll get bolstered from the overall hemophilia profit on the royalties that we are receiving from Sanofi. So I think in terms of profitability of the overall hemophilia franchise, we have a more stable outlook, but this increase of revenues. Another question, we have Robert here. I mean, this is the opportunity to ask some really tricky questions.

The next question comes from the line of Alistair Campbell, with Royal Bank of Canada.

Yes, 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 the profile you've seen with EFA.

So I think in Germany, it's a long traditional prophylaxis was started in the early '70s by Hansen Rackman in the bone 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 severe bleeding. So depending on that if patients who bleed 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 there is still Factor VIII to is the most widely used product for prophylaxis in our patients. And I see some potential, at least for these patients who refused so far to switch from you analyze perhaps that in Germany, still a lot of adults are plus money rise, Factor VIII, because they didn't want to switch. And this is from my point of whom 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 external 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.

Well, I kind of follow up and trying to understand why so many -- the patients who have stayed on plasma derived, what was led them to stay on plasma-derived and whether that could change now with EFA.

It's always difficult. But I told you already that patients were conservative and doctors in Germany are usually conservative too. So 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 these reasons. For the non-inhibitor population, there was a very low uptake because patients and doctors perceive Factor VIII at logical replacement treatment for hemophilia patients. And the older patients, and it depends, they say, okay, it worked for me. I worked for me for a long time now for 20 years, for 25 years. And I don't know if you switch a treatment and ask yourself for that if you switch something, there's always the risk that it might be worse afterwards and not better. And 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 worse due to the better pharmacokinetic and the higher efficacy. That would be my guess about this in Germany.

Robert, I think he also asked before about your opinion on the absence of inhibitors in the XTEND and XTEND-Kids.

Yes, so far, we have no inhibitors -- the EMA doesn't require any more data. So we will see in a real road as always, this is modified drugs, it could go in both directions. I personally seen because the molecule is shielded and fused the less epitops 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.

Mattias Häggblom with Handelsbanken. 2 questions, please. Firstly, for Dr. Klamroth, the 10% of patients that is set as switched from emicizumab to viewing early feedback on the new launch reported by Sanofi. So help me think of the profile of such patients that you think is willing to switch from a weekly subcu therapy back to weekly IV infusion. And then secondly, for Guido, when I look at the first generation of extended half-life factor VIII ELOCTATE sales generated by Sobi and Sanofi in each of your regions last year was broadly the same, roughly EUR 500 million. If we lead differences in pace of getting reimbursement for U.S. and Europe aside, is it reasonable to think about 2 of you also ending up commercially equal in size for the 2 regions over time? Or what would be the difference here?

First, my part. So I think there's a clear population. And this is a population where using Hemlibra and has still breakthrough bleeds -- and of course, we are using in my center because it's the second biggest center in Germany, we are using Hemlibra as an only Inhibitor population. But there's a percentage of 20% to 30% to have regular breakthrough bleeds, every 1 or 2 months where they need Factor VIII, additional Factor VIII. So they need 2 drugs for treatment, Hemlibra and Factor VIII in the case of a bleed because you all know Hemlibra doesn't normalize hemostasis. You're still in the migrate and you can have bleeds. And this is, from my point of view, the population because they are able to infuse because I have to infuse regularly with breakthrough bleeds. And 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 as from my point of view.

And Mattias, with regard to the regions, I mean, we would think that our region in comparison to the -- because Sanofi has obviously global rights, except our region. So our region would probably represent 30% to 35% of the total potential. Now historically, we have been able to achieve a better performance than this year, relatively speaking. And we would have to -- I don't want to speculate, but the U.S. obviously is having a very different price level. So even though we have many more patients that does not necessarily mean that we have in real life right now does not translate 100% into economics. But we are very happy with our region. We know this region very well. We're making good progress, as we said. And I can tell you, the team is super excited to launch this product. And so we will make a very significant -- we think that we can push above our potential. That's clear. But beyond that, I would not like to make estimates, but it will be -- we think that anyway, efanesoctocog alfa will be together with one of our key product for the future.

So a quick follow-up maybe for Dr. Klamroth, -- that was correspondence in the American Journal of Hematology last week with regards to a real-world retrospective multi-institutional cohort using emesis. I think the message from the correspondent was that more patients than shown in the clinical program backing emicizumab experience massive 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.

The problem is far as if you go to the end -- do you have some experience. I think. What I truly believe is that with efanesoctocog, we have better protection compared to EMI -- is concerning what we see in the studies and controlling the Factor VIII levels. And we have patients too. And in my center, personally, I have to switch already 3 patients back from emicizumab to factor concentrate because they used as much factor concentrate as additional treatment as a prophylaxis before. And usually, the per patients who had -- who were very active and had severe muscle bleeds or they had very joint disease before and had the protection was not enough. I think there is a huge difference in individual patients, how much protection emicizumab can offer. And I truly believe that the better protection will be achieved with efanesoctocog alfa.

The next question comes from the line of Christopher Uhde, with SEB.

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 shot. Do you think that you can get faster launches across Sobi territory than you did with Elocta? And then for DR. Klamroth, I'm just thinking about the profile of ethanol that came out of the trial where it's, I guess, 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 to what extent -- we also know that mild hemophilia patients will ultimately experience joint damage over the course of their lifetime. 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 is if you see -- were you as surprised to see the improvements in pain and joint health in the clinical program here. And I guess thinking about the results in the surgical setting, does that kind of greater freedom to have surgery with fewer complications treatment issues make it more attractive for the elderly patients that are on other older therapies?

[indiscernible] faster than with Elocta answer is very likely. And because we think that the market is now -- there's more noise level on therapies. And yes, Robert is not dialing in, so it [indiscernible] no problem, I’ll just finish off the first part, and then you can pick it up from there. And basically, Sobi thinks that we will be faster than Elocta will obviously depend on the reimbursement. But as we do not have too high expectations with regard to cost of therapy in comparison to what is already approved. Hopefully, this will help. Then obviously, it will depend on whether we do a good job -- but the team is in place, we think that we can make a significant impact with a very good product has pointed out. Maybe back to Robert for the other questions.

I think the point of view is very important. That's what was the first -- 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, is one bleed enough to trigger chronic synovitis, which is very difficult to detect clinically or you have to do an MRI or ultrasound. And in Germany, the most popular treatment to treat chronic synovitis is to go for higher Factor VIII levels, above 15% to 30%, and with this prophylaxis, you have already the levels we normally use to treat chronic synovitis -- and that is, from my point of view, the reason that we had such a success for the first time in a pivotal study over a quite short period because in hemophilia, 1 year is quite a short period concerning the settlement of joints that there was an improvement. And my personal hypothesis is that patients came in, in the study, and some of them despite prophylaxis before had a certain chronic synovitis in one or more joint and with this high-intensity prophylaxis efanesoctocog alfa and the full protection against new bleeds with chronic synovitis disappeared over time. And that was improvement because you cannot change the joint structure with prophylaxis. If the bone is destroyed or is there some deterioration, then prophylaxis will not cure. And you need other means like joint surgery. But chronic synovitis is receptible to high levels of Factor VIII. And that from my point of view, my hypothesis why this drug is more successful than other drugs.

And then there was just also in terms of the surgical advantages? Is that something that could help to convince elderly people on older products, but it's worth the risk to change or maybe not such a strong factor?

I think it's already done more often that during surgery or in the hospital, the cost reimbursement that you switch products. And I guess that we will convince a lot of patients who go for surgery because it's so much easier for the patient. You don't need to measure factor VIII so often that we will use this product for surgery.

We've heard a number of people experts mowing the idea of biweekly dosing rather than once weekly. But I guess, yes, we don't know whether or not the -- is that something that makes sense to you or given the chronic sinusitis is that something that would need to be tested prospectively? What are your thoughts around that?

We have now studies for this, but I can tell you that a lot of German treaters love it exactly for this to have full protection over the time. It's not clear that 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 wit 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. And I can tell you, in Germany, and for sure in my center, at the most bigger centers, all hemophilia B patients who on prophylaxis switched to this telltale product, exactly with this prospect to have the once-weekly prophylactic regimen. So I think it's always from a psoriatic point of view, yes, but from a patient point of view, I think it's very appealing to inject only once weekly.

The next question comes from the line of Luisa Hector, with Berenberg.

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. And we've touched on various parameters. But I'm just trying to get a sense of very much this will be a switch, will it be switched from the short-acting and severity age, 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?

Now on the last question, I can tell only for Germany and for my center, with about 20% to 30% of the Hemlibra patients need backup Factor VIII, and it's related to high activity, then mainly muscle bleed 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 severe hemophilia 1 on prophylaxis at least 2x a year. Most of the patients we see up to 4x this year. And switching is normally -- there are 2 main reasons. 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 is a discussion what we can improve. Can we raise the dose, can we use a different product? And then they 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 a patient side, it's mostly regular intravenous injections. And if they skip 1 injection, they get a bleed. So from my side, it's mainly protection because in Germany, all patients keep diaries for most electronized, so I can exactly see when do they inject, is there bleed, [indiscernible] And it was a lot of work to make patients comply with the product to document everything. And with this electronic tools, now we have to capture infusions and bleeding. You can discuss goals of treatment and efficacy and protection, of course. And that will be the first patient, but of course, regularly, we make an update to our patients about new treatment options. And now with gene therapy, we a lot of just as an example, a lot of informative discussions with every patient who might be suitable for gene therapy, for instance.

Could I just follow up and see, so that sort of patient who they're not controlled that you may be saying there's too many bleeds and that they have certain issues. I don't know what proportion that might be? Or maybe the question would be what proportion of your patients come in at each visit and they're perfectly happy. Everything is going well, they're complying and you have no concerns, what proportion that would be?

So unfortunately, the majority of patients come into my office, said everything is fine, give me my sector, I want to go away, I don't want to be -- want to lose too much time because they are doing well. They're doing well. They have their jobs, they are now 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. 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. So it's difficult to say how many patients, but I think there's still room for improvement in about 30% of our patients at least. And it depends always on the goal, 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 individual level, but I can tell you now, I'm in hemophilia now for more than 25 years. And the activity level of patients change 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 and make it possible for our patients.

The last question comes from the line of Viktor Sundberg, with Nordea.

So I have 2 here for Dr. Klamroth. I actually also had a question around the biweekly dosing of that was discussed among experts. But maybe if I turn that question around also, could you dose longer than 1 week as well for patients seeking convenience that are nonactive office workers given how robust the pharmacokinetic profile looks like after 7 days. That was my first question. And secondly, I also wondered, in your practice, was it the most common treatment regimen for Hemlibra. When we have talked to clinicians in Europe, it seems like most are treating patients with once every other week. But just wondering, 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.

So first, the Hemlibra question. So I think 50% of my patients are treating every week, then 30% every 2 weeks and the rest every 4 weeks. So to give you an estimate. And of course, we are treating all inhibitor patients with the same Hemlibra prophylaxis. The other question is, again, with the 2 weekly -- of course, it depends on. When I look back, we never dosed Factor VIII according to the SLBC or due to the prescription. The dose Factor VIII mostly according to levels and according to the need of the patient. And depending in which country you’re using efanesoctocog alfa, you can go for higher doses of a lower dose. 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 and low resources countries, even if you give it on a lower dose one 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 with 50 units per kilogram. And then depending how the patient reacts, we will adapt to this treatment. That would be my strategy.

So 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.

Yes, in my center is. But in other centers I heard there are more every 2 weeks or every 4 weeks. But it depends, again, I cannot speak for other doctors in detail.

We had one very last question, I think, from Eun from Jefferies and then we close in reality. Eun would you please?

So EFA is not yet approved in your territories. So in Europe, approval is expected in early 2024, but do you expect the earlier approval potentially this year? And second question is, given that this is a superior product than other products on the market, how fast do you expect the pricing negotiation to go? And if I can squeeze one more question there, sometimes in rare disease areas, some patients are quite reluctant to switch when they are doing well with brand loyalty. So what percent do you think patients in your take would be in that category? And what do you think you would need to convince them to switch?

So I'll start with the easy one, the regulatory part, in '23, we will enable the usage of patients in end of '23 and some of the Middle Eastern countries. And you're right, that mid of '24, we will get -- I mean, in Q2, we're expecting and subsequently, we would launch in anyone that wouldn't surprise you, Germany would be the first -- and then we will roll it out according to the traditional sequence. I mean we think that the product profile is -- should make it a good proposition for payers, if they cannot -- if basically you get better protection, but similar cost should be a winning proposition given the broad support of the product. And we'll go through some assessments also with -- in some countries to further get -- because we are very convinced that this is a very cost-effective treatment from a payer perspective. So we think that the maybe -- maybe a little bit faster than what we had with locked up. And obviously, we had some learnings so you would expect this. And with regard to the brand loyalty, I mean, as Robert has alluded to. And obviously, this is a very diverse picture. There are patients who are quite loyal to their brand and have not seen enough, let's say, reason to move. And whilst, obviously, Robert sees these patients very frequently, but there are patients who see their physicians only once in the year, I mean, as we know from some surveys. But good care looks very different, as Robert pointed out. And so 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 we will start clearly from where the product has its largest benefit, and this is with those who are seeking an active lifestyle. And we are building upon, obviously, our platform with digital platform, Florio to make sure that people understand that they can monitor the success and foster the dialogue between the patient and their physician treating physician. And we hope that this will be a strong -- that we will break in. But we think that those patients who are now reticent to new therapies may consider -- many of them may consider EFA. But the time will tell, but we again, we don't think this is now one model fits all. I think 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 inVivo for the reasons that we pointed out. So I think at this stage, I don't think I'm in a position here to say how many of those will stay brand loyal. I think it would be nicer to delight you that we have been able to switch a large portion of those then make too many prognoses on the play out. But we have already said we think it's going to be a leading therapy. And with this, we have basically set the mark of a management team believes in, 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. But I think this gives you an indication. I think the portion of patients that basically today is not willing to move, for instance, on from their existing therapy, whether it's short-acting or even plasma should shrink more rapidly. That's our assumption. So I think we have come to the end of this session, and I just want to be respectful of everybody's time. And I'd like to end this session with basic quotation from the new Journal of Medicine, Dr. Leibinger and who was obviously very fond of our data and said in a crowded field of transformative therapies for hemophilia, efanesoctocog alfa, stands out as a winner, a major therapeutic advantage. Well, with this, I hope we -- this is a bold ambition. We have now to live up to it. But I think it signifies what we believe we have in our hands. 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 the delightful afternoon. If you had questions beyond that we were able to address, please refer to Jennifer and Tobias, and we will refer the question to the respective expert. Thank you, and wish you a great day. Thank you.

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