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

Welcome to Sobi's Capital Markets Day 2020. Thank you, all, for joining us today. A warm welcome to all viewers and also everyone that is participating over the phone. I am Paula Treutiger, Head of Communications and Investor Relations. Please pay attention to our forward-looking statements. Today, you will hear from CEO, Guido Oelkers; Ravi Rao, Head of R&D; Norbert Oppitz, Head of Immunology and International; and finally, CFO, Henrik Stenqvist. They will give you an update on Sobi's future growth potential and also financially. You see the agenda on the screen. After the first 2 presentations, we will have a break. After, we continue. We will end with a Q&A session and aim to finish at 4:00 o'clock. In order to ask questions, you need to dial in on the conference call or send in your questions via the webcast site. With that, I would like to hand over to Guido.

Yes. Thank you, Paula. Good morning to those who are on the other side of the Atlantic, and good afternoon to those who are in Europe joining us. Yes. It's really a great pleasure to welcome you to this year's Capital Markets Day. And what we thought about it, when you just stay for 2 seconds with the agenda, is to really let you in a bit in our thinking, on our strategy and also discuss with you a little bit where do we come from, but more importantly, where do we go. And as portfolio and innovation is obviously a key driver for Sobi, we have Ravi here today, our new head of R&D. And you will see in the later part of the presentation that our quest to become a more global company is another source of growth for us. And hence, we have Norbert here and has every strategy, and there will be a growth strategy that will have a transformational character like what we are ahead of. There is also financial implications today and tomorrow. Henrik will share his insights in this regard, and then we are opening up for question and answers. So when it comes to our strategy, let's look at where did we come from 2016. And our business at this stage was a pretty euro-centric business. We had a very significant dependence on our, what we called then, kind of specialty care partnering business, and we had the emerging hemophilia business. The pipeline was a collection of very early-stage assets. We had no late-stage project and basically was subscale for any larger ambition that we had as a company. And we had international aspirations, but we didn't have the means. Now looking back on what -- looking at what we have achieved in this particular last 4 years, we have transformed this business from a SEK 5 billion business into a SEK 15 billion to SEK 15.5 billion business when you think about our guidance. So that means we have grown fundamentally the company by a factor of 2.7. But it is important to note and this is -- this fulfills me and also our team members with a lot of pride. We have grown mostly organically, meaning more than 75%. And yes, we have taken advantage of M&A. But M&A for us is primarily a driver of our future growth, as you're going to see. And at the same time, obviously, we have been able to deleverage our P&L. And as a consequence, we have been able to increase our EBITDA margin and obviously, if you believe our guidance, increase quite radically our earnings. We have not only doing -- we have not been only doing this, we have also improved our agenda, our sustainability agenda, which is no surprise, focuses and starts with patients. And the business model of Sobi is very much patient-centric, and this is a source of innovation because we believe that we understand patient needs. We have a very strong medical professional team that can guide us also in our search for new opportunities but clearly, also, in the profiling. And we are also working a lot on responsible behavior as you would do in a pharmaceutical company, very committed to the Paris Agreement. But today, it's more about strategy. So with this, I share with you the strategy that we shared with the audience in 2017. And for me, it's always good. Strategy becomes real in what you do, not necessarily what you say. It's quite reassuring to see that what we said in September 2017, we actually did. So we grow -- one of our main goals was to get the benefits out of the opportunities in hemophilia and drive penetration. We wanted to develop at that -- at the early stages of second leg, which we articulated as developing the immunology agenda subsequently. We wanted to grow our U.S. business because as a rare disease company, we realized that we had to become critical in the U.S. And we wanted to strengthen our late-stage pipeline, in particular, because we realized that we have some gaps. So what did we do? So when you look at the hemophilia market, in our territory, we took a significant share. We have now a 22% market share with Elocta in the prophylaxis market; 35% share with Alprolix, not necessarily evident when you realize that we are mostly competing with big pharma companies in this territory. We ranked, let's say, by a survey, as a #1 company, let's say, from those who -- health care professionals who responded, and we are also recognized for our scientific engagement. So basically, I think this gives you a flavor. And we also secured our future by opting in early into the strategic partnership with Sanofi on BIVV001. Coming back to immunology. When you basically, you look at the stats on the left and you see that we obviously substantially increased our immunology franchise from 19% in 2016 on a much lower revenue base to around 20 -- 35% on this year's estimate. I mean, these are approximate numbers as we have not guided on the actual that we, hopefully, will come in, in line with our guidance. But when you think about strategy, I think it's important to note that you always need to build on strengths. When we looked at Sobi, we basically realized that Kineret offered a lot of strengths. We felt that this is a product with a much broader opportunity. And when you look at the growth that we have depicted, there was 27% growth, first 9 months this year versus previous year, you get a sense that we lived up to the expectation. We also saw an opportunity with Synagis, not only to complete our immunology portfolio, given the fact that this is in monoclonal antibody, but also broaden our U.S. business in a very distinctive way, and we'll talk more about this. And -- but what -- the thesis was here that we could add substantial value to an asset that bought the secondary -- the priority for a big pharma company and that we could bring our skills from a rare disease business into this. And we felt that this was doing extremely well. And the 19% growth first half of this year is a -- it testifies to this. And we are very happy on how the team has -- is performing, in particular, how we have changed and adapted the value system with regard to distribution but also promotion and, in particular, to medical marketing. When you think about Synagis today, I think it's also fair to say that for this season, we will face -- we are facing some headwinds in terms of virology, as everybody knows, with COVID. There is social distancing. There's less international travel. And as a consequence, let's say, we have -- we are facing some headwinds. On the other hand, we are improving our value chain, and this is helping, let's say, us, to mitigate this. So the jury is still out. We are very optimistic about Synagis' future in the long run, and we are very committed to it. And then we saw an opportunity to acquire Novimmune and the rights to -- global rights to Gamifant. And this is, for us, and was, for us, really a game changer. Because with -- in Gamifant, we saw now an opportunity to take our immunology business to a completely new level, giving it a completely different level of innovation. We understood the biology of interferon gamma from our work on Kineret. And as you know, interferon gamma is a cytokine that regulates the immune system in certain ways, but also is protecting us from infection. Now with every thing in life, there's a dark side. Now when interferon gamma is elevated, then it can have some life-threatening consequences. And in this case, when an infection comes, it can trigger the production of interferon gamma and an immune response. Now if this response fails, interferon gamma is further elevated, and ultimately leading into a cytokine storm. We felt that this is an area, obviously, particularly relevant in today's environment, that we should get excited around. And when you think about it, it is, for us, a fantastic opportunity now to take the interferon gamma blockade or as an interferon gamma scavenger also into other areas. Ravi will share with you very thoughtfully how we are now taking Gamifant into other areas of HLH, meaning into secondary HLH and different permutations, but are also having a shot now at acute graft failure and graft versus host disease. So we see in this product more of a platform business, and we obviously are right at the center of scientific interest. Moving to the next slide and to the U.S. business. When we started, we had a U.S. business of SEK 900 million around. Today, we have a U.S. business of around SEK 5.3 billion to SEK 5.5 billion. That's around sixfold. When you think about, let's say, our portion of the U.S. business, part of the total, it is around 35%. So it's remarkable difference. But I think it's not just a matter of numbers. We are now really entrenched in the U.S. We used to have a team of 50 people. Today, we have a team of 450, so ninefold increase, to more than 250 people field based. So we have become a factor in the market, at least in the rare disease market in our area and are getting more and more recognition. For us, the U.S. is a primary growth driver short term. We are very excited about the growth opportunities, in particular, Gamifant, but also with the acquisition also of Doptelet obviously. So when you think about our strategy, we picked the box on penetration in hemophilia. We took immunology to a completely new level, not only in terms of breadth of portfolio, but also in terms of scientific elevation. And we basically made a substantial difference to our U.S. business. How did we go about our pipeline? So when you think about our pipeline and what we have been doing over the last years, in particular, we completely changed the prospect from essentially 0 late-stage pipeline now to 12 late-stage projects and 4 products or 4 projects under registration. And this is not only a significant difference in terms of breadth and depth. It is also a completely different perspective in terms of economic opportunity. And I will talk a little bit later about some of these projects and why we are so excited. But this is not just a number game. We also were thinking very thoughtfully how these products fit into our strategy, which we will explain a little bit later, but also how we go about it, because, we are, in this regard, still a little bit old-fashioned because we want to make sure that we can deliver on what we promised. And basically, when you think about it, and it's always good to know what you're good at and where you need some help. We basically, as an example, when we did the partnership with Apellis on pegcetacoplan, we picked those indications that we are particularly confident about and competent about. So we thought that the hematological indications would work very well under our ownership. And the reason is very simple because we have quite a few treaters, ex-treaters of those conditions in our team. So we understand these conditions very well. And as Ravi will point out, the TMA-HSCT (sic) [ HSCT-TMA ] connects extremely well also with what we want to do with Gamifant in graft failure and graft versus host disease. So basically, we thought about and picked our battles where we are strong. In the case of Gamifant, we felt this is very much our strong suit, given our history with Kineret, also Ravi's background in immunology. Whilst we would leverage other people's capabilities, like in the case of Selecta or in the case of BIVV001 or 8897. So what we were able to do is to pick our battles and make sure that we can deliver on what we promised here. For us, M&A has been always a catalyst. These are the projects that we have assembled over the last 3.5 years, as you can see, and we will talk a little bit more about it. But M&A is a catalyst and a key driver for our transformation, mostly with regard to our future. And how do we, let's say, think about our future? So when we think about, let's say, taking Sobi to the next level, we basically -- as you can see, we are very proud of our core that we have built today. But we think that our core is not going to be the major source of our future revenue growth. What we think where the major leap for Sobi is going to come from is from our late-stage pipeline and from our launch products that will bring us to the next level. And from, let's say, from our efforts and ambitions in the international markets, foremost, China, Japan and Russia, but also expanding on markets where we are already present like in the Middle East and Central Eastern Europe. We clustered it even growing as new markets, even though we are in some of those. But in the totality, we are not yet as large and material to us. But they're going to become a major source, of course, as Norbert is going to outline. So for the coming years, what is our formula that we have in mind? We want to be a SEK 25 billion company by 2025. We think we were lucky that the numbers actually coincide and how hopefully easier to remember, but I'm sure you are going to remember these numbers when we have quarterly updates. But we are committed to develop the company into this regard. And you can see now the different growth contributions while there is an overlap between the pipeline and the international representation. So we're very committed to build a very strong business. Obviously, given the uncertainty, there is still a certain error margin. But as a team, we want to be a SEK 25 billion company by 2025. So when it comes to Elocta, where are we in our strategy and how do we think about our future? I mean, this -- obviously, here, you can see a very substantial franchise for us that has developed extremely well. This year, a little bit held back by unit erosion on a per capita, on a per patient basis. And we have talked about this during our earnings calls. But we're still with a very strong and healthy patient growth. So we will -- I think it is fair to say that we will expect some further headwinds in the future, more competition, potentially some pricing pressure. And let's say, I'm not sure when these restrictions on unit per capita basis are going to change. So we cannot make here too many promises. On the other hand, we have some opportunities. It's in terms of new launches, such as Russia. We think that there are still markets underpenetrated and we have obviously a clear vision for our future, as you will see later, and this is BIVV001, and we are super excited about the opportunity regarding this product. Very happy also with what we have achieved with Doptelet. I mean, in a very difficult environment, where we have no face-to-face interaction and many of our customers also have other priorities than platelet counts. We have been able at least to make the first big step and achieve over 6% market share in the ITP market on a September basis. And I think this should give you a little bit of a perspective, whilst despite the failure on the CIT trial, we stay very optimistic about this product. And so no reason for changing our guidance. When it comes to Gamifant, I alluded to this from a mode of action, we are now at this intersection where we want to take the product from primary HLH on a more international basis. And we have made some recent strides. And we're very happy that the file was accepted yesterday, and today, we announced that in China, we'll take the product into the larger part of HLH, meaning secondary HLH, and Ravi will share with you that these boundaries between primary and secondary are a little bit blur as many of secondary, so-called secondary patients, have a genetic mutation and could be classified as such as primary. And we also want to take the product into a new horizon with regard to stem cell transplantation in graft failure and graft versus host disease. I talked about opting in early for BIVV001, so I don't want to take too much of the time. Ravi will talk about this in more depth. But we felt that this was a no regret move because we saw the data. And when you realize it, in the majority, let's say, of days in a once a week setting, the product is normalizing a patient. We felt that this is such an important value proposition that we wanted to be part of this from the start and also play a significant role in the clinical development of this product. We're very excited. We think this is, in terms of risk/reward profile in a market that has significant number of new entrants. We think that this is a very, very good prospect for us, particularly for a company of our size and will make a very significant contribution to hemophilia society as such. An important driver for our growth is going to be also SEL-212 and our partnership with Selecta. When we look at the Phase II data that we recently reported on, and Ravi will talk a little bit more in detail about it. We basically figured this is a unique value proposition. It reduces the immunogenicity and has a sustained efficacy. It has demonstrated greater reduction of SUA levels, and it is also provides a better control in patients, and a monthly dosing. So it has -- it ticks a lot of boxes. And when you're just reflecting on it KRYSTEXXA, 4,000 patients, give and take around SEK 400 million product. We know that the market, eligible market, is between around 16,000 to 20,000 patients. So it is a very significant opportunity, as you can appreciate. Our most recent partnership with Apellis, I think, is also super exciting. When you think about we get a blocker of the C3, which is very central to the complement system. And it's differentiated, this product is differentiated by inhibiting C3, by -- not only biologically, but also by the data that we have published together with Apellis as part of the PEGASUS trial. But also mechanistically because it has another -- an additional pathway versus the well-established C5 inhibitors via the extravascular pathway. It opens up a completely new horizon. And even in the PNH indication, which is closest to market, what excited us was this extremely still high unmet medical need. When you think about 70% of patients treated with C5 are still not having adequate hemoglobin levels and 35% require still once a year, at least, transfusion, and the average life expectancy of a PNH patient is around 5 years. So we felt that there is much more ground to cover even though they are existing therapies around. And when you think then about the other indications that Ravi is going to talk about, we are quite a few times first. And so we are very much aligned with Apellis. This is not only a strategic alignment, given the fact that this product sits right at the intersection between hematology and immunology, giving rise to the idea of immunohematology. It's not only strategically, but it's also a very significant economic opportunity in our territory that propels obviously our internationalization. So we think it's a very -- a very important product for the future. But what gives me also a lot of confidence around it that we are culturally, very much aligned with Apellis, who is also extremely patient focused. So we think that this partnership will pay great dividends in the years to come. So coming to our peak sales and how we think about the future. And maybe also to give you some guidance on how we think about 25 by 25. Now these are peak sales and they come obviously at different points of time. So it is not completely correct to add them just up and compare them. But what it gives you is quite a bit of headroom versus our ambition. And what we also wanted to give you a little bit of, let's say, feel, when thinking about hemophilia. When you think about the opportunities we have with BIVV, with Elocta and Alprolix moving forward. And this is including royalties, just to simplify it, that we pay cross royalties with Sanofi. Just elevating yourself and having a longitudinal perspective, we think this is going to remain for us a very significant revenue stream. Because we think that with BIVV001, we will take significant share in this hemophilia A market, again, and be one of the key leaders in this market-based also on the feedback we have obtained at an early stage from the trials, but also from the KOLs. Doptelet, we guided on this $500 million, no change. Gamifant, when you see the programs that Ravi is going to share with you, no need for change. We also guided on $500 million and we see no reasons -- dollar, there to change our view here. Pegcetacoplan, we think it's going to be a very significant product. It depends a little bit on how ALS is turning out. But we are very optimistic about this product. And also here, we said we guided on up to $1 billion. If ALS is going to materialize, we are probably going beyond this quite comfortably. With regard to SEL-212, I mean, I shared with you, right, the stats. This is probably more of a conservative outlook. And in RSV prevention, basically, we have Synagis. We are around the SEK 3 billion. And 8897, if anything, will further derisk us also into the years ahead. And obviously, with double-digit growth on Kineret, you would not aim for anything less. And when you further operationalize this now, what does it mean? And I think this gives you a little bit of a perspective on how we think about it. We have -- I just divided, for simplicity, say, the world into 5 key regions that we are now untapping more and more. And we said, obviously, North America, our key priority. Europe will remain very important. But then obviously newer markets, going to be China, it's going to be Japan, it's going to be Russia. And when you think about the portfolio that we have in terms of new products, and you basically -- and to the right, there are examples of indications, illustrative, for example, all products that we are going to launch in at least one of those geographies over the next years, we will have over 30 launches in these 5 geographies in the years to come. And this, I think, clear to see that for us as a company that's going to be an inflection point around 2023, and a lot of these launches are going to materialize. And this will give us rise for a very significant bolus and acceleration of growth in the years to come. And so whilst we may, let's say, anticipate more single-digit growth in '21 and '22, we clearly foreshadow double-digit growth in the years later, and Henrik will share his insights in this regard. The internationalization strategy, obviously, Norbert is going to cover only so much. Today, this is a business for us, important, around SEK 800 million. But we think that we can multiply this business by 2025 very significantly. Norbert will share you a little bit also how the launch schedule is going to look like during the years to come. But we are very excited about the opportunities in these markets. And also here, things are not just happening by coincidence. We have brought in people who understand these markets. Because we don't want to pioneer and figure out how it may be to be a company in Japan. So we have brought in people who understands these markets extremely well and have built up international businesses on a completely different scale because we want to make sure that we can execute what we are setting out here. So in summary, what we can say is, we want to continue leading in hematology in our territory. We want to grow immunology based on the pipeline that we have. And I'm sure that you will be even more let's say, excited about our prospects in immunology after the next presentation. We want also to make sure that we are now capturing the value of the pipeline, meaning that we can realize these 32 launches within the next 5 years. And we have ambitions to become a much more global company. I think on this note, I'm going to pause and ask Ravi, our Head of R&D, to join the stage and share with you our ideas on innovation management at Sobi. Thank you.

Thank you, Guido. So I'd like to start by just looking at the pipeline and our portfolio at a broader level. And how do we build on where we've been and build on Sobi's strength so we can continue to bring medicines to patients who need them. So our portfolio is both innovative and differentiated, and those are quite lofty statements. But actually, as I'll show you, each of the medicines either has a novel mode of action or has the potential to be best in disease. And with that, we can enable the step change in therapy for patients who need that. We have had a philosophy to lead in immunology and build -- lead in hematology and build in immunology, but we can also reap the synergies between the two. There's a lot of diseases that have immune-based mechanisms resulting in hematological manifestations and many diseases where hematological manifestations are part of a spectrum of symptoms. And I think it gives Sobi a unique opportunity to develop medicines in that space between hematology and immunology. And I'll show you the pipeline in a slightly different way shortly. I think one thing that Sobi has always been really good at is really understanding the needs of patients with rare diseases, wherever they are in the world. And I think taken together, that allows us to take a leadership position in diseases for patients. And finally, why do I think that we're going to be really good at developing medicines? First of all, we have a very integrated view to life cycle management. For those medicines, we know how the label is going to evolve, and we know where those medicines are going to be launched in which countries over time. But I think another unique thing about this portfolio is that many of the medicines have multiple indications. We looked at 3 indications for Doptelet, 4 for Gamifant and 5 for pegcetacoplan. And I'll talk about those in more detail. And as we're developing, we're using novel techniques and innovation. We acquired the Florio app, which is really helping us understand hematologic diseases. I'll talk to you -- to a collaboration where we're using a companion diagnostic to develop Gamifant in the context of graft failure. And also with Gamifant, we're now investing a lot in partnerships to understand the genetics of that disease. And I think these are all things that will unlock more value and more access to patients for the medicines we have in our portfolio. So we currently have 6 products in development with 12 programs as Guido mentioned earlier on. But as you look at the pipeline, I think it's important to recognize that we have a number of products in registration. We have a number of products that are in Phase III, and a number in Phase II. You can see clearly that there are multiple indications for some of these products. And we're very confident that this forms a rich backbone with which we can achieve the launch ambition that we have over the coming 3 or 4 years. Let's look at the pipeline in a slightly different way, which is to say on the left-hand side, we have medicines in hematology. And on the right-hand side, we have medicines that are more traditionally immunology or information. So BIVV001, which is a medicine I'll talk about in a moment for hemophilia; Doptelet, for thrombocytopenia, which can be immune mediated. On the right-hand side, we have SEL-212, a novel treatment for refractory gout. We then have Synergis and MEDI8897 for RSV, but both Gamifant and pegcetacoplan sit firmly in the middle of hematology and immunology. And I think that's something that's really exciting and very unique for Sobi. So let me go into some of these medicines in a bit more detail. We'll start with BIVV001, which has been designed to try and achieve more normal Factor VIII levels in hemophilia throughout a longer period of the dosing interval. How has that been done? Well, this has been built off the same Fc fusion technology that we use in Elocta. But in addition, there's been addition of von Willebrand factor domains as well as the XTEN polypeptides. And taken together, this construct allows a longer half-life with higher sustained factor levels throughout the dosing interval. And we intend for it to be the first product that can be used with a weekly dosing and maintain factor levels at or near the normal range for the majority of the dosing period. Now what does that mean at or near the levels of normal range? It allows patients to be able to live a relatively normal life. That allows them to participate in activities, for example, energetic sport or high-impact sport that they would otherwise not be able to do. And normal factor levels allow them to do that. The other thing it allows is a single product to suit all of their needs. The single product can be used for both prophylaxis and also used for treatment when undergoing surgery. So the data that we've generated already and was recently published in the New England Journal of Medicine was in hemophilia A, which is a genetic deficiency of a clotting factor VIII. This results in excessive bleeds, predominantly in the joint, and severely impacts the quality of life for patients who need ongoing treatment and ongoing care. On the right-hand side, you see a graph where patients were given either a standard half-life factor VIII, and that is shown in gray. And you can see the levels deteriorate over time, requiring more frequent dosing. In the red line, you see the factor levels following administration in the same patients of BIVV001. And the factor levels are within the normal range, so above 40% for nearly half of the week. And they remain within a target range for the remainder of the dosing period. So really, this medicine has the potential to enable more normal fact levels through the dosing schedule. And this isn't possible with standard or shorter half-life therapies. Normalization of factor VIII isn't possible with nonfactor therapies like emicizumab. And those -- those nonfactor therapies also don't show any evidence of significant joint protection. Joint bleeds are probably still going on even when -- unless patients have got factor levels within the normal range. So where are we with BIVV001? We're well in collaboration with Sanofi, the Phase III trial in adults and adolescents started last year and is well underway, and that is a multicenter trial going on across multiple countries. And we hope that, that data will be submitted in the U.S. in 2022. For the EU, the package also needs to include a pediatric program, and that program will start imminently, and we hope to get approval for hemophilia A within the EU in 2023. So I'll turn now to Doptelet, which is potentially a best-in-class treatment for thrombocytopenia as a result of chronic liver disease or immune thrombocytopenia. It's a second-generation thrombopoietin receptor agonist, which are now stimulation of platelet production. That's through proliferation of mega-carrier sites in the bone marrow and, therefore, an increase in platelets as a result of that. The intention for this drug is to have a daily oral dosing without dietary restriction and without the possibility of hepatotoxicity, which is the case with the other first generation molecules that are also on the market. So let me talk about thrombocytopenia. It's characterized by low levels of platelets. And these patients can also get spontaneous bleeding, of course, via a different mechanism than those patients with hemophilia. And thrombocytopenia can be caused either by decreased production, which is what you see in chronic liver disease, or increased destruction or consumption, which often has an immune-based mechanism, so-called ITP. As well as Doptelet, which is approved for these indications in the U.S., there are other TPO-RAs on the market. However, we think it's differentiated because of the convenience it offers the patient. An oral therapy that can be taken without dietary restriction, without the concern around hepatic toxicity (sic) [ hepatotoxicity ]. On the right-hand side of this graph shows the data from our ITP trial, which has been approved in the U.S. and is under review in the European Union. And you can see very clearly with platelet count shown in the solid line. But with the introduction of Doptelet, those can be maintained within the target range as compared to placebo, also allowing the reduction of other therapies for ITP. So with Doptelet, we finished the majority of developments in ITP and CLD, although there is quite a broad range of geographic expansion that Norbert will talk about during his presentation. We have got life cycle studies that are ongoing, including use earlier in the disease with ITP and also a pediatric program. But as I mentioned earlier on, this product is under review, and we hope to get approval within the EU for ITP very shortly. Let me turn to the immunology side of the house in SEL-212. This is a collaboration that we started earlier in the year with Selecta Biosciences. Now I'm just going to pause and just explain the biological products. Of course, there are a number of limitations, and particularly with enzyme therapy, where those enzymes can generate an immune reaction from the host. And that can quite often limit the ability for patients to take a full course of treatment or to take chronic therapy. And why does that happen? Normally, the foreign protein stimulates a response in dendritic cells that ultimately leads to antibody production against the product that's been administered. ImmTOR is a technology that's been developed by Selecta, which consists of rapamycin, which is an immunosuppressant, but that's contained within a nanoparticle and is administered with the uricase enzyme in this case, which then prevents and lowers immunogenicity. That means that you don't have to take concomitant oral immunosuppression, which a lot of patients have to do in this situation. And it also allows patients to have a full course of treatment as a result of the effects of ImmTOR. So it's given together with the uricase enzyme within the same treatment schedule, one straight after the other and allows patients to have treatment once a month, and we hope with sustained efficacy. So this is being -- this is in Phase III in chronic refractory gout. So let me say a couple of words about chronic refractory gout. This is when serum uric acid levels remain elevated with flares in the joint despite conventional therapy, which has been maximized. It results in a painful inflammatory arthritis, normally in the distal extremities that can either be one joint, so-called monoarticular, or multiple joints, polyarticular. And the other thing that happens to these patients is the uric acid or the urate deposits under the skin in what are called tophi. Now this can be unsightly, but it can also be quite painful due to the location of those tophi. And I think more importantly, the presence of tophi is a very poor prognostic sign, not just because of its impact on gout. But also, it's a poor prognostic sign from a broader metabolic perspective. Patients with tophi are more likely to have renal problems or high blood pressure as well as not being able to respond to treatment. So the presence of tophi is really quite important. Currently, there is one approved therapy, pegloticase, which has efficacy rates of around 40% to 45%. And nearly half the patients can't tolerate a full course of treatment with that medicine. So we feel that whilst it's resulted in some improvement, there is more that can be done. And so the COMPARE trial, which we recently announced the results of, looked at the effects of pegloticase versus SEL-212. And we looked at the number of patients who reached the target serum uric acid at month 3 and at month 6. And on the right-hand side, you can see the results from that study. And numerically higher numbers of patients at the primary endpoint have uric acid within the target range in the Selecta group compared to the pegloticase group. And that p-value was 0.056. So actually now it is significant. I will say that this trial was affected by a lot of missing data and a few dropouts as it was conducted during the COVID pandemic. When we looked to earlier patients at month 3, we saw, again, a very clear difference, which, with exploratory statistics, was significant. So what we see here is a drug that has less frequent dosing. It's monthly versus every other week. It seems to have a greater effect on serum uric acid than what's already there. And I'll show you in a moment the effect of this drug in that specific group of patients with tophi. But it also doesn't require additional oral immunosuppression with either methotrexate or MMF, both of which are difficult to take, and in this particular group of patients may well be contraindicated in a large number of patients. Let me turn to the issue of tophi. On the left-hand side is a graph that shows the total number of patients with chronic refractory gout. Not all of these necessarily would be suitable for treatment, but it shows from an epidemiological perspective that around 70% have the presence of one or more tophi. So this isn't just some transient problem. It's actually quite an important problem for patients who aren't responding to conventional therapy. So we looked at that subgroup of patients in the COMPARE study to see how they did. And actually, you can see a much bigger difference between SEL-212 and pegloticase for the primary endpoint, which is a treatment response rate with a target serum uric acid. And that's in the bar chart shown on the middle of this slide, with 58% of patients responding to SEL-212 versus 39%, responding to pegloticase. And if we look at serum uric acid, which is what's measured in the clinic, you can see a much greater percent reduction with SEL-212, which is shown in the blue line, the light blue line, compared to pegloticase, which is shown in the dark blue line. So we really feel that this represents an important difference for patients with gout, a more convenient treatment, a treatment that doesn't require the presence of oral immunosuppression and a treatment that works particularly in those patients with tophaceous gout, who represent the majority of patients. So we're very excited about the possibility that this drug brings to those patients. And where are we? We recently announced the start of the Phase III program, which is called DISSOLVE. There are 2 studies. These have been agreed from a regulatory perspective, the placebo controlled studies, which will hopefully complete in the early and mid part of 2022. We'll probably add to this program because we want to get a broad range of data so that this drug is used more broadly in different geographies, but this is the core program that is going on right now for SEL-212. I'll say a brief word about Synagis and MEDI8897, but I won't go into a lot of detail. As Guido mentioned, in 2018, we acquired from AstraZeneca, the rights to Synagis as well as the right to participate in 50% of the future earnings of the candidate drug MEDI8897. As Guido mentioned, Synagis is used for the prevention of RSV in infants and is the only approved medication for this indication currently. MEDI8897 is a follow-on candidate for Synagis. It's a monoclonal antibody that can be given once and probably in a broader group of patients. So really, whether that drug works or not, we see it as the rights that we have for that derisk the future revenue expectations for Synagis. And we see these really as a package of care for infants with RSV. So now I want to move on to 2 of the bigger programs that we have within the portfolio that sit really in the interface between immunology and hematology. The first is Gamifant, which is the only treatment that targets gamma interferon, which is a major pro-inflammatory cytokine. And that's shown in the schematic on the slide here. Gamma interferon expression really is at the root of a number of inflammatory diseases. And one of those diseases is HLH, which is a severe life-threatening systemic inflammatory condition. I'll talk more about that in detail in the coming slides. Gamifant was approved in the U.S. for the treatment of primary HLH in 2018 and we're looking at a number of additional indications that I'll talk about shortly. Let me first turn to primary HLH. So this is predominantly caused by genetic mutations. Those genetic mutations are in the immune compartment. And they've been described in around 55% of patients. But that still leaves 45% of patients who have unknown genetic mutations. There's a very high prevalence amongst children, and it presents with a really severe disease, often necessitating stem cell transplantation as a curative measure. And there are no approved treatments. The disease itself is normally triggered by an infection, but the more severe the genotype, the more trivial the infection would be. And in some patients, it may be a more severe infection based on the background of genetics, and I'll talk more about that in a moment. So as I mentioned, Gamifant was approved by the FDA a couple of years ago, and that was on the basis of the data that is shown on the right-hand side of this slide. And this again was recently published in the New England Journal of Medicine. But what we looked at were patients who'd had conventional therapy, the so-called HLH protocol with high dose steroids and cytotoxic therapy but had, had an inadequate response or a relapse following initial therapy. And we measured an overall response rate in those patients. This was a single-arm trial, but the expected response rate in these patients was going to be 40%. Actually, the overall response rate that we saw was 63% and we declared statistical significance over the putative expected response rate. And that overall response was made up of different types of response according to clinical criteria. We also looked at survival in these patients. And the Kaplan-Meier graph on the bottom right of this slide shows you that 74% of patients were alive at 12 months after follow-up. And I should say, a number of these patients had stem cell transplantation. And in a number of those stem cell transplantation patients, they were deemed high-risk transplants but the patients did well and still survived. So that tells you that this drug is really doing something. It's doing something in terms of the initial response within the first 8 weeks, but it's also doing something, enabling transplantation and prolonging survival. We recently had a negative opinion for this data from the EU, but we are seeking approval in a wide range of geographies. And as mentioned, we recently submitted in China, and we will be submitting this data in other countries as well because we feel the data is very important. We feel it's very robust, and we feel that children outside of the European Union would still stand to benefit from this drug. The other thing that I think that we need to do is look at those -- that 45% of patients with unknown genetic mutations. So particularly in the U.S., we've started a few collaborations to better understand that, and we started those collaborations with academic centers as well as providers of genetic testing so that we can really investigate whether actually there are more patients who actually have primary HLH but are undiagnosed and who could benefit from Gamifant. So that's primary HLH. We're expanding emapalumab beyond primary HLH, into secondary HLH, which normally has an underlying cause or could potentially have an underlying cause, which might include rheumatologic conditions, it might include malignancy or it might include severe infection. And we're also then moving into graft failure and graft-versus-host disease following stem cell transplantation. And I'll talk more about those in a lot more detail in the coming slides. The expected launch dates are shown on the right-hand side of this graph. So over the next couple of years, we expect primary HLH should be approved in more geographies and the first secondary HLH approval should happen in 2023, and GVHD in 2024. So let me just talk about HLH as a spectrum of diseases between primary HLH, which is shown on the left-hand side of this graph, and secondary HLH on the right-hand side. HLH has a common phenotype, which is made up of some very characteristic clinical and laboratory features, which are listed at the bottom of this slide. And depending on the background, there's a number of triggers, whether they're infective or iatrogenic that can cause this phenotype. And we've seen, actually, in the last few months that HLH-like phenotype has occurred in patients who have very severe COVID infection and has really been implicated in the cause of death in a large number of those patients. So let's just go back to genetics. So we know that a number of patients have genetic mutations, and those have been in the inflammasome or perforin or other immunodeficiencies. But there is this large number of patients in the middle that we need to better understand and better identify. And what we, therefore, need to do is look at the role of infection on the one hand, a very severe infection, maybe with normal genotype could cause HLH or a trivial infection with a particular genotype. A trivial infection with a particular genotype could also cause HLH. And that balance between the 2 is something that we're trying to understand through these academic and other collaborations that we are doing. And we need to understand that a lot better, utilizing all the data that's being collected right now in the context of COVID across multiple countries. And also think about the rise of genetic testing that is allowing us a better insight into what's going on in patients, for example, who are in intensive care with a high ferritin who actually may have genotypes that are consistent with HLH. So we're looking into that before we pounce and do another study or do a study in infection -- infective HLH. And we're just going to take a few months just to examine that a little bit further. One area that we're very confident about is rheumatologic HLH. So this is HLH that's caused really by activation of macrophages and other inflammatory cells, in particular, T cells, and it occurs in association with a known rheumatologic condition. It most often occurs in the context of systemic juvenile idiopathic arthritis or SJIA or it's adult equivalent, adult-onset Still's disease, AOSD, but it can also occur in the context of SLE, lupus, or other vascularities. And despite the advent of treatment for the underlying diseases that are directed at other cytokines, these patients still will develop activation of macrophage, the macrophage activation syndrome, which is a subcomponent of HLH. And so we conducted a study in 14 patients who had either SJIA or AOSD. And despite conventional therapy, either with biologics or steroids, developed macrophage activation syndrome that, in many cases, was really quite florid. In all 14 patients, there was a clinical response according to predefined criteria in the eyes of the investigator. And in all of them, there was an improvement in multiple lab parameters. And those are shown on the right hand graph. On the black line shows CXCL9, which is a downstream biomarker of gamma interferon. So that shows that the drug is reducing gamma interferon levels. But that's also resulting in a reduction in ferritin, which is a hallmark feature of macrophage activation syndrome as well as improvements in AST and ALT shown in blue and red, which are markers of deranged liver function. So we've taken this preliminary data to the FDA. Like us, they are very excited. And what we need to do now is we recapitulate this data in a slightly higher number of patients, and we feel that there's a route to approval for rheumatologic HLH within the U.S. So we're doing a number of different things now in this end of the syndrome of secondary HLH. We'll start another study imminently early in 2021. That will be a global study and in during a particular moment in time, we'll have enough data to add to the original study to take back to the FDA to seek approval for this indication. But we'll also generate a wider data set for patients such that we can get approval for this indication, not just in the U.S., but hopefully in other territories as well. I mentioned that for infectious HLH, we're doing a lot of intensive work, mining, genetic and cytokine databases in different settings across different countries, which will allow us then to decide what the best course of action is for those patients with severe infection who develop HLH. And we're also in the process of conducting a pilot study in patients with malignancy who develop HLH, and the results of those should be available sometime in 2021, and we'll make a decision based on those data, whether to proceed with malignant HLH. So I want to turn now to a new area, which is stem cell transplantation and complications of stem cell transplantation and why we feel that Gamifant could be a really important drug. On the right-hand side is a schematic that just shows 3 potential complications that can arise following stem cell transplantation. These are patients who have stem cell transplantation primarily because of malignant disease, but they also could have had it because of florid inflammatory disease, such as primary HLH. Sometimes, the graft effectively never takes, and that's called primary graft failure, and that can be detected normally at about 2 to 3 weeks following the transplant. By then, it's too late. And the graft is probably going to get lost. Secondary graft failure occurs a little bit later on. The graft is initially been successful, but then subsequently is lost as a result of rejection by the host. So that's graft failure, primary and secondary. The other complication that I want to talk about now is acute graft-versus-host disease. Now this occurs via a different mechanism, where the transplanted cells have an immune reaction against the patient. I'll talk more about that in a moment. The treatment for any of these conditions is actually quite difficult, and there are limited numbers of approved therapies. So we hope that Gamifant would be the first approved therapy for graft failure, another addition to the treatment options for GVHD. There is another complication following HSCT that we're interested in, which is thrombotic microangiopathy, and I'll talk about that shortly when I talk about pegcetacoplan. So let's talk about primary and secondary graft failure. Why do we believe that gamma interferon is implicated? It comes from 2 lines of evidence. One, I told you around -- about earlier on, which is the success of stem cell transplantation in patients with primary HLH, once they've been primed with -- or treated with Gamifant prior to the graft. The other comes from this data set from Italy, which looks at CXCL9, which is a direct and very sensitive and specific biomarker of gamma interferon production. And that can be measured as early as 3 days post-transplant -- where it can be -- elevated levels can be measured as early as 3 days post transplantation in those patients who would go on to lose that graft. So it appears to be an early biomarker, a much earlier biomarker than common normal clinical practice for graft failure. And that's shown in the graph on the right-hand side -- bottom right-hand side of this slide. CXCL9 levels along the y-axis, time along the x-axis. The patients with graft failure have significant elevation early on, and that is maintained, and they're shown in the orange line. And the control patients who had a successful graft are shown in the blue line. So 2 reasons that we believe that Gamifant is important. But in order to do a trial where we look at this as a biomarker, we have to do 2 things. One, we have to further characterize the observations that are seen in this study on the right-hand side, which was a single center in around 20 patients. But we also need a test. CXCL9 can be measured, but at the moment, it's measured differently across different centers and not all centers measure it, which is why we've entered a collaboration to develop a companion diagnostic with bioMrieux, who have a platform and a machine that we know is very well suited for this task. And the VIDAS system that they have has a fast turnaround. It actually exists in a number of centers, and it's what we call a hands-off-machine. So from test to results, it's pretty much fully automated. And actually, CXCL9 using this test was granted breakthrough designation by the FDA earlier on this year. So we'll have, hopefully, a lot of interest and help from the FDA as we go on to develop this assay for use in the context of graft failure. And actually, this assay and this approach could predict other gamma interferon diseases outside of the context of graph failure, and that's something that we can explore in future months and years. So turning now to GVHD. This is a slightly later complication. This is where donor T cells attack the host that results in multi-organ disease, which can be life-threatening. At the moment, it's treated in a number of different ways. But the only approved treatment is the JAK inhibitor, ruxolitinib. But again, there's good evidence that gamma interferon may be playing a role in the context of graft failure. The graph on the right shows the cumulative incidence in patients with high CD4 count and high CXCL9 levels. And what you can see there is a strong probability, when you measure these at 28 days, that GVHD will occur in the subsequent 12 months. So there's strong predictive likelihood that CXCL9 may be implicated or at least interferon gamma may be implicated in patients with GVHD. And so we're further investigating that in the context of a clinical trial. So taking stem cell transplantation, graft failure and GVHD as a whole, what are we currently doing? So our development program will start imminently. Our development program will start imminently. We need to continue developing the companion diagnostic. And that's ongoing. And that will then enable us to put molecules into Phase III. The GVHD program, we need to do a natural history study to really fully characterize the role of gamma interferon in those patients. And we'll start the study, we hope, by the end of next year or early in 2022, with the intent of coming to market in 2024. For graft failure, I mentioned, we need to develop the companion diagnostic. We need to do a bigger natural history study and we're also doing a proof-of-concept study. All of those things need to be in place before we can do a pivotal study using a companion diagnostic for graft failure. The observational study that we're doing helps us in a number of different ways. It really helps us understand the complications of stem cell transplantation, both in terms of graft failure, in terms of GVHD, but also potentially in view of the other complication I'll talk about shortly, which is thrombotic microangiopathy. So a lot of activity that needs to happen, very innovative. Utilization of the companion diagnostic but really addressing quite significant unmet medical need. I want to briefly just pause and talk about COVID-19 because there's been a lot of interest in our products in the context of COVID-19. Both anakinra and emapalumab have the potential to address key pathways that have been implicated in cytokine storm syndrome. Now we did start a study in March of this year, looking at either anakinra or emapalumab against standard of care. That was a very small study, proof of concept, predominantly conducted in Italy. I think what's happened in the last 6 months in the context of COVID, as everybody is aware, is things have changed quite a lot. Standard of care has changed quite a lot. So the standard of care that we specified in the original protocol has really moved on to include dexamethasone to include antivirals to include convalescent plasma, et cetera. And the size of the study was actually really quite small. So we took a decision to stop that study and focus our efforts on anakinra in the short term. And there's a lot of ongoing clinical trial activity with anakinra. We're aware of at least [ 18 ] ongoing RCTs in this space. And we're closely involved in 10 studies, which we are supporting, looking at the use of IL-1 intervention in COVID. Those are across the U.S. and the EU primarily, and there's going to be up to 2,500 patients recruited in those studies. At the moment, we think it's about 1,000 patients who have been recruited. But there's one particular study I'd like to talk about, which is the SAVE-MORE study. This is being conducted in Greece, Italy and the Netherlands. It's about to start. And there'll be 525 patients with moderate disease who are already in hospital, but have a poor prognosis based on the biomarker, suPAR, which stands for soluble urokinase type plasminogen activation receptor. And again, this is a test that's commonly done in the context of acute care to determine whether the patient has a good prognosis, a low suPAR, or a poor prognosis, a high suPAR. And these -- this investigator has already done a trial in a smaller number of patients and showing an improvement in respiratory outcomes and survival outcomes. And there, he used an indirect control, a propensity-matched cohort. And this trial is now a randomized controlled trial of anakinra versus standard of care using an endpoint that now is widely recognized, which was devised by the WHO. And he had discussions with the EMA, the emergency task force of the EMA, and has designed this trial in collaboration with the task force. And the study will start imminently and read out in the new year and leads to a potential route for approval for anakinra in this space. So I want to turn now to pegcetacoplan, which is the most recent addition to our pipeline. And this was a co-development deal that we announced with Apellis a couple of months ago. So let me kind of say a little bit about the complement pathway or the complement cascade, which is a key component of the immuno-inflammatory system. It can be activated via a number of ways, the classical pathway, the alternate pathway and the lectin pathway, which is shown in the schematic on the left-hand side, all of which converge on the molecule C3, which lies at the center of complement activation. Complement activation then results in a number of downstream effects that mediate immune or inflammatory damage or disease, including hemolysis, including optimization of blood cells and including other inflammatory consequences. An uncontrolled complement activation is heavily implicated in a large number of diseases, both autoimmune and hematologic. And so pegcetacoplan was originally developed to elevate the standard of care in a disease called paroxysmal nocturnal hemoglobinuria or PNH, which I'll talk about in a moment, but also has opportunity in a large number of other diseases. And the complement system, as I mentioned, can be implicated in multisystem diseases. We're particularly interested in 3 areas: hematology, nephrology and neurology. In neurology, we're looking at amyotrophic lateral sclerosis. In nephrology, we're looking at membranoproliferative glomera nephritis and C3 glomerulopathy. And in hematology as well as PNH, we're looking at cold abrutinib disease as well as thrombotic angiographic anemia secondary to stem cell transplantation. So let's talk about PNH. This is an acquired rare, chronic and life-threatening blood disorder. Patients have very low hemoglobin, and they are dependent on transfusions as a result of hemolysis. And that hemolysis can occur both within the vascular compartment, so-called intravascular hemolysis, or it can also occur in the extravascular space, in the reticular endothelial system, the liver, the spleen, et cetera. And there are a number of symptoms that occur as a result of hemolysis. And there are current treatments, which are C5 inhibitors, such as eculizumab. And those have been transformative in therapy. But one of the limitations of those therapies is that they only treat intravascular hemolysis. When I showed you earlier on the complement cascade, C3 directly leads to extravascular hemolysis and C5 inhibitors don't affect that. So I think it's quite an important mechanistic and biological differentiator. So to look at that, the PEGASUS study was conducted versus eculizumab, and this was in patients who've had a suboptimal response to eculizumab, and they were randomized to receive either pegcetacoplan or eculizumab. And the primary endpoint was hemoglobin at 16 weeks. And in the graph on the right-hand side, what you can see is the rise in hemoglobin shown in orange for pegcetacoplan and eculizumab shown in the dark blue. And there was a statistical significance at the primary endpoint between the hemoglobin levels with pegcetacoplan, which were, on average, 3.8 grams per deciliter higher than those patients with eculizumab. Today, Apellis and ourselves announced the 48-week data from this trial. So the long-term extension of this data. And I'm really delighted to announce that both the efficacy and the safety of the drug is maintained over the subsequent 48 weeks. So this drug differentiated due to improving hemoglobin versus eculizumab. And that's predominantly due to effects, we think, on both intra and extravascular hemolysis. And as well as hemoglobin, there were improvements in a number of other elements that are related to this disease, including critical parameters like fatigue as well as biochemical parameters like reticulocyte counts and LDH. So very excited for the possibility for pegcetacoplan in the context of PNH. I mentioned as well that there were other hematologic conditions that might be amenable to inhibition of C3. And this includes this disease, cold agglutinin disease or CAD, which, again, is a chronic and severe red blood disorder, again, requires transfusion dependence and also results in the increased risk of thrombosis, and that can lead to heart attack or stroke. There are no current therapies approved. And so therefore, this will be the first targeted C3 treatment for CAD. The graph on the right shows the reason to believe, and this is the interim results from a Phase II study called PLAUDIT, which shows a rapid and sustained rise in hemoglobin in patients with CAD over several weeks and months. Also I want to now turn to TMA following stem cell transplantation. So again, the synergy with what we're doing with Gamifant. So this is a rare complication following stem cell transplantation. It can result in loss of graft. It can result in loss of life. It's quite florid in the most severe cases with hemolytic anemia, a drop in platelets, multi-organ damage and particularly affects the kidneys. Depending on the series and depending on the center, this probably can occur in up to 20% to 30% of patients following stem cell transplantation. And C3 is thought to play a very critical role in the pathogenesis of TMA. That's shown a little bit on the right-hand side, which looks at the levels of C3 -- C3b, which are on the components of C3, but before the development of TMA and after the development of TMA -- sorry, before the transplant and after transplant in patients who developed TMA. And you can see a significant rise in both the mean and medium levels of C3b in that situation. Again, there are no approved therapies for this disease. So this would be the first targeted therapy. Outside of hematologic diseases, we're also looking at nephrologic disease in particular, immune complex mediated membranoproliferative glomerulonephritis as well as C3 glomerulopathy or C3G. These are relatively rare kidney diseases. They're only recently been described. But C3G, in particular, can affect transplanted kidneys and leads to a recurrence in transplant in as many as 85% of patients. Both classic and alternate complement pathways have been implicated, which is why looking at C3 as a central controller makes a lot of sense. A small pilot study has been performed called DISCOVERY and in that study, over 48 weeks, we saw a significant reduction in urinary protein, which is a good marker of renal disease. And we expect to start a further study in 2021 in collaboration with Apellis for C3G. I'll finally turn to ALS, or amyotrophic lateral sclerosis. This is a neurodegenerative disease. I think it's very well known. It's a much bigger disease in some of the ones that we've been talking about. It obviously results in neuromuscular weakness and paralysis. And in many patients, high levels of C3 have been identified within the neuromotor system, which are known to contribute to neuro inflammation. Although the therapies are approved, nothing has been shown to stop or reverse disease progression. And so a Phase II study has started in ALS, which is being conducted by Apellis, which is looking at a series of combined and individual endpoints of function and neuromuscular disease. It's a double-blind randomized study with a 2:1 randomization ratio, with approximately 200 patients in it. And data will be available probably in 2 to 3 years' time. It's called a Phase II study because of the unmet need, there is a small possibility that this study could end up being pivotal. So we watch with interest and we wait with interest and a great deal of excitement, a huge amount of unmet need in ALS. So this shows the multiple indications for pegcetacoplan that are starting and will be conducted over the coming few years, both in hematology, nephrology and neurology. We're not committing to end time lines yet because these studies are being devised and started. But I think it's important to note that Sobi are using our expertise to conduct the hematological program as well as Apellis conducting nephrology and neurology programs. So what does that mean in total? There's a large number of programs, there's a large number of indications and this really underpins and a large number of geographies that Norbert will talk about shortly. But this really underpins our ambition of 32 launches in key geographies by 2025. And the list of indications is on the right-hand side of this slide. So I'll conclude by just saying what we're trying to do is build on our rare strength in R&D. I've shown you our portfolio across a broad range of rare hematologic and immunologic conditions as well as a number of conditions that really span the cusp of those 2 specialties. All of the medicines are either innovative or differentiated or both. And we're using our expertise to develop multiple indications per asset and using a lot of platforms that enable enhanced development, such as digital technology, biomarkers and genetic understanding. We've developed over the last few years a deep kind of level of experience and a partnership with a wide range of different companies that we've talked about a little bit over the last hour. And we're taking the leadership in those partnerships where we have the expertise. So we're playing to our strengths. And from an R&D perspective, we have 4 centers of excellence, as shown on the graph on the right-hand side, 2 in the U.S., 2 in Europe. And 250 team members, and we're deepening our expertise of both hematology and immunology. So with that, I'll stop and hand over to Paula as we go into the break.

Thank you, Ravi. We will now take a short break and start again at 2:45 -- at 2:45. [Break]

Welcome back to Sobi's Capital Markets Day 2020. Now I would like to invite Norbert Oppitz to the stage.

Thank you very much, Paula. Good afternoon. Thanks for bearing with us over the break. I have now the pleasure to talk to you about Sobi's internationalization strategy. As most of you probably know, looking at Sobi at our Capital Markets Day, rare diseases are a very interesting and compelling opportunity in Europe, in the U.S. and outside. In total, we are talking today about roughly 7,000 rare disease, 7,000 different conditions, most of them, about 85%, very serious, potentially life-threatening and a large number of them affecting children and young adults. These 7,000 diseases are today confronted by about 500 designated approved drugs. So it is very evident that there is a huge medical need, a huge gap, and that there are many patients out there who really desperately need treatment options, new drugs in order to be able to lead a normal life and to benefit from the advance of technology. This is a segment that is growing very strong, double-digit across the planet, but with the growth driver being right now those markets outside the U.S., outside Europe. What drives this growth? Many markets are now much better connected, many countries are better connected to science. The way how physicians today interact, share information, share best practices. The way how diseases can be diagnosed, the technology available, the connectivity, the logistics for samples to travel around the world to make an indication. All this is contributing to the medical and scientific capability of physicians around the world to identify and to treat, to diagnose rare diseases. On the other side, many governments now understood the challenge that these rare diseases represent to roughly 0.25 billion people outside the U.S. and the European Union, 250 million patients that are really requiring attention in the lobby. In many countries, we see today new policies and new strategies when governments and societies start to confront and to engage and to, in a certain way, to support the fight against and the war against rare diseases. We, at Sobi, are committed to reach about 80% of this population. We want to be at the spearhead of a science and of a pharmaceutical industry bringing this solution to the patients at a global scale. We've heard Guido say and we've heard also a little bit from the past, how Sobi developed from a more Euro-centric company to a regional real leader in rare disease. This is not only an expansion of business on and by itself. This expansion basically helps us and helped us to build capabilities and capacities in order to be able now to confront larger scale and more global challenges. I believe that especially the last month, where the COVID pandemia have proven that we are able to manage very complex supply chains punctually without missing on patients and really working 24/7 to make able to deliver our solutions to different geographies. Our regulatory capabilities have grown different markets with products and indications, and so as an organization today and being well-established in the U.S. and in Europe, we are now able to go further, to go to all these important remaining geographies. And that means that we are now really aspiring to become a global leader in rare disease. We already did some first steps. We have business in the Middle East, we are very successful there. We learned a lot. I think we are well connected with physicians, with scientists. We have established presences in China, Japan, Russia and Australia, and we are looking also into partnerships in currently underserved regions where we might not be able to go imminently. In other words, we have already expanded our market presence outside Europe and the U.S. You can see here on the map, some examples. As named, Middle East, Russia and China, Middle East being the more mature. We have several years of successful business in the GCC countries, Turkey, North Africa, and actually, we are now also attractive for other companies who look at us as experts in this area and are offering us to team up to bring also their solutions to these markets. We have set up a subsidiary in Russia, which is now built into a fully fledged organization. We have Elocta approved for launch, we have Orfadin already launched and we have basically built a very strong local team of experts, strong in science with a solid knowledge of the market, well connected with the key opinion leaders. In other words, we have been able to connect here the medical dots, the logistical dots and pharmaceutical supply in order to bring our solutions successfully to Russia. We have built up, and I come to it in more detail the presence in China and Japan. We have opened up a subsidiary in Australia, and we are looking, of course, at certain other geographies. So right now, the sales that these territories provide to Sobi, some up to roughly SEK 800 million, outside our core markets, the U.S. and Europe. Now in order to get to this growth, as you have seen, we need to ramp up launches. And this is what really becomes very, very important to connect the dots to have a strong local leadership, local experts who know their markets and who are really able to gauge and to assess and to understand local needs and to match them up with our capability and capacity to provide solutions. That means that each of these more than 18 launches that we are looking at is a single project, is a project on and by itself, and is something that will require a very dedicated effort of a strong team of experts, geographically diverse, functionally diverse but united in the goal to make it happen. It also means that the most important asset that we have here at Sobi to make this through, and Guido hinted to it, is our people. It is our internationally very seasoned global experts who work cross-functionally in order to be able to do these molecules and these launches justice and to bring them to the patients. If we look now, for example, at China. China has set up a very interesting framework around rare diseases. It was clearly understood that there's a very strong and broad medical need and the government has been able to shape rules, regulation, a rare disease list, specified path of entry, designated definitions how drugs qualify to enter. And so basically, what we have done, we have matched this now with a local team that is able to understand the local framework and to really bring our drugs on to a path of success. And actually, despite the fact that 2020 was a little bit driven by COVID, I believe we've done quite a good job bringing the company online late in '19, and then we started with emapalumab in primary HLH. Whilst no travel was possible and everything was limited, we've been able to find the key opinion leaders. We have fantastic ad spots with 20-plus physicians, simultaneous translation, everything on TV, on Internet. We have been able then to bring this together to have a CDE meeting in June, and we have finally submitted the primary HLH file for Gamifant to the Chinese authorities. This very morning, we received the document that acknowledged that we are now filed. So the clock for our first product in China literally is ticking as per today. And that means that we look forward to hopefully have our first commercial patient 2021 on line, the first of many. In parallel, we are also working with nitisinone, which is a similar process. And we are also having similar timelines. So overall, we can say that despite the limitation that the pandemia has brought on us, our local team and our strong team here at the headquarter have been able to set things up, to push things through, and we are on our way to save -- serve these patients as soon as possible with quality solutions for their diseases. On the other side, venturing into Japan. A similar starting point, ultimately setting up a company, but setting up the right company in a different legal framework with different local, strong experts, and then basically looking into more mature and more defined markets and with a broader number of products right now. So we have forwarded into Japan different work streams, which will be accompanied by several local clinical trials or contribution to global ones for emapalumab, for anakinra, avatrombopag and pegcetacoplan. The interesting thing here, but first of all, regulatorily, this is a very, very intense field. So we really need a strong expert team to make sure that we meet all the local clinical study and data requirements. And then also Japan has certain diseases, for example, which are stronger or which are more present than in other geographies. Kawasaki, basically for -- another form of HLH comes to mind, and EBV, Epstein-Barr virus-driven HLH. And that means that we, at Sobi, will have to adapt and will have to work around this and we'll have to make sure that our clinical groundwork preparing now to bring the solution is matching these requirements and is at the state-of-the-art, bringing the solutions that are required in order to serve these patients. We will then also do an analog to this -- similar programs with avatrombopag, pegcetacoplan, and this is only the example of China and Japan. But again, we have Russia, we have other countries. And so overall, we expect by 2025 to make a major contribution to the '25 of about 15% of Sobi's total revenue coming from international markets. So in a nutshell, you have seen from Ravi, we have very exciting, interesting, unique products. We have the experienced professionals in different markets to bring them there, to serve these new audiences and that basically means that we will be with approximately 40% growth per annum, one of the strongest growth contributors to Sobi business. Thank you very much. I'm ready to take questions after the session, and I now hand over to Sobi's CFO, Mr. Henrik Stenqvist.

Thank you very much, Norbert, and good afternoon, everyone. I thought I would start with looking back at Sobi's financial performance over the last 5 years. With revenues of more than SEK 15 billion in 2020, we have almost tripled sales since 2016. And as we heard, about 75% of this growth is organic and the CAGR number for this period is 31%. Hematology in red on the bars has, of course, been the most important engine of growth here. The success of Elocta, Alprolix, but also more recently, the launch of Doptelet in the U.S. In Immunology, we have managed to create a second leg of the company through the acquisition of Synagis, which also provided us with a foothold and very important commercial infrastructure in the U.S. In addition to that, we've successfully launched Gamifant, the first indication, primary HLH in the U.S., and we've seen continued double-digit growth of Kineret. At the same time, we've seen a decline in the noncore Specialty Care as we've seen the generic impact on Orfadin and the termination of almost all the partner business. During this period of growth, we've seen EBITA growing up to the 40% level, and we've maintained it there. And through this profit, we've had a continued strong cash flow generation. Now as we've heard, when we look beyond 2020, we enter into a new stage of the company. With the already very strong market shares in Hemophilia and with the competitive situation in hemophilia A, Hemophilia will no longer be growth -- the growth engine in the same manner as it has been in the past. Instead, as you've seen, we have now built up what is a significant pipeline of late-stage assets that we will now work very hard to bring to the market. And of course, in order to be successful, we need to focus strongly on the multitude of launches that will happen. And last but not least, M&A continues to be on our agenda. During this phase, we will increase spend in R&D. R&D has historically been around, give or take, 10% of revenue in the company. In the next few years, we expect that to increase to about 13% to 15% of sales as we carry out all the programs that we heard about from Japan -- from Ravi, particularly SEL-212, pegcetacoplan through its 5 different indications and emapalumab as we expand the indications into graft failure and graft-versus-host-disease and also the secondary HLH. If we translate these trends into some financial direction of Sobi going forward, how we actually travel from the SEK 15 billion revenue up to the 20 -- the ambition of SEK 25 billion in 2025. In terms of revenue, we foresee in the next 2 years, single-digit growth as we are waiting for new indications and leverage from the internationalization. From '23 and onwards, as we benefit from further internationalization of Doptelet, new indications of Gamifant and internationalization as well and the launches of pegcetacoplan and SEL-212, we expect a continuous opportunity for double-digit growth. As I said, we will invest more into the future in the next few years, r&D, the launches, the infrastructure, internationally, as Norbert said. That will put pressure on EBITA. From 2023, as we expect acceleration on top line, we also expect operating leverage into our business and an acceleration of the EBITA margin as well. A few words about debt leverage. Our strong cash flow has allowed us to make acquisitions over the years, predominantly financed through debt. We expect also in the midterm -- in the short and midterm, a very good continued cash flow. We expect in the short-term that net debt-to-EBITDA would be below 3. That is true also after the acquisition of the license, the upfront of $250 million that we recently paid to Apellis. But we are able to go above 3 and up to 4 in case of acquisitions or M&A because M&A continues to be on the agenda. And we will try to derisk M&A whenever it's possible. In the past, we have been quite successfully derisking our transactions. Looking at the 2 recent deals, pegcetacoplan and SEL-212, these deals were derisked in the way the transactions were constructed. Relatively speaking, limited upfront with most of the consideration coming contingent on regulatory and commercial success. The Dova acquisition contained 3 indications, two of which were already approved and launched in the most important market. And the CIT indication was derisked because we made part of the purchase price contingent on CIT approval. For Synagis, we derisked the mature asset Synagis through the financial state in the follow-on products for the U.S. market. And for Gamifant, Gamifant included multiple potential indications, R&D capabilities, and also a priority review voucher, which we were able to quickly monetize, and thus indirectly reduce the purchase price. To the right of the slide, is an illustration about these potential milestones. We estimate -- or, in fact, the commercial milestones are about 70% that is contingent on commercial success and 30% and obviously regulatory milestones. We estimate that about 65% of potential milestones would become due only after 2025. So it is a very back-ended structure. With that, I'd like to hand over to Guido for his concluding remarks. Thank you very much.

Yes. Thank you, Henrik. And it's my time now to wrap things up. And basically, what we wanted to leave you with is that we have a proven track record. We are not a company that likes to try to figure out how it may feel to do an internationalization. We have people who are credible in -- from an international perspective, but also credible from, obviously, R&D perspective. Next phase requires obviously investments. And frankly, I mean, when you look at it, we have to solve for as a response in the company for a couple of things. First of all, you want to do the right thing for patients. As you have seen in Ravi's presentation, this is where -- I mean these are very debilitating diseases. The prognosis of HLH is not very, very great. Even with diseases like PNH, where you have existing therapies, there are still very significant unmet medical needs. So we are compelled to invest into the portfolio that we have brought to par. We think that this is also important to remain an attractive employer and provide a future for our employees. And whilst we are doing this, actually, we are increasing the value of the company, and then we hope that you'd appreciate us, that we are not short-term focused and myopic, but that we have a much bigger picture in mind and building the value of the company. And when you look at our ambition of SEK 25 billion by '25, I think this is a very doable mission. And when you think back, we have been growing in 4 years by SEK 10 billion. We have now brought to par a very substantial partner pipeline. We have a very nice beat around these launches. So we think we can do this. And we will further improve our organization. We don't profess that we are perfect, we'll never be, but we are now trying new things. We have some digital tools. We bring in some innovative concepts. So we think that we have a formula that will allow us to do this. And then obviously, we will further -- remain further vigilant. We have done a couple of deals. Henrik has pointed out very nicely that we are very thoughtful about M&A, the way we are derisking this and even though not everything is always working out. Actually, we are -- overall, we have -- we don't go into binary situations. We don't risk the bank. We always make sure that we -- that these -- all deals, we are able to enhance value in a very responsible fashion. So in summary, we think that we have a very nice formula together. Obviously, the proof is in the pudding. But at least what we can say is that we have proven quite a fair bit. But as you can see, we have appetite for more. And I think on this note, I think we would like to open the floor for questions, and then we'll see how we can answer this because want to make sure that -- I mean, this has been a kind of a fair amount of information that we have shared with you. I'm sure there are the one or the other things that you may want to further explore with us. Thank you.

Thanks, Guido. We've received some -- quite a few questions here on the web. And operator, I believe you also have some, but I'll start with one here that we've received on the web. You touched on peak sales for Hemophilia earlier on. You're talking about peak sales of SEK 8 billion to SEK 10 billion. How much is BIVV001 contribute to these? In which year do you expect to reach peak sales? And the fact that your projections are up to 2025, does that mean you expect peak sales to be reached in that year for the Hemophilia franchise?

No. I think what we wanted to give the audience is a perspective on how we see this. I mean we are going to launch -- this is our current schedule of BIVV001 in 2023, end of '23. Obviously, all subject to the assumption that the current ongoing COVID crisis is not further delaying the trial, and we will obviously continuously observe this. So there's a bit of risk in this. But so far so good. And basically, you would not expect to peak basically 2 years after launch. So you would basically peak for this product probably more 3 to 5 years from launch. And obviously, we think that BIVV001, given its profile, will be very efficient, substituting many recombinant factor products, including ours given its superior profile and the additional effects. So basically, this was more indicative that actually what we believe is we are roughly today at [ SEK 8 billion ]. We don't see really, if you can afford to have a more longitudinal perspective, that actually that franchise will diminish given the opportunity related to BIVV, but we accept that we will face some headwinds in the short-term with Elocta. Having said this, we have growth opportunities with Alprolix. And having said this, we have a couple of launches, and we have a proven track record. So we -- I think what we wanted to rest assure you, yes, we're facing adversary, but we have a fantastic team that is well recognized by physicians. We have a couple of very acute ideas that we are currently launching in terms of also further life cycle management. We think that this theme of normalizing patients is very important for us and that we are one of the very few companies that have products that are credible in this regard.

Thank you. I'll take one more and then operator, I'll hand over to you. And this is on the same theme. The peak sales estimate assumes a trade-off between Elocta and BIVV001 over the time? I think you touched on that.

Yes. I think this is clear that given its fantastic profile that ultimately, we are not going to hold back. We believe that BIVV001 is going -- the minute it's launched is going to be our future, and that will mean that we will substitute Elocta sales. Up until then, we have still a good run rate. Yes.

Yes. Thank you. Operator, I'll hand over to you.

[Operator Instructions] Our first question is from Viktor Sundberg from ABG Sundal Collier.

My first question here is on the sales goal of SEK 25 billion in 2025. Can you describe a bit more in detail what progress that you see will be fundamental in reaching this goal or what respective contribution each product has on this goal? And also what, if anything, could provide an upside or perhaps some downside risk for reaching this goal?

Yes. I mean, basically, when you look at it, the main growth engines that we will have until then, is going to be obviously Doptelet, it's going to be Gamifant and it's going to be pegcetacoplan. You then have -- you will have a launch in 2023 with SEL-212, which I think will be a nice booster. You will launch BIVV001, let's say, as I pointed out. And then the question is, how are we going to benefit from the launch of 8897? But in our many scenarios, actually, we should be better off with the launch of 8897, considering that we are currently focusing in the U.S.-only on 1% of the babies. So there's -- there are a couple of more percent to gain. So basically, when you think it through, the primary growth engine until then, because they are ramping up now and we are internationalizing them, will come from the first 3 that I mentioned and they're very material, obviously, for us. And then basically, you get a second wave of launches as a result of approvals for the products that I just mentioned.

Okay. And could you also add some flavor on the composition of the pegcetacoplan peak sales guidance, given that's a very wide span. Is anything from ALS included here, for example? Or is that an upside?

I mean, basically, when you look at the one of my slides that I showed at the beginning, there is -- basically, we are very confident around [ SEK 25 billion ], yes. Let's say, this is a [ SEK ] that's basically very much -- there's a very predominant weightage towards PNH and doesn't really include too much from the other, let's say, 2 hematological indication and the 1 nephrology indication. And then ALS is basically the big swing factor. And that could be, in itself, more than what we have guided on in totality, but you don't know at this juncture how it's coming out. So that's the reason why there is a spread. But you get the PNH indication right. You don't have to worry about the lower guidance of the peak sales.

Okay. And just a quick question on R&D cost also after 2022. Are they going back to 10% very quickly? Or is it a more slow ramp down?

No. I think basically, we will have, as you can see, I mean, we have, let's say, until -- we will have a ramp, which is normal given the number of projects that we have. And then basically by the scale that the company is going to create, there's going to be this inflection point in 2023 based on our assumptions, where obviously, we then relatively quickly delever because we get them into this phase of significant growth again, which will then prepare the company for the next phase. And that basically, by definition, will bring down the ratios into, let's say -- but I don't think you want us realistically to go back to 10% because we have more -- we are much more of an R&D-oriented company, let's say, going forward than we were maybe historically. And as a consequence, you will be able to bring the company into ratios over the planning period, obviously, that you are used to with us, probably better ratios, yes. But let's say, the -- it will not go like a switching on the light bulb. And so there will be a gradual phase, but you will have very significant -- the deleveraging process will start at a significant rate, obviously, as of 2023.

Okay. And just a final question here also on Hemlibra and the competitive threat for your Hemophilia franchise or Elocta. Could you share perhaps some KOL feedback on the advantage for BIVV001 compared to Hemlibra? I mean I hear you that you say that high-impact sport can only be done on factor replacement. But I mean Hemlibra KOLs also stress that they think you can go skiing and mountain biking, et cetera, and they stress the joint health as well. I mean can you give some more flavor on maybe how you're thinking here?

Yes. I mean it's all -- it's an expectation also how many bleeds do you want to tolerate or your -- basically your appetite for impairing also your joints. Basically, what is our state of knowledge. And basically, we have the sort leader workshops and quite a close interaction. If you are not, let's say, having normalized factor levels, don't do serious sports, yes? And basically, we -- I mean I have here a data point. I had direct discussions with 15 KOLs on this. The average is telling me, obviously, Hemlibra you have factor activity level, which are not really easy to measure because it is not a factor product as such. But they think between around 10% to 15%. So when you're thinking about normalizing a patient of above levels of above 40, by definition, that is limiting your activity level. And by definition, we believe that's the reason why we have a short -- even also in the short-term with Elocta to help patients and our digital solution with Florio gives rise to the fact because you need to benefit from a peak and not only from a trough. Consequently, we think that there is a case to be made. And the feedback we get from patients who are currently in our Phase III trial are extremely encouraging because they feel substantially better benefiting, obviously, from this area under the curve that is extending for the majority of a weekly treatment. So if anything, we are super excited about this, and we think that the future is in our hands.

Thank you. Operator, I'll take a couple of questions now for Henrik. If I may ask you up on to the stage. Now there are some questions about the royalties to Apellis. Will they be included in COGS? Or will they be reduced sales?

They'd be included in COGS.

And also, there's a question here. Can you talk about SG&A costs in relation to sales 2021 and 2022 as you did in regards to R&D?

What we say is that we will continue to invest, obviously, in Doptelet and in Gamifant and that we will have pre-launch and launch expenses for the new things coming, SEL-212, pegcetacoplan and also BIVV001, but we don't guide on percentages on SG&A.

Okay. Thank you. I'll get in one more quickly, operator, before I come back to you. Someone's saying about points of growth are being presented today. They're seeing geographic expansion and new indications. What more can you talk about in terms of growth?

Yes. No, when you look at it in organizational metrics, there are not so many more dimensions you can think about than the new geographies and new products. And let's say -- so what I think we will probably do it. And this is obviously always difficult to factor in. We have, obviously, more fuel in the tank when you think about some of the additional indication opportunities that are related, for instance, to Gamifant, but in particular, also to pegcetacoplan. And then the question is, obviously, in what kind of beat do we get with SEL-212, yes? Because if you basically follow the logic, let's say, give and take, forget about the international opportunity that is untapped by the existing main competitor, then you think, okay, even in the U.S., if there are 20,000 patients, the current competitor can reach 4,000 and reach is a certain sales line, maybe there is more possible than what we are currently guiding on. But as we like to deliver what we promise. That's basically, I think, for others to judge, and obviously, we are not going to sit still, relax and enjoy the ride and just become executor on what we have, we will be very thoughtful that we can deliver what we have. But we will -- obviously, our business model is predicated on looking for new opportunities to integrate either companies or products. So we want to continue, let's say, on that ride to be a consolidator in the rare disease space in our areas of expertise.

Thank you. Operator, I'll open back up for you.

Our next question is from Eun Yang from Jefferies.

I have several questions. So first, a question to Ravi. So for Gamifant in hematologic HLH. So you look like you would need to do a pivotal study, enrolling 30 to 40 patients. So can you talk about your discussion with the FDA and kind of like a trial timeline? And I think in one of your slides you show data in 2022. So can you give us a little more detail on that indication?

Yes. Thanks, Eun. We had a very fruitful and collaborative discussion with the FDA. I think the data itself is acknowledged on both sides. We don't need 30 to 40 more patients to get FDA approval. We probably need far fewer than that. We haven't had the full minutes through yet, but I would anticipate in a 30-patient trial, we'll be able to do an interim analysis after 15 or so patients and put that data together with the existing data in a package for the FDA. And that's our expectation at the moment. The reason that we talk about a bigger study for a pivotal is that we are sure that we can get global approval for rheumatologic indication in Europe -- potentially in China, et cetera. So the U.S. approval would come a lot sooner and wouldn't require all those patients. It would probably just require a subset. And we've had some further discussion on what sort of patients they would look like. But they were very comfortable with the trial design and very comfortable with the data, just more that probably need a few more patients to make a full package.

So would be interim data from the pivotal study being available in 2021?

It's still a rare disease, Eun. So we're looking at how long it took us to recruit the original 14. We know that there'll be interest in recruitment. And we know that there'll be a number of centers, both in the U.S. and outside the U.S. that will be interested in participating. I think we'll expect to see data in 2022 rather than 2021.

Okay. And I have one question to Henrik and then another question to Guido. So for 2025, you laid out the revenue goal of about $25 billion. So with the expected EBITDA margin acceleration, what is your goal for EBITDA margin in 2024? Would that be reasonable to assume that it's going to be 45% or higher? And then a question to Guido. So currently, the U.S. business accounts for about 35% of the total sales. So what do you expect that to be by 2025? And also you're planning -- any plans for the U.S. listing?

Okay. When it comes to the margin, what we expect is an acceleration in margin from 2023. We are not guiding on the margin in 2025, but we expect it to be strong. The second question?

I think that -- this was, I think, what the 2024 situation. And then the second question was regarding how we think about the U.S., and that what, I think, directed to me. Or how do you want to do this? We can...

No, no. You go ahead.

Yes? Yes. Is this okay? So we basically, we -- the way we basically think about the U.S. The U.S. is going to be, for the next 3 years, a primary source of growth, simply because it's the largest business now that we have. And simply because we have the 2 key products, Doptelet and Gamifant in a full launch phase. And also, you can see the momentum. When you look at some of the slides, discounting now for 2 seconds, price adjustments, I think it's becoming very evident that the product has been coming -- has been going through quite a significant growth phase. And that basically, once price is stable, will obviously result in the right, let's say, further expansion of the product. And the same would apply to Doptelet. Now basically, this -- having said this, I would be personally disappointed, basically, if the U.S. is not at one stage approaching -- I mean, 15% is maybe a big word, but moving from 35%, for sure, over the 45% range during the planning period. And which is, to be honest, is normal. And then what it means is that basically, we become more like another -- other rare disease company that basically follows the economic potential for many of these products. And basically, and we now need to create preconditions in the U.S. so that we sufficiently power to take advantage of the opportunities ahead of us. So that's basically what we are currently trying to do. And basically, the -- from my perspective, we think that we are actually well positioned for this, let's say, you can see the reason. And let's say, the -- from a -- I mean we have not broken the duck up as much that you can see exactly how much growth comes from the U.S., but it's clear that the primary driver sits there. Eun, there was another angle to the question that I may have omitted. I'm sorry for this. Was there another part of the question?

Yes. So the question is, obviously, U.S. business is growing and becoming more important part of this...

The listing part, yes. Yes. Yes. I mean the -- I mean it's always -- we have not concluded as a company so that we can announce anything, but it hasn't escaped our mind that companies that look like us and have a benefit from a dual listing, let's say, have a higher market capitalization than us. And that basically is something we will look at, but it's premature to comment at this stage.

And our next question is from Emily Field from Barclays.

I just have a few very quick questions. Just -- I was just wondering if you could comment on how you saw hemophilia A market shares trending until 2023 when you launched 001, when it would seem that you would expect shares -- to have some share gains? And then also just for Doptelet, do you expect the potential introduction of the FcRn class to have any impact on the competitive dynamics there? Would those be used on top of drugs like Doptelet? And then just piggybacking on that U.S. listing question. Would -- I know there's obviously different mechanisms by which potential U.S. hosting could occur, is an IPO something that you would consider, which could potentially be a source of funds for potential M&A?

Yes. I mean maybe I'll start with the easier question. Let's say, basically, how do we view, let's say, our hemophilia share. It's clear that the primary driver sits here. There was another angle to the question that I may have omitted, I'm sorry for this. Was there another part of the question?

Yes. So the question is, so obviously, U.S. business is growing and becoming more important.

The listing part. Yes.

Yes.

Yes. I mean, the -- I mean, it's always -- we have not concluded as a company that we can announce anything, but it hasn't escaped our mind that the companies that look like us and have a benefit from a dual listing, let's say, have a higher market capitalization than us. And that basically is something we will look at, but it's premature to comment at this stage.

Operator, do you want to take another question?

And our next question is from Emily Field from Barclays.

I just have a few very quick questions. Just -- I was just wondering if you could comment on how you saw hemophilia A market shares trending until 2023 when you launched 001, when it would seem that you would expect to share -- to have some share gains? And then also just for Doptelet. Do you expect the potential introduction of the FcRn class to have any impact on the competitive dynamics there? Would those be used on top of drugs like Doptelet? And then just piggybacking on that U.S. listing question. Would -- I know there's obviously different mechanisms by which a potential U.S. listing could occur. Is an IPO something that you would consider and which could potentially be a source of funds for potential M&A?

Yes. I mean, maybe I'll start with the easier question. Let's say, which basically, how do we view, let's say, our hemophilia share. I mean, I think what we clearly can see is that on the Elocta basis, obviously, we think that we can further expand our share, I mean, from a high basis of 35% in COVID patient. In Elocta, I think -- and on a patient basis, I think we can still do better. And we still see, let's say, actually positive signals in this regard. Okay? We have a very committed team. We believe that we have the best product in our stable, so we will go for it. How this is economically then looking like? That's always the million-dollar question because more competition, that doesn't necessarily mean higher prices. Because that's something that is a little bit the unknown. But we believe that we are, at least for next year, that we can further, in, let's say, gain more share in the patient community, based also on our current trending. And let's say, and then basically, how will this look like in 2022, well, I think, will have to be seen. But I think it is fair to say, and that's the reason when you look at our foundation business, the way, basically, we look at it, the main growth is going to come from the new products. And that's always the reason you -- and that's the reason why we guided you towards looking at the growth of hematology as opposed to hemophilia. Whilst we are optimistic about, obviously, hemophilia, if you elevate yourself more, let's say, look at it from the long-term perspective. We think we're going to be fine. You may have 2022, I mean, if I could predict 2022, I mean, to be honest I would be -- I would feel very gratified. Yes? And may not be even here because I probably could make much more money elsewhere, yes. But by the same token, I think the -- we have to be just realistic that this is a foundation business. We have to build the other businesses. We have to expand our opportunities in new markets, and then we're going to be fine. Regarding the -- regarding Doptelet, we think based on the current trending, I mean, we -- and hopefully, the -- let's say, the centers will open up to more face-to-face interaction that our trending was going to be pretty uninterrupted. And let's say, and to what degree we were then thinking about co-medication or partnering. I think it is probably at this stage, a little bit premature. We were obviously -- we'll use this at a given point of time. But we think that the value proposition that we have today with Doptelet is strong enough, let's say, and we also think because we can see, once we have face-to-face interaction, once we have a more intense interaction, we can see relatively quick responses because we -- the product profile and the advantages related to it is -- are so intuitive. So that, therefore, let's say, we are quite bullish about this. As far as this thing is concerned, to be honest that would be not, I think, serious from my side. Because it would be rather speculative in what kind of model. We will -- obviously, as I said, we have figured this 1 out. And let's say, we also take pride, to be honest in how much value we are creating as a company, and we are not oblivious to the fact. So we will look at the different areas but there's nothing that we can really guide you on in either direction.

I've got a couple more here. A China question. I'm not sure whether you can answer or whether we need Norbert. The number of patients that we showed for HLH and HT-1, is this the total market or realistically accessible patients for Sobi?

Nobert's coming up. Just a moment.

So yes, thanks for the question. I'm happy to clarify. This is a total market potential. These are the patients that are currently identified. Having said that, as there is currently no existing treatment for HLH or no approved drug. We're also talking about disease, that is better and even more investigated every day, and we expect much more dynamics in the development of the real patient numbers. So what we have right now is an estimate based on what is known today. It is probably rather dynamic upwards. It's really early days. And you are to multiply the number of people with existing prevalence, maybe taking -- the closest being Japan. Obviously, that number is -- looks more conservative, yes.

And then I think this 1 here for Ravi. Ravi? So we mentioned the potential approval in the EU for BIVV001 of 2023. With the primary completion of a pediatric study expected late '22 and standard review timelines of a year, this seems like an optimistic assumption is 2024 more reasonable?

We're looking at the regulatory strategy in the EU. At the moment, there's still some discussion ongoing. Remember, well, really, all we'll have to do is add on the pediatric data to the existing adult data. So we don't think it's too aggressive to be projecting to 2023 for the EU right now.

Thank you very much. I'll give them 1 more quickly, operator, and then it's back to you. And I think we've probably touched on this, but the 2025 goal is that sales number adjusted for the probability of success of our future products.

Yes. I mean, that's the reason why gave a small range. Yes, we adjusted for this because we are fully cognizant about the fact that you will ask us about this number as we go along, yes, over the coming years. So it's just the reason why we set it out.

Thank you. Operator, back to you.

And our next question is from Christopher Uhde from SEB.

So I have a number of questions. I think I'll start with Gamifant, if you don't mind digging into some detail right away. So on GVHD, can you -- so explain a bit more why you talked about going for patients resistant to standard of care, which I can only presume is ruxolitinib. The reason I ask is because, I guess, they use the same downstream mediator or they target in downstream mediator effectively JAK1, 2, right? That's my first question.

Yes. So I think there are 2 approaches we could take, Christopher, and thank you for the questions. We can either go for second-line patients and effectively go head-to-head with ruxolitinib. In which case, I think CXCL9 becomes quite critical or we look at ruxolitinib failures. And there is good evidence that in multiple different diseases, even if 2 medications are by and large, targeting the same pathway, failure of 1 doesn't necessarily predict failure in the other. So we're looking at the different options of second and third-line patients. I mentioned a natural history study in the presentation. And I think we need to get a much better understanding of exactly what's going on in GVHD patients. And obviously, with ruxolitinib and you relatively recently approved, we need to try and gather data on patients who had ruxolitinib and who have either failed or relapsed following ruxolitinib. So that's part of the work that we'll be doing over the coming few months. But I think the answer really is we probably got 2 approaches we could take. One in second line, head-to-head against ruxolitinib and 1 in third-line in patients who have either relapsed or failed ruxolitinib.

Okay. And that leads me to my second question on Gamifant. So can you comment a little bit on the biomarker impact as well as the potential impact, let's say, on study design, particularly endpoints in indications for Gamifant in general, not just for this. But also then on -- to what kind of data do you have at present in terms of how it would affect the addressable market, if there would be a label based, let's say, purely on biomarker expression for at least everything but primary HLH.

So in primary, I don't think we're expecting a label that's based on CXCL9 expression, if that's where you're going.

Exactly.

So that's not really in our thinking. I think more is a better understanding of primary HLH from a genetic perspective. Because whilst gamma interferon, obviously is a key driver, it's not the only driver of primary HLH at the cytokine level. We know there's a very clear response to Gamifant in 60% to 70% of patients, but obviously, not all patients. So I don't think we can couple CXCL9 levels with response to treatment for Gamifant. And it be -- given the numbers would be a pretty tough trial to do. I think graft failure looks a little bit different. That data I showed you from Italy has a very clear early elevation of CXCL9 and it tracks very closely with those patients who subsequently undergo primary graft failure. And so we'll have a much better idea about that. I think in part, your question was, would there be other indications that get unlocked by a good biomarker of CXCL9 and that's something that could be...

Well, I'm also wondering about the RHLH and infectious HLH.

So infectious HLH, I think is probably a more complicated story and that's what we're trying to unpack. I think there's going to be this balance between what sort of infection. For example, we've learned a lot or we're learning a lot about COVID-19. We know EBV is a key driver in Japan. And we also know that genetic predisposition plays a role. And if somebody has got potentially quite high penetrants of 2 genes, they probably don't be much of an infection to develop HLH. Other people may need quite a severe infection, and I think with a spectrum, as I mentioned in the presentation. For RHLH, we're looking at CXCL9 more as a PD marker rather than a predictable prognostic marker. And so there, I think what I showed you was pretty prompt reduction in CXCL9 in response to Gamifant. So I think, to summarize all of that, CXCL9 is probably on certain diseases, is going to be prognostic. In certain diseases, it's going to be predictive. And in most, it's going to be a good PD marker of response to Gamifant. So I think we're looking at having multiple options. And I think, again, a lot of biomarkers fall into more than 1 category. So that's how we're thinking about this.

Okay. And then when it comes to SEL-212, I have basically 2 questions there. The first, you talked about potentially building on the program data, on the existing program for more trials to build out the data. And I just wondered if you could give any kind of sort of time scale on that? I mean, are we talking about trials that could potentially read out ahead of launch already? Or is this more of a long-term aspiration? That's the first part of it, yes.

Yes. Sorry.

No, I mean, you can answer. But I think we have -- right now, we have the Phase III program that Ravi has described. Obviously, this is not going to be a one-hit one wonder. We are committed to the franchise. As a consequence, we will expect that we will have further trials that will read out also post-launch. I mean, I think anything else given the opportunity in front of us would not be reasonable. But I don't think we have, at this stage, trials that we can announce. I mean, maybe -- well, Ravi.

No. I think in short, Christopher. If we think about access rather than approval, particularly in Europe, then we may need further data, and we're just trying to evaluate that through kind of more payer based research that's going on right now. So we're probably in a position to comment on that in a little bit more detail over the coming months.

Terrific. And then the second SEL-121 question that I have is -- so when it comes to at least with European commercial opportunity, I guess, the orphan designation works differently in Europe than in the U.S. And so 1 sort of argument to why it will be more challenging in Europe would then be -- while you won't be able to salami slice down to chronic refractory gout or tophaceous gout in the same way you could in the U.S., which has been why Horizon didn't go there. So could you perhaps comment on well, why you might expect to get an orphan designation? What particular aspects there are that you can leverage to do that? Or if you don't plan to go for orphan or whether either 1 is a possibility.

I think, Christopher, I mean, we are not -- I mean, this is something we would like to diverge, let's say, to you at a later stage because there's -- I mean, as you understand, we are now having this fantastic partnership with Selecta for the peaks that we have indicated, clearly, you don't need Europe. I think it's very -- it's a fair assumption. Let's say, and we would come forward with the European plan, I think, in due course because we are currently doing various research, payer research. We're obviously getting really into the depth of it. And then we'll let you know a little bit more. And also when we look at this from a different angle, on how to leverage this given our aspiration for entry into Japan and maybe other markets. So I think it's -- so we -- unfortunately, we cannot answer all questions maybe today.

No, no, that's very understandable. And my last question then would be, can you comment on what it would take coming back to Gamifant to -- well, for the Nacho guidelines to become the way that yes, that payers see reimbursement in the U.S.?

Yes. This is a continuous program. I mean, Ravi pointed out, we are collecting genetic data. There is this overlapping area when you look at -- you probably have in mind Ravi's slide, where you show the 2 spectrums, many of the infectious related HLH patients would probably not -- and we know this from, obviously, external sources, do not get a secondary HLH because they wouldn't have had a dramatic predisposition or the disorder. As a consequence, we are -- this is a very flux process, and we're obviously trying to expand further. And we wish to now -- we could now already show you the formula on how this works. We are working on a registry. It's a combined effort with KOLs. And then at the right time, let's say, the forthcoming months, we'll have a discussion with the regulator and see how this sits, and then we will update you, obviously.

I think we have time for 1 more question, don't you, operator? Short one.

And our next question is from Peter Saddle from Handelsbanken.

It's Peter Sehested.. Fortunately, it's not short because I have three. I'll start with the first one. Do you expect Elocta sales to grow next year? With ex synergies, the season looks weak, as you've said, could you sort of hint as to what we should expect in Q4? I know it's a bit specific. So you might not do that but just to get some flavor on that one. With respect to Gamifant, consensus is that [ SEK 1.3 billion ] for 2022. That seems very aggressive given the approval timelines that you have set forward. I mean, is that an achievable target? And if so, should we view it as very, very back-end loaded towards '22. That is my first question, then I have 2 after that.

Yes. I mean, Peter, it may not totally surprise you that, obviously, at this point of time, I cannot comment on Q4 as much as I wish, let's say. And we would basically, also with the outlook for next year, I think you will find our guidance on the 17th of February for both product Synagis and Elocta much more, I would say, insightful. And it's not like I don't want to tell you, it's just the way, let's say, I guess, it works. And with regard to Synagis, don't forget, yes, daisy, with a low virology, but there is also an improved approach from our team to it and the jury is still out, I mean it's -- on how this is going to play out, but we wanted to make sure that you understand that there is a bit of adversity. And so I would, to be honest with -- I would rather refer those questions when we discuss the Q4 report because, I mean, I understand that this would be interesting, but I'm afraid that I cannot answer it.

And I guess, I think the same would apply for Gamifant. So I mean, I apologize, hybrid nature of the questions. I'll just jump on to the other 2 basically for Henrik, I would guess. I know you don't have to talk, let's say, about the specific cost components for SG&A, or at least not pertaining to the margins. But could you give us some flavor on sort of the components that go into the increase? Could you talk to about how much you expect your number of employees to increase by now in 2023? Could you add some flavor on, let's say, from an index 100 of the additional costs that you're going to put in, how much of that will be increased employees, how much of that will, let's say, be incremental overhead marketing spending, et cetera, et cetera? Just to give us something to go on when we model the costs for the next couple of years. And I will reserve the last questions till afterwards.

Yes. I mean, my answer is similar to Guido's. We don't give that granularity on the guidance. But it's important to note that we, of course, continue to invest in Doptelet and Gamifant. And we have prelaunch activities coming up in this period. But as I said, from 2023, we expect to see operating leverage as we have expect strong growth on top line. But further than that, today is not the day for that. Thank you for asking.

Cool. And the last question goes to the M&A. Overall, I want to say that a successful M&A is more successful if it sort of leverages on the existing infrastructure. So far, your acquisitions have led to substantial infrastructure increases. When you talk about let's say, the potential for further M&A and you look at sort of where you move your cost base going forward, at least for the next couple of years. Are you thinking in ways that such that you are preparing for potential M&A that is more, let's say, leveraging your cost base and adding to the cost base in the near term? So just if you are sort of thinking in those directions?

Yes. I think in M&A, we have -- when you think about historically how it has worked out for us. Synergies was a very strong enabler for quite a few deals that we have been doing now that gave us a funding and, let's say, the earnings to do a lot of things and allow -- and be able to afford a couple of bets for the future. And we hope that you like what you have seen. We have a very strong growth profile, granted not tomorrow but in a foreseeable future. So we would look -- we would now look at this and say, do we -- should we think about on-market in order to create the space. But what we did definitely don't want is make a serious commitment on assets that are not growing just to basically change a little bit the economics short term. So we want to relatively quickly feel the beat of double-digit growth and that basically gives you so many options, and we will -- but we will screen further at the right time. I think when you look at the current programs, this is a very ambitious program. I think we are thoughtful on how we -- how much we do ourselves and how much we can collaborate with. And I think that makes it a much more realistic way to think about it. And when you have -- and then -- and obviously, the big question is how quickly can we get operating leverage? I think this is very important. And we are mindful of this, obviously. So that will be on the back of our mind. I mean, you have seen the, let's say, I think, how we guided towards an inflection point in 2023. And you will have not forgotten this. So the more we do acquisitions that there a synergistic effect is, and as I think it'll be -- alluded to the fact, when you think about Pegcetacoplan in the hematological indication and Doptelet have a certain affinity and share a similar customer base. So there is a synergy. Clearly, there's going to be a synergy between the new Gamifant indication and the TMA HSCT from Pegcetacoplan. So we are, let's say, already seeing forging these synergies as we go along, and these will be synergies on an R&D level, but then also synergies eventually that will translate into operating synergies in the field. I mean, obviously, until you see this in the P&L, and you can ring-fence, those synergies will take a bit of some time, but that's clearly in our mind, okay? That's the reason why we think hematology and immunology feels good. I mean, we don't need to think, to dream too much more because there's so much more that we can cover. So many more opportunities that are already related to our existing franchise, which we can further extend. And the more we build on where we come from, in the core, the more, obviously, the leverage you will get in different functions. So thank you. Yes. I think it's time for us then to wrap up. I mean, obviously, we would have loved to have you in this room, feels a little bit lonely here in -- and get a little bit more of a personal flavor here. I think we make it work. And I hope you find this insightful, and we let you in a little bit into the thought process and how we want to build our business. Granted, we cannot answer in this format all the questions that you have. Sometimes we cannot answer them period because we are not supposed to. Sometimes, the time will not allow. I would say, if you have other questions and you want to register, maybe follow-on meetings, please contact Paula and our IR team. And then we will try to facilitate meetings with the respective management team so that we can give you a full disclosure. We just wanted to leave you with a thought. We are bullish about our future. We are not dreamers. So we recognize there will be also some headwinds that we need to take into consideration. But overall, this is -- it feels good to be part of this company. And we have a very positive outlook. And what remains is really to thank you for your interest and for your support over the last year. And I think it's -- for many, maybe it's already time to think about Christmas. I know that in some countries, you're even encouraged to think about Christmas. Let's say, on this note, I wish you all the best for the festive season and look forward to seeing you very soon. Thank you so much. I wish you a great time during the change of the new year and see most of you, for sure, in 2021. Thank you.