CSL Limited (CSL) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to CSL's Annual Research and Development Briefing. Online with us today is Dr. Bill Mezzanotte, Executive Vice President, Head of Research and Development and Chief Medical Officer. He'll be joined by several of his senior team. Also joining us once again is Bill Campbell, Executive Vice President and Chief Commercial Officer. Bill will be providing us with some market insights on CSL's product portfolio. Please be aware this presentation as well as the Q&A session is being webcast. And lastly, before we start, I draw your attention to the forward statement disclaimer within the slide deck. I'll now pass you over to Bill Mezzanotte. Bill?

Thank you, Mark. Hello, and welcome to all of you wherever you may be in the world. I have the privilege of hosting this event once again this year, and I hope you're all doing well and still coping with the challenges of COVID-19. Speaking of challenges for the first time this meeting is virtual, another unprecedented experience for all of us in a year of unprecedented events. Nevertheless, we're excited to be here today to report to you on the progress made by R&D over the past 10 months since we last reported in December in Sydney. I'm happy and proud to say that we continue to advance our novel research portfolio across our 4 strategic scientific platforms, spanning 6 therapeutic areas and 2 businesses, intended to help patients lead full lives, protect public health and support the growth of CSL. We continue to seek ways to improve upon our current manufacturing processes that yield -- that improve yields while retaining the quality attributes of our important influenza products, PRIVIGEN, HIZENTRA and others. Understanding these businesses, as we do, yield improvements become very important and something we work on every single day because we know how valuable are the starting materials we use. Something we do not take for granted. However, the process of improving an existing commercial process can be complex and even minor processing changes have the potential to impact key process and quality attributes. So like many things in R&D, while we work on these projects every day, the completed product often takes years to finally be realized. But there are other many great things to talk about today, both projects beginning their journey and others having either successfully delivered or getting closer to realization. So let's get started with the next slide, and I'll just show you the agenda. And this year, we plan to run our events slightly different than in years past. We'll have 1 continuous session with 1 extended Q&A session at the end rather than 2 sections as we've had in the past. We've also shortened the duration some due to the virtual nature of the event. And with the shortened time and the fact that we've had a secure specific update the past 3 years, we've elected not to have a separate update on their portfolio. However, we will mention some of their progress along the way. And of course, the collaboration effort with the University of Queensland on a vaccine for COVID-19. This year, you will once again hear from Andrew Nash, now both our Head of Research and Chief Scientific Officer; on our early portfolio and our high-quality scientific efforts. Andrew will also give you a brief update on the COVID vaccine. And of course, you will hear from our Chief Commercial Officer, Bill Campbell, on select commercial topics of interest to this audience, understanding that R&D Day is not meant to be a result free hash. I also have the pleasure of letting you meet 2 of my talented team, both of whom lead important efforts. Mittie Doyle is our R&D Head of the Immunology TA. And in the short time she is available to her, will show you the breadth of activities ongoing in our immunology TA and also update you on other important COVID activities. And Laurie Lee, our R&D Head of the Transplant TA will discuss in depth, both our investigations of Alpha-1 antitrypsin in graft-versus-host disease, and discuss clazakizumab for antibody-mediated rejection following kidney transplant. Hopefully, this will give you a better appreciation of the logic behind these trials and also demonstrate the scientific understanding we have been able to develop since deciding to make transplant one of our therapeutic areas. So let's get going on the next slide, please. So our geographic footprint has remained the same since our briefing last year. We span 4 continents located in geographies that enhance our collaboration and are important to our business. As Andrew will show you, we have also been focusing on upgrading our facilities in those locations to enhance the environment for our own scientists as well as our collaborators. Speaking of collaborators on the next slide, we continue to expand our external partnerships, which is an intentional part of our strategy. No company, no matter how big or successful can pretend to think they will cover all the innovative work that science offers or that a business needs. Our relationship allows us to access those ideas. And by concentrating these partners in proximity to our R&D centers, we're able to create the sort of 2-way scientific relationships with our partners. This allows our own scientists to be actively involved in these programs regardless of where they sit, which is a quality all of our collaborators mentioned as an advantage working with CSL. In this way, collaborators know that we will give their innovation the proper priority and active problem-solving that every promising idea needs to succeed. Next slide, please. As in previous years, our spend in R&D has steadily increased. This additional spend reflects all the excellent opportunities we have uncovered. And this is evidenced by the majority of the spend increase coming from new product development. This is, of course, important for CSL to continue growing into the future. Importantly, this increase in spend remains within the 10% to 11% envelope of revenue that we have communicated before. We accomplished this feat through a thorough stage-gate system that evaluates new spend by looking for cross TA clinical and research efficiencies as well as other cross-functional operational efficiencies. And we look towards the external environment for creative expansion of our capacity and capabilities. Next slide. This slide may be familiar to you as we showed it last year as well, depicting our 6 core therapeutic areas and our 4 major strategic platforms. The only minor changes here are simplifying of our nomenclature, revising the name of immunology and neurology to just immunology, and revising hematology and thrombosis to just hematology. Rest assure, both of these only reflect the name change and do not indicate any change in focus in these areas. We continue to build out our 6 therapeutic areas, adding scientific, clinical and commercial depth each of them. And we also continue to build our capabilities in our scientific platforms. In plasma, we continue to focus on new products, indications, formulations and devices as well as other breakthrough innovation. In gene and cell therapy, we are building both our internal capability to create a viral vector gene constructs, but also our manufacturing capability. And we continue to expand our external partnerships in this space. And later, we will talk more about this. In the recombinant protein space, Garadacimab is the first monoclonal antibody developed internally to enter late-stage development. And as you will see, seeing here is a good one. With our vaccine platform, our work continues to progress on improving the manufacturing yield associated with our exciting cell-based vaccine. Great examples of how our depth and breadth in the 6 therapeutic areas and 4 platforms is starting to pay dividends, would be the agreement to acquire the license rights to EtranaDez. And the acquisition of the tariffs for our rights to clazakizumab. Both of these point out how our therapy areas have identified the right external innovation to strategically complement our in-house capabilities. But perhaps the best example of how our therapeutic and platform and business expertise is paying dividends is our ability to join forces with the University of Queensland on their vaccine. This is a joint effort of both Seqirus and CSLB and requires the know-how of our recombinant protein group, our vaccine manufacturing and the research and clinical know-how of both organizations. Next slide. Here was the high -- portfolio we highlighted in December of last year. And for the first time, we showed you that portfolio using our therapeutic area colors and has showed a robust pipeline with a number of opportunities across TAs and platforms. And we've made progress from that portfolio, as I'll show you on the next slide. There are many things we could highlight in FY '20, and many of them are depicted on this slide. Here, you see that internal progression, acquisitions and alliances all contributed to advancements across our strong portfolio and across our therapeutic areas and business. In immunology, we had a U.S. pediatric approval and a Japan Phase III start for HAEGARDA. Our HIZENTRA Phase III study in dermatomyositis also began and for Garadacimab, an exciting internal offering, we shared encouraging Phase II data in June, and you'll hear about the start of the Phase III trial. In hematology, in December, the first patient with sickle cell disease was selected and began prep for infusion with successful apheresis. And the patient was then infused with our gene therapy candidate, CSL200 in February. They are currently being actively monitored. The first-in-human study is being conducted at the City of Hope in Duarte, California and 2 more centers will be added in Q3 2020. Additional dosing has been delayed due to the current COVID pandemic and site challenges, but is anticipated to start soon. We also initiated another offering for sickle cell disease. This time, a plasma product hemopexin, targeted at the treatment of disease rather than prevention as for CSL200. In respiratory, CSL311, a monoclonal antibody against the common beta chain of the IL-3, IL-5 and GM-CSF receptors with the potential in a number of inflammatory conditions began Phase I with a lead indication for severe uncontrolled asthma. In cardiovascular, our apoA-I program, CSL112 continues and past its first futility analysis. And in transplant, we completed the dose-finding portion of our adaptive Phase II/III study using Alpha-1 in graft-versus-host disease. Seqirus is AUDENZ vaccine for potential pandemic associated with H5N1 flu virus commonly known in bird flu, was improved by FDA in September 2020. AUDENZ is designed to be rapidly deployed to protect the U.S. population. It can be stocked for the first responders in case of a pandemic from our Holly Springs facility in North Carolina. AUDENZ is the first cell-based influenza vaccine, which is made by combining Seqirus' MF59 adjuvant and cell-based antigen manufacturing, which gives us an opportunity to be produced quicker and to use less antigen and, therefore, as doses go further, which is a great quality in pandemics. And finally, on the collaboration front, we're collaborating with Seattle Children's Research Institute to develop stem cell gene therapy using our Select+ technology that you'll hear about from Andrew in a moment. And we agreed to acquire exclusive global license right to commercialize the EtranaDez gene therapy program from uniQure, which is currently in Phase III clinical trials, and this treatment could be one of the first gene therapies to provide potentially long-term benefits to patients with hemophilia B. Of note, this transaction with uniQure is subject to customary regulatory clearances before closing. So we won't be able to comment much about it on today's call. We also acquired Vitaeris, which included clazakizumab and anti-interleukin-6 monoclonal antibody, currently being studied in the IMAGINE Phase III trial for the potential treatment of chronic, active antibody-mediated rejection. And similar to Garadacimab, we believe clazakizumab has great potential in other therapeutic areas. Lastly, our collaborative mindset and organizational agility that have enabled us to build a robust pipeline have also been underscored in our response to the COVID-19 pandemic. As you have seen, we have a strong acumen in vaccines, monoclonal antibodies, recombinant technologies, manufacturing capabilities and external partnerships. And we have for all these to bear in searching for a potential solution in the world's fight against COVID-19. And you will hear about these as well. Next slide. Here in this slide, you see our launches in 2020, which were focused mainly on important quadrivalent vaccine launches in the U.S. and EU, important label expansions for IDELVION and a broadening of the PRIVIGEN label in Japan to represent the full range of primary and secondary immunodeficiency indications. Over the past 5 years, launches of substantial new products and indications have contributed significantly to the well-being of patients and to the growth of our business. Next slide. I showed you the slide on market spend and much of the fruits of our market development and life cycle management spending efforts are depicted on this slide, where we highlight the ever widening reach of our rich exciting portfolio to new geographies. CSL Behring continues to broaden the geography and use of our medicines for rare diseases across the globe with numerous regulatory approvals in immunology and hematology. This year, we also received orphan drug designation approvals in the U.S. for Garadacimab in HAE and CSL964, our Alpha-1 antitrypsin deficiency treatment for prevention and treatment of GvHD. Within the immunology portfolio, regulatory indication expansion and new registrations are primarily focused on HIZENTRA, PRIVIGEN and HAEGARDA. We expanded HIZENTRA label for maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy, or CIDP, to prevent relapse of neuromuscular disability impairment and widened to countries such as Mexico, Brazil, Thailand, Singapore and Taiwan. Additionally, 7 new product registrations were achieved for each of HIZENTRA and PRIVIGEN, and lastly, in immunology, the use of HAEGARDA has now been approved in the U.S. for pediatric patients as young as 6 years of age. In our hematology therapeutic area, the focus in 2019, '20 was the expansion of the current portfolio, IDELVION received key approvals and updated product label for 21 days expanded dosing schedule in Switzerland, Canada, Japan and had incorporation of these study results for the EU. Significant number of new product registrations were received in the Latin American countries and APAC for our recombinant Factor VIII and Factor IX products. For Seqirus, this year brought significant progress in broadening our influenza vaccine portfolio across the world to cell and egg base. Next slide. So here is a slide of our portfolio progression for 2020. We moved a number of programs into the clinic, as we said we would last year, including 2 exciting programs in respiratory. The previously mentioned CSL311 as well as our inhaled plasma-derived Ig program that start. In immunology, we advanced Garadacimab for hereditary angioedema into a global Phase III, which Mittie Doyle will talk about and also HAE into Phase III in Japan. In cardiovascular metabolism, we advanced -- we made the decision to advance CSL346 into Phase II for diabetic kidney disease. And CSL346 is a very novel VEGF-B monoclonal antibody with the potential to be combined with other antidiabetic agents to create better outcomes and avoid the devastating complication of renal disease and dialysis. And of course, we initiated a number of studies to address the sudden unmet need in COVID-19, including our vaccine, hyperimmune and monoclonal antibody approaches. These will be discussed during this session. Of note, none of these programs existed in CSL in February. But now they are all in the clinic, which shows remarkable resourcefulness and relentlessness of our team. Also related to COVID-19, I would be remiss to not mention the business resilience of our clinical trial teams this year. Over 70% of our portfolio was affected to some degree by COVID-19. Most requiring a pause in enrollment due to our clinical research partners being overwhelmed. While some of our programs have had lingering slowdowns, most have rebounded nicely and are recruiting again. This has been due to the remarkable focus and communication of our teams with staff all over the world and excellent planning for reinitiation when regions and hospitals allowed. I'd just like to take this opportunity to recognize my colleagues all over the world for their remarkable efforts. We did have a few disappointments this year as well. We elected to stop the CSL324, our anti G-CSF antibody program for acute lung injury due to COVID-19. While we were very excited about this, this was stopped due to a high level of competition at clinical trial sites for studying new modalities for COVID-19 and our own competing anti-COVID-19 programs. And the important fact that we still require proper dose exploration of this program to avoid any untoward results and the pandemic is a bad time to start doing dose response. This remains an exciting asset in both our immunology and respiratory portfolios. Due to changes in internal priorities and benefit risk considerations, CSL362, our anti-IL-3 receptor antagonist intended for systemic lupus erythematosus was terminated. Garadacimab, which we are progressing in respiratory disease, HAE and COVID-19 was held in the investigation of the treatment of certain thrombotic indications for commercial reasons. We had 2 programs in the study of systemic sclerosis, PRIVIGEN and HIZENTRA. The priority was HIZENTRA and it continues forward and has shown encouraging signs of absorption by these patients despite their skin disease. Thus, we have terminated the backup PRIVIGEN program. And finally, we've made the difficult decision to stop the CSL842 AMR program, also known as the ARMOR study, investigating C1 esterase inhibitor for the treatment of refractory antibody-mediated rejection. This trial has struggled the most with the ongoing and unprecedented challenge driven by the COVID-19 pandemic. Thus, we've carefully considered our options and believe the best course of action for patients in this evolving environment is to prioritize our efforts on delivering 1 study in AMR. Consequently, in consultation with investigators and our external experts, we have chosen to focus our efforts on the IMAGINE study and have made the difficult decision to terminate the ARMOR study. Our commitment to transplant is as strong as ever and the use of complement inhibition in the transplant space is still an attractive idea. We believe the data we have generated in ARMOR will be valuable and able to inform future studies evaluating the role of complement inhibition in AMR. Such difficult decisions of these are very important if we are to maintain our focus and to be excellent stewards of the resources that you, the investors have invested with us. Next slide. CSL112, as you know, is a short-term therapy administered during the high-risk period after a heart attack in addition to optimal medical care that includes other medications for secondary prevention. The ongoing CSL112 AEGIS-2 study is focused on treating those heart attack patients who are at high-risk of recurrent adverse cardiovascular event, such as another heart attack. Treatment has to be initiated within 5 days of the heart attack and the ongoing clinical study. Tended to demonstrate its benefit during the very high-risk 90 days after a heart attack, where other secondary prevention measures have not been able to impact. We more than halfway enrolled in the trial now. And the enrollment was briefly suspended in March due to the COVID-19 pandemic, but through the efforts of the team, sites have been reopened, and we are catching up quickly. And since our last update to you in December, Japan, a traditionally very strong cardiovascular market has joined the trial and are recruiting very well. As data accumulated during the course of the trial, the statistical inference has become more precise. So our second futility analysis is planned for the 2021 calendar year and allows another review of the data with more data and events having accumulated. So this allows for a decision based on more patient data, compared to the first analysis, thus a greater trend toward benefit is required to continue the trial. And so passing the second futility analysis is an important hurdle for the program. Next slide. So here is our new portfolio after all of that movement. Please note that in the early phase and particularly preclinical, this represents only a portion of the products. Still, we are nicely balanced across all phases of development across therapeutic areas and across scientific platforms. This type of balance gives R&D the greatest chance of success which, in turn, gives us the best chance of contributing to the business and delivering on our promised patients. And now I have the pleasure to turn it over to our Chief Scientific Officer, Andrew Nash. Andrew?

Good morning, everyone. Today, it's my pleasure to talk to you about our activities in CSL Research and how we work to provide the organization with a strong and innovative pipeline. I'll be touching on our work in respect of protein therapies, gene therapies and vaccines. Next slide, please. Our CSL Research, and here, I'm talking about both CSL Behring and Seqirus is a global team that exploits our internal and external expertise across 4 drug discovery platforms to deliver innovative opportunities in our therapeutic areas. And below there, you can see the figure that Bill used, which highlights our therapeutic areas and our technology platforms. Plasma, recombinant proteins, gene and cell therapy and, of course, influenza vaccines. As you all know, we have a lot of the expertise and a very strong track record in plasma and recombinant protein drug discovery and also influenza vaccine innovation. We are currently building our capability in cell and gene therapy. And of course, because of our history and our involvement in these areas across many of years, we have a lot of expertise and depth of talent within these TAs. I think really important from a research perspective, we have state-of-the-art facilities located in key precincts around the globe, which give us access to high-quality collaborations. In Melbourne, we're based at Bio21 in the heart of the Parkville precinct. In Bern, we're located in the CTM Institute, which is on the University of Bern Campus. Our Seqirus research in Boston is also very well-located in terms of our ability to collaborate. So really a well-structured organization with great facilities located to optimize our ability to collaborate. Next slide, please. Now our sector to a large extent is all about the competition for innovation. And of course, while we have a very strong record of internal innovation within CSL Behring, it's very important for us to effectively access external ideas and discoveries. We have a research external innovation group, which focuses on sourcing this innovation for us, and they have developed the strategy outlined here. The strategy leverages off the location of our key research sites to firstly, establish strategic partnerships with universities, medical research institutes and hospitals. And I've provided a couple of examples there. We have a long-term collaboration and strategic relationship with the Walter and Eliza Hall Institute here in Melbourne. And just recently, we have established a strategic alliance with the Seattle Children's Institute in terms of our gene therapy work. Beyond the universities and medical research institutes, we know that a variety of other businesses are looking to develop new technologies. So in addition to that work that we're doing with our academic partners, we have also partnered with venture capital funds and those that seek to support early-stage research programs through stage funding. We are an investor in the Medical Research Commercialization Fund here in Melbourne, and we sit on the investment review or say all of the opportunities that come through for funding there with the option to co-invest should we choose to do so. More recently, we've entered into relationships with a number of groups in Switzerland, both Biopole and Baselaunch. We expect these interactions to provide us with early insights into the technologies and innovations being developed by small biotechnology companies within these areas. Some examples of our partnerships with biotech companies are shown at the bottom there, where we've highlighted the relationship with Biosana Pharma and with Elektrofi. Both of these relationships are around the development of new formulations, which will enhance the delivery of some of our existing products. And of course, our research external innovation team participates in all of the partnering and other conference activities that give you insight into innovation occurring outside of our own business. Next slide, please. Now the purpose of this slide is just to demonstrate that we are effectively making use of the platforms that are available to us within CSL Research. So our plasma platform, our recombinant protein platform and our gene therapy platform are all delivering new opportunities for CSL, as you can see in the center there. A number of candidates, which provide opportunities for us within the therapeutic areas that we're focused. So across the 5 therapeutic areas within CSL Behring, you can see that there are a wide variety of indications that are opportunities for the molecules that I've shown. So we have these platforms, we've developed the expertise and we're deploying them effectively to deliver new opportunities, development opportunities for our organization. Where we're unable to pursue these opportunities ourselves, for example, just due to the competitive nature of our own portfolio or the fact that they might not necessarily fit with our strategic intentions, we look to further access value from the investments we've made by entering into partnering relationships. So over the last number of years, we've developed some very effective partnerships with ASLAN, who are developing our monoclonal antibody for atopic dermatitis. Recently, we've entered into an arrangement with Lassen. They're developing our IL-11 monoclonal antibody in fibrosis and oncology indications. And in the past, you would have heard me talk about the work we've done here with the Dental School to develop a vaccine against periodontal disease. Recently, with the MRCF, we established a start-up company called Denteric to pursue the development of that vaccine. And CSL remains an important shareholder within that company and participates to that development. So our own internal assets being developed by CSL plus assets being developed by partner organizations where we don't have the resources. Next slide, please. Now I wanted to provide you with insight into projects within our portfolio across the spectrum of very early to about to enter development. And in terms of the early portfolio I wanted to highlight this particular project, which is the outcome of a long-term collaboration between CSL, the Olivia Newton-John Cancer Center here in Melbourne and also the Doherty Institute. This collaboration has led to the discovery of important signaling molecules that activate gamma delta T cells. These T cells are important in immune surveillance for protection against cancer and also for the response against a range of pathogens. Importantly, we know that they can contribute to autoimmune disease in circumstances where their regulation is uncontrolled. The discovery of the signaling mechanism which activates these T cells was a major finding and was published in the Journal Science this year. What this enables us to do is to further pursue this target and the development of monoclonal antibodies, which can be used in 2 ways. As agonist as molecules that activate gamma delta T cells, we feel that they might be useful in an immuno-oncology setting where we can activate the gamma delta T cells to kill cancer cells. In an autoimmune setting, we're developing antagonist of this signaling pathway, which should be able to dampen the immune response. So a very exciting early-stage collaboration, which is the result of long-term investment and partnership by CSL. Now next slide, please. Looking at a project that has a little further progressed in our portfolio, we are seeking to identify and develop novel inhibitors of the complement system. The complement system is part of the innate immune response and provides an important line of defense against a variety of pathogens. However, when this system is activated in the wrong circumstances, such as in the case of autoimmune disease, it can drive life-threatening pathology. 2 well-known complement inhibitors that are shown here on this slide are our own plasma-derived C1 products and the monoclonal antibody C5 inhibitor eculizumab or SOLIRIS. We think that there's an opportunity to develop more effective inhibitors and that moreover, these inhibitors will be valuable in treating a range of pathology across CSL's 5 TAs. I've indicated there that we're developing an anti-C2 monoclonal antibodies and soluble CR1, both of which are upstream of the anti-C5 antibody, eculizumab, and which we expect to be more potent inhibitors of the complement system. And you can see that we expect these reagents to be useful in indications within immunology, transplantation, respiratory and cardiovascular. So an important pathway where if we develop antagonist -- effective antagonist, we can access a range of disease areas. So just moving on to the next slide. I'd just like to expand on one of those molecules that we're developing. CSL040, which is a soluble complement receptor -- soluble complement receptor 1. This receptor is also known as CD35 and it's the main clearance receptor for complement coded immune complexes. And in its soluble form is a very potent antagonist of this pathway. And indeed in the form shown at the top here and as TP-10, it has previously been into clinical studies in the setting of coronary artery bypass grafting, where it showed very promising results. While this development was halted for strategic reasons, our own scientists have developed a new version of this molecule, which has an increased potency of more than two to threefold. And which we have been testing in a variety of disease settings. Next slide, please. This shows some of our data with CSL040 in a model of delayed graft function. In this model, the kidney of the mouse is clamped to induce ischemia and then unclamped to allow reperfusion. This reperfusion causes injury, which is characterized by the accumulation of complement and neutrophils within the kidney and the appearance of creatinine within the urine. And you can see from the graphs on the right there, that 040 is a very potent inhibitor of complement deposition, a potent inhibitor of neutrophil accumulation and very substantially reduces creatinine in the urine. This program is progressing well, and we expect it to enter pharm toxin product development in mid-2021. Next slide, please. Now I'd like to touch on our work in the area of Factor XII biology. And Bill has already mentioned Garadacimab a number of times so far. CSL has been a global leader in this area of biology for many years now. And through our own work and the work of others, we know that the activation of Factor XII initiates many biochemical pathways that can play an important role in human disease. And you can see those pathways shown on this slide. They lead to many outcomes such as hemostasis, vasodilation, complement activation, fibrinolysis and mitogenesis and inflammation. And indeed, my colleague, Dr. Mittie Doyle, will be talking to you about the use of Garadacimab to treat pathologies resulting from both vasodilation and hemostasis. Vasodilation is particularly important in the context of hereditary angioedema. But in research, we've taken the next step and are looking for opportunities for Garadacimab in a range of other areas. And have data that supports its application in fibrotic disease, cardiovascular disease and inflammatory disease. And I'd just like to show you an example of that data on the next slide. This is a model of pulmonary fibrosis in mice. We introduced pulmonary fibrosis by the intratracheal administration of bleomycin, and we can measure the fibrosis process by the accumulation of hydroxy appetite within tissues. You can see from the data here that the use of Garadacimab or its mouse equivalent, 3F7, reduces fibrosis in this mouse model by quite a large extent. And this level of reduction is very effective compared to a range of other molecules that are used in this model. Beyond testing in mouse models of disease, we have gone on to try and translate these findings into the human disease setting, where we've been studying tissues and plasma samples collected from patients with idiopathic pulmonary fibrosis. And we've been able to see that in patients with progressive disease, you can observe higher levels of Factor XII in their plasma compared to patients with stable disease. And in fact, when we look at the lungs from patients with IPF and we compare those to normal lungs, we can start to see an accumulation of Factor XII within those lungs. So our mouse data -- our mouse model data shows that targeting Factor XII can be effective in pulmonary fibrosis. And our human translational data indicates that Factor XII is there and present in disease tissues in humans. We think this is a really exciting observation, and we expect to commence a Phase II study in this indication in the second half of 2021. Next slide, please. Now I did want to touch on the work we're doing in gene therapy, and there's been quite some progress made since we updated on this last year. As you know, there are a number of modalities for gene therapy. And the 2 we're going to talk about today are both cell-based delivery and the direct delivery. In cell-based delivery, we use lentiviruses to infect hematopoietic stem cells and then we reconstitute patients with those transfected CD34 positive cells. In direct delivery, we deliver the gene of choice using an adeno associated virus. And when that virus moves into the blood into the liver or other organs, it's able to express the gene of choice. Now as you will know, the technology -- our technology, cell-based delivery, the Select+ technology, for example, was acquired as part of our Calimmune acquisition. And we have been pushing forward with CSL200, as Bill has mentioned. But importantly, we've looked to expand beyond sickle cell disease. And to enable this, we've established a collaboration with the Seattle Children's Research Institute. This institute is a world leader in both preclinical and clinical gene therapy using lentivirus-based systems. So we think this collaboration really brings CSL forward in terms of our expertise and our capabilities. And we're using the collaboration to address 2 important primary immune deficiencies where the underlying gene lesion is very well understood. So together with Seattle Children's, we're pursuing cell-based gene delivery, lentivirus gene therapy in both Wiskott-Aldrich syndrome are using our own lentivirus in the Select+ system and targeting XLA, - X-linked agammaglobulinemia, using the Seattle Children's lentivirus. And we expect both of these programs to commence clinical studies in 2022. Now I should point out at this stage that with Wiskott-Aldrich and XLA are both very rare conditions and make up only a minor proportion of the total PID population. The majority of patients have common variable immune deficiency where the underlying genetic lesion is unknown. And these patients, of course, will be -- continue to be treated with molecules such as PRIVIGEN and HIZENTRA. Now additionally, this year, we announced our acquiring of the rights to EtranaDez, AMT-061, which is an AAV gene therapy for the treatment of hemophilia B. This is a really nice program with some very exciting preliminary data showing that hemophilia B patients have sustained expression of Factor XII -- sorry, Factor IX for up to 12 months. The vector uses the Padua variant, which has increased Factor IX activity. And so far, there's been the interesting observation that has been effective in patients even with neutralizing antibodies. The Factor IIb study was effective and the Factor -- sorry, the Phase IIb study was -- has been demonstrated to be positive with high Factor IX levels. The Phase III study is in progress. And as Bill mentioned, upon deal completion, which is subject to regulatory clearances, CSL will have global rights. So next slide, please. Now that, of course, has been a lot of interest in our Ig business and in Fc Mimetics and anti-FcRn antibodies. And in this slide, I just want to clear up a couple of potential misconceptions and highlight our own work in this area. I think it's important for us to understand that molecules like Fc Mimetics and anti-FcRn antibodies, and indeed, other molecules such as hypersialylated Ig, which you may have heard about, will not be used in prime immune deficiencies or secondary immune deficiencies. And for us, this constitutes around 50% of the Ig market. The other 50% of the market is used in the treatment of autoimmune disease. And we expect a subpopulation or a subset of these to be able to be treated with these other molecules. So within the autoimmune diseases where we use Ig, there is a subset that are antibody mediated. And then we expect a subset of these patients to be responsive to Fc Mimetics and anti-FcRn. So this -- the point here is that the majority of the IVIg business will not be impacted by these new molecules, although it seems likely that they will certainly have a place in some areas. Some important points to highlight at the bottom here when thinking about IVIg versus anti-FcRn. With Ig, we're treating autoimmune disease by providing more Ig. So in effect, supplementing existing Ig. This is quite distinct from the use of anti-FcRns, which result in immune suppression. Indeed, some of these agents lead to only 15% of normal Ig levels. So this brings into question the long-term safety, which will pan out over the years to come. The other issue is the persistence of the response, which will again become apparent as the clinical studies progress. So in our view, IVIg, subcutaneous Ig will be -- continue to be widely used in autoimmune disease and primary immune deficiencies. I know that CIDP is a disease of interest to many of you. It's an important disease with respect to the use of IVIg and subcutaneous Ig. And from our perspective, it fits within that group of autoimmune diseases that is less likely to be treated by these new agents. Our own work in this area does continue. We have a collaboration with Momenta recently acquired by Johnson & Johnson pursuing CSL730, which is an Ig-Fc Mimetic. This binds to gamma Fc gamma receptors and inhibits activation of immune cells. This molecule has been shown to be effective in a number of animal models of disease. And here, I'm showing you some recent data in a model of Glomerulonephropathy. And again, you can see that it's very effective in preventing the progression of that disease. The program is progressing well, and we're in a Phase I data at the moment looking at subcutaneous administration. Next slides, please. So just changing gears, I'd like to finish up by summarizing our activity in the COVID-19 vaccine space. As Bill mentioned, this has been done as a partnership between CSL Behring and Seqirus, working with the University of Queensland and CEPI. In addition to the manufacturer of the UQ vaccine, we are, of course, also working to manufacture the AstraZeneca vaccine, AZD1222. Both of these have a different format and fit with CSL's manufacturing capabilities. So the UQ vaccine, V451 is a recombinant virus spike protein and importantly, is formulated with CSL's proprietary adjuvant MF59. The AstraZeneca vaccine is an adenovirus vector to design to express the spike protein in situ. Our responsibility for the V451 vaccine is to manufacture, conduct clinical trials and then supply the vaccine. And as you would have seen from our recent announcements, we have agreements with the federal government to supply 51 million doses for use in Australia. With AZD1222, we're manufacturing the vaccine for AstraZeneca to distribute. These studies are moving along nicely. V451 is in a Phase I study, and we expect to commence the Phase II/III study in December of this year. The Phase III is ongoing for the AstraZeneca product. Next slide, please. Now there are many vaccines in development. And as a result of this, we're very hopeful that a number of them will prove to be effective. You can see that there's in excess of 190 vaccines that are progressing through the various stages of development, 42 in clinical development at the moment and 151 in preclinical development. And there's a variety of platforms that are being used to develop these vaccines, some which would be characterized as classical platforms and some as next-gen platforms. You can see V451 there on the left-hand column, it's a protein subunit vaccine formulated with an adjuvant, and this certainly fits into the category of a classical platform, a lot of experience with this type of vaccine in a range of disease areas and a lower risk in terms of that level of novelty. The AstraZeneca vaccine fits into the next generation of vaccines that are currently no approved vaccines based on this type of adenovirus technology, yet the clinical studies, the initial clinical studies are proving positive. We feel that in terms of technology platforms, the development of a classical platform and a next-generation platform will provide CSL and the Australian population with important options moving forward. And finally, I'd like to just finish up with the next slide, which just gives you some insight into the process that we're undertaking with CSL. So these are some images from the manufacturer of V451 at our biotech manufacturing facility out of Broadmeadows. You can see the 2000 culture -- 2000-liter culture vessel there on the left, the harvest, the drug substance, and then the filling and finish of the product and formulation with MF59. So right at the moment, we've been able to scale up the process, and we're in the middle of producing material for the Phase II/III study. And as I said earlier, we expect to commence that clinical study in December. And importantly, it's a similar manufacturing platform for the AZ vaccine, and we expect to initiate manufacturing of that early in the New Year. And with that, I'd like to hand over to my colleague, Dr. Mittie Doyle, who is the Head of our Immunology therapeutic area.

Thank you very much, Andrew. I'm delighted to present highlights from the immunology therapeutic area. Last year, you heard about some of our early development projects. This year, I'd like to focus on some of our exciting late-stage development program. I'll start by expanding on Andrew's review of our COVID-19 vaccine work and focus on additional efforts we are taking to develop new treatment options for COVID-19. On the next slide, you can see listed, the founders, members, contributors and supporters of the COVID-19 Plasma Alliance. This is an unprecedented industry, academic and government collaboration. The aim of the project is to manufacture an anti-COVID-19 hyperimmune IV immunoglobulin product. The hyperimmune has several potential advantages over convalescent plasma. First, the plasma collected from convalescent donors is sent to manufacturing facilities where it is pooled, processed and purified to concentrate the antibodies. The anti-COVID-19 hyperimmune has a longer shelf life than convalescent plasma, making it easier to store and distribute. Additionally, because it is made from pooled convalescent plasma that has been purified and concentrated, the hyperimmune can be standardized so that it includes a minimum level of antibodies in each unit. Importantly, the anti-COVID-19 hyperimmune contains more virus specific antibodies per volume. Identifying convalescent plasma donors, manufacturing the hyperimmune product and designing and conducting a clinical trial to formally evaluate safety and efficacy requires the collaboration of many people and organizations, as you can see from this slide. On the next slide is the study design of the randomized, double-blind, placebo-controlled clinical trial led by the NIH, National Institute of Allergy and Infectious Diseases, that CSLB is participating in to evaluate the safety and efficacy of the anti-COVID-19 hyperimmune. 500 patients with recent onset COVID-19 will be randomized into 1 of 2 arms. They will receive either a single dose of placebo plus remdesivir, unless contraindicated, or a single dose of anti-COVID-19 hyperimmune plus remdesivir. All subjects will receive background standard of care. Eligible patients are those that have been diagnosed with COVID-19 and require hospitalization, but whose illness hasn't progressed to the state that they have developed acute respiratory distress syndrome or ARDS. The primary endpoint, similar to the endpoint used in the remdesivir pivotal study is based on a 7-point ordinal scale and will be assessed at day 7. The hypothesis is that the anti-COVID-19 hyperimmune will reduce the risk of disease progression and death. We are delighted to share that the first subjects have already been enrolled into the study and we look forward to the results of this unprecedented collaboration. In addition to our work on the collaborative NIH protocol, on the next slide, you can see that we're also advancing an anti-COVID-19 hyperimmune program in Australia using convalescent plasma collected by the Australian Red Cross Lifeblood. We are pursuing a creative regulatory strategy agreed upon by the TGA. A single center Phase I study in 24 healthy volunteers will be conducted that will allow us to leverage the global hyperimmune Ig data from the NIH collaborative trial. Next slide, please. I mentioned earlier that the NIH collaborative hyperimmune study is enrolling hospitalized patients who have not developed ARDS. So we are also conducting a COVID-19 study with our recombinant monoclonal antibody Garadacimab in this more severe hospitalized patient population. Respiratory failure remains the dominant cause of death in patients with COVID-19. We know that there are 3 primary drivers of ARDS in COVID-19. Inflammation, including complement activation and cytokine production, thrombosis and vascular permeability. Factor XII plays an important role in all 3 of these pathways, as you can see on the right hand of this slide. Blocking activated Factor XII could provide a unique treatment approach for treating COVID-19 patients who develop ARDS. On the next slide is the study design of our Garadacimab COVID-19 study. 124 patients with severe COVID-19 complications, including ARDS, will be randomized into 1 of 2 treatment arms, Garadacimab plus standard of care or placebo plus standard of care. The primary objective is to prevent progression to intratracheal intubation or death. The primary end point will be assessed at day 28. On the next slide, you will also see how we are capitalizing on the key role that factor XII plays in vascular permeability and the ability of garadacimab to interrupt this pathway. To advance garadacimab in hereditary angioedema, or HAE. HAE is an autosomal dominant genetic condition, affecting 1 in 10,000 to 50,000 people that can be life-threatening. The disease is mediated by an unregulated protein cascade and is characterized by recurring episodes of swelling in specific parts of the body. Most often affecting the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. The swelling, which can last for 2 to 5 days is characterized by unpredictable onset, severity and attack locations. Laryngeal involvement may cause fatal asphyxiation and death. Vanguard is our clinical development program for the study of garadacimab in HAE. Next slide, please. As you saw in the picture on the previous slide, vascular permeability or angioedema is the hallmark of HAE. The pathogenesis of HAE is well understood. And I'd like to draw your attention to the bottom right of the slide. As you can see, angioedema or increased vascular permeability is the final common pathway that results from activation of the kallikrein-kinin system. Factor XII plays a key role in initiating this pathway. Factor XII is proximal in the pathway, and inhibition of activated factor XII is a highly effective approach to preventing activation of the pathway and subsequent vascular permeability. You can also see that garadacimab interacts with Factor XII at a more proximal point in the kallikrein-kinin pathway than were in landelumab or Takhzyro. On the next slide are highlights from our Phase II study results, which were presented virtually in June, at the European Academy of Allergy and Clinical Immunology. This figure display highlights the reduction in monthly mean HAE attack rate and shows mean percentage reduction versus placebo. Our Phase II dose-ranging study evaluated 75 milligrams, 200 milligrams and 600-milligram doses of garadacimab given as monthly subcutaneous injections. As you can see, garadacimab significantly reduced the mean number of monthly HAE attacks versus placebo. The mean reduction in HAE attacks per month compared to placebo was an impressive 98.94% for the 200-milligram dose group. There is a clear treatment effect from placebo to the 75-milligram dose, some further increase to the 200-milligram dose, but then no further improvement with the 600-milligram dose. Based on these exciting results, we are in the process of initiating our Phase III garadacimab study with the 200-milligram once-monthly subcutaneous dosing regimen. The Phase III study, which is shown on the next slide will be a global program, including Japan. Following a run-in period, 60 subjects with type 1 or type 2 HAE will be randomized to receive either monthly subcutaneous garadacimab or placebo. The primary end point of time normalized number of HAE attacks during the treatment period will be assessed at 6 months. As you can see on the next slide, our R&D organization in Japan is working closely with our global team to improve available treatment options for patients with HAE in Japan. The prevalence of HAE in Japan is similar to the global prevalence rate of HAE, with 85% of patients classified as type 1 and 15% type 2. Importantly, there are currently no approved drugs for long-term prophylaxis of HAE in Japan. As noted, Japan will participate in our Phase III global study with garadacimab. Additionally, we are conducting a Phase III study with HAEGARDA, our plasma-derived C1 inhibitor in Japan. As shown on the next slide, this is an open-label, single-arm study in 8 patients, which is already fully enrolled ahead of schedule, underscoring the unmet need in Japan for long-term prophylaxis treatment options for patients with HAE. Next slide, please. The last program I will highlight today is our Phase III dermatomyositis program with HIZENTRA. Similar to chronic immune demyelinating polyneuropathy, dermatomyositis is a complex autoimmune disease that falls into the larger gray circle in the cartoon that Andrew showed on a previous slide. The pathogenesis of dermatomyositis involves the cellular and humoral immune responses. Dermatomyositis has an incidence rate of 11 per million with a prevalence rate of 14 or 100,000. Clinically, dermatomyositis presents with characteristic skin rashes, as shown in the pictures on the right side of the slide. Mortality remains high for patients with dermatomyositis with rates at 5 years of 10% to 30%. The disease is associated with high comorbidity due to its effects on muscle strength, decreases in pulmonary function, inflammatory arthritis and Raynaud's. Current treatment options include corticosteroids and other immunosuppressive agents, but there are no approved disease-modifying antirheumatic drugs. There is high unmet need for more effective and safer long-term treatments for patients with dermatomyositis. Next slide, please. Immunoglobulin therapy with HIZENTRA, our 20% subcutaneous IG, in particular, is uniquely positioned to address this unmet need. As well as the complex pathogenesis of the disease. Reclaim is our Phase III study of HIZENTRA in adults with dermatomyositis. This is the 1-year double-blind, randomized controlled trial comparing HIZENTRA to placebo with the primary end point of responder status based on the total improvement score at 6 months. This is a global study enrolling patients for more than 75 sites, including Japan. After a COVID pause of several months, the study is back up and running and approaching our previous enrollment target. Thank you very much for your attention. I will turn over the presentation now to Bill Campbell, our Executive Vice President and Chief Commercial Officer.

Thank you very much, Dr. Doyle. Good morning to all of you in Australia and around the globe. I missed my time in both Sydney and Melbourne and wish we were there in person together. We'll make use this technology to the best of our ability. And I think most importantly, I hope that this session finds you and importantly, your family healthy and safe during this extremely trying global pandemic. It is my pleasure once again to share this forum with my R&D colleagues. I look forward to this every year, and I believe that the R&D commercial partnership is extremely strong at CSL. And in fact, I would tell you that I believe this is one of the key competitive differentiators for us in the markets in which we compete. This collaboration has yielded some really successful products, a number of which I'll talk about today. So with that, Ben, if we could move to the next slide, please. And I'd like to begin my session by highlighting a couple of the key bearing highlights from fiscal year '20. And despite the business model change in China, we delivered a robust revenue growth of 8% over the prior year, delivering some $7.7 billion in revenue. I'm extremely proud of our business performance and more I'm proud of the contributions of the more than 1,800 commercial team members across the globe. The team has created strong underlying demand across the portfolio. And as I've said over the last several years, this continues to be strong demand across all therapeutic areas and all key products. Also, as in the past, we've had balanced regional and key market growth, and we take a lot of pride and that all 4 of our regions and all of the key markets that we compete in. Have shown strong year-over-year growth. New products, an important marker of the company's future success contributing -- is continuing to contribute significantly to growth. I think it's a testament to our teams and the quality of the products that have come from the research and development team, and I'll talk about a number of those a little bit later. Our IG growth in fiscal '20 continue to be well above market as it has been for the last several years, I think, owing to the richness of our portfolio. We continue to invest in foundational tools that we think will support future growth. And we've successfully transitioned our business model in China, and this is a topic I'll come back to as I get toward the end of the presentation. If we go to the next slide, please. Our performance in FY '20 continues, I think, the strong path that we've been on. As I mentioned earlier, growth has been broad across the portfolio. You see double-digit growth articulated on this slide across all the key products. PRIVIGEN and HIZENTRA continue to lead the way for us with 20% and 34% growth, respectively, but no doubt, you've noticed the strong growth from our specialty portfolio, including HAEGARDA, KCENTRA and Zemaira/Respreeza. Our coag products are also continuing to grow, in particular, AFSTYLA at 21% and IDELVION, a strong 25%. I'll speak to many of these products over the next 15 to 20 minutes or so. But just before I get there, let's go to the next slide, and I'll just set the context for the broad market that we compete in. The broad segment is currently valued at a bit over $33 billion in revenue. The IG and hemophilia segment are roughly equal at $12 billion to $13 billion a piece. And the Albumin and Specialty segments are valued around $4 billion in each, and this is consistent with appropriate growth as you've seen year-over-year. Let's move to the next slide now. And what I'd like to do is move into some of the therapeutic segments and touch on some of our key products. So we'll start with hemophilia. And this is a segment, as you know, we've been in for a long time. I think we're well over 3 decades now. Our hemophilia business grew 8% in fiscal year '20 and but in many, many ways, this growth of 8% really masks the performance that we delivered with our core products AFSTYLA and IDELVION. Within the hemophilia B space, IDELVION represents a truly transformational product and continues to deliver strong year-over-year growth, and I'll touch on that a bit more in a minute. We have a leadership position now in several key markets, and I'll share some market data on that. And recently, we received approval of 21 dose -- 21-day dosing intervals in the EU, Switzerland, Japan and Canada. Within the hemophilia A space, we're competing extremely hard in what you know is a very, very crowded market. With AFSTYLA, we're continuing to focus on patient retention strategies and ongoing switches in this very competitive segment. We will continue to roll out new launches in this year and beyond. Within the plasma-derived segment, we really have 2 very separate and distinct businesses. One of them is really made up of our products Humate and Haemate, which is our Factor VIII von Willebrand Factor products for the treatment, primarily of von Willebrand disease, and we continue to show year-over-year growth in that segment. And then the other side is our plasma-derived Factor VIII products, which are still highly important to us and quite low price but important in many, many markets around the globe. So with that, let's go to the next slide, let me share some data on how we've done in the segment. So this first slide shows AFSTYLA performance in a number of key markets. The y-axis is patient share of the recombinant Factor VIII prophylaxis segment, the x-axis is time. The markets like Germany and Italy, we have a share, as you can see in the graph of some 9% to 11%, respectively. A bit lower in France and Spain at 4% to 5% each. And in the U.S., a bit lower at 3%. But as you noticed, there's still a nice slope and growth trend in that marketplace. So while this is a highly competitive market segment with many, many, many great products to choose from. We continue to compete quite well and are quite, quite happy with the performance of this business segment. The team has done a great job overall, and this is a segment we'll continue to be quite active in. If we move to the next slide now. I'll touch on the IDELVION share within its respective Factor B segment. So this slide is set up exactly the same as the last one. And as you see, we have extremely strong positions in key markets like Germany, Switzerland and Italy, with market shares in the high 50s to approaching 60%. We've not been in the hemophilia segment in Japan historically, but you'll note a share in Japan within a relatively quick uptake period of 43%. And in the U.S. market, despite having launched 2 years after Alprolix, we now have the leading share at 41%. IDELVION like HIZENTRA, HAEGARDA, KCENTRA and many other CSL products really represents the quality and depth of experience and focus of our R&D as well as commercial teams. We'll go to the next slide now, and I'll switch gears for just a minute and we'll move from hemophilia to the IG business. On the left side of the slide, you see the immunoglobulin market, very similar to how we've portrayed this in the past. We see a total market size of 240 million to 250 million grams and 2/3 of that is utilized across PID, SID and CIDP. On the right-hand side of the slide, I tried to highlight a number of key market dynamics. Clearly, this is a market that's been growing above the historical normal rates of 6% to 8% for the last couple of years. We're continuing to see ongoing expansion in both PID and CIDP as well as expanding use in SID given the success of CAR-T therapies across the globe. The market historically was somewhat tight prior to the COVID-19 pandemic. Having said that, we suspect that given COVID and the impact on plasma collection, this will continue to tighten supply somewhat significantly over the next 6 to 12 months. One of the clear outcomes of COVID-19 has been a shifting preference from IV immunoglobulin to subcutaneous immunoglobulin and home administration. And I guess, really not surprising given the many stay-at-home orders and patient preferences for not going to an infusion center and/or a hospital, but we certainly have seen and continue to see growth quite significantly for HIZENTRA as a result. And we think that this will only bode well for this brand going forward. If we move to the next slide then. I'll highlight some of our IG performance. We delivered an overall IG growth of 22% on the revenue side and corresponding IVIG growth of 16% and slightly higher if you look at just PRIVIGEN. The growth of HIZENTRA was quite strong at 34%. And so these are 2 brands really doing quite well in the marketplace, the 2 brands that we spend a lot of time growing and ensuring widespread distribution across the globe. I won't spend more time on the IVIG segment here, but I'll just simply say, relative to HIZENTRA, we created this market, as you know, about a decade ago. We are the market leader and fully expect to stay in that position. As I mentioned on one of the earlier slides, the one I just presented, the strong preference for home administration. And as you know, we have now in orphan exclusivity in the U.S. for CIDP. So what I thought I would do is give you a little bit more color now relative to the HIZENTRA performance. So if we go to the next slide, this slide shows you the continuing strong success of HIZENTRA in the subcutaneous IG segment. The y-axis shows share of the subcu IG market across the 7 major markets. In this case, the U.S., the big 5 in Europe, and Japan and the x-axis being time again. HIZENTRA has a 61% share across this segment. And while the share has been relatively flat in that 60% to 61% range, as you know, this is a segment that's clearly been growing and growing at more than twice the rate of the IV segment. So a very strong share in a very growing -- very large and growing segment. We'll move to the next slide. This slide is essentially the same format as the one that I just showed, except now specific to our position in CIDP, and this slide does combine both PRIVIGEN and HIZENTRA across the same 7 markets. So I think you would see that from the graph, we're quite well positioned in CIDP. We have a market share of just slightly under 30% and growing. Clearly, the launch of HIZENTRA in this space 18 to 24 months ago has been strong and has given us a nice lift, and we believe will continue to show significant growth. If we move to the next slide then. I'll now turn and touch on some of our specialty products over the next 3 or 4 slides. The specialty products have been and will remain an important business for CSL. In fiscal year '20, the segment totaled almost $1.7 billion in sales, and we've seen strong individual and collective growth across this franchise. While I don't have time today to discuss all of these products, what I'd like to do is add a bit more color with respect to HAEGARDA and KCENTRA, and we'll start that on the next slide. So starting with HAEGARDA, this is a product that, in so many ways, has transformed the treatment of HAE not the least of which is due to its strong efficacy profile in subcutaneous formulation. Due significantly to the launch of HAEGARDA and then the more recent launch of the Prophy segment, we've seen the prophylactic segment grow 25% overall last year. And specific to HAEGARDA, almost 25% of the new patients to the brand came from the newest product to launch in the space, Takhzyro. As a result then, we finished with the most patients we've had on this brand since the launch. So let's go to the next slide, and let me try to bring this last point into focus a little bit. So I tried to show here on the x-axis, the last 3 years of time, the y-axis is number of patients and you can see early on with the launch, the rapid uptake of the brand, primarily in the U.S. marketplace where we launched. We were somewhat product constrained at the time of launch, and we're really careful to make sure that any patient who went on therapy would never be without products. So we constrained some of our global launches. We had a slight decline, and you could see a flattening or a decline in the middle part of the curve during the Takhzyro launch. And you can see a rebound in patients' volume over the last 5 or 6 quarters or so. So in fact, we finished fiscal year 2020 with the most patients on therapy since launch with, I believe, a strong upward trend and a strong upward slope that you can see in the curve. I'd be remiss if I didn't highlight the fact that HAEGARDA or BERINERT subcutaneous as it's known in several markets, has now been launched in Germany, Denmark, Australia, Canada, Spain and Austria. This is truly, truly a special product and one that's transformed this patient population in so many ways. We'll move to the next slide, and I'll just touch on KCENTRA with just a single slide. And I think this is somewhat of a similar slide to what I've shared with you in the past. The left panel of the slide shows Warfarin share of the oral anticoagulant market. There's almost 7 million patients in this space within the U.S. market and almost 2 million still on Warfarin. Warfarin has clearly declined in volume and number of patients utilizing the brand but still really quite a large market segment. The middle panel of the slide shows the curve for both KCENTRA in purple and fresh frozen plasma in the blue color. And up until recently, fresh frozen plasma was the product of choice for reversing the effects of Warfarin. That now has crossed over with KCENTRA controlling about 60% of the reversals. However, it doesn't -- it's not lost on us that there's still a lot of fresh frozen plasma used in the space, and it continues to be a focus for our U.S. team. The right-hand side of the slide, you see the utilization of KCENTRA. And I've tried to give you a bit of sense for how much of its use is in Warfarin reversal, which is just over 1/3, with 2/3 being used in other spaces. I would point out, as I did last year, that case KCENTRA is, however, only indicated for Warfarin reversal and not promoted in spaces outside of that area. So strong year by KCENTRA as well. If we move to the next slide, I wanted to just take a moment and say a couple of words about our successful transition of the business model in China. We highlighted this with all of you more than a year ago, and we talked about the need to make this change. And I'm so proud of our team in China, led by Harold Chan and a regional general manager, Paul Li. The team there did a fantastic job of ensuring that we met all of the milestones and seamlessly transitioned our business to a full CSL control. The left side of the slide, you can see a number of important milestones. However, I would just say that there's none more important than the last one. We made this term to our own business model in 12 months with a tremendous amount of work, and I'm so happy to say that no impact to patient supply happened over the course of this 12-month process. The team did a fantastic job, and we're well on our way to continuing to grow our albumin business in this highly important market. So if we go to my last slide, then I'll wrap up my presentation by saying that we are carefully and thoughtfully executing on all of our strategies, and I mean that broadly, product strategies, therapeutic area strategies as well as our regional and product strategies. We have created strong underlying demand across all of our therapeutic areas and across all of the products, and I hope I've demonstrated that with some of the data that I've shared with you today. We have really terrific balanced regional and key market growth. Our new products are contributing significantly to growth just as our legacy products are continuing to grow quite nicely. The new products, which is, again, I think, an important marker of future success, have really contributed significantly to underlying growth. We have aligned therapeutic and area teams and strategy, and we remain highly focused and agile working through the COVID-19 pandemic. So I'll leave you by -- I'll leave you with a couple of words just to say our business is diverse and strong. We will continue to lead through this global crisis. I'm convinced that we will only grow stronger as a result of the process we're going through. And with that, I'll now turn the presentation over to Dr. Laurie Lee, our Vice President and co-lead of the transplant therapeutic area. Laurie?

Hello, and thank you, Bill, for your introduction. I'm delighted to be here today to share our work in transplant. Let me start by saying that hematopoietic stem cell and solid organ transplants save lives, but they're not without risk. And those risks may in fact, impair utilization of these procedures. So today, I'd like to discuss 2 potential risks of transplantation. The first is graft-versus-host disease or GvHD; and the second is antibody-mediated rejection or AMR. I'd like for you to leave this presentation with an understanding of the biology of these diseases and what we're doing to try and improve outcomes for transplant patients, as shown on the next slide. Patients undergoing hematopoietic stem cell and solid organ transplants face similar challenges before, during and after transplantation, as you see on this slide. Before transplantation, patients would have failed every possible option for treating their underlying disease, and they're at risk of dying. Even then, they often have to wait prolonged periods of time, while an appropriate donor is identified. Now after transplant, many patients do quite well. For those that don't, the complications such as GvHD or AMR can be devastating, essentially, patients trade one life-threatening disorder for another chronic and life-threatening disorder. To add insult to injury, current treatments for these complications can be toxic. They often inhibit both the pathogenic and protective immune responses, which means they pose additional risks such as for opportunistic infection in these already vulnerable patients. So our work in transplant is focusing on the inflammatory events that initiate and drive tissue damage in these diseases, and we're interested in agents that promote immunomodulation. Immunomodulation is really important in the transplant setting because it indicates that protective T regulatory cells have developed, and this is good for patient survival and graft survival. Now in transplant, we have 3 ongoing programs, 2 in GvHD and 1 in AMR. And I'd like to share those on the next slide. Our first study is a collaboration with the Blood and Marrow Transplant Clinical Trials Network. It's a Phase III study of AAT or Zemaira and it's evaluating AAT as treatment for acute graft-versus-host disease. This is our treatment study. The MODULAATE study is our prevention study. This is also evaluating AAT, but for the prevention of acute graft-versus-host disease. And then our third study is the IMAGINE trial. This is evaluating clazakizumab, which inhibits interleukin-6, and we're evaluating clazakizumab in kidney transplant patients who have developed AMR. I'd like to start with GvHD on the next slide. More than 25,000 patients received hematopoietic stem cell transplant in the U.S. and Europe annually. And the most common life-threatening complication of these transplants is GvHD. GvHD occurs when immunocompetent T cells from the donor recognize the host as foreign. And the immune system foreign means danger, and this initiates attack to eradicate the foreign molecules. But in the transplant setting, this attack means an attack on the patient's own tissues, as you see here, graft-versus-host disease attacks a patient's skin, GI tract and liver. Here you see early and advanced stages of GvHD in each of those organs. If we move to the left of the slide, you see that because of the risk of GvHD, all patients receive prophylactic medications. Despite those prophylactic medications, up to 50% of patients still develop GvHD after stem cell transplantation. And of those who developed GvHD, only 50% respond to first-line treatment, which is corticosteroids. Now the severity of GvHD varies with Grades 3 and 4 being the most severe in carrying high rates of mortality. If you've ever seen a patient who has grade 4 GvHD in the skin, you won't forget it. It appears like third degree burns or full-thickness burns that can affect a majority of the body. So patients with GvHD desperately need new and more effective treatment. On the next slide, I'd like to show you the cellular mechanisms of GvHD and where we think AAT may have potential clinical benefits. I'm going to explain GvHD as a 3-step process here, and I'll show where AAT has potential benefits. Starting on the left here, patients undergoing transplantation have damaged tissue. This is a result of their underlying disease, their treatments for their disease, intercurrent infection and finally, by the chemotherapy or radiation that they received prior to their transplant. The damaged tissue releases danger signals, which activates APCs or antigen-presenting cells shown here. That's step 1 for GvHD. In Step 2, the donor T cells recognize the HLA disparity on the patient's tissues and this initiates a strong inflammatory response. And then it's been step 3, effector cells, such as T cells and neutrophils migrate into the tissue and attack the skin, the gut and the liver, as you saw on the previous slide. Now if the disease is not controlled at this point, what happens is the damaged tissue can escalate the process to further higher and more severe stages of GvHD, and that's represented by the circle here. And what's important to recognize that is when their disease reaches this state, it's exceedingly difficult to control. So let me move to AAT, as represented by the Red cross bar here. AAT has the potential to impair each of these steps. First, it inhibits neutrophil elastase, which protects tissue. And this would essentially decrease the danger signal at Step 1. Next, AAT reduces the pro-inflammatory cytokines that initiate and drive the disease. And third, AAT reduces T effector cells and inhibits neutrophils from migrating into damaged tissue. Importantly, AAT doesn't directly inhibit proliferation of T cells, like other treatments do. And this means that AAT would not be expected to increase the risk of infection in these patients. You could look at AAT, therefore, as a gentler yet effective treatment for AAT -- or for GvHD that can be added to existing treatments. And lastly, as shown by the green arrow here, AAT increases IL-10, which is an anti-inflammatory cytokine and promote development of T regulatory cells. On my next slide, I'd like to show you encouraging data from AAT in patients with steroid-refractory acute GvHD. The format of this slide is a study design on the left. And then we have study results in the middle and on the right page. So this was a prospective open-label Phase II study in steroid-refractory GvHD patients. 40 patients received AAT twice-weekly for a month. 70% of these patients had Grade III or Grade IV GvHD. They were the most severe patients. The primary endpoint was the overall response rate at day 28, and this was defined as patients who had a complete response or a partial response after treatment. The results are shown in the middle panel with the bar graph. The red bars indicate patients who had a complete response and the blue bars indicate those who had a partial response. You see that the responders increased in proportion week after week. And at week 4 or day 28, the overall response rate is 65%. Recall that 70% of these patients had Grade III or IV GvHD. Also recall on the previous slide that AAT has the potential to increase T regulatory cells and that's exactly what we see on the right side of this slide. At week 4, these patients had a twofold increase in T regulatory cells. So building upon these encouraging data, we're now evaluating AAT at earlier stages in GvHD. Let me start with our treatment study on the next slide. This is our study that was -- is being conducted in collaboration with the Blood and Marrow Transplant Clinical Trials Network in the United States. There are 3 phases to the study. In the enrollment phase, we're recruiting patients who have acute GvHD. This is their initial diagnosis of GvHD, so they would not have received any previous treatment. In the treatment phase, they'll be randomized to receive either AAT or placebo twice weekly on top of corticosteroids. The primary endpoint is at day 28, the proportion of patients who've had a complete or a partial response. And then in the maintenance phase, patients who have had a response will continue AAT weekly for 4 additional doses. This study started recruitment in January of this year and took a short pause due to COVID-19. It is now recruiting again in the United States. The next slide shows our AAT prevention study. There are 2 parts to this study. We've finished enrolling in Part 1 of the study, which is the open-label dose finding part of the study. Part 2 is the randomized double-blind, placebo-controlled part of the study, and we intend to start enrollment in early in 2021. Here, we'll enroll 260 adults and adolescents. And the study is a global study. I'd like to walk you through the study time lines as shown on the bottom of the slide here. It's a year-long study and day 0 represents the day of the transplant. As shown at the bottom of the slide, patients will receive standard GvHD prophylactic medications, which include methotrexate and calcineurin inhibitors. And then starting just before the transplant, patients will be randomized to receive either AAT or placebo for 56 days. The primary endpoint is at day 180, the proportion of patients who are alive and free of graft versus host disease, and they'll continue in the study for a total of 365 days. Now I'd like to switch gears and discuss Solid Organ Transplant on the next slide. There are over 500,000 patients living with a transplanted kidney around the world. As you see on the right, kidneys are the most frequently transplanted of all solid organs. But what this slide doesn't show you is that a common reason for needing a kidney transplant is failure of the first kidney transplant. So on the next slide, I'd like to show you outcomes after kidney transplantation. Here, you see that AMR or antibody-mediated rejection is a leading cause of long-term graft loss. There are 2 figures here. On the left, we see the probability of developing an abnormal biopsy after transplant. And on the right, you see survival according to those biopsies. Let me start with the left. In the first 6 months after transplant, most patients had no major abnormalities as shown by the green line, or they had T cell rejection, as shown by the red line. After 6 months, T cell rejection declines and is then rare after a year. However, as shown by the dark blue line, at this time point post transplantation, AMR increases and the probability of AMR continues to increase out to 5 years post transplantation. Now if you follow that over to the right side of the slide, you see by the dark blue line that AMR is strongly associated with poor graft survival. So there's a big opportunity here. If we can save 1 kidney from AMR, we prevent a patient from returning to dialysis, and we do not add another name to the already long list of patients who are waiting for a new kidney. On the next slide, I'd like to talk about the cellular mechanisms of AMR. As you see here, IL-6 plays a key role in the development of AMR. AMR is characterized by pathogenic antibodies that are directed at the kidney allograft, and those are donor-specific antibodies or DSAs. At the top of the illustration here, you see that IL-6 plays a role in promoting the development of DSAs. If you follow the DSAs around to the right side of the illustration and down to the bottom, you see that the DSAs binding to HLA targets on the kidney graft. This binding then promotes an inflammatory response that ultimately results in fibrosis, vasculopathy and poor renal function. Now IL-6 also shapes the T cell response. IL-6 promotes a long-lived proinflammatory T helper cell phenotype, such as Th17 cells. Now Th17 cells promote allograft rejection, and they also inhibit T regulatory cells, which are the protective cells. So you can see from this illustration that blocking IL-6 may have a variety of benefits for patients with AMR. It may improve AMR, reduce the tissue inflammation, improve kidney function and ultimately, prevent graft loss. In fact, there are encouraging data with an IL-6 receptor mAb in this population. On the next slide, I'd like to show you our IMAGINE study. This study is evaluating clazakizumab, an IL-6 mAb for patients with chronic AMR after kidney transplantation. Now recall that there are no current treatments for AMR. So clazakizumab has the potential to be a first to market first-line treatment for AMR. I want to walk you through the study design here. On the left, you see that there's a screening visit at visit 1 after which, eligible patients will be randomized to receive either clazakizumab or placebo for -- every 4 weeks for 5 years. And then there's a 5-month follow-up period. This is a global study that will enroll 350 patients. As shown at the bottom, there's an opportunity for expedited approval, however, based on kidney function at week 52. Therefore, we plan an interim analysis with 200 subjects have reached week 52 in the study. This interim analysis will be -- will evaluate change from baseline and mean estimated glomerular filtration rate, or GFR, and this is a marker of kidney function. If we show at this earlier time point that clazakizumab prevents a decline in renal function, then we'll file for expedited approval. Patients will continue in the study, and our final analysis will be time to all-cause graft loss. The data from this final analysis will be very important in demonstrating the full potential of clazakizumab in this devastating disease. On my last slide, I'd like to end by saying that transplantation is one of the most transformative and curative procedures in all of medicine. Many patients do quite well. As we've discussed though, there are unmet needs for those patients who have complications post transplantation. As demonstrated by the green check marks here, we're making progress here. And Andrew's programs and research are aimed at the earlier challenges that patients face in transplantation. We have the ambitious goals in transplant because if we can improve patient survival and improve graft survival, then more -- then transplantation can be offered to more patients in need. Thank you for your attention, and I'd like to turn it back over to Dr. Bill Mezzanotte.

Thank you, Laurie, and thank you to all the presenters for great and clear presentations and presentations that are on time. So we'll have plenty of opportunity for Q&A after we're done. So I just have a few slides left to go through and go to the next slide, please. So once again, just reminding you, here is our portfolio at this current date, so it's our new baseline that we'll be operating from. Again, I want to leave you with the impression this is a well-balanced portfolio across all the clinical phases, keeping in mind that this is only a sampling of the early preclinical portfolio represented. You will also note that, again, all therapeutic areas are represented by the sea of colors, which is a good sign for our overall strategy. And if we go to the next slide, I'll show you the expected launch dates for some of our most significant products and geographies. These products -- these launches over the next few years are some important line extension launches, building on those approvals that we've already mentioned from the previous year. And some exciting new offerings start to come next year. Hopefully, beginning with the successful COVID vaccine program. Of course, there will also be plenty of other launches in other geographies, as I showed you on the world map earlier today, and we plan to recreate that kind of map with that kind of success next year. But this slide and that overall road map represents a lot of value to patients and to CSL. Next slide, please. We anticipate a very busy and very successful year in 2021. We also look forward to hopefully meeting all of you in person again next year to update you on the excellent progress we make. There are many things we are looking forward to, and this slide depicts them quite nicely. I'll just point out a couple in my final remarks. In immunology, starting the Garadacimab Phase III trial that Dr. Doyle mentioned that will build on the encouraging Phase II results. And we look forward to completing the HAEGARDA study in Japan and filing for approval there. In cardiovascular and metabolism, we'll continue to actively enroll into the AEGIS-II trial, hoping to achieve enough MACE events such that we can conduct our second futility analysis as described. And we look forward to initiating our trial with our VEGF-B inhibitor in diabetic kidney disease and expanding that therapeutic area. We look forward to entering our first patient into the KCENTRA trauma trial. And once regulatory clearance occurs, we will work toward U.S. approval of the trial events. In respiratory, we have 2 exciting Phase I offerings, and we'll be considering another indication for Garadacimab as discussed by Dr. Nash. And in transplant, we will initiate the confirmatory portion of our Adaptive Phase II/III trial of Alpha-1 antitrypsin graft versus host disease as just eloquently described by Dr. Lee. In vaccines, we'll continue our Phase II trial of aQIVc and initiating the same investigation in people 50 years and older, a very exciting offering that we'll update you more on next year. And of course, in the fight against COVID-19, we look to complete our trials for the 2 hyperimmunes for Garadacimab and of course, for our vaccine UQ 451. With these hopeful thoughts, I will thank everyone for attending. I will reiterate what Bill Campbell said and hope that you all stay safe and say, well, all and your families do the same. And then I open the virtual floor for questions and answers by turning things back over to Mark Dehring. Mark?

Good. Thanks, Bill. [Operator Instructions]

[Operator Instructions]

And we have our first question from Andrew Goodsall at MST Marquee.

Just on, I think, Slide 77, which is the launch dates, you didn't have hemo cure, which is understandable. So I was just asking sort of when you expect the readout for the HOPE III trial? And then commercialization date sort of roughly, I think, have been seeing FY '22 or '22 is a potential date, but just getting your readout on that?

So I think you were talking about the EtranaDez filing. And of course, you see that we're hoping to file this coming year, assuming regulatory clearance. And it's hard to say much more at this time because, of course, we're still under restrictions with the regulatory filing that we're in clearances we need to do.

Okay. So yes. So it's there in '22, but yes, just so commercialization would be, I guess, presumably, sort of similar year?

It would follow that presumably. But of course, we all have to just wait a bit, unfortunately, and bide our time a bit until the clearance goes through.

Okay. And then with regard to the HOPE III trial assume that sort of time frame?

Yes.

Okay. And my second question just for Bill Campbell, just more generally around the pandemic part of your business that -- the Seqirus business. And just if you could talk to sort of see it or any impact currently with COVID on pandemic reservation? And just going forward, how you see that evolving with the COVID response?

So Bill, I don't know if you want to take that, even though you're not.

Yes. I think -- thanks, Bill. I think what I would say, Andrew, thanks so much. Good to hear your voice and your question. My remit within the broad CSL organization is for the Behring side of the business and not the Seqirus side. Having said that, I know the team is doing quite well and has a number of activities underway. But it would be a bit out of character for me to comment on your business. And I hope you understand that.

Sure. And apologies -- yes, I wasn't sure whether you're just talking everything commercially, but if there's anyone from that team that want to expand, that would be great.

We'd have to come back to you on that one, Andrew. We don't have the personnel to answer your question.

Okay. Thanks, Andrew. I'll give you a call afterwards. Next question comes from Saul Hadassin at UBS.

First question is as it relates to the impact of COVID in the U.S. and the uptake of HIZENTRA, can you just comment on what you're seeing in those 2 key patient populations in terms of the percentage of primary immune deficiency patients that you now think have switched to HIZENTRA and then the same for CIDP?

Before I turn it to Bill, I just want to clarify. The question is, what is the impact of COVID on the uptake by those patients?

Yes. What -- has -- I guess, has it resulted in a faster switch to HIZENTRA from PRIVIGEN in those disease categories? And where do you see those percentage penetration rates now for both PID and CIDP?

Okay. Thank you. Bill?

Thanks very much, Saul, and thanks, Bill, for turning that over. So I'm going to come at this from a couple of different ways. We are clearly seeing an impact of COVID on our HIZENTRA business in not only in the U.S. But in many markets around the globe. We've seen a shift -- a fairly nice ramp in Europe. And of course, we've had a pretty good ramp-up in the U.S., but a continuing ramp in the U.S. because of COVID and as I mentioned in my talk, because of some of the stay-at-home orders and just an overall concern of this patient population around infection and infectious risk. I'd give you a little more color on HIZENTRA by saying we're still early days with our HIZENTRA launch, and we didn't have the benefit of PRIVIGEN in CIDP in the U.S. like we did in many markets. So I would say we're well on our way to success in the U.S. and CIDP. We've done quite well in building relationships with neurologists. They're a tough audience to access but we've done reasonably well now. But I would say our penetration rate is still rather low and lots of work to do there. Broadly, I would say, if you look at our U.S. business historically, HIZENTRA, in the last couple of years, represented about 23%, 24% of our volume. That's now moving closer to 30%. And I would say a lot of that -- or at 30%. And I would say a lot of that is due to COVID but not completely. So I hope that helps, Saul.

That's good. And if I could just squeeze one more in. Just as it relates to CSL112, I think historically, there've been a milestone of a first interim readout in the calendar year '21. Just based on the delays that have occurred again with COVID, any sense of when a first interim readout might be available? Or is it looking like 2022 would be the likely time frame for that?

So I assume you're talking about the first efficacy analysis that's done at 70% of the events?

Correct.

We anticipate that will happen in 2022.

Thanks, Saul. Our next question comes from Chris Cooper from Goldman Sachs.

I think a question for Andrew Nash first. During the discussion you made in the Fc antibodies, you did pass mention on hypersialylated Ig, but you perhaps didn't go into as much detail on that as you did with some of the other programs on the slide. Just be curious, can I ask your thoughts on the product at this stage? In what way might that impact the industry? And I guess, how impactful could it be? And is it something that might make sense for CSL to be exploring themselves?

Look, before I turn it over to Andrew, I'll just say it is an interesting product. But we didn't include it for brevity purposes. But go ahead, Andrew.

Yes. Look, I was going to say, just to follow up on Bill's comments. It is interesting in clinical stage at the moment. We'll watch the outcome of those studies with interest. It's a complex product. It's not well understood why it works and why it does what it does at all. We don't think it'll impact the primary or secondary immune deficiency market. It may have some impact in the autoimmune disease space. But I think there's too many unknowns at the moment, both in the production of the sialylated Ig and its mechanism of action to make any firm comments.

Got it. And one on gene therapy, if you don't mind. So just curious on your interpretation of the FDA's recent decision on [ haptoglobin ] in heme A. I mean that was a bit of a surprise to us. I mean were you yourselves surprised? And I guess, to what extent might that impact any efforts that are being explored in heme B.

I'll take that, Andrew. So I mean, I think that I'm never completely surprised by any FDA action. I think that this is a new area. And so they want to be sure when they ask for more data, how it might affect the EtranaDez filing is hard to say at the moment. And of course, again, we're not in the driver seat. We'll know more and be able to interact more once we get regulatory clearance.

Thanks, Chris. Next question comes from Lyanne Harrison at Bank of America.

The first one is on Garadacimab. I can see on Page 77, you've got the candidate there for HAE. Can you give us possible timing on the other indications for Garadacimab?

So I -- was the question -- thanks, you were a little muffled. I think the question was on timing on other indications?

That's right. Because obviously, Garadacimab is in the pipeline in clinical trials for a number of other indications but you've already got HAE you mentioned on Page 77.

Yes. So HAE, of course, is the primary one and the one for which we have the clearer states, which is why we mentioned it on 77. For COVID-19, we will be finishing the Phase II trial in the first quarter of the next -- this coming calendar year. And honestly, what happens next depends on, a, the data; and b, the disease; and c, other vaccines. And so it's -- we don't list it because we're just -- there's that much uncertainty. And then the third indication would be in fibrotic or interstitial lung diseases, and we're just getting started in Phase II. So we don't have a good view yet of time lines there.

Okay. And just my second question is on HAEGARDA. Obviously, you had quite an interesting chart on the patients who are on HAEGARDA. Apologies because my phone dropped out at that time. But can you explain, I guess, the reason for the decline and the recovery in patient numbers?

Sure. Bill, maybe I'll ask you to take that one on the chart on the HAEGARDA uptake.

Yes. Sure. No problem. And Lyanne, thanks for the question. So the comments that I was making is when you go back and refer to that chart, you see really quite rapid uptake at the time of launch as we think that HAEGARDA really transformed the space and brought a very different level of efficacy and frankly, convenience to patients. We saw a bit of the decline at the time of the Takhzyro launch, which is somewhat normal for patients wanting to try some new products and see how they would respond. We have seen an uptick over the last, I think, 5 or 6 quarters of patient growth, and we finished the last 3 -- at least 3 quarters, higher each quarter and each one of those at the highest level we've had. And there's a number of reasons for that. HAEGARDA's extremely effective. Patients do really well on it. They respond quite well. And there's also a bit of growth in the overall prophylaxis segment of this marketplace as more products and more people talking about the benefits of treatment on a prophylaxis regimen, we're seeing a growth in patient numbers as well. So for all of those reasons. And frankly, this is primarily still -- this is U.S. data that I'm showing you. And as I mentioned, we've now launched in multiple other countries. And as we move through the year and get to this point next year, we'll be able to talk about much more of a global perspective as well.

Our next question comes from David Low at JPMorgan.

Bill, if I could start with your comments on plasma supply, you talked about the supply being somewhat severe in the months ahead. Just kind of wonder if you could talk to a little bit about how CSL plans to manage that.

David, do you mean managed from a customer basis?

Any explanation you could provide, if it seems like a fairly challenging period ahead.

David, we've been quite strong in opening new centers over the last several years, and that will continue. And we think that, that has put us in a relatively good place going into this year. Having said that, it's not a secret that because of stay-at-home orders, because of donor concern for their safety, donations have been down. Our plasma team has been doing an amazing job, frankly, of reaching out to existing and past donors they've relaid out our centers. They've spent a lot of time ensuring patient safety. They spent a lot of time trying to do some of the preliminary work that new donors would have to go through and move that to online activities. And so we think all of those activities will continue to enhance donations in the months ahead. And in fact, donations have been up in each of the last several months. And they're not where we'd like them to be yet, and we won't rest comfortably until they get back to a level of pre COVID, and then, frankly, beyond. So that's some commentary around that. And then there's a number of things that we're doing with respect to the volume of product. We've been growing quite substantially and expect to continue to do so. Having said that, we recognize we can't make up the shortfalls, if there are large competitors that have shortfalls. So we've done a number of things to ensure existing CSL customers will continue to receive product. We put measures in place to ensure that there is no hoarding of product at various parts of the supply chain, et cetera, et cetera. So there's a number of physical activities the plasma team has been doing, and there's a number of activities and planning on the commercial side, customer-facing side, customer support side have been put in place as well.

Great. And my other question for Dr. Lee. Just with the IMAGINE study, you talked about the early read after 52 weeks. And then I see from the follow-on slides at the launch time tables of mid-2023 to '25 range. Just wondering sort of what timetable is possible if there's some success with the early read.

Laurie?

Thank you for your question. I overlook discussing the dates in my presentation, I apologize for that. So the study started enrolling in late 2019. It did take a pause due to COVID-19 but we don't expect any delays due to COVID now. Enrollment has restarted. And we're planning on a 2-year enrollment rate, and then that interim analysis would occur after the last patient, after the 200th patient has reached 52 weeks in the trial. So that would be about 3 years after enrollment started.

So that would get us to 2022. And presumably, that's still sort of in the launch window of 2023 to '25 then?

Correct. Yes.

Thanks, David. Next question comes from David Stanton at Jefferies.

Look, firstly, CSL730, we've been waiting for some kind of disease target that you go for CSL to go after -- CSL Momenta to go after. I know that you've drawn out the glomerulonephritis. Is that going to be the target going forward? And is there -- can you explain any of the changes that have occurred as a part of the agreement now that J&J has taken over Momenta, please?

Sure. Let me start, and then I'll turn it over to Dr. Doyle. So as far as the arrangement with J&J, there are some provisions in the contract. We're reaching out shortly to Janssen to discuss the options that exist to continue the collaboration. CSL730 is still an active part of our portfolio. And in fact, we are going to be pivoting to a subcutaneous form, which we know is the preferred route of administration, and one we've been working towards being able to do. And so therefore, we're still in Phase I pivoting to that administration rather than bridging later on, which is -- can be a dangerous proposition in drug development. And so as far as indication searching and the therapeutic area strategy leads to that, I'll turn it over to Mittie.

Yes. Thank you very much, Bill. Yes, as you mentioned, we have pivoted from our initial IV formulation to a subcutaneous study, which is being conducted in normal healthy volunteers. And in parallel, we're investigating of large list of potential indications. But our current focus is on generating the safety and PK data from the subcutaneous from a healthy volunteer set.

Thanks, Mittie.

Understood. And I guess my next question regards your COVID-19 immunotherapy or immunoglobulin therapy. Approximately how many patients do you need to get to a minimum amount of antibody that you had mentioned as a part of this COVID-19 study?

So it changed -- that number can modify slightly based on the antibody titers and the donors and dose needed. But at this point, it's about 5 donors per dose.

Thanks, Dave. Our next question comes from David Bailey at Macquarie.

Just within transplant, last couple of years, there's been -- 2 kind of shots on dealing with that, the CSL842 arm is complement-dependent [ in this ] study and then also clazakizumab. I'm just wondering, is clazakizumab now the focus within AMR? And has there been any updates in relation to the ARMOR trial that I might have missed?

So I'm sorry, I did mention during the earlier slide that we have terminated the ARMOR study. And we did that because of challenges in recruitment prior to COVID starting to some amendments that were needed. And then finally, COVID-19 became a major challenge. And because of that -- and because of the challenge that sites in running these trials within our current COVID-19, we made the choice to focus on clazakizumab.

Got it. Apologies, I missed the first part of call.

No problem. No problem. It wasn't on the slide, it was a verbal update. But I just will say that -- and maybe Dr. Lee wants to mention that complement remains an interesting target in the transplant space.

Right. And to add to that, I would say that we will still have the opportunity to look at the data from the patients that did complete the study, and we hope that it will help inform future studies for AMR [ and just really that may involve complement ] in patient.

Yes. Okay. Got that one. Then just in relation to IDELVION. If we look at Slide 51, there's been some really strong uptake over time but it looks like those sort of, I suppose that penetration has slowed a little bit. I'm just wondering as to what you think will drive growth for that product going forward. And then thinking a bit further into the future, as we think about AMT-061 as complementing or competing with IDELVION. And then within AMT-061, is there any patient groups that you think are more likely to give gene therapy a try? Any comments there would be appreciated.

So Bill, I'll let you talk to the share and to the patients, but just start by saying from a therapeutic area perspective, and we don't have the hematologists on. There's an exciting, we think, synergy between the 2 that there are places for IDELVION and places for patients needing gene therapy, particularly in more severe patients. But Bill?

Yes, thanks, Bill and David. I may just talk a little bit to the slide that you're talking about. You're right, the curves are starting to flatten, but I always have to chuckle a little bit when I get this question because these are shares that heretofore have been unseen in the hemophilia B space. When you're a 57% to 58%, 59% share is pretty incredible. And so nevertheless, is there still growth with this product? We believe, absolutely there is. We think that there's still growth in markets like the U.S. and markets where we haven't yet launched. And there are some large markets where we haven't launched such as France, such as Australia, such as Canada, and a number of others. So we think that there is growth not all of these patients have come on -- quite some time ago, some of these patients are still coming on, which is driving share, which will continue to drive volume in the future. So in so many ways, a model success story, I think, for our product to launch in the space. Transformational in so many ways, and we think that, that will continue. And I think you still see some growth in the markets that I've mentioned. In terms of AMT-061, I don't want to comment a lot on it. I think that there's a lot of regulatory mileage we have to go through at this point in time. I think that there are natural segments of patients that are going to look for that product. As great as IDELVION is, you're still infusing the product twice a month or in some countries now up to every 3 weeks but you're still infusing. I think there is a segment of the population that a single infusion would be quite exciting. And while it would be way too early to call the product or gene therapy broadly a cure, we start to move down that pathway if the data continues to hold up. And you could have a single infusion and not have to reinfuse for 4, 5, 8, 10, 12, whatever number of years, it's quite compelling, I think, for people. So I think there are some natural segments. And I think assuming regulatory approval and our formalization of the partnership with uniQure, we will spend a lot more time talking about what those segments are and where we think those patients will come from within product and across products.

Thanks, David. Our next question comes from Sean Laaman at Morgan Stanley.

I also have a question on potential development of the hemophilia B market. So sorry for laboring the question, but you gave away sort of essentially 2 years head start to Alprolix with IDELVION, but it's a real testament to the company in terms of giving away such lead time, the market share that you've been able to generate. So really talks to your commercial expertise and I guess, the quality of the product. And looking forward, you talked about EtranaDez potential commercialization in 2022. Our best guess for Freeline in 180a is 2024. But look at the, I guess, sort of small data sets we have to date, I think you're talking to median activity levels with EtranaDez of Factor IX of about 41%, where I think, I think Freeline is showing between 50% to 150%. So is there any commentary that you can give us on why the bet on uniQure and not elsewhere? And perhaps see some broad comparisons, if you're able, of the 2 technologies? And why or why not that clinical data might be relevant or irrelevant?

So thanks for the question, and thanks for listening. So we really can't say much. As we've said before, I think we are very -- we're very assured of the quality of the data that we investigated before we made the deal and the quality of the science that goes into it. And like the program that was put together. But beyond that, I'm talking about competitive nature and comparing technologies, I really can't say much at this time.

No problem. That's the only question that I had.

Thanks, Sean. Our next question comes from Hashan De Silva at CLSA.

One for Dr. Doyle or Bill Campbell here. Just on Garadacimab. I'm just trying to figure out where it will sit in the treatment paradigm for HAE given patient familiarity with C1 restoration and anti-kallikrein therapy. And is there anything in the data that you're seeing at the moment that might indicate superiority over Lanadelumab? And if so, will you look to do a head-to-head trial?

Yes. So I'll ask Dr. Doyle to comment first on our profile, and then Bill Campbell, maybe can add to that.

Yes. I mean as Bill has mentioned, it's not our practice to comment on competitors but we're very encouraged by the data that we've seen from our Phase II study with Garadacimab and really looking forward to initiating our Phase III study, and -- which will be obviously in more patients than we were able to study in Phase II. But so far, the results are very impressive.

And I would just add before I turn it to Bill, that head-to-head trials in rare disease is a really hard thing because it's hard enough to do a placebo-controlled trial and get enough patients to see the margins. But to see a margin beyond active product becomes very, very challenging to do. But -- not impossible, but very challenging. Bill?

So Hashan, I think what I would say is a couple of things. We've been in this space a long time. We've talked to a lot of treaters, and we've talked to a lot of patients over the years. And while convenience is nice, efficacy trumps everything. We think that was the case with HAEGARDA when it came to the marketplace. And while it's way too early to project the Phase II results on a Phase III trial. If, in fact, they hold up, we think it is another level of performance relative to efficacy that would be quite difficult for patients to not want to try and use. Number two, it is a small dose. Subcutaneous therapy with, we believe, what will be -- sorry, true monthly dosing, not dosing every 2 weeks, or maybe stretching that dose to a month and getting lower efficacy. We think we'll have a very strong efficacy profile with monthly dosing. And that's what the trial will have to prove out. We've got a lot of effort around designing the trial and talking about what a target product profile would need to be the leading product in this marketplace given HAEGARDA and given Takhzyro. And we have proceeded with a very strong bullish approach. We think this is a game-changing product, much like HAEGARDA was in the space.

Great. And my second question, just on GvHD for Dr. Lee. Can you just talk about the adverse events or the tolerability profile of AAT in this indication? And given the unmet need, is there any plans to initiate a trial in pediatric patients?

Thank you for your question. I will answer the question about pediatric patients first. As in the prophylaxis study, we will be -- after our last interim analysis, we will be -- in the dose-ranging part, we will be adding adolescents to the double-blind, placebo-controlled part of the study. I believe your other question was about the safety and tolerability. As seen in the previous studies, it's very much like the tolerability profile that's been already demonstrated with Zemaira in patients with congenital deficiency of alpha-1 antitrypsin.

So generally benign adverse event profile, we would say and encouraging, of course, in this population that gets so many adverse events.

Thanks, Hashan. Next question comes from Gretel Janu from Crédit Suisse.

Firstly, just on transplants, just given the limited treatment options available for GvHD. Do you think doctors are already using AAT for the treatment? And do you expect more off-label usage or off-label usage to start as the trial is ongoing here?

So we won't comment on off-label use, whether doctors are using it already, Laurie?

I'm not aware that they're using it already in treatment or in prophylaxis for that matter.

Okay. Fair enough. And...

It is why we wanted to partner with a bone marrow transplant group to make sure we got ahead of that with a well-controlled trial early.

Yes. Makes sense. And then just on HAE and the market there. I guess how much more do you think that prophylactic market can grow? Are we at a point where we are reaching full penetration of the prophylactic market?

Bill, I think that question's for you on the prophylaxis market.

Yes. Thanks, Bill, and thanks, Gretel. I think there is more room. I don't think we're at the top end yet. It is a market that's surprised to the upside a little bit in terms of the speed at which it's grown. But I do believe there is some additional growth for a number of reasons. I think the products that are out are largely well tolerated. There's greater promotional noise around the value of prophylaxis. There is an oral product that you're likely aware of from BioCryst as well, and that will add another voice and set of activities around it. So I absolutely think that there is more growth. I think there's patients that are still to this day, treating with a protocol of kind of high on-demand therapy use. And I think could benefit from a prophy regimen. And then there are some non-biologic patients out there -- using non-biologic products for treatment as well. So I think that there is some. I think it's not the majority, Gretel. I think it's -- we're -- we probably have tipped to the 80% range at this point.

Thanks, Gretel. Next question comes from John Deakin-Bell at Citigroup.

My question was just to Andrew. Going back to Slide 27, where you talked about the anti-FcRn mAbs. You commented that for CIDP, you think it's less likely that, that will work, and it's probably the #1 question I get from investors given the size of that indication for Ig. Could you just elaborate a little bit more? And I think you and others in the firm have repeatedly said that over the last few years, but with not much detail. Just elaborate what is it that makes you think whether it's the mechanism of action or some other reason why it's less likely that FcRns will work with CIDP.

Andrew?

Yes. So it is related to the mechanism of action. So if you have a look at the diseases where the anti-FcRn antibodies have been trialed in the first instance, it's myasthenia gravis and ITP. And they are 2 autoimmune diseases that are very clearly mediated by autoimmune or auto antibodies. And what the FcRn antagonists do is lower the general antibody levels by around 80%. And so at the same time, they reduce all antibody levels, they reduce the levels of the autoantibody. It's much less clear that CIDP is an autoantibody-mediated immune disease. There's some evidence of the role for autoantibodies, but the jury is still very much out as to whether antibodies are playing a role in that pathology. So that's the main rationale.

And I'll just also -- thanks, Andrew. I'll just also repeat that we've now conducted the largest, best controlled clinical study, dose-ranging of CIDP out there. It was a challenge to run. We're proud to have run it and had excellent results. And so good luck to the next developer. That's all.

Good. Thanks, John. Next question comes from Dave Stanton at Jefferies.

Again, just a follow-up from a previous question. Could you tell us the time -- I just want to reconfirm the time line for the readout of the IMAGINE trial that you talked to on Page 73, is calendar -- sometime calendar '24. Is that what we should be thinking about?

Good luck.

If I can talk to the enrollment. So it will be a 2-year enrollment period. So that would put us at the end of 2021 for enrollment and then 52-week treatment period. And after that, we would have the data analysis and the time to file. So I'd imagine that would be file in sometime in 2023.

So yes, sometime in the beginning of 2023 or something, we take to file, depending on enrollment.

Okay. So it's just that it says up to week 260 here. So can you explain the week 260 comment there?

Right. So the interim analysis is based on kidney function. So by definition, a decline in kidney function means you're on the way to graft loss. And with this, the FDA has agreed to consider accelerated regulatory approval based on preventing a decline in kidney function after patients have been treated for a year. So that's what our interim analysis is based on. And that's based on 200 patients who have been treated for a year. Patients will continue to enroll in the study, and we'll enroll a total of 350 patients. And the final analysis will be on all of those patients after they have completed 5 years, and that's a time-to-event analysis for graft loss.

All right. I get it now. Sorry it's for the dummies here. But -- so you're counting as a part of its expedited approval -- or potential expedited approval at this stage, do you -- you don't have expedited approval because you haven't got the interim analysis data as yet?

That's correct. We don't want -- I mean, we can't get the approval until we file. We have had regulatory interactions that would support that strategy though.

Thanks, Dave. Ladies and gentlemen, we've actually run over time, but we do have a few more minutes for a few more questions, but we'll have to draw at a hard close on the quarter hour. Our next question comes from Chris Cooper at Goldman Sachs.

A quick follow-up. Just I know this truly wasn't a focus on the conversations today, but I noticed you've had an mRNA vaccine, your preclinical flu pipeline. Should we be thinking of that as a very long-term project? Or is it possible that the huge body of work in that space has sort of made that a slightly near-term opportunity than you might otherwise think?

Sure, Chris. I mean I think at this point, it's a longer-term opportunity, yes. You're right, there has been a lot of interest in mRNA vaccines right now. And whether they help or hurt the cause, I guess, we'll find out over the next year. But we'll continue to progress this and let you know more next year.

Good. Thanks, Chris. Our next question comes from Sean Laaman at Morgan Stanley.

As it relates to BERINERT and just the future of that product. I mean given the success of HAEGARDA and where you are at that time line with respect to converting patients over to prophylaxis, I'm wondering if you could give us some comments on forward looking on the future of BERINERT and maybe even sort of the relative market positions of BERINERT versus HAEGARDA would be really useful.

Thanks, Sean, for the question. Bill, maybe you take that?

Sure. Thanks. And thanks, Sean. It's -- I always enjoy talking about the HAE business, and BERINERT has been a critical part of that. It has declined, as you would expect. The volume has declined. BERINERT, as you know, was never indicated for prophylaxis and was really a fantastic product but used for on-demand therapy. There was a number of patients that used it as a prophy before the launch of HAEGARDA, and that's largely now gone away. BERINERT still, however, serves an important role for patients that might have a breakthrough attack on one of the products that they're on, whether it's one of the other biologics or something else that they may be on. So there's still a strong position for BERINERT. It is not anywhere near the size of HAEGARDA. And it may get a bit confusing as we go forward and report out on some of our global launches now because in many markets, HAEGARDA will be referred to as BERINERT subcutaneous. And so you think of it as HAEGARDA but it will be under the BERINERT subcutaneous label. But BERINERT, on its own, still an important therapy for us. Still contributing, frankly, significant revenues for the franchise, and I think will for the foreseeable future.

Thanks, Sean. So last question comes from David Bailey at Macquarie.

Just focusing on KCENTRA on Slide 59, I think. I just wondered if you could talk to the role of KCENTRA in diet reversal versus some of the Factor X -- will be Factor X product out there maybe from a clinical outcome perspective. I just want to try to understand when that use will be an ongoing driver going forward. And then of that 66% being off-label, just wondering what proportion is relevant to diet reversal versus other uses?

So I'll just -- before I turn it over to Bill, I just will mention that these Factor X reversal agents are out there but there's still a lot of clinical interest in KCENTRA in this area as well. Bill?

Thanks, Bill. And David, clearly KCENTRA is used to reverse a number of the oral agents. And you don't see it on this slide, but it's picked up within the all other, as you would suspect. And to sort of put a little finer point on it, I would call it, a bit more than 20% to 22% of overall KCENTRA use.

Thank you David Bailey for the last question. And thank you, ladies and gentlemen, for your interest today. If you do have further questions, of course, reach out to me, and I'll follow-up with the team. And with that, I'll close the meeting. Goodbye.

Thank you very much.

Thank you. That does conclude our conference for today. Thank you for participating. You may now disconnect.