Ladies and gentlemen, good morning, and welcome to CSL's Research and Development Briefing. It's Chris Cooper speaking, and online with us today is Dr. Bill Mezzanotte, Executive Vice President, Head of Research and Development at CSL. Bill is also joined by several of his senior team, and each will be introduced in a moment. As a reminder, the purpose of today's event is to share with you the strategy and progress across our research and clinical stage programs. In keeping with industry practice, we reserve detailed commercial updates for results cycles and next Capital Markets Day. 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-looking statement disclaimer within the slide deck. I'll now pass over to you, Bill Mezzanotte.
Thanks, Chris, and good morning, good afternoon, and good evening. It's a pleasure to be with you today, and I look forward to updating you on all the movement in our portfolio and try and answer your questions to the best of our ability. Next slide, please. So just a few opening comments on this agenda slide. Today's session is solely an R&D presentation, so there will be no commercial speaker as you're used to in the past, since our one R&D organization now seamlessly supports all three business units, making a single commercial representative in our minds, as we've had in the past, kind of incomplete. You heard from our commercial leaders from each business unit at last year's Capital Markets Day, and our plan is to alternate R&D days with capital market updates in the future.
There will, of course, also be commercial updates at both the half and full year results. Today's presentation and questions will all be directed towards R&D, and we will likely need to defer any commercial questions that you might have. Joining me today on the virtual stage are four of my senior R&D leaders. First, Doug Lee, our Head of Plasma Product Development, will take you through some of our exciting advances for IG, as well as our plasma platform in general. Doug has spent most of his career in the plasma space and has been with CSL for about 10 years. He's also one of the principal architects of our Horizon 2 program. Doug will then hand it over to the newest member of our leadership team, Marie-Pierre Hellio, Head of Strategic Development, who will give you an update across our therapeutic portfolio.
Reporting into Marie-Pierre are our therapeutic TAs and clinical strategy. Marie-Pierre joined us this past February, having spent more than twenty years at Pfizer in diverse roles across therapeutic areas, scientific platforms, and multiple geographies. She led the team responsible for their blockbuster Xeljanz, and more recently oversaw development approval for both the Comirnaty COVID mRNA vaccine, as well as the oral COVID therapy, Paxlovid. She holds a Doctor of Medicine as well as doctorates in immunology and molecular biology. Marie-Pierre will then hand over to Jon Edelman, who leads our Vaccine Innovation Unit. Jon initially joined CSL Behring in 2011, then was recruited to the Seqirus team in 2015. Since being at Seqirus, he has had primary clinical responsibility for all of our vaccine improvements, development, and approvals, which have led to our strong position in flu today.
Jon will give you an update on our later-stage influenza and COVID-19 programs. Jon will then hand over to Deirdre BeVard, who heads our very diverse Strategic Operations group, which includes project management, clinical operations, asset development, patient engagement, and R&D digital initiatives. Deirdre's been with CSL for over five years now, and she brings to us experience in the diversity of roles and company types that matches the diversity of her responsibilities here. Deirdre will touch upon some of those recent efforts, some of our recent efforts, sorry, in automation, externalization, and patient engagement. Then I'll return for a short wrap-up. Also, unlike in years past, there will be no research update today. This was solely a decision on how to prioritize our time with you today, given the amount of information we in R&D have to share with you.
Be assured that our research efforts remain robust, and Deirdre will briefly touch upon that and Andrew Nash, our Head of Research, plans to attend the upcoming Wilson Asset Management meeting so for those listeners planning to attend, you can touch base with Andrew there. I did want to give you an additional update regarding Andrew. After almost twenty years of service, Andrew has decided to retire. He will be with CSL until the end of March, but will hand over the reins of day-to-day global research leadership to Mike Wilson in early December. This is a good news story of internal development and succession. Mike joined CSL in 2008 as the Head of Molecular Biology, and since then, he's had roles of increasing responsibility and influence-
Pardon me, we've temporarily lost connection with the speakerline. Please continue to hold and the conference will start shortly.
Hello, this is Bill Mezzanotte. I hope we're back. Somebody in Australia or Jon, confirm you can hear us?
Bill?
It's loud and clear. Please go ahead.
Okay.
You were, you were talking about Mike when you lost the audio.
Okay, so sorry about that. So as I said, Mike Wilson is taking over as head of research in December, and this is a good news internal transition and talent succession story. Mike's been with us as head of molecular biology and most recently head of the Melbourne Research Hub. I just wanted to acknowledge Mark Dehring for his support over the last seven R&D updates as he's retiring as well, and we appreciate all of his contributions. I think we'll go to the next slide then. On this slide, I'll talk about the five key takeaways I'd like everybody to take away from this meeting, other than the audio not working.
One is that we amplify our strengths. We continue to invest and innovate in our core platforms of IG, vaccine, and plasma to support future growth. Two, we're relentlessly focused on execution and on rapid advancement of our research and early development programs towards the late-stage development and registration. And to that point, we have four compounds close to registration and approval for key indications and key in key regions, which suggests our efforts are generating value in the near term. And fourth, we have experienced a few late-stage setbacks, which unfortunately is not unusual in R&D. However, each of these products have promising follow-on indications, which we are actively pursuing. And last, with our exciting Phase 2 and Phase 3 portfolio, which you'll hear about today, the future remains very bright for CSL. Next slide, please.
On this slide, I wanted to update you on the key submission and approval activity for the four important products I mentioned on the last slide. In the red are either submissions or pending approvals. First, let's go to Hemgenix. We now have approvals in many major markets and expect even more in twenty twenty-five, particularly in European countries. In Japan, we just recently had our last patient in, which was over one year early, earlier than we had planned. We will plan to file for accelerated approval as soon as we can integrate data from this patient into our overall data set, which will take a while. Marie-Pierre will speak more later regarding the continued positive data from our long-term Hemgenix studies.
Second, for Kostaive, our self-amplifying mRNA COVID vaccine, we are now approved in Japan as a COVID booster and are anticipating EMA approval in 2025 as well. In the U.S., we anticipate filing for approval in 2025. We're weighing some additional CMC data on a different presentation of Kostaive, and we'll need to integrate some data on the latest COVID-19 variant to support the FDA submission. But we plan to do this in the next calendar year, and Jon will update you more. Regarding RiaSTAP, Doug will discuss our updated process for Europe, then Marie-Pierre will discuss our trial to support an EMA submission for acquired fibrinogen deficiency. I'm happy to say that in the U.S., we plan to already file for the same indication in 2025 based upon our current data and process.
As Marie-Pierre will mention, these efforts will importantly contribute to the overall company Patient Blood Management strategy. Finally, for garadacimab, we are in the late phases of regulatory review with the EMA in Europe and the PMDA in Japan, and remain hopeful for on-time approvals in both regions by early twenty twenty-five. In the US, we received a Complete Response Letter from the FDA due to needing more information on our manufacturing process, such as our method of sterile filtration. Importantly, there were no safety or efficacy issues identified, and Marie-Pierre will refresh the exciting clinical data we have on this medicine and why we remain excited about its potential. Many of the issues were raised during the FDA review and inspection, and we've actually already been working closely with the agency during the review.
However, our supplemental submission with data occurred late in the review cycle, and the FDA needed more time to review our data. We are currently working with the agency to address outstanding questions as quickly and completely as possible. Pending confirmation of our plans with the FDA at an upcoming meeting, we expect to refile soon and anticipate a U.S. approval in the first half of twenty twenty-five. Our projected timelines for EMA and PMDA approvals remain on track. Next slide. This slide reflects the FY twenty-four objectives R&D had as an organization. The format should be familiar to many of you. While this slide represents some of the success we planned to achieve last fiscal year, it is first and foremost a standard of excellence in execution we want to meet or beat.
Experiments may succeed or fail, health authorities may come to different conclusions than we do, and standards of care may evolve during the course of a trial. However, in our R&D organization, we focus on those things we can control, such as delivering on or ahead of time, to budget and to quality, and getting to critical decision points as soon as possible. Across this wide spectrum of results delivery on the slide, I want to highlight the only three objectives which we did not meet. First, in immunology, as a result of strategic portfolio review, we elected to deprioritize the indication of hidradenitis suppurativa with CSL324, and so we did not start the planned Phase 2 trial as listed.
Instead, we pivoted the same molecule to prophylaxis of sickle cell disease, where our preclinical evidence is strong, and where we will be starting a Phase 2 trial for this indication this year. Second, in the transplant area, regarding the clazakizumab program for antibody-mediated rejection, we stopped the trial early for futility and so did not reach the hoped-for 200 patients. Antibody-mediated rejection is a very challenging area. However, we still made scientific progress and substantially enhanced our reputation within the transplant community. Marie-Pierre will discuss this program a little more, as well as our progress and other indications for clazakizumab. And finally, in vaccines, we did not file Kostaive in the U.S. as planned due to FDA requirements that I mentioned earlier. We're confident, though, that we can integrate the additional clinical and stability data that are already underway to support filing in the U.S. in twenty twenty-five.
As a note, all the other objectives on this slide were met. On this next slide, CSL continues to spend 10%-11% of our global revenue on R&D efforts. As you see on the left-hand pie chart, these efforts are split into four main buckets: our work on plasma, vaccines, recombinant, and other platforms, and our post-marketing efforts. Another way to look at our overall budget is by category. On the right, 65% is spent on new product research and development across the platforms, activities that are focused on innovative new therapies for life-threatening diseases. The other 35% is spent across the platforms to bring our current therapies to new markets and to make improvements to products or processes. Either way, we are mindful of not just following exciting science, but also of our financial stewardship.
We use active portfolio management to constantly review and winnow our portfolio to spend on our most promising programs. We also employ strategic partnerships across the value chain to efficiently add to our own expertise, to help accelerate programs and improve their probability of success. We are also continuously seeking productivity gains to achieve more cost efficiency or develop more products for the same cost. We also phase our investments and programs across our stage-gate system. And importantly, in our larger clinical trials, where appropriate, especially in Phase 3, we employ futility analyses with clear go, no-go criteria. While at times, this strategy leads to unexpected stopping of programs, such as with clazakizumab, it is one way for R&D to use our resources in the most cost-efficient way possible, while still allowing us to take the kind of risk that is necessary to achieve true breakthrough therapies.
So we plan to continue all of these practices I mentioned in the future. Next slide. On this slide, we show our updated therapeutic areas and strategic platforms as a result of our annual portfolio review. On the bottom platform bar, our four focus areas have not changed. Our genetic medicine efforts will combine our emerging expertise in both gene therapy as well as mRNA. However, we plan to build this expertise methodically for both preventative and therapeutic approaches to support the next generation of rare and serious diseases. Looking at the therapeutic areas, importantly, we have now created a separate TA for immunoglobulins to ensure we maximize efforts and focus for this critical enterprise asset. Our work will span across devices, presentations, and indications, and Doug will mention some of them, and consider complementary opportunities to the core products. Within this TA, we'll set the nebulized IG program.
Except for our Alpha-1 antitrypsin program, we have deprioritized the other respiratory programs to enhance our focus. We've taken the remainder of non-IG immunology efforts, such as garadacimab, and combined them with our legacy transplant area, because many of these research and clinical efforts are complementary, but we remain committed to both of these areas. Hematology and vaccines remain largely the same as before. Finally, as many of our cardiovascular opportunities and renal opportunities overlap, we've combined our cardiovascular efforts and renal efforts across the enterprise into one TA, primarily supported by CSL Vifor. With that, I would like to turn the podium over to Doug to speak about amplifying our strong heritage in both plasma proteins and particularly IG. Doug?
Thank you, Bill, and it's a pleasure to speak to everyone today to bring this focus and to focus on the update of those R&D activities that are associated with the plasma technology platform. This platform, as Bill indicated, is foundational to CSL, both from a patient as well as a commercial aspect. As a platform, we continue to provide innovation to the larger business in more modern processes, new drug presentations, as well as new plasma therapy opportunities. In the next few slides, I'll provide you some insight into a few of these development areas. The plasma product platform has a lot of focus. It's got a lot of focus on the IG space while maintaining vigilance in other plasma protein development areas.
Over the next set of slides, I will take some time to update you on some of the areas of our IG franchise and the multifaceted approaches that R&D is using and doing to provide for a solid supply chain, therapies, and patient convenience. The latter slides will focus on new product opportunities that are non-IG related, but plasma-derived nonetheless, and then finally, I'll close with a description of a new platform area that's intended to provide R&D support to our plasma collections business, and this will be referred to as the Plasma Innovation Platform Strategy Group, so let's begin and first speak on the yield maximization work that we're doing, and this slide is intended to provide a perspective on our Horizon 1 and Horizon 2 activities, which is a series of categories of work.
While both are operating in parallel, each one has its unique level of complexity and timing. Horizon 1 is a set of activities that builds on the already well-established, solid Privigen and Hizentra process. In a series of multiple improvements, the goal is to obtain more yields from the current process. These are near-term improvements, which are currently in various stages of deployment in the manufacturing network. Horizon 2 is a set of activities that focuses on the development of new, highly innovative, and proprietary IG process. It's important to note, our intention is to have both Horizon 1 and Horizon 2 processes interchangeable. That is, producing Privigen and Hizentra from either process, resulting in a product that's considered comparable from a regulatory and patient perspective.
I'll elaborate more on this point in a couple of slides. The next slide goes into a few more details on these two important programs.
As I indicated before, Horizon 1 is about taking something that's very good and making it better. Today, the current Privigen and Hizentra processes are effective ones for providing a highly purified, safe product to our patients. The current process that's in operations is the starting point for our Horizon 1 work. The Horizon work entails modifying targeted unit operations and their associated processing parameters to increase yield while maintaining product quality. Once in place, the combination of these activities is expected to provide higher IG yields relative to the current platform, additional manufacturing capacity or production throughput, while providing a straightforward regulatory path to introduce these improvements. In fact, some of these improvements have been recently approved and are in various stages of network deployment. Finally, the analytic data derived from the Horizon 1 work will underlie the Horizon 2 work as well.
For Horizon 2, this is considered a next-generation IG process. It's intended to be an exceptionally higher-yielding process compared to today's processes, and provide product comparable to the current Privigen and Hizentra products, in both terms of safety, purity, quality, and all those attributes that make Privigen and Hizentra the products they are today. We expect it to operate at a smaller footprint, being industry disruptive. It will be a novel, proprietary process for us, with novel patents in creating new intellectual property positions for CSL. As a totally new process, the Horizon 2 will require a new regulatory filing, which I'll go to on the next slide.
The reminder I stated earlier, the intention here is to have both the Horizon 1 and Horizon 2 processes interchangeable, producing products that, from either process, will be considered comparable from today's processes, both from a regulatory and a patient perspective. To achieve these goals, we're partnering with health authorities early and consistently to update them on our progress for both programs. Obviously, we need to be transparent as early in the development process as possible, to communicate our progress and address health authority concerns in a proactive manner. Obviously, this will be a data-driven exercise. So to this end, we intend to provide data from all key development streams, ranging from process analytics to preclinical animal studies. We'll use that same data to refine our development and development direction and strategic goals.
Also, this data will be used to demonstrate in the future process reliability and to ultimately demonstrate product comparability between the current and these next-generation processes. Our intention is to build a healthy and open relationship between the health authorities and ourselves. The next slide shifts the conversation from an innovation of production processes to innovation that provides for patient convenience. The prefilled syringe program for Hizentra represents those lifecycle management activities intended to bring more convenience to the patients, and these particular offerings are currently available to the patient market. The Hizentra prefilled syringe represents CSL's commitment to offering the best patient experience, and we are the first and only provider of such devices for subcutaneous IG. We provide a variety of delivery sizes for subcutaneous IG, ranging from five to 50 mL. The 50 mL prefilled syringe is the newest offering.
It's approved in the U.S. and Canada, and launching in Europe. The 50 mL size is an important addition for patients requiring higher volumes of Hizentra, such as those suffering from CIDP. These combination product offerings have a unique health authority requirement that combine those requirements for drug product, as well as those associated with device regulations. For IG, CSL continues to seek new options for drug delivery and patient convenience. The next slide shows another new presentation for IG that's unique and opens up a new market opportunity. Nebulized IG, as Bill mentioned, is a new product in development to treat non-cystic fibrosis bronchiectasis. My colleague, Marie-Pierre, will address the clinical aspects of the program in a few moments. But from a process development standpoint, this represents a new drug product for CSL. Combination product development, as I noted up earlier, has distinct challenges.
Through the course of product development, the required synergy between the protein and the device can be uniquely challenging. That said, R&D has been able to address these challenges to progress this program as we head toward a Phase 2 clinical trial. Nebulized IG is a new drug product that requires a novel, unique formulation designed to maintain product stability and is appropriate for nebulized drug delivery. From a pure drug delivery standpoint, we're partnering with a device company to provide a state-of-the-art nebulizer that's protein-friendly, meaning that the IG retains its native structure and function during the course of delivery. As a device, operationally, the nebulizer must deliver the product with the correct droplet size and correct velocity, such that the IG is available in the appropriate region of the lung while maintaining the protein's efficacy.
As challenging as this task is, our efforts in this specific combination product space continues to demonstrate promise. To date, we have a solid preclinical and Phase 1 package for the program, and now we are preparing for a Phase 2 clinical trial. Next slide, please. The prior slides were intended to demonstrate CSL's leadership in the plasma-derived IG space. While IG is clearly an important product to us, to patients, and the company, R&D's commitment includes other areas of plasma. The next set of slides shows R&D's commitment to a few of these other plasma or non-IG-related areas. This slide talks specifically about RiaSTAP and hemopexin, and it highlights these two plasma-derived opportunities, fibrinogen and hemopexin, which R&D has provided significant contributions. Both of these programs are in various stages of execution.
RiaSTAP or fibrinogen is a very familiar product to the industry and has and we have recently modernized this process with the introduction of an additional virus reduction step. We've established a facility at our Marburg site to produce the new product, and this new process is now approved in Europe. The other opportunity I'll mention here is hemopexin or CSL 889. This is a new plasma therapy offering coming from our research colleagues that's intended to address complications associated with sickle cell disease. From a process development standpoint, we've completed development of a production process that enabled our Phase 1 clinical trial. This same process is producing our Phase 2 drug substance, and the production is targeted to be completed this week for that clinical trial.
The next series of development activities for hemopexin will focus on the final process to enable both the Phase 3 and commercial production. The next slide brings forward a new area of interest for R&D, which I mentioned earlier, the Plasma Innovation Platform Strategy Group. In this new entity, R&D is partnering with plasma operations, that is the collection side of the business, and our I&T colleagues to support innovation in the area of plasma collection. This is a highly collaborative construct that incorporates key innovation areas from the three functions mentioned. It goes without saying that plasma is a critical raw material to CSL and is the source of our key commercial products. Our goal with this new PSG is to bring innovation opportunities to our collection side of the business, to ultimately benefit the donor and the donor experience, and ultimately, the patient.
We also desire to support the optimization efforts of the collection platform to further reduce the overall cost per liter. I'm excited about this new Plasma Strategy Group, and I look forward to seeing the innovation it will bring in the future, so in the next slide, I'll bring my section to a close, so I have a couple of comments before I transition to Marie-Pierre. CSL continues to invest in innovation for the plasma protein platform. These innovations include process modernization, improvements, and in some cases, completely new processes for our existing commercial plasma products. Horizon 1 and 2 are today's prominent examples. In addition, we are continuing to mine plasma for new opportunities, including new plasma protein therapies. I mentioned hemopexin and nebulized IG.
As in the case of Hizentra, the subQ product, CSL continues to look for opportunities to improve the lives of our patients with additional convenience offerings, such as the prefilled syringes. In conclusion, I'll add CSL is continuing to build on a legacy of innovation for plasma product development that provides a solid platform for future expansion. Immunoglobulins continue to be an important focus for CSL's plasma platform and CSL as a whole. IG is recognized as a key product to fuel future CSL growth. CSL R&D continues to innovate in the plasma therapy space with new product offerings in development, as well as novel technological innovation for existing products. These plasma innovations from R&D demonstrate CSL's commitment to patients, and now I can add donors.
As I close, I'd like to hand over the presentation to my colleague, Marie-Pierre, who is responsible for our clinical, strategic, and therapeutic development areas. Thank you for your time.
Thank you, Doug, and good day, everyone. As our leader, Bill Mezzanotte, keeps reminding us, we are in the business of hope. Today, I am pleased to have the opportunity to share our excitement for CSL's therapeutic portfolio and give updates on some of the programs where we are delivering hope to the patients who wait for these medicines. Over the next decade, we will bring innovative new medicines to patients with rare and serious diseases, where the unmet medical need remains enormous. Rare diseases are individually rare, but collectively common. They affect nearly 400 million people globally, and only 5% of the greater than 10,000 known rare diseases have U.S. FDA-approved treatments. Our portfolio is anchored by our immunoglobulin franchise and our hematology patient blood management products.
We have also built a transformational pipeline, which includes a robust set of recombinant and gene therapy programs in our refocused therapeutic areas. Next slide, please. IG replacement, building on Doug's presentation, I'll start with ongoing development programs that aim at expanding our immunoglobulins franchise. We have several programs focusing on both immunoglobulin replacement and immunomodulation. With Privigen and Hizentra, we already serve patients with primary immunodeficiency, chronic immune thrombocytopenic purpura, and chronic inflammatory demyelinating polyneuropathy, and in Europe, secondary immunodeficiency. We are looking at a number of life cycle opportunities, including expanding our label in the U.S. with SID, and treating other autoimmune disease disorders, like post-COVID POTS. Starting on the next slide with IG replacement.
Hizentra and Privigen are approved for secondary immunodeficiency in multiple countries outside of the U.S., and achieving an SID indication in the U.S. will expand IG use in, into hematologic malignancies and B-cell targeting therapies to manage serious and recurrent infections, which are major causes of death in diseases like chronic lymphocytic leukemia and multiple myeloma. Placebo-controlled randomized trials of IG replacement in patients with CLL and hypogammaglobulinemia are extremely difficult to enroll, because IG replacement therapy for the prevention of infections is already well-established and recommended in clinical guidelines. Therefore, novel approaches to demonstrate benefit for registration are necessary, and we are actively engaged with health authorities to discuss opportunities for data generation. For example, in CLL, we plan on conducting a hybrid study in patients with hypogammaglobulinemia and at high risk of four infections.
This study will include a prospective treatment arm of Hizentra that will be compared to a real-world evidence control arm. We are also exploring opportunities to generate data in multiple myeloma and CAR T-cell therapy. As you can see on the next slide, a natural expansion of our expertise in autoimmune therapy with Hizentra is to develop and launch an indication for post-COVID postural orthostatic tachycardia syndrome, a complication of COVID infection. This condition, known as POTS, is a dysregulation of the autonomic nervous system, for which there are currently no approved treatments. Symptoms can leave patients unable to work and even partially bedbound. The incidence of POTS has risen dramatically with the COVID pandemic.
While the exact mechanisms behind post-COVID POTS are not well understood, we believe several could be directly impacted by IG therapy, including the role of complement activation, immune complexes, and presence of autoantibodies targeting the autonomic nervous system. All three mechanisms are also documented in CIDP, for which Hizentra has demonstrated significant benefit and is already approved, and as described on the next slide, we are currently conducting a single pivotal trial in agreement with the FDA. This is a double-blind, randomized, placebo-controlled study in participants with post-COVID POTS. Patients will be randomized to receive subcutaneous infusions of Hizentra or placebo for 24 weeks, followed by an open-label treatment period. The primary endpoint is the proportion of participants no longer meeting diagnostic criteria of post-COVID POTS. The study recently started, and enrollment is ongoing.
Now let me share the outcome of our Phase 3 trial of Hizentra in dermatomyositis, another complex autoimmune disease for which there is a need for effective and safe therapies. In the RECLAIM pivotal trial, we investigated the safety and efficacy of Hizentra in patients with dermatomyositis. The study was composed of three periods, enrolled 134 participants, and period one recently completed. The primary objective was to assess the efficacy of Hizentra in comparison to placebo, as measured by responder status based on the Total Improvement Score assessment at week 25. This score records all improvement in six core set measures of DM associated with disease activity. Unfortunately, the study did not meet the primary efficacy endpoint. The responder rate in the Hizentra treatment group was within the expected range, but was not different from the placebo group.
As a result, we've made the decision to discontinue the trial. There were no safety concerns that contributed to this decision, and importantly, Hizentra remains a safe and effective treatment option for its currently approved indications, but we are not done with immunomodulation, and we will continue to explore the potential benefit of immunoglobulins in helping patients with other complex autoimmune diseases, as we are doing with post-COVID POTS. Now turning to our nebulized IG program. You have heard earlier from Doug how we are innovating by delivering IG directly into the lungs to reach the site of action to exert its biological activity. CSL787 is a novel human polyclonal plasma-derived IgG formulation designed for nebulization, and our next IG opportunity to potentially transform the lives of patients with non-cystic fibrosis bronchiectasis by preventing infection-related exacerbations.
Globally, the estimated prevalence of bronchiectasis is on the rise, with approximately one million diagnosed patients in the United States, Europe, and Japan. As you can see in the schematic, patients with this condition often present with excessive mucus production and recurrent exacerbations. Over time, chronic inflammation may predispose to future infections, manifesting as a sick, vicious cycle, resulting in structural damage to the airways, leading to significant morbidity and mortality, as well as a decrease in quality of life. Today, there are no approved treatments modifying options beyond supportive care. Therefore, there is an urgent need for novel treatments. We believe that a nebulized delivery of IG to the lungs can provide broad-spectrum anti-infective activity without risk of resistance development, and also reduce localized inflammation and restore immunity in these patients.
As you can see in the next slide, we have recently generated preliminary Phase 1 data in patients with mild non-cystic fibrosis bronchiectasis that support our confidence in this delivery approach of IG. One daily administration of CSL787 over two weeks was safe and well-tolerated and showed signs of pharmacodynamic activity with reduced mean bacterial load, as well as counts of Pseudomonas aeruginosa. Our next clinical trial will be a Phase 2b study to explore the safety and efficacy of CSL787 on pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis, and we plan on initiating this study in the first quarter of 2025 . For more than forty years, CSL Behring has had a strong legacy of delivering innovative therapies for patients with hereditary angioedema. Garadacimab is the first monoclonal antibody discovered and developed entirely by CSL.
It will complement Haegarda and is a significant advancement in the management of HAE. Garadacimab is a first-in-class recombinant factor XIIa monoclonal antibody inhibiting the top of the HAE cascade, leading to edema formation. Garadacimab consists of a once-monthly subcutaneous self-injection via an auto-injector and will be indicated for long-term prophylaxis of HAE attacks in adults and adolescents. It has orphan drug designation in both the U.S. and Europe, and is currently under regulatory review in the U.S., Europe, Japan, and Canada. As you heard from Bill, questions related to manufacturing and not safety or efficacy emerged during the FDA review, and we have been working with the FDA to ensure these questions are addressed as quickly and completely as possible.
We will continue to work closely with the agency, and we remain very confident in the potential of garadacimab, given its strong efficacy and safety results in patients with HAE, and on the next slide, you can see some of the robust efficacy results from the Lancet publication of our pivotal VANGUARD study, showing that once-monthly subcutaneous injections of garadacimab resulted in rapid and drastic reductions in HAE attacks. We recently reported long-term durability results from our open label expansion study, showing that garadacimab continues to provide sustained attack reduction over a median exposure of thirteen point eight months. Compared to the run-in, garadacimab reduced the mean HAE attack rate by 95% across the open label expansion treatment period. 85% of patients had greater than 90% reduction in attack rate, while 60% of patients were attack-free.
The long-term data also shows that garadacimab demonstrates a favorable safety profile suitable for chronic use. Our pediatric program is ongoing and expected to conclude by the end of 2025. We are very confident in the benefit-risk of garadacimab and continue working with health authorities during the regulatory reviews. As you may have heard from Hervé Gisserot at Capital Markets Day last year, minimizing blood loss, bleeding, and the need for transfusion through patient blood management is a key strategic area for CSL. I will now provide updates on two critical plasma and pharma general products of our PBM portfolio, starting with RiaSTAP. RiaSTAP is our fibrinogen concentrate, indicated for the treatment of acute bleeding in patients with congenital fibrinogen deficiency. Expanding the label to include acquired fibrinogen deficiency will enable CSL to fully unlock the PBM opportunity....
During the course of surgery, there is an increased risk of hemorrhage. Fibrinogen is the first coagulation factor to decrease in the surgical setting, where bleeding becomes problematic. Currently, the standard of care is cryoprecipitate or whole plasma to supplement the fibrinogen levels, which may be consumed during the course of the procedure. And as you can see on the next slide, we have aligned with German regulators on the study design for a Phase 3 study to compare RiaSTAP to cryoprecipitate in patients undergoing abdominal surgery for a slow, progressive, rare tumor, a procedure associated with excessive intraoperative blood loss. And I'm happy to report that the first patient was enrolled this month. I am also pleased to report that we have recently received positive feedback from the FDA on our proposal to file for an indication of fibrinogen replacement therapy, and we are actively preparing this submission.
The second cornerstone of our patient blood management strategy is Kcentra, our four-factor prothrombin complex concentrate currently indicated for warfarin reversal. To expand Kcentra's label, we have considered three potential indications: treatment of traumatic hemorrhage, perioperative bleeding, and DOAC-related bleeding. Let me start by explaining why we have recently decided to terminate the last Phase 3 trauma and PCC study we initiated last year. The primary objective of the TAP study was to assess the efficacy of a single IV infusion of Kcentra on all-cause mortality within six hours of randomization of patients with severe traumatic injury and acute major bleeding. Approximately 1,400 patients were enrolled. However, the blinded mortality rate was found to be lower than anticipated.
In many hospitals, the time needed to determine eligibility and for the study drug administration preclude sites from dosing the patients with the highest risk of mortality, and patients die before being treated with investigational product. Therefore, the feasibility of the study to achieve its objective under the current investigational conditions is unlikely. A strategic business decision was made to terminate the study. Importantly, there were no safety, no quality concerns involved in this decision. We will carefully analyze the data to learn more about how we can help address unmet needs for this patient population. As you can see on the next slide, we are immediately pivoting to the two other indications of perioperative coagulopathy and DOAC-associated bleeding. Firstly, perioperative coagulopathy is a frequent and a serious complication that can result in massive bleeding requiring transfusion.
Morbidity and mortality increase with the number of units transfused, and reduction of perioperative transfusion as a result of improved patient blood management practices, has been associated with a decrease in postoperative morbidity and mortality. PCC is included in international guidelines for the treatment of perioperative coagulopathy. We have developed a Phase 3 protocol that will be discussed with FDA this week. Secondly, the use of direct oral anticoagulants has steadily increased over the past decade. While DOACs have a lower risk of major bleeding compared to warfarin, acute major bleeding is the most common side effect of DOACs and occurs in 2% to 4% of patients. Bleeding cases are associated with high mortality rates. Currently, treatment choices include andexanet, as well as off-label use of PCC and fresh frozen plasma.
Kcentra to treat DOAC-related bleeds is already well established, included in guidelines, and noted as an option for reversal in all of the Factor Xa inhibitors prescribing information. We are designing a program for Kcentra to show efficacy in DOAC-associated bleeding, and we will discuss this with FDA soon. Let me now turn to another exciting program that has the potential to significantly change the standard of care of transplantation recipients. Hematopoietic stem cell transplant is a common treatment for hematologic malignancies. Stem cell transplant rates have steadily grown and are expected to continue growing. The main risk of transplantation is graft-versus-host disease. GVHD occurs when the donor immune cells attack the recipient cells, usually in the skin, GI tract, or liver, recognizing them as non-self.
Up to 50% of patients develop GVHD after hematopoietic stem cell transplant, and of those who develop acute GVHD, only 50% respond to corticosteroids. GVHD is associated with poor outcomes and high morbidity in both the acute and chronic setting, and mortality associated with the more severe grades of GVHD remains very high. We are studying the potential benefit of plasma alpha-1 antitrypsin to treat newly diagnosed acute GVHD. If shown to be effective in the acute GVHD, AAT would differentiate from other therapeutic options because of its safety profile. We are collaborating with the NIH Blood and Marrow Transplant Clinical Trials Network. We have been conducting a Phase 3, multicenter, randomized, double-blind trial of AAT versus placebo in patients with high-risk acute GVHD on background corticosteroids. The primary objective is to compare the overall response rate on day 28 post-randomization between AAT and placebo.
Patients that are non-responders or progress are considered to be steroid refractory, and we start next line therapy, mostly with ruxolitinib. Responders at day 28 continue to receive treatment until day 56. The trial has recently completed follow-up, and key data are expected early next year. We look forward to public disclosure by our NIH partner in the first half of 2025. Now turning to clazakizumab. As you are aware, we undertook a novel Phase 3 trial to explore the role of IL-6 inhibition to treat antibody-mediated rejection in kidney transplantation. Our decision to go forward was based on positive preclinical and Phase 2 data. Unfortunately, our planned fertility analysis indicated that we were unlikely to meet our ultimate primary efficacy outcome upon completion of the trial.
There were no major or new safety concerns with clazakizumab, and we consider the trial an important advance in transplantation for patients and CSL. We created a roadmap for regulatory success using a surrogate endpoint in this difficult area. We also created an important high trust partnership with academic investigators and health authorities, which will serve us well in the future, and as Deirdre will touch upon later, we've uniquely brought the patient to the forefront of the urgency of clinicians to engage in well-designed clinical trials, so while we are obviously disappointed in these results, we are proud of the efforts of the team, and we have in parallel, been investigating the role of clazakizumab in patients with end-stage kidney disease, which I will address on the next slide. End-stage kidney disease is defined as a permanent reduction of kidney function, which results in death without dialysis or transplant.
The prognosis of patients undergoing dialysis remains poor, and the mortality rate in the U.S. is significant. Cardiovascular disease is the leading cause of death in patients undergoing dialysis, accounting for at least 50% of mortality and contributing significantly to morbidity. To date, there are no treatments which have been proven to improve cardiovascular outcomes in dialysis. The role of inflammation in atherosclerosis and cardiovascular events is well documented, and chronic inflammatory response is known to be a prominent feature in dialysis patients. Markers of inflammation, including IL-6 and CRP, are strong predictors of cardiovascular outcomes in dialysis. In the CANTOS study of canakinumab, a monoclonal antibody that targets IL-1 beta, biomarker analysis showed that the risk of CV and all-cause mortality and MACE was positively correlated with IL-6 and CRP.
Importantly, IL-6 levels appeared to be predictive of the benefits of the treatment. As depicted on the graph, a reduction of CRP less than two milligrams per liter at three months led to a highly significant 25% reduction in cardiovascular risk. Clazakizumab is a monoclonal antibody that blocks IL-6 and has the potential to be a first-in-class transformative therapy for reducing cardiovascular events in patients with ESKD undergoing dialysis. In the next slide, you can see the design of the Phase 3 ESKD study. Our ongoing combined Phase 2/3 study to demonstrate that clazakizumab, added to standard of care, will reduce the risk of cardiovascular events in dialysis patients who have evidence of systemic inflammation and either atherosclerosis, cardiovascular disease, or diabetes mellitus.
The Phase 2b portion of the trial was a dose-finding study based on safety and CRP reduction, and the Phase 3 portion is the ongoing pivotal study to demonstrate a reduction in the risk of cardiovascular events with clazakizumab versus placebo, administered intravenously during the dialysis session. The Phase 2b portion completed earlier this year, and as you can see on the graph, clazakizumab at all three doses reduced robustly CRP at twelve weeks. This data was recently published in Nature Medicine. Approximately 2,200 subjects will be randomized and will continue until the target number of primary cardiovascular event is reached. The primary endpoint is the time to first occurrence of cardiovascular death or myocardial infarction. Enrollment is ongoing, and we plan on executing this study globally, including in China and in Japan, enrollment has already started.
The next two products I am going to talk about are all small molecules that came from our Vifor acquisition, and I'll start with Filspari. There is a strong rationale for developing new therapies for rare kidney disease, which account for greater than 30% of patients with kidney failure. We are innovating in this space through our partnership with Travere Therapeutics to bring to market Filspari for the treatment of IgA nephropathy, known as IgAN, and we have launched Filspari in Europe in August. IgA is the most common type of primary glomerulonephritis, and is characterized by the deposition of immunoglobulin A in the kidneys, leading to altered glomerular filtration and a progressive loss of function and kidney failure. Filspari is an oral, once daily, highly selective dual endothelin and angiotensin receptor antagonist, that directly targets glomerular injury by blocking these two critical pathways of IgA disease progression.
Filspari is the first non-immunosuppressive treatment approved for this indication, and as you can see on the next slide, in the PROTECT Phase 3 study, Filspari delivered superior long-term kidney preservation in adults with primary IgA, compared to the active comparator, irbesartan. At week 36, Filspari reduced significantly proteinuria, and at two years, Filspari improved the chronic slope of eGFR compared to irbesartan. Filspari is now approved in the U.S., Europe, and Switzerland. The second Vifor product that I will highlight is vamifeport, in clinical development for hemochromatosis, a genetic condition related to increased iron absorption from the GI tract, that leads to chronic deposition of iron in tissues. Vamifeport is a potent and selective ferroportin inhibitor that blocks intestinal iron absorption. Patients with hemochromatosis face a burdensome treatment with phlebotomy, which is ineffective and not well tolerated in about 20% of patients, and second line treatments have toxicities.
Ferroportin is a transmembrane protein that plays a vital role in iron homeostasis. It is regulated by the hormone hepcidin, which binds to ferroportin and causes its degradation. This limits the amount of iron that can be released into the bloodstream and made available to other tissues. In hemochromatosis, inadequate hepcidin results in increased intestinal iron absorption through unregulated ferroportin. Importantly, published Phase 2 results in patients with hemochromatosis have demonstrated clinical proof of concept with rusfertide, a peptide mimetic of hepcidin. Vamifeport has shown efficacy in two mouse models, reducing serum iron levels and preventing liver iron loading. Vamifeport was safe and well tolerated in a Phase 1b study in sickle cell disease patients, and we are currently planning a Phase 2 study in patients with hemochromatosis. Let me now touch on sickle cell disease, for which we have a couple of programs in clinical development.
There are no approved therapies for the excruciating pain of acute vaso-occlusive crisis in sickle cell disease. Sickle cell disease is the most common rare blood disease. It is an inherited disorder of red blood cells that causes vaso-occlusion and hemolytic anemia, leading to the recurrent severe pain crisis, organ ischemia, and other systemic complications, and reduced life expectancy. Intravascular hemolysis produces free hemoglobin that releases heme. Extracellular free heme is a potent inducer of inflammation, and in normal conditions, is cleared by hemopexin, a high affinity heme scavenger, plasma protein. However, in sickle cell disease, hemopexin is naturally consumed, with the extra free heme present in plasma. So as you can see in the next slide, hemopexin is our new plasma opportunity to reduce this extra free heme.
The goal of the clinical program will be to demonstrate hemopexin's effectiveness at reducing or possibly eliminating vaso-occlusive crisis. CSL889 has shown robust relief of VOC in sickle cell mouse model. It was safe and well tolerated in our Phase 1 clinical trial in adults with sickle cell disease. Our Phase 2 placebo-controlled dose escalation study will evaluate the efficacy and safety of CSL889 in patients experiencing VOC, and is planned to start enrolling in early 2025. CSL889 has the potential to be the first drug to market for acute treatment of VOC, and has orphan drug designation in the U.S. and Europe, as well as fast track designation in the U.S. As you heard from Bill, Hemgenix, our gene therapy for hemophilia B, is now approved in a total of nine countries worldwide.
I am pleased to report that three-year data from our clinical development program confirm the long-term effectiveness and safety of Hemgenix. Hemgenix has consistently demonstrated a favorable safety profile, with no new safety events reported at three years. Mean Factor IX levels remain elevated and sustained, showing durability of effect. 94% of patients did not require Factor IX prophylaxis, and 46% received no Factor IX replacement over three years. At four years, the data confirmed durability of effect, with activity levels at 37% and a decrease in Factor IX consumption by 96%. Our Hemgenix program for registration in Japan is fully recruited, and we are progressing our various post-marketing commitments with FDA and EMA. As I conclude this part of the presentation, I want to highlight for you some key numbers from our robust therapeutic pipeline with multiple modalities.
We have 21 products total in clinical development, of which 29% are plasma-based programs, 38% are recombinant, and 9% are genetic medicines. Six programs are in Phase 2, and nine are in Phase 3, all of which will have begun dosing by the end of 2025. As you can see from this chart, our portfolio is well-balanced across therapeutic areas, and our vaccines portfolio and technology play an integral role in CSL's R&D strategy. I will now hand over to Dr. Jon Edelman, our head of the Vaccine Innovation Unit, who will walk you through some of the key development vaccine programs. Jon, over to you.
Okay. Thank you, Marie-Pierre, and hello to everyone online. The Vaccine Innovation Unit that I lead is responsible for developing new vaccines and improving the ones we have. To do that, we leverage CSL's vaccine platforms, which I'll touch on during this presentation, and I'll focus on influenza and COVID. Let me start with flu on the next slide. Flu vaccines have long played a critical role in avoiding influenza morbidity and mortality, even contributing in the past several years to the extinction of one of the human flu viruses. Despite these benefits, there is still room for improving the level of protection current flu vaccines offer, and of course, with flu, there is always the threat of a pandemic arising when a non-human influenza virus makes the jump to humans. A quick history lesson on the next slide.
Since the start of the twentieth century, the world has experienced four influenza pandemics, each one changing the influenza subtype that remains in circulation among humans in its wake. Over that same period, the number of influenza subtypes that were circulating among people was increasing. As a result, the content of vaccines had to evolve, first from monovalent H1, then to bi, tri, and eventually quadrivalent vaccines covering H1, H3, and the two B lineages. Because since 2020, the B/Yamagata lineage has not been detected anywhere in the world, the WHO concluded in 2023 that this lineage is extinct, which, by the way, is a pretty uncommon occurrence for a virus to become extinct. As a result, flu vaccines no longer require B/Yamagata. The FDA was the first regulatory agency to demand that the B/Yam component of flu vaccines be removed.
And on the next slide, you will see that CSL has led the way in transitioning all of our flu vaccines back to the trivalent formulation, a task we were the first to complete for this current Northern Hemisphere season in the U.S., and that is for all of our flu vaccines. They are all trivalent. And in alignment with regulators in the U.K. and the E.U., we are on track for trivalent vaccines in the Northern Hemisphere of twenty twenty-five, and the rest of the world will follow shortly in Southern Hemisphere, twenty twenty-six. So that is really good news. What's more concerning, however, is the ever-increasing presence of avian influenza around the world, as shown on the next slide. At CSL, we are uniquely prepared to partner with governments around the world with the technologies that we have to be... Sorry about that.
Let me get myself back to the right slide. In the past year, a highly pathogenic H5N1 avian flu virus has made its way to the Western Hemisphere in all sorts of birds, as shown on the map, and most worryingly, has crossed over into multiple mammalian species. In the U.S., this now includes dairy cattle, and the virus has been passed from one herd to the next across many states. Normally, mammals who are infected with bird flu have direct contact with infected birds, and that's how they get infected. The fact that this bird flu has evolved to be able to be transmitted from mammal to mammal means that the virus has already gained the capability of significant concern to public health agencies and to us at CSL, and as we've seen before, people in close contact with infected animals have contracted the virus.
While so far in the U.S., the disease that people in the dairy industry have experienced is mild and self-limited, it's one step closer to the virus obtaining the ability to be transmitted from person to person, which is the prerequisite for another flu pandemic. As I was saying, at CSL, we are uniquely prepared to partner with governments around the world with the technologies that we have to be responsive to the threat from a potential future pandemic. Today, 30 governments have contracts with us using our cell culture technology and our MF59 adjuvant to be used to combat pandemic flu. And in the future, we expect to add self-amplifying mRNA technology to this effort.
Each of these technologies offer an important tool to make pandemic-specific vaccines in high quantities in a short time period, which is critical in responding to a pandemic. On the next slide, you can see that we offer three zoonotic vaccines. That is a vaccine approved for use in humans today that is targeted against animal flu disease. These three, Panvax, Audenz, and Aflunov, have all been adapted to target the current H5N1 threat and have already been approved in Australia, the U.K., and the E.U. In the U.S., the file has been submitted and is under review. In Finland, they have actually decided to vaccinate workers in their fur industry because they are at high risk of exposure by working with animals infected with this avian flu threat, and they are using CSL's Aflunov.
When it comes to seasonal flu vaccines, CSL is working to make improvements as well, and here's why. We know that being vaccinated with a flu vaccine has a very significant positive impact on your risk of getting sick from the flu and dying. But you can see from this slide of flu-related mortality in the U.S. over the past eight years, that flu continues to be a significant concern. Deaths from flu are a consequence of a variety of things, top among them, not getting vaccinated. But twenty seventeen-eighteen was a particularly bad season because the flu virus that was circulating that season was an H3N2 virus, and the egg-based vaccines that year were mismatched to the circulating strain. So people who did get vaccinated, and remember, the majority of flu vaccines are made in eggs, were also at higher risk.
And then during the COVID pandemic, influenza disease activity dramatically declined. But what you see in the post-COVID era is a return not just to the prior levels, but actually even higher levels of mortality. One factor that is amplifying this observation is the vaccine fatigue that people are feeling after so many COVID boosters. So it is no surprise on the next slide, that the U.S. Ad Council, the American Medical Association, and the CDC, have all undertaken a campaign this year to urge people to take advantage of this technology and get a flu shot as the best way to protect themselves, their loved ones, and their community. At CSL, we fully support this effort, but there are other things that R&D can do to make better flu vaccines using CSL's flu technology platforms, and that is what we are doing.
On the next slide, you will see that we are taking a three-pronged approach to produce a more effective flu vaccine using adjuvant, cell-based virus growth, and an optimized dose. Depicted on the left of this slide is an antigenic map, like the one that the WHO creates each flu season. It's based on the antigenic relatedness of all the flu viruses that they collect from worldwide surveillance of flu viruses. Each dot is a flu virus, and the distance between the dots indicates how closely related they are to one another. The WHO picks a virus for each of the three strains that manufacturers should use to make their vaccine against, one for egg-based manufacturers and one for cell-based manufacturers, and ideally, the virus they pick is antigenically related to the ones with the highest prevalence on the map.
Of course, they would always like to choose egg and cell viruses that are similar, but sometimes they must pick an egg virus that is less antigenically related to the cell virus because it has to adapt in order to grow in eggs. CSL is taking advantage of these three technologies to produce a new vaccine. The first is our adjuvant, MF59. MF59 is a booster of the immune response seen with standard dose vaccines. This is a meta-analysis of studies that compare the protective effect of Fluad, which is our standard dose egg-based vaccine containing the MF59 adjuvant, compared to unadjuvanted standard egg vaccines. Across multiple seasons in multiple studies, the adjuvanted vaccine provides better vaccine effectiveness than standard vaccines. On the next slide, you will see that the second thing CSL has to offer is our cell-based technology.
Here, we make the vaccine from viruses grown in mammalian cells, which always allows us to have an exact match to the target virus for the vaccine. In this meta-analysis, comparing egg-grown and cell-grown vaccines, again, over multiple seasons, you can see that there is an advantage to having that exact match with the cell-based vaccine. It's greater in seasons in which there was an egg mismatch, like in 2017-2018, but the advantage persists even when the egg vaccine and the circulating virus are matched, and that's because even when viruses grown in eggs are antigenically the same as the target virus, they must nonetheless have mutations that are required in order for them to grow efficiently in eggs.
We are combining these two technologies, plus the benefit of an optimized antigen dose that is higher than the standard, to create a new, better vaccine that uses the power of the adjuvant, the MF59, and the benefit of higher dose of antigen to be as broad as possible, covering as many of the viruses that people may encounter in a season. You can see that our Phase 2 data confirm the advantage that this vaccine offers for all tested strains compared to the standard vaccine. Our Phase 3 study is underway, with readout expected late in the first half of calendar year 2025. I'll note that while we did these studies using a quadrivalent vaccine, the data will support, and we are making the trivalent version. Let me turn my attention now to another approach to improving flu vaccines, and that's mRNA.
Conventional mRNA vaccines have been amazing during the pandemic, but there are still limitations that have been observed in the context of COVID. These vaccines are capable of offering protection, but with significant reactogenicity levels, at levels that are much higher than what has been seen with the flu vaccines that are currently used, but more importantly, the protection that these vaccines offer against COVID appears to wane fairly quickly, requiring frequent boosting to maintain protection. In the RSV field, where there have been both mRNA and protein-based vaccines, the protein-based vaccine, whether it has an adjuvant or it doesn't, has performed better, has offered better protection than the RNA vaccine, and in flu, the initial work with mRNA vaccines has confirmed the higher reactogenicity that was seen in COVID, but additionally, has shown inconsistent immunogenicity, particularly against the B strains.
Meaning that while RNA might be effective in raising antibodies that could be protective against the A strains, an effective flu vaccine needs to be effective against all possible influenza strains, including B. And furthermore, there's inconsistency in the efficacy that vaccines based on mRNA have demonstrated in older adults, which is the particular group at highest risk of complications from flu. We think that the next generation of mRNA-based vaccines that can offer a better approach are those based on the self-amplifying methodology that we at CSL are pursuing through our collaboration agreement with Arcturus. As a reminder, what self-amplifying mRNA vaccines add is an additional component called the replicon, that when introduced into the cell as part of the lipid nanoparticle, allows it to make copies of the mRNA of the antigen included.
As a result, for the same amount of mRNA administered, you get a much higher level of antigen produced over a longer time period. The consequence of this difference is the possibility of a better immune response, which is more durable and provides broader protection, all at a much lower dose. We've seen this come to reality in the context of COVID with Kostaive, CSL's self-amplifying mRNA COVID-19 vaccine. In the pivotal efficacy study targeting the original Wuhan strain, where Kostaive was used as a two-dose primary vaccine during the Delta wave of the pandemic, Kostaive provided protection against any disease of more than 50% and over 90% protection against severe disease. When Kostaive was used as a booster, on the next slide, you can see evidence of its durability.
Compared to the conventional mRNA vaccine in open circles, immunologic protection with Kostaive in the closed circles persists up to one year in both younger and older adults. In fact, at the end of one year, the titers against the Wuhan strain with Kostaive are about the same level as those seen at the peak effect with the mRNA vaccine at one month, and this is at a dose of five micrograms compared to 30 micrograms for the conventional mRNA vaccine, and next, importantly, the advantage of sa-mRNA over the conventional mRNA vaccine out to one year was not just against the variant in the vaccine, the Wuhan variant, but also against variants of concern that emerged as the pandemic continued, like the Delta variant and the BA and XBB variants of Omicron.
Just to be clear, these are patients vaccinated with Wuhan, but tested to see if they made antibodies against these emerging variants. This durability and breadth of coverage is a real advantage in COVID. Just this month, as you'll see on the next slide, Kostaive was launched in Japan, with vaccinations beginning on October eighth. The dossier is currently under review in the EMA, and we do expect action on that soon. As Bill said, we anticipate filing in the U.S. sometime in the first half of 2025, with an updated formulation. Looking into the future, of course, the next step for us in the sa-mRNA world is its application in the flu space. We're very excited with the ongoing Phase 1 programs that we have, and we look forward to updating you further at the next R&D Day with the progress we're able to make.
To conclude, what I'd like you to take away from my presentation is the importance that CSL's vaccine platforms play in bringing new and better vaccines to support public health in flu and COVID, and along with our recombinant protein expertise, we will continue to use these platforms to develop new vaccines in the future. Thank you for your attention, and let me now turn the presentation over to Deirdre BeVard, who leads our Strategic Operations group at CSL R&D. Deirdre, over to you.
Thanks, Jon, and greetings to everyone listening in. You just heard from my colleagues about how R&D has a diverse and exciting portfolio of promising opportunities for new therapies and vaccines. At CSL, we have a strong legacy of delivering on our promise, and doing so requires that we continuously innovate while also focusing on the sustainability of the business and the communities in which we work. So I have the honor of sharing some highlights, and by no means an exhaustive list, of the work we're doing, innovating in alignment with that strategy. In the next slide, I'll highlight some of our digital capabilities in product development. We recognize that a lot of companies talk about automation and AI activities, and although we're leveraging these capabilities, we don't often talk about it, so I want to bring that to your attention today.
Across our global R&D sites, we have autonomous labs that leverage automation and are connected with AI-powered data analysis in order to enable more productive and more efficient product development. Our scientists employ scalable, multifunctional technology platforms across our entire portfolio to facilitate data collection. This includes our scientific platforms for plasma, recombinant, and gene therapies. The technology has augmented several areas of process development. For example, we've experienced a decrease in the turnaround time for data collection and analytics results, enabling faster decision-making for process optimization activities. You heard reference to the importance of this data collection and the analytics in both Horizon 1 and Horizon 2 from Doug. The benefits of this technology support this strategically important program, as well as ongoing work in our current monoclonal antibody programs.
The advantage of these technology platforms is that they take a large portion of the routine lab work associated with compliant process development out of scientists' hands. Doing so provides a very efficient way to collect data, which maximizes our throughput. With this automation, not only is the data collection accelerated, it's done so with improved reproducibility and robustness. So this is just one area where CSL is leveraging automation and AI. An application of these capabilities in our product development allows us to advance these process science programs with higher throughput, getting us into the clinic faster and ultimately leading to a licensable process quicker and with better quality. By removing these tasks, the added benefit is that it also allows scientists more time for innovation. And while we'll continue to innovate and expand these global capabilities, it's not enough to do so just within our own walls.
We also collaborate for innovation externally, and that's where I'm going to focus on this next slide. R&D really operates with a partnering mentality, and we apply that to growing our portfolio and advancing our current pipeline. We operate as one R&D, supporting all CSL business units, and we enjoy strong collaboration against our strategically placed R&D global sites, as well as across the CSL enterprise. Now, earlier, you heard about a number of new product opportunities coming out of our research team. Well, we combine that internal talent and capabilities with long-standing relationships with the scientific community through research collaborations, especially those in and around where our global sites are located. This has been and will continue to be the ongoing focus of our robust research, external innovation engagement strategies.
Also, on the right-hand of this slide, you'll see that we directly invest in venture funds with partners such as Brandon Capital and Kurma Partners to generate potential new opportunities. Flipping over to the left, you'll note we've got an active business development strategy that brought us strong partnerships with companies like uniQure, Arcturus, and Travere that you heard mentioned in both Marie-Pierre and Jon's presentations. We rely on close collaborations with clinical research organizations, digital and disruptive technology providers, and many more to partner with us on the advancement of our current pipeline. This partnering allows us to have flexible capacity and to access talent, technology, and geographies beyond our organization. Critically important is how we partner with patients and patient advocacy groups to include their perspectives, insights, and lived experience in our development strategies.
I'll speak more about that in a moment, but first want to highlight how our collaborative and partnership approach results in cutting-edge therapies for patients. Highlighted here is our partnership with uniQure that allowed us to deliver Hemgenix, an innovative gene therapy that has had significant impact on patient lives. This collaboration was recognized with the 2023 Prix Galien USA Award for Best Product in Rare Orphan Disease. This is the result of being patient-focused and a truly collaborative partner. We are stronger together when we focus on shared value for all involved, and what you'll see on the next slide is that this approach to shared value and partnering are also important aspects of our sustainability strategy. All of this contributes to a sustainable future for CSL, our shareholders, employees, partners, and patients, and to our vision of creating a healthier world.
So now I want to go back to that steadfast focus on patients. We not only focus on patients, we partner with them and for them, actively working with a number of organizations to develop programs for patients and their communities. You see here examples of the many partnerships we have with the industry, such as BIO and EFPIA, where we collaborate for continuous improvements in industry and with policymakers. We partner with specific disease-focused patient advocacy organizations, where we have long-standing relationships with organizations such as the World Federation of Hemophilia and the Jeffrey Modell Foundation. And we partner with those that share our focus on rare disease, such as the National Organization for Rare Disorders. You heard from Marie-Pierre that there are many unmet needs for rare diseases, and for many of them, they don't all have formally organized advocacy.
So we share in NORD's vision to elevate care, advance research, and drive policy in a purposeful and holistic manner to lift up the rare disease community overall. We partner across this diverse community of organizations to empower the patient communities, and we work with many of them, together with government authorities, to explain the unique needs of rare disease communities to help them understand the real value our therapies provide. Now, on the next slide, I'm going to share how we pull this focus into our day-to-day work to benefit patients in our development programs. CSL prioritizes the patient perspective, and we have the greatest opportunity to do so in the work we do within our pipeline. As you're aware, new therapies will only get to patients through clinical trials, many of which struggle to enroll adequate number of patients, especially in rare indications.
You heard Marie-Pierre mention the importance of building strong relationships with regulators and building leadership and trust with the transplantation community. CSL's clazakizumab ABMR team took a unique patient-focused approach to recruit patients in the Phase 3 IMAGINE trial, utilizing a peer review publication that noted, and as you'll see highlighted here, even led with a patient commentary as a call to action for transplant providers to consider clinical trials as an option for the patients in their care. Ensuring treating physicians are aware of clinical research opportunities is a critical step to including the right patients and providing research opportunities for both provider and patient. Our strong relationships across these medical communities allows us to do so. But increasing awareness is not enough. Once patients are enrolled, we strive to make their participation as manageable and empowering as possible.
Here is an example of how we embed patient insights into our study design to help them, and in this case, their parents and caregivers, take control of their participation. That friendly bear you see in the middle is the clinical companion, and that's being used in our ongoing garadacimab pediatric trial. CSL is the first company to partner with Empath Labs to use this innovative approach within a clinical study. The companion helps the children understand the procedures they will experience by simulating it with their bear, in other words, their companion throughout the study. It incorporates an empathic approach with an informative and entertaining app, enhancing adherence and retention, two very big challenges in clinical trials.
Now, in conclusion, I want to emphasize that our R&D strategy brings together innovation for scientific advancement and efficient drug development, a strong partnering mentality because we don't do all of this alone, and an unrelenting focus on patients because we do this for them and with them. As was mentioned earlier, we are in the business of hope, and we want that hope to endure through a sustainable strategy to forge a healthier future for patients and for CSL. And with that, I'm going to turn it back to Bill for a wrap-up.
Thank you, Deirdre, and all the speakers for your clear and robust presentations today. I have a few summary slides and comments I'd like to cover as we end our presentation today. Next slide. First, here's our updated going forward portfolio, which is a sort of a variation of the slide that Marie-Pierre showed you with a pie chart of our programs. This portfolio picture reflects the result of all the activities mentioned today, as well as the impact of other strategic portfolio decisions we have taken during the year. It also aligns our opportunities with our new therapeutic areas and with the framework, and we will be the way we report in R&D going forward. Our portfolio includes Phase 2 and 3 opportunities across our therapeutic areas and our three primary strategic platforms, with the majority right now in our plasma platform.
These opportunities all address one major unmet medical need and, if successful, will have a clear place in clinical practice. Importantly, they all support the key strategic imperatives of our three commercial business units. Next slide, please. So as I mentioned earlier, this slide represents both the success we want to achieve and the standard of excellence and execution we expect to meet or hopefully exceed. You've heard about almost all of these milestones during the presentations today, so I won't repeat them now. Just to note, the few programs we did not cover are equally exciting to us. And as we push forward our efforts this year, we plan to update you on our progress to these milestones in four complementary ways, depending on the program and situation. So first, where and when appropriate, we'll issue press releases. Second, of course, external scientific presentations.
Third, at our half and full year corporate results, and lastly, next year's Capital Markets Day. Each of them will play some part in updating you on our progress, so please stay tuned. And next slide, please. So I'd like to end where I started, by summarizing the programs and progress we've highlighted during the multipronged presentation today and the takeaways I'd like you to take with you. First, we're amplifying our strengths as evidenced by continued investment and innovation in our core platforms of IG, plasma, and vaccines. And examples include the secondary immune deficiency, nebulized IG, Horizons One and Two, and saRNA. Second, we will remain relentlessly focused on execution and moving programs forward and rapidly advancing the portfolio wherever and whenever possible.
Third, programs like Hemgenix, Kostaive, RiaSTAP, and garadacimab are nearing important approvals and highlight that our R&D efforts will generate value in the near term. Fourth, our setbacks with Kcentra and trauma, Hizentra and DM, and clazakizumab and ABMR are disappointing, but not unexpected in the business of R&D. We plan to overcome these by already shifting to equally exciting follow-on indications for all three assets. And fifth, our Phase 2 programs, such as vamifeport and hemopexin, and our Phase 3 programs like aTIVc, CSL964, Hizentra, and POTS, all underscore that the future of CSL remains bright. Lastly, and most importantly, all of our work is underpinned by our commitment to collaboration and to improving the lives of the public and patients we serve across our enterprise. And with that, I'll close and open for your questions. Thank you. Over to you, Chris.
Thanks, Bill. We'll now move to Q&A. Before we start, I will just point out that in addition to each of today's speakers, we are now also joined by another member of the executive team here in Melbourne, Ken Lim, CSL's Chief Strategy Officer. As usual, questions will be queued, and in the interest of giving everyone an opportunity, please limit your questions to two. You are, of course, welcome to rejoin the queue should you have further questions. Our first question comes from David Stanton at Jefferies. Go ahead, David.
Thanks very much, team, and good morning and good evening to everyone. Look, I'd like to discuss the complete response letter from the FDA on garadacimab. Wonder if you could give us a little bit more color on that, specifically whether there's another trial required and the scale of time of delay, you know, is it... It sounds to me like it might be nine months or could it be longer before, based on previous sort of updates, that we might see this drug on the market? Thank you very much.
Yeah, thanks. Thanks, David, for the question. I'll answer that. So there is, as I mentioned, there were no safety or clinical or efficacy concerns, and so no additional clinical work is required. It's all in the manufacturing processes. And in fact, if you look at recent CRLs, CMC CRLs are becoming, unfortunately, a little more common in the CDER space. These kind of CRLs normally ask for a standard six-month review period, up to six months, and so they can be earlier.
What we're doing to shorten that time as much as possible, we've already scheduled a meeting with the FDA, which will happen in some time in early or mid-November, where we'll confirm that all the work we have ongoing or planned is meets their needs, and then, based on that, we will turn around and file as soon as possible, and then the review clock starts.
Okay.
That puts us still within the first half of 2025.
Thank you. And I guess my follow-up then is one of your smaller peers in the Australian listed market at least has had an issue and had to do another trial based on sterility of the mixing, I guess, of the manufacturing. I mean, there's no requirement for another clinical trial. I just wanna make that clear, at this stage?
No requirement for another clinical trial.
Great.
We are generating data from the manufacturing side, but that is not a trial.
Understood. Thank you very much. I'll get back in the queue.
Thank you, David. Next question comes from Andrew Goodsall at MST.
Oh, thanks very much for taking my questions. Just on the Horizon 2 , I was wondering if you could be more expansive on your discussions—what the discussions with health authorities involve. I'm reading that you're, I guess, trying to understand what their requirements are or what you have to meet to go forward, I guess, with future registrations, but just trying to get clarity around that.
Yeah. So I'll turn it over to Doug for a moment. Yes, we're very excited about the Horizon 2, but as Doug tried to point out, we're trying to go purposefully so we can go quickly. And I think that relates to what we're gonna do when we meet with the authorities. So, Doug?
No, I think that's right, Bill. We're trying to. This is, as I indicated in my section, this is about data and providing satisfactory levels of data, quantity and quality, that will satisfy the regulators that we have comparable products with Privigen and Hizentra. So really, what the goal here is to talk a lot with the regulators, look for every opportunity to inform, and then get their feedback along the way. So far, those exchanges have been very good, and we've been very pleased with them.
And what we wanna do, Andrew, just to follow up and put a finer point on that, we wanna provide as much robust non-clinical information, and then when that's ready, go to them, to meet their needs and progress the program.
Excellent. Thank you. And I know on a day like today, you can't update on everything, but I was just going to see if there's any comments you can make on CSL334. I know the ASLAN gone through a few financial difficulties, so just sort of what the wash up is of that and your programs with them.
I don't really have a lot to say on the ASLAN program, but I do note their difficulties. It's a competitive space they're in, and I think they're, you know, I'll watch with hope that they can make some progress.
So potentially someone take that over and just continue?
Perhaps. It won't be us, but perhaps.
Yep. Okay. Terrific. Thank you.
Thanks, Andrew. Our next question comes from Saul Hadassin at Barrenjoey.
Yeah, thanks, Chris, and good morning, everyone. My first question is around RiaSTAP and the Phase 3 program for acquired, you know, acquired fibrinogen deficiency. Can you just clarify? I'm not clear. So you've mentioned the study there that you're undertaking in what looks like a fairly specific indication with this, you know, cytoreductive surgery. Is the intention here just to get a label for that specific indication, but for it to be used, you know, much more broadly? What's the actual indication that you're seeking for fibrinogen in the U.S., particularly?
Yeah, so first, before I turn it over to Marie-Pierre, let me just clarify. In the US, we need no other clinical work to be able to file for an indication of acquired fibrinogen deficiency. That was a result of some creative work done with the regulatory and the therapeutic area earlier this year. In Europe, we are doing that study, but the study is not just for the indication. The indication is the basis for an approval on acquired fibrinogen deficiency as the broad indication. That trial has been used by other companies as well to as a proxy for the general disorder, because these people bleed so much, and they do lose a lot of fibrinogen. That is why we're doing that study, and that's what it will be used for.
Marie-Pierre, anything else to add to that?
No, I think you've summarized it very well. It's different in Europe than in the U.S. In the U.S., we just need to file the data that we have to get an indication for fibrinogen replacement therapy. And in Europe, we will use a new clinical trial at a single site in the U.K. to generate the data that we need for this acquired deficiency indication for Europe.
Thanks. That's very helpful. So just to be clear, FDA filing, you said first half 2025. Is the assumption there that we shouldn't be thinking maybe first half 2026 for a potential decision, or could it be sooner?
I think your assumptions are fair.
Thank you very much, and then last question, just on aTIVc, again, I note, Phase 3 data, first half calendar year 2025, I think, was the guide. Does that effectively mean it will miss production schedule for the end of next year's winter season? In other words, it's more likely end of calendar year 2026 that that product gets to market?
I'm sorry, what was the product? I didn't hear the beginning.
The aTIVc, so adjuvanted trivalent cell-based vaccine.
Yeah. So before I turn it over to Jon, so the regulatory landscape with that program is evolving, I think, in vaccines in general. And so we are planning and waiting for the twelve-month data in order to be able to have the most robust assessment of the approvability of this overall, of course, and whether it's gonna qualify for accelerated approval. That we still have to go back to the FDA to clarify when the data come in. Jon?
Yeah, I think your assumption is about right. We'll file with the data, assuming that it's all that we expect. P robably just after the first half, so sometime in the beginning of the second half of 2025, and then it's typical a one-year review. So it depends on exactly when we file, but whether we'll have a product approved in time for the Northern Hemisphere, or it'll be, you know, the full next Northern Hemisphere, but the product will be available during the Northern Hemisphere of 2026. If that makes sense. 2026, 2027.
Yep. Great, thanks. That's all I had.
Thanks, Saul. Our next question comes from David Low at JP Morgan.
Thanks very much. Could we just on Kcentra and trauma after the trial outcome, just I'm trying to understand what's next for trauma. Is there any pathway to getting some sort of approval in that space with Kcentra, please?
Yeah, thanks for the question. You know, obviously, that we were disappointed in having to stop the trial, but I think we made the right decision. And the vexing thing is that the mortality is still there. It's just extremely early, and you just can't practically run an ethical clinical trial that you have to do all the enrollment and investigator work before you can start the trial and get it done in the timeframe that's required in that emergent situation. If we could have given it in the ambulance, we probably would have been continuing the trial now. So, certainly there are physicians that use this product in this space. And so we're gonna look at that, whether we can use real-world evidence approaches or not.
I think we're just coming down off of hearing the results, so we're reconsidering that. But I do think they're, you know, assessing other ways of doing this would be possible. But we'll probably first focus on getting the CT surgery bleeding trial going and looking at DOAC while we're considering what our options would be.
Great. Thank you for that. Just, my other question, just with the nebulized immunoglobulin. I mean, I heard the comment about with these exacerbations, there's no current therapeutic treatment. Yet, what, what would you hope to-- what would you hope the benefit would be from immunoglobulin? I mean, this is still a chronic condition. This is not something that's gonna treat the condition, I presume?
Yeah, well, I mean, I'll turn it to Marie-Pierre in a moment. You know, it is a chronic inflammatory condition that's marked by recurring infections. And so if you think about it more like an asthma condition, you don't cure asthma with medications, but you make people live a life free of the complications and the disease. So we wouldn't be curing bronchiectasis, but we would certainly make their lives better if it worked. Marie-Pierre, you know what we're hoping for from the program?
I think you're right, is that with delivering IG to the lungs, we really believe that we will have an effect on the infections because we can provide broad-spectrum anti-infective activity, and that this will in turn reduce localized inflammation. As I shown in the vicious cycle, this should in turn have some effect on the destruction of the airways and help restore immunity in these patients. So we believe that it will have an impact on the disease.
And so potentially, this could be quite a large patient population?
Potentially. It depends on the data. Yes, but the disease is expanding, as Marie-Pierre mentioned, so we're excited about this opportunity.
Just apologies to Chris with another follow-up. I mean, is the usage of the volume of immunoglobulin likely to be, you know, quite small versus existing patients? I mean, how should we think about the quantities that could be used?
Yeah, I think it'll depend on the dose we choose, how much we need. I mean, it'll more likely be a more regular administration than current IG, but at a much lower amount. So where it nets out, month by month will depend on the dose, I think.
All right. Thanks very much. I'll get back in the queue.
Thank you, David. Our next question comes from Laura Sutcliffe at UBS.
Hello. Thanks for the detail you've provided today and, for taking my questions. On garadacimab, do you have a sense of whether you're looking at a Class 1 or a Class 2 resubmission at this point? The reason I'm asking is, if it's a Class 2, then you're presumably potentially looking at a facility reinspection.
Yeah, we're not sure right now which it is, but certainly if it requires a reinspection, there's plenty of time in the process to do it, and we're prepared for that.
All right, thanks. And then my second question is more of a high-level one. Are you happy with the overall risk-reward profile in the mid to late-stage pipeline at the moment? Or do you think it needs to be inorganically augmented in some way, or perhaps subject to further tough decisions around deletions in the next twelve months or so?
Yeah, thanks for the question. So we did some portfolio prioritization earlier this calendar year, which I think helped us enormously. And of course, we just had a couple of Phase 3 studies that we discontinued. I think we have the capacity to run the programs we're running. We put each program through a pretty rigorous PTRS process and a robust commercial R&D assessment of the viability of the program. That being said, I'd always love my programs to be less risky, but the less riskier programs maybe not have breakthrough treatments. We always consider external opportunities. Deirdre mentioned it.
I may ask Ken to just comment for a moment on our business development thinking, but certainly, programs we're looking at right now, I don't think we need to overspend on a Phase 3 program, but we certainly will be continuing to scan the external environment for opportunities aligned to our therapeutic areas to help us give value to patients, and to CSL. Ken, maybe you want to make a couple comments on our business development activities?
Yeah. Thank you, Bill. So just to echo some of the comments that you've heard earlier, we've spent a lot of time focusing our efforts in R&D, and, overall, we've remained confident in our ability to drive double-digit growth over the medium term. We have also spoken about, our efforts selectively to in-source external innovation, and some of the programs, which you heard about today, such as Arcturus, and uniQure, and Travere, are, are examples of that. We continue to see, opportunities. There's hundreds of biotechs out there with interesting programs, and many of them look at a company such as CSL as an attractive partner to help them, complete the development programs and industrialize and commercialize those products.
So I think there's an opportunity to complement our internal innovation with selective external innovation as well.
Thank you. I'll get back in line.
Thank you, Laura. Our next question comes from Steve Wheen at Jarden.
Thanks, Chris. I just wanted to ask a follow-up question on the Horizon 2 manufacturing improvement. My understanding, and I'm just trying to understand this regulatory filing, but my understanding was that you already have achieved equivalence from the new manufacturing process versus the old, and that the remaining, I guess, endpoint was the stability study, which was progressing well. So how do I reconcile that with a regulatory filing, just given it was only down to stability that was required for its final sign-off?
Sure. This is Doug. I would take what you said, and yes, you're right. We have demonstrated at the scales we've operated at product comparability. We're happy with what we're seeing right now. And in addition to that, there's more to it than product comparability. We have to demonstrate process robustness with a lot of data to be generated that then can be translated to the larger scales and ultimately to the commercial scale. So we're in the process now. We're operating in our pilot plant scale, and that scale is continuing to provide data which we'll use to translate upward to the larger scales. So yes, we're very encouraged by what we're seeing in terms of product comparability, but from a filing standpoint, it's a bit more complex than just that.
It goes beyond that and to include demonstration of process robustness, and as you indicated, stability as well.
And toxicology as well. And so,
Yes, the preclinical work.
Just because we're comparable doesn't let us off the hook from the preclinical safety we need to demonstrate as well, and those studies are ongoing and will deliver in the first half of 2025.
Okay, great. Can I just confirm then that you don't anticipate you will need to do a clinical trial on the new, on the resulting product that comes out of the new manufacturing process? And in a perfect world, if this all gets approved as you expect, is there a potential benefit in reducing the timeframe around the manufacturing process down from sort of nine to twelve months to something shorter?
Yeah, you sound like my boss, but so, like, first of all, you know, we'll have this discussion with the FDA as to what we ultimately need to do for approval. Obviously, we're doing all this work ahead of time, and we're being careful in the comparability and the preclinical area to obviate the need for a clinical study. Still, that'll come down to a discussion with the FDA. How that will translate into vein to vein efficiency, we haven't really mapped that out right now.
Thanks, Steve. The next question comes from Andrew Paine at CLSA.
Yeah, morning. Thanks for taking my question. Just looking at slide 46, and the weighting of your pipeline by each platform, looking at the recombinant gene therapy, it looks like it's about 50% of your R&D portfolio versus 29% for plasma therapies. And j ust thinking if these weightings are representative of product launches, do you see gross margin uplift to Behring over your transition? Not fully away from plasma, but add more antibodies and recombinants over the medium to longer term.
Yeah, I think we're not gonna get into the margin business today. Obviously, some recombinants are higher margin. Some, you know, depending on the relationship, may be about the same. Of course, some of our plasma opportunities are like hemopexin and inframarginal, and that will have some uplift as well. But as you've heard from Joy before, we're all in together, including R&D, at improving our Behring margin and our overall enterprise margin. So we certainly will keep that in mind as we continue to progress the portfolio.
Okay, no problem. Just looking at slide 54, interesting, the mortality rates. They're recently looking at data that showed the Southern Hemisphere flu shot effectiveness against hospitalizations for high-risk groups was quite low, and, you know, may be a concern for the Northern Hemisphere. Just trying to wonder if that's a concern in relation to flu shot uptake rates, and do you think your adjuvanted trivalent vaccine can address this decline and, you know, potentially see increased support from regulators looking to kind of stop the hospitalizations from flu?
Yeah, I'll comment, and then I'll ask Jon to say something as well. I was in a meeting with the FDA and five different flu manufacturers this summer, and certainly there's great concern about continuing to promote flu vaccination to a greater degree. They want to partner with CDC in the U.S., this was a U.S. meeting, to do that, but I think the same message will go around the world. Obviously, some of the other regions are doing better than the U.S., but I think most countries in the world could do with encouragement of using their flu vaccine more. Jon?
Yeah, Andrew, I think you hit the nail on the head. Flu vaccines have room for improvement, but without a doubt, getting vaccinated is far better than not in terms of mortality, particularly for the at-risk. And that's why we think taking technologies that have already shown their advantages separately, putting them together, as we're planning to do with aTIVc, has a chance to make the flu vaccine even better, but you still have to take it. So we're 100% behind the efforts everywhere in the world to emphasize the value of flu vaccination, and then having a product that's even better in the way it protects people, maybe that's a reason for them to take it. But I think you got it exactly right.
Okay. That's great. Thanks.
Thanks, Andrew. Our next question comes from Sacha Krien at Evans & Partners.
Thank you, Chris. Thanks for the presentation today. My first question is a clarification question on Kcentra. Just want to confirm that whether you think there's any risk to the current off-label usage of Kcentra for trauma, given the termination of the trial?
We don't believe there's any risk to the usage today. There's no safety concerns raised from the program. This is merely a clinical trial operational challenge that we couldn't overcome.
Okay, thank you. And second question, also around the Horizon 2 initiative. I think you've, you've previously indicated that Horizon 2 will only be applied to liters fractionated for IG and albumin. I'm just wondering if you can provide any sort of indication of what proportion of fractionation that represents.
Yeah, I don't think we have those answers today. But as Doug mentioned in his presentation, Horizon 1 and 2 are meant to be complementary, and Horizon 1 is our standard process, just improved, which can get all plasma proteins out of it, as it always has, and will still be able to. What ultimately Horizon 2 is able to be able to do will depend on our creativity and research and development. I don't think we're done there yet either. But I don't think either Horizon 1 or 2 will completely dominate. These two will work together.
Okay. Just a very quick add-on, if I can. Is the yield initiative really just focused on the IG side, or is there also an albumin yield benefit that we could see out of Horizon 2?
I think it's too early to say on albumin. We're starting with IG, but we'll apply the same thinking and approaches to our albumin as well.
Okay, great. Thank you.
Thanks, Sacha. We've got a follow-up question from Andrew Goodsall at MST.
Oh, yeah, thanks very much. It was just actually more of a follow-on to Sacha's question. With Kcentra moving into perioperative, just didn't seem to have a timetable there. Just if you've got a timetable on sort of first steps there.
A timetable on the Kcentra. Well, of course, first of all, we're gonna be going to the FDA imminently, this month, to discuss the program. If assuming that is a positive interaction and we can come to a reasonable trial, we'll move towards starting at some time in twenty twenty-five. I don't have an exact date for you.
That's great. Thank you. Appreciate it.
Thanks, Andrew, and a follow-up question from Laura Sutcliffe at UBS.
Hello. Yeah, I've got a couple more. Thanks for taking them. Just on the vamifeport, I'm curious to know if you have established what you think is an optimal dose for that drug, given that I think, earlier in its development, there were some question marks over that, sort of when it was being developed for beta thalassemia, for example, which I know has now, been put to one side. But do you think you've got the dosing right for vamifeport?
Yeah, so we're working on two-prong on that approach. First, Doug and his team have been working on increasing the duration of the product, and so we have an extended release product that we're working on, and that will help. And secondly, of course, we will dose range in this trial. Now, what you need to understand is what you need to do in hereditary hemochromatosis in the gut, it might be quite different than what you need to do for beta thalassemia. So I think between the attractive opportunity, the unmet need, and the likelihood that vamifeport, how it works, will be better married to this indication, is why this is our lead indication for vamifeport.
Okay, understood. And then maybe just on post-COVID POTS, that's been difficult for others to get to work. Could you maybe just elaborate on why you think you have a better chance with your approach?
I think Marie-Pierre mentioned it earlier, that it some of the elements of post-COVID POTS have some of the same themes as we saw in CIDP. I can tell you also that the regulators are extremely interested in this program and have been extremely supportive with us in working on this. And so, look, it's still an experiment, but it's really important and worth a try. We do have a futility analysis built into this trial, as I mentioned earlier. That's part of the way we do these trials when they're a little higher risk, but certainly the opportunity is worth it, and some of the elements of POTS mimic the elements of CIDP.
Thank you. Thank you.
Thank you, Laura. We have no further questions in the queue, so I'll go ahead and draw this briefing to a close. Thank you for your interest in CSL, and goodbye.