During the call. After the presentation, there will be a question- and- answer session. You are invited to send in questions for this throughout the entire session using the Q&A functionality of Zoom. In addition to that, you may also raise your virtual hand to address your questions verbally. For participants joining via phone, to raise your hand, use star nine on your phone's dial pad. When you then get selected to ask your questions, please follow the instructions from the phone and press Star six to unmute yourself. One last remark, if you would like to follow the presented slides on your end as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks a lot, Henry. Can I have the first slide, please? Welcome to our third IR call in 2023, this time focusing on crovalimab, the crovalimab development program, especially on PNH, with the results presented at EHA, and also on our emerging nephrology franchise. Let me quickly make an upfront statement here. I think the nephrology franchise, which today already consists of four medicines, will have a first major readout to come next year in 2024 with Gazyva and lupus nephritis. Based on the very strong phase II results, this indication also got a Breakthrough Therapy designation.
The overall opportunity, which we flag here for Gazyva in lupus nephritis, in SLE, in membranous nephropathy, or in childhood-onset idiopathic nephrotic syndrome, is significantly more than CHF 1 billion, and this will also, of course, involve some market development in the future. With that said, let me quickly take you through today's agenda. We have three speakers with us. The first one is Peter Ahnesorg, our Global Franchise Head for Hematology, responsible for the global product strategy. Peter will provide a quick update on our hematology franchise strategy, providing the latest information on our CD20, CD3 bi-specifics program before he will dive into the crovalimab development program in more detail. Our second speaker for today is Dr.
Alexander Röth, a well-known hematology specialist and a researcher with a focus in PNH and a crovalimab clinical investigator, who will lead us through the two pivotal studies, which were presented over the weekend at EHA in Frankfurt. These two studies are firstly, the randomized Phase III study, COMMODORE 2, for crovalimab versus Soliris in PNH patients naive to C5 complement inhibitors. Secondly, the randomized open label Phase III switching study, COMMODORE 1, for crovalimab in PNH patients previously treated with Soliris. Finally, we will close today with a presentation by Jay Garg, our Global Development Head for Nephrology and Rheumatology. Jay will provide us an update on our nephrology pipeline, which currently includes 4 molecule with Gazyva, our antisense oligonucleotide Factor B, and crovalimab, all in Phase III testing already.
Our latest addition, CD20, CD3 bispecific, here, mosunetuzumab, also known by the name Lunsumio, which just entered phase I testing. Overall, for today, we have 60 minutes. We will leave, I would say, probably 40 minutes presentations, and we will have 20 minutes for a Q&A. I just want to flag here for the Q&A, we will have two additional people joining. We will have Ben Stewart, the lifecycle leader for crovalimab, and then Pippa Postins, our integrated strategy lead for the franchises, nephrology and hematology, who are happy to take your questions. On the next slide here, I just wanted to quickly use this to give a quick update on the latest news flow.
This is the slide as we have shown it at Q1. Since Q1, a couple of things happened. Just to go from the top to the bottom, I think on May 9th, we announced that we have filed Vabysmo and RVO in the United States, with the user fee date set now for December 22nd. On April 26th, we announced that we got positive, a positive CHMP opinion for Columvi in third line DLBCL, so the EU approval is now expected for later this year. Then I think on the other results, or the pivotal results, where we had readouts, COMMODORE 1 and 2, these are the data we will talk about today in more detail. Then I think on the bottom line, you see two additional pieces of information, which we had lately.
This was where the phase II data for our BTK inhibitor, fenebrutinib, in RMS, where we will have the data to be presented at an upcoming conference. Actually, if everything goes as planned, this already could be in July. The other positive piece of information is just from last week, from ASCO. This was the early data, phase I, phase II data, for our triplet combination, tiragolumab plus atezolizumab in liver cancer, where we have announced that we, based on these data, will have a phase III initiated. I also wanted to quickly use here on the bottom to provide an outlook on what are additional IR events we have scheduled now for the remainder of the year. On September eleventh, we plan our annual Roche Pharma Day, which again, will be a live event in London.
For November, we have scheduled now the 29th of November, our third Roche Digitalization Day. I think, later on in December, we also will go for I will have an ASH event, again, an ASH IR call, which will be virtual. We I think we have so many data here to present and, coming in hematology, especially with the late-stage reach out, like STARGLO or SUNMO, that we will have a pretty, busy, event there. With that, I will hand over to Peter for an update on our hematology franchise and the crovalimab deep dive. Peter, please.
Thanks a lot, Bruno. Hi, everybody. Great to have all of you on the call. Very excited to talk to you about updates from our hematology franchise, and then talk a little bit about crovalimab and some of the recent data that we shared at EHA. We're also very privileged to be joined by Professor Alexander Röth today, who is a key expert in PNH, and will be able to walk us through some of the clinical data from EHA. We are quite proud of our hematology portfolio, which is pretty unique in the industry, spanning both the non-malignant as well as the malignant space. By now, we have seven medicines on the market.
We're really interested in investigating both established indications like lymphoma, follicular lymphoma, and CLL, but also venture into new areas, particularly multiple myeloma, to pick out one of those. We have a broad portfolio, as I mentioned, seven medicines on the market, 12 NMEs in clinical development. We believe based on that, we have a pretty unique opportunity to combine modalities. We're particularly interested also in exploring a costimulatory approach, in lymphomas, but also in multiple myeloma, mimicking the signal one, signal two approach in immunotherapy that's known from the CAR T cells. As I mentioned, we're spanning a lot of different modalities.
We are one of the leading developers of bispecific antibodies, and we're seeing that across different disease areas, also ophthalmology, for example, but also in hemophilia within our hematology franchise. Now we're quite excited to bring two bispecific molecules to the treatment of lymphoma, and I will speak a little bit more in detail about Columvi and Lunsumio on an upcoming slide. This year already, we've had a quite significant news flow. We've had the approval of Polivy in 1st-line DLBCL in the United States and the approval of Lunsumio in the United States and in other markets. We're looking forward to more to come for the rest of the year.
Lastly, one of the paradigms that we're following as we're building our strategy in hematology is really to redefine the patient experience. One of the hallmarks that we're exploring there, particularly in the malignant hematology space, is the concept of fixed-duration therapy. Really breaking with the paradigm in oncology, that patients have to be treated forever in order to keep the tumor at check, but introduce the idea that you can treat for a finite amount of time, and achieve impressive results for patients. We've just been able to share some updates from our bispecific antibodies at ASCO and at EHA, this week in Lugano at ICML, we'll be able to share some more data that's really underscoring the opportunity we believe that exists with finite duration of treatment.
On the next slide, as promised, I wanted to talk a little bit about the future opportunity we see in hematology. As you can appreciate from the left side of this slide, we and others expect hematology to continue to grow significantly in the future. As you can see from the right side, we have built quite a comprehensive portfolio in all the major areas of growth, with more than 10 different diseases that we're covering and 18 molecules that we're exploring. Particularly in multiple myeloma and DLBCL, we feel we're quite uniquely positioned to really grow the franchise in the next decade. On the next slide, I wanted to talk about Columvi and Lunsumio.
As I already mentioned, as one of the leading developers of bispecific antibodies, we've took a very deliberate approach to develop two differentiated molecules for lymphoma. In Lunsumio, we not only have the first-in-class CD20/CD3 bispecific, that was approved already last year in Europe and now at the beginning of the year in the United States. This molecule is really unique because it brings high CR rates and durable responses, but at a very favorable toxicity profile that requires no hospitalizations. We believe this molecule is uniquely suited for the outpatient setting, and for patients that have indolent disease, so where you really want to maximize patient convenience.
We're exploring Lunsumio in follicular lymphoma, particularly, we're looking forward to looking at the CELESTIMO study, which is the second-line study, where we're investigating Lunsumio in combination with lenalidomide. We're also looking to develop Lunsumio in combination with Polivy, in the second-line DLBCL setting, where we believe there is a specific unmet need for outpatient treatment for patients, and we should see data for that study either later this year or probably more likely next year. It's an event-based study, so it will really depend on the events in the study. On the other hand, we're quite excited about Columvi. We recently, as Bruno mentioned, have gotten a positive CHMP opinion on Columvi.
We're expecting approval in Europe just around the corner. Similarly, we're expecting approval in the United States in the very near future. With Columvi, we believe we have a best-in-class molecule that really has efficacy similar to CAR T in this setting, but obviously comes with all the advantages of being off-the-shelf and being able to treat patients for a finite period. We're seeing also a very favorable profile of the molecule in the first-line setting, combined with R-CHOP.
We are in the process of starting a first-line phase III study in combination with the POLARIX regimen, so pola-R-CHP, and have gotten really positive feedback from investigators all around the world about participating in that study, where we'll randomize patients either to the new standard of care with pola-R-CHP or pola-R-CHP and Columvi. The next big milestone beyond the approvals in third-line DLBCL will really be at the STARGLO study. This is really the study where for the first time, we will see randomized data of the CD20/CD3 bispecific, comparing against a standard of care, so in this case, our GemOx. This is in the context of second-line transplant-ineligible patients in DLBCL. We're looking forward to seeing data for this study.
There is an interim analysis, which could happen anytime mid-year this year, so we're quite looking forward to seeing that data. The final analysis will be more towards the end of the year, and the primary endpoint for this study is overall survival. It will give a very definitive answer on the add benefit that a CD20/CD3 bispecific like Columvi can bring in this setting. On the next slide, as teed up by Bruno, we wanted to spend the majority of our time today to talk not about the malignant part of our hematology portfolio, but the non-malignant part, and specifically crovalimab.
Obviously, we're quite excited because just on Friday at EHA in Frankfurt, we've been able to present the data from the COMMODORE 1 and COMMODORE 2 phase III studies. All in all, we now have three positive phase III studies for crovalimab, including the China-based COMMODORE 3 study, and are in the process of obviously filing all across the world for the molecule. Professor Röth will talk in a bit more detail about the mode of action and why the recycling antibody technology is particularly suitable for the treatment of PNH. On the next slide, I wanted to just sort of level set about the unmet need.
Obviously, it's well known that PNH can be treated with C5 inhibition, and we continue to believe that C5 inhibition will be the mainstay of therapy for these patients. It's also quite clear that there's still unmet need. One and there's really sort of three dimensions in our mind, how you can think about the unmet need in PNH. One is those patients require lifelong therapy, so there really is a question about the convenience of administration, and we believe that the subcutaneous administration of crovalimab provides a significant benefit here for patients.
There's also a significant unmet need still in many countries across the world because current access to C5 inhibition is not the same everywhere, and so we believe there's also an opportunity, particularly for a company like Roche, with our global footprint, to make C5 inhibition more accessible to patients all across the world. Lastly, about 20% of patients experience clinically relevant extravascular hemolysis, and we believe this is also a dimension where additional treatment options can really provide value. On the next slide, I already mentioned our clinical program, and the fact that now we have a body of evidence of three positive phase III studies. One thing that's really underscored by all of these studies is that the dosing convenience of crovalimab really translates into significant patient preference.
We see 96% of the patients prefer crovalimab over eculizumab in our studies. This is really thanks to the once-every-month subcutaneous administration at a pretty low volume. It's fast, it can potentially be done by the patients themselves, and really, in the context of a lifelong therapy that affects patients that are in the middle of their lives, that have jobs, that want to lead a normal life, we believe this can be a very liberating offering to patients. On the next slide, I wanted to also highlight that we're obviously looking at developing crovalimab in other diseases.
aHUS is another signature disease for C5 inhibition, and similar to what I mentioned for PNH, we believe that there is significant unmet need here, particularly on the basis of better forms of administration and re-enabling broad access to C5 inhibitors to patients all across the world. It continues to be a disease that has a significant mortality rate, so we believe that additional treatment options will be very meaningful here. We already have an ongoing phase III program for crovalimab in aHUS, and we look forward to reading out those studies and demonstrating that the molecule can really be a significant new treatment option for those patients.
On the next slide, the third sort of non-malignant heme disease that we're exploring with crovalimab is sickle cell disease. We have some very intriguing preclinical data that suggests that complement is involved in the vaso-occlusive crisis that happen in patients that present with sickle cell disease, which continues to be one of the significant barriers or the significant burdens to patients suffering from this disease and improving quality of life. If you can appreciate from the right chart here on the slide, is one of the key treatment goals. We believe that complement inhibition can be a novel MOA for patients suffering from sickle cell disease that really makes a difference for vaso-occlusive crisis.
We have two ongoing exploratory studies that look at either using crovalimab to prevent vaso-occlusive crisis or for the acute treatment of these types of events. We're looking forward to looking at that data and making a decision for the future development program of crovalimab in this space. Going beyond the non-malignant heme space, as was already mentioned for by Bruno, we actually have my colleague Jay Garg, who's the head of nephrology and rheumatology development at Roche and Genentech on the call, who will talk in much more detail about our new nephrology franchise and what's exciting about our development program there.
I already wanted to set the stage that, based on the foundation we're laying with Gazyva, which we will take a look at the phase III study next year. We're also moving forward with developing crovalimab in this disease, and we started a phase I study of crovalimab earlier this year, and are looking forward to seeing if with complement inhibition, there is a second MOA that we can potentially move forward with for this disease. With that, I am excited to pass on to Professor Alexander Röth, who will talk about the key data presented on crovalimab at EHA on Friday.
Hello, everybody. My name is Alexander Röth. Ladies and gentlemen, it's a great pleasure to present the data of crovalimab in the PNH, mainly COMMODORE 2 and also COMMODORE 1. Next slide, please. How about crovalimab? It's not just another C5 inhibitor, but it's a highly engineered antibody. It has this special affinity to C5 and the preferential uptake of fully loaded antibody, which is relevant. Due to the affinity manipulation and the high affinity to the neonatal Fc receptor, it also gives this antibody the recycling property, reducing and extending the half-life, reducing the frequency of dosing. I think that's important always to remember if we talk about this antibody, it was a pleasure for me.
I was the national, an international coordinator for the COMMODORE 2 trial, it's a pleasure to present the data about those trials. Next slide, please. Crovalimab was first analyzed and studied in the COMPOSER trial, we were happy to use crovalimab first in Germany in the COMPOSER trial. It was a four-part adaptive study for C5 inhibitor in naive as well as experienced patients. COMMODORE 2 trial was a single-arm study of C5 inhibitor-naive patients in China only. COMMODORE 2 trial was a randomized study of C5 inhibitor-naive patients, the COMMODORE 1 trial was a randomized study of C5 inhibitor-experienced patients, all the details are given here in this slide. Next slide, please. Here are the results.
One co-primary endpoint was the hemolysis control, defined by the reduction of the LDH below or equal to 1.5x the upper limit of normal. As you see in the COMMODORE 2 trial, we were able to show non-inferiority with a hemolysis control of around 8% for crovalimab, as well as similar to the eculizumab arm. In COMMODORE 1, crovalimab showed hemolysis control in around 93% versus 93% for the eculizumab arm. Pretty comparable. More details about hemolysis control. In this slide, you see the proportion of patients with central LDH below or equal to 1.5x upper limited normal on this side.
You see the increase and improvement until week five, and this was maintained throughout the study for 25 weeks. Similar results for the mean normalized LDH. The LDH went down until week five and was maintained below 1.5 times up the limit of normal for the crovalimab arm, where it was slightly above 1.5x the upper limit of normal for eculizumab. Next slide. Another co-primary endpoint and was reached for transfusions avoidance. Here for COMMODORE 2, around 66% of the patients in the crovalimab arm reached transfusion independence, and around 68% of the patients in the eculizumab arm, and showed clearly non-inferiority.
Similar results for COMMODORE 1 for crovalimab, as well as eculizumab, with around 80% for crovalimab and 78% for the eculizumab arm. Clearly, for the COMMODORE 2 trial, clearly showing, demonstrating non-inferiority for the co-primary endpoints. Next slide, please. Other endpoints, secondary endpoints were also studied, like the risk for, or the frequency of breakthrough hemolysis. And this slide gives you the proportion of patients with breakthrough hemolysis. In the COMMODORE 2 trial, it was around 10% for the crovalimab arm and around 15% for the eculizumab arm, and also demonstrated non-inferiority. In the COMMODORE 1 trial, similar results, around 10% for crovalimab, and around 40% for eculizumab. Next slide.
The hemoglobin stabilization, which was another secondary endpoint, here also, was crovalimab showed non-inferiority to eculizumab, with around 63% for crovalimab and around 61% for eculizumab. For COMMODORE 1 trial, it was around 60% for crovalimab and 70% for the eculizumab arm. Next slide, please. Another important point, and this is a big issue for patients with untreated PNH, is the fatigue, which is really crippling and really a chronic issue. You see here from the analysis of the FACIT-Fatigue Scale, patients started off with really low FACIT-Fatigue Scale, meaning severe fatigue, with around 35 or 36 points.
In COMMODORE 2 trial, patients showed a dramatic improvement of the FACIT- Fatigue Scale of around 8 points, almost normalizing their FACIT- Fatigue Scale in a scale of 43 or 44 points, and it was in the eculizumab arm, it was 5 points. For patients in the COMMODORE 1 trial, switching from standard treatment, similar results was the FACIT- Fatigue Scale were maintained. We consider for your background, for this background information, we consider an increase of 0.5, at least one, or at least five points from baseline to be clinical, meaningful, or significant. Next slide, please. How about safety? If we talk about a complementary safety, it's always an issue. In general, for this population, crovalimab was well tolerated.
There were three fatal AEs in the COMMODORE 2 trial. They were mainly related, or they were related to the underlying disease, PNH, with the myocardial infarction and under a coexisting disease with a respiratory hemorrhage. There was also one fatal case in the eculizumab arm with an ischemic stroke, also related to the underlying disease and not to the treatment. Next slide, please. The patients were also asked about their preferences and how they liked the treatment with crovalimab in comparison to eculizumab. This took place in the COMMODORE 1, 2 and COMMODORE 1 trial. For the COMMODORE 2 and COMMODORE 1 trial, these are the results for patients who were randomized to eculizumab and then switched to crovalimab in the existing period.
You see, the majority of the patients, over 80%, clearly preferred crovalimab over eculizumab. For the patients who were randomized to crovalimab, coming from eculizumab pretreatment, also similar results were obtained, over 80%. The main reasons for the patients reporting about the preferences were fewer hospital visits associated with the treatment. The way the treatment was given was easier for the patient, time to administer, treatment was shorter and a better quality of life. Really, some convincing, and this was also my experience here with my patients in the trial. Next slide, please. In summary, in conclusions, COMMODORE 2 trial met its co-primary endpoints, demonstrating non-inferiority in comparison to eculizumab for hemolysis control and transfusions avoidance.
crovalimab is also non-inferior to eculizumab for breakthrough hemolysis and hemoglobin stabilization. There was a clinically meaningful improvement in the Fatigue Scores occurred in both arms, with a numerically greater improvement for crovalimab. Patients who switched from eculizumab to crovalimab continued to maintain disease control. Taken together, COMMODORE 1 and II show that crovalimab is well tolerated in both C5 inhibitor-experienced and naive patients with PNH. In an exploratory analysis, the majority of both COMMODORE 1 and II patients switching from eculizumab to crovalimab, who completed a preference survey, stated a preference for crovalimab. crovalimab also has the potential to offer clearly a new treatment option for people with PNH, that allows a low volume subcutaneous self-administration with every four-week dosing. With this, I'd like to finish, and I thank you for your attention. Thank you very much.
Thank you. My name is Jay Garg, and I'm the Global Head of Nephrology and Rheumatology here at Roche, in the late stage organization. Roche has actually been in nephrology, even though we're not known as a nephrology company. This is really anchored on CellCept, Rituxan and Mircera and our long-standing experience there. Our vision and strategy to really provide significant benefit for patients with kidney disease really rests on four pillars. We want to have an industry-leading portfolio in nephrology, and we think we're well on our way there with four late-stage molecules in kidney disease. We want to develop close partnerships with patient communities to tailor our efforts for the needs of the patients. We want to leverage our capabilities in pharma and diagnostics to really provide an integrated solution to address patient needs.
Importantly, we want to try to ensure the best possible access for as many people as possible. Kidney disease is really a growing burden globally. Chronic kidney disease, or CKD, affects about 1 in 10 people worldwide. The total prevalence of kidney disease is estimated to be about 1.1 billion and anticipated to grow by about 18% over the next decade. Importantly, CKD does have a significant effect on healthcare systems worldwide. It's estimated to be about 25, about a quarter of the US Medicare budget and EUR 140 billion annually in Europe. As I mentioned, the portfolio we have spans both established and late-stage products, and we have seven pivotal phase III trials ongoing. Can you go to the next slide?
A disease area of particular interest for us, and has been for quite a while, is lupus. We believe that B cells are central to the pathogenesis of lupus and have run a number of trials over the last 15 or 20 years, targeting B cells. We haven't been as successful as we would have liked, but we have learned a lot about this disease and about B cells in general. In looking at the data from our previous trials, as well as data provided by academic investigators in the lupus community, we believe that greater B-cell depletion can lead to greater responses in lupus patients. We have two molecules that can help us test that hypothesis.
The one that's furthest along in development is Gazyva, which is a type 2 anti-CD20 monoclonal antibody, that has been approved for follicular lymphoma, but now we have taken into autoimmune disease. This molecule was engineered to have greater B-cell depletion than type 1 anti-CD20 monoclonal antibodies like Rituxan. It has a higher affinity for Fc gamma receptor, which leads to increased antibody-dependent cellular cytotoxicity and cellular phagocytosis. It also has increased direct cell death, which we think is important in lupus patients or in treating these patients. Based off some encouraging phase II data, we've actually initiated two phase III studies, 1 in non-renal lupus, which we've termed ALLEGORY, and one in lupus nephritis, which we've termed REGENCY.
In addition, we have a bispecific that you heard about earlier, Lunsumio, which binds both CD20 for in the B-cell, as well as CD3 with the T-cell, and it uses the T-cell to deplete the B cells. We think that this will provide greater B-cell depletion in these patients, including importantly, in the tissue B cells, which then may lead to greater responses. This is in an ongoing phase I-B study in lupus patients. Can you go to the next slide? What really got us excited about Gazyva was really the phase II study that we conducted in lupus nephritis, which we termed NOBILITY. This study evaluated the safety and efficacy of Gazyva in patients with proliferative lupus nephritis after four infusions given at days 1, 15, weeks 24, and week 26.
The study met its primary endpoint at week 52, but what really excited us was the continued increase in responses over time through week 104, where we ended up seeing a 22% delta in complete response, which is better than what's been seen with other therapies. Based off this data, the FDA actually granted us Breakthrough Designation, and we initiated our Phase III study, REGENCY, again in proliferative lupus nephritis, where we'll be evaluating Gazyva dose at days 1 and 15, weeks 24 and 26, and then every 6 months thereafter, to see if we can confirm and maybe increase on the benefit that we saw in our Phase II study. We also know that lupus is a heterogeneous disease.
It has different patients may have different drivers of their disease, we know that complement plays a significant role in autoimmune disease and potentially in lupus nephritis as well. As mentioned before, we've started a phase I-B study with crovalimab, hoping to test whether inhibiting C5 can provide additional benefit in these patients. Based off the confirmation of the hypothesis that we can achieve greater B-cell depletion with Gazyva in autoimmune disease, which may lead to greater responses than seen with other B-cell-targeted agents, we rapidly started two additional phase III pivotal studies in membranous nephropathy and childhood-onset idiopathic nephrotic syndrome. Membranous nephropathy is an orphan disease with high morbidity and mortality, with no currently approved treatment options.
About a third of these patients will progress to end-stage renal disease, and the pathophysiology of this disease really makes it amenable to treatment with an anti-CD20 monoclonal antibody. There are autoantibodies that are pathogenic, the most prevalent of which is anti-PLA2R, and we've seen that other B-cell-directed therapies can provide benefit. What is interesting about Gazyva is that there are case reports that in patients who have failed treatment with other B-cell targeted therapies like Rituxan, actually respond to Gazyva, suggesting that Gazyva can give you that greater B-cell depletion in this disease, which will then lead to a better clinical response. That phase III stage, which we term MAJESTY, is ongoing. The last indication for Gazyva that we're evaluating is childhood-onset idiopathic nephrotic syndrome.
This is the most common kidney disease in children with really limited therapy options available. While the majority of patients can achieve some sort of remission with steroids, the problem becomes that the use of ongoing steroids, we all know about the adverse effects, especially in kids, it can be quite devastating. The key unmet need here is how do you maintain remission without requiring additional steroids? Approximately 70% of patients will either experience relapses or can't get off steroids. Our goal with this trial, which we've termed INSURE, is to try to maintain that remission without the need for additional steroids, and we've initiated that study. Next slide. Peter already talked about atypical hemolytic uremic syndrome.
The role of complement, this disease, in this devastating disease is quite well known, and for the reasons highlighted by Peter, we believe that crovalimab can provide benefit and meet some unmet need in these patients, especially kids who are more likely to develop this disease. We have one study in adults and one study in children. Next slide. Lastly is our most recent phase III pivotal study that we started in IgA nephropathy with our antisense oligonucleotide that inhibits Factor B production. IgA nephropathy is the most common primary glomerulonephritis worldwide that can progress to renal failure. We know that complement is involved in the pathogenesis of IgA nephropathy, so complement is activated, which causes inflammation then, which will cause damage.
The goal of this program, or with a complement inhibitor, is to minimize that inflammation and minimize that ongoing damage. We are excited about ASO factor B, mainly because its mechanism suggests that it could provide the most complete Factor B inhibition that we have in currently evaluated clinical trials. The antisense oligonucleotide will bind, will inhibit complement Factor B production in the liver, where the majority of complement is produced. We also know from preclinical data that there is production of Factor B within the kidney. That's a site of action for IgA nephropathy. By inhibiting this local production, we'll get more complete inhibition of Factor B, which then may offer us best-in-disease efficacy due to complement inhibition.
We have some early phase II data suggesting that the majority, about 80% of patients, do have a reduction in proteinuria and high levels of reduction. We're hoping to test this hypothesis in our ongoing phase III study, which we've termed IMAGINATION. This is a study that randomizes patients 1:1. The primary endpoint is at 9 months, based off of proteinuria, where we would then look for accelerated approval, similar to other therapies that have been approved. Then we'll continue treatment until 2 years, where we hope to get data for full approval. With that, I will pass it back to Bruno.
Thanks a lot, Jay. With that, we will open the Q&A. The first question actually comes from Charlie Mowat, from Morgan Stanley. Charlie, please.
Thanks, Bruno. Charlie Mowat from Morgan Stanley. Firstly, I was wondering if you could dig a little bit more into the reasons for the higher levels of AEs in the switch patients on crovalimab. Does this have anything to do with the formation of drug-target, drug complexes once the switch has been made? Does it mean you sort of see a potential, a greater potential in naive rather than switch patients? Along the same lines, I'd be interested how you think about the PNH paradigm more broadly, Professor Röth. Do you expect to switch patients that are already stable on C5 onto crovalimab, or mainly present crovalimab as an option for new patients? Thanks very much.
Should I take it? I think, I mean, switching from a preexisting C5 inhibitor to another C5 inhibitor could be of high interest. If you consider, I mean, that's an issue. What our young patients always tell me is we cannot imagine that you have a significant burden of treatment. If you have to come in to get an IV access, you have to take it one day off, you have to disclose it to your family, to your company, that you have a chronic disease, and then you get your treatment. I think for those patients, and this is a big fraction, actually, such a subQ treatment, which gives you a high independency or independency for traveling, is something which is really interesting.
The IE you mentioned, is one thing is the, for naive patients, of course, it's transfusion, IEs or related to transfusion, and it's typically the first dosing of a complement inhibitor, of a terminal complement inhibitor. It means you are effectively blocking the complement, and you're having more nitrous oxide available, and that's a phenomenon we know is from the beginning of the usage of terminal complement inhibitor. It just shows you, and it's only limited for the first dosing of this drug.
The other thing is switching from one C5 inhibitor to another, that's mainly related. This was known from the beginning, and it's not only related for crovalimab, but also a class effect of any C5 inhibitor, is the formation of immune complexes of C5 and the anti-C5 antibodies. This was clear from the beginning, and the situation and the reaction varies from patient to patient. Every patient gets those immune complexes, and the side effects start after two weeks and last, can last up to two weeks. It's a well-known side effect we know from other antibodies, for example, ATG, which is especially known for two colleagues with other.
who deal with patients with aplastic anemia, and it's manageable with topical steroids or systemic steroids. I think it's a manageable thing, I'm not worried about to use crovalimab in our patients or in patients at all.
Cool. Thanks very much.
Okay. The next questions would come from Emmanuel Papadakis from Deutsche Bank. Emmanuel?
Yes, thank you for taking the question. Maybe a follow-up on the same line of questioning, I guess. Professor Röth, I'd be very interested to hear your perspective as to what proportion of patients in PNH are going to remain on C5 monotherapy over the next few years versus either combinations or alternative options such as a C3 or oral Factor B. Perhaps for one of the team, do you plan to generate any data in combination with proximal inhibiting agents, like for crovalimab, or you don't think that would be a relevant clinical approach? Maybe a question on IMAGINATION, the trial you're just kicking off in IgAN. I noted it was versus placebo.
Is that still the right design, given you now have a couple of approved options in that setting, and do you have any additional combination development plans there for that Factor B? Thank you.
The first question was for me, I guess, on concern of switching patients from one C5 inhibitor, is there a reason for that or any combinations in, with the developing field? I mean, there are a significant proportion of patients who remain stable on a C5 inhibitor. We know C5 inhibitors for almost 20 years. They are safe. We are know how to deal with any side effects or complications, I think that's, it's a good reason to continue a C5 inhibitor treatment. Ultimately, of course, it's up to the patients, the patients will able to decide what is the best treatment for them.
As I remember from the beginning, subcutaneous treatment was also something the patient wished to have available, and I think this will be fulfilled by crovalimab.
Thank you, Professor Röth. I'm happy to take the combo generation, data generation question. Thank you, Emmanuel. As you noted, we do have the ASO Factor B program internally currently in development in IgAN, and I think as we stand right now, our primary focus is on bringing both crovalimab in PNH and Factor B into the IgAN space. We definitely keep our options open, but I think it's worth noting as well that this is an incredibly dynamic and busy clinical development field. Given the ultra-rare nature of PNH, we want to make sure that if we enter with anything in that direction, that we do so intentionally and in keeping with the emerging standards of care.
That's an assessment we're constantly making.
Maybe I can follow- up on the IMAGINATION question. Thank you. That's a good question. What I would say is that there are two approved therapies. One is the gut-specific steroid, I guess, budesonide, and the other is sparsentan. budesonide has shown GFR effects, benefits on GFR, but it is a steroid, how different is it from regular or typical conventional steroids? I'm not sure. I don't know what the community feels about that. For sparsentan, while it has received accelerated approval based off of a proteinuria reduction, we don't know the GFR results.
Right now, in conversations with health authorities and IRBs, they have approved our study to go forward versus placebo, but it is something that we'll have to monitor to see what the long-standing harder outcomes on renal function are for these therapies.
Thank you.
Emmanuel, did we answer all your questions?
Thank you. Yeah.
Okay. We move on. Next in the row would be Peter Welford from Jefferies. Peter?
Hi, hopefully you can hear me. I've got three questions left, please. Just sticking first of all on IgAN. In a similar vein, I guess, but really two parts to this. Firstly, just with regards to the stage of IgAN patients you're looking at in IMAGINATION, I just wonder if you can talk about where you think this sits in terms of the severity of patients versus those that are perhaps targeted by the current therapies, but also some of the more recent studies that have also been initiated by some competitors.
Equally, just on the UPCR six-month filing, given what's just been said, and the fact eGFR data is coming, do you still think, by the time this trial really gets to the six-month endpoint, regulators will still be open to a UPCR endpoint? I guess, you know, the pros and cons are, I guess, by then we'll have more data supporting that as a surrogate, perhaps with eGFR, but equally, perhaps there will be, if you like, no longer as much a medical need potentially, and therefore, eGFR data potentially going to be required by then. Secondly, then, you made the comment, in the crovalimab section, potentially self-administered by a patient. Curious with regards to that, is that because the patient, you know, is particularly complex to learn how to do it?
Is that something to do with the device? I guess you just talk a bit, little bit, why potentially? It would seem to be that surely you'd, you know, the desire would be to do it if you can. What was the experience out of interest in the clinical trial with that, and perhaps what proportion of patients, if any, did self-administer? Just finally, quickly, crovalimab in China. Just curious on your thoughts around that, given obviously this is a relatively undeveloped market, particularly what your thinking is with regards to going through the, I guess, the government route versus on the other hand, do we consider this a private pay market for you in China for crovalimab? Thank you.
Maybe I can start with the first two questions and just to make sure I remember them correctly. The first one was around the type of patient that we're enrolling in our trial and then the positioning relative to maybe other kind of therapies. The second question was the value of a proteinuria-based approval in the setting of additional data for other competitors that may have eGFR. Maybe with the first one, you know, a lot of these trials are the same. Our target is, you know, UPCR greater than one, but you will have a spread of patients above one. What we've seen with the labels, with both the sparsentan and budesonide, is they say generally progressive, greater than 1.5 for the UPCR.
There's nothing to me that tells us that would be different. That would be kind of the positioning of where this therapy would be targeted, but we'll have the data across various levels of proteinuria. You know, you have the endothelin receptor antagonist, you'll have the steroid, and then you have the complement inhibitors. The question is what are you trying to treat, right? We know that with the endothelin receptor antagonist, that will reduce proteinuria, mainly through a hemodynamic mechanism, right, at the level of intraglomerular pressure. Nothing to do with either the pathogenesis or the ongoing inflammation that occurs. Yes, it will provide benefit in terms of slowing eGFR reduction, but our goal with complement inhibition, reducing inflammation, is to stop eGFR decline. We'll see what the data show once we do that.
The second question was around the value of the proteinuria reduction. I think it's really what's the magnitude of proteinuria reduction? The approvable endpoint based off the surrogate data, based off the meta-analysis that Lesley Inker et al. published, is that a 30% reduction is the minimum required requirement at either six or nine months that would suggest a benefit on renal function. What you can see is that if you show a higher level of proteinuria reduction, you'll have a greater effect on the magnitude of eGFR reduction. I think it will depend on how much reduction in proteinuria we see at nine months to say how competitive it will be. Again, we're using a 9-month primary endpoint as opposed to six. I hope that answered your question.
Maybe I'll hand it over.
That was great. Thank you.
To Ben or Peter.
Yeah. Thanks, Peter. Great question. You're kind of calling me out on maybe, you know, not the right choice of words. We're absolutely confident that patients can self-administer crovalimab. In fact, we believe that in part, the strong preference for crovalimab that we've registered in the studies is driven by that experience. I'll pass to Professor Röth in a second, to give sort of his perspective hands-on from the study. Certainly, in the study setting, we allowed patients to self-administer after week nine. We would expect that in the real world, this would actually happen earlier. We definitely didn't see any sort of dosing errors that happened in the study based on self-administration. Just quickly on the China topic.
It's a bit premature, obviously, to comment on exactly the pricing, given that we're still in the approval stage, and haven't obtained regulatory approval. We're absolutely confident that there is an interesting business case for bringing complement inhibition to PNH patients in China, and we're quite confident that we can find a pricing model that will be sustainable, will ensure access to Chinese patients, and at the same time, be interesting, and sort of a sustainable part of our global strategy. I'll pass it to Professor Röth for his experience on the self-administration.
I think self-administration of crovalimab was really easy. I was training it with the patients from the beginning of the trials, the COMPOSER trial, and it's really, really easy. The patients love it, as it gives them the independence. It's just fill the syringe, and then you administer it subcutaneously. It's really, really a great and easy thing for the patients.
Thank you for these insights. If there are no more questions, I think we would be at the end of our event for today. Maybe just looking, but I think there is no more.
Peter, we answered all your questions?
Yeah,
looks like. Okay. I would like to thank again all the speakers for their time and their commitment, and also the IRT members who were involved in preparing the individual slide decks. This is Lilit Sprieth and Jan-Philipp Lautenschläger here on our side, and also Eva, who was responsible for the event organization. I hope that this event was helpful, providing an update here on our hematology franchise and especially on crovalimab, and also summarizing our efforts in nephrology.
If there are any remaining questions, then please reach out to the IRT anytime. Other than that, I wish you a good day and hope to talk to you soon. Bye.