Roche Holding AG (ROG) Earnings Call Transcript & Summary

[Operator Instructions] 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. And can I have the first slide, please? So welcome to our third IR call in 2023, this time focusing on crovalimab. The crovalimab development program, especially on PNH, the results presented at EHA and also on our emerging nephrology franchise. And let me quickly make an upfront statement here. I think the nephrology franchise, which today already consists of 4 medicines, we'll have a first major readout to come next year in 2024, with Gazyva and lupus nephritis. And based on the very strong Phase II results, this indication also got a breakthrough therapy designation. So the overall opportunity, which we flagged here for Gazyva in lupus nephritis in SLE in membranous nephropathy or childhood onset, idiopathic nephrotic syndrome is significantly more than 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 3 speakers with us. The first one is Peter Ahnesorg, our global franchise head for hematology, responsible for global product -- for the global product strategy. Peter will provide a quick update on our hematology franchise strategy, providing the latest information on our CD20, CD3 bispecifics program before he will dive into the crovalimab development program in more detail. Our second speaker for today is Professor Dr. Alexander Röth, a well-known hematology specialist and the researcher with a focus in PNH and the crovalimab clinical investigator, who will lead us through the 2 pivotal studies, which were presented over the weekend at EHA in Frankfurt. And these 2 studies are, firstly, the randomized Phase III study, COMMODORE 2 for crovalimab versus hemolysis in PNH. Patients live to C5 complement inhibitors. And 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 data on our nephrology pipeline, which currently includes 4 molecule with Gazyva, our antisense oligonucleotide Factor B; and crovalimab, all in Phase III testing ready. And then our latest addition, CD20, CD3 bispecific mosunetuzumab, also known by the name Lunsumio, which just entered Phase I testing. Overall, for today, we have 60 minutes. We believe, I would say probably 40 minutes presentations, and we will have 20 minutes for a Q&A. And I just want to flag here for the Q&A. We will have 2 additional people joining. Ben Stewart, the lifecycle leader for crovalimab; and then Peter Ahnesorg our integrated strategy lead for the franchises nephrology and rheumatology, who can also -- happy to take your questions. So 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. And since Q1, a couple of things happened. Just to go from the top to the bottom. I think on May 9, we announced that we have filed a Vabysmo RVO. In the United States with PDUFA date set now for December 22. On April 26, we announced that we got a positive CHMP opinion for Columbia in third line DLBCL. So the new approval is now expected for later this year. And then I think on the other results or the pivotal results where we have [indiscernible] COMMODORE 1 and 2. These are the data we will talk about today in more detail. And then I think on the bottom line, you see 2 additional pieces of information which we had lately, this was -- we had the Phase II data for our BTK inhibitor, fenebrutinib, in RMS, where we will have the data to be presented at an upcoming conference. And actually, if everything goes as planned, this already could be in July. And 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 Tecentriq and Avastin in liver cancer. And where we have announced that we based on these data, we'll have a Phase III initiated. I also wanted to quickly use here on the bottom to provide an outlook on what are additional other events we have scheduled now for the remainder of the year. On September 11 and 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 Digitization Day. And then later on in December, we also will go for an additional -- we'll have an ASH event again, ASH IR call which will be virtual, but we have so many data here to present and coming in hematology especially with the late-stage reach out like Stage or -- that we will have a pretty busy event there. So with that, I will hand over to Peter for an update on our hematology franchise and to 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. And we're also very privileged to be joined by Professor Alexander Röth, 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 nonmalignant as well as the malignant space. By now, we have 7 medicines on the market. And we're really interested in investigating both established indications like lymphoma and follicular lymphoma and CLL, but also venture into new areas, particularly multiple myeloma to pick out one of those. And we have a broad portfolio, as I mentioned, 7 medicines on the market, 12 NMEs the clinical development. And we believe, based on that, we have a pretty unique opportunity to combine modalities. And we're particularly interested also in explore costimulatory approach in lymphomas but also in multiple myeloma mimicking the Signal 1, Signal 2 approach in immunotherapy that's known from the CAR T cells. As I mentioned, we're spending 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. And now we're quite excited to bring 2 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. And this year already, we've had a quite significant news flow. We've had the approval of Columvi first-line DLBCL in the United States, and the approval of Lunsumio in the United States and in other markets, and we're looking forward to more to come for the rest of the year. And lastly, one of the paradigms that we're following as we're building our strategy in hematology is really to redefine the patient experience. And one of the hallmarks that we're exploring there, particularly in the malignant hematology space is the concept of fixed duration therapy. So really breaking with the paradigm in oncology that patients have to be treated forever in order to keep the tumor at check but introduced the idea that you can treat for a finite amount of time and achieve impressive results for patients. And we've just been able to share some update from our bispecific antibodies at ASCO and at EHA and 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. So on the next slide, as promised, I wanted to talk a little bit about the future opportunity we see in hematology. And as you can appreciate from the left side of this slide, we and others expect hematology to continue to grow significantly in the future. And 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 in 18 molecules that we're exploring. And particularly in multiple myeloma and DLBCL, we feel we're quite uniquely positioned to really grow the franchise in the next decade. So 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 took a very deliberate approach to develop 2 differentiated molecules for lymphoma. In Lunsumio, we not only have the 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. And 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, and so we believe this molecule is unsuited 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 are investigating Lunsumio in combination with lenalidomide. And then 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. And so we're expecting approval in Europe just around the corner. And similarly, we're expecting approval in the United States, in the very near future. With Columvi, 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. And we're seeing also a very favorable profile of the molecule in the first-line setting combined with R-CHOP. And 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 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. So 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, and this is in the context of second-line transplant ineligible patients in DLBCL. And so we're looking forward to seeing data for this study. There is an interim analysis which could happen anytime midyear this year. So we're quite looking forward to seeing that data. And then the final analysis will be more towards the end of the year. And the primary endpoint for the study is overall survival. So it will give a very definitive answer on the ad benefit that CD20 CD3 bispecific like Columvi can bring in the setting. So 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 nonmalignant part and specifically crovalimab. And 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. So all in all, we now have 3 positive Phase III studies for crovalimab include a 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 of action and why the recycling antibody technology is particularly suitable for the treatment of PNH. But 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. But it's also quite clear that there is still unmet need. One -- and there's really sort of 3 dimensions in our mind how you can think about the unmet need in PNH. One is those patients require live long 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 is 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 actable to patients all across the world. And lastly, about 20% of patients experienced clinically relevant extravascular hemolysis. And we believe this is also a dimension where additional treatment options can really provide value. And so on the next slide, I already mentioned our clinical program and the fact that now we have a body of evidence of 3 positive Phase III studies. And one thing that's really underscored by all of these studies is that the dosing convenience of crovalimab really translates into significant patient preference. So we see 96% of the patients prefer crovalimab over eculizumab in our studies. And this is really thanks to the once every month subcutaneous administration had a pretty low volume. It's fast. It can 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. So on the next slide, I wanted to also highlight that we're obviously looking at developing crovalimab in other diseases. So 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 really 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. And 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 nonmalignant disease that we're exploring with crovalimab in sickle cell disease. We have some very intriguing preclinical data that suggests that complement is involved in the vaso-occlusive crisis that happened 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. And so 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. And we have 2 ongoing exploratory studies that look at either using crovalimab to prevent basis of crisis or for the acute treatment of these types of events. And we're looking forward to looking at that data and making a decision for the future development program of crovalimab in the space. So going beyond the nonmalignant team space, as was already mentioned by Bruno, we actually have my colleague Jay Garg, who is 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. But 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 have -- we started a Phase III study -- sorry, a Phase I study of crovalimab earlier this year and are looking forward to seeing if with complement inhibition, there is a second ad that we can potentially move forward with for this disease. So 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 PNH, mainly COMMODORE 2 and also COMMODORE 1. So next slide, please. So how about crovalimab, is not just another C5 inhibitor, but it's a highly engineered antibody. Yes, the special affinity to C5 and the preferential uptake of fully loaded antibody, which is relevant. And due to the affinity manipulation and a 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. And it was a pleasure for me. I was the national -- an international coordinator for the crovalimab 2 trial and it's a pleasure to represented the data about those trials. Next slide, please. So crovalimab was first analyzed and studied in the COMPOSER trial, and we were happy to use crovalimab first in Germany in the COMPOSER trial. It was a 4-part adaptive study for C5 inhibitor in naive as well as experienced patients. Then 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. And the COMMODORE 1 trial was a randomized study of C5 inhibitor experienced patients. And all the details are given here in this slide. So next slide, please. So here are the results. So one co-primary endpoint was the hemolysis control, defined by the reduction of the LAH below or equal 1.5x the upper limit of normal. And 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. And COMMODORE 1, crovalimab showed hemolysis control around 93% versus 93% for the eculizumab arm. So pretty comparable. So more details about hemolysis control in this slide. You see the proportion of patients with central LDH below or equal 1.5x upper limited normal. On this side and needed increase and improvement until week 5, and this was maintained throughout the study of 25 weeks. Similar results for the normalized LDH. So the LDH went down until week 5 and was maintained below 1.5x limit of normal for the crovalimab arm, where it was slightly above 1.5x upper limit of normal for eculizumab. So next slide. So another co-primary endpoint and was reached for transfusion avoidance. Here for COMMODORE 2, around 66% of the patients in 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. So clearly, for the COMMODORE 2 trial, clearly showing -- demonstrating noninferiority for the co-primary endpoints. Next slide, please. So other endpoints, secondary endpoints were also studied like the risk for -- the frequency of breakthrough hemolysis. And this slide gives you the proportion of patients with breakthrough hemolysis. In the COMMODORE 2 trial was around 10% for the crovalimab arm and around 15% for the eculizumab arm and also demonstrate noninferiority. In COMMODORE 1 trial, similar results, around 10% for crovalimab and around 40% for eculizumab. And next slide, and the hemoglobin stabilization, which was another secondary endpoint. He also was crovalimab showed non-inferiority to eculizumab with around 63% for crovalimab and around 61% for eculizumab. And 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. And you see here from the analysis of the FACIT-Fatigue scale, patients added off with really low FACIT-Fatigue scale, meaning a severe fatigue, with around 35 or 36 points. And in COMMODORE 2 trial, patients showed a dramatic improvement of the FACIT-Fatigue scale of around 8 points, almost normalizing their FACIT-Fatigue scale and the scale of 43 or 44 points. And it was in eculizumab arm was 5 points. For patients in the COMMODORE 1 trial switching from standard treatment, similar results was the FACIT-Fatigue scale were maintained. And we consider for your background -- for this background information, we consider an increase of 5 -- at least 1 -- at least 5 points from base 9 to be clinical meaningful or significant. Next slide, please. About safety, if we talk about the complementary safety is always an issue. But in January, for this population, crovalimab was well tolerated. There were 3 fatal -- in COMMODORE 2 trial, but they were mainly related -- related to the underlying disease PNH with the myocardial infraction and under a coexisting disease with the respiratory hemorrhage. There was also one fatal case in the eculizumab arm with 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 like to end with crovalimab in comparison to eculizumab. This was took place in the COMMODORE 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 switch to crovalimab in the existing period. And 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%. And 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. So really some convincing, and this was also my experience here with my patients in the trial. Next slide, please. So in summary, in conclusions, COMMODORE 2 trial met its co-primary endpoints, demonstrating non-inferiority in comparison to eculizumab for hemolysis control in future avoidance. Crovalimab is also non-inferior to eculizumab for breakthrough hemolysis in hemoglobin stabilization. There was a clinically meaningful improvement in the FACIT-Fatigue scores around occurred in both arms with a numerical grade improvement for crovalimab. Patients who switched from eculizumab to crovalimab continue to maintain disease control. And taken together, COMMODORE 1 and 2 show the crovalimab is well tolerated in both C5 inhibitor experience and naive patients with PNH. In exploratory analysis, the majority of both COMMODORE 1 and 2 patients switching from eculizumab to crovalimab, who completed preference survey stated a preference for crovalimab. Crovalimab also has a potential to offer clearly a new treatment option for people with PNH, that allows a low-volume subcutaneous self-administration with every 4-week dosing. And with this, I'd like to finish, and I thank you for your attention. Thank you very much.

Thank you. So my name is Jay Garg, I'm the Global Head of Nephrology and Rheumatology here at Roche in the late-stage organization. So 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. So our vision and strategy to really provide significant benefit for patients with kidney disease, really rest on 4 pillars. So we want to have an industry-leading portfolio in nephrology. We think we're well on our way there with 4 late-stage molecules in kidney disease. We want to develop close partnerships with patient communities to help 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. And importantly, we want to try to ensure the best possible access for as many people as possible. So kidney disease is really a growing burden globally. So chronic kidney disease or CKD is about 1 in 10 people worldwide. The total prevalence of kidney disease is estimated to be about $1.1 billion and anticipate to grow by about 18% over the next decade. And importantly, CKD does have a significant effect on health care systems worldwide. So it's estimated to be about 25% -- about 1/4 of the U.S. Medicare budget, and EUR 140 billion annually in Europe. So as I mentioned, the portfolio we have since both established and late-stage products and we have 7 pivotal Phase III trials ongoing. Can go to the next slide. So a disease area of particular interest for us and has been for quite a while is lupus. So 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. So in looking at our -- the data from our previous trials, as well as data provided by academic investigators in the lupus community, we have -- we believe that greater B-cell depletion can lead to greater responses in lupus patients. And we have 2 molecules that can help us test that hypothesis. So the one that's furthest along in development is Gazyva, which is a type 2 [ anti-CD20 ] antibody, that has been approved for follicular lymphoma. But now we have taken into autoimmune disease. So this molecule was engineered to have greater B-cell depletion than type 1 anti-CD20 monoclonal antibodies like Rituxan. So it has a higher affinity for gama receptor, which leads to increased antibody-dependent cellular cytotoxicity and cellular phagocytosis. And it also has increased direct cell death, which we think is important in lupus patients or in treating these patients. So based off some encouraging Phase II data, we've actually initiated 2 Phase III studies, one in nonrenal lupus, which we termed allegory; and one in lupus nephritis, which returned REGENCY. In addition, we have a bispecific that you heard about earlier, Lunsumio, which finds both CD20 and 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 a port -- in tissue B cells, which then may lead to greater responses. And this is in an ongoing Phase Ib study in lupus patients. Can we get the next slide. So what really guys excited about Gazyva was really the Phase II study that we conducted in lupus nephritis, which we term nobility. So this study evaluate the safety and efficacy of Gazyva in patients with proliferative lupus nephritis after 4 infusions given at days 1, 15, weeks 24 and week 26. So the study met the 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 22% delta and complete response, which is better than what's been seen with other therapies. So 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 dosed at days 1 and 15, weeks 24 and weeks 26 and then every 6 months thereafter to see if we can confirm and maybe increase the benefit that we saw in our Phase II study. Now we also know that lupus is a heterogeneous disease that has different patients may have different drivers of their disease. And we know that complement plays a significant role in autoimmune disease and potentially in lupus nephritis as well. So as mentioned before, we've started a Phase Ib state with crovalimab, hoping to test whether inhibiting C5 can provide additional benefit in these patients. So 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 started 2 additional Phase III pivotal studies in members nephropathy and childhood onset idiopathic nephrotic syndrome. So members nephropathy is an orphan disease with [indiscernible] mortality with no currently approved treatment options. About 1/3 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. So there are autoantibodies that are pathogenic, the most prevalent of which is anti-PLA2R. And we've seen that other B-cell therapies can provide benefit. But 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. So that Phase III [ stage 2 ] Majesty is ongoing. So the last indication for Gazyva that we're evaluating is chided onset idiopathic nephrotic syndrome. So this is the most common kidney disease in children with really limited therapy options available. And 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. And so the key unmet need here is how do you maintain remission without requiring additional steroids. So approximately 70% of patients will either experience relapses or can't get off steroids. And so our goal with this trial, which we turned into is to try to maintain that remission at the need for additional steroids. And we've initiated that study. The next slide. And so Peter already talked about atypical hemolytic uremic syndrome. So the role of complement is disease or this devastate 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. So we have one study in adults and one study in children. The next slide. And so lastly is our most recent Phase III pivotal say that we started in IgA nephropathy with our antisense oligonucleotide that inhibits Factor B production. So 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 complements activated, which causes inflammation then which will cause damage. So 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, really because its mechanism suggests that it could provide the most complete Factor B inhibition that we have in currently evaluated clinical trials. So the antisense oligonucleotide will bind hit complement factor B production in the liver where the majority of complement is produced. But we also know from preclinical data that there is production of Factor B moved into the kidney. And so that's a site of action for IgA nephropathy. So by inhibiting the local production, we'll get more complete inhibition of Factor B, which then may offer us best-in-disease efficacy due to complement inhibition. So we have some early Phase II data suggesting that the majority of about 80% of patients do have a reduction in proteinuria and at high levels of reduction. And we're hoping to test this hypothesis in our ongoing Phase III study, which we've termed imagination. So this is a study that randomizes patients one-to-one. The primary endpoint is at 9 months based off proteinuria, where we would then look for accelerated approval, similar to other therapies that have been approved. And then we'll continue treatment until 2 years where we hope to get data for full. So with that, I will pass it back to Bruno.

Thanks a lot, Jay. And with that, we will open the Q&A.

The first question actually comes from Charlie from Morgan Stanley.

Charlie from Morgan Stanley. So 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? And does it mean you sort of see a potential -- a great potential naive rather than switch patients? And then 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 as it already stable on C5 onto crovalimab or mainly present crovalimab as an option for new patients?

Should I take it? So I think -- I mean switching from a preexisting C5 inhibitor another C5 inhibitor could be of high interest, how if you consider. I mean that's an issue that 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 1 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. And I think for those patients, and this is a big fraction actually such a subcu treatment, which gives you a high independency -- also independency for traveling is something which is really interesting. You mentioned as one thing is for naive patients, of course, it's transfusion i.e., or related to transfusion. And it's typically the first dosing of complement interterminal complement inhibitor. It means you're effectively blocking the complement and you're having more nitrous oxide available. And that's a phenomenon we know from the beginning of the usage of terminal complement inhibitor. And it just shows you, and it's only limited for the first dosing of this drug. And the other thing is switching from one C5 inhibitor to another. That's mainly related, and this was known from the beginning, it's not only related for crovalimab, but also a class effect of C5 inhibitor, is the formation of complexes of immune complexes of C5 and the anti-C5 antibodies. And this was clear from the beginning and the situation and the reaction varies from patient to patient. Everyone got those immune complexes. And the side effect starts after 2 weeks for last -- last up to 2 weeks. And it's a well-known side effect we know from other antibodies, for example, ATG, which is especially known for 2 colleagues with other who deal with patients with [ eblastinemia ] and it's manageable with topical steroids or systemic steroids. So I think it's -- it's a manageable thing and I don't -- I'm not worried about to use crovalimab in our patients -- in patients at all.

The next question will come from Emmanuel Papadakis from Deutsche Bank.

Maybe a follow-up on the same line of question. 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 the C3 oral factor B? And then perhaps one of the team, do you plan to generate any data in combination with proximal inhibiting agents for crovalimab or you don't think that will be a relevant clinical approach? And then maybe a question on Imagination, trial you're just kicking off in IgAN, 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 have to be?

So the first question for me, I guess, on concern of switching patients from one C5 inhibitor, and is there a reason for that or any combinations with the developer field. I mean there are a significant proportion of patients who remain stable on C5 inhibitor. We know C5 inhibitors for almost 20 years. They are safe. We know how to deal with any side effects or complications. And I think that's -- it's a good reason to continue C5 inhibitor treatment. And ultimately, of course, it's up to the patients and the patients were able to decide what is the best treatment for them. And -- but -- as I remember, from the beginning, subcutaneous treatment was also something the patient wish 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. And 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. And 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 in keeping with the emerging standards of care. So that's an assessment we're constantly making.

And then maybe I can follow up on the imagination question. So yes, so thank you. That's -- it's a good question. So what I would say is that there are 2 approved therapies. One is the gut specific steroid, I guess, Budesonide, the other is sparsentan. So Budesonide has shown GFR effects, the benefits on GFR, but it is a steroid. So -- how different is it from regular or typical [indiscernible] I'm not sure. I don't know what the community feels about that. But with Sparsentan, while it has received accelerated approval based off of a proteinuria reduction, we don't know the GFR results. So 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.

Then we move on next in a row would be Peter Welford from Jefferies.

I've got 3 questions left, please. Just to give, first of all on IgAN. In a similar vein, I guess, but really 2 parts to this. Firstly, just with regards to the stage of IgAN patients you're looking at 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. And equally, just on the UPCR 6-month filing, given what's just been said and the fact that eGFR data is coming, do you still think by the time this we get to the 6-month end point, regulators will still be open to a UPCR endpoint? And I guess the pros and cons are, I guess, by then will have more data supporting that as surrogate perhaps with eGFR, but equally perhaps there will be, if you like, no longer much of a medical need potentially and therefore, eGFR data potentially going to be required by then. Just 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 is particularly complex to learn how to do it? Is that something to do with the device? Or I guess just talk a little bit why potentially because it would seem to be that surely you the desire would be to do it if you can. And what was the experience out of interest in the clinical trial with that, perhaps what proportion of patients, if any, did self-administer? And then just finally, quickly, crovalimab in China. Just curious on your thought on 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?

So maybe I can start with the first 2 questions and just to make sure I remember them correctly. So the first one was around the type of patients that we're enrolling in our trial and in the positioning relative to maybe other kind of therapies. And then the second question was the value of a proteinuria-based approval in the setting of additional data for other competitors that may have eGFR. So maybe at the first one. So a lot of these trials are the same. Our target is UPCR greater than 1, but you will have a spread of patients above 1. What we've seen with the labels with both the sparsentan and -- as they say, generally progressive greater than 1.5 for the UPCR. So there's nothing to me that tells us that would be different. So 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 have the endorphin receptor antagonist, you'll have the steroid and then you have the complement inhibitors. And so the question is, what are you trying to treat, right? So we know that with the endothelin receptor antagonist that will reduce proteinuria mainly through a hemodynamic mechanism, right, at the level of intraglomerular pressure. So nothing to do with either the pathogenesis or the ongoing inflammation that occurs. So yes, it will provide benefit in terms of slowing eGFR reduction. But our goal with complementing ambition, reducing inflammation is a stop, EGFR declines. So we'll see what the data show once we do that. And then the second question was around the value of the proteinuria reduction. So I think it's really what's the magnitude of proteinuria reduction. So the approvable endpoint based on the -- data based off the meta-analysis that at all published is that a 30% reduction is the minimum require requirement at either 6 or 9 months that would suggest a benefit on renal function. But what you can see is that if you show a higher level of proteinuria reduction will have a greater effect on the magnitude of eGFR reduction. So I think it will depend on how much reduction in proteinuria we see at 9 months to say how competitive we will be. And again, we're using a 9-month primary endpoint as opposed to 6. I hope that answered your question. And maybe I'll hand it over to..

Thanks, Peter. Great question, and you're kind of calling me out on maybe not the right choice of words. We're absolutely confident that patients can self-administer crovalimab. And 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 9, and we would expect that in the real world, this would actually happen earlier. And 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. But 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 in sort of a sustainable part of our global strategy. And I'll pass it to Professor Röth for his experience on the self-administration.

Yes. I think self administration of crovalimab was really easy. We are -- I was training it with the patients since the beginning of the trials, the COMPOSER trial. And it's really, really easy. The patients love it as it gives there the independence. It's just fill the syringe and then you administer 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 or -- yes, it looks like. Okay. So then I would like to thank again all the speakers for their time and their commitment and all the IR team members who were involved in preparing the individual slide deck. So this is [indiscernible] and [indiscernible] here on our side. And also 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 IR team any time. And other than that, I wish you a good day and hope to talk to you soon. Bye.