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At this time, it's my pleasure to introduce you to Karl Mahler, Head of Investor Relations and Group Planning. Karl, the stage is yours.
Thanks a lot, Henrik, for the kind introduction. Welcome to our ASH science call today. This is the last one for this year. It's close to Christmas, and this is also a testimony of good signs which we had in the past year, I think, on various occasions. Very excited to present an update on the probably largest and broadest hematology pipeline in the industry. Maybe from my side to highlight definitely two things. There's lots of things you hear today, but maybe two things. One is the phase II for our bispecifics and mosunetuzumab and glofitamab, which got an oral presentation here. One other highlight definitely was the late-breaking abstracts for POLARIX. I mean, it was the first improvement we will hear about it since 20 years in first time DLBCL.
Going with the presentation, there was in parallel a presentation or a publication in New England Journal of Medicine. In summary, strong progression-free survival improvement and good safety. Looking at the feedback so far on the data which we have presented, and specifically also here on the POLARIX, very good feedback. There was an Evaluate Pharma survey which was just put out after ASH with key opinion leaders asking about the future standard of care and really practice-changing data. One actually we have to say also the CAR-T actually had a good show up here at this ASH. Everybody also mentioned POLARIX as a potential standard of care. In line with a recent...
This is also in line with a recent physician survey we did on the data and the strengths of the data. Let's go to the overview and the agenda, please. Yeah, this is the program for today. We have with us Peter Ahnesorg. He's the Franchise Head of Hematology in the Global Product Strategy group. As I said before, I mean, this is the broadest and deepest hematology pipeline in the industry. We have six different approaches. We have in eight therapeutic areas, so there is a lot of data now already available and to come. Then we have Charlie Fuchs. He will talk about the focus on five assets. He's the Global Head of Oncology and Hematology Product Development.
Just to mention here, Charlie just published a book on cancer. I also want to get some benefit for this one. I just wanted to mention that, Charlie, that is a standard book in cancer treatment. You can buy it on the book market. Then we have Franck Morschhäuser with us, a leading investigator, key opinion leader for hematology, working on probably new standards of care in hematology, but also on the bispecifics, not just only probably. With this one, over to you, Peter.
Thanks a lot, Karl. Welcome everybody to this investor call at the end of ASH 2021. My name is Peter Ahnesorg. I'm the franchise head for hematology at Roche and Global Product Strategy, and I'm extremely pleased to be with you today. This has really been an historic ASH for our organization. We've contributed almost 100 abstracts to this meeting, showcasing advances in research across a multitude of malignant and benign hematologic indications. We had more than 30 oral presentations, and most importantly, we presented three datasets that we believe have the possibility to change standard of care in the future. The POLARIX study in frontline DLBCL, the HAVEN 6 study with Hemlibra in mild to moderate hemophilia A patients, and pivotal data for our bispecific antibody mosunetuzumab in follicular lymphoma.
A lot to talk about, but before we hear from Charlie about some of the detail, I just wanted to take a couple minutes here to talk more comprehensively about our hematology portfolio, and why we're extremely optimistic about the outlook. If we go to the next slide, as you've heard at Pharma Day, if you joined that and in other communication from Roche, we really have a bold vision in providing more patient benefit, but also being mindful about the impact to healthcare systems and to society that our therapies have. That's also the guiding principle to our strategy in hematology. There's three key pillars to how we're thinking about moving forward our portfolio. The first one is to really focus on our areas of strength.
That's why you see us bring forward important new advances in non-Hodgkin lymphoma, an area where Roche has been present for the past two decades. We're extremely excited about continuing to move forward in that space. Similar things apply for AML and hemophilia. Secondly, we're not gonna stop there, but we're really targeting to go into areas that are new to us. Most importantly, really, to call out multiple myeloma. Well, we believe we have a very strong pipeline, and you'll hear some about that. Then thirdly, we believe we continuously need to innovate to stay relevant and to move our pipeline forward.
You see that if you, for example, look at our bispecifics program, where we're really taking a diverse number of approaches in how we're engineering these antibodies to meet different needs of the market out there, but also in how we're approaching combination therapies, the partnerships we're striking and how we're exploring novel endpoints. On the next slide, I'm not going to go very deep into this. You just see the breadth of our portfolio across both malignant as well as benign hematology and across a multitude of different modalities. But as you can appreciate on the next slide, we really, you know, understand that just the breadth of the portfolio in and of itself is not gonna make us successful.
We're really building on our ability to understand the space, and we've demonstrated that. If you just look at the number of Breakthrough Therapy Designations in the U.S., that's really a reflection of the impact we've been able to make in hematology and the knowledge we have in that space. More importantly, really, we're quite focused on going to lines of therapy where we can meaningfully cure patients, because we believe that is really where future value lies for healthcare systems, and not only sort of addressing late line therapy, but ultimately curing patients in earlier stages of the disease.
One great example of that, if we go to the next slide, is how we're thinking about first line DLBCL, where for the past 20 years, obviously MabThera Rituxan has been instrumental in defining therapy for patients. We've had quite good success with roughly 60% of the patients being cured in that setting. That conversely means that four out of ten patients still remain uncured, and we're convinced that those patients deserve new treatment options, and they deserve these treatment options in a timely fashion. The reality is that in these frontline settings, the treatment effect of therapy goes on for a long time.
Focusing on overall survival is really difficult and therefore it's important for us to bring forward endpoints like progression-free survival that are appropriate because they demonstrate meaningful benefit for patients. In front line DLBCL, that's clearly the case where preventing patients from progressing, preventing relapse, preventing subsequent therapy that is often costly and certainly psychologically really detrimental for patients is something that is very meaningful. On top of that, as you can appreciate on the right side of the slide, it's also been demonstrated and accepted in the community quite broadly that PFS in this setting is predictive of a treatment effect on overall survival ultimately. If you go to the next slide. I'm not going to go into the details of the POLARIX study.
We have Professor Morschhäuser here, who's a distinguished expert and president of the LYSA group, so he will speak about POLARIX to you. You know, just sort of pointing out that we're really excited about these results. We're excited about them because there's many patients in the first line setting of diffuse large B-cell lymphoma that deserve better new therapies. We believe that with the first study that's positive here in almost 20 years, and there's been 11 negative studies in the meantime, we're really making a meaningful advance here. On top of that, there are some distinct benefits of Polivy that we're quite excited about. One is that physicians all across the world already have experience with this drug.
Second, it's an off-the-shelf and fixed duration therapy, so it has a lot of advantages also with regards to payers understanding what does a course of therapy cost and, you know, being able to appreciate that in the context of preventing progression for patients. Lastly, we know a lot about Polivy, and we most importantly understand that it has a very well-tolerated safety profile that is well documented in many patients suffering from non-Hodgkin lymphoma. So we're also quite confident that this drug can be easily moved to the frontline setting, and we'll see some of the data obviously from Professor Morschhäuser. But we're not stopping with Polivy, so if we go to the next slide.
You will also hear some of the updates from ASH from Charlie Fuchs later on about our bispecifics program. What I wanted to point out here is really on how much as a company we're focusing on developing differentiated and well-designed bispecific antibodies. We've demonstrated that with Hemlibra in hemophilia. We've demonstrated it again earlier this year with Vabysmo in ophthalmology, two really carefully designed bispecific antibodies. We're excited to bring this forward in NHL, and we have two differentiated molecules, mosunetuzumab and glofitamab. We believe that because they are different, we'll be able to address very, very different needs that exist for patients with non-Hodgkin lymphoma that have different types of diseases, are in different care settings.
We believe these two molecules can really make a meaningful benefit for those patients. In addition, have significant advantages over, for example, CAR-T therapy, as they are much more readily available, can be given in a community setting, don't require hospitalization, for example. A lot that we're excited about here. On the next slide, I just briefly wanted to point out that sort of some of the corner posts of our development strategy for these bispecific antibodies is also to move to the curative setting. We definitely see opportunities in the frontline setting in non-Hodgkin lymphoma for these drugs. Also we see a huge potential to combine, and the other sort of really great thing with bispecific antibodies is their ability to combine with other modalities.
We're quite excited to explore that. As you can see from the slide, we have quite a broad program already in place that is exploring that. On the next slide, what I wanted to talk about is another bispecific antibody, cevostamab, which is actually in multiple myeloma. I said in the beginning that this is an area where we are really looking to venture into. What's very interesting and unique about cevostamab is that in what is a very crowded field in multiple myeloma with a lot of BCMA-targeted agents, this bispecific antibody has a very unique target, which is FcRH5. We believe that sets it apart nicely and Charlie will present some of the data that we showed at ASH, a little later on.
We're excited about moving this molecule forward. We're planning for a broad program, and we think this is going to be a first really important step into multiple myeloma for Roche. On the next slide, and to conclude, my presentation on the malignant side of hematology, I just wanted to point out how strong the year has been for Venclexta. We're really seeing this as being a standard in CLL and AML, and we're seeing very strong performance in those spaces. We're also really excited about the future for the molecule as we in collaboration with our partner AbbVie here are thinking to hopefully have seven new indications for Venclexta in the next five years.
A lot more to come here. Also if we look into next year specifically, we're excited to be reading out data in multiple myeloma, and we're looking forward to making progress in MDS. Two important steps forward for this molecule. If we move to the benign side of the hematology, we're obviously very much focused on hemophilia A and the progress we've been making with Hemlibra this year has really been profound despite the pandemic. We're seeing very strong growth and uptake and truly in many countries across the world, Hemlibra is now an accepted standard of care. As you know, we have a very broad study program with more than 1,000 patients. We have about 13,000 active patients on commercial Hemlibra at the moment.
A lot really to be very proud of here. At ASH, we demonstrated new data from the HAVEN 6 study in the mild to moderate population, which we believe is further going to substantiate the benefit that Hemlibra is bringing to hemophilia A patients. On the next slide, I wanted to just briefly also give a shout-out to our partners at Spark Therapeutics, who is really our hub for gene therapy. We're very excited about the progress that they are making and we're making in collaboration with them on SPK-8011 in hemophilia A. We do think that gene therapy still has a road to go in hemophilia A.
We definitely believe that the bispecific class and Hemlibra specifically will continue to remain a really big driver in that space. But we also think that there is opportunity for gene therapy, and we are very excited about the progress and getting to a place where we can really demonstrate predictability and durability for these gene therapies, which are really going to be the two important criteria to watch out for to determine how successful these therapies can be for patients with hemophilia A. Finally, before I pass it on to Charlie, I wanted to illustrate that beyond hemophilia A, we're also looking at other benign hematologic diseases. Most importantly, we're excited about crovalimab, our anti-C5 monoclonal antibody.
This year has really been a terrific year for crovalimab. We've made tremendous progress in the development program for the molecule. Next year we're really looking forward to reading out the first pivotal data in PNH, which is going to be an exciting milestone. This year we were also able to expand the program in atypical hemolytic uremic syndrome, where we've been able to initiate studies, and also really importantly in sickle cell disease where we believe that this molecule can make a big impact. We're excited that the clinical program is also moving forward in that indication.
With that brief overview of our hem pipeline, I hope that I leave you with some of the same confidence that we have in the future and what we're going to bring to patients with blood disorders. To focus a bit more specifically now on what we've presented at ASH and how to think about that, it's my distinct pleasure to introduce you to Charlie Fuchs, who is our Global Head of Development in Oncology and Hematology. Over to you, Charlie.
Peter, thank you. And Karl, thank you for the plug for the book. It's very kind of you. You know, as Peter very nicely discussed, you know, this year's ASH meetings saw an unprecedented number of high-profile presentations. Coming out of our portfolio. While I won't be able to cover all of those data sets, I would like to share with you some key studies highlighting the work in Hemlibra, our CD20/CD3 bispecific, cevostamab, and Venclexta. I also want to point out that beyond today's speakers, we also have with us today Marion Ott, global head of our myeloid malignancies and multiple myeloma franchise, Ginna Laport, leader of our lymphoma and CLL franchise, and John Passey, global head of our rare blood disorders franchise.
Marion, Gina, and John will be available to answer your questions during the Q&A portion. As Peter outlined, HEMLIBRA has transformed the treatment landscape for people with severe hemophilia A. Nonetheless, in patients with mild to moderate hemophilia A, Factor VIII deficiency may still result in spontaneous bleeding, particularly into joints, resulting in joint damage, pain, impaired mobility, and reduced quality of life. As such, beyond severe hemophilia A, mild to moderate disease represents an important unmet need. At ASH this past week, we presented results from the HAVEN 6 trial evaluating the safety and efficacy of HEMLIBRA in patients with mild to moderate disease for whom Factor VIII prophylaxis is warranted, as deemed by the treating physician.
In this interim analysis of 71 patients, 72 patients, 72% had moderate severity, and among all participants, the mean number of bleeds in the past 24 weeks rather was 3.4. With respect to the secondary endpoints of the trial, participants on HEMLIBRA reported an improvement in treatment burden as assessed by the CATCH score, and an improvement in mean total hemophilia joint health score. Additionally, on HEMLIBRA, 96% of patients preferred HEMLIBRA over their previous treatment. Turning on the next slide to the primary results. Across the majority of bleeding event categories, the median annual bleeding rate was 0, and all model estimates showed an annualized bleeding rate of 2.3 or less per year, with several well below 1. As shown in the bar graph on the right, more than 90% of patients reported having 0 treated joint bleeds.
Finally, no new safety signals were identified, there were no thrombotic or microangiopathic events or deaths reported, and there were no adverse events that led to treatment discontinuation, reduction, or interruption. We believe that the HAVEN 6 data demonstrate that HEMLIBRA offers a favorable safety profile and an effective treatment option for patients with mild to moderate hemophilia A, while meaningfully reducing the treatment burden. Turning next to our CD20/CD3 bispecifics, we presented results from our pivotal phase II trial of mosunetuzumab monotherapy in patients with relapsed refractory follicular lymphoma. As seen in the baseline characteristics, patients on this trial were heavily pretreated and had refractory disease. Patients had received a median of three prior lines of therapy, 53% were double refractory, and 53% had experienced progression or relapse within 24 months of diagnosis as characterized by POD24.
As the waterfall plot documents, Mosun conferred an impressive depth of response with an 80% overall response rate and a 60% complete response rate by independent review. A complete response rate that is significantly greater than the 14% historic CR rate in this setting with prior therapies. Additionally, on the next slide, the median duration of response was 22.8 months, and the median progression-free survival was 17.9 months. Realize these are relatively immature data because follow-up is still ongoing. With respect to tolerability, cytokine release syndrome, CRS, of any grade occurred in 44% of patients, which was predominantly grade one and two. Adverse events leading to Mosun discontinuation was very uncommon at 2%. Finally, and no less importantly, Mosun was routinely administered as an outpatient.
In sum, mosunetuzumab is the first T-cell engaging bispecific antibody to demonstrate clinically meaningful efficacy in patients with relapsed refractory follicular lymphoma, and thereby offers a first-in-class, off-the-shelf outpatient option to these patients that we believe can also be administered in community settings. Turning to the next slide, beyond monotherapy, we are equally optimistic and enthusiastic about the potential for Mosun in combinations and in earlier lines of therapy. Specifically, we reported the results of our phase Ib/II study for the combination of Mosun with polatuzumab in patients with relapsed refractory B-cell lymphoma. Patients on this trial were heavily pretreated, having received a median of three prior lines of therapy.
Moreover, 40% of patients had received prior CAR-T therapy, and 76% were refractory to their last therapy. As shown on the right-hand side of the slide, among all patients with diffuse large B-cell lymphoma who received the recommended phase II dose, the overall response rate was 65% with a complete response rate of 48%, which was virtually identical in patients who had received prior CAR-T therapy. Follow-up data in this trial are still relatively immature. However, of the 29 patients who achieved complete response, 28 remain in CR, and the one patient with progressive disease actually received retreatment and re-achieved a new complete response. CRS of any grade was reported in 17.5% of patients and was confined to grade one and two, with only one grade two event.
Ultimately, we believe that Mosun-Pola demonstrates compelling efficacy and very manageable tolerability in this heavily pretreated population, and we are launching a phase III study of this regimen in the second-line therapy of DLBCL patients. Of note, we also presented data at ASH for the combination of Mosun and lenalidomide in relapsed refractory follicular lymphoma, showing a 90% overall response and a 66% CR rate in that population with very manageable tolerability. In light of those results, we have also started a phase III trial of Mosun lenalidomide in relapsed refractory follicular lymphoma. At the same time, turning to the next slide, we reported on a number of studies with glofitamab, including this trial in patients with relapsed refractory mantle cell lymphoma.
As you know, mantle cell is an aggressive subtype of non-Hodgkin lymphoma, and patients with progressive disease following a BTK inhibitor have a very poor prognosis. In this trial, the majority of patients had previously received the BTK inhibitor and were refractory to prior therapy. Nonetheless, among all patients, the overall response rate was 81%, with a complete response rate of 67%. Although follow-up remains immature, the swimmers plot on the right shows that the vast majority of patients continued to have ongoing responses at the time of the data cutoffs. Finally, most CRS events were grade one or two, and there were no adverse events leading to treatment discontinuation. We believe that this fixed duration, off-the-shelf therapy of Glofit in mantle cell lymphoma supports further investigation as an important new treatment option for patients with this malignancy.
Turning next to multiple myeloma, we presented updated results from our phase I dose escalation trial of cevostamab in relapsed refractory multiple myeloma, assessing both a single step-up and a double step-up dose schedule in cycle one to mitigate CRS. Patients on this trial were heavily pretreated, having received a median of 6 prior lines of therapy, and 85% were triple class refractory. Turning to the results on the next slide, among patients who received a target dose of 132 mg or higher, the objective response rate in this heavily pretreated, highly refractory patient population was 57%, with 33% of patients experiencing VGPR or better. In addition, MRD negativity, as assessed by next-generation sequencing, was detected in 7 of 10 evaluable patients with VGPR or better.
With follow-up ongoing, these responses appear quite durable, with a median duration of response now in the range of eleven and a half months. 81% of patients experienced CRS, which were predominantly grade one or two, and AEs leading to treatment discontinuation were uncommon. Based on these results, cevostamab appears to be a unique, new efficacious treatment option for multiple myeloma. This is the only FcRH5 targeted agent and therefore, beyond monotherapy, offers the potential to combine with other agents currently in practice or in development, including BCMA targeted therapies. As such, we will be expanding our clinical development program in 2022. Turning next, as Peter described, Venclexta, our BCL-2 inhibitor, has an important impact on the care of patients across the gamut of hematologic malignancies.
In higher risk MDS, myeloblasts overexpress anti-apoptotic proteins, including BCL-2, and are thus potentially vulnerable to directed therapies like Venclexta and azacitidine that can inhibit these pathways. At ASH this week, we provided updated results of our phase I/B trial for the combination of Venclexta and azacitidine in treatment-naïve, higher risk MDS. 84% of patients responded to treatment, representing a combination of complete response or marrow complete response. The median time to response was just under one month, and follow-up, with follow-up still maturing, median duration of response is over one year. Additionally, clinical and molecular responses were observed across the spectrum of mutational events, including poor prognosis mutations.
Building on our investment in Venclexta, we launched a phase III trial of Ven-Aza in higher risk MDS in late 2020, which offers the promise of meaningfully improving the treatment landscape for MDS patients. In closing, at this year's ASH, we presented a wide range of exciting new results from our portfolio. My colleagues and I, as I mentioned, will be happy to take your questions later. First, let me now turn to Professor Franck Morschhäuser, a thought leader in the field of lymphoma, an innovator and Franckly, a leader of our POLARIX trial, to present the results of yet another practice-changing study, the study of POLARIX. Franck, thank you.
Thank you so much, Charlie, for this very kind introduction. On behalf of all the authors and the creators, it's my great pleasure to present you the data of this trial. Next slide. First of all, to set the stage, it should be very important to remind everybody that CHOP has been the standard of care in first-line DLBCL for over 20 years. There have been many attempts to improve over our CHOP with introduction of new drugs, dose intensity, maintenance regimen. At least 13 big randomized phase III trials failed to demonstrate any significant improvement. With this standard of care, let's also keep in mind that up to 40% of the patients either will have refractory disease or would relapse following complete remission after R-CHOP. This clearly underlines the unmet need in this population.
CD79B is a component of the BCR receptor, and polatuzumab vedotin is an antibody-drug conjugate composed of an anti-CD79B monoclonal antibody coupled to a MMAE, a potent microtubule inhibitor that is internalized upon antibody binding to make it fast. Single agent data with polatuzumab vedotin were promising with an overall response rate of 52%. Pola was incorporated with CHOP in R-CHP pola combination that looks extremely promising in this one. The second is a 77% complete response rate and a promising 18-month PFS that led to think of a randomized phase III trial to compare it with the standard of care. Next slide. This was the purpose of the POLARIX study, which was a randomized double-blind study, placebo-controlled, international, phase III randomized trial. Patients were eligible if they had previously untreated B-cell lymphoma.
Their age 18-80 years, had an IPI score of two to five. That means incorporating intermediate and high-risk patients according to IPI, and a reasonable PS of 0-2. Patients were randomly assigned in a 1:1 ratio to either pola-R-CHP or R-CHOP, given for up to six cycles plus two additional cycles of 50. Patients were stratified according to their IPI score, two versus three to five. Bulky disease less than 7.5 or more than that. The geographic regions were from Europe, U.S., Canada, and Australia versus Asia versus rest of the world. Next slide. The primary endpoint was the investigator-assessed progression-free survival, and the secondary endpoints examined hierarchically were event-free survival, complete response rate at the end of treatment according to the central review, and overall survival.
We also had an additional sensitivity analysis on disease-free survival as assessed by the investigator. Other key secondary endpoints of the safety endpoint were the incidence, nature, and severity of adverse events. 875 patients were enrolled in this trial, and to have this first analysis and final analysis, there was a need to have at least 228 PFS events with a median follow-up of at least two years for all the patients included. At the time of this primary analysis, a median follow-up of 28.2. Next slide. These are the baseline characteristics of the patients. You can see here that they were well-balanced between the two groups. The median age was 65. Close to two-thirds of the patients had a high-risk IPI score of two to five.
Most patients at the event, you see, according to Ann Arbor staging and baseline characteristics were also well balanced in terms of the biologic subgroups, COO classification, double hits or double expressors. Next slide. With the median follow-up of 28 months, the risk of progression, relapse or death was significantly lower in the pola-R-CHP group than in the R-CHOP group, with a stratified hazard ratio of 0.73. That means that the landmark analysis showed that the percentage of patients surviving without progression at two years was 6.5% higher with pola-R-CHP than with R-CHOP, meaning a 27% reduction in the relative risk of disease progression, relapse or death versus R-CHOP. Next slide. Similarly, the event-free survival was significantly better for pola-R-CHP with a hazard ratio of 0.75.
Remember that event-free survival also included beyond progression, death and relapse, the introduction of another treatment that was not recommended in the protocol, so subsequent treatment or a positive biopsy at the end of treatment. A very meaningful result. Next slide. The CR rate was 78% with R-CHP/POLA versus 74% with R-CHOP. The difference was not statistically significant. Still, the disease-free survival, as assessed by investigator, was significantly better with a hazard ratio of 4.7, probably meaning that the quality of the CR achieved with R-CHP/POLA was better than with R-CHOP, leading to a better disease control. Next slide. With a 28-month median follow-up, that means a relatively short median follow-up in terms of overall survival, there was no difference at this point with a hazard ratio of 0.94. Next slide.
It is important in this context of so far lack of difference in overall survival to see that the percentage of patients receiving a subsequent treatment for disease progression or relapse was always higher in the R-CHOP group. 30% versus 22% for any treatment. 13 versus 9.3% for predetermined or unpreplanned radiotherapy. 23.5% versus 17% for any kind of systemic therapy. 7.1% versus 4% for autologous stem cell transplantation. 3.6 versus 2% for CAR T. Next slide. The safety profile was pretty similar between the two groups in terms of the overall incidence of adverse events or the percentage of grade three, four or grade five for serious adverse events.
What was interesting to note is that adverse events leading to either discontinuation of any drug, especially polatuzumab vedotin or bendamustine treatment or dose reduction of any study drug, was numerically lower in the R-CHP/POLA arm. Next slide. On this tornado plot, you see that there is a kind of mirror showing that the safety profile was really similar. Overall, what slightly stands out is the higher incidence of diarrhea with R-CHP/POLA and a slightly higher incidence of febrile neutropenia, 13% versus 8%. Please keep in mind that this is well within the range of what has been observed in other trials. Remember that, for example, in the GOYA trial, which is the most recent one with R-CHP/POLA, the incidence of febrile neutropenia was 15%. Nothing to us as clinicians is clinically relevant. Next slide.
In conclusion, I think we can say that pola-R-CHP significantly prolonged PFS compared to R-CHOP. Hazard ratio was statistically significant in the primary analysis. In patients with intermediate and high-risk previously untreated diffuse large B-cell lymphoma, very clearly the safety profile of R-CHP/pola and R-CHOP were comparable. We are now doing virtual analysis to look at various subgroups, but this is more hypothesis testing. Clearly the POLA results support the use of pola-R-CHP in the initial management of patients with diffuse large B-cell lymphoma. I'm happy to take a few questions. This was my last slide, and I turn over again to Karl.
Here we go. Thanks a lot for all the presenters. Maybe a bit of a housekeeping. We have about 200 people on the call, which is a lot, I have to say. Thanks for your interest in Roche and the presentation today. Before we go into the Q&A, I already wanted to thank the speakers for their contribution today. I wanted also to thank Lauren from our U.S. team, who did the heavy lifting on all the slides and the storyline development. Thanks a lot, Lauren. I wanted to thank Sonia already for all the organizational things to set up the call.
We have about 45 minutes for Q&A now, and today we have to be in time, I have to say, because I know that Charlie and the whole hematology team, they have a Christmas party today, a virtual Christmas party, and he asked me really to be in time here to close it because they will be the key speakers, so all of them for this party, we don't want to intervene here. So what we can do here, I will open the questions now. We have about seven questions now in the line, and we have about six here on the chat. I will try to mix it a bit in the sense of clustering the questions together and mention also who asked the question.
Simon Baker would be the first, but maybe we can limit the questions to two per person. That would be super, because otherwise we may not give a chance to the others in the line also to ask questions. Simon, I'll open the line now.
Thank you, Karl, for taking questions. Thank you for the presentation. I will stick to two. Starting with POLARIX. Professor Morschhäuser, you did say that the subgroup analysis was exploratory, but I'll ask anyway if there are any analysis that you can share at this stage in terms of performance by subgroup. Also one thing that I noticed was going back to the performance of R-CHOP in GOYA and comparing it with POLARIX, it's remarkably similar. And over time we often see the performance of standard of care improvement, but it stayed very, very constant. I just wonder if there any reasons for that. Obviously, it makes trial comparisons easier, but it's slightly unusual. Then moving on to Hemlibra.
Roche is probably unique in being able to give an unbiased answer on gene therapy versus existing therapies because you've got a foot in both camps. I wonder if you could give your thoughts on what gene therapy needs to demonstrate to displace or compete with existing products like Hemlibra. Also just a quick one on the dose frequency. Is there any clinical or commercial justification for pushing beyond four weekly dosing? Thanks so much.
Yeah. Maybe I can just add here because we had some questions here in the chat for you, Franck. What, how important are these data for you as a clinician? Let's say, is it practice-changing for you, the POLARIX data that was just read down here from. Maybe you can just put that into your answer for the first question.
Very clearly, we have been dying for a positive trial in the last 20 years. As I said, 13 big trials that were well-designed with new drugs, dosing intensity, whatever, all failed. For the first time, after 20 years after R-CHOP data, we have a positive trial with a significant improvements in terms of progression-free survival. To me this is extremely meaningful. That without any costs in terms of additional toxicity, similar safety. I think this is the best answer that can be said to tell you how important data are to me. Now to answer the two questions of Simon. The first one, the subgroup analysis. I really need to remind you that the study was neither designed nor powered to look for this subgroup analysis and significance at this point.
When you look at those estimates, it's really to generate some hypothesis and see what the future can tell, especially the biology subgroups, for example. No conclusions can be drawn from this data. The take home message is that the POLARIX data apply to the strict eligibility criteria IPI 2-5, and no subgroup analysis should be done to select a group of patients that should only get R-CHP POLARIX. Regarding your second question, we were surprised to see that the standard arm was doing so well. Of course, as you said, the more we go with clinical trials, the more we get the impression that the standard of care is always doing better. We have had this impression also with ABC. You may remember the ABC patient was supposed to do so poorly.
When you look in the current, in the last trial, the ABC patients treated with R-CHOP were 15% higher. In this context of such a high bar with the standard of care, it's even more impressive to see a benefit in terms of progression-free survival.
Yeah. Thank you, Franck. Maybe for the gene therapy, Charlie Fuchs, could you maybe just give it a start? Yeah. Mm-hmm.
Please. No, Simon, thank you for that question. You know, as I mentioned earlier, and Peter did, we really think Hemlibra sets a high bar in terms of transforming the therapeutic landscape. But it's, you know, we're obviously excited about the data from Spark and other gene therapies. Let me introduce John Passey, who leads our rare blood disorder franchise, just to offer some additional insights. John?
Yeah. Thank you, Charlie. I think the first thing for me to say is just to reiterate what Charlie said, that Hemlibra set an incredibly high bar in terms of how we look at hemophilia, severe hemophilia now. That needs to be set in context with the huge excitement that there is within the community about the possibility of gene therapy. I think it comes to the question that was asked about what do we need to show. In terms of what we've got, we are in a very fortunate position in which having Spark as a member of the team complementing our existing abilities to expand into gene therapy. There are still unmet needs for patients. The bar has been set very high with Hemlibra, and that is absolutely true.
Coming to your question, what do we actually need? I think if you look at anybody's presentations about gene therapy, whether it's from industry or whether it's from experts in the field, there are four words that keep coming through. Reliability, variability, durability, and safety. At the moment, we've got a lot of data from phase I studies. We need to see phase III data across the board to decide how best we can take these forward. You know, it's a really exciting time in terms of opportunities for what we have. The other question I think you mentioned was about four-weekly or greater dosing for Hemlibra. Is there a need for it?
I think patients will always look to see that hemophilia has got a treatment burden, and there is a psychological burden of always having to treat. There's always a greater need to expand and increase the interval if that is possible in any way. I think there is always a view that this is something we're gonna be looking to do. Hemophilia is very exciting at the moment. Lots of opportunities, but there are still some questions out there across the board.
Thank you very much.
Thanks a lot, Simon, for the questions. Next one would be Emmanuel Papadakis. Emmanuel, open your line from Deutsche Bank.
Thank you for taking the question. Karl Mahler, since I know this will be one of your last events, perhaps I can take the opportunity to thank you for all your collaboration and support over the years and wish you the best for the future. Perhaps I'll take a follow-up on POLARIX, please, just on the overall survival data, and then perhaps a question on the FcRH5 asset. You highlighted the correlation of PFS and OS in DLBCL in the answer to the presentation. How confident are you this PFS benefit will actually translate into an OS benefit over time? Have you got any comment on the early OS inversion we saw in those two curves? For one, for Franck Morschhauser in particular, how important do you think OS is to driving clinical utilization broadly across the globe?
I'm thinking particularly outside the U.S. here. The question on the FcRH5 would be, I mean, interesting phase I update. It seems to have moved. Mario, I remember us discussing this a year ago when we were optimistic that perhaps you could move fairly quickly into a pivotal setting, but we're still at phase I. The data relative to the GPRC5D update we've seen at this ASH again seems that's slightly inferior, and also that asset has moved somewhat faster in terms of development plan. I would love to hear your perspective on how those two targets stack up relative to each other and what exactly your plan to expand the clinical development program in 2022 will look like. Will that include a BCMA combination, for example? Thank you.
We had basically just to close the line here, a similar question from Marietta Miemietz, but just on the first one on importance of PFS, OS, separation of curves, how important it is for a physician to use those data. Will it be future standard of care? Just to close the loop here. Yeah.
Again, it was extremely important to have a positive trial with an improvement in PFS after 20 years of failure. This is the first step. Without this first step, nothing is possible. The second is that the median follow-up is still short, but regarding the possible translation of this PFS benefiting in OS, I think we should be very reasonable in terms of our expectations with OS now. This has been the dogma before ARCHER. After ARCHER, we had many trials that showed a PFS improvement without any OS benefit. Let's have reasonable expectations here. That does not mean that with a longer follow-up, we won't have something. But if we do not have something, this does not diminish at all to me the value of this data.
I just would like to point out that in this ASH meeting, we had three randomized trials in the relapsed/refractory setting for diffuse large B-cell lymphoma, CAR-T versus autologous transplantation. Two were positive, and for these two, one with a reasonable median follow-up, hazard ratio was 0.36. In these two trials with such a hazard ratio and a PFS or OS benefit, there was no significant OS benefit at this time. This shows you that things have changed. The dogma might not be as true as before, and that with the new therapy, you have to have a new thinking on this transplantation.
To me, this PFS benefit is this very strong message, and this would not be diminished by a lack of OS benefit in the future, especially looking at the incidence of subsequent treatment control arm and the lower percentage of patients getting a subsequent treatment in our R-CHP arm. This is the strongest argument to me.
Thank you, Franck. Multiple myeloma, Marion, one for you.
Yeah. Thank you for that question. First, I want to mention that for SDH5 is we have here the potential that is really like the first in class. In terms of the target, what we know so far is that we don't have any soluble forms, and we don't have any sheddings. What is important actually is what QPSC files he mentioned. We don't have any really clear on-target toxicities for SDH5. For the dose, we are currently would like to highlight that we are still in dose escalation. It is important to mention that when we further increase the dose, we do see higher responses, but we can also maintain the safety profile of the specificity CRS. The dose optimization is currently absolutely key. That's why I really cannot comment at the moment on the exact sequencing.
We are interested to go very much into earlier lines, specifically standard of care combinations. We are interested to combine it with BCMA. I also want to highlight that we really have encouraging activity in heavily pretreated patients, specifically post-BCMA, post-CAR-T, and also post-ADC. This is also potentially positioning additionally here as well. We have internally also an interesting early pipeline as well, where we're also internally combining with novel combinations.
Thank you. Thank you, Emmanuel, for the flowers, and thanks for all your continued support. That was really a privilege.
Flowers and political.
It's a privilege working with all of you, I have to say. The next one is from an anonymous attendee, but it's going to you, Ginna. It's in light of the POLARIX data. Will Roche move forward glofitamab or mosunetuzumab into first-line DLBCL as a combination? How do you see the future standard of care developing?
Yes. Thank you, Karl. I see the future standard of care developing with POLARIX and beyond POLARIX. We are exploring both glofitamab and mosunetuzumab in the first-line setting with other combinations with polatuzumab or antibody-drug conjugate, but also with standard chemotherapy.
Okay. We keep it for autumn.
Yes. Those results.
Yeah.
Those results will be presented at future meetings.
Okay, good. More to talk about in the future. Next one I take from the line here. Richard Vosser. I open your line, Richard, from JPM organ.
Thanks very much, Karl. A couple of questions, please. Just to go back, I realize you mentioned we shouldn't look at subgroup analyses, but I think the presenter at ASH was asked a question about high-risk patients, and the idea that they may do better in the POLARIX trial. I think the suggestion was that they would do better. Just could you expand on that a little bit and whether that is in the data? Then second question, on Mosun, data looks really strong in follicular lymphoma. Just thinking about the subcutaneous version seems to be going relatively slowly, prioritizing IV at the moment. You know, just thoughts on that, given the competition is coming with subcutaneous versions as well, and staying ahead here. Thanks very much.
Yeah. When we looked at the forest plot for the different estimates in the predefined subgroups, it looks like the benefit was higher for IPI 3-5 versus IPI 2. This was the sense of the answer of Hervé Tilly when he was asked the question. That does not mean to me that there is no benefit for the IPI 2 patients, since the study should be taken as a whole. Now, high-risk group might be seen in many other different ways, and this is why we are now performing other studies to look at the ctDNA levels, to look at the metabolic tumor volume. Maybe this is more meaningful to try to segregate patients that will drive the highest benefit from the POLARIX. So far, it's really investigation.
Yeah. I think we had some questions also here in the chat. If you should now focus future trials only on certain subgroups and neglect the overall picture. I guess you gave the answer now, Franck. No, we shouldn't. We should really take an exploratory analysis. An exploratory analysis in the totality of the data. A totality of the data and take it as a future standard of care. Subcut maybe one for you, Peter.
Yeah. Thanks a lot, Karl, and great question, right? I think across the board, we're seeing subcut used for bispecifics to manage CRS. We're actually really happy with the profile that mosunetuzumab is showing at the moment. We believe that hospitalization is a key factor, and we don't require mandatory hospitalization, which we believe will really enable practitioners across the board to use mosunetuzumab at launch. You know, we are looking into subcut, and that is certainly something that, you know, we're curious to see the data. We're also actually quite confident that what we have in terms of the profile is going to be very interesting and in this space where infused medicines are used, you know, very regularly.
We don't really think that subcut, yes or no, is going to be a big determinant on the success of the drug.
Maybe you can, one from the chat here is asking, can you provide more details around the ability of mosunetuzumab to be utilized in the community setting? I mean, it goes a bit along the same question. Maybe you can also address this one.
Yeah. No, thanks, Karl. I mean, look, everybody is very excited about CAR-T, right? It's amazing technology, and certainly something we're also interested in. What we're seeing, even after years now, is that it remains very limited in terms of the ability of physicians to give it to patients. There's many patients with non-Hodgkin lymphoma that don't have access, right? I think what we're very excited about in particular with mosunetuzumab is that a drug that's infused, you know, can be given in any sort of practice setting, doesn't require mandatory hospitalization, really has a profile that is going to be quite broadly applicable and hence be able to address many patients with non-Hodgkin lymphoma and certainly follicular lymphoma, which is going to be our launch indication.
Thank you. Thanks for the question, Richard. Hope you could address it. Luisa Hector will be the next one. Luisa, open your line.
Thank you, Karl. Thank you to everyone for the presentations. Still on POLARIX, I wonder when we might see overall survival data that could be more meaningful. I was intrigued by Dr. Morschhäuser's statement on a lack of OS benefit would not diminish the result. Just, that's great. I'm just wondering what the regulators might feel about that. Can we be confident that the regulators would have the same view on that OS endpoint? Maybe I can have a quick question on the bispecifics. Maybe just a reminder about how you're differentiating those, because I can see now it does look like in second line DLBCL, you've got both Mosun and glofitamab going into phase III there. How do you see those two being positioned?
I know the combinations are different, Polivy and then the GemOx, but how do you see those being used by different patient groups, perhaps? Thank you.
Maybe I can add one here, one for you, Peter. Most likely it's from Sougato Roy. He was asking about the uptake of those data, the POLARIX data in the market. Would you expect, let's say, a more faster uptake, a slow uptake based on the subgroups? How would you say that? I mean, I think the question is going to both Franck and Peter, to you.
Maybe I shall start answering Luisa's question. I think the next analysis for looking at the PFS and OS data will be in one year from now. We have discussed within the steering committee the possibility of having a much longer follow-up and to generate those data to eventually see an overall survival benefit. What the regulators are going to think of that, they'll lean on the old dogma and rules, and they probably have to get the full picture with the reports of the current physicians and their impression of the data to best integrate this PFS benefit and the lack of OS benefit so far, just the way I did it and other of my colleagues are thinking to really reconsider whether a lack of OS benefit would really affect their appreciation of this data.
I cannot answer for them.
Yeah. Thanks a lot.
Oh, please, Charlie. Sorry.
Franck, thank you. I would just add, Luisa, that, you know, as far as the Food and Drug Administration is concerned, progression-free survival is an established, approvable endpoint in the first-line therapy for large cell lymphoma. Moreover, studies of many thousands of patients in first-line large cell lymphoma show that PFS is an effective valid proxy of OS. You know, as I think Franck indicates, the field has changed over the past two decades for the better, including the availability of salvage therapies. You know, even with recurrence, the vast majority of patients fortunately are alive at two years. I think as Franck points out, probably long, you know, considerably longer follow-up is going to be needed for OS in this study, recognizing that regulators do accept PFS.
Peter, I'm sorry. I didn't mean to interrupt you.
No, no, thanks. I think great points, Charlie. Luisa, maybe building on sort of more the uptake questions, right? I mean, what we saw in POLARIX is a very meaningful improvement in progression-free survival, and that is the primary endpoint of the study. This is essentially exactly what we had planned for, right? At this point, we never expected to see overall survival, right? As Charlie pointed out, at this point, the vast majority of patients who have been part of the study are still alive, right? There are no OS events to report. It's not surprising that we're not detecting a difference regardless of whether, you know, Polivy would or would not have an impact on that.
It's been part of our launch plan from the very beginning to have this type of very meaningful PFS data. When we've explored that with physicians all across the world, to Franck's earlier point, after 20 years of not being able to move the needle, we do expect that this will be used and taken. Franckly, you know, I think patients don't wanna be part of the 40%, right? I mean, you know, if you're a frontline DLBCL patient, then you know that there's a hopeful cure, and you have a 60%-40% probability, right? You wanna do everything to push your luck.
Also avoid the psychological trauma of having to go through multiple relapses, thinking about, you know, subsequent therapies. From a healthcare system perspective, we're actually also really quite confident that preventing future therapy is going to be very meaningful in terms of the cost impact.
Yep. For the bispecific one. You're on mute.
Yes. Okay. Yes. I'll take that one. Thank you. For the bispecifics and about our plans for second-line DLBCL, we do have a phase III trial of Polivy and GemOx versus Rituxan and GemOx. We also have a phase III trial of Glofit GemOx versus Rituxan and GemOx. To start with the Glofit plus GemOx, that is a trial that's ongoing to combine obviously glofitamab with chemotherapy because early results show encouraging efficacy and safety. With Polivy and GemOx, we're also exploring that combination because we understand that across the globe access, there are access issues. Not all countries will have access to both bispecifics and/or Polivy. I should also mention that the Polivy-GemOx phase III trial is a post-marketing requirement to give full approval to Polivy plus bendamustine Rituxan in the second-line and third-line setting. One last comment, too.
We're also combining mosunetuzumab with polatuzumab as well in relapsed/refractory DLBCL setting. That trial has not started yet, however.
Thank you. Yeah, we get a lot of questions on potential combinations. I can imagine.
Yes
It's not only because of Roche but also because of competitors on how to combine maybe the PI3K inhibitors with the immuno-oncology assets and so on. Would you like to give a kind of a more general view on how you see the development? I mean, you have already answered a lot of the questions, but I guess your answer is that you really wanna keep it as broad and open as possible. But the question is: How do you wanna position this POLARIX data in the future? Will the things be now compared to POLARIX in the first-line DLBCL, or will they be used in combination? I mean, maybe this is one of the questions which we have here from the chat. How do you wanna position our POLARIX data?
Will it be standard of care and they have to combine it, or is it in combination always with POLARIX now in first-line?
Well, we hope that POLARIX will become the standard of care for the population studied. As people know, that was for the IPI 2-5 population. We also are planning to launch other trials in the first-line setting with POLARIX, with a POLARIX backbone, to perhaps add some of our bispecifics to this. Looking at specific populations, I think Franck mentioned that we plan to look at a segment, what we call ctDNA positive, the patients with high molecular loads, as possibly a prognostic tool in addition or in place of IPI. In the first-line setting, we're looking at other subsets too. We're looking at the elderly population. We currently have a study of mosunetuzumab with polatuzumab in the elderly frail population. That's the population who perhaps cannot tolerate chemotherapy.
We're looking at different populations at that large first-line DLBCL, entire population.
Yeah. Thank you. Luisa, I hope we could address your questions. I open the next one for James. I open your line, James. Okay.
Thanks, Karl. A couple of questions. One on POLARIX and then one on myeloma. I don't wanna labor the subtype or subgroup analysis point too much. But in the forest plot, another population that did very well was the ABC subtype population. With the cell of origin testing on diagnosis, is that common, or is that only in sort of specific circumstances? Just trying to get an idea of if you will know for patients if they're ABC subtypes up front or not. Then on the again on the subgroup analysis, there wasn't an OS curve for the populations that did better.
In the older population in the ABC subgroups and the IPI 3-5, if you did a OS curve, is it starting to separate already or is it very much similar to the whole population? In myeloma for cevostamab, is the potential combination with BCMA a key consideration there, cytokine release syndrome, as we've seen with both bispecifics. Another quick one on myeloma. Venetoclax in the t(11;14) population, is that something you're going to pursue, given the data we've seen so far, just because I think Peter mentioned that cevostamab would be the first move into multiple myeloma. Thank you.
POLARIX, one for you again, Franck.
Yes. As you may know, there has been a lot of debate on Cell of Origin. Again, after probably 10-15 years trying to use that to classify and to design trials, this has been now slowly abandoned. Still, everybody or all the physicians or still the clinical scientists always look at the subgroup analysis, still incorporating Cell of Origin just because it's easy to compare with other trials. Polatuzumab is COO agnostic, molecularly agnostic. It should not be impacted by Cell of Origin. Still we get the impression that in this subgroup there is a clear benefit. We have not looked at OS according to that.
Another point I would like to underline is that you probably heard it at this conference. There was a kind of stumbling on the molecular classification in diseases like B-cell lymphoma. Everybody realized that it's still a very long way to go to get a valid subclassification that could lead to stratification in the first-line setting at the time of randomization. Again, so far it's just an element of different comparison, and it cannot be an argument to make a choice to drive the choice.
Thank you. Multiple myeloma. Marion, maybe we are going to you.
Yeah. A short answer to the BCMA combination. This is something we're really very interested in, and we are here close to, let's say, with collaborations with external partners to start this combination soon. For the venetoclax t(11;14) population, thank you for the question. This is where we really have exciting data for venetoclax, and this is also absolutely what we want to combine this. We're preclinical data looking really very promising, and we will also planning to do so.
Okay. Yeah. Thanks a lot. Did you address all your questions, James? The next one would be Peter Welford from Jefferies. Open your line, Peter.
Hi. Thanks for taking my questions. Few last. Just on POLARIX, sorry this is going back to the subgroups again. But this is slightly different, I guess. I'm curious, if you look at the over sixties and also you look at those without bulky disease, which I guess are two fairly sort of unequivocal classifications, if you like, for people, it does look as though those two groups basically drove all the benefits. But I guess rather than ask, you know, rather than restricting the drug, I guess I'm more curious, is there some medical explanation do you think as to why those with no bulky disease or equally those who are over sixty could drive most benefits with Polivy? I guess I'm thinking in particular the toxicity of the various different profiles.
You know, have you looked at, for example, did you get more withdrawals or something due to the side effects, and maybe the role of vincristine or something? Or is there something maybe that can explain that? Or is it just, do you think? 'Cause they're quite big groups, this is just something you think is just a sort of honesty in the data. The next one is just on the bispecific CD20. Firstly, just on polatuzumab, I think there was a comment made, it should be routinely administered as outpatient treatment. Curiously, just explain, will the first dose and the dose of escalation always be given as an in-hospital administration, do you think?
Is this really after the first doses that we should then think about this as outpatient treatment? Or can this be used outpatient from the very first dose of therapy? Is what I'm asking. And if you could just then explain as well, you made the comment about subcut versus IV. I guess part of the argument you raised in terms of the profile's interesting obviously from a financial benefit. But also I guess from a time perspective, can you just talk a little bit about a lot was made about this at ASCO and EHA, the length of time that it takes to infuse subcut versus IV, to give us some sort of idea of, you know, the potential duration and time we're talking in a chair with these respective therapies. Thank you.
POLARIX. Again, Franck Morschhauser.
Regarding the subgroups, one point that is important is that the percentage of patients with ABC increases with age. There is a mix in terms, I'm not surprised to see that there is a benefit over 60 and also a benefit over ABC. This we need to dig a little bit more. As I said, ABC by itself is not enough. We have to do more molecular classification and use, for example, the new classification that have been published by Chapuy, and to test that, and even that result, it needs to be further refined to try to find a scientific explanation for this possible benefit in those subgroups. Whether there was a difference in terms of toxicity, with increasing in elderly patients, then it comes subgroup of subgroups of patients.
It might be interesting to have a look at that, and we have not done that so far. I have no data to provide on that side, but this is certainly something we should look at.
You know, Peter, to your question about Mosun. The bottom line is that all doses of Mosun are administered as an outpatient. There is no hospitalization required, nor was there any hospitalization required in our study. It's 100% outpatient. With regard to the sub Q, before I turn to Peter, I'll just tell you know, from an oncologist standpoint, no question, if you can reduce chair time, that's something that cancer centers and patients and nurses welcome. You know, there is that advantage. Peter, did you wanna add?
Yeah, no, Charlie, I completely agree, right? Peter, as you nicely point out, you know, we have a long legacy of exploring subcut formulations, and we're certainly doing that for the bispecifics. I guess what I tried to say earlier is because, you know, the question was asked obviously in a competitive context. From a time perspective, right, I'd much rather get an IV and don't have to be hospitalized than getting subcut and still having to have a mandatory hospitalization, which takes much more time and much more resources. You know, I think that's a little bit the comparison we're looking at at the moment, and that's why we're quite confident that we have a good profile here with mosunetuzumab, despite the fact that we won't have subcut in the very beginning.
On the long run, right, we may even be able to build on top of that if the data for subcut pans out nicely.
There was, I think, one question also on the regulatory status, filing question. As always, we will keep you updated as soon as we have heard back from an official, let's say, letter from the health authorities. We are in active, good, positive discussions with all of them. I just can really say that. Usually we do updates then at the full year, so you should be in a position of update. We are in a position to have a bit more confirmed, let's say, letters from the health authorities at that point in time. This is all progressing well. Keyur, you have the privilege to have the last question here on the line. I open your line, Keyur, from Goldman Sachs.
Thanks, Karl. I will not bore anybody with further subgroup questions on POLARIX. Let me take kind of two separate ones. The first one for you, Dr. Passey. Good to see you on the corporate side after so many years in academia. You've very eloquently in the past spoken about the need for therapy beyond kind of Hemlibra. As you think about the Roche portfolio beyond Hemlibra, can you kind of give us a sense for what is exciting you? As you think about kind of what that hemophilia treatment landscape looks like over the next three to five years, kind of how you see that developing and what role the early-stage Roche compounds might play on that. Then secondly, on crovalimab. Maybe I'm misunderstanding the slides on slide number 18.
Can you just help us understand kind of what the primary endpoint on the phase III is? Kind of given if it is indeed kind of non-inferiority to Soliris, kind of given how established Soliris is, given kind of Ultomiris, is this a good enough clinical outcome at this point of time, or do you actually need to show superiority for commercial success? Thank you.
Okay. Thank you. Thank you very much. Yeah, beyond Hemlibra. Well, clearly, we're looking at all sorts of things because there is still significant unmet need in the hemophilia world. Hemlibra has changed the game absolutely dramatically. As you point out, that doesn't stop us wanting to look forward to see what else we can do. There is a lot of fundamental thinking going on, researching into molecular mechanisms to see if there are other modalities that may be applicable in the future. Obviously, we talked about gene therapy already, and this is something that we're very keen to explore with our partners in Spark. I think it. We've talked about how Hemlibra has changed things, and undoubtedly it has.
It has also changed patients' expectations to a large degree because they really just strive for more because they've seen such a huge improvement in what they can have. It is sort of beholden to all of us to continue to look, to continue to see what more we can do, because we have taken a big step. We've taken a huge step with Hemlibra, but that doesn't necessarily mean that's the last step that we need to look for. We're looking at different things at a preclinical level, research, understanding, all those sorts of components to drive things forward to improve medicines for patients as they come through. In terms of crovalimab, yes, we are looking at non-inferiority at the moment.
What we can also say, though, is that for patients who are able to receive crovalimab, they will get a big reduction in treatment burden because this is gonna be a subcutaneous therapy. I think you've got to also weigh that into the bargain as well.
Very good. I would say that was it, huh? Thanks again to the speakers. I think we have addressed also all the questions here in the chat. Thank you, Franck, Peter, Charles, Ginna, Marion, John. Thanks for all the help over the past years. Wish you all the best, and stay safe and healthy. Wish you all the best and good luck. Bye-bye.
Thank you. Bye-bye.
Good Christmas festival for you, Charles.
Karl, thank you.
Bye-bye. All the best to you.
Thank you, really, for your leadership, Karl.
Sure. Pleasure.
Thank you.
Bye-bye.
Bye-bye.
Bye-bye. All the best. Bye-bye. Bye-bye.