Good morning, good afternoon, ladies and gentlemen. Thank you for standing by. Welcome, and thank you for joining the ASH 2023 Investor Event with MorphoSys management and medical experts. Throughout today's recorded presentation, all participants will be in a listen-only mode. The presentation will be followed by a question and answer session. If you would like to ask a question, you may do so by pressing star and one. Press the star key followed by a zero for operator assistance. It's been my pleasure to turn the conference over to Julia Neugebauer. Please go ahead, ma'am. Thank you. Yeah, welcome, everybody, welcome to those who are in the room, and also welcome to those who are on the webcast. Quick reminder, we will be making forward-looking statements, so we ask you to please have a look at slide two of our presentation. Also, all comments we make today speak as of today. And with that, we can get started, and I hand it over to Jean-Paul. Thanks, Julia. Good morning, everyone. Big ASH for us at MorphoSys. I hope you could attend the session yesterday, which was actually very well attended. We had a full room of probably 400 or 500 people attending the oral presentation that Dr. Rampal gave on our phase III trial. Basically, we're extremely pleased with the data, and I'm glad that we could—we can speak now that the full data set is out there, and it was a bit tricky to interact over the last two or three weeks since we released the data. So basically, in a nutshell, we have the opportunity here to establish a new paradigm of the treatment of myelofibrosis first line. We have the most impressive data set in terms of myelofibrosis here and the opportunity really to establish a new standard of care. We'll talk more about that. We address the four hallmarks of the disease: the spleen size, the symptoms, the anemia, the bone marrow fibrosis, and all that with very pleasant safety despite the combination or the add on. So very, very pleased, and the feedback we get from the doctors on the KOLs is extremely positive. I'd like also to point on the fact that I don't know if you remember that the study was supposed to read later, and we have accelerated the study execution by more than six months since we acquired Constellation. That's a tribute to the work of our teams in terms of excellent operational execution and also from the investigators who worked very hard for enrolling the largest myelofibrosis study with 431 patients. I think I learned yesterday that we were short by one patient of being the largest. So we are almost the largest study ever in myelofibrosis and in a very quick fashion, which is also a very good proxy of the next steps that we continue to entertain with the work here, and obviously file for approval based on this strong data set, that data package in the U.S. and ex-U.S. And we believe based on all that and unmet medical need, that we have a multi-billion dollar market opportunity here. Last but not least, we're well-financed to prepare for the next steps, which is very important with cash available into 2025. So our vision is simple. I mean, pelabresib will become the new standard of care in myelofibrosis, and it's the best asset out there. And today we're going to dive into data, give you the opportunity to ask any question you'd have on the, on the rich set of data that we presented yesterday. And for that, we have with us two top medical experts in the field of myelofibrosis. Professor Claire Harrison of Guy's and St Thomas' NHS Foundation Trust in London, and Dr. Ruben Mesa, President and Executive Director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center. So Claire and Ruben, thank you very much for being with us. They will answer the questions that you have, and without any further ado, I'll pass on to Professor Harrison. Well, good morning, everyone. Thanks very much for the opportunity to talk about this data. I'm just minded that it's, what, 12 years since we were at ASH, presenting the data from the COMFORT-I and COMFORT-II studies. So a decade on, this is a really exciting time for us in the field. This is just a summary slide about this condition and just really a reminder. Myelofibrosis is a severe blood cancer and remains so even after the approval of ruxolitinib and the other JAK inhibitors that have followed in its wake. And unfortunately, none of the current treatments we have do target those four key features of the disease that are summarized on this slide: splenomegaly, anemia, bone marrow fibrosis, and disease-related symptoms. There's a snapshot on the right-hand side of the slide, just relating to something called DIPSS, which is a prognostic, one of several prognostic scoring systems that we use, for this condition. There are four different groups within the DIPSS score, and this is the score that we used for, to make patients eligible for, the MANIFEST-2 study. Across the DIPSS scores, of the four scores, the intermediate risk categories, intermediate one and intermediate two, are by far the most prevalent of the disease categories, and around 9%-11% of patients, as shown on this slide, have high-risk disease. When you use these prognostic scoring systems, we use them to guide prognosis as well as obviously for trial eligibility. But you can see that the overall survival for patients using when these scores were derived was between four and 14 years for intermediate-risk patients, longer obviously for patients in the lower category, and about 1.5 years for high-risk patients. As we have understood over the last 15 years or so, the JAK-STAT pathway is critical to the pathogenesis of myelofibrosis, and targeting it with JAK inhibitors has been an important modality for us. But the BET proteins and their effects, downstream effects, are also important to the pathogenesis of this disease. So the BET family proteins influence the expression of cytokines such as transforming growth factor-beta, NF-κB. They affect the Bcl-2 family and c-Myc, among others. And the downstream effects of those cytokines leads to the key features of disease, as you can see summarized on this slide. So the abnormal features that we see, which are characteristic and diagnostic in the marrow, so abnormal megakaryocytes, inflammation, which leads to poor performance status for our patients, fibrosis, and also then anemia. As we've discovered in the past few years, the combination of BET inhibition and JAK inhibition, in vitro and in vivo, broadly suppresses these pro-inflammatory molecules. And we've shown before in patients, in our earlier studies, that this also has an effect on the bone marrow, features as well as clinical benefits. So, in the past, we, Ruben, myself, and others, have collaborated in investigating, the BET inhibitor pelabresib alone and in combination with ruxolitinib in a number of different categories of patients. And we started with monotherapy, and then we added pelabresib to patients with... on ruxolitinib who were failing disease, treatment, which inevitably all patients ultimately do. And, during the study, we were working with Constellation at that time, and we pressed them, "Please, could we open a population of patients who were JAK inhibitor-naive?" And so we were able to do that, and you can see that this is a non-randomized study. You'll be familiar with this data, but this shows you the spleen and symptom responses across a spectrum of patients in this JAK inhibitor-naive cohort of patients. So you know, for us, this was important and impressive because we know that JAK inhibitors don't hit the button for all of the issues for our patients. And, so now we're going to share with you the next step that we've taken on the journey, which is working with Constellation and MorphoSys in delivering this randomized study. So this is then the study schema for MANIFEST-2, as was presented yesterday. As you've already heard, it's a very large study and 430 patients, and the eligibility criteria for the study really matched those for the monotherapy arm of the MANIFEST-1 trial. So DIPSS intermediate-1 or higher, significant splenomegaly, and patients had to have a symptom score of 10 or at least two, three or more for two symptoms. There were three randomization stratification factors, which are shown on the slide. So DIPSS risk, platelet count, because that influences our ability to dose with JAK inhibitor and spleen volume. And then, the study was randomized. The patients were randomized one to one, and this was double-blind. And you can see the endpoints on the right-hand side of the slide. The endpoint we're used to, which is SVR35, which is the only endpoint which links to survival benefit for our patients. A couple of symptom-related endpoints, and we have the symptom guru in MPN sitting to my right. And of course, safety is really important. And this is the patient disposition. You can nicely see that, here are the 430 patients. Most of these patients received treatment, over 99% of them, and discontinuation rates are relatively low, and you can see the reasons for discontinuation nicely and openly laid out for you here. So around three-quarters or so of the patients are ongoing in treatment. Now, when we worked with Constellation in the design of this study, and this was really, truly a collaborative process between key opinion leaders and the company, we were really pressing them to say, "It's really important that we maintain a good dose of ruxolitinib for these patients." And so in the study schema, patients started on one dose below the normal dosing of ruxolitinib, so we called it R minus one, as far as I remember. And then, after the first cycle of treatment, all patients went up to the standard dosing of ruxolitinib, which we believe is really important. Another important fact you can see on this slide, probably more important actually, is the mean daily dose for ruxolitinib in this trial was equivalent between the two arms and is actually the mean dose that was achieved in the COMFORT-I and COMFORT-II trials. So that's approximately a total dose of 15 mg twice daily. You can also see the mean daily dose of pelabresib and median follow-up on study of 45.4 weeks. I think this is my last slide, but these are the baseline characteristics. Good luck to you for reading this in detail, but they are nicely balanced and really what we would expect to see in this disease. So the age range of patients is wide. The youngest patient in study was 19, but the... We're not afraid of using this combination for our patients. So you can see the oldest patient entered in study was 88. Age distributions and disease distributions are as we would expect. You will note that the vast majority of patients who went on this trial were intermediate-risk patients, but again, this is roughly what we would expect with the distribution of DIPSS patients in the disease area. Many patients were anemic, and you can see that around a third of patients on both arms had a hemoglobin of less than 10 as a key hallmark of disease. Furthermore, slightly more patients, interestingly, at baseline, were requiring red blood cell transfusion on the pelabresib arm of the study compared to the ruxolitinib-only arm. And then you can see details here about spleen volume and symptom scores, et cetera. There you go. You get the best slide. Wonderful. So, these data were presented yesterday, and let me first frame this, this key slide as it relates to the primary endpoint, showing the clear superiority of the combination of pelabresib and ruxolitinib versus ruxolitinib plus placebo, as you see there, with a significant difference of 65.9% versus 35.2%. But to frame this, you know, as Dr. Harrison was alluding to, you know, it was roughly 12 years ago that ruxolitinib was both launched. And I still remember us enduring many of the painful teething here, in San Diego as we were having many aspects with the launch of that first approved therapy, in myelofibrosis. But what's happened over the last 12 years is that there have been dozens of combination studies that have occurred in the phase II setting. Dozens. I would estimate probably over 40, you know, if I was to try to put pen to paper. And why none of those came to phase III studies is that almost without exclusion, they never really exceeded a 35% reduction in spleen volume that really suggested a clear increment over single-agent ruxolitinib. You know, these data, which were presented yesterday, really, you know, were very exciting and I think very well received by our field as being a clear difference over this past 12-year period of really showing what sort of difference one can experience with this, with this combination. Important for a range of reasons, as we've realized that, you know, improvement in splenomegaly can be an important surrogate of long-term benefit for the patients in a range of ways, and analysis in the COMFORT studies suggested even then, greater than 10% reduction in splenomegaly being associated potentially with survival advantages. So very, very significant difference. Now, the second is looking at the issue of symptoms, and again, as someone who spent, you know, many years looking at this in parallel, wanted to frame how we look at symptom responses. So first, our tools for investigating symptoms now have been highly, highly validated, so they can clearly measure a difference for a patient experiencing a difference in symptoms. What really has not been validated is what is the best way to look at them in terms of response for comparison. In part, that may be because, again, we've not had additional new phase III studies with comparison of very active arms. Historically, we had really had the JAK inhibitor approval pathways, which usually had comparisons with placebo or things of that nature. As we look at it, a total symptom score, that, again, these instruments are, you know, zero to 10. You have a cumulative score that the patient can experience. The TSS 50 or a 50% reduction is just one arbitrary way of looking for a difference. Now, one of the limiters for that is, as you can see here by these kind of three different situations, that if you have a delta or absolute change in total symptom between two arms, a treatment arm and a control arm, you know, if both of them are under 50%, you really do not see that benefit. Or if they're both over 50%, again, you may not see that delta. So it's really best for that situation two, scenario. So there are limitations to that way of looking at the data. So in this study, it was really looked at in two, distinct ways. The first was just the absolute total symptom score difference between the two arms. And here you see it, it nearly reached statistical significance, and you see that difference between the, the two arms, as it relates to the, total symptom score. If you look at TSS 50, that was not statistically significant, but again, there could be confounders, as I showed by those situations, that really, again, kind of, do not really call out the, the delta sufficiently. If we look at the individual symptoms, and again, this is an aggregate of these individual symptoms, you see that there is numerical, greater response by each individual symptom for patients with pelabresib plus rux versus, placebo plus rux, across, each of them. Now, patients obviously are not individual endpoints. They are individuals in which all of these things are aggregated together. Indeed, you know, clinical benefit for patients is, again, in both the treating physician's eyes as well as the patient. What is the cumulative benefit, of what I experience, and what is the downside in terms of any toxicity or other pieces? That's how we, that's how we practice medicine. You know, here you see that the... We look at both of those endpoints, both in terms of symptom response, even by TSS 50, as well as spleen volume response. You see that over 40% of patients experienced both of those responses, versus 18.5% in the placebo plus ruxolitinib arm. So again, you know, over a doubling of patients really feeling that they'd had a significant response to the combination from both of these different parameters versus with ruxolitinib alone. As we look at subgroup analysis, on the left, you'll see as it relates to spleen volume response, you know, very significant differences almost across the board, regardless of subset that one looks at for these individual patients. Now, with the TSS data being more closely linked, you'll see that these overlap. You know, I'll highlight the DIPSS high risk as it relates to symptoms. The numbers there were really very, very small. So you see confidence intervals that pretty much extend kind of across the board. So I know that there has been, you know, much discussion of why the high-risk patients seem to have had less of a symptom response. I think that's really just an outlier in terms of the number of patients treated as so modest that any number of things could have really confounded that difference. As you look at prespecified hematologic subgroup analysis based on hemoglobin or platelet count, again, you see, as it relates to spleen volume reduction, strongly favoring the combination approaches. And again, with TSS, there is clearly, you know, a closer delta between these. So again, no clear distinction between them, at least by these subset analysis. Now, as we look at these high-level pieces, as the high risk, both the SVR and the TSS 50 response, you have here as it relates to a SVR, both in MANIFEST-2 as well as the arm three of the MANIFEST study. You see those response rates of, you know, 66% and 64% for all patients versus high risk, respectively, for MANIFEST-2. The MANIFEST arm three, this was again, the treatment-naïve, so this was the phase II arm that that was the basis for the phase III study. And again, you see 68% across all comers and 54% for high risk. As it relates to TSS, again, that high-risk group did perform worse in this subset, but the numbers are really so small, it is very difficult to make any sort of conclusions regarding that. And it's distinct from, again, a small group, but the high risk, there were high-risk patients on the arm three of MANIFEST than on MANIFEST-2, where again, that number was higher. So I think a bit of an outlier as it relates to just the number of patients. Now, clearly beyond spleen and symptoms, we're, there's great interest in the broader benefits that can be experienced, you know, and here we see the difference as it relates to the hemoglobin response. You see here the difference between pelabresib and rux versus, placebo plus, ruxolitinib, clearly, with a very nice difference that we're seeing as it relates to anemia. And again, when we look at benefits, both in terms of spleen and anemia, recognizing we're really trying to capture two different sets of things. So first, less drug-induced anemia that may occur with ruxolitinib alone or benefit from baseline. And likewise, with symptoms, part of the purpose that we track symptoms are both to see a benefit from baseline, but also to document that a combination approach does not really cause a decrease in symptom response. So each of these, both of these are relevant, in that we're, again, always trying to have the cumulative benefit for the patient. What is that efficacy benefit, and is there any detraction as it relates to response? Now, clearly, additional formative studies were of interest. Let me hand it back to Professor Harrison to walk us through these. Please. I just wanted to also point out just one thing, here, and this is something that I observed in my patients who were on the JAK inhibitor-naïve arm of MANIFEST-1. I should say that actually we recruited a substantial number of those patients before the pandemic, and of those patients, and they're all still on that combination, or they've moved successfully to transplant. One of the key benefits that they saw, as well as the spleen and symptoms, was this one. It was improvement in anemia. So, you can see that here numerically represented in terms of the hemoglobin, but you can also see, if you look at the table, the data with regard to requiring transfusion. Now, we've been looking at that in some detail in the field recently. You'll remember that Ruben and I have both been discussing the benefits of momelotinib in terms of transfusion independence, et cetera. And here is the interesting data with regard to the Pela combination in that context. So you can see that more patients were requiring transfusion at screening in the Pela arm, but when you move forward in the study, that actually flips the other way, and you have more patients requiring transfusion in the ruxolitinib alone arm. So we add another drug, and we see less requirement for transfusion. So I just wanted to emphasize that point. And then, the other interesting factors here, which, we're super excited to see, are not only spleen symptoms and anemia, are these other effects on the hallmarks of the disease, and digging deeper into these at a biological level. We've been focusing on that a lot in the field recently. So if you just focus on the left-hand side of the chart, you can see two pie charts, showing you what happened to the bone marrow fibrosis grade at central review at week 24. And you can see that 38.5% of the combination patients had improvement versus only 24.2% of the single agent, ruxolitinib. Unchanged was similar between the two arms, and it's quite early to see a change, so I'd expect these responses to deepen over time. But worsening of fibrosis grade, and fibrosis grade is incorporated in one of our prognostic scores, in the MIPSS score. You can see that's more prevalent, almost double, actually, in the ruxolitinib-only arm. And then on the right-hand side, I'm just gonna bring you back to the basic biology that we spoke about earlier on. So, these are some of the key cytokines that are hit, that are characteristically elevated for patients treated, or not, with JAK inhibitors and with myelofibrosis. And you can see that, there's a reduction of all of them in the combination, and for the vast majority of them, that is more significantly so with the pelabresib therapy. I just want to draw your attention to the outlier here, which is IL-8. IL-8 is strongly correlated with survival in this disease. Now, we've seen benefits, but what about safety? So here's a very nice butterfly plot laying out for you safety features, as seen in the study. You can see, interestingly, that grade three or above treatment-emergent adverse events were actually more common for the ruxolitinib monotherapy arm. You can also see figures with regard to dose reduction, et cetera, on this slide. I just want to move to a more detailed slide, which talks to, you know, the adverse effect profile that we would expect to see with JAK inhibitors, and we've got used to some extent with pelabresib. So again, just to orientate you, the darker proportion of these bars are actually those events that were at grade three or above. Here, you nicely see the story with anemia playing out again, that there was more anemia with the ruxolitinib monotherapy. Thrombocytopenia, on the other hand, slightly more with pelabresib, and just drawing your attention to the fact that it's reported in two different ways in this slide, thrombocytopenia and platelet count decreased. Then you can see that most of the other adverse events were actually pretty much balanced. But I would want to draw your attention to the fact that fatigue was actually less with the Pela combination, which is probably in keeping with the anemia benefits, possibly. I'll remind folks that when we compared the fatigue between the two, that clearly seemed to favor the combination arm as well. And fatigue is one of our biggest issues in the disease. It's the commonest symptom, and it's one that we, as we have over the last decade, surveyed patients, this is what they want to see improved. So this is the conclusion slide. I won't read through it. I'll just leave you to take a look at it. But in essence, I think this data is very strong. It shows that pelabresib is addressing the four key hallmarks of the disease. It's totally in keeping with what we saw in the JAK inhibitor non-randomized arm of the MANIFEST study, which is much more mature, and as I told you, my personal experience is excellent. And in my opinion, this is really a paradigm shift, potentially, for how we treat patients with myelofibrosis. And am I handing to you or Tim? There you go. Thank you. Thank you, Professor Harrison. Thank you, Professor Mesa, for reviewing the MANIFEST-2 study results and sharing your insights. Your dedication to the myelofibrosis community is truly inspiring, and it's such an honor to be on stage with the two gurus in myelofibrosis this morning. I also want to acknowledge Dr. Rampal, who presented the results last night. Beautiful presentation, very full room, a competing session. But yeah, I hear there's a vote ongoing between the two. After the oral presentation, we also met with some of the principal investigators of the MANIFEST-2 study to review and discuss the results, and it was truly gratifying to hear level of excitement in the physician community and that potential for a paradigm shift in myelofibrosis. By the way, that punchline you saw on the last slide was something the investigators actually convinced us to put on the slides. They really felt that we ought to be more bullish on that one. So, thank you for that feedback, as always. That sentiment has been echoed as well by members of the patient advocacy community, who we had a chance to meet with over the last few days here at ASH. So this is a truly exciting time for the myelofibrosis community. Ahead of the readout of the phase II of the phase II study, we conducted research with physicians. The target audience for this research was the U.S.-based physician community in the community setting, as well as in the academic setting. What came out very clearly was that they are ready for combination therapy in myelofibrosis, and they very uniformly said that combination therapy is the way of the future in this disease. When we asked them to rank the top attributes driving treatment decisions for the Pela/Rux combination versus other treatment paradigms in myelofibrosis, Pela/Rux consistently came out on top. What these physicians were most excited about was the impressive efficacy profile that we put in front of them together with the great tolerability profile. What they were particularly intrigued by, and Professor Harrison mentioned this, was the potential for anemia benefit that is so super important in this patient population. With the MANIFEST-2 data now in hand and showing that this combination truly seems to impact the four hallmarks of myelofibrosis, we're now at a point where this hypothesis that went into the physician research is turning into reality for patients with myelofibrosis. So very exciting days. What's ahead of us is, clearly to bring pelabresib to the patients, who are in dire need of new therapies as quickly as possible. So we are laser-focused on two key objectives. That's number one, and shown on the left-hand side of the slide here, the preparation of the regulatory submission. We intend to submit to U.S. FDA as well as EMA in the middle of 2024, next year, and we are very, very confident that the data package we have in hand provides a strong basis for understanding the complete benefit-risk profile of this first-line population for this first-line combination therapy in patients with myelofibrosis. We will follow very standard regulatory procedures, and we're working diligently and efficiently on this submission, always mindful on how we can expedite and accelerate the process. Number two, and shown on the right-hand side of the slides, is a very heavy focus on scientific publication as well as medical education. As you know, the phase II MANIFEST study and Claire mentioned some patients are first or all patients still receiving benefits, which is very, very impressive and still staying on therapy or having moved on to transplants. That study continues to provide us with key insights into the potential long-term benefits of the Pela/Rux combination in the first-line setting. What we've seen so far in the study that has been published are deep and durable responses so far up to 60 weeks. And of course, we hear that the study is continuing, and it's great to see that patients continue to benefit from this treatment. Now that we have the initial phase III MANIFEST-2 results in hands, we will of course continue to collect safety and efficacy data, as well as duration of treatments data, which is very important, together with quality of life and survival data from this study. Of course, we will be sharing this data at upcoming scientific conferences, and I hope in 12 years at ASH, we will be reminiscent about that first big splash on pelabresib. We have a strong U.S. medical affairs infrastructure in place with our tafasitamab that is commercialized in the U.S., of course, and we're therefore well prepared to support the medical education work for pelabresib that is so important to inform the scientific community. The greatly experienced MSLs we have in place in the U.S. are well established in the field. They know the key opinion leaders in academia as well as in the community setting, and they are already having these very important conversations at ASH over the weekend, and of course, they will expand and continue to do so. I myself joined MorphoSys just about a year ago. At that time, this MANIFEST-2 readout seemed super far away.... We've since accelerated the data, to Jean-Paul's points, by at least six months. Here we are today with top-line results in hand, exciting results in hand, and we're talking about a paradigm shift in the treatment of patients with myelofibrosis. I couldn't be more excited for what's to come, and with that, I'll hand it over to Jean-Paul. Thank you. Thank you, Claire, Ruben, and team for this comprehensive overview of the data. We gave you the full package here. I think, it's a lot of information, very good information. I'm not going to repeat, all the, key points here, except that we really believe that we have the most impressive data set here in myelofibrosis. The four hallmarks are being addressed, and that, we intend to submit based on this wealth of data and hopefully bring this product to patients here as soon as possible. These are a couple of quotes, here, from other, key actors and experts in the field. We're very honored to have the, the backing of, of the field. So this excitement is shared, and, on that, I'd like to open up for questions- Yeah. from the audience here and from the webcast. Correct. Thank you. Yeah, we start with questions. We start here in the room. We like to ask you that you please identify yourself with your name and affiliation, and we also would want to give the people on the line the opportunity to ask questions. Hi, good morning, and congrats on the data and great presentation. Thanks. Derek from Wells Fargo. Just two questions, mainly for the docs on the, on the panel here. So I guess first, can you put in the context that 2-point reduction or so on the mean TSS and how that, you know, relative to, I guess, the MCID, and also in the real world, what does that really mean for patients? And then the second question is really around, you know, the, the deeper response that we're seeing on SVR, in terms of, you know, pelabresib combo versus rux alone. Again, how do you think that impacts the overall outcomes when we get to overall survival? Thanks. Ruben? So without question, the delta as it relates to spleen volume reduction is dramatic. You know, this was not, you know, a slight superiority. This was nearly a doubling, you know, and I think that is gonna be, you know, the main driver, the main case of why the two drugs. I think it's gonna lead to longer-term disease control, you know, as well as other aspects that are difficult to measure in the context of the phase III, but longer term in terms of survival compared to real-world evidence and other pieces that really will be very compelling. I mean, the difference in the symptoms, I think was very, very relevant. You know, we presented at yesterday's in a poster, looking at kind of minimally clinically differences as it relates to TSS differences compared to the patient's global impression of change, you know. And again, continuing to demonstrate in a range of ways that there's very meaningful benefit that can be, you know, even in individuals that have less than kind of a TSS 50. You know, if you have 48% reduction in your symptoms, that really matters, you know, quite, quite a bit. So I think there's data that is clearly superiority of the combination compared to single agent, but the reduction in splenomegaly, I think, is gonna be the biggest driver. And why not a further benefit in symptoms? People ask this question. I do think as one looks at the dynamics of the symptom improvement, there is also a bit of a ceiling effect. You know, this is really, again, one of the first two phase III studies in a combination in the front line in this sort of setting, compared to really our historical, where had really been JAK inhibitors versus placebo or other control arms like danazol, where, again, you have a very active delta. There's a ceiling effect, you know, and again, when we look at those that don't achieve that, there's not really that much delta left in terms of symptom response to be able to really achieve kind of that delta. So, like anything, we learn more about symptom response, and now in combination, as it's a little bit different paradigm to be looking at these groups of patients, and we'll learn more as we, you know, just as we had learned a lot when we looked at symptoms for the first place with single-agent JAK inhibition. Thanks. Andy Berens, Leerink Partners. My question is also for the doctors on the panel. In terms of your practice now for the intermediate risk ones, what percentage of those patients are you treating with Jakafi monotherapy? And then, when you think about adding a drug on top of Jakafi in your practice, what patients would you do that for? Would that be the ones that are more advanced, less advanced, or everyone across the board? Okay, Libby. Sure. So I think I'll probably start with answering the last of your questions. Now, what I was always taught as a hemato-oncologist was give your best treatment first to the patient. You do your best shot at the beginning, and you do something that is going to modify disease. Because if you wait until the disease has progressed, is more complex at a molecular level, which we know happens with time, certainly historically for these patients, then we don't know the data for pelabresib, but we know certainly for ruxolitinib, it doesn't work as well. As I look forward and hope to have this agent in London, I see you're going first in the U.S., which I understand, but I have a slight gripe about that. I would be wanting to give this to my patients who I would think need treatment. I mean, some patients would only be intermediate-1 risk by virtue of age, right? So if they don't have a big burden of disease, they don't have splenomegaly, they don't really have symptoms, but they happen to be 66 and have very early disease. Clearly, we're not going to be thinking about giving this treatment. But the vast majority of patients progress over the course of a year or so. So I would say for the majority of my patients with intermediate-1 risk disease, where they're just not intermediate-1 risk by virtue of age, I would be wanting to give this because I want to give my best shot first. There are some patients who perhaps we have less experience of giving it, for example, those with marked thrombocytopenia, but that's not a feature generally of intermediate-1 risk. I don't know if you want- Yeah, maybe Ruben as well. Sure. Yeah, I would echo that strongly. One, you know, intermediate one, you know, the majority of patients need treatment. You know, I think, although the term makes it sound like it's an indolent disease, it really is not. You know, there are many different prognostic scores, and we clearly have recognized there are many patients with intermediate one, based on their splenomegaly symptoms and their disease burden, clearly require therapy, you know. And strongly agree, I think everything we've learned over time is that using effective therapy, you know, as early as we can in the arc of disease, is probably the most effective for long-term disease control, as well as for hopefully kind of avoiding progression, you know. So I would think it would, again, become the new standard in, you know, in, patients who were newly diagnosed. I mean, if I was diagnosed with myelofibrosis, would I want to receive the best treatment, or would I want to wait to, until my disease progressed and had a less likelihood of potentially responding or, or worse outcome? So I think, I think there'd be a strong interest. I think that's one of the reasons we saw that there was such great interest and great accrual. I mean, accrual, again, with multiple competing studies in myelofibrosis, accrual in one of the largest studies in myelofibrosis, you know, is, is testament to the enthusiasm people felt toward, combination therapy. During COVID. During COVID. Yeah. Yeah. I mean, you know, it clearly real headwinds- Yep. You know, yet there was, you know, great enthusiasm. Yep. Perfect. Further questions in the room? Greg. Thanks, Graig Suvannavejh at Miz uho Securities. So I've got, maybe three questions for the company and one for the KOL. So, in terms of the absolute improvement on hemoglobin, could you remind me if you've quantified what that improvement is on a, I think a gram level, or milligram level? I don't remember the, the scale. Secondly, could you provide a, a view of what you think the longer-term effect of this drug would be? And then just thirdly, if you could just go back, with regards to expectations around approval, right? There was always a view that you needed to hit on a secondary and don't have a positive, statistically significant, impact. So the fact that you brought up TSS, I just want to go back to, like, how that conversation came about, and was that perhaps in response to like, maybe what you had heard that AbbVie had done and wanted to go to the FDA to see what their thoughts were there. So just want to kind of clear that up. And then a question for the KOLs is, you know, given the recent approval of momelotinib, how do you think that product, in terms of its profile, where would that fit versus where you see pelabresib fitting? Thanks. Thanks, Greg. So let's try to organize your five questions. Maybe the KOL question is my first momelotinib question. Go on, Ruben. Sure. So what I view this as is really, you know, get complementary. I mean, clearly, this makes the case that in JAK inhibitor-naïve patients, you know, pelabresib plus ruxolitinib, you know, is the standard. You know, so I think it's really in parallel. The momelotinib approval of myelofibrosis with anemia, you know, being a clearly very helpful kind of comparative position as it relates to single agent JAK inhibition. I mean, clearly, there's logical questions that kind of flow from the field, you know, pelabresib and momelotinib, you know, undoubtedly, there will be off-label use of that if there were an approval and other things, and clearly, you know, data to be determined in all of that. But I think we think about it really more in that setting, you know. Likely in our field, again, I think to be proven by data, but we think of pelabresib plus JAK inhibition, you know, with ruxolitinib kind of being the holding place in there. You know, likely that would be the evolution, I would speculate. Right. Yeah, I mean, I totally agree. I mean, how many hematologic malignancies, other than CML and myelofibrosis, do we treat with one drug, right? We know we need to do kind of a multidirectional approach. I actually think that if you think about the SIMPLIFY study, ruxolitinib and momelotinib are actually pretty, pretty similar. Yes, there's the ACVR effect, but I think it's about modality, exactly as you said, Ruben, it's a JAK inhibitor or a JAK inhibitor combination. You wouldn't treat Hodgkin's disease with just A, you treat it with ABVD, I think is my perspective. Fabio, you want to comment on the hemoglobin or NLT? Yep, sure. Hey, Greg. So, when you look at slide 14 of the presentation that was showed yesterday with the hemoglobin curve, the mean delta for hemoglobin at week 24 is about 1 gram per deciliter. ... Also important to point out that the hemoglobin response rates is almost double in the combo arm versus the monotherapy arm. Granted, it's very early on to Professor Harrison's point. It's actually very exciting to see this hemoglobin response so early on, and I guess when you look at the trends, we're actually one would imagine even greater separation between the hemoglobin curves. On the long-term data for pelabresib, I would point to arm three of MANIFEST, and there it's very clear, the responses on spleen and symptoms are fast in onset, they're deep and durable. They seem to be deepening over time, and when you look at the JCO manuscripts, there's a low rate of discontinuations overall of the combination therapy. And I think what we heard yesterday in the presentation, that combination really seems to be very well tolerated. Also at the investigator event last night, there was a great level of enthusiasm for the fact that this is the first combo treatment in first-line myelofibrosis with very little additive toxicity, which is very, very remarkable. Regarding your question on the approval path, with the high unmet medical need that you just heard expressed by doctors here, plus the strength of the data, we're very confident on the approval of the product based on that, and we have announced that we will file midyear 2024. I just had a question on momelotinib. Could you compare the magnitude of the anemia effect on monotherapy momelotinib versus combination Rux plus pelabresib as in this trial? I know it's cross-trial comparison, so apologies for that. I think it's quite tricky, actually, because I've just kind of... I know you haven't come to whichever one of us yet, but I'm just kind of almost looking for a conversation here because the patient populations are totally different, right? So MOMENTUM is a second-line study, MANIFEST is a front-line study. Eligibility is slightly different. So we're, we're kind of comparing chalk and cheese to some extent- SIMPLIFY-1. SIMPLIFY-1? Mm-hmm. I think for all the reasons that Professor Harrison said, it's difficult to say, you know, as well as kind of the, you know, the entry criteria and other pieces. You know, it looks not too dissimilar, but I think we really have not done that analysis kind of in an in-depth way, you know, to do that question justice. I think, I mean, clearly, though, spleen is massively different, and spleen is the thing that actually links to survival, and the community is really clear on that. You know, there's a huge delta for spleen benefit here between a JAK monotherapy, whether that's momelotinib or ruxolitinib or the combo. I know that's not directly your question, but I'm just saying, you know, anemia is one thing, but what is the thing that links to survival benefit for our patients is spleen, for me. Oh, you know, I think without question. That's why I think it, you know, you see us both struggling a little bit because I think medically, we really think about them as two kind of two different things. You know, I don't really view necessarily single-agent momelotinib as a necessary comparator for the combination. I think things will evolve, you know, as we look at these things. And by the way, it's we made the comments a couple of times that we are JAK agnostic. We have to start by Rux because Rux is standard of care, and by chance, we have 80% of the market, so that also helps the commercial question on not being fragmented amongst different other JAKs. But there is avenue for exploring combination with new JAKs, and, I mean, not being secretive here, but there are conversations happening. Perfect. I heard we also have some people on the line who have questions, so why don't we give them also a chance to ask their questions? Operator, please. Yes, the first question comes from Xian Deng from UBS. Please go ahead. Thank you. Thank you for taking my questions. Could you hear me all right? We do. Oh, great. Thank you. Three questions, if I may. So the first one is to management, please, most likely Lucinda. So just wondering, how do you think about the cash runway, into, you know, next year? Just wondering if you have any comment or color on the preference of, for example, equity raise, monetizing pelabresib versus, you know, monetizing other assets. Any preference, please? And then the two other questions are for Dr. Harrison and Dr. Mesa, please. So the first one is, related to, anemia. So anemia data looks really positive, and you have several data points, all pointed towards the same direction, you know, hemoglobin response, transfusion dependence rate, et cetera. On the other hand, you also have TSS miss on both TSS endpoint. So for the sake of argument, let's say anemia looks better and TSS looks worse, just for the sake of argument. Just wondering, is there a consensus for physicians? If you have to pick one, would you pick TSS or anemia? Do you, I think for physicians, is there a preference that one is more important than the other? And the second question is also for the two KOLs, please, on the SVR relationship with OS. So this is one thing we've also been hearing from other doctors, that SVR 35 is very important because of an association with OS. But I never quite understand the scientific link there, because Jakafi doesn't modify the disease. So just wondering, where does the OS come from? So fundamentally, I'm trying to understand how strong is the scientific link between SV, SVR and OS. Is it like a sort of measure, like ORR or is that sort of do you think this is stronger or worse than ORR? Thank you very much. Thank you. Claire, do you want to take the TSS versus anemia question? Yes. So, I think that a few comments. Thank you for that question. I couldn't quite hear all of them, but I think I got that one. A couple of points. One, we haven't linked TSS response to overall survival benefit. As far as I remember, for patients in the field, patients do feel better, but you know, there's a certain ceiling effect, as Ruben said, I think if all of us was to do a TSS score in this room today, especially me, because I'm very jet-lagged, might I would have a TSS of something. So is it reasonable to expect to reduce it by 50% and then 50% again? Secondly, I think that anemia is really important for patients. It's important for their quality of life, as measured in a different way, perhaps, than TSS. But also, there was a question in the room about momelotinib and anemia response, and actually, anemia response has also been linked to an OS benefit for patients. Anemia is also a surrogate for bone marrow function. What we've also seen from the MANIFEST-1 study is some restoration of marrow features. For me, actually, anemia benefit is more important. That's right. Would be interesting to see actually, what would be combined pelabresib with momelotinib and what kind of anemia benefits we would get, right? Yes, we're very keen to do that study. Yeah. I'm sure you would. No, we are as well. Ruben, maybe on the SVR to OS link. Sure. So one, you know, I strongly think that there is a correlation between the improvement in spleen reduction and survival, you know. And I think as we look at these kind of last 12 years of experience, I think this is unquestionable for those of us that treat patients. You know, I have been involved with the care of myelofibrosis patients since the early 1990s, you know, and remember well the face of myelofibrosis prior to JAK inhibition. You know, those were individuals with severe cachexia, massive splenomegaly, many of whom passed away in two to three years. And we have individuals. I saw an individual last year that had been on the phase I of ruxolitinib and had been alive for 14 years, when looking back by his risk score, should have been dead in under three. So I think it is really a fallacy, you know, to think that there is no disease modification by successful JAK inhibition. I think there is. Now, mind you, I think that there's a lot of room to build on that, and I think combinations like this, you know, clearly do. But there clearly is an alteration in the natural history of the disease, at least for some of the patients. And we've learned over the years, there are important caveats to that. First, the correlation with spleen response. Second, the ability to receive an adequate dose of JAK inhibition has also been linked with that. So I think that's one of the reasons we're so enthusiastic about, you know, the depth of the spleen response here. Really, I think for us, suggests, you know, as the data continue to mature and we have the experience, again, comparing to, you know, well over a decade of real-world evidence of single-agent ruxolitinib, you know, it'll just become more and more clear over time, the superiority of the combination. Now, why do patients live longer? I don't think any of us know that for certain. I don't think that it's just a mechanical effect of the spleen being smaller. I think that it is really a biomarker of the quality of the response. Mm-hmm. You know, I think that's really why shrinking the spleen matters. It's not, you know, it's not that these patients die of intestinal obstruction because the spleen is too big. It is a biomarker. Likewise, I think symptoms are a biomarker of response, you know. And I think the ability to have seen, you know, the symptom improvement that was seen in this study, even despite adding a second agent, I think is very notable in a lot of ways. There was really no loss, if anything, really, a gain, in addition to those other benefits, and that's very significant. It would have been very easy for a second drug to have made people feel worse because of, you know, toxicities or things of that nature. So I think that's a really positive, positive, aggregated way of looking at the response. Can I just add one thing? I think about the way I teach our interns is I teach them that the spleen is a marker of tumor size, like you're actually- Mm-hmm ... shrinking the tumor. And then the second thing I just wanted to add was, both Ruben and I do a lot with patient advocacy. So I decided to poll our patient advocates recently on, "Actually, what would you want from a symptom?" You know, they, they all know we're going to ASH, and they're all super excited to see this data, you know. "What do you want from a therapy for your myelofibrosis? Do you want a therapy that is, looks like it's going to potentially change the course of your disease, or do you want one that knocks another two or three points off your symptom score? ... And the answer was pretty clear. I don't know if you've asked your patients the same thing, but I deliberately decided to ask them because just for interest. And so from their perspective, it's really about altering the trajectory of the disease, and they all fill in these symptom scores all the time. Everyone who comes to my clinic does it. So they, you know, they all know the vagaries of one or two points on a scale, a bad night, whatever. So just a perspective. Yeah. Really insightful. Thank you. And I don't want to lose the cash runway question, a bit anticlimactic, but important. Yeah, in answer to your question, we've got a nice cash position, as you know, EUR 640 at the Q3. Gives us a lot of flexibility. You know, we'll continue to explore avenues that make most sense from obviously a timing, quantum, and economic perspective. Thank you very much. Thank you. The next question comes from James Gordon, from JP Morgan. Please go ahead. Hello, James Gordon, JP Morgan. Thanks for taking the questions. A couple of questions, please. When you headlined the study, it wasn't clear why there was this small proportion of high-risk patients that saw some harm on TSS 50 rather than benefit. So now you've had a bit more time to analyze the data, any updated thoughts there? I heard, I think it was Dr. Mesa's comments on small patient numbers, but the counterargument could be that if there were small patient numbers, it wouldn't have distorted the overall result so much on TSS 50. So any further thoughts on why that might be that there was this different effect there? Second question was that the presentation last night was very focused on the ITT population, i.e., all comers, whereas there was more of a focus on intermediate versus high risk in the initial release. So what is the thinking there now? Is it that you're going to file the ITT data with the FDA and try and get an approval in everyone, or are you going to file ITT, but you're really looking for an approval with just the intermediate patients? And, third and finally, just have you had any opportunity to have an early discussion with the FDA about the data? And has there been any commentary about filability or any questions from them? James, thank you for the questions. I'll take the number two and number three. We intend to file for the all comers, again, based on the strength of the data and everything we've been discussing here. And in terms of discussion of in the real world, it takes a bit of time to organize that and come to the FDA, and there is a process. Remember that we just had our top-line results two weeks ago. We scrambled to get all this wealth of data organized for the communication yesterday and today. A lot of work, more work to come for the FDA. It's another stakeholder. It's not exactly the same thing. We have to think of how we do that. This is another exercise that is very consistent with what we have, and again, based on the strength of the data, we're super confident. There have been conversations earlier on, as you know, during the follow-on on the phase II. But they've not seen the phase III except the public data yet. So things will come. Let us work on that, and we'll update you. Then the question number one, which I'm not sure I completely got. Maybe someone who has an English accent. I think the question is why the TSS data in the high-risk patients. And I don't think we've done that deep dive into that subgroup, looking at it a case-by-case basis. I still think it's probably just an outlier based on the fact that, you know, we saw really no problematic signal from the single arm of the MANIFEST study. I suspect it's just the vagaries of a handful of patients. But I can't say we've done enough of an analysis on that small subgroup to be able to answer that in detail. Very low end as well, right? Yeah. I mean, it's very low- 35 patients, 2,000. 10 patients. Yeah. Yeah. You know, so you still have a couple patients that have, you know, have an AE or something, and it could really throw it off. So the MorphoSys team actually looked at the patients patient by patient, and the conclusion was exactly as you stated. It's a numerical abnormality. There's nothing that really sticks out here. And to Claire's point, one patient equals 10% response. It's almost a phase I setting. So you can easily see how one patient going over to the other arm potentially completely tips the results. So extensive analysis was done, no smoking gun detected. And to Dr. Mesa's point, in arm three of MANIFEST, patients at the same level of TSS benefit, in addition to that spleen benefits, like the Int-2 patients. And what we see very consistently in MANIFEST-2 is that very, very good spleen response also in the high-risk patients, in addition to the biochemical responses, anemia responses, and a good safety profile. Yep. Thanks. Next question comes from Charlie Mabbutt from Morgan Stanley. Please go ahead. Hi, thanks for taking my questions. Charlie Mabbutt from Morgan Stanley. So I guess firstly, I'd be interested from the KOLs to just hear what your average daytime currently is with intermediate risk patients on Jakafi in first line. And I know you've discussed several times, I guess, the two other JAKs that have been approved with specific labeling for anemia and thrombocytopenia. But it seems the NCCN guidelines are still driving sort of treatment choices by platelet levels as opposed to anemia at baseline. So please, could you give us an idea as how you see the relative importance of those two factors at this stage? And then just quickly for the company, I guess what further data would you actually need to generate in your mind to use pelabresib in combination with those other agents? Thanks very much. ... Who wants to take the first question? Maybe I'll take that because the second one was about NCCN, so that's definitely you. Okay. But I think the first question, is it James, was about the current data for JAK inhibitors in the first line for intermediate-risk patients. Really, they're no different from the data that you see here. I don't think there's any reason to suspect that the patients that are on monotherapy ruxolitinib in this trial are any different from what we would see in the community setting, to be honest. And you see that the patients are nicely balanced between the two arms. So, we would expect to see the same benefit of effect and the same magnitude of effect. However, the data you don't yet see from this study is the duration of response and whether those responses deepen over time. My anticipation would be that, given my experience in treating patients with this combination well before the pandemic and through the pandemic, is those patients chose to stay on and have a maintained response. So I would expect to see more durable and probably responses, hopefully deepening over time, but that's, that's really speculation. Ruben, the question was about hemoglobin versus platelet count driving treatment choice in the NCCN guidelines, I think. Sure. You know, so one, the NCCN guidelines, I think, are largely created to create kind of a safe space, if you would, you know, for treating physicians to have all the options available to them. You know, I think there was an earlier question, you know, which parameter do we prioritize? I think we really look at the patient in aggregate, you know, as it relates to their spleen symptoms, cytopenias, disease goals, and other. I think as momelotinib was approved, again, they really added it into the existing paradigm, you know, where that again had been driven by platelets to some degree as a historical artifact of kind of when we had started with ruxolitinib. You know, I... You know, how an approval would fit in the guidelines, I think, would leave up to clearly the panel. You know, I think history being precedent, they probably would again, you know, include as an additional frontline item with discussion in there as to, you know, the physician's pick consideration, you know, and may well recommend it as the preferred first option. But again, the guidelines are meant to really give practicing physicians maximum flexibility in terms of their options for caring for their patients. Is it driven by pacritinib, the platelets less than 50 versus the other JAK inhibitors, really? Correct. It's really around both of this point, which was really that at 50 as a number, you know, and then they included momelotinib. There's both an algorithm as it relates to anemia, as well as kind of the upfront algorithm. Now, that may evolve as we have a combination, 'cause again, this would be the first combination study that would be inserted into the guideline. So speaking of first combination, we still have a lot of work to unfold the opportunity here, which is very large. But I want to answer the last question, I mean, the last question of this question on the work on momelotinib. I mean, we have had many, many meetings with pharma during this conference. Interest is tremendous, as you can imagine, with the quality of this data and the strength of this data. So more to come. Let us do the work and trust us on the opportunity here. Last question from, Yep. I have one more question from the line, and then we also want to be mindful of the time of our KOLs, and we know we have a packed agenda. Well, last question from the line. Operator, please. The last question is from Rajan Sharma for Goldman Sachs. Please go ahead. Hi. Thanks for taking my question. Again, I've got a couple for the company and a couple for the KOL. So maybe just for the company, just thinking ahead, and now that you have phase III data in hand, how are you thinking about pelabresib's value proposition? Do you expect that the dataset supports pricing in line or at a premium to Jakafi, which would imply at least, I guess, a doubling of total cost of first-line therapy for the combination versus standard of care? And I guess, do you think the data is sufficiently supportive of that? And then for the KOLs, could you perhaps provide some perspectives on why there were higher levels of thrombocytopenia and platelet count decreases with the pelabresib combination? And then, I guess, just on the TSS or the TSS 50, are you surprised there wasn't a more pronounced benefit on fatigue given the anemia benefit that was achieved? And we hear from other physicians that one of the big drivers of the fatigue component of the TSS 50 is the anemia. Yes, the last one or the first one? The first one I called up. What is the first one? What was the first question again? I'm so sorry. Could you repeat it? The first one was corporate on the filing. Yeah. No, it was just on pricing- Pricing ... and how you think of whether you think you can justify kind of pricing in line with Jakafi or even at a premium to Jakafi, which would then essentially double the combination therapy, cost of therapy at the front line, if you think the data is supportive of that. Cost. Cost of therapy. Yep. Okay. Yeah. Well, we have time to sort that out. Again, in terms of access and pricing, it's always based on the value proposition here, and first and foremost, the data strength, and we work on making something at the same time, rewarding innovation, but sensible for the society. So more to come on that, I think. I suppose the other thing I'll just to reflect is that ruxolitinib is going to be generic, so- Correct. So the cost of your partner is going to drop, at least if it's ruxolitinib. Then the question was, why was there more thrombocytopenia, I think? So, you know, we've seen actually, we've been exploring the benefit of pelabresib in normalizing the platelet count for patients with ET, which is also potential a big interest of mine. But, I think this is just about, the added effects of the two drugs upon the, the marrow, and, for me, I don't find that to be particularly problematic. And we see a readout of that in terms of the dosing of ruxolitinib. We have to dose ruxolitinib according to the platelet count. So you can see that those platelet count changes didn't affect the important backbone of the study, which is the dosing of ruxolitinib. Then I'll just comment on anemia versus fatigue. Actually, I probably didn't point it out to you enough. We did see less fatigue with the combination and actually reported as an adverse event. Whether that read out or not in TSS, I think that just illustrates the vagaries and of that endpoint and all of the data that we collect the patients. But Ruben, maybe you also want to comment on those two. So one is, as we showed, there, I mean, there was a delta between the two without question. The two, the fatigue, you know, has a relationship to anemia, but I think it's frequently been a misinterpreted fallacy that fatigue is only because patients are anemic, and that is really not the case. I mean, the overall broader impact of the disease clearly contributes to the fatigue. Now, there are other factors, having a chronic disease, you know, fear of the unknown in the future, the uncertainty of having such a disease. All these things really do weigh in. That's why, you know, even in great responders, that's why we really don't see symptoms kinda go down to zero. You know, in therapies, again, that really help to control the disease to a greater degree, but still, you know, patients still are left with, you know, with aspects of disease burden. Show the subjectivity of some of these symptoms by a sense, right? Well, without question, you know. But in addition, you know, patients have clearly improvement in anemia, but still it's not normalization of Right ... of oxygen carrying capacity either. So again, there still is that the- Well, these are also still patients in their sixties with other comorbidities- Yeah. -right? So. Yeah. Great. Okay. Great. Well- Thank you so much. Yeah, thank you so much. Thanks, everyone. Thank you very much, Claire and Ruben. Much appreciated, and I hope we will have a great next session next time. So you want to close or I close? No, I think you said it all. Thank you. I can close. Have a great rest of ASH. Ladies and gentlemen, the conference is now concluded, and you may disconnect your telephone. Thank you very much for joining. Have a pleasant evening. Goodbye.