Ladies and gentlemen, goo d morning and good afternoon. My name is Julia Neugebauer, Head of Investor Relations at MorphoSys. It is my pleasure to welcome you to today's investor call, that will focus on the potential of pelabresib, our investigational BET inhibitor in myeloproliferative neoplasms. Before we begin, I'd like to remind you on slide two, that some of our statements made during the call today are forward-looking statements, including statements regarding our expectations for the commercialization of our products and our development plans and expectations for the compounds in our pipeline. These forward-looking statements are subject to a number of risks and uncertainties that may cause our actual results to differ materially, including those described in MorphoSys 20-F and annual report for the year ended December 31st, 2022, and from time to time in other SEC documents of MorphoSys. It is important to keep in mind that our statements on this webcast speak as of today. I would now like to turn the call over to Jean-Paul Kress, our Chief Executive Officer. Jean-Paul, over to you. Thank you, Julia. Good morning and good afternoon, everyone. Thanks for joining us today. The past two years have been transformative for MorphoSys. We established a clear strategic focus in oncology, growing and developing a best-in-class late to mid-stage pipeline. Pelabresib, our investigational BET inhibitor, is a potential first-line treatment for patients with myelofibrosis. It represents our largest and most immediate opportunity. In April, we announced that we completed enrollment of Phase 3 MANIFEST-2 study of pelabresib in first-line myelofibrosis ahead of schedule. As a result, the top-line data from the trial are now expected by the end of 2023, months earlier than previously anticipated. With pelabresib, we have the potential to improve the standard of care. Currently, depth and durability of responses are limited with available first-line therapies. The Phase 3 MANIFEST-2 trial is supported by findings from the Phase 2 MANIFEST study of pelabresib in patients with myelofibrosis. Interim data from this Phase 2 study suggests that pelabresib, in combination with ruxolitinib, provided prolonged improvement in both spleen size and symptom severity at and beyond 24 weeks, with potential modifying disease. Beyond myelofibrosis, we also see opportunities for pelabresib in other myeloid diseases. Tim will speak about this later. We also have a medicine currently on the market, MONJUVI. This CD19 targeting immunotherapy is approved in combination with lenalidomide to treat certain adult patients with relapsed or refractory diffuse large B-cell lymphoma, also known as DLBCL. Because of this, we have a strong U.S. commercial infrastructure in place that can facilitate the launch of pelabresib following positive data and approval. We see a large overlap in treating physicians for DLBCL and myelofibrosis, especially in the community setting where we have established relationships. Beyond the currently approved indication, we see potential upside with MONJUVI in the first-line DLBCL setting, which we are exploring in our Phase 3 Frontline study. This Phase 3 trial is also fully enrolled, with nearly 900 patients randomized, and the data will be available in the second half of 2025. We also have an investigational agent in mid-stage development, tulmimetostat. tulmimetostat is a next-generation dual inhibitor of EZH2 and EZH1. It is designed to improve on first-generation EZH2 inhibitors through increased potency, longer residence time on target, and a longer half-life, offering the potential for enhanced antitumor activity. Initial data from our Phase 1/2 basket study showed encouraging monotherapy responses in heavily pre-treated patients with advanced types of cancer. These preliminary results are promising, and we look forward to learning more as the trial progresses. As you can see, our pipeline offers a wealth of opportunities that have the potential to address the critical needs of patients with blood cancers, including myeloid malignancies and those with solid tumors. We are well-financed to deliver on these opportunities, with more than 12 months of cash available after the top-line readout of the pelabresib Phase 3 MANIFEST-2 study. Today, we will focus our attention on pelabresib. During this event, topics will include an overview of the disease burden for patients with myelofibrosis, including treatment gaps.... a recap of encouraging findings in myelofibrosis from the pelabresib Phase 2 MANIFEST study in combination with ruxolitinib, and background on the Phase 3 MANIFEST-2 study. New proof of concept results and expansion plans for pelabresib in other myeloid diseases. For this, we are joined by top medical experts in this field, Dr. John Mascarenhas, Professor of Medicine and Director of the Adult Leukemia Program at the Tisch Cancer Institute at Mount Sinai, New York, and Dr. Gabriela Hobbs, Assistant Professor of Medicine at Harvard Medical School and Clinical Director of Leukemia Service at Massachusetts General Hospital. I would now like to turn the call over to Gabby Hobbs, who will provide an overview of myelofibrosis, the burden of disease, and the critical medical need she sees. Gabby, over to you, please. Thank you so much. I'm thrilled to be here. Today I will talk a little bit about the burden of living with a disease like myelofibrosis, and then discuss our current treatment approach, as well as medical needs that are still necessary to investigate. Next slide. Myelofibrosis is a unique and rare and debilitating progressive blood cancer, and it's characterized by four main findings. The first is that patients, unlike with other leukemias, they live with really significant constitutional symptoms that can very negatively impact their quality of life. Myelofibrosis is a myeloproliferative neoplasm that is caused by genetic abnormalities in the bone marrow stem cells. In addition to having constitutional symptoms, like I mentioned, the fibrosis in the bone marrow ends up leading to enlargement of the spleen, which also causes significant symptoms. The fibrosis in the bone marrow also leads to an inability to produce blood normally, and therefore anemia, as well as other low blood counts, like thrombocytopenia and leukopenia, are also an important hallmarks of this disease. We use a variety of different risk stratification scores to prognosticate survival for our patients. In a diagnosis, over 90% of patients will be in the intermediate or high-risk categories. The median overall survival for intermediate risk patients is significantly reduced, anywhere from 3 years-6 years, and for high-risk patients, it can be as short as about a year. Next slide. As I mentioned, patients with myelofibrosis can suffer from a lot of different symptoms that really significantly impair their quality of life. I can't overestimate how meaningful these symptoms are and impactful in the life of patients with myelofibrosis, and how different it is to treat patients with this disease compared to other hematologic malignancies. Fatigue is really probably the most common symptom that patients suffer from, and it is severe and debilitating. Patients can also suffer from bone pain. They can have fevers, night sweats that can be drenching, symptoms from really massively enlarged spleens. The disease also ends up leading to weight loss from a variety of reasons, including having the massive splenomegaly, but also the inflammatory cytokines that characterize this disease, and itching, which may sound like a trivial symptom, but actually can really be very debilitating as well. Next slide. As I mentioned, there are several different scores that can be utilized to risk stratify patients. Probably the ones that are most commonly used in clinical practice are the Dynamic International Prognostic Scoring System-P lus, and the MIPSS70 or molecular IPSS version 2. Really, regardless of what risk score is used, patients can be divided into the lower risk categories, intermediate risk, or high risk. Here, I put a summary of our approach to the management of patients with myelofibrosis, which has gotten a little bit more granular with the approval of new medications. Patients that are in the low-risk category tend to be asymptomatic, and if their blood counts are preserved, then observation at the moment is the standard of care. Patients that have symptoms from their spleen or constitutional symptoms are candidates for consideration of JAK inhibitor therapy. At the moment, we have three JAK inhibitors that are approved, and it is likely that we'll have a fourth JAK inhibitor approved sometime in 2023, although that continues to be postponed. Patients that are diagnosed with myelofibrosis and have symptoms from splenomegaly as well as constitutional symptoms and platelets of greater than 50, are eligible for ruxolitinib or fedratinib in the frontline setting, though usually ruxolitinib is used first, as that has been around for longer. Patients that have thrombocytopenia with platelets of less than 50 can be treated with pacritinib, and that was recently added to our armamentarium in 2022. All three of them can be used in second line, regardless of platelet counts. Patients that are in the higher risk groups of patients, those that have pretty significant cytopenias, have molecular markers that make them high risk, really should be considered for transplant upfront. We know from studies that the vast majority of patients do not actually end up undergoing transplantation for a variety of reasons. Now, you can see from this, little algorithm that cytopenias is a separate box. Although we do have some medications now that can address cytopenias to some degree, cytopenias really is an unmet need. Anemia can be treated with agents such as erythropoietin-stimulating agents, testosterone analogs like danazol, immunomodulatory drugs like lenalidomide or thalidomide, or clinical trials. That's definitely an area of unmet need. Next slide, please. With the algorithm in mind and our approach to treating patients with myelofibrosis, I'm going to talk about some of the unmet needs that we have in the care of our patients. The first unmet need is the watch and wait approach of those low-risk patients. And this is something that may seem like it would be okay for patients to have this watch and wait approach, but actually it can be very anxiety-provoking because patients know that they have a disease, they have a disease that's progressive, and it seems counterintuitive to have a malignancy and not do anything about that. Our colleagues in the solid tumor world would think, of course, that that would be ridiculous. We have a diagnosis of breast cancer, and we don't wait for it to get worse before we treat it, but that's currently what we do with myelofibrosis. The reason why we do this for this disease is that we do not have drugs that can consistently and predictably modify the disease course. Really, the only curative therapy for this disease is allogeneic stem cell transplantation. Because the overall survival of this low-risk group of patients is over a decade and a half, offering an allogeneic stem cell transplant at the early stages of the disease is still not recommended because the risk of the procedure is still greater than the risk of the disease. There is a lot of interest in utilizing therapies that could modify disease early on to see if, you know, we can change the natural history of the disease. In this regard, interferons have been studied, but they have not yet yielded consistent results. This is definitely an area where we need additional investigation. Next slide. Next is cytopenias, which I hinted at when I was talking about the algorithm for the approach of patients with myelofibrosis. The focus of drug development really has been in the development of JAK inhibitors. However, most of the JAK inhibitors really do not consistently improve blood counts. It's possible that pacritinib and momelotinib do improve the blood count somewhat, but it's not in the majority of patients. Really, a very significant% of patients with myelofibrosis, either at diagnosis or throughout their treatment, will develop both thrombocytopenia and anemia. In one study, you can see that the prevalence of thrombocytopenia diagnosis is pretty significant. Patients can be diagnosed either with severe thrombocytopenia, with platelets of less than 50,000 at diagnosis, although that's in a minority of patients, or moderate thrombocytopenia, with platelets in the 50-100 range in about a quarter of cases. The other thing to keep in mind is that when a patient has one cytopenia, they usually have other cytopenias or other high-risk molecular markers. All of these things tend to travel together. The patients that are thrombocytopenic at diagnosis are likely to also have anemia, transfusion-dependent, constitutional symptoms, and an enlarged spleen. Cytopenias are utilized in all risk scores and give patients a worse survival, in addition to significantly decreased quality of life. Next slide, please. Cytopenias, again, do not live in isolation. They usually come with other factors that are associated with worse risk. Here what I'm showing you is the, one of the graphs from the MIPSS70 risk stratification score. You can see the patients on the top line that are in the low-risk category can expect a pretty good survival, but those patients in the very high-risk or high-risk categories really do have a dismal prognosis. Those patients are usually in the high-risk categories for two reasons: because they have cytopenias and also because they have high-risk molecular markers. You can see that their survival is significantly impacted, and their quality of life is also significantly impacted by the cytopenias. Patients that have transfusion-dependent anemia or thrombocytopenia are really wedded to the clinics that they, that they go to, and they have to be seen fairly frequently for transfusions. Next slide. The second unmet need would be anemia. This is thankfully starting to be addressed. As I mentioned, you know, the JAK inhibitors historically really had not improved cytopenias. Ruxolitinib and fedratinib usually are associated with the worsening of anemia and thrombocytopenia over time. Pacritinib was recently approved, and because its mechanism of action is slightly different than the other JAK inhibitors, as it blocks the ACVR1 pathway, some patients treated with pacritinib, about a fourth, will see an improvement in their hemoglobin or red blood cell parameters. Momelotinib is another JAK inhibitor that is expected to be approved this year, and it similarly blocks the ACVR1 pathway and has also been associated with an improvement in anemia in about a third of patients. Luspatercept is a drug that's under investigation. It's currently approved for myelodysplastic syndromes, and although it's just undergoing investigation in myelofibrosis, since it's already approved for myelodysplastic syndrome, we can use it off-label, and many of us have started doing that fairly frequently. In addition to single-agent therapies, there's, of course, a lot of combination studies, and here I only mentioned two agents, but there are many agents in development, and some of which have started to demonstrate improvements in anemia. We're encouraged that there is a little bit of progress in the anemia front. Unmet, next slide, please. Thrombocytopenia is a really significantly unmet need. Most clinical trials for patients with myelofibrosis have traditionally excluded patients with thrombocytopenia. Some of the studies have included some degrees of thrombocytopenia, but most of them have excluded patients with pretty significant thrombocytopenia or platelet counts of less than 50. The development of thrombocytopenia on trials is also a problem 'cause it leads to dose reductions, dose interruptions, and many times patients cannot continue on studies. Many of the studies that are underway right now don't study a pretty significant group of patients with myelofibrosis. Pacritinib is really the only drug that's been approved that has been studied in really severely thrombocytopenic patients. As I mentioned before, current therapies generally worsen thrombocytopenia. Next slide. Why have the cytopenias not really been addressed with current studies? Up until this point, or up until fairly recently, the main endpoints of clinical trials have been to focus on improvement of splenomegaly as well as systemic symptoms. As I mentioned before, patients with cytopenias have really traditionally been excluded from trials, in part because the therapies that have been studied worsen cytopenias. This is in part because drugs that are being studied are myelosuppressive, and therefore, this discourages the inclusion of patients that already have cytopenias. This is kind of interesting because, you know, myelofibrosis is a form of leukemia, and therefore, we expect our patients to have abnormalities in blood counts, and the cytopenias really are a symptom of the disease. Therefore, excluding patients because of their disease characteristics, has sometimes, to me personally, seemed somewhat counterintuitive. Next slide, please. Another really important unmet need in the area of myelofibrosis is novel endpoints that measure disease modification. Like I mentioned before, really the focus of clinical trials has been the improvement of splenomegaly and symptoms. Why is that? At the center of myelofibrosis disease biology is the abnormalities in a pathway called the JAK-STAT signaling pathway, and therefore inhibiting this pathway has seemed, of course, like a logical target. JAK inhibitors that block this pathway lead to improvements in splenomegaly as well as in symptoms, and they were logical targets to be the initial endpoints of the first clinical trials with JAK inhibitors. The other aspect that's more challenging is that it has been difficult to define pathological and biological markers that would define myelofibrosis progression and disease modification. The combination of having drugs that can consistently improve spleen and symptoms, and targeting a pathway that leads to the improvement in spleen and symptoms, and the challenge of defining disease modification in this disease, has led us to have these endpoints with which we have been stuck with for the last decade and a little bit more. Next slide. Really, novel endpoints are needed. There is a pretty significant tension between regulatory requirements as well as what patients think would be important endpoints and what physicians think would be important endpoints. As mentioned, the JAK-STAT pathway is, of course, a logical target, and those, thus, most efforts have really focused on tyrosine kinase drug development in this space. However, most novel compounds are really still held to that spleen volume response and total symptom improvement endpoints, and they really do neglect the bone marrow failure component that is really just as important in managing patients with myelofibrosis. Coming up with novel endpoints, I think, is really important, especially as we enter a space in myelofibrosis where we are going to start to be utilizing combination therapies and not just single-agent JAK inhibitors. Improvements in cytopenias, improvements in bone marrow fibrosis, improvements in progression-free survival and overall survival, as well as leukemia-free survival, really should be the goal of novel therapies. Next slide. Lastly, an important unmet need in myelofibrosis, and myelofibrosis is not unique in this regard, is education. Myelofibrosis is a rare disease. Oncologists that practice in a general community setting, and treat a variety of different malignancies, really don't encounter myelofibrosis patients frequently in their practice, and therefore, it's difficult for a general oncologist to have expertise, as they see only a few cases per year. Education, I think, is really important in helping community oncologists with early diagnosis, with therapy initiation, as well as appropriate therapy escalation and therapy modification. One of the important aspects of education as well is to connect doctors in the community with doctors in academic centers, so that these patients can either be referred, either to take over the care completely or just to be, somebody that can co-manage patients with patients with physicians in the community. This education is also really critical in order to ensure that the current therapies are used appropriately and on time, and to help with the uptake of new drugs that are approved. Next slide. In summary, myelofibrosis is a debilitating, progressive, and unfortunately, often deadly blood cancer. Current treatments are not really addressing all the patient needs, and therefore, new therapies are really desperately needed in this space. Thank you so much for your attention. Thank you, Gabby, for this very compelling overview. As you can all see, myelofibrosis is an extremely debilitating and often deadly disease. The current standard of care doesn't work for the majority of patients. New treatment options are in critical need. Now we would like to show a video of Gail, a patient living with myelofibrosis since 2018, to help you better understand the patient burden and the patient need. Please play the video. My name is Gail, and I have myelofibrosis. I was diagnosed with polycythemia vera in 1999, and then 20 years later, I was diagnosed with myelofibrosis. The diagnosis was just so scary. We were all very fearful of this crazy thing called myelofibrosis. The spleen, for me, has just grown, maybe the size of an eggplant, and it's supposed to be very small. It sticks out, and it makes you look like you might be pregnant or have a really big belly. I look down at myself, and there's, like, this thing. It actually sticks out of my stomach like a mountain. It is squishing my kidneys, it squishes my lungs, and it squishes my stomach, so that you're, you know, you're hungry and you're trying to eat, but you can't because you get full so fast. On top of that, I have lost a lot of weight. I lost 30 pounds, and a lot of that's muscle. Fatigue with myelofibrosis is probably one of the worst parts. It's hard to describe the fatigue unless you've experienced it. It's not like a good tired, like, "I've worked a hard day, I'm tired." It's like you can't do anything. My bones actually hurt. Like, if I touch my bones, they feel bruised. I also get these sores on my back. I would have T-shirts that were just full of blood on the back. Night sweats are a big, huge problem. I haven't had many night sweats lately, but, you know, you might be waking up twice a night to change your pajamas. I am dependent on blood transfusions. I go every 2 to 2 and a half weeks to get 2 units of blood. A great day, I've had some recently, would be, me being able to get in the car by myself and drive a short distance. My mother lives in a assisted living right nearby. I can drive by myself to her place, help her out, I still have energy maybe to run into Walgreens or something like that, and still have energy to make dinner, clean up after dinner. You know, some basic stuff, but it, stuff that I really appreciate. I really appreciate being able to get in the car and drive myself. On a tough day with myelofibrosis, my legs hurt, I'm extremely tired. I will not do anything. Sometimes those days come after my good days, like, where I'm out being active. I'll have a bad day, and I will have to do nothing, and it's like it's just the only thing that feels good is to lie on the couch or lie in my bed. I'm fairly an optimistic person, and I always have hope. My hope for the future of myelofibrosis, that I get better. I know everyone's working really hard towards getting something to help us live a normal life. Gail's story is one of many and underscores the important work we are doing in myelofibrosis. I would now like to turn the call over to Dr. John Mascarenhas, who will provide an overview of the myelofibrosis treatment landscape and recent data presented on pelabresib in this disease. John, over to you, please. Okay, thank you for the introduction. My name is John Mascarenhas. I'm on slide 21. I'm happy to present the pelabresib in myelofibrosis update. I'm gonna move to slide 22. Here I'm showing a schema or cartoon of why we believe that there is synergy between BET inhibition and JAK inhibition. That's based off of preclinical modeling conducted by many of my colleagues here in New York City, demonstrating in murine modeling both a synergy in terms of downregulating JAK-STAT signaling with a JAK inhibitor, as well as downregulating NF-kappa B and NF-kappa B-related gene expression with a, with a pan BET inhibitor. The two work well together in both improving splenomegaly, reducing disease burden and fibrosis in a murine model. The preclinical rationale for this combination is set and demonstrated very nicely, which inspired the MANIFEST trial, which is now shown on slide 23. This is the schema for the Phase 2 study. You'll appreciate that there are multiple arms of this trial. Arm 1 is those patients who were treated with ruxolitinib, who have failed therapy and now discontinued, and they receive monotherapy pelabresib. They're stratified by whether they're transfusion-dependent or independent, and the primary endpoint depends on whether they are receiving red blood cell transfusions or not. The Arm 2 are the salvage arm, patients who are receiving ruxolitinib and continue to have unmet disease burden or progressive disease, in which pelabresib is added to ruxolitinib at their steady dose, again, stratified by transfusion dependence or independence. Arm 3 is the most exciting arm in which we move forward into a Phase 3 setting, and this is JAK inhibitor-naive patients with myelofibrosis in need of therapy, that receive both pelabresib and ruxolitinib upfront, with a primary endpoint of spleen volume response and a key secondary endpoint of symptom response. This is a paradigm shift in the treatment of myelofibrosis, in which we're moving the treatments earlier on in combination to maximize response and optimize outcome. With that introduction, I'm gonna move to slide 24 to impress upon the audience, recently presented durability data for response and safety in the MANIFEST arm 3, the combination of pelabresib and ruxolitinib in JAK inhibitor-naive patients, that was presented at EHA in Frankfurt earlier this month. Slide 25 demonstrates the patient disposition. A total of 84 patients were enrolled in this arm. 84 patients with treatment-naive myelofibrosis, receiving pelabresib at a dose of 125 milligrams, two weeks on, one week off, at a three-week cycle, and ruxolitinib at a dose that's determined by their platelet count and protocol-defined. You can see that 42% of patients remain on treatment at the time of data cutoff, and you can see the primary reasons for treatment discontinuation listed below. I will point out that the fact that 12% or 10 patients went on to receive stem cell transplantation, which Dr. Hobbs pointed out is the only curative option, is a very positive aspect, as this would demonstrate the ability for patients to go on from this initial therapy and receive life-saving and curative intent therapy with transplant. The reasons for discontinuation through week 60 and beyond are listed on the right. I'm moving to slide 26, which demonstrates the patient demographics and disease characteristics. I've purposely highlighted in blue those features that I think are pertinent to keep in mind when looking at the efficacy data. The majority of these patients were intermediate to and high-risk disease. 66% of patients had a hemoglobin less than 10, with a median hemoglobin of 9 grams per deciliter. If you look at the symptom score, these were symptomatic patients with a TSS of 16, and the majority of the patients, 56%, had a high molecular risk mutation. Of course, these mutations have prognostic significance and correlate with and associate with outcome. Slide 27 shows the response over time. At 24 weeks, the primary endpoint, the spleen volume response rate, was 68% of the patients met SVR, 35% or greater. What I like about this slide is it demonstrates the durability in that response over time, going even beyond week 60, in which 54% of patients maintained that SVR 35% response. There's durability in response. The median time to response was rapid in 12 weeks, and the median follow-up for this data set is 84 weeks. Slide 28 similarly shows the response in terms of symptom improvement. These are deep symptom improvements that are rapid. By week 12, you can see significant depression in the symptom score. 83% of patients at any time had a TSS 50% or greater, and by week 24, 56% of patients met this key secondary endpoint. maintained over time to week 60, as demonstrated in this graph. Rapid and deep spleen and symptom improvement with durability in both responses. What about anemia? Slide 29 demonstrates a very important curve. This is the curve in mean hemoglobin with patients treated with the combination upfront. You can see that there is an anticipated drop in the hemoglobin within the first couple of cycles. This is anticipated. This is what we see with ruxolitinib monotherapy and was documented in the COMFORT studies. Although I would make the point that this curve is muted, it's not as deep and as significant as single-agent ruxolitinib. Perhaps more importantly and notable is, over time, there is a trend upwards in the hemoglobin curve that is distinct and different from monotherapy ruxolitinib. The hemoglobin response rate, as shown on the right, was 27% of patients. You don't really see this with single-agent ruxolitinib. The median time to response was 60 weeks, and the duration of response was 28 weeks. Half of the patients who were receiving transfusions had a 50% reduction in transfusion burden, and as you heard from Dr. Hobbs, this is a major unmet need, a significant reduction in quality of life and functionality if patients are receiving transfusions, and even a reduction by 50% is clinically meaningful and appreciated by patients. Slide 30 shows evidence of biomarker modification or disease modification with biomarker evidence. 27% of patients who were treated with this combination in the first 24 weeks had at least one grade or greater reduction in bone marrow fibrosis. By week 24, you can see the percentages in the columns listed there. 40% of patients had at least one grade of improvement at any time on study. A very novel biomarker that I'm gonna highlight in a second is distancing of megakaryocytes. Not looked at before, not appreciated before, the fact that there's atypical megakaryocytes that congregate in a pathologic fashion in myelofibrosis, the hallmark, the biologic pathologic hallmark of myelofibrosis, is modified with the combination of these two drugs, in which there was a 15% or greater increase in distance between CD61 positive. Those are megakaryocytes in the bone marrow, demonstrating a force or a movement towards normalization of this atypical feature of myelofibrosis. We're in the process of validating and looking at this novel biomarker as a means of correlating it with response. I'm moving to slide 31, which demonstrates that 38% of patients treated with this combination had a 20% or greater reduction in their JAK2 V617F variant allele fraction, with a median reduction of 14%. You can see by the waterfall plot that some patients had very significant reductions in JAK2 driver mutation with this combination of therapy, and there was associations with modulation of the driver mutation with bone marrow fibrosis reduction, SVR35, and TSS50, as well as hemoglobin responses, as shown by the boxes below and illustrated in the text on the right. Demonstrating correlation between biomarker, bone marrow fibrosis, JAK2 V617F allele reduction, and clinical outcome measures such as spleen symptom and anemia response. Slide number 32. This is a well-tolerated therapy. The combination of the two drugs together was well-tolerated with very few grade 3, 4 events. One does see, to some degree, grade 3 for anemia and thrombocytopenia, although I would make the argument that this is less than one would expect by adding a drug to Jakafi. The GI toxicity is limited. It's mostly grade 1, 2 in the first two cycles, easy to manage, rarely a reason for discontinuation. There were 8 grade 5 treatment emergent adverse events that were reported in 7 patients, and you can see the events that are listed on the text on the right. I will point out that only 1 of these events was listed as possibly related to the study drug by the PI, and this was multi-organ failure due to sepsis, secondary to pneumonia. Slide 33 is a very interesting analysis. This is called a MAIC analysis, which is a match adjusted indirect comparison analysis, which is to adjust for differences in baseline characteristics of patients and is an attractive method for indirect treatment comparison using individual patient data from 1 study, so from the MANIFEST Phase 2 study, with aggregated study-level data from comparator studies. You can see from the MANIFEST study, this is looking at spleen volume response rates of somewhere between 66.7%-68.8%. I will explain that the ITT and MITT accounts for those, uh, small fraction of patients that were included that were intermediate 1 risk disease. What you see are the SVR rates across the different studies in which the patients were JAK inhibitor naive, so ruxolitinib in the COMFORT-I, COMFORT-II, and SIMPLIFY-1 study, so as, you know, a similar patient population. Momelotinib, in the SIMPLIFY-1 study, fedratinib in the JAKARTA study, and then fedratinib at 500 milligrams, also another dose explored in the JAKARTA study. The point being made here is that the effect on spleen volume response was significantly higher than what we saw across these trials. What I'm not showing you is if you look at the forest plots from this analysis that was presented at EHA by Vikas Gupta last year, and is soon to be published, that no matter what patient population or how you accounted for the variables, there was superiority in terms of spleen volume response and symptom response in patients treated with pelabresib and ruxolitinib, compared to ruxolitinib, momelotinib, or fedratinib alone in these other historic studies using a MAIC analysis. Of course, a MAIC analysis is enticing, it's exciting to see, it is reassuring to see, but it's the Phase 3 study results that we're all anticipating to confirm this analysis from these results. I'm moving on to slide 34. This is Arm 1 that I showed you previously of the MANIFEST multi-arm Phase 2 study of pelabresib monotherapy in myelofibrosis. These are patients who had failed ruxolitinib. They were either refractory, resistant, intolerant, or ineligible for JAK inhibitor therapy with a platelet count of greater than 75,000, and the patients were either transfusion-dependent, 1A, or independent, non-transfusion dependent, cohort 1B. You can see the primary endpoints that were associated with each of these cohorts. On slide 35, I'm showing you the impact of pelabresib monotherapy for anemia improvement. Conversion of transfusion dependence to independence in 16% of patients, with a median duration of 41 weeks, that's not a small amount of time, and median time to conversion of 32 weeks. If you look at Arm 1B, the non-transfusion dependent patients, hemoglobin response, which is a 1.5 gram/deciliter increase in hemoglobin, was attained across the board in 38% of the patients treated with low hemoglobins. If you look at the anemia curves on the right, I think it very beautifully demonstrates the mean improvement in hemoglobin over time with monotherapy pelabresib. The reason why I point this out is it demonstrates activity of this agent alone, even in a very advanced, sick patient population that has already failed ruxolitinib, in which the median survival is predicted to be less than 1.5 years, and there are very limited treatment options. Pelabresib demonstrates activity, and particularly from an anemia perspective, as monotherapy. On slide 36, you will see, but it also demonstrates spleen volume reduction. Again, in the relapse refractory setting, 18% SVR, 35% at week 24 in the non-transfusion dependent. That's the primary endpoint in this group. If you look at all the patients together, the SVR 35% was 11%, 25% SVR of 31%. This is an endpoint that is increasingly being recognized by the FDA as a valid endpoint in the second-line setting, and it is meaningful to patients to have even a 25% or greater reduction in your spleen volume as a second-line agent. Again, demonstrating activity of pelabresib as monotherapy in the second line from an anemia perspective and a spleen perspective, and on slide 37, symptom improvement. I treated many of these patients. I will tell you that they felt significantly better in a rapid fashion with a TSS 50% of 28% and a median TSS% change of reduction of 40%. This is a very significant symptom improvement, particularly in the face of JAK inhibitor failure. Slide 38 demonstrates bone marrow fibrosis improvement. Again, as monotherapy in the JAK inhibitor failure setting, it's about 22% of patients had at least 1 grade reduction. 71% or 5 out of the 7 patients also had improvements in hemoglobin, and 47% or 14 out of 30 patients that had grade 3 bone marrow fibrosis at baseline, and 19% with grade 1, 2 fibrosis at baseline had bone marrow fibrosis worsening. Significant improvements across the board on multiple aspects of the disease, even with monotherapy. Of course, our expectations would be less in the relapsed refractory setting and even less with pelabresib alone. Nevertheless, there is activity of the agent as a single agent. Slide 39 moves on to Arm 2, which is a suboptimal responders to ruxolitinib. I've highlighted it in the red box. These are the patients, many of them are out there in the community, receiving ruxolitinib but have lost response or had a suboptimal response, never enjoyed full response from a spleen or symptom benefit. Again, they're stratified by transfusion, dependent or independent. Slide 40 shows you the anemia responses with this add-on strategy in Arm 2. The circles demonstrate when the patients received transfusions. The graph nicely makes the point that the frequency of transfusions were significantly reduced with the combination of pelabresib added to their current and steady dose of ruxolitinib. The conversion rate from transfusion dependence to independence is 36.8%. That is rather remarkable. The treatment, the transfusion independent duration was 37 weeks. The median time to transfusion independence was 66 weeks. We're seeing an effect on erythropoietin, a positive effect on erythropoiesis with the addition of salvage pelabresib to a steady dose of ruxolitinib. In slide 41, I'm showing you spleen responses with the add-on strategy. Here we're seeing week 24 SVR, 35% in all comers of 17%. In the non-transfusion dependent, that looked a little bit better at 21%. Again, SVR, 25%, which is still meaningful in the second line setting, is 26%. You can get a sense of the spectrum of responses by these waterfall plots. These are not small responses. The best reduction in spleen volume shown on the right demonstrates a 31% SVR, 35% at any time. We're salvaging these responses despite initial suboptimal response with ruxolitinib. Slide 42 shows symptom improvement. Again, TSS 50% at week 24. In all comers, 38%, and in non-transfusion dependent, 39%, with a median reduction of 46%, 48%. Slide 43, again, is going back to biomarkers, making the point that this drug or combination of ruxolitinib and pelabresib has effect on biomarkers that can associate and correlate with clinical outcome measures. If you look at the circles on the left, I'll try to talk you through this. 40% of the SVR 35% responders had a JAK2 V617F VAF reduction of 20% or greater and/or bone marrow fibrosis improvement. The numbers I think that are most interesting is the numbers where the three circles in each category overlap. 8 patients enjoyed both SVR 35%, JAK2 reduction, and bone marrow fibrosis reduction. In each case, these were patients who were treated in Arm 3, in the combination up front, making the point that one should not wait to try to introduce drugs too late in the disease course. As Dr. Hobbs pointed out, that's probably not a winning strategy in treating patients with myelofibrosis. The fact is that in each case, whether it's TSS50 or anemia response, the trifecta of clinical outcome, JAK2 V617F reduction, and bone marrow fibrosis reduction was met in each case in Arm 3, in the combination used upfront, the strategy that is being moved forward in the randomized Phase 3 setting. I'm gonna move to slide 44. I alluded to this earlier, a very innovative, I think, very interesting, and novel biomarker of disease response in myelofibrosis, first demonstrated here with pelabresib and presented by Joe Scandura at ASH in New Orleans in December of 2022, demonstrating distancing of megakaryocytes, a pathognomonic feature of myelofibrosis with pelabresib therapy. You can see 2 patients, patient A and patient B, with staining for CD61, which stains for megakaryocytes. There's an abundance of megakaryocytes, and they cluster in this atypical fashion. At week 24 in these demonstrative patients, you can see significant reduction and distancing of the megakaryocytes, almost moving towards the normalization of a histopathologic picture of the bone marrow. You can see on the right, that there's even a correlation between this de-clustering effect that's seen in the bone marrow with combination therapy, pelabresib and ruxolitinib, which is statistically significant at week 36 and beyond in terms of distancing of megakaryocytes and spleen volume reduction of 35% or more. Very importantly, tying in correlative science with clinical outcome measures. Slide 45, I think very nicely makes the point that we know that the BET inhibitor affects many different aspects of the disease biology, NF-κB, c-MYC, TGF-beta, all pathways that are relevant and upregulated in myelofibrosis. What we're showing you here are select cytokines that are reduced, that are NF-κB regulated and reduced with the combination of pelabresib and ruxolitinib, as well as an association with the downregulation of those cytokines with spleen volume reduction, which is on the Y-axis in each case. An association between reduction in plasma levels of these cytokines, these inflammatory cytokines that are pathologically upregulated, and many of which are NF-κB mediated, and a spleen outcome measure at 24 weeks. Slide 46 is the summary. I think in summary, that inhibition is a rational approach. It's supported by robust preclinical data. The combination of pelabresib and ruxolitinib is clinically active, as demonstrated in this Phase 2 setting. We have deep and durable spleen and symptom data in the JAK inhibitor-naive setting, that's Arm 3. Evidence of salvage in spleen and symptom in the add-on strategy, that's Arm 2, and single-agent spleen symptom and anemia activity in the relapsed/refractory setting, that's Arm 1, and it's a well-tolerated therapy. It's easy to manage. There's low-grade GI toxicity. This is not a major reason for discontinuation. Importantly, as Dr. Hobbs pointed out, cytopenias, which can be limiting to the treatment of patients with myelofibrosis, were reversible and rarely led to discontinuation with this combination. That is one of the, I think, the important points in terms of the ability to translate this therapy into the commercial space and into the clinic. The ease of administration of 125 milligrams, 2 weeks on, 1 week off, that allows for the recovery of platelets if they're to decline during that holiday. The correlative evidence of biologic disease modification is there. There's bone marrow fibrosis reduction in a third of treated patients, and 38% of treated patients had a 20% or greater reduction in their driver mutation, as well as early evidence of megakaryocyte declustering and distancing that was associated with spleen response. I would personally label this as a paradigm shift, in which the MANIFEST-2 now is a Phase 3 study exploring the addition of pelabresib to ruxolitinib versus placebo and ruxolitinib in JAK inhibitor-naive patients with myelofibrosis, in which we're anticipating the readout in October. This would be a very exciting step forward for the field in myelofibrosis. I'll leave you with Slide 47. This is my own personal 3-year outlook for myelofibrosis, this is what it could look like in the future, in which platelet counts determine, in many respects, the initial treatment approach, with thrombocytopenia, for the most part, being owned by pacritinib. For those patients that would normally get ruxolitinib, the ability to add pelabresib as a combination strategy upfront to deepen the spleen symptom, potentially anemia response, and modify the disease at its core for better, longer-term outcomes. Momelotinib may get approved, but it's not approved at this point for red blood cell transfusion-dependent. We don't know whether the label will be for stipulate for second-line, or it will be agnostic to line. Of course, there's fedratinib, and as Dr. Hobbs pointed out, luspatercept, the active and ligand trap, that can also be added for red blood cell transfusion-dependent patients. One can even see on the right, in the second-line setting, many different options and sequencing JAK inhibitors, but also the potential to add pelabresib based on Arm Two data to ruxolitinib if the response is deemed suboptimal by the, by the treating physician. One can see a paradigm shift in the treatment of myelofibrosis to combination therapy and even the potential for salvage therapy using pelabresib, a rational pan-BET inhibitor in myelofibrosis. With that, I thank you. I will turn it back over to MorphoSys. Thank you, John, for this great presentation. I'd like now to turn the call over to Tim Demuth, our Chief R&D Officer, who will tell us more about the paradigm shift, through our Phase 3 MANIFEST-2 study of pelabresib in myelofibrosis and our plans to expand the asset in other myeloid diseases. Tim, please, over to you. Thank you, Jean-Paul. The Phase 3 MANIFEST-2 study is our number one priority. MANIFEST-2 is a global, multicenter, double-blind study of patients who were naive to JAK inhibitors. Patients were randomized one-to-one to pelabresib in combination with ruxolitinib or placebo plus ruxolitinib. Recall that after we acquired Constellation, we optimized the MANIFEST-2 study by increasing our target enrollment from 310 to 400 patients. In the end, we randomized 431 patients. The primary endpoint of the study is the proportion of patients who achieve a 35% or greater reduction in spleen volume at week 24, known as SVR35. Reduction in spleen size is used as a clinical endpoint in myelofibrosis, as we heard from Dr. Hobbs, because spleen enlargement causes significant pain, abdominal discomfort, and is associated with disease activity. The key secondary endpoint of the study is the proportion of patients achieving a 50% or greater improvement in Total Symptom Score, known as TSS50. This is measured by the Myelofibrosis Symptom Assessment Form or MF-SAF at week 24. As we saw with Gail's story earlier, patients with myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, bone or joint pain, fever, and weight loss. The MF-SAF is a validated tool specifically for myelofibrosis patients that can track changes in these symptoms. As Jean-Paul mentioned earlier, we completed enrollment of the MANIFEST-2 study ahead of schedule. We believe this underscores the enthusiasm of investigators and treating physicians for the pelabresib, ruxolitinib combination therapy, reflecting the dire need for new therapies to treat myelofibrosis. Based on the body of data, which Dr. Mascarenhas just reviewed, our confidence in pelabresib and the Phase 3 MANIFEST-2 study is high. Right now, we are laser-focused on delivering results on the MANIFEST-2 study by the end of 2023. That said, we're also exploring pelabresib's potential in treating patients with other myeloid diseases, including lower risk myelodysplastic syndromes, also known as MDS, and essential thrombocythemia, also known as ET. Recently, at the ASCO and EHA annual meetings, we presented results from Arm 4 of the Phase 2 MANIFEST study. This arm of the study is exploring pelabresib as a monotherapy in patients with high-risk ET, who are refractory or intolerant to hydroxyurea, the chemotherapeutic agent most used to treat the disease. The primary endpoint of this arm of the study is confirmed complete hematologic response. The secondary endpoints include confirmed partial hematologic response and symptom improvement, as evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form, or MPN-SAF, the validated tool that can track symptom changes in MPN patients. The results from Arm 4 of the MANIFEST study suggest potential clinical benefit with pelabresib monotherapy in this ET patient population. Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time, without incurring grade 4 or 5 treatment-related adverse effects. 90% of patients had a complete or partial hematologic response. At the data cutoff, 14 of 20 patients were still undergoing treatment. Importantly, an early normalization of platelet count was achieved in many patients. Additionally, white blood cell counts and hemoglobin were stable throughout treatment. This shows that pelabresib monotherapy can normalize platelet counts without causing anemia or thrombocytopenia. Like patients with myelofibrosis, ET patients can experience a variety of symptoms that impact their quality of life. These include, but are not limited to, tingling or burning in the hands and feet, itching, weight loss, weakness, headaches, and dizziness. The data from the MANIFEST study show that half of the patients had a 50% reduction in total symptom score from baseline at any time. By week 12, median total symptom score had been reduced by 31%, Symptom reduction was observed across all domains of the MPN-SAF. These proof of concept results support the potential clinical benefit with pelabresib in other myeloid diseases. In 2023, we will remain focused on pelabresib in first-line myelofibrosis, delivering the Phase 3 MANIFEST-2 results by the end of this year, and simultaneously preparing our regulatory filings in the U.S. and Europe. Beyond myelofibrosis, our next step is to continue to assess the efficacy and safety of pelabresib in lower risk MDS and ET. Following the outcome of these further assessments, we will then determine our Phase 3 development strategy. Despite available therapies, there is still a significant medical need in MDS. Patients experience low response rates and inconvenience with currently available treatments, requiring frequent blood transfusions or injections. We plan to assess pelabresib in lower risk MDS, with the goal of having a Phase 2 study up and running by 2024. For ET, we will continue our evaluation of pelabresib in this disease area based on the data derived from the Phase 2 MANIFEST study. We are committed to unlocking the full potential of pelabresib. We will continue to focus our resources in areas where we can have the greatest impact for all stakeholders. With that, I will now turn the call back over to Jean-Paul. Thanks, Tim. Before we go into Q&A, I'd like to conclude with a few words. With pelabresib, we have the opportunity to bring a foundational first-line treatment to patients with myelofibrosis, with the potential to improve the standard of care. Based on the body of data we have presented thus far, our confidence in pelabresib and the Phase 3 MANIFEST-2 study is high. We continue to be laser-focused on delivering the top-line data from this trial by the end of this year. Beyond myelofibrosis, new proof of concept data in ET provide evidence of the potential clinical benefit of pelabresib in other myeloid diseases. We will continue to explore its use in lower risk MDS and ET. Very importantly, we are well-financed to deliver on our priorities, and we look forward to the future. With that, we'll now start the Q&A portion of the call. Julia, over to you, please. Thank you. As a reminder, you can submit your questions through the chat function of the webcast platform. The first question is from Jason Butler, from JMP Securities for Dr. Mascarenhas. John, what benefit would you need to see from MANIFEST-2 to give confidence that pelabresib will be practice-changing? Are the results from Arm 3 of the MANIFEST-2 study of the MANIFEST Phase 2 study the right benchmark? I would say yes. I think that the data that we have so far that we've seen from Arm Three of MANIFEST-2 is what we wanna see. We, you know, we wanna see synergy both in terms of clinical activity and response in spleen, symptom, the anemia responses that we reviewed, and then this evidence of disease modification. Importantly, the ability to try to correlate those markers, whether it's reduction in bone marrow fibrosis, modulation of the driver mutation, with outcome measures like spleen and symptom burden. The endpoint that I'm also very interested in the Phase 3 setting, which I think will be important and convincing as we roll the drug out or as the drug is rolled out into the commercial space and into the community setting, which many myelofibrosis patients are treated, is durability of response. That was demonstrated in large part with the data I showed you from the follow-up Arm 3 EHA presentation. I think what will be most telling, and most importantly, in a prospective comparative fashion, where you have one arm, which is ruxolitinib alone, and the experimental arm of the combination. The durability of response and extension of treatment, I think is really important and would provide additional confidence in introducing the combination up front in the community setting. Perfect. Thank you. There's a follow-up question on that, a bit more specific. You mentioned the megakaryocyte clustering. What data are available to support the impact of this biomarker on disease prognosis? Are there any data available, and are academic centers evaluating this biomarker routinely in clinical practice? Important question. Very important question. I think To me, the biomarker data that was presented by Dr. Scandura is very provocative and novel. Of course, things that are provocative and novel always get a lot of attention and are exciting, but are meaningless unless it's followed and developed in the context of what we can expect in terms of changes in megakaryocyte distancing or clustering with single agent ruxolitinib. There are ongoing efforts in within the academic community to better contextualize that data in order to understand what the significance of it is. This was, I think, hypothesis-generating and intriguing data, the onus is on us as the academic community to validate and to substantiate that those findings are particularly meaningful in the combination of pelabresib as combination therapy, and importantly, correlating as we began to do with these clinical outcomes. More to come. Yes, I mean, I'm intrigued by that, and I'm anxious to see that data unfold. There are definitely ongoing projects to better understand megakaryocyte clustering and distance in multiple settings and treatment settings. Thank you. Also a question for our KOLs, John and Gabby from Derek, from Wells Fargo. Would you expect to use pelabresib with any JAK, meaning Rux, VONJO, or momelotinib, regardless of there is data from a trial? Why or why wouldn't you use that? If not, what level do you need to see, just safety data, full-blown efficacy data? Gabby, why not, why don't I let you have a chance at answering? Yeah, that's a great question. I mean, I think that, you know, following pure science, of course, you would have to have clinical trials with the other JAK inhibitors to know if there's safety and efficacy in the combination. I think in clinical practice, ruxolitinib is so entrenched in our armamentarium and our algorithms for use, that I would be surprised if ruxolitinib becomes, is not the first-line agent that is utilized. I think for the most part, ruxolitinib will be the drug that is used as the backbone in combination with pelabresib or other agents if they get approved. That being said, I mean, I'm sure there's going to be some scenarios where a patient, especially for add-on, is maybe on their second-line JAK inhibitor. In clinical practice, I'm sure that some practitioners will utilize the combination with pelabresib, even though it hasn't been studied. I don't necessarily think that we need to see combination studies, in order to start using it that way. Even I don't know if, John, you have any other take on that? I would agree with you. I would be very interested to see some, you know, limited, but maybe Phase 2 data demonstrating safety and efficacy of adding pelabresib to momelotinib, to pacritinib, to fedratinib. I would have no reason to think that they wouldn't be functionally effective together. In fact, there may be some distinct advantages, as some of these other agents also have, you know, non-JAK inhibitor targets like IRAK1 or ACVR1. One could see synergistic effects that may be even more impressive with ruxolitinib. I agree, the combination moving forward in the bulk of the patients will be Rux plus Pela. Perfect. Thank you. Then there's a question to the MorphoSys management, from Derek. Can you discuss the powering of the MANIFEST-2 trial, and what do you need to hit on TSS50 for statistical significance? Yeah. Hey, Derek, this is Tim. First and foremost, we're super confident in this study design and the way the study is powered. Recall, we'll have data by end of this year, and also recall that we made a number of enhancements to the trial when we took over the study from Constellation, increasing the sample size from 310 to 400 patients. We feel very, very confident that the study is powered for success. Second of all, we have, and John has beautifully reviewed stats, Phase 2 MANIFEST data. We have seen very strong data in that arm 3 in first-line patients with SVR35 at week 24 and 68% of patients, TSS50 in 56% of patients. I think that's additional important piece of context is that MAIC analysis, that also Dr. Mascarenhas referred to, really demonstrating that we have at least 12 percentage points delta in that TSS50 over a historic Rux control arm. Based on discussions with the regulators, we know that the expectation is to win on SVR35 and also to win on the total symptom score. Of course, we know from experience that regulators will look at the totality of the data. Again, great confidence on making it on both endpoints, since we powered the study appropriately. Thank you. There is a question from James Quigley from Morgan Stanley. What proportion of first-line MF patients are treated in the community versus in academic centers? What kind of what key novel endpoints are being measured in the MANIFEST-2 study, which could support the bone marrow fibrosis score in terms of disease modification? How receptive do you think the community physicians will be to these novel endpoints? Maybe Gabby, John, that's a question for you. I'll let John comment as well, I can start with some of the, some of the parts of your question, and maybe you can repeat some of them. I think the majority of patients are probably initially treated in the community. I don't have the numbers specifically. One of the things that I was gonna add is, you know, in the community, utilizing medications such as ruxolitinib, for example, has been easy because it's a well-tolerated medication, doesn't have a lot of side effects, et cetera. In thinking of the uptake of a new treatment like pelabresib, I think that if we can demonstrate that it's an easy-to-tolerate medication, which I think the studies have shown, and has durable response, and also helps to improve easy-to-see and measure endpoints such as splenomegaly and anemia, I think that that is an easy, those are easy endpoints to demonstrate to community practitioners to help with the uptake of pelabresib in the community. I think, you know, if the drug required lots of modifications, had a lot of specific toxicities and a lot of dose modifications, et cetera, then I think that it would be harder to get community practitioners that aren't that comfortable with myelofibrosis to utilize it. To show them that, you know, those very impressive spleen volume response assessments, as well as improvements in hemoglobin, I think those are easy sells. For academicians, et cetera, talking about, you know, morphology changes, variant allele fraction changes, those other things, that makes it exciting for us in the academic centers to start thinking about the combination. I don't necessarily know that we need to have that be part of the pitch to the community, Doc. I think, you know, it sort of depends on the audience. Perfect. There is a question for the MorphoSys management. Can you comment on regulatory timelines? When would you expect an approval in the U.S. and/or in Europe? We obviously stay very focused on generating our Phase 3 results, which we announced to be released at the end of the year. Of course, in the meantime, we start preparing for the filing, and that's a work which takes a lot of steps. Obviously, also, we will put the same momentum and execution excellence in terms of this preparation, and we will submit in time, as soon as possible, to make this product, pelabresib, available to the patients as soon as possible because of the high unmet need. Being more specific, assuming usual timelines, we're gonna assume filing in 2024 and approval in 2025, we will guide more precisely on those one later on. Thank you. There's a question from James Gordon for Gabby. James Gordon from JP Morgan. What is the minimum benefit on TSS50 that you would consider clinically meaningful? Good question. I think that that is one good example of how clinical trial endpoints are just that, really, they're clinical trial endpoints. Of course, having patients have an improvement in symptoms is critical, you know, and for regulatory endpoints in clinical trials, we wanna see, you know, half of the patients having an improvement in them or having a 50% reduction in the TSS. In clinical practice, however, the actual percentage, I don't think is as critical. You know, it's wonderful to see with pelabresib and in clinical trials that there is such a significant increase in or such a significant decrease in symptoms. When you're sitting in front of a patient, it's hard to quantitate really, you know, if they have a reduction in itching, for example, from 10 to 9, is that meaningful or not? It's really what the patient in front of you is telling you. It's not something that's as precise and quantitatable. I mean, I certainly, as a myelofibrosis doctor, will keep track of their Myelofibrosis Symptom Assessment Form or the MPN Symptom Assessment Form. It's really difficult to say, you know, a TSS reduction of this% is meaningful, whereas this other one is not. You know, if I have a patient that has debilitating itching, and they tell me that they can now take a shower, that's a meaningful endpoint. It's hard to put that in a%. It's not that I'm not trying to answer the question, but it's just hard. You know, the quantification of symptom improvement is helpful globally to keep track of your patients and obviously for regulatory endpoints, 'cause you make something quantifiable that's usually subjective. As the practitioner, I think just seeing that, like I said, you know, your patient had a symptom, and now that symptom went away or is significantly improved, where they can now do things that they couldn't do before, that's really where it's meaningful. Thank you. There's a question for the MorphoSys management. How do you view pelabresib compared to other BET inhibitors? Do you see any differentiation potential? I think it's very clear that pelabresib is a very advanced molecule. We're talking late-stage development. We're talking data before the end of the year. I think a comparison really would not be very fair. I think it's very clear from the presentations from Dr. Mascarenhas and Dr. Hobbs that really the tolerability profile of pelabresib in combination with ruxolitinib really gives us a lot of excitement for a potential serving patients with myelofibrosis. Thank you. Here's a question. I think it was already partially answered, but I still wanna read it. To the KOLs, from a clinician's point of view, will a community oncologist have any difficulties managing pelabresib when adding it onto Rux? Maybe I'll complement what Dr. Hobbs has said. I think not. I think one of the advantages of pelabresib is its ease of administration. As an oral agent that's dosed at 125 milligrams for 2 weeks on, 1 week off, is thankfully not a complicated regimen and allows for recovery of thrombocytopenia, if that is potentially limiting. I don't think it would be hard to adapt this in the community setting. As you know, as you saw from the safety data, it's not limited by a lot of hematologic or non-hematologic toxicity. I think, as Gabby pointed out, you know, rightly so, is although we pay a lot of attention in the obviously, so in the clinical trial setting, in terms of% and thresholds, that make a study positive or negative based on statistical planning, the reality is, in the clinical setting, particularly in a busy context of a practitioner in the community, what they're looking for is gratification and improvement, and they're not quantifying it in the way that we're doing in these trials. I can tell you that when you have the combination in place, the symptom benefit is quite significant. The spleen reduction is quite rapid and deep. The perception by the practicing physician, which will be appreciated in the community, is very active combination without a significant price tag of toxicity. I do think it would translate very neatly into the community setting. I think that you will probably have a range of adapters, early adapters and late adapters to the field. Those people that practice with the combination therapy approach in oncology and appreciate that aspect and, as Gabby pointed out, have a, you know, sense of myelofibrosis and the, and the natural history of the disease, would probably be more inclined to pick up the combination up front. You will, of course, get those practitioners that will continue to treat with ruxolitinib and may add pelabresib based on Arm 2 data, you know, to salvage the response if it's suboptimal. I think you'll see a myriad of uptake in the community. As Gabby pointed out, rightly so, you know, the onus is on. It will be on MorphoSys and the rest of the community to educate the clinicians in the community to understand the nuances and benefits of combination therapy, particularly using the combination early on, which we saw the best results in Arm 3, and that's gonna be paramount to message. Thank you. There's a question to the MorphoSys management from James Quigley at Morgan Stanley, probably, for Tim. How important is it to achieve a statistically significant benefit on the TSS50 score? Is there a scenario where MANIFEST-2 hits on SVR35 but misses on TSS50? Do you think pelabresib would still be used in the first-line myelofibrosis setting? Yeah, thanks, James. This is Tim. Based on discussions with regulators, the assumption is clearly we need to win on SVR35 and TSS50. That means positive p-value. Of course, we know from experience that regulators will look at the totality of all data. As we also mentioned earlier on, we increased the sample size from 310 to 400 patients, enrolled 431 patients. We feel very confident on making also the p-value on TSS50. Okay. Thank you. Next question is, selinexor and navitoclax are running Phase 3 studies in first-line MF as well. How does pelabresib compare to selinexor and navitoclax? Well, actually, selinexor is actually in a much better, much earlier stage, so it's not in Phase 3 in first-line myelofibrosis. The only other regimen investigated in combination in first line is indeed the AbbVie asset. I think we were all expecting to see some data lately at some conferences, which we didn't see, so, you know, we can't really comment on that. What we know is that we are making progress, and we have been beating our timelines and at the same time providing strong data. We keep focused on our own program, and we are confident in its outcome. Another quick one for Tim. If you talk about Phase 3 response till the end of the year, is there a special month that you can point to? I think end of the year is already a very major acceleration which we just announced earlier this year. I think at this point in time, we leave it at the end of the year and hope for a very good news by the end of the year. Thank you. We have a question on, probably relating to, Gabby, what you said on other endpoints, and a question also on the trial. Are you looking for S benefit in the trial as well? I'm sorry, I missed the part of your question. I heard about endpoints, but then what did you say the last part? The question was whether in trials, OS is looked at, and specifically in MANIFEST, OS or MANIFEST-2, OS is an endpoint. Probably it's a question to be answered by the management team and also by the KOLs. Tim, do you want to start? Yeah. Maybe I'll start very quickly. Yes, we are looking at overall survival as part of the MANIFEST-2 study very clearly. At the same time, it's also very clear, particularly for patient stats, there will be very few OS events at the time of the primary analysis. That's of course, a data points that we will follow over time. Okay, let me quickly go through that. There is a follow-up question on something that I think was already partially discussed. How would you think about using pelabresib with other JAKs, and do you think new agents could displace Rux in first line? That's a question from Rajan, from Goldman. Looks like it was addressed already, you know, with by our KOLs on the Rux prominence right now, but obviously we don't exclude any potential exploration of combinations in the future. You know, we'll follow the data from other companies and see what would make sense. We start by the beginning. Rux was obviously the obvious and expected choice because of the regular regulatory situation and the standard of care, but it doesn't stop here, I would say. Perfect. I mean, we talked about that as well. There was a more high-level question on the disease modification. What is the best measure in your view? Is it bone marrow fibrosis? Is it anemia improvement? What is the best measure for disease modification? Probably for John or Gabby, no? I'll try to answer that 'cause it's a difficult question to actually answer. You know, we don't have a uniform consensus agreement on what actually defines disease modification, and it's one of those things where you know it when you see it, but sometimes it's not so obvious. I think that all of those things are elements of disease modification. If you have reduction in bone marrow fibrosis, reduction in JAK2 V617F allele burden, distancing of megakaryocytes, improvements in cytopenias are all elements of disease modification. One could argue spleen reduction is an example of disease modification and symptom improvement by virtue of reduction in cytokine expression analysis. I think they're all elements and aspects of disease modification. For me, it's gratifying when they start to overlap and when they start to correlate. When you start to see... Again, I hope I conveyed to the audience that we do see glimpses of this with the MANIFEST Phase 2 data. When you start to see the associations between, particularly the multiple overlaps between fibrosis reduction, driver mutation reduction, and anemia responses, spleen responses, symptom responses. You know, that to me is where it becomes more meaningful. I think if we can some of the endpoints, I think that will be meaningful, you know, or one of the endpoints, as I stated before, that I'm very much looking forward to in the Phase 3 results, is disease course modification. We talked about disease modification, but it's the course of the disease that we ultimately want to modify. What's one readout that would be, I think, meaningful to me would be a longer median duration of therapy in the combination arm versus the single-agent arm. That would be a meaningful secondary endpoint. It may not be the approval endpoints, but to me, that would be a disease course modification endpoint that's actually meaningful to a patient. Because reduction of fibrosis is not appreciated by a patient unless it actually predicts for an outcome measure that matters, like progression-free survival or overall survival. I'm hoping that MANIFEST will shed light and bring light to that. It's a very actually, academically, and for, not just for pelabresib itself, but actually for the whole field, it's a very important opportunity to get more insight into the disease biology and contribute to advancing disease understanding. Thank you, John. Maybe we have time for one last question, to MorphoSys. Given that momelotinib is better for anemia, do you think pelabresib plus momelotinib perhaps prevents the need for transfusion in the early cycles? Yeah, this is Tim. I think that's a very reasonable question. I think Dr. Hobbs very nicely showed us that cytopenias are, of course, a sign of the disease, number one. Number two, Rux is known to cause significant anemia. We've seen that in the COMFORT studies. At the same time, in the recent JCO publication of our MANIFEST study, John Mascarenhas reviewed some of this data as well, we actually see that Pela improves on anemia. If you now have a JAK inhibitor, such as momelotinib, that is not as harsh in terms of causing cytopenia, I think that combination would be a very rational one. In addition, I think there is obviously a lot of mechanistic synergies between a BET inhibitor and a JAK inhibitor, very generically. Why not combine, pelabresib in the future with another JAK inhibitor as well? Certainly a very logical thought. Perfect. Thank you very much. Thanks, everybody. I think with that, we come to the end of the call. Thanks, Gabby and John, for these, great insights. Thanks, everybody, for joining the call. Have a good day, and goodbye.