Yes. All right. Good evening, and welcome to all of you in person here in New Orleans, and of course, those of you who are participating via webcast. It's really wonderful to be here again in person this year. We have a busy agenda, let's begin. Let's start with the next slide. I think one slide back. Yep. Genmab has a science-anchored and innovation focused culture, and collaborations and partnerships have always been part of our DNA. During tonight's presentation, we will reference some of the products being developed under these strategic collaborations, this slide actually acknowledges those relationships. Let's move to slide three. We'll begin this evening with a review of the excellent progress we made this year as we progress towards our ambitious 2030 vision. We are fortunate to have with us here Professor Torben Plesner, who will present the preliminary dose escalation data from the first in-human trial of HexaBody-CD38, which was also presented at ASH yesterday. We will then move on to some of the highly anticipated epcoritamab data that was presented at this year's ASH. For this, we are very happy to have with us Dr. Lorenzo Falchi of the Memorial Sloan Kettering Cancer Center in New York. We will then conclude our data review with a look at the preliminary GEN1042 data that was recently presented at ESMO IO in Geneva. To share a summary of this data, we are very pleased to have a pre-recorded presentation by Dr. Ignacio Melero from the Clínica Universidad de Navarra in Spain. Finally, we will have a brief discussion of our key 2023 priorities, and we will conclude the evening with what I'm sure will be a very lively Q&A session. Let's now begin with a reminder of the progress Genmab has made, both in the past year and since we last met in person, believe it or not, in 2019. Next slide, sir, please. When we met in Orlando in 2019, we were concluding a momentous year, celebrating our 20th anniversary and our extremely successful IPO in the US. We have moved from strength to strength since then, expanding and maturing our product pipeline and further solidifying our already very strong financial foundation and evolving our organization for continued success. This consistent and solid track record is possible because of a of a world-class team of unstoppable colleagues who are driven to improve the lives of patients through innovative and differentiated antibody therapeutics. Now let's move to the next slide and look at some of the, of the events from the past year that have further built on our track record of success. Next, slide. As you just saw, we have experienced significant growth over the past few years in all areas of our business. Based on this progress, we determined it was time to look beyond our ambitious 2025 vision for the company to see how we can actually continue to impact the lives of patients and the healthcare community even further in the future. This led us to the 2030 vision you see here. As we noted when we unveiled this vision, the biggest change is the expansion of our focus from just cancer to cancer and other serious diseases. We know that our antibody novel assets and technologies can be applied to diseases outside of cancer. While we will continue to create and develop new treatment concepts in oncology, we will be open to other potential indications outside of cancer, with the ultimate goal of improving the lives of as many people as possible through our innovative and differentiated antibody therapeutics. We know this goal is possible because of the 6 therapies already on the market for indications both in and outside of oncology. These include TIVDAK, our first medicine on the market, which we are co-developing with Seagen, as well as five other therapies which are powered by our innovations and technology, which also provide us with our growing recurring revenue streams that we are particularly pleased about. As we have done in past years, throughout 2022, we continued to use this revenue to invest in a focused and disciplined way, both in the strategic growth of our company and in multiple business development deals and collaboration expansions, like the expansion of our successful collaboration with BioNTech. You can see some of the results of these investments in the updates to our pipeline on the next slide. Some of the most exciting developments of 2022 are related to epcoritamab. There are now three phase III studies either ongoing or announced with more in the planning. In March, the FDA granted orphan drug designation to epcoritamab for the treatment of follicular lymphoma. In April, we along with our partner AbbVie, published top-line results from the EPCORE NHL-1 study, which were subsequently presented in a late-breaking oral presentation as part of the Presidential Symposium at EHA in Vienna. These results form the basis of regulatory submissions for epcoritamab in both the US and in Europe. We recently announced the FDA accepted the submission for priority review with a PDUFA date of May 21st, 2023, write that down in your calendars. A truly remarkable year for epcoritamab, and we are hopeful that next year will be even more eventful with the anticipated potential approvals that would bring epcoritamab to people living with certain hematological malignancies who are in need of a new treatment option. Looking to earlier stage programs, we had 2 new investigational medicines enter the clinic this year with the 1st patients dosed with DuoBody-CD3xB7H4 and our latest product in co-development with BioNTech, HexaBody-CD27. This year was also notable for our data presentations. 19 total abstracts showcasing our work in hematologic malignancies were accepted at ASH, including the preliminary dose escalation data for HexaBody-CD38 and 10 presentations highlighting clinical data from Eculizumab studies, four of which are oral presentations. Also, as we will review very shortly, there was the preliminary GEN1042 data at ESMO IO. Last month, we had preclinical data at SITC, including the first preclinical disclosure for HexaBody-CD27. Earlier in the year, we and Seagen presented tisotumab vedotin data, both from the innovaTV 207 study at ASTRO and the innovaTV 205 study during oral sessions at SGO and ASCO. If you look beyond our own proprietary pipeline and include all products that leverage Genmab's innovations, there were more than 50 industry-sponsored abstracts accepted for presentation at this year's ASH here in New Orleans. A number of these involved investigational medicines that were created using our DuoBody technology. Now let's turn to a few of the 2022 highlights for these DuoBody-powered programs. Next slide. In 2012, we entered into a collaboration with Janssen to create and develop bispecific antibodies using our DuoBody technology platform. One of the products subsequently discovered and developed by Janssen is Teclistamab, a bispecific antibody targeting CD3 and BCMA. This year, Janssen announced that they received approvals in both Europe and the U.S. for subcutaneous Teclistamab, marketed as Tecvayli, for the treatment of patients with relapsed or refractory multiple myeloma. This is the second DuoBody based medicine to receive regulatory approval following the approval last year of Janssen's Rybrevant for certain non-small cell lung cancer patients. Looking ahead to what might come next from this collaboration, we have Janssen's Talquetamab, a bispecific antibody targeting CD3 and GPRC5D, which in June was granted breakthrough therapy designation by the FDA for patients with relapsed or refractory multiple myeloma, and a BLA was filed by Janssen last Friday. For both Teclistamab and Talquetamab, Janssen has posted multiple new phase III trials on ClinicalTrials.gov, including in combination with Daratumumab. Beyond this collaboration, there was also Mim8 being developed by Novo Nordisk in hemophilia. As Novo Nordisk announced during their Q3 earnings, treatment with Mim8 has now been initiated in the first phase III- study in hemophilia A. We believe that the success of these programs highlight the potential of our innovative bispecific DuoBody technology, and we look forward to seeing their future development. Next slide. It's now my pleasure to introduce our first guest speaker for the evening, Professor Torben Plesner. I'm sure you all know Torben very well by now. He played a key role in the development of daratumumab, and we are thrilled that he is here with us again this evening to present the preliminary dose escalation data for HexaBody-CD38. Torben, warm up the team and the floor is yours. Thank you. Thank you very much, Ian. Thank you for inviting me, thank you for being here tonight. It's a great pleasure speaking to you about our experience with HexaBody-CD38. This is a next generation CD38 antibody, as you know. I'm presenting this on behalf of my co-investigators. This is a truly international collaboration, you can see here the mode of action of HexaBody-CD38, which looks very similar to what you know from daratumumab, there are certain differences, the most important being that the hexamerization of the antibody results in a very much enhanced complement activation and a cytotoxic killing by this method. Another aspect is that the inhibition of formation of adenosine, the enzymatic activity of CD38 is enhanced by CD38 compared to daratumumab. Otherwise, you can see the same modes of action as you know from Daratumumab. The study is a standard phase I dose escalation study. We have two cohorts of patients. One group that is naive to CD38 antibody therapy. That's about 1/3 of the patients, and 2/3 of the patient had prior CD38 antibody exposure. But there was a rule for a washout period, and most of the patients, 2/3 of the patients that had been exposed, had a washout period of more than six months, which is what is needed to get rid of the last Daratumumab in the body. We dose escalated from 0.2, 0.6 milligrams per kilo up to 24 milligrams per kilo stepwise and ended up with a recommended phase II dose of 16 milligrams per kilo. That was one of the primary goals of the trial to find the right dose for an expansion phase and phase II study. The follow-up period for these patients is short, only 7.3 months. I'll present to you some of the parameters, PK parameters, pharmacodynamics, and antitumor activity. These are the characteristics of the patients. The median age was 65 years with a range from 45 to 84. A decent performance status, measurable disease for all of them. As you can see, the patients that had been exposed previously to CD38 antibody was about two-thirds of the patients, and one-third were naive to CD38 antibody. The median time since last anti-CD38 treatment was 9.5 months. The patients received a median number of cycles of 4, ranging from 1 to 17. The median duration of treatment was 3.5 months. 50% of the patients had dose delays due to treatment emergent adverse events. The reasons for discontinuation were mostly due to biochemical disease progression or clinical disease progression, with 54% and 13% of the patients respectively. Few patients stopped the study because of adverse events. Here you can see the safety, the treatment emergent adverse events. On the left-hand part of the diagram, you see all grades of adverse events occurring in 10% of patients or more. On the right hand, you see grade 3 and 4 adverse events. You can see clearly that there is a low number of high-grade adverse events, and the adverse events are mostly infusion-related reactions that we are used to and can manage. Then comes neutropenia and anemia. One of the patients had a dose-limiting toxicity at 24 milligrams per kilo due to neutropenia and sepsis and thrombocytopenia and appendicitis, and that was the reason for going back to 16 milligrams per kilo as the recommended phase II dose. We saw no cases of tumor lysis syndrome and of course no cytokine release syndrome. No treatment emergent adverse events that led to death. No anti-HexaBody-CD38 antibodies emerged. Next part is the response to treatment. The patients are divided in those that were CD38 antibody naive and those that had been treated previously with CD38 antibody. 5 and 16 patients were ready for assessment of the response at this time point. The clinical benefit rate was 60% for the non-exposed patients and 19% for those that had been exposed. What's really interesting is that you can see among those that had not received CD38 antibody previously, you had 2 patients in complete remission. For the previously exposed patients, their responses were more modest, with 2 patients with minimal response and 1 patient with a partial response. This is also depicted in the waterfall plot you can see here. On the right-hand side, you see the 2 patients in complete remission, and on the left-hand part, you can see 4 patients that had progressive disease as their best response. Interestingly, we saw clear evidence of activation of complement by this antibody immediately after infusion of the antibody. There was a drop in the C2 and CH50, which were the markers of complement activation. Soon after, the level of complement factors returned to the baseline, showing that there was no depletion of complement factors, only a temporary consumption that was intended by the construct of the antibody. The conclusion, conclusions are that this first-in-human study of dose escalation with HexaBody-CD38 has shown a tolerable safety profile. The most common adverse events are infusion-related reactions and hematological events. No tumor lysis syndrome. No DLTs up to the dose level of the recommended phase II dose, which is 16 milligrams per kilo like daratumumab. We have seen early clinical activity of HexaBody-CD38, both in CD38 antibody naive and CD38 antibody-treated patients. The biomarkers show the activity of complement activation. The ongoing expansion part of this trial will evaluate HexaBody-CD38 at the recommended phase II dose of 16 milligrams per kilo in patients with relapsed refractory multiple myeloma. Thank you for your attention. Thank you very much, Torben, and thank you for that excellent presentation. I'm sure there will be many questions here in the Q&A. Next, I would like to introduce you to Dr. Lorenzo Falchi of the Memorial Sloan Kettering Cancer Center in New York. Lorenzo is a medical oncologist and hematologist, and a hematologist, and an expert in the treatment of lymphoma. As an investigator, he's intimately involved in the development of epcoritamab. So yesterday he presented during oral sessions at ASH both the initial results from arm 6 of the EPCORE NHL-2 trial and updated data from the arm 2B of the study. We are delighted that he's here today to present a summary of the epcoritamab data that many of you have already been speaking with us about that has been presented at ASH. Lorenzo, please, the floor is yours. Thank you. Thank you for having me. Oh, there you go. I'm going to go through Well, all the presentations that were held here at ASH regarding epcoritamab couple were our presentations, some of my colleagues as well. The first I'm going to cover is a paper presented by my colleague, Dr. Tycel Phillips, looking at some post-hoc analysis of the epcoritamab monotherapy study and looking at some of the response rates in individual specific patient subgroups, including according to minimal residual disease status. As a brief reminder, this was a, albeit a single arm, very large study. Over 150 patients were enrolled in a median follow-up of over 10 months. Patients with recurrent CD20-positive B-cell lymphoma were included after two or more prior lines of therapy, and you can see the treatment schema here on the right-hand side. Epcoritamab was given weekly for the first three cycles and then every other week up until cycle 10, and then monthly thereafter until progression or an acceptable toxicity. This is the population of patients, as I said, included 157 patients. Median age was 64 years. Just highlighting some of the high-risk subgroups here, particularly the high-grade lymphomas with rearrangements of BCL6, BCL2, commonly referred to as double-hit or triple-hit lymphoma. They were certainly represented here. The median number of prior lines of therapy was three. These were really heavily pretreated subjects. Importantly, over 30%, close to 40% of patients had had previous CAR T-cell therapy. The majority of patients that had had CAR T-cell therapy were refractory or early recurrent after CAR T-cell therapy. It's very, very difficult to treat population for treatment options are really limited and outcomes unfortunately dismal. In terms of safety, epcoritamab was associated with cytokine release syndrome. As we know, this is the predominant adverse event related to this drug. This was observed in 50% of patients and by far in a way, events were grade 1 or grade 2. Very rarely did we see grade 3 CRS. Also in terms of neurotoxicity, which has always been a concern, sort of coming from the CAR T-cell experience, very limited. As you can see here on the right-hand side panel, the incidence of adverse events tends to decrease over time, partly because patients who have tolerated therapy then really don't experience additional adverse events, partly because cytokine release syndrome, it really is the dominant adverse event. Other than that, the administration of epcoritamab is really really safe. The responses were durable, as you know from top-line results. 63% of patients had a objective response, 39% of patients had a complete metabolic response. As far as the duration of response, you can see it here on the Kaplan-Meier on the right side, very, very encouraging, as was the progression for survival and the overall survival curve in the study. Here is the breakdown according to subgroup, and kind of looking at patients who were CAR T-cell naive or CAR T-cell exposed. Very reassuringly, patients who had been exposed to CAR T-cell still had a very promising complete response rate of over 30%, 34% to be exact here, including almost 30% of patients who were refractory to CAR T-cell. These are patients who have a PET scan a month after CAR T-cell and don't have a response, or sometimes at three months and don't have response or progress through CAR T-cell. Very, very difficult to treat. Among the double hit or triple hit lymphomas, also over 30% of patients had a complete response to therapy. We know that complete response is really a key ingredient for long-term disease-free survival for these patients. Here according to Lugano, sort of response of the lymphoma, patients who had a complete response, as I just said, had really an excellent prospect of medium-term outcome, and we feel that this is going to translate into a longer-term outcome. Even partial responders, which are commonly perceived as patients who have not a particularly satisfactory outcome, unfortunately here seem to do better than our sort of historical controls that we all have in our minds as lymphoma docs. And then the point about MRD negativity as it correlates with not only response but outcome for these patients. You can see that essentially regardless of the risk group to which these patients belong, if you had achieved an MRD negativity, this essentially means, checking, doing what's popularly referred as to liquid biopsy, looking at tumor DNA, in peripheral blood. No matter the risk, the risk group, these patients tend to do all very well. If you were MRD positive, obviously less well, and that's unfortunately an unmet need currently. In conclusion, I think this subcutaneous administered off-the-shelf, very potent T-cell engaging therapy continued to show really powerful activity as a single agent. This is important. Most of what's out there, particularly if the approved strategies are all combination-- almost all of them are combination therapies, really led to high rates of response in patients with otherwise very limited treatment options, very robust progression-free and overall survival figures. For patients who achieve a deep response, really promising outcomes. We really have a feeling that these patients are likely to maintain that status for a very long time. My colleague, Paolo Caimi, presented results now moving on to moving, I guess, up in the algorithm, to the second line, results of epcoritamab combined with a commonly used platinum-based salvage therapy, which is R-DHAX or R-DHAC, depending on the platinum agent that the doctors used, in patients with recurrent large cell lymphoma eligible for stem cell transplantation. This was a smaller study with 29 patients on it, with 2 steps in the dose finding phase, with 24 mg in the first sort of three-patient cohort, and then 48 mg in the subsequent patients. Epcoritamab was administered exactly in the same way that it was administered as a single agent and sort of superimposed to the R-DHAX chemoimmunotherapy, which was given for three cycles before proceeding to autologous stem cell transplantation. These were all high-risk patients with recurrent Diffuse Large B-Cell Lymphoma. Here I really point your attention to sort of the red box down there, where the majority of patients progress within 12 months of therapy. About two-thirds of them, as you know, this is the population that's currently the target, or the patients that are a candidate for CAR T-cell therapy. Importantly, there was a very high number of patients with primary refractory disease, which means disease that does not respond to frontline chemoimmunotherapy. Particularly hard to treat, unfortunately. In terms of safety, cytopenias dominated the adverse event the side effect profile of the combination. Not surprisingly, R-DHAX is a immunosuppressive therapy. The rest of the adverse event profile, with the exception of CRS, also probably attributable to R-DHAX. Epcoritamab didn't add, at least in our hands and in our colleagues' hands, particular toxicity to the overall regimen. We were able to deliver it and eventually get to transplanting the majority of patients. Here, I think a little bit more on CRS. Now in combination with R-DHAX, of course, there is a cytotoxic effect of the chemotherapy component, so not unexpectedly, some of the CRS rates were lower. Very encouragingly, again, we did not observe grade 3 and or higher CRS. All events resolved. All events resolved very quickly after a median of 2 days, and we're really sparingly used tocilizumab. Certainly, no patient discontinued therapy because of CRS. As you can see there on the right-hand side, histogram, the majority of CRS events occurred quite predictably after cycle 1, day 15, which is when the first full dose of epcoritamab is administered. As you know, epcoritamab is administered on a step-up dosing schedule. These are the responses. The in the red box in the far right there, you can see 85% of patients of the 27 evaluable patients overall responded, and the majority of them had a complete metabolic response. That's a figure you don't typically see with standard chemoimmunotherapy. In the second line, we're looking more at a maybe 25%-30%, so we're sort of doubling there the response rate. Although it's extremely pleasing to see the patients who actually went on to receive autologous transplant, all of them had an objective response, and in most cases, that was a complete response, which is the key ingredient for essentially curing the second line. Even those patients who, for one reason or another, didn't proceed to autologous stem cell transplantation had a quite interesting response rate, particularly 45% complete metabolic response rate, all of which, as I'll show you in a second, are maintained. That's a very encouraging piece of information, piece of news for those patients who cannot proceed or who do not want to proceed to autologous stem cell transplantation for a number of reasons. You can see it here in the swimmer plot. Most of the patients had maintained their response. The swimmer plot is divided into patients who did not proceed to transplant and those who did. Among those patients who did proceed to transplant, you can see all of them are either on ongoing treatment or in response. None of these patients has lost their response. For those patients who did not undergo a transplantation, including two patients who had prior CAR T-cell therapy, these were not all second line, as some of these patients were third line, I think. Most of them, essentially all but two, had maintained their response as well, and that includes the two patients who had CAR T-cell therapy previously. Progression-free survival curve, extremely encouraging, not reached and, at the, I would say 6 and 9 months mark, we're close to 80%. This is very, very encouraging for a non-CAR T type of treatment. Overall survival, even more encouraging. I don't think we're used to seeing these kinds of curves. If you think about the SCHOLAR studies, what our benchmark would be, it'd be a much lower curve. We're looking at a very promising overall survival curve here with a median follow-up that's relatively generous over 12 months. In conclusion, I think epcoritamab incorporated into a platinum-based second-line therapy really did prove highly effective. Higher complete metabolic response rate, which is what you're aiming for. Responses that were deep durable in almost essentially all patients. Progression-free and overall survival curves, very encouraging. I think importantly, this was also a feasibility study where we showed that you can really incorporate a highly effective therapy with non-overlapping toxicity into an otherwise quite intensive chemoimmunotherapy regimen. I'm gonna now talk about the two studies that we presented yesterday. The two studies were looking at subcutaneous epcoritamab in combination with rituximab lenalidomide, sometimes referred to as R- squared, in patients with follicular lymphoma. The first study here looks at patients with recurring disease. This is the study schema. You can focus here on the right-hand side. Epcoritamab was administered a little bit differently. It was given weekly for the first two cycles. Each cycle is 28 days, and then every four weeks thereafter, patients are treated up until two years or unacceptable toxicity. R-squared was given, according here to the AUGMENT protocol, which has five months of rituximab, weekly in the first month and then monthly. Lenalidomide is given, 21 days out of 28, for each cycle up to 12 months. This cohort had a follow-up of 6.4 months, and the cutoff was September this year. These are the patient characteristics. We start having a, nice sample size. 76 patients were evaluable here. Most patients had advanced disease, stage 4 disease. Over half the patients had a high FLIPI score. This is a risk score we calculate at baseline to determine the likelihood that patients will stay in remission after first and second-line therapy. Here on the right-hand side in the red box, you can see that there's a 30%-40% incidence of highly or high-risk disease. Here we defined it as primary refractory disease. Disease that failed to respond to frontline chemoimmunotherapy, not particularly frequent, but here is enriched in this population. Double refractory disease. POD 24 means patients with disease that recurred within two years of completion of frontline chemoimmunotherapy, and obviously patient refractory to the last line. Notably here, very few patients have received CAR T. In terms of safety, again, this is after a median of six cycles of epcoritamab. Adverse events of high grade that were related to epcoritamab were observed in less than half of the patients, 38% to be exact. I wanna point out we unfortunately had three fatalities, all related to COVID-19 pneumonia. I wanna really point out that this study and the next were actually all these studies, almost all the, almost in their entirety, were conducted during the COVID pandemic. This we can't forget when we think about the dose delays that were observed in over half of the patients. A lot of those dose delays, at least in our hands, were related to intercurrent COVID illness, and we were fortunate to be able to get patients through the COVID disease and resume therapy. It was not easy, it was a lot of work, but very happy to report we were able to complete therapy in most of our patients. You can see at the last line there, no patient discontinued therapy due to epcoritamab-related adverse events. The rest of the toxicity profile, other than the injection site reactions, really relates to the R-squared portion, you know, fatigue, skin rash, nausea, et cetera. Neurotoxicity, another important point, extremely contained. There was a patient that had a grade 1 neurotoxicity that resolved very quickly, possibly multifactorial. CRS, a little more in detail, 43% incidence. Importantly, no grade 3s, and also, very few grade 2 here, at 11% grade 2. Grade 2, you know, is essentially prolonged fever. Grade one means just a single or multiple episodes of fever that respond to very simple measures. Very well-tolerated. Very predictable after a median of two days after the first full dose of epcoritamab. You can see again on the right-hand side, very predictable timing, all events resolved after a median of two days. We used very little tocilizumab. You can see it here, 10% of cases. What was impressive to us obviously was the efficacy. We really observed high overall and complete metabolic response rate. Here we had 66 evaluable patients, 80% complete metabolic response rate, which is predicted to be quite a bit higher what you would expect with R-squared alone. 95% of patients on objective response. We don't have it here, but several of the partial responders did convert their response into a complete response with further follow-up. I'm very eager to see the full analysis of the full data set, which is still being analyzed. Another reassuring point here you can see, I remember I mentioned all the high-risk patient populations, response rate, particularly complete response rate, quite consistent across all those subgroups. We enriched the population with a further data cutoff, thanks to the Genmab team for working so hard to get that second cutoff. You can see that the response rate, as I mentioned, go up 96% overall response rate, 83.5% complete response rate. I'm hopeful that that will go even further up, and the duration of response is not reached. Progression-free survival is not here, but it's over 90% at six months, and that curve including accounting for those three COVID-related deaths, looks very, very promising. Again, a very promising combination, very well-tolerated. Almost all patients have a response, most of them complete, very consistent across subgroups. I didn't mention this response was achieved almost all early at the six-week time mark, so very, very quick onset of action. Very well-tolerated, no high-grade CRS. These results are the ones that form the basis for the EPCORE FL-1 study, which is a randomized study looking at R-squared plus minus epcoritamab. There was a trial and poster, progress poster that I just left, and some of you were kind enough to stop by. This is a second study in front line, same combo, same concept. These are patients with high burden follicular lymphoma, again, with the needed treatment for the GELF criteria. Epcoritamab given in a very similar fashion, weekly for eight weeks, and then monthly up to two years. R-squared given per the RELEVANCE trial, so with rituximab for six months, lenalidomide for 12. The dose of lenalidomide was adjusted per the physician discretion, and the follow-up of this study is not too long for a front line study, but still eight months is not too short either. 41 patients enrolled at the time of this analysis, again, mostly advanced disease. A good 34% of patients high risk disease, so what you would typically expect for a high burden follicular lymphoma population. Here in terms of safety, very reproducible safety profile. You can see again about a 30% high-grade epcoritamab-related adverse events. We unfortunately have had two fatalities here as well. One was a COVID-19 pneumonia, one was a septic shock. Neither was deemed related to epcoritamab by the treating physicians. Very few patients had to discontinue epcoritamab especially due to epcoritamab-related adverse events. Again, very contained neurotoxicity. Only one patient, mild event, quickly resolved. In terms of the other adverse events, I won't spend too much time because it's really the same profile that you had seen in the relapsed refractory setting. Very reassuringly did not go up significantly in the front line setting. I'll just spend one word on CRS. You can see here the incidence was 54%, so more or less the same. Again, reassuringly, no grade 3 events. This was something we paid a lot of attention to because frontline patients have an immune system that's potentially more intact, if you will. Certainly not exposed to cytotoxic chemotherapy, you know, we were eager to you know, to see whether CRS rates and severity particularly would change. We were very happy to see that no patient had a grade 3 event. This was very important. Also very reassuringly, no patient discontinued treatment due to CRS. Again, very predictable after the first full dose of epcoritamab, all events resolved relatively quickly. In terms of efficacy, 36 patients were evaluable. Almost all of them had a response, and 86% had a complete metabolic response. This is very encouraging data. If you put it in context, chemoimmunotherapy, we're looking at maybe 70%, 75% complete response rate. This is a chemo-free regimen. Definitely as effective, if not more effective than chemoimmunotherapy. Again, very promising combination here. Epcoritamab did not add toxicity to R- squared, the two toxicity profiles remain non-overlapping. Very encouraging activity. 86% CMR is something that we really like to see. Neurotoxicity, I don't wanna say it's a non-issue, but it's certainly very contained, this triple combination is also being looked at for further development and further evaluation in this front line setting. I think a word on the Richter's population. This was presented by Dr. Cater, or Cater. This was a small patient cohort, but very important. Richter's a very rare complication of CLL. 2%-5% of patients. It's very, very difficult to treat, particularly those case, Richters that occur at later in the course of CLL, particularly when chemoimmunotherapy up front fails, and this unfortunately happens quite often. Epcoritamab here was given in the same way that we saw at the beginning because this was an expansion cohort of the same study. 10 patients, in most cases, the underlying CLL was TP53 mutated. For those of you who have been familiar with this, p53 mutations come for significantly adverse prognosis in patients with CLL. These patients had a median... I don't think it's here, but they had a median of three prior lines of therapy. There's really no viable treatment option for these patients at all. One of the problems that we have in this population, we can't get them into a remission to even think about consolidation therapies. Very difficult to treat patient population. This is a look at the adverse events, perhaps a little bit more grade 2 CRS. You know, this is obviously a very small population. It's very hard to compare this incidence of CRS to the populations that I described before. Sort of diverse adverse events profile here. Not sure how many of these adverse events would be related to disease, how many would be related to treatment. I suspect the former is a little bit more likely. Little bit closer look at CRS here. nine patients had an event, but again, all grade 1 and 2 CRS. We can talk about later what that means practically speaking, because I think it's important to understand the difference between grade 2 and grade 3 CRS. And in no case, in no case this led to a treatment discontinuation. This is I think the really exciting part. I mean, six out of these patients had an objective response, and almost all of them had a complete metabolic response. This is not something I would've actually expected to see. I was very sort of excited when I was looking at these lines. It's not something that I see that often in my practice. Very difficult to treat population, very high risk, off-the-shelf subcutaneous, mostly outpatient therapy. Resulted in half the patient having a complete metabolic response. Very well tolerated in general, very manageable toxicity profile. Very eager to see continuation of the study, see how long those responses last and what the outcome of this patient is going to be. Sorry for running through all these slides, but there was a lot of ground to cover. I hope that I did a reasonable job. We can talk more about it then. Thank you. Thank you, Lorenzo, for that very inspirational presentation. It was more than a reasonable job, I think. It was actually an excellent job. Turning now to the GEN-1042 data at ESMO IO, I'm pleased to introduce a video of Dr. Ignacio Melero. Ignacio is a co-director of the Department of Immunology and Immunotherapy at the School of Medicine of the University of Navarra in Spain, and a senior researcher at the Center for Applied Medical Research, and a professor in immunology on top of that. As the lead author for the GEN-1042 abstract at ESMO IO, we are truly fortunate that he was able to film this summary presentation for you this evening. Let's start the video. Enjoy. My name is Ignacio Melero. I'm a tumor immunologist. I work at the University Clinic of Navarra in Pamplona, Spain. I'm going to present you some information that has been released in the ESMO Immuno-oncology Meeting on the safety and preliminary efficacy of GEN1042, a bispecific antibody targeting CD40 and 4-1BB in an agonistic fashion, in combination with chemotherapy and PD-1 checkpoint inhibitors in patients with advanced solid tumors. As you will see in the next slide, this was the expansion of a clinical trial that first tested the safety of this bispecific agent in a dose escalation to test the safety and the maximal tolerated dose of the agent. The first part of that trial it was communicated in the SITC meeting in 2021. The treatment was very well tolerated. There were two objective responses and a very attractive disease stabilization. That gave rise to the expansions that I'm going to comment to you. In this part of the trial, the key inclusion criteria were to have a measurable metastatic or refractory disease to monitor or resist in a good performance status of the patients with an ECOG zero to one, with adequate renal, hepatic, and bone marrow function, and no prior therapy would have been given to these patients, including PD-L1 agents. These patients are immune checkpoint naive. The idea was first to test the combination with the checkpoint inhibitor, the PD-1 pembrolizumab, and then the combination with chemotherapy, and with chemotherapy together with pembrolizumab. This was going to be tested in patients with melanoma, head and neck cancer, non-small cell lung cancer, and pancreatic cancer. A running safety cohort of 3+ 3 patients with the dose recommended by the first part of the trial was performed in order to document the safety of these potential combinations. The trial is ongoing, testing the treatment in patients with first-line melanoma, with non-small cell lung cancer, head and neck cancer, and pancreatic cancer. In this regard, the patients are receiving a standard of care checkpoint inhibitors, pembrolizumab in this case, or chemotherapy plus checkpoint inhibitors or chemotherapy. This trial is testing as a primarily endpoint the safety of the combination approach. In these expansion phases, overall response rate by RECIST 1.1 criteria and disease control rate and progression-free survival are also monitored. As you will see in the next slide, the patients that were include in these trials include as planned so far, patients with non-small cell lung cancer in first line of treatment, melanoma patients in first line, pancreatic adenocarcinoma patients, and carcinoma patients of head and neck. In some instances, patients would receive the experimental agent plus pembrolizumab. 24 patients have been treated, or patients with head and neck cancer or pancreatic cancer would have received a combination with pembrolizumab and chemotherapy. At the point of cutoff in October, this year, in mid-October of this year, treatment keeps on going in 37% of the patients treated in combination with pembrolizumab, and 53% of the patients treated with a combination with pembrolizumab plus chemotherapy. The most common reason for discontinuation has been progression of disease. While in the case of the combination with pembrolizumab, 12% of the patients were discontinued because of adverse events, and in the case of the combination with chemotherapy, 15% of the patients were discontinued because of adverse events. From the point of view of safety, the most important part is that a fraction of these patients developed transaminase elevation without clinical repercussion or liver failure that reached the levels of a grade 3 in a few instances. This kind of side effect was also seen in two patients in the dose escalation part. Pruritus is suggestive of skin rash, fatigue and pyrexia were observed in some of the patients, as well as mild nausea. In the head and neck cohort of patients who were receiving the combination of GEN1042 plus pembrolizumab, plus the standard chemotherapy of a platinum, either cisplatin or carboplatin, together with 5-FU. What has been seen is that the in the four evaluable patients reaching the first CT scan examination, these 4 patients experience a response by RECIST 1.1 criteria. It must be said that all these patients were HPV negative, were negative for human papillomavirus. As it can be seen in the slide, two of these patients reached a complete response, while the other two had a deep partial response. As the spaghetti plot is showing, this response looked durable. In conclusion, GEN1042 is a novel agonist bispecific antibodies that combines the targeting of 4-1BB and CD40. In this regard, these bispecific antibodies work by acting agonistically on the receptor, enforcing its signaling. To do that, they need to cross-link several molecules on the plasma membranes of antigen-presenting cells in the case of CD40 and of T cells in the case of 4-1BB. Only when the juxtaposed plasma membranes come together, this cross-linking can occur. ta set from the safety running and expansion cohorts of this phase I, II study investigating GEN1042 in combination show that in combination with pembrolizumab plus chemotherapy, the treatment is well-tolerated. We have not observed dose-limiting toxicities. Most adverse events were grade one and two and manageable. In the cases in which elevation of transaminases happened, this was reversible when treated with steroids and never led to increases in bilirubin or alterations in liver function. GEN1042 plus pembrolizumab plus chemotherapy shows very encouraging early activity in patients with advanced metastatic head and neck squamous carcinoma, with responses that have been observed in the four evaluable patients thus far. GEN1042 is able to mediate immune activation that These effects on the immune function were preserved even when chemotherapy was added to the treatment regime. Enrollment keeps on going in all cohorts, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, and squamous carcinoma of the head and neck. Thank you very much for your kind attention. Excellent presentation. Now let's move briefly to our key priorities for 2023, where you will see that we have a lot to look forward to in the coming year. Next slide. 2022 was an exceptional year for Genmab. Overall, we made significant progress towards achieving our vision. In 2023, we will continue to work towards our new 2030 vision, where our KYSO antibody medicines are fundamentally transforming the lives of people with cancer and other serious diseases. We'll start with bringing our medicines to patients. First, we have epcoritamab, which, as a reminder, we are developing together with AbbVie. And we are very much looking forward to expanding development with new phase III studies, and excitingly launching epcoritamab in the U.S. and in Europe. Of course, that is subjective to approvals in both territories. If epcoritamab should be approved in 2023, it will join TIVDAK as the second Genmab owned product on the market. In 2023, we plan to work with our partner Seagen to continue to broaden the clinical development program for TIVDAK, and establish it as a clear choice for patients with metastatic cervical cancer. Now turning to our world-class differentiated product pipeline. We very much look forward to data from the clinical expansion cohorts and progress to next steps for both of the DuoBody molecules in development with BioNTech targeting 4-1BB, and you just heard one of them being described by Dr. Melero. We anticipate expanding and advancing other early-stage programs, including the potential for additional INDs or CTAs in the coming year. We have a number slotted, I can tell you. Having the right people and culture in place is essential for our success, and we intend to continue to scale our organization based on a planned portfolio development and business needs. Finally, we intend to leverage our solid financial base to support our growth, which could entail external opportunities. Taking all of this together, we have a lot to be excited about in the next 12 months. Let's move to the next slides. Now it's time for Q&A, and I'm very pleased to note that we also have several members of our executive committee here this evening to answer your questions. Our Chief Development Officer, Judith, is sitting here next to our Chief Medical Officer, Tahi Ahmadi. Then we have our CFO, Anthony Pagano, and Genmab Chief Operating Officer, Anthony Mancini. We will begin by taking questions from the room, and then we will open up, open the floor to questions from via the webcast. I see several hands up already here, so that's a good sign. To ask a question over the webcast, simply click the Ask a Question button located above the slide window and type in your question and then click Submit, and then Andrew will read out the questions later. Please, when you ask a question, just mention your name so that you, that the webcast viewers can actually hear easily quite easily who is asking the question. I think Thomas was first. Thomas, and then Michael here. Thomas, I think you get a microphone now. Brooke is getting very, very good exercise this evening because he's running around with microphones. That gives you an extra minute, Thomas, to think about a very sharp question here. Yes. Thank you. Thomas from Danske Bank. Just a couple of questions on HexaBody-CD38. Based on the current safety profile and also quite encouraging early signs of efficacy, is this something that you believe will actually be able to replace daratumumab also in the first line setting? Secondly, just on the PK/PD profile. You had a DLT at 24 mg. I'm just wondering when looking at the target saturation, how does daratumumab at 16 mg compare to the RP2D? Also the 16 mg you're using for HexaBody-CD38. Thank you. Thanks, Thomas. I will ask Torben, and then later on Tahi to give their perspective. Torben. Realizing that patients with myeloma and prior exposure to CD38 antibody is a very difficult patient population to treat. The idea is to focus on enrollment of CD38 negative patients, naive patients, and target them with a dose expansion. I also think that you deserve some time in the future to have a head-to-head comparison of daratumumab with HexaBody-CD38, and you will get that. Maybe the second question on the PK/PD profile, or maybe Tahi wants to go into that. Tahi. Maybe give me Answer. The first thing is, the PK profile of CD38 antibody is to a large degree driven by the sync CD38. That's a consistent depending, regardless of what antibody you use. The second part is the PK profile of HexaBodies by and large behaves like a normal antibody. Consequently, the PK for HexaBodies CD38 looks very similar to daratumumab. That was also part of the idea of settling on a dose that is very comparable because it makes some of the arguments when you get into head-on-head comparison a little bit more cleaner, because you are actually comparing apples to apples to some degree. Now, daratumumab sub-Q in dose X is using a higher dose, but from a bioavailability it behaves more or less a little bit on the plateau, a little more than 16, but more or less like 16 mg IV. That's what we are aiming for. As Torben was saying, all of this has been already discussed and a lot of times communicated. We have an expansion cohort that's enrolling right now in Dara-naïve, and then the next step will be the head-to-head comparison. I think it's probably fair to say that Dara sub-Q will not necessarily behave exactly the same way in a population that is enrolled today than in the population that Torben was involved early on, GEN501 or the SIRIUS study, which was just a different time and a different set of cares were available. That's why in comparison we'll give the final answer on this. We'll see. Judith, yes, please. You ask about the PD biomarker. If you compare the degrees of C2, which is the complement two, which is a surrogate of CDC, and the drug is doing what meant to be. When you compare the data that we presented with the data published for Dara, like six years ago, you see that the degrees of C2 on average by time point is like 48% with the HexaBody, and it's around 20 with Dara. I mean, showing again that what we showed pre-clinically in terms of more potent CDC, high, you know, translates in the biomarker that measures CDC. The dots are starting to connect, of course, you know, the proof is in the pudding. Thanks, Judith. I think Torben wants to give some further color on perspective. If you look at the early data for daratumumab from GEN501 and the SIRIUS trials, 52% of the patients did not have a formal response according to IMWG criteria, but they have a doubling on their survival. That speaks into the fact that CD38 is a very special target. Thank you. I think we move on to the next question from Michael Novod. He is here, Brooke, in the middle. The nice gentleman here with the blue jacket. Can't miss him. Thanks, Jan. Michael Novod from Nordea. Two questions for Dr. Falchi. There's been a lot of discussion also at this conference around how do you actually sort of pick the right bispecific because they're at least four in development, and they all seem highly active. How do you say are the sort of the top criteria you think going forward in regards of picking the right one between this jungle of bispecifics? The second one on Richter's, maybe that's more for the panel as such. What is the combination strategy in Richter and CLL also given the pirtobrutinib data we saw in the same session? Regarding how to pick the bispecific, there's factors that are beyond anybody's control is approval, label, setting, access. In terms of product themselves, one of the things that you need to remember about epcoritamab has been developed as a subcutaneous administration since the start, and it's a very pure product, and which is probably the reason why it's a one-to-one drug that's probably a couple orders of magnitude more powerful than most of them, for example. The subcutaneous administration with a really reasonable, really low rate of injection site reactions, most of which are grade one, is certainly an asset, certainly a strength. The fact that it's administered so conveniently also makes it a very combinable agent as well. This is true for some of the studies that are ongoing, some of the studies that I presented. You know, if you have a two-hour infusion, that makes your schedule a lot difficult, more difficult than if you have a subcutaneous injection. It is associated with lower rates of CRS than you would expect for a drug with that kind of EC50 in vitro, which is potentially best in class. You would have expected a little bit, you know, sort of an important CRS rate, which you don't see. Part of the reason is the way that the step up dosing schedule was developed, which I thought was clever, with lower doses early on, leveraging the power of B-cell clearance and then higher doses later on. Part of that is subcutaneous administration for sure, or very, very likely. But that makes the drug very suitable for outpatient administration. That's the second edge you have. I might have forgotten to mention in the presentation, but the phase III study is going to have no longer mandatory, but optional hospitalization on day 15. This is key, both in comparison to direct competition, but also in comparison to CAR T-cell. As you know, CAR T-cell is not offered everywhere in the United States or worldwide. There are patients who have to drive 5, 6, 700 miles to go get CAR T-cell. Some can't access that or can't access high-dose therapy and transplantation. The next best thing is, frankly, single agent epcoritamab. You have several strengths, convenience, power, safety, that position EPCORE very, very well. I'll let Tahi comment on the Richter side. Sure. Thank you. Yeah. On the Richter study, I think the first part is to reemphasize what Lorenzo was saying. For those of us who, for me, this is a little bit long ago, but still, have treated these patients. I mean, Richter is essentially MYC transformed large cell lymphoma out of CR. It's an incredibly hard to treat disease. Mm-hmm. The first part was to show that you actually, with the second agent, get efficacy and in some cases, as it appears, doable CRs. As it relates to combination strategy, what we always say is that we don't, you know, preface what we're going to do before we're going to do it, but I think this is also not rocket science. The standard, if there is such a thing as standard of care, how these patients get treated, or they get not the best of all responses, is essentially an approximation how a few such pieces gets treated. That happens to also be a regimen for which we have already generated safety data. I think you should stop here, Tahi. There's a lot... 'cause they're trying to fish, of course, for the right combinations. Of course, we are willing to tell you that, Michael, but there's also some competitors who are also probably listening into this call. Yes. A question from Citi. Peter. Busy photographing I saw during the presentation, so you're really keenly on topic, huh? Thanks, yeah. Peter Verdult, Citi. Two questions. Just coming back, EPCO, NHL six. When will that data read out? Is that enough to get a regulatory filing in the outpatient setting? Maybe just to bring Professor Falchi back in, you're clearly very relaxed to use this agent in the outpatient setting, but how would you, what's your sense about the wider community, their willingness to use T-cell bispecifics in the outpatient setting? That's question number one, and I'll pause there and wait for my follow-up. I think the readout should probably be Judith, I think. Yeah. Dr. What is it? Readout of NHL 6. It shouldn't be dependent on the question. The readout of what? The NHL 6. Six. When is six readout- Inpatient study. Outpatient study. Okay. We cannot provide the answer. What we can say is, as you know from ClinicalTrials.gov, that the study's actively enrolling. Look, that's a complex conversation, right? You know, it depends on what stance the FDA is gonna have. You know, this is not something that we can really speculate too much about. What I can say is the first step to even think about outpatient administration is lack of grade 3 CRS, right? Because that means patients require vasopressors, high level oxygen supplementation. We just haven't observed that. The other thing is there's a learning curve to this drug that's not even long where if you look at adverse events by quote unquote era, some of the grade 3s you would observe early on, even in NHL-1 study, just kinda went away. We haven't observed any grade 3 CRS. That's the first step. The second step is e-education, which many of us are going to be very willing to do with our colleagues, community colleagues. You know, eventually this will hit the community and, you know, like any new drug, there will be a learning process, but there is a community there to be served which are not currently served with CAR T-cells. As complex as it seems now, I think it's actually going to be... I don't know. I just have experience, but, hey, we all started somewhere, so. Thank you. Jan, second question. You talked about your 2023 priorities, but I thought one of the 2022 priorities was to make a phase III go no-go decision on at least one of these GEN1042 or GEN1046. We've seen the head and neck data, but we haven't seen you make a commitment to go into phase III. What data are we waiting for, and when will we hear anything? We're following the data in time, Peter. It's not the end of the year, remember. We still have, we still have time to go this year. We are at Genmab, so we will generate the data in a rational way. We'll then take a very clear data-driven decision, not only for ten forty-two but also for ten forty-six. I will update you then on the timing, Peter. Let me take one, let me take two more, three more questions here from the room, and then we go to the webcast. I think in the back. Maybe you can give your name and then step in 'cause it's dark here. Hey, Jan. It's Michael Schmidt with Guggenheim. Oh, Michael. Thanks for taking my questions. That's you. just another one on HexaBody-CD38. I wasn't clear, was there a dose response, and would you expect higher activity at the recommended phase II dose in the CD38 experienced patients? That's question 1. The second question was, I was just wondering if you could help contextualize the EPCORE combination data in the second-line DLBCL transplant-eligible patient setting, that was presented earlier. What, what is, you know, what is the strategy here, and what is the benchmark in this setting for activity? Thanks so much. Okay. Thanks, Michael. I think let's start with Torben and then Dr. Falchi. My expectation would be that there will be a dose response curve, that we will need to stick to these 16 milligrams per kilo. I think that we saw a very excellent response at, already at 4 milligrams per kilo. It can differ from patient to patient, but as a general rule, I think we will need to stick to this recommended phase II dose. Thanks, Torben. Lorenzo? As far as the second line, well, the strategy obviously I can't speak. I'll let Tahi speak about and the panel. In terms of the data, we were impressed with the data. You know, in that very session, you know, it starts emerging the idea that if you just, if you don't just do platinum, you can actually jack up the complete response rates. Now all of a sudden you're competing with CAR T-cells, right? Mm. You didn't think so initially. That was very pleasing to us. You know, delivery of the combination is something that you know, you need to pay attention to, but those curves are really high up, and that's not what you see with chemotherapy by a long stretch. In terms of further developing it, that's more complex, so. Thank you. First Emily. Wait on the microphone, and then Matthew, and then we'll get one more question here from the room. Hi. Thank you. Emily Field from Barclays. A question for Dr. Falchi. The point you made in one of the follicular lymphoma trials about the conversion of, PR to CR, is that something that you're seeing, as you accrue longer follow-up in these trials and could potentially be an advantage versus the fixed dosing regimen bispecifics? Also just a practical question on the HexaBody CD38, head-to-head trial, just how challenging you would expect enrollment- Given that it might be more difficult to find the CD38 naive patients. Mm-hmm. Dr. Falchi? As far as the conversions are concerned, there are conversions, but they're not super late conversions. You kind of see them within the follow-up that we had available, in fact. I would separate the conversion and the maintenance sort of or prolonged therapy issue. The prolonged therapy is something that has been put in place to prolong progression-free survival, potentially survival, particularly in later lines as much as possible. You know, you have the gathering data, you have the second line maintenance data. You know, it's something's frequently done. Obviously, that's with mono-specific antibodies, which are arguably orders of magnitude less powerful than epcoritamab. I'm actually very eager to see. Because beyond the first couple of cycles, injections of epcoritamab are incredibly easy for us and for the patients. Mm-hmm. It's just literally coming in, get an injection. In fact, injection site reactions are much less, frequently observed. The convenience factor is also important for a subcutaneous, you know, administration. Yeah, I think those are two separate issues, though. Okay. I think Kai wants to. Judith, you want to. Yeah. For the other part of the question is picking the right countries and the right sites. Yeah. Very good. I think Matthew, and then it's Asthika. Matthew? Recruitment of patients for HexaBodies. Yeah. I don't know where you- More to the back. Yeah. All right, Matthew. Thanks. Matthew Harrison, Morgan Stanley. I guess two for me. One on Epco. I was just wondering, Dr. Falchi, if you could just talk about how you think about durability, especially in the post-CAR T setting or CAR T experience setting, and how you think about the durability of the agent and, you know, thoughts on maybe long-term durability for some patients. Mm-hmm. The, the second question on HexaBody-CD38. Just remind us, should we expect head-to-head daratumumab data next year? Or, you know, what should we be thinking about in terms of timing there? Thanks, Matthew. As far as the durability, I would refer you to the presentation, looking at the progression-free survival and overall survival curves, where we see a plateau at some point in the curves, and that is always very promising. Obviously, this is continued therapy. It's going to be very hard to say what would happen if you were to discontinue, but this is also a setting in third-line-plus where you don't wanna play with fire. If you have a winning team, it's hard to change it. As I said before, such a convenient therapy, you know, easy to give. I don't know that I would do the experiment, you know, at this point. The overall survival curve, particularly that stays up at over 40%, I think it was 50%, is something that you wouldn't, you wouldn't have seen up until now. Large cell lymphoma is a disease where when you see a plateau, you automatically start thinking about cure rates. Obviously, longer follow-up's necessary to kinda demonstrate that, but all the good studies have started like this. Hopefully we'll see some good results with this too. Thanks. Then I think Judith wants to comment on the timing. Yeah. We have firm plans to start next year, the head-to-head. All right. Let's Asthika. Here in the front. Yep. Hi, guys. Thanks. Sorry, I'm losing my voice at the end of ASH here. In his presentation yesterday or two days ago, Dr. Hutchings discussed how CD20 loss might be a mechanism of resistance. Mm-hmm. There was some debate on the frequency in which this occurs and the different lymphomas. Doctor, I was wondering if you could maybe tell us a bit about your experience with EPCO and some of the other bispecifics out there. Is there any difference between the different bispecifics that maybe you see a different rate of? Mm-hmm. CD20 loss, with that? Then maybe for, maybe Judith, there's also discussion on fixed dosing, and how some doctors like, that this can help you better manage the late onset, infection risk. I'm wondering, do you think that that's a valid, angle to play at? Maybe is that something that you will also look at doing, maybe do a fixed, dose regimen of EPCO as well? Dr. Falchi first on the CD20 loss. Yeah. As you know, there's data across studies that look at mechanisms of resistance, and CD20 loss is the obvious one, which is consistent with the you know, dynamic mechanism of action. I have seen it in the EPCORE studies for sure, but I've seen it in other studies as well. I can't really say that the incidence is higher. Also, CD20 loss is only one of the mechanisms of resistance. I can refer you to a review we put out just a month ago, looking at some of the other mechanisms of action. The truth is we know very little about this. At least I know very little about this. CD20 loss can... may or may not be reversible because it's been shown that some of it is related to... It's genetically determined. The cases that are not, we actually don't know if CD20 can reemerge over time. I don't get a sense that the incidence is different, which is not surprising. Thanks. Fixed dosing? Yeah. I'm gonna add something to that. Okay. I also think it's a red herring. It's a described phenomenon, but it is not the predominant mechanism of resistance for this mechanism. There are probably other biological mechanisms that are more relevant. To the, to the notion of fixed dosing and the potential infection risk, that's a big topic. I think the first part is the idea that continuous T-cell activation may lead to T-cell exhaustion. We actually had a poster on that, instead of doing this in a tube, actually answers that question in patients, which is probably more relevant. What you will find on the poster is that they are not getting exhausted. I think it's the first part, and it probably is the difference between just throwing bispecifics in a lab and publishing some blood and continuously exposing them towards, you know, what's actually happening in vivo. The second part is, you saw, Leonard actually was emphasizing this, on one of the slides in the updates of the one study. We actually are showing that there are less events over time. So, in general, and also related to infections, as patients progress on treatment, as the disease gets better under control, and they are getting also in better shape because of better disease control, we see a significant reduction over the years. It's something I actually can answer. If you look at some of the CAR T-cell data, CAR T-cell live a long time, up to two, three years, and we've had more than one patient coming in with HIV levels, you know, T-cell numbers, getting opportunistic infections that you wouldn't have expected to see two, three years in remission. We have not seen that within the available follow-up with EPCORE. Thanks. Let's see whether there's any questions from the from the webcast. Andrew? Sorry, there are no questions from the webcast. No questions. All right, we go continue with the room here in the back. Thanks for taking my question. Christopher Uhde from SEB. I guess this is a question for Dr. Falchi. Would you please talk a little bit about the trade-offs that you make when you would decide the timing of the dose schedule in frontline LBCL with R-CHOP or CHOP and, yeah, basically, the CHOP first or simultaneous? I think the R-CHOP, and we presented this at ASCO this year. The R-CHOP/EPCORE experience was very educational for us. First of all, it showed, and I alluded to this before, the combinability of EPCORE being a subcutaneous administration. R-CHOP, as you know, particularly in cycle one, it's a day-long treatment, right? Having a drug you can combine is extremely valuable. The second, and maybe this is a point of difference with competition, I think administering R-CHOP together with EPCORE together with R-CHOP, as opposed to later on as it's been done elsewhere, is another point of strength 'cause you leverage any synergism that you can get or additive effect you can get without detrimental effect on either component. I also like the idea that we were able to start EPCORE on cycle 1, day one, as opposed to cycle 1, day three or day two, because most of the benefit you get in large cell lymphoma you really get in the first two cycles of therapy. I think that perhaps that's the arm of the study where versatility and combinability of EPCORE was shining the most. Thank you. There was another. Yes. wait on the microphone. Thanks. Thanks, Brooke. Hi. Matt Phipps from William Blair. On the GEN3014, do you guys have any data on CD38 expression levels for the patients that were prior treated? Do you see any correlation with paraprotein activity? Secondly, did you expect to see any kind of dose response in some of the complement pharmacodynamics that you showed? Tahi, can you do this? I'll start with the first one. We collected the samples. They are not yet analyzed for CD38 expression. What was the second one? The dose exploration. Did you expect to see? I couldn't hear. Dose response with the complement. Yes. -pharmacodynamics? Yes. Yeah. Yeah. Yes. You see relatively early, and this maybe also helps a little bit to give more context to the initial question on PD. There are two things I would like to draw your attention to, and these are complement and other CD38 positive cells, such as NK cells that work as pharmacodynamic markers. Mm-hmm. In both cases, what you see is an effect at lower doses for axicabtagene ciloleucel compared to the artuma, and a more profound effect at the recommended phase II dose for both aspects. Thanks, Tahi. We have time for one more question. Who wants to ask the last burning question? Yes. The lady here in front, Brooke. Please go ahead. Hi. Sorry. Kara Morelli from RBC. Maybe just a quick comment on the grade 2 and 3 CRS events. We've heard at the conference that anything above grade 1 requires monitoring, and there might be some concern that something that is grade 2 could progress to grade 3 and above. Is there interested in your thoughts here and whether there will be an education thing for physicians? Thank you. Yeah, yeah. I agree. When I talk about the learning curve, some of the reduction incidence of grade 3, I think is related to us learning to use the drug better and intervene earlier when a grade 2 is there now. You're correct. Patients were admitted for that cycle 1, day 15, and I have had patients that would have had a prolonged hospitalization by one day or two days because they might have had some additional fever and obviously you're never sure if there's an infection or not, and, you know, there's only so much control you have on a patient when he's admitted. If I thought of those patients as an outpatient, truthfully what they had was fever. Blood pressure might have been in the hundreds, 110s or, you know, high 60s, maybe 70s. There wasn't symptomatic hypotension. There's no end organ damage. There's no oxygen requirement of any real sort. I think it's something that exists, but at one point, at least from my point of view, we have to be a little bit courageous and then keep patients in outpatient, give them clear instructions, give them a 24/7 access line. These are all things that are going to be implemented if and when the drug would be... You know, I would imagine. That's what I would do. I'm confident that the grade 2s can be kept outpatient. Yeah. I'm gonna comment on this as well because this is my favorite topic. It really is actually. The issue with that is that the grading for CRS was developed in the context of CART. Yes. It was intended to identify patients who go to the ICU versus the rest. Yep. Basically it was focusing on grade three. Grade 2 CRS, as it is currently defined, is a hodgepodge, and the hodgepodge is the equivalent of a patient who has fever, as Lorenz was just saying, and maybe you give him 500 CCs of fluids, and that's basically it. The patient where you call the ICU to get the bed. That granularity is not there. We've tried to provide that granularity, and I would encourage you to pay attention to how many patients actually require oxygen and how many patients just require fluids, because I think that actually differentiates. Thanks very much, Tahi. On that note, I think we're going to end our Q&A here. Thank you all very much for your questions. Next slide, please. Thank you all for joining us this evening in New Orleans. A special word of thanks, and I think a big applause to the truly exceptional speakers who have joined us here today in person, and also virtually. From all of us at Genmab, we wish you happy holidays and a healthy, happy, and wonderful 2023. Thank you. Thank you.