Genmab A/S (GMAB) Earnings Call Transcript & Summary

All right. So 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. So let's begin. So let's start with the next slide. I think one slide back. Yes. Genmab has a science-anchored and innovation-focused culture, and collaborations and partnerships have always been part of our DNA. And during tonight's presentation we will reference some of the products being developed under these strategic collaborations. And this slide actually acknowledges those relationships. So let's move to Slide 3. We'll begin this evening with a review of the excellent progress we made this year as we progress towards our ambitious 2030 vision. And 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. And for this, we are very happy to have with us Dr. Lorenzo Falchi of the Memorial Sloan Kettering Cancer Center in New York. And we will then conclude our data review with a look at the preliminary GEN1042 data that was recently presented at ESMO IO in Geneva. And to share a summary of this data, we are very pleased to have a prerecorded presentation by Dr. Ignacio Melero from the Clínica Universidad de Navarra in Spain. And then 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. So 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. So next slide, 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 U.S. 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. And this consistent and solid track record is possible because of a world-class team of unstoppable colleagues who are driven to improve the lives of patients through innovative and differentiated antibody therapeutics. So now let's move to the next slide and look at some of the events from the past year that are 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 that 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 health care community even further in the future. And this led us to the 2030 Vision you see here. And 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. So 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. And 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 codeveloping with Seagen, as well as 5 other therapies that are powered by our innovations and technology, which also provide us with growing recurring revenue streams that we are particularly pleased about. As we have done in past years, throughout 2022, we continue to use this revenue to invest in a focused and disciplined way, both in the strategic growth of our company and the 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 and the updates to our pipeline on the next slide. So 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 under planning. In March, the FDA granted orphan drug designation to epcoritamab for the treatment of follicular lymphoma. And then in April, we along with our partner, AbbVie, published top line results from the EPCORE NHL-1 study, which was subsequently presented in a late-breaking oral presentation as part of the presidential symposium at EHA in Vienna. These results then form the basis of regulatory submissions for epcoritamab in both the U.S. and in Europe. And we recently announced, the FDA accepted the submission for priority review with a PDUFA date of May 21, 2023. So 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. So looking to earlier stage programs, we have 2 new investigational medicines enter the clinic this year with the first patients dosed with DuoBody-CD3xB7H4, and our latest product in codevelopment with BioNTech, HexaBody-CD27. This year was also notable for our data presentations. Nineteen 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 epcoritamab studies, 4 of which are oral presentations. And 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. And earlier in the year, we had Seagen present the tisotumab vedotin data, both from the innovaTV 207 study at ASTRO and the innovaTV 205 study during oral sessions at SGO and at ASCO. And 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. So 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. So 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 IIIa study in hemophilia A. And we believe that the success of these programs highlight the potential of our innovative bispecific DuoBody technology, and we look forward to seeing the 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 very much, and thank you for inviting me, and 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. And I'm presenting this on behalf of my co-investigators. This is a truly international collaboration. And you can see here the mode of action of HexaBody-CD38, which looks very similar to what you know from daratumumab, but there are certain differences, the most important being that the hexamerization of the antibody results in a very much enhanced complement activation and cytotoxic killing by this method. Another aspect is 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 patients 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 6 months, which is what is needed to get rid of the last daratumumab in the body. So we dose escalated from 2.6 milligrams per kilo up to 24 milligrams per kilo stepwise and ended up with a recommended Phase II dose of 16 milligrams per kilo, and that was one of the primary goals of the trial to find the right dose for an expansion phase and Phase II study. So the follow-up period for these patients is short, only 7.3 months. And I'll present to you some of the parameters, PK parameters, pharmacodynamics and antitumor activity. So 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 2/3 of the patients and 1/3 were naive to CD38 antibody. The median time since last anti-CD38 treatment was 9.5 months. So 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. And on the right hand, you see grade 3 and 4 adverse events. And you can see clearly that there is a low number of high-grade adverse events, and adverse events are mostly infusion-related reactions that we are used to and can manage, and 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, and no treatment-emergent adverse events that led to death. No anti-HexaBody-CD38 antibodies emerged. So 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. And the clinical benefit rate was 60% for the nonexposed patients and 19% for those that had been exposed. And 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, the responses were more modest with 2 patients with minimal response in one 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 side, 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 C2 and CH50, which were the markers of complement activation. But 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. So the 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. And 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. And I'm sure there will be many, many questions here in the Q&A. So 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 an expert in the treatment of lymphoma. And as an investigator is 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. And we are delighted that he is 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. So Lorenzo, please the floor is yours.

Thank you for having me. So I'm going to go through all the presentations that were held here at ASH regarding epcoritamab, a 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 single arm, very large study. Over 150 patients were enrolled with a median follow-up of over 10 months. Patients with recurrent CD20-positive B-cell lymphoma were included after 2 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 3 cycles, and then every other week up until cycle 10, and then monthly thereafter until progression or unacceptable toxicity. And 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 that were certainly represented here. The median number of prior lines of therapy was 3. So these were really heavily pretreated subjects and 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. So it's very, very difficult to treat a population for whom treatment options are really limited and outcomes, unfortunately, dismal. So in terms of safety, epcoritamab was associated with cytokine release syndrome. As we know, this is the predominant adverse event related to this drug. But this was observed in 50% of patients and by far and away, 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. And 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 had tolerated therapy then really don't experience additional adverse events, partly because cytokine-release syndrome really is the dominant adverse event. And other than that, the administration of epcoritamab is really safe. The responses were durable, as you know, from top line results. 63% of patients had an objective response, 39% of patients had a complete metabolic response. And as far as the duration of response, you can see it here on the complement on the right side. Very, very encouraging, as was the progression for survival and the overall survival curve in the study. But 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 3 months and don't have response, or progress through CAR-T cells. So very, very difficult to treat. Among the double-hit or triple-hit lymphomas, also over 30% of patients had a complete response to therapy. And 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 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 doing what's popularly referred as liquid biopsy, looking at tumor DNA in peripheral blood, no matter the risk group, these patients tend to do all very well. And if you were MRD-positive, obviously less well. And that's unfortunately an unmet need currently. So in conclusion, I think this subcutaneously administered off-the-shelf very potent T cell engaging therapy continues to show really powerful activity as a single agent. This is important. Most of what's out there, particularly 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, very limited treatment options, very robust progression-free and overall survival figures. And for patients who achieve a deep response, really, really promising outcomes. And we really have a feeling that these patients are likely to maintain that status for a very long time. My colleague, Pau Abrisqueta, presented results -- now 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 doctors used, in patients with recurring 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 milligrams in the first sort of 3-patient cohort and then 48 milligrams 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 chemo-immunotherapy, which was given for 3 cycles before proceeding to autologous stem cell transplantation. So these were all high-risk patients with recurrent diffuse large B-cell lymphoma. And here, I really point your attention to sort of the red box down there where the majority of patients progressed within 12 months of therapy. About 2/3 of them, as you know, this is the population that's currently the target -- or the patients are a candidate for CAR-T cell therapy. And importantly, there was a very high number of patients with primary refractory disease, which means disease does not respond to frontline chemo-immunotherapy, particularly hard to treat, unfortunately. So in terms of safety, cytopenias dominated the side effect profile of the combination. Not surprisingly, R-DHAX is a myelosuppressive therapy. The rest of the adverse event profile, with the exception of CRS, also probably attributable to R-DHAX. Again, 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 transforming 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. And very encouragingly, again, we did not observe Grade 3 or higher CRS. All events resolved very quickly after a median of 2 days, and we 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 in a step-up dosing schedule. These are the responses. 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 the figure you don't typically see with standard chemo-immunotherapy in the second line. We're looking more at maybe 25%, 30%. So we're sort of doubling there the response rate. And although it's extremely pleasing to see that 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 cure in 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, particularly 45% complete metabolic response rate, all of which, as I'll show you in a second, were maintained. So that's a very encouraging piece of information, piece of news for those patients who cannot proceed or do not want to proceed to autologous stem cell transplantation for a number of reasons. And you can see it here in the zoomer plot, most of the patients had maintained their response. This zoomer plot is divided into patients who did not proceed to transplant and those who did. So among those patients who did proceed to transplant, you can see all of them are either on ongoing treatment or in response. So none of these patients has lost their response. For those patients who did not undergo a transplantation, including there are 2 patients who had, had prior CAR-T cell therapy, these were not all second line, some of these patients were third line, I think. Most of them -- essentially all but 2 had maintained their response as well. And that includes the 2 patients who had, had CAR-T cell therapy previously. Progression-free survival curve is extremely encouraging, not reached. And at the, I would say, 6- and 9-month 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. So we're looking at a very promising overall survival curve here with a median follow-up that's relatively generous over 12 months. So in conclusion, I think, epcoritamab incorporated into a platinum-based second-line therapy really did prove highly effective, high 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, very encouraging. And 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 chemo-immunotherapy regimen. And I'm going to now talk about the 2 studies that we presented yesterday. These 2 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's schema. You can focus here on the right-hand side. Epcoritamab was administered a little bit differently. It was given weekly for the first 2 cycles, each cycle is 28 days, and then every 4 weeks thereafter, and patients are treated up until 2 years or obviously unacceptable toxicity. R-squared was given according here to the AUGMENT protocol, which has 5 months of rituximab weekly in the first month and then monthly, and 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 with having a nice sample size, 76 patients were evaluable here. Most patients had advanced disease, stage IV disease. Over half of 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. And then here on the right-hand side, in the red box, you can see that there's a 30% to 40% incidence of high-risk disease. And here we defined it as primary refractory disease. So disease failed to respond to frontline chemo-immunotherapy, not particularly frequent, but here is enriched in this population double-refractory disease. POD24 means patients with disease that recurred within 2 years of completion of frontline chemo-immunotherapy, and obviously, patients refractory to the last line. Notably, here, very few patients have received CAR-T. So in terms of safety, again, this is after a median of 6 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 want to point out, we unfortunately had 3 fatalities, all related to COVID-19 pneumonia. And I want to really point out that this study and the next -- actually, all these studies, almost in their entirety, were conducted during the COVID pandemic. We can't forget, when we think about the dose delays, that we're observing 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. And you can see 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, 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 bit more in detail; 43% incidence; importantly, no Grade 3s, and also very few Grade 2 here at 11%. Grade 2 is essentially prolonged fever. Grade 1 means just a single or multiple episodes of fever that respond to very simple measures. So very, very well tolerated. Very predictable, after a median of 2 days after the first full dose of epcoritamab, you can see again on the right-hand side, very predictable timing, and all events resolved after a median of 2 days. We used very little tocilizumab, you can see here in 10% in cases. And 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 than what you would expect with R-squared alone. 95% of patients had objective response. And we don't have it here, but several of the partial responders did convert their response into complete response with further follow-ups. So 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, and 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. And 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 6 months and that curve, including accounting for those 3 COVID-related deaths, looks very, very promise. So 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 6-week time mark, so very, very quick onset of action; very well tolerated; no high-grade CRS. And 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. And there was a trial-in-progress poster that I just left and some of you were kind enough to stop by. This is a second study in frontline, same combo, same concept. These are patients with high grade follicular lymphoma, again, with the needed treatment for the GELF criteria. Epcoritamab given in a very similar fashion, weekly for 8 weeks and then monthly up to 2 years. R-squared given per the RELEVANCE trial, so rituximab for 6 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 frontline study, but still 8 months, it's not too short either. 41 patients enrolled at the time of this analysis, again, mostly advanced disease; good 34% of patients with high-risk disease. So what you would typically expect for a high grade follicular lymphoma population. And then 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 2 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. And very few patients had to discontinue epcoritamab, especially due to epcoritamab-related adverse events. Again, very contained neurotoxicity, only 1 patient, mild event, quickly resolved. And 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 frontline setting. I'll just spend one word on CRS. You can see here, the incidence was 54%, so more or less the same. And 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. And we were eager to see where the CRS rates in 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, and 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. To put it in context, chemo-immunotherapy, we're looking at maybe 70%, 75% complete response rate. This is a chemo-free regimen. So definitely as effective, if not more effective than chemo-immunotherapy. So again, very, very promising combination here. Epcoritamab did not add toxicity to R-squared, and the 2 toxicity profiles remain nonoverlapping. Very encouraging activity, 86% CMR is something that we really like to see. Neurotoxicity, I don't want to say it's a nonissue, but it's certainly very, very contained. And so this triple combination is also being looked at for further development and further evaluation in this frontline setting. I think a word on the Richter's population. This was presented by Dr. Kater. This was a small patient cohort, but very important. Richter is a very rare complication of CLL, 2% to 5% of patients. It's very, very difficult to treat, particularly those cases of Richter's that occur later in the course of CLL, particularly when chemo-immunotherapy upfront 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. So 10 patients; in most cases, the underlying CLL was TP53 mutated. For those of you who have been familiar with this, p53 mutations confer a 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 3 prior lines of therapy. There's really no viable treatment option for these patients at all. And one of the problems that we have in this population, we cannot get them into a remission to even think about consolidation therapies. So very, very difficult to treat patient population. This is a look at the adverse events. Perhaps a little bit more Grade 2 CRS. This is obviously a very small population. It's very hard to compare this incidence to CRS to the populations that are 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. A little bit closer look at CRS here. 9 patients had an event. But again, all Great 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 this led to a treatment discontinuation. And this is, I think, the really exciting part. I mean 6 out of these patients had an objective response, and almost all of them had a complete metabolic response. This is not something I would have actually expected to see. I was very sort of excited looking at these slides. It's not something that I see that often in my practice. So very difficult to treat population, very high risk, single-agent off-the-shelf subcutaneous, mostly outpatient therapy resulted in half of the patients having a complete metabolic response, very well tolerated in general, very manageable toxicity profile. We are eager to see continuation of the study to see how long those responses last and what the outcome in these patients is going to be. So 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 later.

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 GEN1042 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 GEN1042 abstract at ESMO IO, we are truly fortunate that he was able to film this summary presentation for you this evening. So let's start the video enjoy.

My name is Ignacio Melero. I'm a chemo-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 was communicated in the SITC meeting in 2021. The treatment was very well tolerated. There were 2 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 RECIST in a good performance status of the patients with ECOG 0 to 1 with adequate renal, hepatic and bone marrow function, and no prior therapy would have been given to these patients, including a PD-L1 agent. Therefore, these patients are immune checkpoint naive. The idea was first to test the combination with the checkpoint inhibitor, anti-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 plus 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. And then 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. And in this regard, the patients are receiving standard of care checkpoint inhibitors, pembrolizumab in this case, or chemotherapy plus checkpoint inhibitors, or chemotherapy. Therefore, this trial is testing, as a primarily endpoint, the safety of the combination approach, and 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 would see in the next slide, the patients that were included 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 and 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 mid-October this year, treatment keeps ongoing in 37% of the patients treated in combination with pembrolizumab and 53% of the patients treated with the 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 Grade 3 in a few instances. This kind of side effect was also seen in 2 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 cisplatinum or carboplatinum, together with 5FU, what has been seen is that in the 4 evaluable patients reaching the first CT scan examination, these 4 patients experienced a response by RECIST 1.1 criteria. It must be said that all these patients were negative for human papillomavirus. As it can be seen in the slide, 2 of these patients reached a complete response, while the other 2 had a deep partial response. As the spaghetti plot is showing, this response looked durable. So in conclusion, GEN1042 is a novel, agonist, bispecific antibody 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. And 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. And only when the juxtaposed plasma membranes come together, this cross-linking can occur. The preliminary data 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 1 and 2 and manageable. And 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 4 evaluable patients thus far. GEN1042 is able to mediate immune activation and these effects on the immune function were preserved even when chemotherapy was added to the treatment regime. Enrollment keeps ongoing 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. So 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. So 2022 was an exceptional year for Genmab. Overall, we made significant progress towards achieving our vision. And 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 will start with bringing our medicines to patients. First, we have epcoritamab. This, 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. And of course, that is subject to approvals in both territories. And if epcoritamab should be approved in 2023, it will join Tivdak as a second Genmab-owned product on the market. And 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. So 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 step 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. And 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. And finally, we intend to leverage our solid financial base to support our growth, which could entail external opportunities. So taking all of this together, we have a lot to be excited about in the next 12 months. So let's move to the next slide.

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. And then we have our CFO, Anthony Pagano; and then our Chief Operating Officer, Anthony Mancini. And we will begin by taking questions from the room, and then we will open the floor to questions via the webcast. I see several hands up already here. So that's a good sign. And 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. So please when you ask a question, just mention your name, so that the webcast viewers can actually hear quite easily who is asking the question. And I think Thomas was first, and then Michael here. Thomas, I think you got a microphone. And Brook is getting very, very good exercise this evening because he's running around with microphones. And that gives you an extra minute, Thomas, to think about a very sharp question here.

Thomas from Danske Bank. Just a couple of questions on HexaBody-CD38. So based on the current safety profile and also some 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? And then secondly, just on the PK/PD profile. So you had a DLT at 24 mg. So I'm just wondering, when looking at the target situation, how does daratumumab at 16 milligrams compare to the RP2D also at the 16 milligrams you're using for HexaBody-CD38.

Thanks, Thomas. I will ask Torben and then later on Tahi to give their perspective. Torben?

So 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 naive patients and target them with dose expansion. And 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.

And then maybe the second question on the PK/PD profile, maybe Tahi wants to go into that dive.

So the first thing is the PK profile of CD38 antibodies to a large degree is driven by the zinc CD38. So that's a consistent regardless of what antibody it is. And then the second part is the PK profile of HexaBodies by and large behaves like a normal antibody. So consequently, the PK for HexaBody-CD38 looks very similar to daratumumab. And 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 a head and head comparison, a little bit more cleaner, because we are actually comparing apples to apples to some degree. Now daratumumab subcu, DARZALEX, is using a higher dose, but from a bioavailability, it behaves more or less -- a little bit on the plateau, more than 16, but more or less like 16 milligram IV. And so that's what we are aiming for. And as Torben was saying, all of this has been already discussed and multiple times communicated. We have an expansion cohort that's enrolling with non-dara. And then the next step will be the head-to-head comparison. I think it's probably fair to say that the subcu 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, 501 or the SIRIUS study, which was just a different time and a different set of cases were available. So that's what in comparison will give the final answer on this. So we'll see.

Yes, please.

You asked about the PD biomarker. So if you compare the decrease of C2, which is the complement 2, which is a surrogate of CDC and the drug is doing what meant to be. So when you compare the data that we presented with the data published for dara, like 6 years ago, you see that the decrease of C2 on average by time point is like 48% with a HexaBody and it's around 20 with dara. I mean, showing again that what we showed preclinically in terms of more potent CDC, high translates in the biomarker that measures CDC. So the dots are starting to connect. Of course, the profits are going to pool in.

Thanks, Judith. I think, Torben wants to give some further color and perspective.

If you look at the early data for daratumumab from 501 and the SIRIUS trials, 52% of the patients did not have really formal response according to MWG criteria where they have adapting of their survival. So that speaks into the fact that CD38 is a very, very special target.

Thank you. I think we move on to the next question from Michael Novod. And he is here, Brook, in the middle. The nice gentleman here with the blue jacket. Can't miss him.

Thanks, Jan. Michael Novod from Nordea. So 2 questions for Dr. Falchi. So there's been a lot of discussion also at this conference around how do you actually sort of pick the right bispecific. Is there at least foreign development, and they all seem highly active. So 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. And then the second one on Richter's. Maybe that's more for the panel as such. What is the combination strategy in Richter's and CLL also given the ibrutinib data we saw in the same session?

Yes. So regarding how to pick the bispecific, there's factors that are beyond anybody's control, that is approval, label, setting, access, those are... But in terms of product themselves, one of the things that you need to remember about epcoritamab is it has been developed as a subcutaneous administration since the start, and it's a very pure product, which is probably the reason why it's a one-to-one drug that's probably couple of orders of magnitude more powerful than most tuzumabs, for example. And so the subcutaneous administration with really reasonable, really low rate of injection site reactions, most of which are Grade 1, is certainly an asset showing 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. If you have a dara infusion, that makes your schedule a lot difficult, more difficult than if you should 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. So you would have expected a little bit 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 likely. But that makes the drug very suitable for outpatient administration. And that's the second answer you have. And 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 compares to CAR-T cell. As you know, CAR-T cell is not offered everywhere in the United States or worldwide. There are patients that have to drive 500, 600, 700 miles to go get CAR-T cell. Some can't access that or can't access high-dose therapy and transplantation. And the next best thing is, frankly, single-agent epcoritamab. And so you have several strengths: convenience, power, safety, that position us very, very well. Now I'll let Tahi comment on the Richter's study.

Sure. Yes, on the Richter's study, I think the first point is to reemphasize what Lorenzo was saying. I mean, for those of us who -- for me, this is a little bit long ago, but I have treated these patients and Richter's is essentially mixed transformed large cell lymphoma out of CLL. So it's incredibly hard to treat the disease. And so the first part was to show that actually the single agent got efficacy, and in some cases, as it appears, double CRS. As it relates to combination strategy, we always say is that we don't preface what we're going to do before we're going to do it, but I think this is also not rocket science, but the standard, if there is such a thing as standard of care, how these patients get treated, though they get not the best of all responses, is essentially an approximation how diffuse large B-cell gets treated. That happens to also be a regimen for which we have already generated safety data.

I think you just stop here, Tahi, because they're trying to fish, of course, for the right combinations. And 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? Basically photographing us all during the presentation. So you're really keenly on topic?

Peter Verdult, Citi. Two questions. Just coming back, EPCORE NHL-6. When will that data read out? Is that enough to get a regulatory filing in the outpatient setting? And 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 read out should probably be Judith, I think, and then Dr. Falchi...

So we cannot provide the answer. What we can say is, as you know, from clinicaltrial.gov that the study is actively enrolling.

And look, that's a complex conversation. It depends on what stance the FDA is going to have. It's 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, some ventilation. 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 "era", some of the Grade 3s you would have observed early on even in NHL-1 study kind of went away where we haven't observed any Grade 3 CRS. So that's the first step. And then the second step is education, which many of us are going to be very willing to do with our community colleagues. Eventually, this will hit the community. And like any new drug, there will be a learning process. But there is a community there to be served, which we are not currently serving CAR-T cells. So as complex as it seems now, I think it's actually going to be -- I mean, like we have had experience, but we all started somewhere, so...

And then Jan, second question, GEN10 -- well, you talked about 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 1042 or 1046. So we've seen the head and neck data, but we haven't seen you make a commitment to go into Phase III. So what data are you 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 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 1042, but also for 1046. I will update you then on the timing, Peter. Let me take 3 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 because it's dark here.

It's Michael Schmidt with Guggenheim. 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? So that's question one. And then 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. I guess what is the strategy here? And what is the benchmark in this setting for activity?

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 and that we will need to stick to this 16 milligrams per kilo. But I think that we saw a very excellent response already at 4 milligrams per kilo. So it can differ from patient to patient. But as external rule, I think we will need to stick to this recommended Phase II dose.

Thanks, Torben. Lorenzo?

Yes. As far as the second line, well, the strategy, obviously, I can't speak. I'll let Tahi speak about it in the panel. But in terms of the data, we were impressed with the data. And in that very session, it starts emerging the idea that if you don't just do platinum, you can actually jack up the complete response rates. And now all of a sudden you're competing with CAR-T cells, right, and you didn't think so initially. So that was very pleasing to us. Delivery of the combination is something that you need to pay attention to. But those curves are really high up, and that's not what you see with chemo-immunotherapy by a long stretch. But 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.

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. And then also just a practical question on the HexaBody-CD38 head-to-head trial, just how challenging you would expect enrollment to be given that it might be more difficult to find the CD38-naive patients?

So as far as the conversions are concerned, there are conversions, but they're not super late conversions. So you kind of see them within the follow-up that we had available in fact. So 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 potential to survival, particularly in later lines as much as possible. You have the GADOLIN data, you have the second line maintenance data. It's something that's frequently done. Obviously, that's with monospecific antibodies which are arguably orders of magnitude less powerful than epcoritamab. So I'm actually very eager to say -- because beyond the first couple of cycles, injections of epcoritamab are incredibly easy for us and for the patients. It's just literally coming in, getting an injection. In fact, injection site reactions are much less frequently observed. So the convenience factor is also important in a subcutaneous administration. So yes, I think those are 2 separate issues, though.

I think Tahi wants to argue that you want to...

Yes. And for the other part of the question is picking the right countries and the right sites.

Very good. I think, Matthew, and then its Asthika.

Matthew Harrison, Morgan Stanley. I guess 2 for me. So one on EPCORE. 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 thoughts on maybe long-term durability for some patients? And then the second question on HexaBody-CD38. Maybe just remind us, should we expect head-to-head daratumumab data next year? Or what should we be thinking about in terms of timing there?

Thanks, Matthew.

So 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 want to play with fire. So if you have a winning team, it's hard to change. And as I said before, such a convenient therapy, so easy to give, I don't know that I would do the experiment 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 have seen up until now. So large cell lymphoma is a disease where when you see a plateau, you automatically start thinking about cure rates? Obviously, longer follow-up is necessary to kind of demonstrate that, but all the good studies have started like this. So hopefully, we'll see some good results with this too.

Thanks. And then I think Judith wants to comment on the timing.

Yes. We have further plans to start next year the head-to-head.

All right. Asthika, here on the front.

Sorry, I'm losing my voice at the end of ASH here. So in his presentation yesterday or 2 days ago, Dr. Hodgkins discussed how CD20 loss might be a mechanism of resistance. And there was some debate on the frequency in which this occurs into different lymphomas, and Doctor, I was wondering if you could maybe tell us a bit about your experience with EPCORE and some of the other bispecifics out there? And is there any difference between the different bispecifics, maybe you see a different rate of CD20 loss with that? And then maybe for 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 mean I'm wondering, do you think that, that's a valid angle to play out? And maybe is that something that you will also look at doing, maybe do a phased dose regimen of EPCORE as well.

Dr. Falchi first on the CD20 loss.

So 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 pharmacodynamic 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. And 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. And the truth is we know very little about this, at least I know very little about this. And CD20 loss may or may not be reversible because it's been shown that some of it is related to -- it's genetically determined. But the cases that are not, we actually don't know if CD20 can re-emerge over time. I don't get a sense that the incidence is different, which is not surprising.

I'm going to add something to that, but I also think it's a bit heavy. So this is a quiet phenomenon, but it is not the predominant mechanism of resistance for this mechanism. There are probably other biological mechanisms that are more relevant. And then 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 post on that, that instead of doing this in a tube, actually answers that question in patients, which is probably more relevant, and what you will find on the process that they are not getting exhausted. I think it's the first point. And there probably is a difference between just drawing bispecifics in the lab and publishing this on Blood and continuously exposing them towards what's actually having in vivo. And the second part is, as you saw, Lorenzo actually was emphasizing this one of the slides on the update 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 of AEs.

I actually can answer that. If you look at some of the CAR-T cell data, CAR-T cells live a long time, 2, 3 years, and we've had more than one patient coming in with HIV levels, T cell numbers, getting opportunistic infections that you wouldn't have expected to see 2, 3 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 webcast. Andrew?

Sorry, there are no questions from the webcast.

No questions. All right. Then we continue with the room here in the back.

Christopher Uhde from SEB. So 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, and -- yes, 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 1, it's a day long treatment, right? So 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, as in EPCORE together with R-CHOP as opposed to later on, as it's been done elsewhere, is another point of strength as you leverage any synergies in 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 1 as opposed to cycle 1, day 3 or day 2, because most of the benefit you get in large cell lymphoma, you really get in the first 2 cycles of therapy. So I think perhaps that's the arm of the study where versatility and combinability of EPCORE will shine the most.

Thank you. There was another. Yes. Wait on the microphone. Thanks, Brook.

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? And then secondly, did you expect to see any kind of dose response in some of the complement pharmacodynamics that you showed?

I will just answer the first one. We collected the samples, but they are not yet analyzed for CD38 expression.

So you see relatively early -- I mean, this maybe also helps a little bit address and give more context to the initial question on PD. There are 2 things I would like to draw your attention to, and these are complement and other CD38 positive cells such as AK cells that work as pharmacodynamic markers. And in both cases what you see is an effect at lower doses for HexaBody-CD38 compared to daratumumab and a more profound effect at the recommended Phase II dose for both aspects.

Thanks, Tahi. We have time for one more question. So who wants to ask the last burning question? Yes, the lady here in front, Brook.

Zoe Karamanoli 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, so is there -- yes, interesting in your thoughts here and whether there will be an education thing for physicians?

Yes. So I agree. When I talk about the learning curve, some of the reduction in incidence of Grade 3, I think, is related to us learning to use the drug better and intervene earlier when agreed to it there. Now you're correct. Patients were admitted for the cycle 1, day 15, and I have had patients that would have had a prolonged hospitalization by 1 day or 2 days because they might have had some additional fever. And obviously, you're never sure if there's an infection or not. And there's only so much control you have on a patient when he is admitted. But if I thought of those patients as an outpatient, truthfully, what they had was fever. Blood pressure might have been in the 100s, 110s, or high 60s, maybe 70s. There wasn't symptomatic hypotension. There was no end organ damage. There was no oxygen requirement of any real sort. And so 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 -- I would imagine, that's what I would do. And I'm confident that the Grade 2s can be kept outpatient.

Yes, I'm going to comment on this as well because this is my favorite topic, it really is actually, and the issue with that is that the grading for CRS was developed in the context of CAR-T. And it was intended to identify patients who go to the ICU versus the rest. So it basically was focusing on Grade 3. Grade 2 CRS, as it is currently defined, is a hodgepodge. And the hodgepodge is the equivalent of a patient who has fever, as Lorenzo was just saying, and maybe you give them 500 cc of fluids, and that's basically it. And the patient where you call the ICU to get a bed, and that granularity is not there. So we've tried to provide that granularity and I would encourage you to pay attention to how many patients actually require oxygen, 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. So next slide, please. So thank you all for joining us this evening in New Orleans, and special vote of thanks and I think a big applause to the truly exceptional speakers who have joined us here today in person and also virtually. So from all of us at Genmab, we wish you happy holidays and a healthy, happy and wonderful 2023. Thank you.