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

Hello, and welcome to Genmab's 2023 R&D Update and ASH Data Review. I'm Jan van de Winkel, President and CEO of Genmab, and I'm delighted to share with you some of the highlights for Genmab in 2023 as well as data from this year's ASH meeting. As always, we have a busy agenda. So, let's jump right in. Next slide, please. As a reminder, this presentation may contain forward-looking statements, and as such, may contain certain risks and uncertainties. Let's move to Slide 3. Genmab has a science-anchored and innovation-focused culture. Collaborations and partnerships have always been part of our DNA. During today's presentation, we will reference some of the products being developed under these strategic collaborations and this slide acknowledges those relationships. Let's move to our agenda on Slide 4. We will begin with a review of the excellent progress we made this year, as we advance towards our ambitious 2030 vision. Next, we will have a summary of the preliminary results presented yesterday at ASH from a dose expansion cohort in the ongoing trial of HexaBody-CD38. We are pleased to be able to provide you with a pre-recorded presentation of this data by Professor Andrew Spencer. We will then move to an overview of some of the epcoritamab data that was presented at this year's ASH. And for this, we are pleased to have a pre-recorded presentation by Dr. Martin Hutchings. With regards to our 2024 priorities, we will have a brief discussion of some key events we are anticipating. Finally, we will conclude the evening with what I'm sure will be a lively Q&A session. So, now, let's take a look at some of the highlights of the past year. Next slide, please. When we look at the events of the past year, the context of our strategy, the progress we made in 2023, is a reflection of our overall positive trajectory. Let's start with our expansion into the therapeutic area of Immunology & Inflammation or I&I. Last year, when we unveiled our 2030 vision, we expanded our focus to include both cancer and other serious diseases, where our antibody expertise could make an impact. This year, we announced that we would be entering the therapeutic area of I&I as a steppingstone to achieving this vision. This knowledge of specific -- the knowledge of specific immunological pathways that can be harnessed to fight cancer can always -- also be leveraged to create therapies for immune-mediated and inflammatory diseases. With our deep scientific knowledge about antibody biology and antibody technology, an expansion into this therapeutic area was a logical next step. To begin to accomplish this, we entered into a multi-year collaboration in April with argenx. Together, we have begun to jointly discover, develop, and commercialize novel therapeutic antibodies with applications in immunology as well as in oncology. And like Genmab, argenx has an impressive track record, and our companies share a science-focused and purpose-driven culture. We believe that by working together with innovative partners such as argenx, we can be faster, stronger, and help patients in need sooner, with the ultimate goal of improving the lives of as many people as possible through our innovative and differentiated antibody therapeutics. Hence, we are well on our way to that goal. At the end of 2023, there are now 8 medicines on the market that are powered by our innovation and antibody expertise. Excitingly, 2 of these, Tivdak and EPKINLY or TEPKINLY as it is called in Europe, and 4 of these approved therapies were created using our proprietary DuoBody technology. All of these products provide us with growing recurring revenue streams and significantly underlying profitability. As we have done in past years, we continue to use this revenue to invest in a focused and disciplined way throughout 2023, and this investment is reflected in key highlights from the past year. Next slide, please. 2023 was a truly remarkable year with multiple regulatory approvals for epcoritamab. As a reminder, Genmab is the commercial lead for EPKINLY in both U.S. and Japan, a first for our company. This is extremely exciting for us and a major milestone in Genmab's history. Our teams along with our partner, AbbVie were in place and fully prepared prior to the approvals. We are pleased with how the launch is progressing so far, but the current approvals are only the first step to potentially establishing epcoritamab as the core therapy across diffuse large B-cell lymphoma, follicular lymphoma and beyond. In June, we announced positive top line results from the follicular lymphoma cohort of the Phase 1/II EPCORE NHL-1 trial. This data, along with preliminary dose optimization, will be presented to you today by Dr. Hutchings. It also supported 2 exciting regulatory actions that we announced last month that the FDA had granted breakthrough therapy designation to epcoritamab for adults with relapsed or refractory follicular lymphoma after 2 or more lines of therapy and that the EMA had validated a Type II variation application for epcoritamab for the same indication. Together with AbbVie, we are advancing a robust clinical development program for epcoritamab across B-cell malignancies. In addition to the data in follicular lymphoma, you can also see this in the multiple Phase III studies currently in the planning that we anticipate will be initiated in 2024. Let's move to the next slide, before I look into our broad clinical development plan for epcoritamab. Together with AbbVie, we have an ambitious vision for the development of epcoritamab. In 2023, we had 3 ongoing Phase III trials. And for '24, we aim to potentially double that number with the addition of new trials that you see here highlighted in purple. These include a Frontline study in follicular lymphoma as well as additional Phase III trials in relapsed or refractory diffuse large B-cell lymphoma. The current encouraging data we have seen so far, including the data presented over the past few days at ASH, further support epcoritamab's combinability and highlight its potential to move into these earlier lines of therapy. Next slide. We also saw exciting progress with TIVDAK this year. With the positive results from both the confirmatory innovaTV 301 study in cervical cancer, and the data in head & neck cancer from the innovaTV 207 study. TIVDAK has cleared a very high bar for continued investment in development. We are very pleased with our plans to actively engage with health authorities on the next steps for TIVDAK in both of these indications, along with our partner, Seagen. Next slide, please. Another program that cleared a very high bar in 2023 is Acasunlimab, formally known as GEN1046, which we are codeveloping with BioNTech. We were very pleased to announce in November that we have planned engagement with health authorities on the design of a pivotal trial for Acasunlimab in second-line non-small cell lung cancer, and that we would share the data on which this decision was based at a medical conference in 2024. In addition to maturing this program, we are also expanding it with a Phase II trial in endometrial cancer that was initiated in September. Moving to progress we saw with other pipeline programs, we also noted in November -- and also, as we noted in November, we remain very encouraged by the clinical efficacy data we are seeing with GEN1042, and we are anticipating that we will have the data we need to determine next steps for this program in the coming months. Looking at some of our earlier stage programs, the Phase I/II trial of GEN1047 or DuoBody-CD3xB7H4, is currently in the dose expansion phase, an important step in progressing our CD3-based bispecific platform in solid tumors. And GEN3017 or DuoBody-CD3xCD30 started recruitment for our first-in-human clinical trial. Finally, we had 2 IND submissions near the end of 2023, GEN1059 or DuoBody-EpCAMx4-1BB and GEN1055 or HexaBody-OX40. Both of these antibodies are being codeveloped with BioNTech. You may recall that we announced GEN1059 during our Q3 results. At that time, I mentioned that we would have another IND this year and this is GEN1055, which just had its first preclinical disclosure during ESMO-IO Conference in Geneva. We look forward to both of these programs entering the clinic. Next slide. In 2012, we entered into a collaboration with Janssen to create and develop bispecific antibodies using our DuoBody technology platform. Three approved medicines have now come from this collaboration; RYBREVANT, TECVAYLI, and TALVEY. TECVAYLI and TALVEY have both been approved for the treatment of patients with relapsed or refractory multiple myeloma; TECVAYLI in 2022 and TALVEY just this year. According to Janssen, they are encouraged by the early success of both of these therapies, disclosing at a recent enterprise business review that both assets have $5 billion plus potential, and both are also being studied in combination with DARZALEX. At this time, I would like to briefly note that excitingly, the first presentation of data from the Phase III PERSEUS trial was presented as a late-breaking oral presentation at ASH today. This is a collaborative study between Janssen and The European Myeloma Network, evaluating a [ quadruplet specimen ] of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone in the treatment of patients with newly diagnosed multiple myeloma, who are transplant eligible. And as a reminder, this is the same indication as was explored in the Phase II GRIFFIN study. Turning back to Janssen's DuoBody therapies. The first DuoBody-based bispecific to be approved was Janssen's RYBREVANT. And for this therapy, Janssen announced additional regulatory submissions in non-small cell lung cancer based on the Phase III MARIPOSA-2 and PAPILLON trials. We believe the success of these bispecific programs highlight the potential of our innovative DuoBody technology and we look forward to seeing their continued development. Next slide. So, turning now to the HexaBody-CD38 data at ASH, it's my pleasure to introduce a video of Professor Andrew Spencer. Professor Spencer is the Head of Malignant Haematology, Transplantation and Cellular Therapies Service at The Alfred Hospital in Melbourne, Australia. He is an expert in multiple myeloma, and in addition to his many accomplishments, he is a primary Chief Investigator on the ongoing Phase I/II trial of HexaBody-CD38. We are very grateful to Professor Spencer for providing us with a review of this exciting data recently presented at ASH. Please play the video.

[Audio Gap] Haematologist from Melbourne, working at The Alfred Hospital, and I'd like to present on behalf of my co-authors the results from a Phase I/II study of GEN3014 in anti-CD38 monoclonal antibody-naive patients with relapsed or refractory multiple myeloma. As we all know, targeting CD38 has been a transformative event in the treatment of myeloma, now being incorporated into IMiD, a proteasome inhibitor-based therapy in frontline patients. So, GEN3014 is a product of a HexaBody platform, which results in enhanced complement-dependent cytotoxicity and stronger inhibition of CD38 cyclase when compared to daratumumab. It's hypothesized that targeting CD38-positive immune cells and reducing adenosine in the tumor microenvironment may relieve immune suppression and lead to enhanced activity of GEN3014 compared to available anti-CD38 targeting agents. This Phase I data using GEN3014 route showed preliminary activity in both dara-refractory and dara-naive patients. And what I will describe is small dose expansion among steroid-naive relapsed and/or refractory multiple myeloma patients. This was to confirm the initial efficacy findings and to add to these safety data. So, this is the expansion Part A of the trial. The primary objective of this was to evaluate the antitumor activity of GEN3014 with secondary endpoints, including safety, tolerability, pharmacokinetics and exploratory pharmacodynamics. So, GEN3014 is administered IV initially weekly at the recommended Phase II dose of 16 milligrams per kilogram in 28-day cycles, until disease progression or unacceptable toxicity. With respect to this particular presentation, data cut-off was at the median follow-up of 7.4 months. And based on this data, there is now a Part B of the trial that's been initiated, which is a direct comparison of GEN3014 to daratumumab. This dose expansion Part A enrolled 11 patients with the median age of 66 years and a median of 4 prior lines of therapy. Important to note that only 1 of the 11 patients has achieved a VGPR better to their prior line of therapy. And while numbers are small, it's important to compare this to what we've seen with responses to GEN3014. The median duration of treatment at the time of this analysis was 4.6 months. 4 patients discontinued treatment due to AEs, 2 we deem not related to GEN3014 and 5 patients discontinued treatment due to disease progression. Of the 11 patients who received GEN3014, 9 patients were evaluable for response, 6 patients achieved a response, including a stringent CR, 2 VGPRs and 3 partial responses, and 2 additional patients achieved minor responses. Therefore, the clinical benefit rate was achieved in 8 out of 9 patients. And responses were rapid with median time to response of 2 months. There were no new safety findings observed in this study compared to the initial Phase I data with 3014, and findings were also similar to those seen with daratumumab and isatuximab. Treatment-emergent adverse events are shown in Figure 3, and include hematologic events, headache, infusion-related reactions in 3 patients, maximum of Grade 2, and upper respiratory tract infections. None of these led to treatment discontinuations. There were 2 Grade 5 events, 1 cardiac arrest and 1 respiratory tract infection, but neither case was thought to be causally related to GEN3014 in these heavily pre-treated myeloma patients. Two patients were reported as having treatment-related serious AEs. One patient developed anemia requiring hospitalization and transfusional support after 4 cycles of treatment and 1 patient with an extensive cardiac history, including hyperlipidemia, hypertension, and AV block had a cardiac event requiring hospitalization. There was no QT interval prolongation related to the GEN3014 infusions and the exact cause of this event is unknown, but it was sought to be potentially or reported to be potentially related to GEN3014, with an abundance of caution. There was a range of pharmacodynamic studies done. They showed a rapid and sustained decrease in peripheral blood natural killer cells, and importantly, T-cell expansion was observed in 4 of 7 evaluable patients. GEN3014 induced transient reduction in total complement lytic activity, consistent with the hypothesized increased CDC activity of GEN3014, but it did importantly not exhaust complement activity. In conclusion, the results from this Part A expansion show encouraging clinical activity, with 8 of 9 evaluable patients showing a clinical benefit rate. And importantly, the depth of responses seen in these patients was markedly improved compared to the responses seen in the immediately prior line of therapy that patients had received. There were no new safety signals, and as was hoped to be seen, there was potent CDC activity generated with GEN3014. All of these have led to the opening, as I've indicated to a trial comparing GEN3014 with daratumumab to further evaluate the potential of GEN3014. So, on behalf of my authors, I'd like to thank the patients, study investigators, site personnel, for their participation and help in undertaking this study. Thank you very much.

So, turning now to the epcoritamab update at ASH, I would like to introduce a video by Dr. Martin Hutchings. Martin is a Hemato Oncologist at Rigshospitalet in Copenhagen, Denmark. He is an expert in the treatment of malignant lymphoma and a key investigator on the first Phase I/II study of epcoritamab. We appreciate Martin being with us once again, to review some of the epcoritamab data presented at the 2023 ASH. Please start the video.

Hello. My name is Martin Hutchings. I'm a Senior Consultant at the Department of Hematology and the Phase 1 Unit at Rigshospitalet in Copenhagen, Denmark and a Professor of Hematology at the University of Copenhagen. And it's a privilege for me to be able to share with you selective data from the different abstracts involving epcoritamab that's being presented here at the Annual ASH meeting in San Diego, California. And the first and perhaps most important one was presented by Dr. Linton from the U.K. and involves the first data from the pivotal expansion cohort in follicular lymphoma patients with a relapsed/refractory disease going into the EPCORE NHL-1 study, which is monotherapy epcoritamab in different B-cell lymphoma histologies. So, this is a disease setting where there is no real established standard. It's a pretty -- and there are a couple of standards in first-line treatment for newly diagnosed patients. But with the relapsed/refractory disease, there are many treatment options, and particularly for those patients with high-risk disease, including patients with so-called POD24, that's relapsed or progressing within the first 2 years of completion of primary treatment or with a primary refractory disease, there are really no good standards of care. So, this is a place where there is room for improvement. This is the design of the NHL-1 study in the follicular lymphoma expansion cohort. Patients were involved if they had relapsed/refractory disease. They needed to have at least 2 prior lines of treatment, the measurable disease and follicular lymphoma of Grade 1 to 3A, so no transport of follicular lymphoma patients in this study. The study included also an optimization phase, and this was a group of patients treated towards the end of the study, where the step-up dosing, which is used always with epcoritamab was extended by 1 week, with an extra intermediate dose of 3 milligrams and this in order to even further optimize the toxicity profile by mitigating further the risk of particularly high-grade cytokine release syndrome, which is the most important toxicity of the bispecific antibodies. These were the characteristics of the patients going into the study, total of 128 evaluable patients, quite a sick group of patients. You can see that the majority of patients had in fact what we call POD24, so high-risk patients, and more than 2/3 of patients with primary refractory disease. So, these are difficult to treat follicular lymphoma patients, [ actually ] a bit different from the classical follicular lymphoma patients, which are generally expected to live quite long on each treatment line. So, of the 128 patients who went into the study, the median follow-up was just under 1.5 years, and the median number of treatment cycles given to each patient was 8. The patients who discontinued treatment, which is just under 2/3 of the patients, the majority of those discontinued due to progressive disease, but also adverse events played a role. And of the 19% of patients who left the study due to adverse events in my -- and half of these were caused by COVID-19. And it should be noted, when we look at the outcomes of this study so far that it was entirely carried out during the COVID-19 pandemic and that plays a role in understanding the results of a treatment, which apart from its nice effects of the high anti-cancer efficacy, also has a consequence which is B-cell depletion and B-cells are the cells that you need to respond to vaccine and to fight viral infections. Nevertheless, the benefit/risk ratio looks really good. That is because the vast majority of patients respond to the treatment. The overall response rate is 82% despite them being really high-risk in refractory patients, including 63% with complete responses as assessed by PET-CT. You see in this slide a number of different high-risk groups singled out, and you can see that despite these patients being on high-risk with POD24, refractoriness to the most recent treatment line, double refractory, meaning refractoriness to both an anthracycline and -- sorry, to an alkylating agent and rituximab-containing therapies. The high response rates and high complete response rates were consistent even across these high-risk subgroups. As we generally see, when patients are exposed to epcoritamab, the median time to response, and indeed to complete response is very short. It is synonymous with the first PET-CT assessment of disease in this study, which is after 5 to 6 weeks. So that's why the median time is just under 1.5 months. You can see that the median progression-free survival in the overall population is over 1 year; at this point, 15.4 months. That's a moving target because, like I already said, the median follow-up is relatively short, it's under 1.5 years. You can also see that just over 2/3 of the patients reached not only a response but also the important MRD negativity. This is progression-free survival. The gray curve represents all the patients and the green curve represents the majority of patients who achieved a complete response. So, you can see that despite the limited follow-up, this looks like a long-term benefit of the treatment. When looking at the toxicity, not surprisingly, did we see cytokine release syndrome as the most common adverse event. Also injection site reactions because this is a subcutaneously administered drug, which sometimes gives a little redness of the skin, where it's injected. But these are really manageable side effects, including the cytokine release syndrome, which in the vast majority of cases were of Grades 1 and 2, which means easily manageable and quite a commonly transient phenomenon. But you also see that COVID-19 happened in a relatively large proportion of patients and in some of these patients indeed of high grade, meaning that it required hospitalization or even intravenous antibiotics. The safety was generally regarded as manageable. We had just over 1/3 of the patients with treatment-emergent adverse events considered related to epcoritamab, so that also, as you've always seen in relapsed/refractory cancer population, adverse events, which are not necessarily related to the treatment, but to the disease or the condition of the patient a priority of the treatment. And like I said, this study was conducted during the COVID pandemic and this not only reflected the adverse event profile, but also the number of patients who had to discontinue treatment due to the COVID-19 infections. I mentioned that parts of the patients going into this study were treated according to a dose optimization schedule in Cycle 1. That meant that they had an extra intermediate dose, and you can see in this slide that this had indeed a very favorable effect on the risk of cytokine release syndrome and particularly of high-grade cytokine release syndrome. You'll see here that going -- the rate of cytokine release syndrome generally in the pivotal cohort was 66%. Albeit, the vast majority being a Grade 1 or 2, it's still a relatively high number and that was reduced down to 48%. And particularly, the number of Grade 2 and 3 cases would really reduce markedly Grade 2 from 25% to 8%, and Grade 3, which is where cytokine release syndrome is beginning to get quite tricky to manage from 2 to 0 patients. And this is really important, particularly if you want, as is the case for epcoritamab to deliver the treatment in a purely outpatient setting. So, the conclusions from this presentation, first disclosure of results from the pivotal cohort in follicular lymphoma treated with single-agent epcoritamab is that the responses were very common and so far, quite durable even though the follow-on is relatively limited at this point. Overall response rates were 82%, including 63% with complete response. And importantly, at the end of treatment, 67% of patients achieving MRD negativity as assessed by the clonoSEQ. Depth of response, good, but also the duration of response looking quite good so far, even though, like I said, the follow-up is relatively limited. And the side effect profile as expected with epcoritamab, as we've seen in other histologies and very positive to see that the dose optimization schedule during Cycle 1, quite markedly and clinically relevantly reduced the rate of cytokine release syndrome, particularly of Grade 2 and higher. So, another abstract was presented by Julie Vose from the U.S. And this was also a study looking at optimization of the side effect profile of epcoritamab. This is in the -- in another cohort from the NHL-1 study in diffuse large B-cell lymphoma. This is the study, which was the background for the approval of epcoritamab in this clinical setting, which is the treatment of large B-cell lymphoma with 2 more prior treatment lines. So, in this setting, also, just like in follicular lymphoma, the most important side effect is cytokine release syndrome. It's generally manageable, but it can be improved, and this cohort was an attempt to improve on the cytokine release syndrome profile in the histology of diffuse large B-cell Lymphoma. This is an overview of the study as it's given. So, patients are given a weekly epcoritamab for the first 3 cycles, and then twice a month, bi-weekly, and then from Cycle 10 and onwards, every 4 weeks. And in this cohort, patients were instead of any steroid, prednisolone or methylprednisolone, given dexamethasone instead of the more commonly used steroids. This had a marked effect on the side effect profile, I'm just skipping quite quickly to the results of this optimization. You can see that in the general expansion cohort, which has repeatedly been reported, 157 safety evaluable patient cytokine release syndrome was observed in just over half of the patients. And even though the majority of cases were mild Grade 1 or 2, there were individual cases with Grade 3 cytokine release syndrome. This is where treatment requires evasive presses and mechanical or high-flow oxygen. And look at the cytokine release syndrome frequencies after the optimization, including not only dexamethasone instead of any steroid, but also an improved hydration scheme, as noted on the right, you'll see that this frequency of cytokine release syndrome went down from 51% to 22%. So, a marked reduction in the number of patients experiencing this sometimes challenging side effect and importantly, no cases in the small cohort with optimization of Grade 3 or higher cytokine release syndrome. This was not only seen clinically, but also when measuring the predominant cytokine -- leading to cytokine release syndrome, Interleukin-6, you can see that with the optimization regimen, much lower concentrations in plasma of Interleukin-6 than observed in the pivotal cohort of 157 patients where dexamethasone was not mandatory in use. We'll skip quickly to the next presentation, which was given by Dr. Kim from South Korea. This was from the NHL-5 study, which is a study looking at epcoritamab given in combination with lenalidomide in relapsed/refractory diffuse large B-cell lymphoma. So, this is a combination study of epcoritamab in [ relapsed/refractory ] large B-cell lymphoma setting. This is the line-up of the study. In fact, it's a multi-arm study, and we're here looking only at the arm-1 of this study, where patients could be included if they had a large B-cell lymphoma histology, including high-grade lymphomas or follicular lymphoma Grade 3b, and they needed to have a relapsed/refractory disease that could be included even with just 1 prior line of treatment, if they were not eligible for high-dose chemotherapy with transplant or CAR-T. They could have had prior CAR-T, but not a prior exposure to a bispecific T-cell engaging antibody. So, in this study, patients were treated with the normal, I would say, step-up dosing of epcoritamab. So over 2 -- a priming and an intermediate dose to the first full-dose of epcoritamab on Cycle 1, day 15; then weekly treatment for the first 12 weeks; then bi-weekly for the next 6 months; and then from cycle -- sorry, for the next 9 months and then a fixed duration treatment, so no treatment beyond Cycle 12. Along with this, Lenalidomide was given at the full dose of 25 milligrams in the typical 21 out of 28-day schedules of the first 3 weeks of each 4 weekly cycle. In this study, the optimized steroid strategy to mitigate cytokine release syndrome was not used. It was possible to use dexamethasone but also accepted to use, for example, prednisolone. The patients were few, but quite difficult to treat. 35 patients with relatively high-risk features, including a few patients actually with triple-hit lymphoma. You can see that the revised IPI, which tells you about the prognosis of these patients, the majority -- a small majority of patients had a risk score of 3 to 5, which is what we consider high-risk. Of these patients, the median number of prior lines of therapy was 2 ranging from 1 to 4, and in fact, just under 1 out of 4 patients had been exposed to and failed a prior CAR-T treatment, just under half of the patients had primary refractory disease. So, testament of a relatively difficult-to-treat population. These patients had a median follow-up of 8.2 months. So these are not particularly mature results. So we have to take, of course, the durability of the benefit that we see with a pinch of salt. But the responses are what they are, and they are frequent, so overall response seen in 72% of the patients, including 53% of patients with complete responses as assessed by PET-CT. And comparing, even though it's an indirect comparison between different cohorts, comparing with the pivotal study in the same patient group, it seems as though the addition of Lenalidomide adds at least 10% to both the overall and the complete response rate when compared with single-agent epcoritamab treatment. You can see on the right that the subgroup analyses did not identify any patients with less or more chance of benefit to this treatment independent of different prognostic and predictive subgroups. I already said that the follow-up is really quite short. So, it's very early to assess the durability of these responses. But you can see in the swimmer plot and also testified by the durability of complete response, survival curve on the right, that there are indeed a hint that many of these responses, at least at this point in time, quite durable. The benefit is also observed when looking at minimum residual disease. These are measurements of circulating tumor DNA and you see negativization of the ctDNA levels already at the first assessment point which is Cycle 2, day 1. So, already very early during treatment, we see negativization of MRD, which is commonly regarded as a very good prognostic sign which is predictive of long-term benefit of any treatment. The safety observed in this small cohort was consistent with the individual components of the treatment. We know the side effect profile of Lenalidomide really well because it's a drug that's been used for decades, and it seems as though the addition of Lenalidomide to epcoritamab does not give any synergistic safety concerns. There is cytokine release syndrome as in any treatment with epcoritamab alone, and then we see the rest of the side effect profile dominated by the side effects of Lenalidomide, constitutional symptom, constipation rash, and then a few side effects where there is overlap in the profile between epcoritamab and Lenalidomide particularly the cytopenias; neutropenia and thrombocytopenia. Cytokine release syndrome was observed as in any study of bispecific T-cell engagers and it seems as though the rates of cytokine release syndrome were more or less the same as when this -- as when epcoritamab is given on its own. So 69% of patients experiencing some degree of CRS with the majority being of Grade 1-2. So, the conclusion from this study was that you could add to the efficacy of epcoritamab by adding Lenalidomide and there are many good explanations why Lenalidomide and its immune modulation might help the mechanism of action of the T-cell engaging but time does not allow for me at this point to discuss this any further. Another presentation was given by Dr. Belada and this is from another multi-arm study, the NHL-2 study, which is so far a 10-arm study of epcoritamab given with different standards of care treatment in different histologies and different treatment situation. And this presentation was from the Arm-8 of this study, which is a combination of epcoritamab with what we call R-Mini-CHOP, which is a version of CHOP with [ 56% ] doses of the cytostatic agents of the chemotherapies, usually given to elderly and frail patients with newly diagnosed diffuse large B-cell lymphoma. This was indeed the setting of a disease for this study. We can cure a few patients with R-Mini-CHOP, but the majority of patients do not achieve a cure or long-term disease control. So, it's not considered an optimal treatment, but it can be a good treatment for patients who are unable to tolerate full doses of R-CHOP. This was the design of the study. So you can see that epcoritamab was given weekly for the first 2 cycles, which is 8 weeks and then every 3 weeks until the end of the 6 cycles of multi-agent chemotherapy and then for another 2 cycles every 4 weeks. So, it's a fixed duration treatment in first line. These are the characteristics of the patient, a relatively small group of patients, 28 all in all. And, as you would expect, a high median age of 81 years, because these are patients who could not be eligible for full dose CHOP-like chemotherapy. So, with high median age and also a relatively high level of co-morbidity. You can see on the right that some of them had adverse prognostic features with more than half of the patients having, by the definition, of 6 centimeters bulky disease and also more than half of the patients with elevated LDH or lactate dehydrogenase, which is generally a testament of aggressive and high-risk disease. The majority of patients, 86% had de novo diffuse large B-cell lymphoma, 11% transformed disease mainly from follicular lymphoma. The median follow-up is relatively short, 9.4 months. So the median follow-up beyond treatment is actually not more than 4 to 5 months after the end of treatment. The majority of patients continue the treatment, including the 8 cycles of epcoritamab. Importantly, the addition of epcoritamab to R-Mini-CHOP did not affect the dose intensity of the chemotherapy, and this is really important when you try to improve chemotherapy, if it's at the expense of dose intensity. We know from several study settings that this will compromise the efficacy. This was not the case in this study, you can see the relative dose intensity is maintained for all the components of the R-Mini-CHOP. It was a safe combination, even in the frail group of patients, cytokine release syndrome observed in half of the patients, but in all cases of Grade 1 to 2. And then, we saw the expected toxicities of the multi-agent chemotherapy, including neutropenia where there might be some overlap between the CHOP components and the epcoritamab itself. When looking specifically at CRS, like I said, 50% of patients experienced the cytokine release syndrome, half of them with a maximum of Grade 1 and half of them with a maximum of Grade 2, but no cases of Grade 3 or higher cytokine release syndrome. All cases were resolved, and in order to resolve the cytokine release syndrome, half of the patients had to receive tocilizumab. So, in this frail and elderly population, the combination of epcoritamab and R-Mini-CHOP was indeed very effective. Responses were seen in all patients. So, overall response rate of 100% which is a rare phenomenon, including 87% of patients with complete metabolic response as assessed by the PET-CT. And among the patients who completed the 6 cycles of R-Mini-CHOP with epcoritamab, this is all patients, [ but too ] in this observation, the overall response rate was 100% including 86% with complete metabolic responses. Again, the median time to complete response was 1.5 months, which is the same as 2 cycles of R-CHOP chemotherapy. So the first -- sorry, R-Mini-CHOP chemotherapy, which is the first point of assessment of disease. It's a little bit immature in my eyes to talk about durability when you have a median follow-up, which is less than 1 year, but this is the take on it. So, what you see here is the durability of the responses, which, like I said, in the vast majority of cases were complete. So, at least at this point, early point in time, the responses seem durable beyond the end of treatment, which is approximately 4.5 months, 5 months. Median progression-free survival, of course, not reached because the mass majority of patients had complete responses and they were so far durable. But of course, this requires extended follow-up. So, the conclusions from this study was that even in a very frail and elderly population, R-Mini-CHOP could safely be combined with epcoritamab and at least in a preliminary view, leading to surprisingly or very high response rate, very high complete response rates, and hopefully, many of these responses will be durable, which is not always the case when R-Mini-CHOP is given on its own. So, I'll move on to the next presentation, which was given by Dr. Brody, and this was another take on one of the cohorts from the NHL-2 study. That was the arm with the combination of epcoritamab and GemOx in patients with relapsed/refractory diffuse large B-cell lymphoma. And these were patients who were not eligible to receive high-dose chemotherapy with autologous transplants, so a difficult to treat patient population R-GemOx is a -- it's not the best treatment for relapsed/refractory diffuse large B-cell lymphoma, but it is a standard of care therapy for those patients ineligible for more intensive regimens. So, in this cohort, which is the Arm-5 of the NHL-2 study, patients had to have relapsed/refractory disease and they needed to have at least one prior line of treatment and assessable disease as you see on the left. The schema of the treatment was to give GemOx for 4 cycles in the standard doses of that regimen, and then with epcoritamab given weekly for the first 3 cycles, then every 2 weeks for the next 6 cycles, and then from Cycle 10 and onwards until progression, the maintenance treatment of epcoritamab, every 4 weeks. These were the characteristics of the 65 patients who went into this study. A median age of 71 years, reflective of the fact that they couldn't be candidates for aggressive treatment, and you can see that the majority of patients had de novo DLBCL with 22% of patients having transformed disease. Looking on the right in the red box, you see the real prognostic features of these patients showing that they were really a high-risk group. More than half of the patients with primary refractory disease, 3 out of 4 patients with refractoriness to the most recent treatment line and even 29% patients with a prior CAR-T of whom the majority were refractory to the CAR-T treatment. So, despite these patients being ineligible for intensive therapies, almost 1/3 of them had been exposed to and failed CAR-T. The median follow-up for this cohort so far is just under 1 year, 11.4 months. And you can see that while just under half of the patients are still on treatment, because there is treatment with epcoritamab until progression, you see that just over half of the patients have discontinued treatment. The majority of these patients discontinued due to progressive disease, testament of the high-risk and difficult-to-treat situation that they're in. Nevertheless, responses were very frequent with overall response rate of 80% including 57% achieving a complete metabolic response as the best response. The median time again to response was 1.5 months. So that's the time, the timing of the first PET-CT response assessment after 6 weeks of treatment. Again, you can see that with the caveat that the follow-up being relatively short, the responses seemed to be, in many cases, durable. This is the durability of the complete responses, and you can see that very little drop-off is seen during the first 6 months, and then after the end of the multi-agent -- the dual-agent chemotherapy treatment, there are progression events, which lead to a drop off of durability of responses. Median overall survival for this group not reached, so the majority of patients are still alive at this point for follow-up. Subgroup analyses do not really show any significant differences between the different prognostic and clinical subgroups, including patients with prior CAR-T, there is a signal that they might respond a little bit poorer but, but it's not really significant out of these subgroup analyses, but of course, the number of patients is relatively small. What about safety? This is a combination of chemotherapy with the bispecific, so we see the most common side effects are the cytopenias; thrombocytopenia and neutropenia, which are -- where there is overlap in the toxicity profile between the bispecific and the chemotherapy. But apart from the cytopenias, the most common side effect is cytokine release syndrome, which fortunately is almost invariably seen of low grades, so Grade 1 or 2, although there are a few cases of Grade 3 cytokine release syndrome observed in this population. So, really consistent with previous reports and consistent with the well-known side effect profiles of the individual components of the combination. Like I said, cytokine release syndrome observed quite commonly in 51% of patients, the vast majority of Grade 1 or 2 and result in all cases, with 18% of patients needing tocilizumab for the treatment of Grade 2 or higher cytokine release syndrome. Like in most of the studies of epcoritamab, the most common timing of this cytokine release syndrome is following the first full dose of the antibody, which is on Cycle 1, day 15, so after 2 weeks of treatment. So, again, 80% with responses, 57% with complete responses, which is quite favorable also in comparison to our GemOx which is given alone and has been given in this situation for many years. So, these are -- this is a treatment that we know quite well even though it's not a direct comparison, of course. The median duration of complete responses so far, 13.3 months, but this, of course, needs further follow-up because the median follow-up for this cohort is still relatively short. Interesting to see that even in CAR-T exposed relapsing patients, there seems to be a high benefit with this combination. So, this was my selection of the different epcoritamab containing abstracts presented here at ASH in 2023 in San Diego. I hope you have enjoyed this selection. I want to direct your attention to the highlights, which is the impressive efficacy seen in the pivotal cohort of follicular lymphoma patients treated with monotherapy epcoritamab with very high overall and complete response rates and many of these really durable. It's a meaningful single-agent treatment for a difficult-to-treat population with relapsed/refractory disease. I also showed you different results from interesting combination studies and also results from the different dose optimization cohorts, both in follicular lymphoma, but also in patients with diffuse large B-cell lymphoma, where we see that in the case of follicular lymphoma, extended step-up dosing really reduces the risk of cytokine release syndrome and severe grades of cytokine release syndrome and in diffuse large B-cell lymphoma, introduction of dexamethasone and optimized hydrating schemes also significantly reduce the risk of cytokine release syndrome leading to epcoritamab being a treatment which can safely be given in a purely outpatient setting. Thank you very much.

Thank you to our inspiring speakers for excellent presentations. So, now let's move to some of the key events we are anticipating for 2024. You will see we have a lot to look forward to in the coming year. Next slide. In 2023, Genmab made key strides towards meeting its 2030 vision, making for a transformative year in our company's history and of patient care. But we are not resting on our laurels, 2024 is shaping up to be just as momentous, further establishing our independent destiny as a company and giving the people we help new ways to fight disease. Here is how. We anticipate multiple approvals for epcoritamab. This dual body-based bispecific, co-developed with AbbVie is Genmab's second company-owned product to hit the market, and we expect to receive European and U.S. approvals in follicular lymphoma in the second half of 2024. In the meantime, we look to file for approval in Japan in this indication in the first half of 2024. As I already mentioned, we will also start multiple Phase III trials with epcoritamab with the goal of moving into earlier lines of therapy. TIVDAK, our company-owned therapy is ready to file with regulatory authorities in Europe and Japan for cervical cancer as soon as the first half of next year and we are engaging with health authorities on next steps in head & neck cancer. Promising data from GEN1046, now known as Acasunlimab is forthcoming as early as in the first half of 2024, while we engage with health authorities planning for a Phase III. Not far behind, we are eager to share data of GEN1042 in 2024. This may include head & neck and squamous and non-squamous lung cancer. As these progress, we will also be pushing forward with other promising programs including data from GEN1047. Final, we look forward to a highly anticipated results of the head-to-head trial of GEN3014 and DARZALEX FASPRO in the second half of next year. Let's move to the next slide. Now it's time for a Q&A session. And I'm very pleased to note that we also have members of our Executive Committee to answer your questions. Our Chief Development Officer, Judith Klimovsky and Chief Medical Officer, Tahamtan Ahmadi will be here with us to answer your questions. And we will begin by taking questions from those of you participating in the teleconference,. And to ask a question over the webcast, please click the "Ask-a-Question" button, type in your question and click submit. I think Sophie is moderating the Q&A. So let's start for a lively Q&A.

[Operator Instructions] So to start, we would like to take our first question. And our first question comes from James Gordon from JPMorgan.

Hello, James Gordon, JPMorgan. A couple on HexaBody-CD38, please. The first one was about cardiovascular risk based on the Phase I data. So, there was a comment on a Grade 4 cardiac event being potentially treatment-related. So, would that make sense mechanistically, and how much of a concern is that? And I know some of it was probably comorbidities that didn't seem to be a lot, but 2 out of 9 patients having a serious cardiac event does look quite high. So, any thoughts on whether that does look like it's actually mechanistic or start of a trend or just noise. This is the first question, please. Second question, I'm assuming the HexaBody-38 Phase II head-to-head data, which could next year if J&J opt-in, just latest thoughts on what a Phase III program might look like or what range of scenarios? Has this been discussed with the FDA? Would it be -- do you go straight to frontline and you could use a fast surrogate endpoint or it might take quite a long time and DARZALEX could already be well-established as the add-on to [indiscernible] bispecifics by then. And then third and final question, just J&J hosted an event last week, and there was quite a lot of chat about multiple myeloma, but they were talking a lot about bispecifics and CAR-T and they didn't mention HexaBody-38. How would you interpret that? Have you had any feedback from them about this data or about how excited they are? That will be the third and final question.

Thanks, James. Excellent questions, and I think I'm going to hand over first to Tahi, who can, I think, address all 3 and maybe Tahi, you can start with the cardiac Grade 4 events and take it from there.

Yes. So, I do want to thank you for the questions. I'm going to try to address them one by one. Cardiovascular, I think we were clear in the last call and I think also if you had followed what Andrew Spencer was describing. These cases are heavily confounded. I mean, we're dealing with a Phase 1 population, first-in-human trial population by and large in this part of the trial. The trial was originally, they ran in jurisdictions where it was incredibly difficult to find actually dara-naive patients or CD38, I should say, naive patients. And so, while this was rated as possibly related because in a way-- this is the way it works in a first-in-human trial, a patient who had all these confounding factors, including a pre-existing AV block, I think the cardiac event in our mind and also in the internal DMCA as well as the external DMCA that sits on the study, doesn't really get to be associated with the CD38-HexaBody. And so, we also -- we don't really have a good explanation as Andrew was mentioning in his presentation. We actually have concomitant EKGs who didn't show any electrophysiological changes which is the one thing that you would want to pay attention to. So to take your words, we consider this to be noise, and I think I've said this many times before the actual truth around the safety profile and efficacy profile will come from the head-to-head. We have a direct comparison in a comparable population and that study is well underway, and this is also in running in jurisdictions where access to CD38 patients that are naive -- patients who are naive to CD38 therapies is somewhat noisier. And so it's a less sicker population that is getting involved in that study. So that was the first question. The second and the third question, are actually easily answered. They are in one sentence and that is, it is Janssen's right to opt-in by contract. And then Janssen can do and decide how to develop HexaBody-CD38 by their own preferences on how they like to. We didn't have any discussions with them. We have a regular data exchange on the data, and that's basically where it stands. And similarly, I think like because they haven't opted and I think it's prudent for them not to talk too much about something that they have not yet opted in. So I don't pay too much attention to why they may have not mentioned it because they haven't yet opted in.

Thanks, Tahi. Do you want to comment on the second question on the potential Phase III type strategy or do you want to leave that to J&J?

Well. I mean, as I mentioned, I think it would be most prudent for J&J to comment. But I mean -- obviously, J&J has a number of tools in multiple myeloma. Obviously, J&J has been very public about that they want to continue to own that space. And so -- and that CD38s are a key component of that space. I think that's probably where we should leave it.

Thank you. Thank you Tahi. Thanks James. Sophie, let's move to the next question.

Our next question comes from Christopher Uhde at SEB.

So the first would be on HexaBody-CD38, which is -- so how -- I mean, apart from obviously going -- choosing sites where dara is not super widely used, how well can you do to maximize the accrual rate? Because I guess we heard some experts in the program talk about -- well, sounding a little bit concerned that it would be difficult to recruit too. So that's the first question. And then, for the EPCORE NHL-5 data, do you have plans ahead of Phase III to optimize the dosing of Lenalidomide because obviously, there was a super high dose reduction rate there. And then, thirdly, can you comment on what you can do on the issue of Grade 2 CRS, either management or prediction? I guess we saw some data from Roche on that with Glofit. But obviously, it could be quite important to get on top of that to get wide use in community setting. So those are my questions.

Thanks, Chris, for the questions. I think I'm initially going to hand them over again to Tahi, and maybe for the last question, maybe Judith also step in on the Grade 2 CRS. But Tahi, why don't you get going on HexaBody-CD38 and the NHL-2 data.

Well, so, there was a couple of questions, right. There were questions on Epcoritamab and there were questions on HexaBody-CD38. And the question on HexaBody-CD38 was about the core. I think we've been very clear that we are on track and the core exactly as we predicted -- how am I going to say this? I think the people that you talked to, the standard KOLs, don't necessarily live and operate in the countries where the study is going to majority recruit. I think it's probably the truth. If it's actually public, you can look at the clinicaltrials.gov disclosure and absolutely with your question pointed to the right direction, the flip side of the massive success of daratumumab is that it is not that easy to find places in the world where daratumumab is not made available by J&J. But there are still countries in the world, where this is not that easy, and they are predominantly in Eastern Europe, and this is where we are running this study. And patients exist there as much as in any patients in other countries. And so we actually have no core problems right now. We're right on track actually exceeding it now. So, that's the CD38 question. And then, the second question was on Lenalidomide and the data. Well, this is like an age old story, right? Lenalidomide was, the dosing was essentially approved for multiple myeloma and it doesn't necessarily behave the same way in lymphomas. It's slightly less well tolerated. Nonetheless, the label dose is 25 milligram and that's what you start. This is what you -- if you do a registration study or are being asked to adhere to, unless you want to get into discussions with the agency around what the contribution of component is again. So, from that, I think the most prudent way to move forward is to use the labeled dose and then have very well-standardized and also like in clinical practice utilized dose reduction criteria for the reduction of Lenalidomide I think this is straightforward. I'm going to make a comment on the last one, and I think Judith can also add on that. So it's absolutely correct that Glofit presented data on tumor metabolic volume. We have the same data as well. I think it's also connect the work that allows investigators to identify -- really actually, in my mind, it's about 2 things, right; to identify the risk of CRS Grade 2 or above and/or give them guidance on what degree of pre-medications they should aim for, is going to be incredibly helpful and frankly needed in order to move these drugs into settings away from these larger institutions to community settings. And so, I think everybody is working on the same thing. We have the same data. We have a pretty large data set that we are analyzing and we will, I think in the near future, present some form of an algorithm that they can guide actually physicians on when to use what and what the risk is. A lot of this needs validation, and so it takes some time.

Thanks, Tahi. Judith any further comments on the reduction?

Yes. So, I want to make 2 comments. One, with regard to the [ EPCORE LEN ], in fact, the dose reduction of LEN is not so high. It's only 30% of the patients, which is even less than other combinations using LEN as the setting. And as Tahi alluded, this is because the starting dose is the dose as per label, which is 25, and the most common reason for adjustment is neutropenia which is quite common. So we, in general, the [ EPCORE LEN ] regimen is very well tolerated. With regard to the Grade 2, in addition to what I said as a comment, as you saw, the dose optimization in both settings, DLBCL and FL, with very simple measures as hydration or dexamethasone allows for outpatient dosed and seems to control very well, not just the rate, but even the grade 2. So we are confident that with this algorithm that Tahi alluded and the measures implemented in the optimization, this will be a drug that can be used in the community centers.

Yes, and I may want to add. This is actually one of the delays that we had that -- we had an had an algorithm that was irrelevant now because we've been able to reduce the CR8 significantly. So, the algorithm in the past is useless because we've been able to reduce Grade 2s to a point where you have to develop a new algorithm.

Thanks. Thanks, Tahi. Thanks, Judith. I think we need to go into the next question.

Thank you. So the next question is from Michael Schmidt at Guggenheim.

This is Yige on for Michael. Two quick ones from us. The first one on CD38 HexaBody. So, what should we look out for beyond response rates that would give you confidence in the head-to-head study from the ASH update, such as PD biomarkers or durability or maybe safety data? And then the second question on EPCOR, you've talked about some interesting findings on the dose optimization for both DLBCL and follicular. Is there any potential to apply your optimized dosing schedule to EPCOR label for DLBCL and how do you plan to integrate this schedule into your ongoing clinical trials?

Thank you for the questions. And I think, Tahi, you can probably start with both, and then Judith can probably step in for the diffuser B cell lymphoma optimization. Tahi?

Yes. So, I think I mentioned this on the Q3 call, maybe the initial hypothesis on hexamerization was that it would increase the response rate to a degree and it would increase the depth of response. The depth of response in multiple myeloma, very clearly directly relates to the duration of response. And so I think that was what I indicated. I think that's also what I think makes more sense to pay attention. I think the depth of response in this relatively small data set looked extremely impressive to us. And there's 1 stringent CR, there is this 3 VGPRs, some of these patients may very well continue to improve, and so that's where we are in terms of definite response. And I think the ultimate truth, of course, will come in the head-to-head comparison, that's when we will see this in a head-to-head comparison. But this is where we take our confidence from. But we believe the drug doesn't really have a different safety profile by and large. It looks like daratumumab more or less, if you ignore these cardiovascular events, which are very noisy. But the depth of response looks very impressive. That's where we are coming from. On optimization, yes, the ultimate goal is to get this in label and we have the data and we already had the interactions. And yes, these things already have been implemented in all ongoing trials, both for follicular lymphoma and diffuse large B-cell.

Thanks, Tahi. Judith, you want to add anything to that?

Yes. Only that it takes time to amend the protocol, so some of the data -- most of the data that was presented at ASH this year was with a prior regimen before we implemented the optimization. So, we are doing this as we speak across the world. and for the cohort, either in both indications, meet the number of patients that could satisfy regulatory requirements or a change of label. So you are absolutely right.

Thanks Judith. Thanks, Tahi. Let's move to the next question.

Our next question comes from Xian Deng from UBS.

Thank you for taking my questions. So, three please. So the first one is just on timing. So you have 3 -- you will be initiating 3 Phase III trials next year for epcoritamab. So just wondering, could you give us a sense of roughly how long each of the trial will take? Is it fair to assume the second line, DLBCL? Probably they're going to be faster than frontline follicular lymphoma? So just roughly some timing, roughly how many years each trial would take, that'd be great. Second one is epcoritamab. So, and I noticed you run this trial with our [indiscernible]. So sorry, apologies if I missed this. So just wondering, is your trial for this going after sort of all comers in front line? Or are you focusing on some sort of high-risk patients? And, is the goal sort of to reduce the chemo part or it has a Rituxan part? So just sort of thinking going forward, do you think this could be a differentiating factor if you're trying to reduce, let's say, the chemo part? And the third one is that sort of just -- you have several data sets now with some sort of small data set on patients with prior CAR-T, and knowing this is all sort of early- stage dataset, but just wondering, from your end with all the data you've seen, what is the general sense about any sort of potential impact on EPCOR post-CAR-T?

Thank you very much for the questions. Let's move first to Tahi and then maybe Judith, you can take the last one, and then see whether we can then ask Thai to step in there. Thai maybe you can start.

Lots of questions on EPCOR. So the first question was on how long it takes for Phase 3s to run, and you're absolutely right, it takes not as long in the relapsed/refractory diffuse large B-cells setting that it takes in frontline follicular lymphoma. I don't think it makes a lot of sense to be specific here because a lot of this is related to assumptions on accrual and the time to event, but I can guide you a little bit when for follicular lymphoma, there are 2 more recent Phase III that were won on a so-called relevant study and the other one is the so-called GALLIUM study, that gives you a little bit a sense of scale, scope, and timelines. And for diffuse large B-cell, I think the studies are more or less all on the same range, and then -- and will probably take the same timeline. So, taking other studies in the relapsed/refractory setting that you can probably look at, but I think it's important to point out that this is, just as Jan was saying, showing our continuous commitment to EPCOR and our very ambitious and aggressive expansion of data generation. And then I think the question to Mini-CHOP, I think the best way to frame this is actually to look at the totality of all of our data generation and our strategies. So, we have an ongoing Phase III in combination with R-CHOP that focuses on patients with IPI 2 and above. We just generated and presented, and Martin very nicely summarized the data for R-Mini-CHOP. These are patients who are ineligible for the full dose of anthracycline, usually because of age and cardiac comorbidities. And there is a third data set not presented at this ASH but still nonetheless in ClinicalTrials.gov, a public trial that's just generating data in frontline diffuse large B-cell patients who are anthracycline ineligible. There, it is essentially monotherapy or a combination with LEN. And so what you can see is already an idea to capture every single patient wherever they are, maybe that they are elderly, usually these patients have been in the past excluded from clinical trial development. So not eligible for clinical trials in the past or even not eligible for chemotherapy, which is the easiest way to show that you can generate data without a chemo regimen that is somewhat comparable in outcomes as it relates to CR and duration of CR. And then the last thing was about CAR-T, and I think if you look at all the data, the CAR-T refractory patients are very, very sick patient population, so obviously, drugs on any treatment, actually, frankly, doesn't work that well in this very, very sick patients. But nonetheless, I think it's very encouraging that you have quite remarkable and meaningful efficacy in these patients.

Thanks, Tahi. Maybe Judith, some further reflection on the CAR T -- the prior CART data?

Yes. So, two comments. One, with regard to the combination with R-CHOP and EP, the very high unmet medical need, of course, is the patients with high EP and they are enrolled in the ongoing Phase III study, which focus on EP 2,3 and 5, but with a focus on 3 to 5, which is the highest unmet medical need. With regard to CAR-T, we have generated, I would say, bispecific had, you know, revolutionized with the efficacy that they show after CAR-T. Now, having said that, as we know, the results from CART are in a kind of biased population, because patients tend to be younger, patients tend to be less rapidly progressing, and other limitation derived from a vein-to-vein time. So we think that the sequences and data from the CART registry shows that patients that are exposed to bispecific, respond as well as CAR that if they wouldn't. So I think that this sequence is an important question. We think that an off-the-shelve, subcutaneous convenience with a very good efficacy, safety, and convenience, could be a good option before CART.

Thanks. Thanks, Judith. I think we will move to the next question now.

So the next question is Vikram Purohit from Morgan Stanley.

Vikram? I think you're on mute, Vikram. Maybe we can move to the next question and then go back to Morgan Stanley after this one Sophie.

Sure. So the next question is Rajan Sharma from Goldman Sachs.

Hopefully, you can hear me okay. So first one, just a clarification, should we expect any further data updates for HexaBody-CD38 ahead of that head-to-head data that we're expecting in the second half of next year? And then, just thinking about development, and I just wanted to get your thoughts on the FDA's project FrontRunner, and just wondering if that's something that you can utilize for EPKINLY to accelerate the path to the frontline setting in DLBCL or are you now too far in development for that to really benefit timelines? And then, similarly, could that be something that's applied to HexaBody-CD38 in frontline multiple myeloma, assuming those head-to-head data are positive?

Thanks very much for these questions. Thai, maybe you can give an update on the data dissemination for the head-to-head. And then maybe also initial thoughts on the FrontRunner program, which is still a concept from the FDA. And then Judith, you can probably add to that FrontRunner potential then. Thai?

Yes. So, I mean, once CD38 have been clear, the data will be shared in '24 second half, and then the -- so I think that's the only disclosure we will have, but we're not going to have something in the middle. I don't think it helps anyone, particularly if you look at how scrutinized the data gets for a single patient, I think it's best to have the total data in hand, and then we will have a clear answer to what we think will be a positive outcome. FrontRunner is -- we actually had discussions with the FDA on this and I think it's very, very clear that there is no regulatory path that exists, that's called, FrontRunner at the FDA at this point. This is a conceptual idea about inspiring companies to focus on frontline but it doesn't actually constitute a separate regulatory path. Nonetheless, we will do whatever we can, generate whatever data we can, and use whatever regulatory mechanisms exist to accelerate access for patients in frontline based on the data that we are generating.

Thanks, Thai. Judith, anything to add there on FrontRunner?

No, I think that Thai was on the money. I think it's all data dependent, but we are considering innovative endpoints to potentially have this option.

Thanks. Thanks very much. Let's move to the next question.

So we'll go back to Vikram from Morgan Stanley.

Hopefully, you can hear me now.

Perfect. Perfect, Vikram.

Great. So, we had 2 on GEN3014 and then one on 1046. So, on 3014, going back to cardiac safety for a moment, we just wanted to make sure we heard your commentary correctly during prepared remarks. There was a mention of QT interval prolongation, which we didn't fully grasp. So I just wanted to see if you could clarify your observation on that signal. And then secondly, for the 6 responses you have seen of the 9 evaluable patients, have you had a chance to see whether there are any specific baseline characteristics or aspects of prior treatment history that are associated with the different levels of response you're seeing so far and the different levels of benefit you're seeing so far? And then lastly, for 1046, your pipeline slide mentioned Phase III planning anticipated in 2024 and we were just wondering if you could unpack for us specifically what the key items will be that you're working on throughout next year, and if it's also possible for the Phase III to start in 2024.

Thanks, Vikram, for the questions. So, Thai, why don't you take the first 2 on HexaBody-CD38, and then Judith can comment on the 1046 planning for the Phase III in '24. Thai?

Thank you for giving me the opportunity. So what Andrew Spencer says, there was no QT prolongation. They have never seen any QT prolongation with any CD38, and this one included, does not have any QT prolongation in any patients, including the one with a cardiovascular event. But what the patient did have was an AV block preexisting and he indeed was morbidly obese and did have other cardiac factors, including a significant cardiac history. That is to the patient. And I think all the other questions were for -- the other one was about the characteristics. So you know what, the 6 patients becomes a little bit hard to figure out what characteristics are. I think the only thing that actually stands out is what has always stood out. There is a variability of CD38 expression and the HexaBody does to some degree address it, but not completely. Some patients have just very low CD38. But broadly speaking, 6 patients, the more -- you cannot derive from that.

Thanks, Thai. And then maybe, Judith, you can get some color on 1046, the plans because you are very busy with that program?

Yes, thank you, Jan. So as you know, for Acasunlimab, we are very encouraged with the data that we are getting in non-small cell lung cancer in post-chemotherapy and checkpoint inhibitor setting. And as we speak, we are engaging with health authorities to [ ultimate ] details on the study design, and based on this feedback we are firmly planning and on track to start the Phase III in 2024.

Thanks Judith. I think back to Sophie for checking whether there are more questions or new questions.

Our next question is Yifeng Liu from HSBC.

Any questions from HSBC? We don't hear anything.

Can you hear me?

Yes. Now we can hear you. Sorry about that.

I have two, please. One is on HexaBody-CD38. So in terms of head-to-head trial, can I just clarify and against daratumumab, is it daratumumab only monotherapy or is combination with, for instance, [ pomalidomide ] or something else? And if it is monotherapy, then what sort of background therapy are we sort of expecting to see for these group of patients? And the second one is the -- your collaboration with BioNTech. Just in general, how the decision-making process between you and BioNTech in terms of clinical development?

Thank you for the questions. I think Tahi, you can probably start with both, and then we will see whether Judith has something to add on the BioNTech Joint Steering Committee principal. Thai, maybe the easy one, the monotherapy one. Maybe start...

Well, I'm going to start with the easy one. And the easy one is, it is -- daratumumab, as in the subcutaneous one, as a monotherapy, and that's the first part of the randomized study, and what data should you look for? Well, that's a little bit tricky, because there's 2 datasets you can use the daratumumab IV or the daratumumab subcu data, both generated in patients who are refractory to IMiD and proteasome inhibition, which is a very similar population that we're also running it, but also run in a completely different time because different mechanisms that are available to patient, which is now on clinic trials not necessarily available back then. But broadly speaking, if you benchmark this, it's roughly a 30% response rate, 30%-ish response rate. It's roughly 15%-ish patients who have VGPRs or better, and it's roughly a 7 months duration of response, which is a direct function of the depth of response, which is why I keep saying that the weight of VGPR and stringent CR is important on both studies, by the way. If you add them together, there's a -- in a total of 400 patients treated with daratumumab IV and subcu, there is 3 stringent CRs. So that's why these things matter a little bit from the initial response. And as it relates to the BioNTech JC, which I said, I think it's a very, very collaborative -- collaboration that we have with BioNTech and with their leadership, with Ugur and Ozlem and it's a very fruitful and very collaborative and very effective decision-making process.

Thanks, Tahi. Judith, you want to add anything to that?

Yes. No, nothing to add only if the questions targeted on the operationalization of the clinical trials for Acasunlimab, it will be operationalized mainly by Genmab, but as Thai said, the decision making process that is highly collaborative, is shared by both companies.

Thanks. Thanks Judith. Thanks for that further color. Let's move to the next question.

We have time for one more question. And the final question will come from Asthika Goonewardene from Truist.

Asthika, are you there?

Guys, can you hear me okay?

Yes. Now we can hear you. Please go ahead.

Okay. So just wanted to get a quick -- a couple of quick questions on HexaBody CD38. From the expansion data, directive on the Phase III dose cohort that was presented at ASH, what further updates should we expect from that cohort specifically in 2024? And then when we think about the magnitude of benefit that you showed over Dara, in our own cross-trial comparisons, it was like [indiscernible] maybe doubling that of what [ dara's SC ] would achieve. I know these are small numbers, but is this a good indicator of what we should be achieving in a head-to-head study that you're running? And then lastly, if I can squeeze one in on EPCORE, as we saw some data on resistance mechanisms for mosunetuzumab and glofitamab, just wondering what work you're doing on this regard with EPCORE? And do you believe that your 2F2 binder might be differentiating here in this population in this late -- in a late line population who has obviously seeing quite a bit of Rituxan?

Thanks, Asthika, for the questions. So, Tahi maybe you can start with the HexaBody-CD38 questions and how to look at the data. And then Judith, you have been at ASH, you asked at ASH I think. Maybe you can talk a bit about resistance mechanisms for T-cell engagers, targeting CD20. And then Tahi can potentially step in there at the back as well. But Thai, why don't you start with HexaBody-CD38?

Thanks for the question, Asthika. What I usually do is, like I start with the old [indiscernible] which was the, summary and analysis of 501, which was first in human trial, which had an expansion cohort for daratumumab and the SIRIUS trial, which was the pivotal study led to the approval and it merged these 2 data sets, and it looked at CD38 expression and complementary protein expression and mapped that across the entire population related to response. And if you take that paper, you can see 2 things, that there is a clear threshold that daratumumab required in order to actually really work, roughly somewhere in my memory, around 150,000 copies. And there's a clear threshold or the expression of complement inhibitory protein at which daratumumab doesn't really work well. At some point, we were actually -- when this was in development, we're thinking about creating a quotient between the 2, became a little bit too complicated. And the [indiscernible] hypothesis of hexamarization, preclinically was that it would lower the threshold for HexaBody's -- for CD38 expression. And it would also lower the threshold -- increase the threshold, sorry, for complement inhibitory protein expression in order to become. So it's not completely black and white. So if there's a very high expression of complement inhibitory proteins, hexamarization will not work. But the threshold was higher than daratumumab. If you overlayer these 2 things, which you can mathematically, and you could look at the -- all preclinical data, you will see that roughly what should happen is that you will have a 50%-ish to 60% response rate, and yet roughly a doubling of the VGPR beta rate. And that's why I'm always so intrigued by this, because it's very small data, but it actually exactly mimicked what you predicted. You wanted to see based on this preclinical understanding that all we are doing is lowering the threshold. It's not a mechanism, right? We are just lowering the threshold for how much CD38 has to be on the cell, and we are increasing the threshold for how much complement inhibitory protein we can tolerate. And the distribution of these 2 factors is stable between the past and now. That's just the way multiple myeloma is somewhat variable. And so I think that's where we have good paper to look for it if you want to understand why we are kind of like, having the confidence that we have in CD38 -- HexaBody-CD38.

Thanks, Tahi. Any further updates on the expansion cohort you can foresee following these patients further into the future or updates?

Well, I think, if it makes sense if there's something new to report, we'll report it. By the way, we've been very transparent. We continue to be transparent, I think, on both axes.

Okay. All right. Very good. Judith, maybe some reflections on resistance mechanisms to T-cell engagers targeting CD20, like inspired what Roche was presenting at ASH.

Yes. Thank you, Jan. Thank you, Asthika. I guess so there seems to be some day there, there speaks to the fact that such systems can come from losing CD20 expression or the epitope express. So that and as we said, [ Eco ] is a recurring than rituximab and could be an advantage. Now having said that, because patients that achieved a CR or an MRD negative, have so long sustained CRs or MRD, the amount of data that we have to assess the systems unfortunately is very limited. So as you said, it seems that could [indiscernible] expression. So CD20, lots of expression. I think it's preliminary, and somebody said in the meeting, I mean, the Kaplan-Meier correspond duration of response, are pretty boring, when patients achieved the CR or MRD negativity and this is what we're going to achieve, but boring Kaplan-Meier for these patients.

Thanks, Judith, and it will probably get even better when we start combining the epcoritamab with more and more combinations. We will do that Asthika in the coming time. So more to discuss in the future for sure. Having said that, I think we need to stop here also in respect of all of your time. So thank you all very much for the excellent questions and reach out to our Investor Relations colleagues if you have any further questions. We are delighted to come back to you, and then maybe you can switch to the last slide, operator. So thank you all for joining us today. And a special word of thanks to the truly exceptional speakers who have joined us here virtually. And from all of us at Genmab, we wish you happy holidays and a healthy, happy and wonderful 2024.