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, 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, in 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 and 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 stepping stone to achieving this vision.
This 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. Unlike 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, and we are well on our way to that goal. At the end of 2023, there are now eight medicines on the market that are powered by our innovation and antibody expertise. Excitingly, two of these, TIVDAK and EPKINLY, or TEPKINLY, as it is called in Europe, and four 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 the in past years, we continued 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 the 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 I phase II EPCORE NHL-1 trial. This data, along with preliminary dose optimization, will be presented to you today by Dr. Hutchings. It also supported two 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 two or more lines of therapy, and that the EMA had validated a Type 2 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 for a 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 three ongoing phase III trials, and for 2024, 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 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, uh, study in cervical cancer and the data in head and neck cancer from the innovaTV 207 study. TIVDAK has cleared our very high bar for continued investment and development. We are very pleased with our plans to actively engage with health authorities on the next step for TIVDAK in both of these indications, along with our partner Seagen. Next slide, please. Another program that cleared our very high bar in 2023 is acasunlimab, formerly known as GEN1046, which we are co-developing with BioNTech. We were very pleased to announce in November that we have planned engagement with the, with health authorities on the design of a pivotal trial for acasunlimab in the second...
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 our 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 step for this program in the coming months.
Looking at some of our earlier-stage programs, the phase I phase II trial of GEN1047, or DuoBody-CD3xB7-H4, is currently in the dose expansion phase, an important step in progressing our CD3-based bispecific antibody platform in solid tumors. GEN3017, or DuoBody-CD3xCD30, started recruitment for our first-in-human clinical trial. Finally, we had two IND submissions near the end of 2023, GEN1059, or DuoBody-EpCAMx4-1BB, and GEN1055, or HexaBody-OX40. Both of these antibodies are being co-developed 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 are, 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 quadruple treatment of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone in the treatment of patients with newly diagnosed multiple myeloma who are transplant eligible. 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 highlights 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 Hematology, Transplantation, and Cellular Therapy Service at the Alfred Hospital in Melbourne, Australia. He's an expert in multiple myeloma, and in addition to his many accomplishments, he's a primary chief investigator on the ongoing phase I phase 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.
Hematologist 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 phase 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.
There's phase I data using GEN3014, where it showed preliminary activity in both dara-refractory and dara-naive patients, and what I will describe is a small dose expansion among dara-naive, relapsed, and/or refractory multiple myeloma patients. This was to confirm the initial efficacy findings and to add to the 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 was administered IV, initially weekly, at the recommended phase II dose of 16 mg/kg in 28-day cycles, until disease progression or unacceptable toxicity.
With respect to this particular presentation, data cutoff was at the median follow-up of 7.4 months, and based on this data, there is now 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 a median age of 66 years and a median of four prior lines of therapy. Important to note that only one of the 11 patients had achieved a VGPR or 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. Four patients discontinued treatment due to AEs, two were deemed not related to GEN3014, and four patients discontinued treatment due to disease progression.
Of the 11 patients who received GEN3014, nine patients were evaluable for response. Six patients achieved a response, including a stringent CR, two VGPRs, and three partial responses, and two additional patients achieved minor responses. Therefore, the clinical benefit rate was achieved in eight out of nine patients, and responses were rapid, with median time to response of two 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-emerging adverse events are shown in Figure 3 and included hematologic events, headache, infusion- related reactions in three patients, maximum Grade 2, and upper respiratory tract infections. None of these led to treatment discontinuations.
There were 2 Grade five events, one cardiac arrest and one respiratory tract infection, but neither case was thought to be causally related to GEN3014 in these heavily pretreated myeloma patients. two patients were reported as having treatment-related serious AEs. One patient developed anemia, requiring hospitalization and transfusional support after four cycles of treatment, one 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 thought to be potentially, or reported to be potentially related to GEN3014, with an abundance of caution. There was a range of pharmacodynamic studies done. These showed a rapid and sustained decrease in peripheral blood natural killer cells, and importantly, T cell expansion was observed in four of seven 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 eight of nine evaluable patients showing a clinical benefit rate. 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.
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 data at ASH, I would like to introduce a video by Dr. Martin Hutchings. Martin is a hemato-oncologist at Rigshospitalet in Copenhagen, Denmark. He's an expert in the treatment of malignant lymphoma, and a key investigator on the first phase I phase 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 I Unit at Rigshospitalet in Copenhagen, Denmark, and a professor of hematology at the University of Copenhagen. It's a privilege for me to be able to share with you selected data from the different abstracts involving epcoritamab that are being presented here at the annual ASH meeting in San Diego, California. The first, and perhaps most important one, was presented by Dr. Linton from the UK, 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. This is a disease setting where there's no real established standard.
It's a pretty, a couple of standards in first-line treatment for newly diagnosed patients, but with 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 relapse or progression within the first two years of completing the primary treatment or with primary refractory disease, there are really no good standards of care. So this is a place where there's 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 two prior lines of treatment, they needed measurable disease and follicular lymphoma of grade 1-3A, so no transformed 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 one 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 two-thirds of patients, 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, well, 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 90% of patients who left the study due to adverse events, half of these were caused by COVID-19.
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, the high anticancer 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 and 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 of high risk, 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 5-6 weeks. So that's why the median time is just under one and a half months. You can see that the median progression-free survival in the overall population is over one 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 one and a half years. You can also see that just over two-thirds 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 one and two, which means easily manageable and quite, commonly, transient phenomena. 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 and even intravenous antibiotics. The safety was generally, regarded as manageable. We had, just over one-third of the patients with, with treatment-emergent adverse events considered related to epcoritamab, so that also, as you always see in a 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 priori of the treatment.
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 the study were treated according to a dose optimization schedule in cycle one. 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 the rate of cytokine release syndrome generally in the pivotal cohort was 66%, albeit the vast majority being a grade one or two, it's still a relatively high number, and that was reduced down to 48%.
Particularly, the number of grade 2 and grade 3 cases were really reduced markedly, grade 2 from 25% - 8%, and grade 3, which is where cytokine release syndrome is beginning to get quite tricky to manage, from two to zero patients. This is really important, particularly if you want, as is the case for epcoritamab, to deliver the treatment in a purely outpatient setting. 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-up is relatively limited at this point. Overall response rates were 82%, including 63% with complete responses, 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 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 one 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 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 two or 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 the 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 three cycles, and then twice a month bi-weekly, and then from cycle 10 and onwards, every four 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 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 patients, cytokine release syndrome was observed in just over half of the patients, and even though the majority of cases were mild, a grade 1 or 2, there were individual cases with grade 3 cytokine release syndrome. This is where treatment requires vasopressors and mechanical or high flow oxygen.
Look at the cytokine release syndrome frequencies after the optimization, including not only dexamethasone instead of any steroid, but also an improved hydration schema, as noted on the right. You'll see that this frequency of cytokine release syndrome went down from 51% - 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, 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 one 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 three B, and they needed to have a relapsed refractory disease. They could be included even with just one 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 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 a priming and an intermediate dose to the first full dose of epcoritamab on cycle one, day 15, then weekly treatment for the first 12 weeks, then bi-weekly for the next six months, and then from cycle—sorry, for the next nine 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 three weeks of each four-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 three to five, which is what we consider high risk. Of these patients, the median number of prior lines of therapy was two, ranging from one to four, and in fact, just under one out of four 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 response 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 the 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 hints that many of these responses, at least at this point in time, are quite durable. The benefit is also observed when looking at minimal 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 two, day one.
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, but the majority being a grade one or two. 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 engager, 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 eight of this study, which is a combination of epcoritamab with what we call R-miniCHOP, which is a version of CHOP with 50% doses of the cytostatic agents of the chemotherapies, usually given to elderly and fragile 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-miniCHOP, 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 two cycles, which is eight weeks, and then every three weeks until the end of the six cycles of multi-agent chemotherapy, and then for another two cycles every four 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 a high median age and also a relatively high level of comorbidity.
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 DLBCL, 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 four to five months after the end of treatment. The majority of patients continued the treatment, including the 8 cycles of epcoritamab.
Importantly, the addition of epcoritamab to R-miniCHOP 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-miniCHOP . 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, a grade 1-2. 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 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-miniCHOP 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 responses assessed by the PET-CT.
Among the patients who completed the six cycles of R-miniCHOP epcoritamab, this is all patients but two in this observation, the overall response rate was 100%, including 86% with complete metabolic responses. Again, the median time to complete response was one and a half months, which is the same as two cycles of R-CHOP chemotherapy. So the first R-miniCHOP chemotherapy, which is the first point of assessment of the 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 one year, but this is a 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 four and half-five months. Median progression-free survival, of course, not reached because the vast 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-miniCHOP 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-miniCHOP is given on its own. So I'll move on to the next presentation, which was given by Dr. Brody.
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. These were patients who were not eligible to receive high-dose chemotherapy with autologous transplant, so a difficult to treat patient population. R-GemOx is 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. 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 R-GemOx for four cycles in the standard doses of that regimen, and then, with epcoritamab given weekly for the first three cycles, then every two weeks for the next six cycles, and then from cycle 10 and onwards until progression, the maintenance treatment of epcoritamab every four weeks. These were the characteristics of the 65 patients who went into the study. A median age of 71 years, reflective of the fact that they couldn't be candidates for aggressive treatment. 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, three out of four patients with refractoriness to the most recent treatment line, and even 29% of 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 one-third of them had been exposed to and failed CAR- T. The median follow-up for this cohort so far is just under one 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 1.45 months. So that's the time, the timing of the first PET-CT response assessment after six weeks of treatment. Again, you can see that with the caveat of the follow-up being relatively short, the responses seem 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 six months, and then after the end of the multi-agent chemo the dual agent chemotherapy treatment, there are progression events which lead to a drop-off, the durability of the responses.
Median overall survival for this group not reached, so the majority of patients are still alive at this point of follow-up. Subgroup analyses do not really show any significant differences between the different prognostic and clinical subgroups, including the patients with prior CAR- T. There is a signal that they might respond a little bit poorer, 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, 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 at low grade, so grade 1 or 2, although there are a few cases of grade 3 cytokine release syndromes 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 resolved in all cases, with 18% of patients needing tocilizumab for the treatment of grade 2 or higher cytokine release syndrome. Like in most other 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 one, day 15, so after two weeks of treatment.
So again, 80% with responses, 57% with complete responses, which is quite favorable, also in comparison to R-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 of 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.
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 our patients' 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 DuoBody-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. Tisotumab, 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 and 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 for GEN1042 in 2024, which may include head and 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. Finally, we look forward to 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 our 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. We will begin by taking questions from those of you participating in the teleconference. 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.
Thank you very much. So we'll now move into our Q&A session. For those of you who are joining us via Zoom, if you would like to ask a question at this time, please raise your hand by clicking the Raise the Hand button under Reactions at the bottom of your Zoom window. If you've dialed in via phone, please select star nine to raise or lower your hand, or star six to mute or unmute. Once called upon, please unmute your audio to ask your question. Thank you. So to start, we would like to take our first question, and our first question comes from James Gordon, from JP Morgan. Please unmute your audio to ask your question.
Hello, James Gordon, JP Morgan. Thanks for taking the questions. 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. There did seem to be a lot, but two out of nine patients having a serious cardiac event does look quite high. So any thoughts on whether that does look like it's actually mechanistic or the start of a trend or just noise? This is the first question, please. Second question.
Assuming the HexaBody-CD38 phase II head-to-head data looks good next year in J&J opt in , just latest thoughts on what a phase III program would be, might look like, or what range of scenarios? Has this been discussed with the FDA? Would it be that you go straight to front line, you could use a fast surrogate endpoint, or might it take quite a long time and DARZALEX could already be well established as the add-on to CARVYKTI 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-CD38. But how would you interpret that?
Have you had any feedback from them about this data, about how excited they are? That would be the third and final question. Thanks.
Thanks, James. Excellent questions, and I think I'm going to hand over first to Tahi, who can, I think, address all three. And maybe, Tahi, you can start with the cardiac grade four event-
[Interruption].
and take it from there.
[Interruption].
Okay. Uh-
[Interruption] .
I don't know if-
[Interruption].
I don't know what this is, but did you guys see this as well? But anyway, I tried to thank you for the questions. I'm gonna try to address them one by one. Cardiovascular, I think we were clear in the last call, and I think also, if you followed what Andrew Spencer was describing. These cases are heavily confounded. I mean, we're dealing with a phase I population, first-in-human trial population, by and large, in this part of the trial. And the trial was originally ran in jurisdictions where it was incredibly difficult to find actually dara-naïve patients, or CD38, I should say, naïve patients.
While this was rated as possibly related, because, you know, this is the way it works in the first 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 at least also in the internal DMC, as well as the external DMC that sits on the study, doesn't really appear to be associated with daratumumab with the GEN3014 HexaBody. We also don't really have a good explanation. As Andrew was mentioning in his presentation, we actually have concomitant EKGs, which didn't show any electrophysiological changes, which is the one thing that you would want to pay attention to.
So, you know, to take your words, you know, 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, where you have a direct comparison in a comparable population. And that study is well underway and is also running in jurisdictions where access to CD38 patients that are naïve, patients who are naïve to CD38 therapies is somewhat more easier. 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 there in one sentence, and that is, you know, 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'd 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 in, 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.
Thank you.
Do you want to comment on, on the second question, on the potential phase III type strategy, or, 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, and 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.
Thank you. Our next question comes from Christopher Uhde at SEB. Christopher, please unmute yourself.
Hi there. Yeah, thanks for taking my questions. So the first would be on HexaBody-CD38, which is... So, how, how, I mean, apart from obviously going, choosing sites, you know, where, where there is not super widely used, how, what can you do to maximize the approval 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 to. 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're—you can do on the issue of grade two CRS, either management or prediction? I guess we saw some data from Roche on that with Glofi. 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. Thank you.
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 can 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, there were a couple of questions, right? There were the questions on EPCORE and then there were the questions on HexaBody-CD38 . The question on HexaBody-CD38 was about the core. I think we have been very clear that we are on track, and the core exactly as we predicted. You know, I, how am I gonna say this? I think the people that you talk to that are the standard KOLs don't necessarily live and operate in the countries where the study is going to majority accrue . I think it's probably the truth. If it's actually public, you can look at the clinical trials of the disclosure. You 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're running the 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. 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 to multiple myeloma, and, and it doesn't necessarily behave the same way in, in lymphomas.
It's slightly less well-tolerated. Nonetheless, the label dose is 24 milligram, that's what you start, and this is what you, if you do a registration study, are being asked to adhere to. Unless you wanna get into discussions with the agency around what the contribution of component is again. So, from that, I think, you know, the most prudent way to move forward is to use the label dose and then have very well-standardized and also, like in clinical practice, utilize those reduction criteria for the reduction of lenalidomide. I think this is straightforward. I'm gonna make a comment to the last one, and I think Judith can then also add on it. So it's absolutely correct that Glofi presented some down data on tumor metabolic volume.
We have the same data as well. I think it's also correct that that the work that allows investigators to identify, really, actually, in my mind, it's about two things, right? To identify the risk of CRS, grade two or above, and/or gives them guidance on what degree of pre-medications they should, they should aim for. It's gonna be incredibly helpful and, and, frankly, needed in order to to move these, these drugs into into settings away from these larger institutions to community settings. And so I think everybody's 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, 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?
Yeah, so I want to make two 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 in this setting. And as Tahi alluded, you know, 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 two, in addition to what Tahi said, as a comment, as you saw, the dose optimisation in both settings, DLBCL and FL, with very simple measures as hydration or dexamethasone, allows for, you know, outpatients dose and seems to control very well the, not just the rate, but limits even the grade two.
So we are confident that with this algorithm that Tahamtan alluded, and the measures implemented and the optimization, this will be a drug that can be used in the community centers.
Yeah.
Thanks.
I may want to add, this is actually one of the delays that we had, that we had an algorithm that is irrelevant now because we've been able to reduce the CR rate significantly. So the algorithm in the past is useless because we've been able to reduce grade twos to a point where you have to develop a new algorithm.
Thanks. Thanks, Tahi. Thanks, Judith. I think we need to go on to the next question.
Thank you. So the next question is from Michael Schmidt at Guggenheim. Michael, please feel free to unmute yourself.
Hi. Hello, this is Yaron for Michael. Thanks for taking our questions. Two quick ones from us. The first one on CD38, the 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 EPCORE label for DLBCL? And how do you plan to integrate this schedule into your ongoing clinical trials? Thank you very much.
Thank you for the questions, and I think, Tahi, you can probably start with both, and then Judith can probably step in for the diffuse large B-cell lymphoma optimization. Tahi?
Yes. So, I think I mentioned this on the Q3 call, 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, you know, 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, you know, there's one sCR, there's three VGPRs, you know, some of these patients may very well continue to improve, and so that's where, that's where we are in terms of depth of 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, right? That 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 labeled, 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. I don't know-
Thanks, Tahi. Judith, you want to add anything to that?
Yeah, only that, you know, 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 the prior regimen before we implemented the optimization. So we are doing this as we speak, across the board, and for the cohort, either in both indications, meet the number of patients that could satisfy regulatory requirements for change of label. So you are absolutely right.
Thanks. Thanks, Judith.
Yeah.
Thanks, Tahi. Let's move to the next question.
Our next question comes from Xian Deng from UBS.
Hi, thank you for taking my questions. So three, please. So the first one is sort of just on timing. So you will be initiating three 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 is probably gonna be faster than front-line follicular lymphoma? So just roughly some timing, roughly how many years each trial will take, that'll be great. Second one is epcoritamab. So I... And I notice you run this trial with R-miniCHOP trial. So sorry if 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 is that the rituximab 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.
Knowing this is all sort of early stage data set, but just wondering from your end, with all the data you've seen, what is a general sense about any sort of potential impact on epco post-CAR- T? Thank you very much.
Thank you very much for the questions. Let's move the first two to Tahi, and then maybe, Judith, you can take the last one, and then see whether we can then ask Tahi to start in there.
Tahi.
Tahi, maybe you can start.
Lots of questions on epco. So the first question was on how long it takes for phase IIIs to run, and you're absolutely right. It takes not as long in the relapsed refractory diffuse large B-cell setting than 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 the call and time to event, but I can guide you a little bit. For follicular lymphoma, there are two more recent phase IIIs that you know where one is the so-called Relevance 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, you know, the studies are more or less all in the same range and then will probably take the same timeline. So, there are other studies in the relapse refractory setting that you can probably look at too. But, I think it's important to point out that this is just as Jan was saying, showing our continuous commitment to epco 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 all our strategies. So we have an ongoing phase III in combination with R-miniCHOP that focuses on patients with IPI two and above.
We just generated and presented, and Martin very nicely summarized the data for R-miniCHOP. These are patients who are ineligible for the full dose of anthracyclines, usually because of age and cardiac comorbidities. There's a third data set not presented at this ASH, but still nonetheless in clinical trials of a public trial that is generating data in front line diffuse large B-cell patients who are anthracycline ineligible. There, it is essentially monotherapy or 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 the 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, but, and, I think if you look at all the data, the CAR-T refractory patients are a very, very sick patient population. So, obviously, drugs and any treatment, actually, frankly, doesn't work that well in these very, very sick patients. But nonetheless, I think it's very encouraging that you have quite remarkable and meaningful efficacy in these patients. So yeah.
Thanks, thanks, Tahi. Maybe Judith, some further reflection on the CAR-T.
Mm-hmm
... the prior CAR-T data?
Yes. So two, two comments. One, with regard to the combination with R-CHOP and epcoritamab. The very high unmet medical need, of course, is the patient with high IPI, and they are enrolled in the ongoing phase III study, which focuses on IPI 2, 3, and four to five, but with a focus on three to five, which is the highest unmet medical need. With regard to CAR-T, you know, we have generated, I would say, you know, bispecifics have, you know, revolutionized, you know, with the efficacy that they showed after CAR-T. Now, having said that, you know, as we know, the results from CAR-T are in a kind of biased population because patients tend to be younger, patients tend to be less rapidly progressing, and other limitations derive from a vein to vein time.
So we think that, you know, the sequence and data from the, the CAR-T registry shows that patients that are exposed to bispecific, you know, respond as well as CAR-T that if they wouldn't. So I think that the sequence is an important question. We think that an off-the-shelf subcutaneous convenience with a very good efficacy, safety, and convenience could be a good option before CAR-T.
Thanks. Thanks, Judith. I think we'll move to the next question now.
Thank you. The next question is from Vikram Purohit from Morgan Stanley. Please feel free to unmute yourself and ask your question.
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.
Hi, thanks for taking my question. 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, 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. Tahi, 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. Tahi?
Yeah. So, one, two, three have been clear. The data will be shared in 2024 second half, and then the. So I think that's the only disclosure we will have, but we're not gonna have something in the middle. I don't think it helps anyone, particularly if you look at how scrutinized the data gets for senior patients. I think it's best to have the total data at hand, and then we'll have a clear answer to what we think will be a positive outcome. And Frontrunner is, you know, 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. It'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 and generate whatever data we can, and use whatever regulatory mechanisms that exist to accelerate access for patients in frontline based on the data that we are generating.
Thanks, Tahi. Judith, anything to add there on Frontrunner?
No, I think that Tahi 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.
Thank you. So we'll go back to Vikram from Morgan Stanley. Vikram, please feel free to ask your question.
Hi, good morning. Hopefully you can hear me now.
Perfect. Perfect, Vikram.
Great. Well, thanks for taking our questions. So we had two 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 six responses you have seen of the nine 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?...
Then lastly, for 1046, your pipeline slide mentions 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. Thank you.
Thanks, Vikram, for the questions. So, Tahi, why don't you take the first two on the HexaBody-CD38, and then Judith can comment on the GEN1046 planning for the phase III in 2024. Tahi?
Thank you for giving me the opportunity. So what Andrew Spencer says, there was no QT prolongation. We 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 who had a cardiovascular event. But what the patient did have was an AV block pre-existing. And he was morbidly obese and did have other cardiac factors, including a significant cardiac history. That is to the patient, and I think the, all the other questions were for... I don't know, the other one was about the characteristics. But, you know, 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.
You know, there is a variability of CD38 expression, and the HexaBody does to some degree address it, but not completely. Some patients are just very low CD38, but, broadly speaking, six patients, the more you cannot derive from that.
Thanks, Tahi. And then maybe, Judith, you can give some color on 1046, the plans, because we're very busy with that program.
Yeah, thank you, Jan. So as you know, Judith, for acasunlimab, we are very encouraged with the data that we are getting in non-small cell lung cancer in a post-chemotherapy, chemotherapy and checkpoint inhibitor setting. And as we speak, we are engaging with health authorities to align 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. Thanks, Judith. I think back to Sophie for, for checking whether there are more questions or new questions.
Thank you. Thank you. So our next question is Yifeng Liu from HSBC. Please feel free to unmute yourself.
Any questions from HSBC? We don't hear anything.
Can you hear me?
Yes, now we can hear you.
Oh, yes.
Sorry about that.
Right. Thank you very much. Thank you for taking my question. 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 it's combination with, for instance, pomalidomide or something else? And if it's monotherapy, then what sort of background therapy are we sort of expecting to see for these group of patients? And the second one is, your collaboration with BioNTech, just in general, how the decision-making process between you and BioNTech in terms of clinical development? Thank you.
Thank you for the questions. I think, Tahi, you can probably start with both, and then we'll see whether Judit has something to add on the BioNTech joint steering committee principle. Tahi, maybe the easy one-.
Yeah.
T he monotherapy one. Maybe start with that.
Well, I'm gonna start with the easy one, and the easy one is it is the daratumumab as the subcutaneous one as a monotherapy. And that's the first part, that's the randomized study. And what data should you look for? Well, that's a little bit tricky because there's two data sets. You can use the daratumumab IV or the daratumumab subQ 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 patients now on clinical 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 a 15%-ish patients who have VGPRs or better, and it's roughly a seven month duration of response, which is a direct function of the depth of response. Which is why I keep saying that the rate of VGPR and stringent CR is important on both studies, by the way. If you add them together, there's in a total of 400 patients treated with daratumumab, IV and subQ, there's three stringent CRs. So that's why these things matter a little bit from the depth of 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 Özlem.
It's a very fruitful and very collaborative and very effective decision-making process.
Thanks, Tahi. Judith, you want to add anything to that?
Yeah. No, nothing to add. Only if the question targeted on the operationalization of the clinical trials for acasunlimab, it would be operationalized mainly by Genmab. But as I 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.
Thank you. We have time for one more question, and the final question will come from Asthika Goonewardene from Truist. Please feel free to unmute yourself and ask the question.
Asthika, are you there?
Hi, guys. Can you hear me okay?
Yes. Now we can hear you. Please, please, come.
Love.
Go ahead.
Thanks for squeezing me in. Okay, so, just wanna get a quick, a couple quick questions on HexaBody-CD38. From the expansion data, the readout in the phase II 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 the VGPR rate maybe doubling that of what Dara 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 Epco.
At ASH we saw some data on resistance mechanisms for mosunetuzumab and glofitamab. Just wondering what work you're doing in this regard with epcoritamab, and do you believe that your 2F2 binder might be differentiating here, in this population, in a late line population who's obviously seen quite a bit of rituximab? Thanks.
Thanks, Asthika, for the question. 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 are still at ASH, I think. Maybe you can talk a bit about resistance, resistance mechanisms for CD3 T-cell engagers targeting CD20, and then Tahi can potentially step in there at the back, as well. But Tahi, why don't you start with HexaBody-CD38?
Thanks for the question, Asthika. What I usually do is, like, I start with the old Niels van de Donk paper, which was the, you know, summary analysis of GEN501, which was the first-in-human trial, which had an expansion cohort for daratumumab. And the SIRIUS trial, which was the pivotal study that led to the approval, and it merged these two data sets, and it looked at CD38 expression and complement inhibitor protein expression, and mapped that across the entire population related to response. And if you take that paper, you can see two 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.
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 were thinking about creating a quotient between the two. Became a little bit too complicated. The a priori hypothesis of hexamerization preclinically was that it would lower the threshold for HexaBody expression for CD38 expression, sorry, 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 protein, hexamerization will not work, but the threshold was higher than daratumumab.
If you overlay these two things, which you can mathematically, and you could look at the preclinical data, you will see that roughly what should happen is that you will have a 50 % -ish-60% response rate, and yet roughly a doubling of the VGPR rate. And that's why I'm always so, so, so, so intrigued by this, because very small data, but it actually, 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 – another mechanism, right? We're 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.
The distribution of these two factors is stable between, you know, the past and the now. That's just the way multiple myeloma is somewhat variable. And so I think that's a very good paper to look for it in if you want to understand why we are kind of like in having the confidence that we have in CD38. I think somebody CD38.
Then thanks, Tahi. Any further updates on the expansion cohorts you can foresee following these patients further into the future for updates?
Well, I think if it makes sense, if there's something new to report, we will report it, right? 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 by what Roche was presenting at ASH.
Yeah. Thank you, Jan. Thank you, Asthika. Yeah, so there seems to be some data that speaks to the fact that resistance can come from losing CD20 expression or the epitope expressed. So that then, as you said, epcoritamab is a different epitope than rituximab and could be an advantage. Now, having said that, because patients that achieved a CR or MRD negative have so long sustained CRs or MRD, the amount of data that we have to assess resistance, fortunately, is very limited. So, as you said, you know, it seems that could be CD20 expression, so CD20 loss of expression, I think it's preliminary.
As somebody said in the meeting, I mean, the Kaplan-Meier curves for duration of response are pretty boring when patients achieve the CR MRD negativity, and this is what we want to achieve, boring Kaplan-Meiers for these patients.
Thanks, Judith, and it will probably get even better when we start combining the upfront rituximab with more and more combinations. And 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.
From all of us at Genmab, we wish you happy holidays and a healthy, happy, and wonderful 2024.