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

During this telephone conference, you may be presented with forward-looking statements that include words such as believes, anticipates, plans or expects. Actual results may differ materially, for example, as a result of delayed or unsuccessful development projects. Genmab is not under an obligation to update statements regarding the future, nor to confirm such statements in relation to actual results, unless this is required by law. Please also note that Genmab may hold your personal data as indicated by you as part of our Investor Relations outreach activities in order to update you on Genmab going forward. Please refer to our website for more information on Genmab and our privacy policy. Thank you. I will now hand it over to our CEO, Jan van de Winkel. Please go ahead.

Good afternoon, and good evening. Welcome to Genmab's Virtual ASH Data Review. I'm Jan van de Winkel, President and CEO of Genmab. We have hoped to see you all in sunny San Diego this year, but just like the ASH annual meeting itself, we have gone fully virtual to update you on exciting data presented at this year's conference. For those of you who joined us for our earnings webcasts, the format of today's event will be very familiar. Like in earlier Genmab has stated events, the operator will open the line for Q&A, and as always, we have a busy agenda, so let's begin. Please move to Slide 2. As a reminder, the presentation may contain forward-looking statements and as such, may contain certain risks and uncertainties. Let's move to Slide 3. The virtual nature of this year's ASH annual meeting did not mean the data was less exciting. On Sunday, Dr. Martin Hutchings, who we are very fortunate to have with us today, presented an update on the dose escalation data for epcoritamab. This is data that I know you have all been anticipating. There was also an enormous amount of data presented on daratumumab at ASH this year, with nearly 40 [indiscernible] acceptance. To present some of the highlights from the many data presentations, we are extremely pleased to have with us again Dr. Meletios Dimopoulos. And we are joined, for the first time, by Professor Efstathios Kastritis. We will conclude the event with a brief discussion of both our key priorities for 2021 and why we are confident that Genmab is positioned for continued success. So let's begin with a reminder of some of what Genmab has achieved during this past transformational year. Please move to the next slide. Genmab has a strong foundation of innovative science and an unparalleled history of repeated success in R&D. Over the course of the past few years, we built on that foundation with a goal of evolving from an innovation powerhouse into a fully integrated end-to-end biotech. And in 2020, we reached an inflection point in this evolution due to events like our broad oncology deal at AbbVie in June, the opening of cutting-edge translational research labs in Princeton, the development of new internal capabilities across all our sites, including our newest site in Tokyo, Japan. So we are confident that we will continue to evolve successfully, both because of our strong foundation and because of the consistent progress we have had with our pipeline, as you will see on our next slides. Next slide, please. At the conclusion of our 2019 event at ASH, I predicted that we actually would build on our 2019 momentum with progress across our pipeline. From the partial list of achievements, you can see here, it's evident that we have more than achieved this goal. Our pipeline both matured and expanded this year as new antibodies entered the clinic and 2 DuoBody molecules entered Phase III trials, including epcoritamab, which we are codeveloping with AbbVie. We expect our clinical stage pipeline to expand again very soon with HexaBody-CD38, our second IND submission for 2020 as well as the subject of an exciting preclinical data presentation at ASH. Also presented at 2020 ASH was, as I mentioned, updated epcoritamab data. We were especially pleased that this data was selected for a prestigious oral presentation at the conference. Two other important data sets from this year were the very favorable results from the innovaTV 204 study of tisotumab vedotin which we are developing with Seagen, which was chosen as a late-breaking presentation at ESMO; and the first clinical data for DuoBody-PD-L1x4-1BB, which we are developing together with BioNTech, which was presented at this year's SITC conference. Partners who are developing Genmab-created antibodies also had tremendous success this year, both with data and with regulatory actions. Amivantamab, a bispecific fare developed by Janssen, became the very first DuoBody awarded a Breakthrough Therapy designation and was recently submitted for FDA approval in the United States. And there are now 3 general creative medicines available for 2 patients with the U.S. approvals of Kesimpta and TEPEZZA. And the key U.S. and European approvals of the subcutaneous formulation of DARZALEX, known as DARZALEX FASPRO in the United States. We are now looking forward to the first quarter of next year and the first BLA submission of our own product for tisotumab vedotin. I would like to hear more -- if you would like to hear more about Genmab's tremendous progress in 2020, I would encourage you to listen to the replay of our 2020 Capital Markets Day event, which is available from our website. Now I would like to move to the next slide and introduce you to our first expert speaker. Dr. Martin Hutchings is a hemato-oncologist at Rigshospitalet in Copenhagen, Denmark. Martin is an expert in the treatment of malignant lymphoma and is a cohort of the ESMO guidelines for the management of ultra high-risk patients with malignant lymphoma. He's an investigator on the first Phase I/II study of epcoritamab. And as I mentioned, he presented, in a very strong presentation, the updated dose escalation data from this trial during an oral session of the 2020 Virtual ASH conference on Sunday. Relapsed/refractory B-cell non-Hodgkin's lymphoma continues to be an area of unmet medical need for patients, and we really appreciate Martin being with us today to review this important epcoritamab data. Martin, the floor is yours.

Thank you very much, and thank you for the opportunity to give you a boiled-down version of the presentation that I had the privilege to give Sunday during the ASH conference on behalf of my co-investigators and of the excellent Genmab team for epcoritamab. So epcoritamab is used in the treatment of B-cell non-Hodgkin lymphomas and CLL, which is also a lymphoid malignancy. When the indolent and aggressive B-cell lymphomas relapse, particularly when the aggressive lymphomas relapse beyond 2 lines of therapy, there are really very few or no standards of care, and many of the patients find themselves in a very difficult situation, refractory to most versions of static chemotherapy. So there is a high unmet need in this situation, goes for both aggressive and indolent lymphomas. Epcoritamab is a bispecific CD3/CD20 antibody, which is developed for subcutaneous use. And it binds to the CD3 epitope or antigen on the T cells and the CD20 antigen, which is universally present at least from diagnosis on the malignant B-cells and B-cell lymphomas. So this binding leads to T-cell activation by the binding -- by the simultaneous binding to CD3 and CD20 and that leads to T cell-mediated killing of the tumor cells, which express CD20. Epcoritamab is not only special in the way that it's given subcutaneously, it also binds to a distinct epitope on CD20, which is different from the epitopes that are bound by rituximab and obinutuzumab and which are also the epitopes used in the CD3/CD20 molecules, mosunetuzumab and glofitomab. And this is important because these patients have been heavily pretreated with usually several lines of chemotherapy, which contains also anti-CD20 antibodies, usually in the form of rituximab or obinutuzumab. We know from preclinical studies excellent work that epcoritamab retains the activity in the presence of CD20 monoclonal antibodies. And this is really important in the patients as well because many of these patients have failed very recent therapies with anti-CD20-containing therapies. Next slide, please. So this slide presents some features which we knew for the study and some features which have become apparent over the last couple of years' work. Now epcoritamab is, like I said, administered subcutaneously. It's a very easy to administer 1-milliliter infusion, which is given rapidly. You don't have to give it over 10 minutes, you don't have to wait. It has a very favorable safety profile, as I will come back to. One of the reasons for this is that given subcutaneously, it has a more gradual increase and lower peak concentrations in plasma compared with intravenous bispecifics. And this is probably a very important factor in the mitigation of serious CRS, which is the most important side effect of this class of drugs. It also leads to a long half-life. And it also means that you can probably keep giving this antibody for a longer time than you otherwise would because the safety profile is so good that very few patients go off study because of side effects. It's a very potent drug, high affinity. In the preclinical work, there was high potency, like I said, even in the presence of monoclonal anti-CD20 antibodies. It's practical. It can be given off the shelf. The mechanism of action of the bispecifics are -- have a lot in common with the mechanism of action of CAR-Ts. But as a clinician, there is no comparison between something which is essentially a drug that can be taken off the shelf, diluted in the pharmacy and given to the patient on the same day versus a strategy where you need to wait 3, 4, sometimes 5 to 6 weeks for manufacturing before you can actually treat the patient. During this dose escalation study, which I will present, the recommended Phase II dose was identified. It was 48 milligram, not because we could not administer more of the drug because the maximum tolerated dose was not met and we did not read any serious dose-limiting toxicity, but PK and PD modeling showed us that it would not improve the receptor occupancy or the efficacy to the patients to move beyond the 48 milligrams. Next slide, please. So this is the design of the study. Primary objective, this first Phase I/II dose escalation study was to determine the maximum tolerated dose. So that was not a success because there wasn't such a dose, but also, of course, to find the recommended Phase II dose, which indeed was successful. So what I'm showing you here is basically the final results of the Phase I portion of the Phase I/II study, which is the dose escalation part. Secondary objectives are, of course, safety and tolerability and antitumor activity, which I will present. The inclusion criteria were relapsed/refractory B-cell non-Hodgkin lymphoma. Reasonable performance status 0 to 2, so including some relatively frail and sick patients, which is unusual for a Phase I study like this, prior treatment and failing both gene therapy and anti-CD20 monoclonal antibodies and measurable disease, as is always the case in a study like this. You can see that we started at very low doses -- sorry, 12.8 micrograms and actually the -- this was not the priming dose, the priming dose for [indiscernible] was 4 micrograms, going all the way up to the recommended Phase II dose, which like I said is 48 milligrams. This doesn't mean that all the patients get 48 milligrams from day 1. We still have step-up dosing, which is a strategy -- successful strategy to mitigate cytokine release syndrome. The patients receive 160 micrograms on day 1; after a week, 800 micrograms and the final dose reached after 2 weeks of treatment is 48 milligrams. Next slide, please. So this is an overview of the patients treated in the study so far in the dose escalate -- well, in the final number of patients in the dose escalation study was 68. And you can see that the majority of these patients had diffuse large B-cell lymphoma which are also the -- is the largest group of lymphoma patients generally, and it's certainly overrepresented among the patients who have refractory disease and who are difficult to treat. There are not so many treatment options. You can see that the vast majority of patients who discontinued, discontinued due to disease progression, but there are also a large number of patients still on treatment, 25% at a median follow-up of 10 months. May not sound to everyone like a lot of patients, but actually in a dose escalation study like this, this is a high number because as you can imagine, the majority of patients were treated at doses which, in retrospect, had been biologically suboptimal. Next slide, please. Now we will move to the adverse events because safety, of course, is a very important endpoint of the study. The class side effect of the T-cell engages to which epcoritamab belongs is cytokine release syndrome, which is an immunological response syndrome, which looks very much symptomatically like infections. So on 1 end, it's mono-symptomatic fever, ranging over fever plus hypotension and hypoxia towards the severe grades, which might include multiorgan function, i.e. intensive care treatment and even fatal cases. Fortunately, we have not seen any of such serious events in the study of epcoritamab. All the patients who have experienced cytokine release syndrome, which is 59% of all patients, have had the CRS as either grade 1 or 2 as maximum severity. And grade 1 means basically mono-symptomatic fever. Grade 2 means fever plus either hypoxia, which is the lack of ability to oxygenate the blood properly, or hypotension, which is low blood pressure. But in order to stay at grade 2, it needs to be managed with low flow oxygen in the nose or just fluids in order to help the blood pressure, something which can be managed either at home eventually or in a normal hospital department setting, so without the need for intensive care or any specialized treatment. Other side effects that we have seen apart from pyrexia, which means fever, that's just a part of CRS, have been injection site reactions. They have been very mild, a bit of redness in the skin where the injections have been given, usually disappearing within hours or just a few days. And then what we call constitutional symptoms, which appear in any study of anticancer therapy: fatigue, diarrhea, anemia, tachycardia. And these are treatment emergent adverse events. That doesn't mean that it's necessarily caused by the treatment. It just means that these symptoms have been seen in time-wise connection with the treatment. But important -- the important message really here is that we do see cytokine release syndrome, but really in 68 patients who have had very much benefit from the treatment, it's quite stunning to see no cases of grade 3 or 4 cytokine release syndrome. Next slide, please. And this waterfall chart or these waterfall charts display the antitumor activity in patients who have been treated at what we, in retrospect, can regard as clinically meaningful doses. So on the left, patients with diffuse large B-cell lymphoma treated at 12 milligrams of epcoritamab or above. The green waterfall chart, follicular lymphoma patients treated at doses of 760 micrograms or above, and on the right, a few patients with mantle cell lymphoma who have been included in this slide because they had 2 of the 3 evaluable patients have really had dramatic clinical activity and benefit from the treatment. You can see that the vast majority of patients have had meaningful tumor reductions, many of them living up to the criteria of either a partial or a complete response and the patients with diffuse large B-cell lymphoma who have not responded have, in the cases -- in the majority of cases, would be treated at doses which are lower than the recommended Phase II dose. This is a swimmer plot. It shows you the durability of the responses in responding patients. And you can see that many of these patients are still on treatment that is displayed by the arrow on the right of the lanes. And you can also see that a few patients have been brought into remission, allowing for a subsequent, either autologous or allogeneic stem cell transplantation, which might have led to the cure of these patients. Looking at the right, and we're looking at diffuse large B-cell lymphoma patients here, as we have said that and looking on the table on the right is really what your eye should be fixed on, that is the overall and complete response rates. And particularly when looking at the 12 patients who have been treated at the recommended Phase II dose, which is the dose which is being further developed in the Phase II part of the study and the combination studies, you see a staggering overall response rate of 91%, which is, in my experience, absolutely unheard of in such a difficult-to-treat treatment population. And also complete responses in 55% is beyond anything what we're used to seeing in relapsed/refractory diffuse large B-cell lymphoma. Next slide, please, which shows you the durations of responses and response rates in follicular lymphoma in the few patients with mantle cell lymphoma. You can see all the responders with these diseases, and they are all these patients' response has been quite durable. Some of them just under half a year and many of them still with responses ongoing. And those are the patients who have been treated at the recommended Phase II dose again. You can see on the right, the overall and complete response rate. Overall response in 90%, which is 9 out of 10 patients with follicular lymphoma and complete responses in 5 of those 10 patients, and that is probably even underestimated a bit because in these patients, some of them did not have PET CT but only CT to determine response, which makes it somewhat easy -- is somewhat more difficult to demonstrate complete responses. Next slide, please, which leads us to the summary, which is that epcoritamab is subcutaneously administered CD3xCD20 bispecific antibody, is a novel and it's off-the-shelf therapy, which is administered once every week. Currently in the dose schedule that we're using at this point for 3 months, then bi-weekly for 3 months and then every 4 weeks until progression and many patients are still on treatment with this schedule. The recommended Phase II dose of 48 milligrams was, like I said, reached without experiencing any dose-limiting toxicity, and thus, the maximum tolerated dose has not been reached. The Phase II expansion part of the study is ongoing as well as combination studies, which have recently been done or are underway. The safety profile, this is a take-home message, is very favorable. Also, I think, without any direct comparison, it looks more favorable than some of the competitors, which do lead to some degree of grade 3 and even grade 4 cytokine release syndrome. In the case of epcoritamab, perhaps in part because of the subcutaneous administration, we have only seen cytokine release syndrome grades 1 and 2, which like I told you, is really quite easy to manage in the clinical setting. The antitumor activity is very impressive in diffuse large B-cell lymphoma, where we are used to novel agents having response rates of 30%, 35% at best and complete response rates typically between 10% and 20%. Here, we saw 91% response rates and complete responses in 55% of patients treated at the target dose of 48 milligram or above. And similar responses seen in follicular lymphoma, it's hard to say anything about the response rates in mantle cell lymphoma, but we are quite encouraged by a few patients getting very deep and durable responses even with that difficult-to-treat disease. As I told you, epcoritamab binds to a distinct epitope, which is different from the anti-CD20 antibodies registered for the first time in subsequent lines of treatment in this disease, rituximab and obinutuzumab. And thus, it has the potential to be the partner of choice in combination with standard of care therapies, even those that contain rituximab, which is used in almost all patients receiving first- and second-line therapy, both for diffuse large B-cell lymphoma and follicular lymphoma. And as I've alluded to, epcoritamab is being investigated in several trials across the different B-cell non-Hodgkin lymphoma histologies and in various combinations, and these are the clinical trials numbers that you can search in order to find these combination studies. So with that, I thank you for your attention and give the word back.

Thanks very much, Martin. Let's move to the next slide, for sharing that fabulous data on epcoritamab with us all. Now we will have a review of some of the key data sets for daratumumab as represented at ASH. Daratumumab has now expanded out of multiple myeloma with data from the ANDROMEDA study in AL amyloidosis. And to provide you with a summary of this data, I'm very pleased to introduce Efstathios Kastritis, who is Associate Professor of Clinical Therapeutics at the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine. So Dr. Kastritis is an expert in multiple myeloma, Waldenstrom microglobulinemia and amyloidosis. And he has presented the primary results from the ANDROMEDA trial as a late-breaking oral presentation at the EHA25 conference in June this year. Efstathios, we look forward to your presentation.

Thank you very much for the introduction. I'm very happy to be with you and discuss briefly the results of the ANDROMEDA study and especially, next slide, please, the presentations that were present and is that [Technical Difficulty] That comes by cardiac stage. [indiscernible] Of the systemic AL amyloidosis, a liver plasma cell disease, by the extracellular deposit of amyloid on organs and tissues and particularly, deposition in the heart. This leads to progressive organ dysfunction, and this may lead to death or other unfavorable outcomes such as, for example, terminal stage of renal failure and need for dialysis. However, the extent of cardiac involvement is a major prognostic factor for the outcome of these patients with AL amyloidosis. One of the major limitations in this disease is the fact that we have delayed diagnosis, and diagnosis of AL amyloidosis is oven delayed because the symptoms of the disease are overlapping with other symptoms from more common diseases, which leads to significant delays, so the patients come to us at advanced multi-organ dysfunction, which, of course, affects their overall outcome of their prognosis. However, so far, there are no approved therapies for the treatment of AL amyloidosis. The treatments that we use today are treatments that have been adopted by treatment combinations, by regimens we use in multiple myeloma, with usually those reductions that are used for these patients because of the common plasma cell clone. Today, the most widely used and, let's say, standard treatment for the patients -- for the treatment of patients with AL amyloidosis is the combination which is called BCD, which stands for bortezomib, cyclophosphamide and dexamethasone. However, we definitely need more therapies in order to improve patient outcomes, which can induce deeper and faster hematologic responses in order to improve the function of the organs and the overall outcome of the patients. So the ANDROMEDA study is a randomized, open-label, active control Phase III study, in which the combination of cyclophosphamide, bortezomib and dexamethasone with daratumumab is compared to the standard therapy of bortezomib, cyclophosphamide and dexamethasone. And this study included patients with newly diagnosed AL amyloidosis. As presented a few months ago, treatment with the combination of subcutaneous daratumumab with BCD resulted in deeper and more rabid hematologic responses, also with an acceptable safety profile, which was consistent with what has been preserved -- with what has been observed for dara subcutaneous alone or BCD. Next slide, please. So 1 major issue with AL amyloidosis is that it's considered a rare disease. However, as you can see in this slide, it is one of the hematologic diseases that is, let's say, not the most rare. It is as common as other hematologic diseases such as CML or smoldering myeloma. Also, we have to appreciate that this disease is often under-recognized so probably, the incidence of the disease is significantly higher. Overall, we would say that we have 1 to 2 amyloidosis patients for every about 10 myeloma cases. So actually, it's not that rare. Next slide, please. So here, you can see the design of the ANDROMEDA study. As you can see, patients were randomized to receive either subcutaneous daratumumab with BCD for 6 cycles, followed by up to 24 months of daratumumab monotherapy. Or to receive 6 cycles of the standard therapy with BCD. The primary endpoint of the study was the overall complete hematologic response rate, and this endpoint was chosen because complete hematologic response is the most important determinant of the overall outcome of these patients and is associated with the highest probability of organ function improvement. Next slide, please. As we said, the primary endpoint of the study was met, and significantly more patients in the daratumumab+BCD group achieved a complete hematologic response at any time during the study compared with the standard BCD regimen. And actually, this improvement was substantial. As you can see, 53% of patients with daratumumab+BCD achieved a complex hematologic response versus 18% for standard BCD, and this was statistically significant -- highly statistically significant with an odd ratio of 5.1. These results were consistent across all prespecified subgroups. And also, it is very important that treatment with daratumumab+BCD prolonged major organ deterioration progression-free survival versus the standard of care treatment, which is an endpoint that evaluates hematologic progression, terminal organ dysfunction or death. Also, and this is very, very important and one of the most important findings of the study, the rates of cardiac and renal responses, which means significant and substantial organ improvement at 6 months was significantly higher with the combination of daratumumab with BCD and was almost double with this combination. Also, as we said, the safety profile of dara+BCD was consistent with the number of files of daratumumab monotherapy, subcutaneous and BCD. Next slide, please. As you can see in this slide, in every different hematologic response system that was evaluated, the combination of daratumumab with BCD was associated with substantial improvement in complete hematologic response rates. These are different measures of very deep hematologic responses. These are, let's say, different measures of complete hematologic response. All of these measures have been associated with substantial improvement in overall survival and organ improvement. And as you can see across all these different systems and types of evaluation, the combination of daratumumab was associated with substantially high rates of complete hematologic responses. Next slide, please. And of course, this was associated with a significant improvement in the major organ deterioration progression-free survival. In this slide, you can see that with every different response assessment system that we use, the deep hematologic responses were associated with substantial improvement in this time-to-event end point. And of course, as we said in the previous slide, this complete hematologic responses by every different system, were 3 to 4 to 5x higher in the BCD plus daratumumab arm. Next slide, please. Also, what we observed, and this was presented in this year's ASH, is that the more rapid and faster is the complete hematologic response, the better the outcome of the patients. And as you can see here, patients who achieved a complete or a very good part of hematologic response at 1 month after the start of therapy had substantial improvement in their progression in the MOD PFS, major organ deterioration and progression-free survival or at 3 months. And this is very important because roughly twice as many patients who received the combination of daratumumab with BCD achieved this endpoint. So daratumumab with BCD is not only associated with substantial improvement in the rates of deep hematologic responses but can also achieve these deep hematologic responses very, very fast. Next slide, please. Also, what is very important is that treatment with daratumumab with BCD was associated with a substantial improvement in the MOD PFS and the MOD event-free survival across all different target stages. As we said, cardiac stage, which actually shows the degree of cardiac dysfunction because of amyloidosis is the most important prognostic factor. And as you can see, there is substantial benefit with the combination of daratumumab and BCD across every different cardiac stage, especially in patients who have more advanced cardiac disease, which are the patients with stage 3 disease, which is shown here in green for dara+BCD and in purple for BCD alone. As you can see, there is a substantial improvement for these patients. Next slide, please. And overall, as you can see, the major organ deterioration progression-free survival was substantially improved for patients who received the combination of daratumumab with BCD. The hazard ratio is 0.58, which means a 42% reduction in the risk of progression to end-stage organ dysfunction to hematologic progression or death. Next slide, please. And as you can see, the organ response rates, which shows the improvement in the organ function was also significantly higher in patients who achieved early deep hematologic response. And as we said, patients who received daratumumab with BCD were those that had higher responses of early hematologic responses and also these were substantially higher. Next slide, please. So in conclusion, achieving a complete hematologic response or a very good partial hematologic response at 1 and at 3 months was associated with substantial improvement in the risk of major organ deterioration and death in patients with new diagnosed AL amyloidosis. And this was also associated with substantially higher rates of organ responses, which, of course, means improvement in organ function of the organs that have been affected by amyloidosis. This data confirms that initial therapy that sees rapid and deep hematologic responses, such as daratumumab with BCD is essential in order to improve the outcomes of patients with AL amyloidosis, and we can see that after a median follow-up of about 16 months. Also, complete hematologic responses and organ response rates were consistently high, substantially higher across cardiac stages in patients who were treated with a combination of daratumumab with ECB versus BCD. MOD PFS and the MOD EFS were better in the daratumumab+BCD arm than in the BCD group across every cardiac stage. And I think here, this is very important, especially across patients with Stage 3, which are patients with the more problems, the patients with, in which unmet needs are higher. Rates of serious adverse events were higher in patients with more advanced cardiac states, but this was independent of the treatment that was used, and this is mostly associated with the underlying major cardiac dysfunction. These results support that the combination of subcutaneous daratumumab+BCD is a potential standard of care. And in my opinion, it is now the new standard of care for patients with newly diagnosed AL amyloidosis irrespective of baseline cardiac stage. And with this, I would like to complete this presentation. Thank you very much.

Thank you very much, Efstathios, for that very good overview of the ANDROMEDA data. I will now ask you to progress, also presenting as an overview of the APOLLO, MAYA and GRIFFIN data because we just heard that Dr. Dimopoulos cannot make the presentation because of an urgent meeting with the President in Greece.

I am here.

Oh, sorry.

Hello. Yes, I made it. Thank you.

Thank you, Thanos. You are a world-renowned specialist for multiple myeloma, in plasmacytoma [indiscernible] and we are delighted by -- just in time. Please go ahead.

Okay. Next slide, please. Hello? Next slide, next slide. Hello? The APOLLO trial is a randomized Phase III study of subcutaneous daratumumab with pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in patients with relapsed and/or refractory myeloma. This study was based on the notion that pomalidomide and low-dose dexamethasone is a standard of care for patients with relapsed/refractory myeloma who have failed emits and immuno and proteasome inhibitors. Furthermore, there were data that daratumumab has single-agent activity in the treatment of relapsed and/or refractory myeloma, and also subcutaneous administration of daratumumab appear to be equally effective and associated with fewer effusion-related reactions as compared with intravenous daratumumab. Here, we report the primary analysis of the Phase III APOLLO study by the use of subcutaneous daratumumab, which was the first prospective randomized trial using subcutaneous daratumumab in combination with other agents. Next slide. This is a study design of the study comparing pomalidomide and dexamethasone with daratumumab, pomalidomide and dexamethasone given in patients who have received at least 1 prior line of therapy, which included both lenalidomide and the proteasome inhibitor. Treatment was continued until there was evidence of unacceptable toxicity or progressive disease. Both pomalidomide and dexamethasone and also daratumumab were given at the usual fashion, and daratumumab was given subcutaneously. Next slide, please. These are the patient disease characteristics. I would like to note that approximately 1/3 of patients had high-risk disease based on cytogenetic profile. All patients were pretreated with PI and the limit. And also about 80% of the patients were refractory, had refractory disease and 1/2 of the patients had refractory disease to both a PI and lenalidomide. The characteristics of the patients were well balanced between treatment arms. Next slide, please. This is the main finding of the study. The main objective was difference in progression-free survival, and we can appreciate that the median PFS in the control arm was 6.9 months and the investigational arm 12.4 months for the hazard ratio of 0.63, indicating that the addition of subcutaneous daratumumab to pomalidomide and dexamethasone improved the PFS with a 37% reduction in the risk of progression or death. Next slide.

Speaker, please continue. The slide will show up as soon as possible.

I need -- okay, this is the PFS in prespecified subgroups. And we can appreciate that the combination of subcutaneous daratumumab with pomalidomide and lower-dose dexamethasone was beneficial across all patient subgroups, including age, ISS stage, number of prior lines and refractoriness to lenalidomide. There were a few patients who have received only 1 prior line of therapy, about 10%. And also in these patients, the hazard ratio was 0.7. Next slide. Response was also improved in favor of the combination with an overall response rate of 69% versus 46% for pomalidomide and low-dose dexamethasone, and also MRD negativity was improved 4x in favor of the triplet. Next slide. The most common adverse events are shown here. It is noteworthy that they were essentially equally distributed between the 2 arms, and they were consistent with the known profiles of subcutaneous daratumumab with pomalidomide. The difference was grade 3 or 4 neutropenia and febrile neutropenia, which was more often seen with the addition of daratumumab to pomalidomide and low-dose dexamethasone and also a slightly higher incidence of pneumonia. Next slide. Infusion-related reactions were low due to the subcutaneous administration of daratumumab. They were about 5% and all of them grade 1 or 2. And adverse events leading to treatment discontinuation were similarly low in both groups. The same applied for deaths during treatment due to possible side effects, which was about 7% in each group and the rate of secondary malignancy was equally low at 2%. Next slide. To conclude, this is the first Phase III study of subcutaneous daratumumab in combination with another regimen. And in this particular study with pomalidomide and low-dose dexamethasone, it significantly reduced the risk of progression or death by 37%. And also, it was associated with a higher response rate, including a 6x higher complete response rate and a 4x higher MRD negativity rate. DPD was associated with longer progression-free survival in the whole group of patients and also in patients refractory to lenalidomide. And it was associated with a manageable toxicity profile consistent with the known safety profile of subcutaneous daratumumab and pomalidomide and dexamethasone alone. The infusion-related reactions were low and the administration was short, thus increasing the convenience for patients and decreasing treatment burden. Next slide. The MAIA study was also updated during ASH. This is a study that has been previously reported and published, and it included intravenous daratumumab with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in the frontline treatment of transplant-ineligible patients. And here, it was -- the investigators reported an updated safety and efficacy profile of this study with an approximate follow-up of 4 years. Next slide. This is the design of the study. Previously untreated patients with symptomatic myeloma with a creatine clearance of 30 ml per minute or more were randomized to receive either standard lenalidomide/dexamethasone at the standard dose or the same regimen with the addition of daratumumab. Treatment was continued until there was evidence of disease progression or unacceptable toxicity with the known endpoints. Next slide, please. Patient characteristics were well balanced among the 2 groups of patients. Median age was 73 and approximately 1/2 of the patients were older than 75. Approximately 1/3 of the patients had stage 3 disease and also about 15% of patients had high-risk cytogenetics. Next slide. This is the main finding of the update with a median follow-up of 4 years. Median PFS has not been reached. It is 60% in the dara-D arm and it is at 34.4 months in the lenalidomide and dexamethasone arm, with a hazard ratio of 0.54, indicating that the addition of daratumumab to lenalidomide+dexamethasone resulted in a 46% reduction in the risk of progression or death. The addition of daratumumab to lenalidomide and dexamethasone resulted in deeper responses with higher rates of complete response and very good partial response or better as compared with lenalidomide and dexamethasone alone. Next slide. Subgroup analysis indicated that there was a PFS benefit across subgroups in favor of the triplet. It is of particular interest to focus on patients with high-risk cytogenetics, where we had a hazard ratio of 0.57 and also in patients with stage 3 disease, again, a hazard ratio of 0.59 and also in elderly patients more than 75 years of age with a hazard ratio of 0.58. Next slide. MRD negativity was evaluated during the study, and what we can see is with a longer follow-up, there is an increase in the MRD negativity rate in the dara-RD arm ranging from 24% at the first analysis to 31% at the updated analysis at 4 years. Furthermore, the sustained MRD negativity indicating MRD sustained for more 6 months was clearly improved over time, and it was clearly higher in patients treated with dara-RD, 20% at 6 months and 16% at 12 months. Next slide. To conclude, with the median follow-up of 4 years, the addition of daratumumab to lenalidomide and dexamethasone continues to demonstrate a superior PFS benefit, and more patients continue to have deeper and more durable responses, including a tripling of the MRD negativity rate versus lenalidomide and dexamethasone alone. So this longer follow-up also demonstrated a significant benefit in PFS, too, favoring dara-RD without any evidence of new safety concerns. Next slide, please. Finally, I would like to share with you an update of the GRIFFIN study. This is a very important randomized Phase II study, which evaluated the addition of daratumumab to VRD in patients with transplant-eligible, previously untreated patients with myeloma. And in this particular meeting, the update analysis of GRIFFIN was presented after 12 months of maintenance therapy. Next slide. So the GRIFFIN trial, this is the design. Patients who were transplant-eligible up to the age of 70 years of age and without severe renal function -- dysfunction were randomized to receive either VRD before transplant as an induction, high-dose therapy consolidation and then maintenance with lenalidomide, whereas for 3 years, whereas the investigational arm consistent of the same regime with the addition of daratumumab. Next slide. Patient and disease characteristics are shown here. They were well balanced between the 2 groups. And we had about 1/5 of the patients with high-risk cytogenetics and also about 1/2 of the patients with ISS stage 2 or 3. Next slide. This is an interesting slide, which shows the deepening of response over time. In the VRD-dara arm, with 12 months of maintenance therapy, we have a complete response or better rate, which is 82% versus 61% in the VRD arm. Next slide. Subgroup analysis of stringent complete response and MRD negativity by the 12 months of maintenance therapy cut-off indicates that for all prespecified subgroups, there was an advantage of adding daratumumab to VRD, including high-risk cytogenetics, advanced stage disease and patients older than 65 years of age. Next slide. PFS and the overall survival data are not yet mature. You can see that there is actually an excellent PFS with both arms. And at 2 years, at the 2-year cutoff, it is above 90% for both arms. And of course, we need a significant follow-up to see whether this improvement in the response rate and the MRD negativity rate will translate in PFS benefit. This has been the case for almost all studies in myeloma so far. So we need more follow-up to confirm this possibility. As far as overall survival is concerned, it's excellent, above 93% in both arms. Next slide. To conclude, the VRD-daratumumab followed by daratumumab and lenalidomide maintenance significantly improved response rate and depth of response versus VRD followed by lenalidomide maintenance. In this subsequent analysis, the interesting finding was the deepening of response, both conventional response and also MRD response with further treatment. So far, PFS and overall survival data are excellent in both groups. And we need more follow-up to see the very likely improvement of PFS in favor of dara-VRD. And I believe that this randomized Phase II study indicates that dara-VRD is a new standard of care for transparent-eligible patients with early diagnosed myeloma. And of course, we have the Phase III PERSEUS study, which has completed accrual about a year ago and we are waiting the data to mature. And this study will, of course, establish beyond any doubt, the significant activity of VRD+daratumumab in the frontline setting of newly diagnosed symptomatic patients with transplant-eligible myeloma. Thank you.

Thank you very much, Thanos, for that excellent overview of some of the daratumumab data presented at ASH over the past few days. We'll now move to a Q&A session. So please move to the next slide. So since our expert's time is very precious, we don't have a lot of it. [Operator Instructions] So operator, please open the line for questions.

[Operator Instructions] We are now taking our first question from the line of Wimal Kapadia from Bernstein.

Wimal Kapadia from Bernstein. Can I just ask about duration of use for the CD3xCD20 as a plus? Just curious to hear your thoughts on the fixed dosing period versus treating to progression. And then how do generally think about the idea of maintenance treatment? And then tied to that, what impact do you think that will have on the commercial outlook for specific drugs, given costs, convenience and toxicity need to be considered?

Thanks, Wimal. I'm going to pass this on to Martin and then probably to [indiscernible]. Martin, please give your feedback on the duration of use of CD3xCD25 specifics and potential on maintenance use, how you see it.

Yes, this is an excellent question, particularly from a clinician's point of view as well. So I mean, these are Phase I studies, an I'm sure that the final way in which we're going to use these antibodies in a couple of years' time will -- is not settled yet. So epcoritamab is being used until progression. And the good thing when you think about side effects, which is what you allude to, is that the vast amount of side effects that we see, particularly cytokine release syndrome are experienced during cycles 1 and patiently, cycle 2. So in the patients who've gone on with treatment, we've seen very, very little toxicity. So I think from a safety point of view, giving patients an injection once every 4 weeks is really not a problem. Other bispecifics such as glofitamab and [indiscernible] are being used in the Phase I studies with a fixed duration of treatment but with the option of retreatment upon progression in patients who have left the study in remission. Whether 1 strategy is better than the other, it's really too early to tell. But in terms of safety, I do not see any problem keeping patients on treatment with epcoritamab.

Thanks [indiscernible] Martin. Maybe Tahi, you can give a further perspective of potential maintenance use, how we see it, Tahi Ahmadi?

Sure. Sure. I will try to expand on what Martin has said. And I would basically try to say that the concept of duration of treatment, I think, makes sense to think about the setting in which you are treating. So in the current Phase I population, we are dealing, as Martin very eloquently pointed out in the beginning of his presentation, the patient population, that for the most part, has exhausted any available therapies and has a very short over survival, meaning this is the last line of therapy for many, many patients. And so in a disease setting like this, trying to continue the treatment, particularly as Martin just said, when the safety profile is such that most of the AEs are happening within the first 1 or maybe 2 cycles and thereafter, it's extremely well tolerated, from our point of view, makes sense. In other disease settings within the lymphoma space, that may be a different equation that we will then address in the respective clinical trials as we get there.

Thank you very much Thanks, Wimal, for the question. I think we move on to the next speaker.

We are now taking the question from the line of Kennen MacKay from RBC Capital Markets.

Congrats on the data as well. Also a question on epco. I would love to hear the perspective from the KOLs as to how the CD20xCD3 field is beginning to develop as any of the agents do appear preferable to them? Obviously, epco has some very, very high complete response and response rates in both follicular and DLBCL. And also from that perspective, which characteristics, just sort of beyond efficacy, stand out as the most critical for these agents to really become the future of standard of care across lines of therapy?

Thanks, Kennen, for the question. I'm going to hand this over to you, Martin, because I think you have a very good experience with several CD3xCD20, so you can probably put it in perspective for Kennen and the other listeners. Martin? Martin, are you on mute? Maybe while we cannot reach Martin, I'm going to hand it over to Tahi Ahmadi.

Yes. So I'm not sure if I can give you the same perspective as Martin Hutchings could because obviously, I work for [indiscernible]. But I think in general, the whole class of T-cell [indiscernible] has shown a level of efficacy that previously had not been seen, particularly in this [indiscernible] refractory B-cell lymphoma. This is where a lot of the excitement comes from, I think. And I would say that the characteristics that in the end will allow for this to truly get to the ambition of transforming the [indiscernible] in general, has to be that, A, it all has to be safe. And by that has to be safely combinable with some of the treatment modalities that already exist. Its mechanism should not be negatively impacted by such a combination or potentially might be a synergism. And you are hopefully having the translation of the responses into less pretreated patient population way than would like to see a much higher CR rate or even beyond CR, control of the minimal residual disease such that patients are hopefully cured, which is a very difficult thing to show over time, but then at least have a very long duration of response and benefit from that. I think that's how we think about epco and we, from our point, I believe epco has all of these criterias. And that's, I think, all I can say from where I spend. I don't know if Martin's back online.

Thanks, Tahi. That's understood.

I'm back on the line. This is Martin. I broke out the line program, I'm back on the line, sorry.

You heard the question, Martin, so maybe you can get some [indiscernible]

No. Sorry, I didn't hear it, sorry.

So why don't we ask you, Kennen, to repeat the question? It's basically about the perspective of different CD3xCD20s. What do you think are the effective and less effective features of the key players? Maybe you can really put it a bit more in perspective. Kennen, I hope I summarized that correctly.

And so in that case, I hope I answer what I understood correctly. So can you hear me all?

Yes, perfect.

Great. So I mean, I have this disclosure to make that I only have personal experience with glofitomab and epcoritamab. But on the other hand, I think I'm the only one who has experience with more than 1 of the CD3xCD25 specifics. They are a little bit different in their mechanism of action, obviously. They're also different in their toxicity profile, which is really the easiest thing at this point to compare. I think the safest 1 in our hand so far has been epcoritamab. I think that's supported by the clinical data that we have, both from the ASH conference this year and from presentations over the last couple of years. The cytokine release syndrome is really the key. That's the key thing. That's the main obstacle towards safe treatment of the patients and the main obstacle in treating patients in -- safely in an outpatient setting. So there, I would say I haven't seen anything safer than epcoritamab. If anything, that would be mosunetuzumab. That leads us to the efficacy. I think mosunetuzumab in the field of 4 to 5 competitors in the CD3xCD20 field is probably the weakest one. That doesn't mean it will not find its use, probably in indolent lymphomas. But I think the relative safety of mosunetuzumab compared with glofitamab and epcoritamab comes with the territory of less efficacy. So that we -- I would say the strongest in terms of efficacy probably are glofitomab and epcoritamab, and the safest 1, epcoritamab, perhaps in par with mosunetuzumab. So from a clinician's point of view, this looks very good. Looking at the individual responses to the patients, I think perhaps, and this is experience rather than supported by data, the more rapid responses are seen with some of the IVs, particularly with glofitomab. And this is very nice and very impressive for us clinicians when we treat our patients. But having very, very quick tumor reductions is not necessarily what the patient needs. Actually at certain points, it can be quite unsafe. You see, what we call tumor lysis syndrome, which is another acute reaction to anti-cancer therapy, which can be quite dangerous like cytokine release syndrome. We have not experienced this with epcoritamab. We have experienced this in the setting of, for example, glofitomab, but I think it has been seen with [indiscernible] as well. So it's a complex question to answer, but this is as far as we can go without any direct comparisons.

Thanks very much, Martin. That's really appreciated. Operator, let's move to the next question.

We are now taking our next question from the line of James Gordon from JPMorgan.

James Gordon from JPMorgan. Just a follow-up question from [indiscernible] before, actually. This was just, ultimately, if all the agents end up doing a subcu, do you think that the side effects will then ultimately all be the same? Is the difference in side effects in terms of CRS really just a function of seeing subcu and having lower buildup and systemic exposure?

Thanks, James, for that question. I think I'm going to pass it over to Martin as well, because he has most experience with CD3xCD20. So Martin, do you think that the side effects will be similar when they are all given subcu at some point?

Yes. This is a really good question and impossible to answer. I'll just give you a few reflections. Mosunetuzumab is being developed for subcu use already. We have very little data from that at this point. And already mosunetuzumab is, like I already said, a weaker drug, in my eyes. So it's difficult to compare with epcoritamab, which is a lot more effective. Then we have glofitamab that has not yet been developed. The drug is ready for a study. So we will have to wait for a year's time to assess that directly and compare it indirectly with epcoritamab. When I say that subcutaneous use of epcoritamab is one of the factors responsible for the very favorable safety profile, that is a belief. We can't be sure that's the case. So in the absence of any direct comparisons of the subcu formulations, it will have to be an open answer. But I think the hope definitely from the competitors is that the safety profile, when they develop properly, their agents into subcu use will be that the safety comes a bit more on par with what we see from epcoritamab.

Thanks, Martin. Thanks for that very good answer. Let's move to the next question, operator.

Yes. We are taking the next question from the line of Jonathan Chang from SVB.

Congrats on the ASH updates. Can you talk about how you're thinking about the mechanistic risks of combining epco with chemotherapy and steroids in your future development plans versus with other, let's say, immunotherapy-based approaches?

Thanks, Jonathan, for the question. I'm going to probably hand this over to Tahi Ahmadi.

The question, I couldn't really hear it. I'm sorry, there was like a little bit of noise on my end.

The mechanistic risks of combinations of CD3xCD20 with chemo and steroids.

Very good. Thank you. Well, I would say there was a part of the mitigation strategy for trying to reduce the risk of cytokine release. So in effect, the clinical data that we and others are presenting already documents that the addition of steroids does not negatively limit or hamper the ability to activate and redirect T-cells, but they're probably also something through that in the crowd space. With chemotherapy, we and others are running safety combination studies where efficacy is 1 readout, safety is another one. And clearly, also we interrogate the impact on T cell function. There, not all chemotherapies are made equal. Some chemotherapies by mechanism are known to have more of an impact on T cell functions than others. And so for the more commonly used standard regimens, we are not necessarily concerned. And I think others have already shown that this can be combined.

Thank you very much, Tahi. Let's move in the context of the time to the next question.

We are now taking the question from the line of Michael Schmidt from Guggenheim.

Congrats on all the updates. I had 1 for the physicians on epcoritamab and the other bispecifics. I guess what level of cytokine release syndrome do you think would be acceptable for these drugs to be broadly used in a community setting? And on clinical development, I was just wondering, first-line DLBCL is obviously an obvious place to go. I think Regeneron has already committed. Will we be in a situation where each of the CD20 bispecifics will be combined with R-CHOP? Or are there more creative ways to think about earlier lines of lymphoma treatment with these agents?

Thanks, Michael, for the question. I'm going to hand it over first to Martin and then maybe to Judith Klimovsky to see whether there's a different angle. Martin?

Yes. Thank you very much. These are really good questions. I think there are, in fact, 2 questions so I'll begin with the first one. So that's the question, whether the bispecifics will eventually be handled well in a community setting such as a way to give anticancer therapy in the U.S. So I think the answer is yes, generally, in the vast majority of patients. So we are already at this point -- at a point in time when we've treated well over 1,000 patients with CD3xCD25 bispecifics across all the studies. We already have a pretty good idea which patients are likely to develop severe CRS. So we have risk factored profiles that have been developed quite rapidly. So within a relatively foreseeable future, we'll be able, with some precision, to predict which patients we need to really be careful about. And the remaining patients will likely be at risk of only CRS grade 1 or CRS grade 1 or a mild grade 2. These are patients that can be managed in an outpatient setting. And then I think for all these effective molecules, you will need to be able to identify a smaller group of patients where you say in order to be safe, we need to start therapy maybe with a 24-hour hospitalization on the first full dose such as being used in the Phase II part of the epcoritamab study. So -- and just like the CAR-Ts that are being developed for outpatient use, then there will be reservations such as if you have a patient who lives far, far away from the specialized treatment centers, perhaps we would recommend the patient be within a certain reasonable travel distance of the facility. So these are just my thoughts about this. The vast majority of patients will be treated in an outpatient setting. And I'll just add before going on to the chemotherapy and biological combinations, just compare this with R-CHOP, which is the standard of care first-line for all these lymphoma patients. That is a lot more risky to give. We give all our patients R-CHOP in an outpatient setting. They experience a lot of different range of side effects, most importantly, febrile neutropenia. They all have developed some degree of neutropenia. And that can be quite dangerous and quite unpleasant to the patients. And sometimes, it can develop very rapidly. Nevertheless, we are very safe giving that in a community setting. So with time and with experience building in the community, predicting, first of all, and also managing CRS, I think this will not be a problem. Then the second question is about the combinations. Would you like to take that, Jan or...

Yes, please, so why don't you go on, Martin?

So I mean, R-CHOP is the standard of care in first-line. And every successful drug in the last 20 years has been tested in the context of R-CHOP and failed. And maybe because these bispecifics are so much more potent than the other novel drugs that we've tested over the last decade or 1.5 decades, that might -- the story might change. Like Tahi said, there are many different chemotherapy combinations. Some are biologically more attractive to combine with T-cell engaging therapies than others. But maybe, at least in later lines of therapy, more attractive combinations are really with other immunotherapeutic approaches that might support the mechanism of action rather than oppose it or other biological agents, which also might modulate the immune system to facilitate the actions of the T cells. But of course, we will need to develop also chemotherapy combinations. And like Tahi just said, this is already ongoing with some of the other bispecifics. It looks so far to be safe, whether that's to the efficacy is really too important to tell. But the combinability of anticancer agents is very much about avoiding overlapping toxicity. And I'll get back to the point, the toxicity of epcoritamab is cytokine release syndrome and a little bit of neurotoxicity, very little. That is in its -- it's a phenomenon that occurs during the first 3 to 4 weeks of treatment, then it's over. It basically means you can -- in terms of safety, combined with more or less anything. The caveat is not combining, it was something that hampers the efficacy of the drug. I think that's all for me.

Thanks very much, Martin. I think we will move on to the last part of the presentation, and then there's another Q&A period, so you can all think about questions there. So thank you for the questions now. Next slide, please. So let's now move to our key priorities for 2021. As you will see, we have a lot to look forward to in the coming year. Next slide. As I noted during our 2020 Capital Markets Day event recently, we have already begun to deliver on our commitments to patients, and we will continue to do so in 2021 with a strong focus on differentiated Genmab-owned antibodies and our own therapeutic pipeline. Excitingly, in the first quarter of the new year, we are anticipating the filing of our first BLA along with our partner Seagen, with the JNDA submission for tisotumab vedotin. If approved, tisotumab vedotin would become the first Genmab-owned product on the market, a major milestone for the company. We are also planning along with partner AbbVie to accelerate development of our potential best-in-class epcoritamab with the advancement of expansion cohorts and additional Phase III trials. In addition to advancing our late-stage product candidates, we will also focus our resources on continuing to further develop and expand our world-class antibody product pipeline in general. We will also continue the strategic development of our internal capabilities with the goal of building a smart commercialization model and as we aim to not just create medicines that transform cancer treatment but to fight these medicines to doctors and patients in the most effective way possible. Finally, we will further strengthen our already extremely solid financial foundation, and we will provide you with details on our specific 2021 guidance when we publish our 2020 annual report on February 23. So let's move to our next slide and an additional brief Q&A session. Let's move into the next slide and then see operator whether there are any further questions. Operator?

[Operator Instructions] We are now taking a question from the line of Laura Sutcliffe from UBS.

It's Laura Sutcliffe from UBS. I'd just like to go back and ask a clinical question on epco if I can, please. Could you tell us how you distinguish between a patient who has grade 1 CRS, which I think you described as mono-symptomatic fever and a patient who has fever, because you report those 2 as separate things on Slide 11? So to put my question another way around, why are those patients that you counted as having fever not Grade 1 CRS patients?

That's a really good question. Sorry, sorry, I'll take that. So this is a really good question. Okay, sorry.

Because I'm a little bit more familiar how we actually collect the data. So the way we do it at Genmab is we collect all AEs that are part of the composite endpoint AE or cytokine release individually and separately. And then we -- on a separate form, also collect cytokine release. So they are essentially double-counted at this point in time and that's on purpose because we -- this is a first in human trial. We want to truly understand in quite detail the safety profile of the drug.

Any further point of view, Martin?

Maybe if you'll allow, maybe I can add from a clinician's point of view, this is Martin speaking. Essentially, you can have fever without CRS but you cannot have CRS without fever. So there will -- with that simple math, you will always have a few cases of fever that are not CRS. You cannot have a CRS that's not fever.

All right. Thanks, Martin. Laura, I hope that is clear. Otherwise, give us a ring.

We are now taking the question from the line of Graig Suvannavejh from Goldman Sachs.

Maybe a question for the clinicians. I know we've spent a lot of time on epcoritamab. But for subcu DARZALEX, I was wondering if the physicians could give their perspective around what their current impressions are with their current adoption of the product is. And is there any reason 1 would either not start someone with subcu DARZALEX or transition to subcu DARZALEX? Just trying to get the physician's perspective on their experience with that product.

Thanks, Graig. Thanks for the inaugural question on daratumumab. So maybe Thanos, maybe you can start or start us on the perspective of subcu dara usage by not putting a patient on subcu when it is available. Thanos, are you there? Maybe on mute. Or Efstathios?

This is Efstathios. Can you hear me?

Yes, we can hear you now.

So unless Professor Dimopoulos has been connected, I can comment on the use of subcutaneous daratumumab. We have extensive experience now. It's not still yet commercially available in Greece. However, we have extensive experience in clinical trials, and we have extensive experience with patients who are on intravenous daratumumab and they are switched to subcutaneous daratumumab. First of all, the patients are very happy because they really have to stay like a few minutes in the hospital, especially after the third or fourth infusion, which of course, is very convenient for the patient and it's very convenient for the hospital and the oncology department. Second, what we have observed and also has been observed is that the subcutaneous for daratumumab is associated with significantly lower risk of adverse reactions during the infusion so the patients tend to have less and less often and less severe infusion-related reactions like fever, chills, cough, DSP, et cetera, et cetera. So in perspective, I don't think that there is a single reason why 1 should not use subcutaneous daratumumab instead of IV daratumumab when this becomes available across Europe like is in U.S. The convenience and the safety are excellent and also the efficacy is the same as the intravenous formulation of the drug.

Thank you very much, Efstathios. And I don't know whether Thanos is on the line and unmuted. Otherwise, we'll move on to the next question, maybe the last one. Thanks, Efstathios. Maybe operator, the last question for now.

We are now taking the question from the line of Peter Welford from Jefferies.

Okay. I wonder if we could just go back to, sorry, epcoritamab again and just talk a bit about the neurotoxicity. Just curious there, if you can give some comments about what you've seen there. And is that also something you think is at all mitigated by subcu dosing and whether or not you can talk about whether or not there are any neurological symptoms that were reported during the course of the study.

Thanks, Peter. Martin, can I hand the discussion to you?

Yes, obviously. So we have to distinguish between treatment-emergent and treatment-related neurological symptoms. If you have a high fever, many patients will have a little bit of headache, a little bit of dizziness. So that is not necessarily a neurological symptom. It's something that goes with the territory of fever. If we're looking at actual treatment-related neurological events, we've seen 4 all in all in these 68 patients, 2 are grade 1, 2 are grade 3, and they have all been transient and self-limiting without any permanent damage and without no specific treatment needed. So actually, in comparison with CAR-Ts, which have a similar mechanism of action, this is a much milder phenomenon. And also, I think it looks pretty good in comparison with the IV bispecifics. This is really a reflection of the cytokine release syndrome. So why are the neurological symptoms so mild? I think it has -- goes hand-in-hand with the less -- well, not lesser frequency but the lesser grades of the CRSs that we see.

Sorry, I was on mute. So thanks, Martin, for the question. Let's move to the next slide. Thank you all for interesting questions and for joining us for this virtual event and a special word of thanks to all the truly exceptional speakers who have joined us here today, managing despite the challenges of the presentation being made virtual. So from all of us at Genmab, we wish you happy holidays and a healthy, safe and very positive start of a beautiful 2021. This concludes our ASH update. Thank you all.

That concludes the conference for today. Thank you for participating. You may all disconnect.

Thank you. Bye.