Good afternoon and good evening. Welcome to Genmab's Virtual S Data Review. I'm Jan van de Winko, President and CEO of Genmab. We have hoped to see you all in sunny San Diego this year. But just like the Annual Meeting itself, we have gone truly virtual to update you on exciting data presented at this year's conference.
For those of you who joined us for our earnings webcast, the format of today's event will be very familiar. Like an earlier Genmab S data review event, the operator will open the line for Q and A. And as always, we have a busy agenda, so let's begin. Please move to Slide two. As a reminder, the presentation may contain forward looking statements and as such, may contain certain risks and uncertainties.
Let's move to Slide three. The virtual nature of this year's ASH Annual Meeting did not mean the data was less exciting. On Sunday, Doctor. Martin Hutchins, who we are very fortunate to have with us today, presented an update on the dose escalation data for efcoritamab. 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 abstracts accepted. To present some of the highlights from the many data presentations, we're extremely pleased to have with us again Doctor. Meletius Demopoulos, and we are joined for the first time by Professor Astartios Castritas. 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 and 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 with Epi 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 focus we have had with our pipeline, as you will see on our next slide.
Next slide, please. At the conclusion of our 2019 event at ASH, I predicted that we actually would build on our 2019 momentum with focus across our pipeline. From the partial list of achievements you can see here, it's evidence that we have more than achieved this goal. Our pipeline both matured and expanded this year as new antibodies entered the clinical the clinic and two dual body molecules entered Phase III trials, including eptaritamab, which we are co developing 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 twenty twenty ASH was, as I mentioned, updated eptinezumab 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 INNO2VATE-two zero four study of tisotumab vedotin, which we are developing with CGM, which was chosen as a late breaking presentation at ESMO. And the first clinical data for DuoBody PD L1x400B, 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 developed by Janssen, became the very first neurobody awarded a breakthrough therapy designation and was recently submitted for FDA approval in The United States. And there are now three Genmab created medicines available for two patients with The U. S. Approvals of Crecynta 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 focus in 2020, I would encourage you to listen to the replay of our twenty twenty 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. Doctor.
Martin Hutchins is a haemato oncologist at Rijks Hospitalet in Copenhagen, Denmark. Martin is an expert in the treatment of malignant lymphoma and is a co author of the ESMO guidelines for the management of ultra high risk patients with malignant lymphoma. He's an investigator on the first Phase onetwo study of efgartigimod. 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 twenty twenty Virtual ASH Conference on Sunday. Relapsed or refractory B cell non Hodgkin 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 efgartigimod 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 efpiritamab. So efpiritamab 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 two 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 standard chemotherapy. So there is a high unmet need in this situation.
It goes for both aggressive and indolent lymphomas. Epiritamab is a bispecific CD3CD20 antibody, which is developed for subcutaneous use, and it binds to this 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. Epirituximab 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, mosinutuzumab and glafitamab. 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 bimezizumab.
We know from preclinical studies, excellent work that efgartigimod retains that 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 efgartigimod is, like I said, administered subcutaneously.
It's a very easy to administer one milliliter infusion, which is given rapidly. You don't have to give it over ten 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 the 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 long plasma 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. So 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 three, four, sometimes five to six 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 forty eight milligram, not because we could not administer more of the drug because the maximum tolerated dose was not met and we did not meet 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 forty eight milligrams. Next slide, please. So this is the design of the study. Primary objective of this first Phase onetwo 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 two dose, which indeed was successful. So what I'm showing you here is basically the final results of the Phase one portion of the Phase onetwo 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 relapsedrefractory B cell non Hodgkin lymphoma, reasonable performance status, performance status zero to two, so including some relatively frail and sick patients, which is unusual for a Phase one 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, one hundred sorry, twelve point eight micrograms.
And actually, was not the priming dose. The priming dose was as low as four micrograms going all the way up to the recommended Phase II dose, which like I said, is forty eight milligrams. This doesn't mean that all the patients get forty eight milligrams from day one. We still have step up dosing, which is a strategy successful strategy to mitigate cytokine release syndrome. The patients receive one hundred and sixty micrograms on day one after a week, eight hundred micrograms and the final dose reached after two weeks of treatment is forty eight 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 sixty eight. And you can see that the majority of these patients had diffuse large B cell lymphoma, which are also 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, twenty five percent at a median follow-up of ten 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 have been biologically suboptimal. Next slide, please. Now we 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 efgirutamab belongs is cytokine release syndrome, which is an immunological response syndrome, which looks very much symptomatically like infection.
So on one end, it's monosymptomatic fever, ranging over fever plus hypotension and hypoxia towards the severe grades, which might include multi organ function by intensive care treatment and even fatal cases. Fortunately, we have not seen any of such serious events in the study of efgartigimod. All the patients who have experienced cytokine release syndrome, which is fifty nine percent of all patients, have had the CRS as either grade one or two as maximum severity. And grade one means basically monosymptomatic fever. Grade two 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 two, 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 timewise connection with the treatment. But important the important message really here is that we do see cytokine release syndrome, but really in sixty eight patients who have had very much benefit from the treatment, it's quite stunning to see no cases of Grade three or four 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 twelve milligrams of efgartigimod or above. In the green waterfall chart, follicular lymphoma patients treated at doses of seven sixty micrograms or above and on the right, a few patients with mantle cell lymphoma who have been included in this slide because they had two of the three 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, been 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, I should have said that.
And looking on the table on the right is really what your eyes 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 ninety one percent, which is, in my experience, absolutely unheard of in such a difficult treatment population. And also complete responses in fifty five percent is beyond anything what we're used to seeing in relapsedrefractory diffuse large B cell lymphoma. Next slide, please, which shows you the durations of responses and response rates in follicular lymphoma and a few patients with mantle cell lymphoma.
You can see all the responses with these diseases. And in 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 ninety percent, which is nine out of ten patients with follicular lymphoma and complete responses in five of those ten patients. And that is probably even underestimated a bit because in these patients, some of them did not have PETCT but only CT to determine response, which makes it somewhat easier.
This is somewhat more difficult to demonstrate complete responses. Next slide, please, which leads us to the summary, which is that efcharitamab, this subcutaneously administered CD3, CD20 bispecific antibody is a novel and it's off the shelf therapy, which is administered once every week. Currently in this dose schedule that we're using at this point for three months, then biweekly for three months and then every four weeks until progression. And many patients are still on treatment with this schedule. The recommended Phase II dose of forty eight 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 begun 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 three and even Grade four cytokine release syndrome. In the case of efgartigimod, perhaps in part because of the subcutaneous administration, we have only seen cytokine release syndrome, Grades one and two, 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 thirty percent, thirty five percent at best and complete response rates typically between ten percent and twenty percent.
Here, we saw ninety one percent response rates and complete responses in fifty five percent of patients treated at the target dose of forty eight milligram or above. And similar response is seen in follicular lymphoma. We can't 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, efgartigimod binds to a distinct epitope, which is different from the anti CD20 antibodies registered for the first line in subsequent lines of treatment in this disease, rituximab and obinutuzumab? And does it has the potential to be the partner of choice in combinations 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, efparizumab is being investigated in several trials across 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 epiritamab with us all. Now we will have a review of some of the key data sets for daratumumab that were presented 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 am very pleased to introduce Astarteos Kastritis, who is Associate Professor of Clinical Therapeutics at the Department of Clinical Therapeutics at the National and Cape Codestrian University of Athens, School of Medicine.
So Doctor. Kastritis is an expert in multiple myeloma, Waldenstrom's microglobulinemia and amyloidosis. And he has presented the primary results from the ANDROMEDA trial as a late breaking oral presentation at the EHA twenty five Congress in June. Stathis, 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, The presentations that were present systemic AL amyloidosis and liver plasma cell disease by the extracellular deposition 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 the 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 often 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 and 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 treatment combinations by regimens we use in multiple myeloma with usually dose 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 a treatment of patients with AL amyloidosis is the combination which is called VCD, 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 controlled Phase III study in which the combination of cyclophosphamide, bortezomib and dexamethasone with daratumumab is compared to the standard therapy of bortezol 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 VCD resulted in deeper and more rapid hematologic responses, also with an acceptable safety profile, which was consistent with what has been observed for daratumumab VCD. Next slide please. So one 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, 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 one to two amyloidosis patients for every about ten myeloma cases. So actually, it's not that rare.
Next slide, please. So here you can see the design of the ANDROMENA study. As you can see, patients were randomized to receive either subcutaneous daratumumab with VCD for six cycles followed by up to twenty four months of daratumumab monotherapy or to receive six cycles of the standard therapy with VCD. 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 VCD group achieved a complete hematologic response at any time during the study compared with a standard VCD regimen. And actually, this improvement was substantial. As you can see, fifty three percent of patients with daratumumab VCD achieved a complete hematologic response versus eighteen percent for standard VCD, and this was statistically significant highly statistically significant with an odds ratio of five point one. These results were consistent across all specified subgroups. And also, it is very important that treatment with DIATOVAL VCD 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 six months, was significantly higher with the combination of Daratumumab with VCD and was almost double with this combination. Also, as we said, the safety profile of dara VCD was consistent with the non profiles of dara tumor monotherapy subcutaneous and VCD. Next slide, please. As you can see in this slide, in every different hematologic response system that was evaluated, the combination of Daratumumab with VCD 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 endpoint. And of course, as we said in the previous slide, these complete hematologic responses by every different system were three to four to five times higher in the VCD 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 achieve a complete or a very good partial hematologic response at one 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 three months.
And this is very important because roughly twice as many patients who received the combination of daratumumab with VCD achieved this endpoint. So daratumumab with VCD 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 VCD was associated with a substantial improvement in the MOD PFS and the MOD event free survival across all different cardiac stages. As we said, cardiac stage, which actually shows the degree of cardiac dysfunction because of amyloidosis is the most important prognostic factors.
And as you can see, there is substantial benefit with the combination of diatomav and BCD across every different cardiac stage, especially in patients who have more advanced cardiac disease, which are the patients with Stage three disease, which is shown here in green for daratumumab and VCD, and in purple for VCD 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 VCD. The HISA 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 VCD 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 one and at three months was associated with substantial improvement in the risk of major organ deterioration and death in patients with newly 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 confirm that initial therapy that sees rapid and deep hematologic responses, such as the tumor with VCD is essential in order to improve the outcomes of patients with L amyloidosis, and we can see that after a median follow-up of about sixteen 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 diatoma with ECD versus VCD. MOD PFS and the MOD EFS were better in the diatoma VCD arm than in the VCD group across every cardiac stage. And I think here this is very important, especially across patients with stage three, which are patients with the more problems, the patients in which unmet needs are higher.
Rates of serious adverse events were higher in patients with more advanced cardiac stage, but this was independent of the treatment that was used, and this is mostly associated with the underlying major cardiac dysfunction. This result support that the combination of subcutaneous diatomone with VCD is a potential standard of care, and in my opinion, it is now the new standard of care for patients with newly diagnosed L amyloidosis irrespective of baseline cardiac stage. And with this, I would like to complete this presentation. Thank you very much.
Thank you very much, Statos, for that very good overview of the ANDROMELA data. I will now ask you to progress also presenting us an overview of the APOLLO, MAIA and GIFEN data because we just heard that Doctor. Demopulos cannot make the presentation because of an urgent meeting with the President in Greece.
I am here. Hello. Yes, I made it. Thank you.
Thank you, Thanos. You are a world renowned specialist multiple myeloma, in plasma acetoma and Waldenstrom. We are delighted you very
much. Be
Just in time. Please go ahead.
Okay. Next slide, please. Hello? Next slide. Hello?
Okay. The APOLLO trial is a randomized Phase three 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 IMiDs and immunomodulatory and proteasome inhibitors. Furthermore, there were data that daratumumab has single agent activity in the treatment of relapsed and refractory myeloma. And also subcutaneous administration of daratumumab appear to be equally effective and associated with fewer infusion 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 one 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. Would like to note that approximately onethree of patients had high risk disease, benign cytogenetic profile. All patients were pretreated with API and the limit. And also about eighty percent of the patients were refractory, had refractory disease and one half of the patients had refractory disease to both API 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 and in the investigational arm, twelve point four months for hazard ratio of 0.63, indicating that the addition of subcutaneous daratumumab to pomalidomide and dexamethasone improved the PFS with a thirty seven percent 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 pre specified subgroups. And we can appreciate that the combination of subcutaneous daratumumab with pomalidomide and low dose dexamethasone was beneficial across all patient subgroups, including age, ISS stage, number of prior lines and the refractoriness to lenalidomide. There were a few patients who have received only one prior line of therapy, about ten percent. And also in these patients, the hazard ratio was zero point seven.
Next slide. Response was also improved in favor of the combination with an overall response rate of sixty nine percent versus forty six percent for pomalidomide and low dose dexamethasone. And also MRD negativity was improved four times in favor of the triplet. Next slide. The most common of various events are shown here.
It is noteworthy that they were essentially equally distributed between the two arms, and they were consistent with the known profiles of subcutaneous daratumumab with formalidomide. The difference was Grade three or four 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 taratumumab. They were about five percent and all of them grade one or two.
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 seven percent in each group and the rate of secondary malignancy was equally low at two percent. 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 thirty seven percent.
And also, it was associated with response rate, including a 6x higher complete response rate and a 4x higher MRD negativity rate. DPD was associated with a 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 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 and updated safety and efficacy profile of the study with an approximate follow-up of four years. Next slide.
This is the design of the study. Previously untreated patients with symptomatic myeloma with a creatinine clearance of thirty ml per minute or more were randomized to receive either standard lenalidomide dexamethasone at a standard dose or the same regimen with the addition of daratumumab. Treatment was continued until there was evidence of disease progression or an acceptable toxicity with the known endpoints. Next slide, please. Patient characteristics were well balanced among the two groups of patients.
Median age was 73, and approximately onetwo of the patients were older than 75. Approximately onethree of the patients had Stage III disease. And also about fifteen percent of patients had high risk cytogenetics. Next slide. This is the main finding of the update with a median follow-up of four years.
Median PFS has not been reached. It is sixty percent in the DARZALD arm, and it is thirty four point four months in the lenalidomide and dexamethasone arm with a hazard ratio of 0.54 indicating that the addition of daratumumab to lenalidomide and dexamethasone resulted in a forty six percent reduction in the risk of progression or death. The addition of daratumumab to lenalidomide and dexamethasone resulted in deeper responses with a 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 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 a stage three 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 DaraRD arm, ranging from twenty four percent at the first analysis to thirty one percent at the updated analysis at four years. Furthermore, the sustained MRD negativity indicating MRD sustained for more six months was clearly improved over time and it was clearly higher in patients treated with RRD, twenty percent at six months and sixteen percent at twelve months. Next slide. To conclude with a median follow-up of four 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 PFAS2 favoring DaraRD 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 two 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 twelve 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 dysfunction were randomized to receive either VRD before transplant as an induction, high dose therapy consolidation and then maintenance with lenalidomide, whereas for three years, whereas the investigational arm consisted of the same regime with the addition of daratumumab. Next slide. Patients with disease characteristics are shown here. Were well balanced between the two groups. And we had about onefive of the patients with high risk cytogenetics and also about onetwo of the patients with ISAID Stage two or three.
Next slide. This is an interesting slide, which shows the deepening of response over time in the VRd data arm with twelve months of maintenance therapy, we have a complete response or better rate, which is eighty two percent versus sixty one percent in the VRD arm. Next slide. Subgroup analysis of stringent complete response and MRD negativity by the twelve months of maintenance therapy cutoff indicates that for all pre specified 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 overall survival data are not yet mature. You can see that there is actually an excellent PFS with both arms. And at two years at the two year cutoff, it is above ninety percent 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 ninety three percent 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 VRD. And I believe that this randomized Phase II study indicates that DARA VRD is a new standard of care for transplant eligible patients with newly diagnosed myeloma. And of course, we have the Phase III PERSEO 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, Tanal, for that excellent overview of some of the daratumumab data presented at ASH over the past few days. We now move to a Q and A session. So please move to the next slide. So since our experts' time is very precious, we don't have a lot of it. Please ask only one question and note that we will have an additional short Q and A session at the end of this event as well.
So operator, please open the line for questions.
Thank you. We're now taking our first question from the line of Vimal Kapadia from Bernstein.
Wimal Kapadia from Bernstein. You ask about duration of use for the CD3, CD20s as a class? So just curious to hear your thoughts on the fixed dosing period versus treating progression. And how do Genmab actually 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 Thay Amadi. Martin, please give your feedback on the duration of use of CD3CD25 specifics and potential maintenance use, how Yes. You see
This is an excellent question, particularly from a clinician's point of view as well. So I mean these are Phase I studies, and 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 ipruritumab is being used until progression. And the good thing when you think about side effects, which is what you alluded to, is that the vast amount of side effects that we see, particularly cytokine release syndrome, are experienced during cycles one and occasionally cycle two. 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 four weeks is really not a problem. Other bispecifics, as glafetamab and osinutuzumab, 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 one strategy is better than the other is too really too early to tell. But in terms of safety, I do not see any problem keeping patients on treatment with efpiritamab.
Thanks very much, Martin. Maybe, Thij, you can give a further perspective on potential maintenance use, how we see it. Thij and Mavi? Sure.
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 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 overall survival. Really this is their 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 as most of the AEs are happening within the first one or maybe two cycles and thereafter is 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, Thij. 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
Hi, Kennen. And thank you for doing this for us. Congrats on the data as well. Also a question on ETSCO. I would want to hear the perspective from the KOLs as to how the CD20, CD3 field is beginning to develop.
Any of the agents do appear preferable to them? Obviously, EBSCO 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 CD3, CD20, so you can probably put it in perspective for Kennen and the other listeners. Martin? Martin, are you on mute? Maybe when we cannot reach Martin, I'm going to hand it over to Tahira Mahdi.
Yes. So I'm not sure if I can give you the same perspective as Martin Hutchins could because obviously I work with Gemma. But I think in general, the whole class of T cell redirection has shown a level of efficacy that previously has not been seen, particularly in these really refractory diffuse large 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 treatment paradigm for B cell malignancies in general has to be that, a, a drug has to be safe and by that it 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 there potentially might be a synergism. And you are hopefully having the translation of the responses into less pretreated patient population where you then 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. And I think that's how we think about Epco. And we, from our point, believe Epco has all of these criterias. And that's, I think, all I can say from where I stand.
I don't know if Martin is
coming
Thiji. That's understood. Back on the line. This is Martin. I broke up.
Line broke up. I'm back on the line, sorry.
You heard the question, Martin. So maybe you can get some
Sorry, 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 CDCs, CD20s. What do you think are the attractive and less attractive features of the key players? Maybe you can really put it a bit more in perspective. Kennen, I hope I summarized that correctly.
So in that case, I hope I answered 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 lofitamab and efpiritamab. But on the other hand, I think I'm the only one who has experience with more than one of the CD3, CD20 bispecifics. 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 one in our hands so far has been epirizumab. 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 safely in an outpatient setting.
So there, I would say I haven't seen anything safer than efgartigimod. If anything, that would be mosinutuzumab. That leads us to the efficacy. I think mosinutuzumab in the field of four to five competitors in the CD3, CD20 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 mosinutuzumab compared with glafetamab and odronextumab comes with a territory of less efficacy. So the I would say the strongest in terms of efficacy probably are glafetamab and efpiritamab and the safest one, efpiritamab, perhaps on par with mosimetuzumab. So from a clinician's point of view, this looks very good. Looking at the individual responses of the patients, I think perhaps and this is experience rather than fortified data, the more rapid responses are seen with some of the IVs, particularly with tafasitamab. 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 syndromes, which is another acute reaction to anticancer therapy, which can be quite dangerous like cytokine release syndrome. We have not experienced this with efirizumab. We have experienced this in the setting of, for example, clufismab, and I think it has been seen with upronexumab as well.
So it's a complex question to answer, but this is as far as we can go without any direct comparisons.
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 one on one 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 in systemic exposure?
Thanks, James, for that question. I think I'm going to pass it over to Maarten as well because she has most experience with CD3, CD20s. Maarten, do you think that the side effects will be similar when they're all given subcu at some point?
Yes. This is a really good question and impossible to answer. I'll just give you a few Q reflections. Mosinutuzumab is being developed for subcu use already. We have very little data from that at this point.
And already, mosinutuzumab is, like I already said, a weaker drug in my eyes. So it's difficult to compare with epiritamab, which is a lot more effective. Then we have aglafizumab that has not yet been developed. The drug is ready for a study. So we will have to wait a couple of years' time to assess that directly and compare it indirectly with efparitinib.
When I say that subcutaneous use of efparitinib 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'll see from efcharizimab.
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.
Hey guys. Thank you very much for taking the question and congrats on the ASH update. 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? Thank you.
Thanks, Jonathan, for the question. I am going to probably hand this over to Tayyah Mari. Quickly, the question, I couldn't really
hear it. I'm sorry. It was like a little bit noise on my end.
Mechanistic risk of combinations of CD3, CD20 with chemo and steroids.
Very good. Thank you.
I would say steroids are 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. Probably also something to that in the CARD space. With chemotherapy, we and others are running safety combination studies where efficacy is one 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 function 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, Thay. 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.
Hey, guys. Thanks for taking my questions and congrats on all the updates. I had one for the physicians on efcoritamab 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 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 our 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 Jurek Sklimovski 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, two 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 the typical 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 CD3, CD20 bispecifics across all the studies. We already have a pretty good idea which patients are likely to develop severe CRS.
So we have risk factors and profiles that are being 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 one or CRS grade one or a mild grade two. 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 twenty four 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 a specialized treatment center, perhaps you would recommend the patient being within a certain reasonable travel distance of the facility. So these are just my thoughts about this. The vast majority of patients will be treatable 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 sort of 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 and predicting, first of all, and also managing CRS, I think this will not be a problem. The second question is about the combinations. Should I take that, Jan? Or
Yes, please. So why don't you go on, Martin?
So I mean, the, R CHOP is the standard of care in first line. And every successful drug in the last twenty 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 one 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 Taj just said, this is already ongoing. And with some of the other bispecifics, it looks so far to be safe. Whether it adds 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 eptinezumab is cytokine release syndrome and a little bit of neurotoxicity, very little. That is in a it's a phenomenon that occurs during the first three to four weeks of treatment, then it's over. It basically means you can, in terms of safety, combine this with more or less anything.
The caveat is to not combining it with 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 and 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 twenty twenty 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 in 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, C Gen, with the FDA submission for tisotumab vedotin.
If approved, tisotumab vedotin would become the first ternop owned product on the market, a major milestone for the company. We are also planning, along with partner Epi, to accelerate development of our potential best in class efgartigimod 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 provide 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 and A session. Let's move into the next slide and then see operator whether there are any further questions. Operator?
We are now taking a question from the line of Laura Stratford from UBS.
Hi. It's Laura Stratford from UBS. Thanks for taking my question. 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 one CRS, which I think you described as monosymptomatic fever, and a patient who has fever because you report those two 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 one CRS patients? Thank you.
That's a really good question. Martin? Sorry, sorry. I'll take that. So this is a really good question.
Okay, sorry. Martin?
Because I'm a little bit more familiar on how we actually collect the data. So the way we do it at GemUp is we collect all AEs that are part of the composite endpoint AE of 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 wanted to truly understand in quite detail the safety profile of the drug.
Further
perspective Maybe from you, I if you 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, but you cannot have a CRS that's not fever.
All right. Thanks, Martin. Laura, I hope that is clear. Otherwise, give us a ring. Question please, operator.
We are now taking the question from the line of Greg Suvannavej from Goldman Sachs.
Hey, Craig.
Are you there, Craig?
Thank you very much, Jan. Hey, Jan.
you very much for Welcome. The
had 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, what their current adoption of the product is? And is there any reason one would either not start someone with subcu DARZALEX or transition to subcu DARZALEX? Just trying to
get the
physicians' perspective on their experience with that product. Thank you.
Thanks, Greg. 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 Stathis?
This is Stathis.
Can you hear me? Yes, we can hear you now.
So unless Professor Demopoulos 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 is very convenient for the hospital and the oncology department.
Second, what we have observed and also has been observed is that the subcutaneous for the tumor is associated with significantly lower risk of adverse reactions during the infusion. So the patients tend to have less less less often and less severe infusion related reactions like fever, chills, cough, dyspnea, etcetera, etcetera. So in perspective, I don't think that there is a single reason why one should not use subcutaneous daratumumab instead of IV daratumumab when this becomes available across Europe like 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, And I don't know whether Tan is on the line and unmuted. Otherwise, we'll move on to the next question, maybe the last one. Thanks, Tatis. Maybe, operator, the last question for now.
We are now taking the question from the line of Peter Welford from Jefferies.
Okay. Yes. I wonder if we
could just go back to, sorry, epirizumab again and just talk a little 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 this question 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 four all in all in these sixty eight patients, two of grade one, two of grade three, 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 has goes hand in hand with the less well, not less the 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 and 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. And this concludes our ASH update. Thank you all.