Y-mAbs Therapeutics, Inc. (YMAB) Earnings Call Transcript & Summary

[Audio Gap] strategy of Y-mAbs Therapeutics.

Thank you, Sara. Good morning, and welcome to Y-mAbs R&D Day. Unfortunately, it's virtual today, but we are very happy to have it done today. Let me quickly remind you that the following discussions contain certain forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, and the disclaimer is on the screen right now. I'll give you a second. Okay. So to the big news, the BLA for DANYELZA was approved November 25, and which was a fantastic milestone for Y-mAbs. This -- the first trial was started way back in 2003, so it's a big milestone. And today, we'll learn more about the very encouraging data that -- from the use of DANYELZA in clinic. First, we are pleased to have Dr. Shakeel Modak from the Memorial Sloan Kettering Cancer Center, talk about our HITS protocol, treating high-risk chemo resistant patients using naxitamab in combination with chemotherapy, and we believe showing very encouraging results in a very difficult-to-treat patient population. Thereafter, we are pleased to hear from Dr. Mora on our frontline study treating high-risk neuroblastoma patients with naxitamab and without having patients first go through a bone marrow transplant before getting on antibody, which is also very, very encouraging. Dr. Brian Santich, who joined Y-mAbs December 1, which we are very excited about, will give us a presentation on our newest in-licensed technology platform, namely the self-assembly disassembly radioimmunotherapy antibody platform or better known to everyone as SADA, which we like to refer to as liquid radiation, which potentially can treat tumors without kidney liver or bone marrow toxicities. So Y-mAbs is working hard on getting our first SADA construct into clinic in late 2021. Dr. Claus Moller, our Chief Executive Officer, will give a company update on omburtamab 131. And here, as you know, we are working very hard towards the goal of resubmitting the BLA, and we will get an update on naxitamab use in relapsed osteosarcoma and more. And without further ado, I'm very pleased to hand over the word to Dr. Shakeel Modak. Thank you.

Thank you, Thomas. And I want to congratulate him and Y-mAbs' team for really a fantastic achievement in getting DANYELZA or naxitamab approved by the FDA. So congratulations. I'm going to be talking today about an off-label use of naxitamab in combination with chemotherapy for very high-risk neuroblastoma. And this protocol has been called HITS, which is humanized 3 F8 irinotecan temozolomide and sargramostim or GM-CSF. It's a Phase II trial, which is currently underway. And these results today will be the interim results, which were presented in September or October last year. Since then, we have accrued a lot more patients, but the final analysis should be complete early next year. Next slide, please. These are my disclosures. And so if you can go to the next slide, please. So why do we need chemoimmunotherapy is the first question you've got to ask. We know that antibody therapy with anti-GD2 monoclonal antibodies has improved outcomes in patients with high-risk neuroblastoma. And the approval of dinutuximab was for patients who had completed upfront chemotherapy and transplant and radiation that was for consolidation of remission. So we -- from that experience and from our own experience with murine 3f8 and naxitamab, we know that antibodies combined with cytokines are very effective against osteomedullary disease, that is disease in the bone and bone marrow, but they are relatively ineffective in patients with chemo-resistant soft tissue disease and when the osteomedullary disease burden is high. Our colleagues in Children's Oncology Group initially published data of dinutuximab plus irinotecan, temozolimide in GM-CSF in a randomized Phase II trial, reporting initially about 50% responses in chemoresistant neuroblastoma. Although the update in the Phase II trial is more like 40%, but the ballpark is about 40% to 50% of patients do respond to dinutuximab, irinotecan, temozolimide and GM-CSF. So what is the place or role for naxitamab in this setting? There's a sound rationale for considering naxitamab because anti-GD2 antibodies defer in their in vitro and in vivo properties. So next slide, please. So when we look anti-GD2 antibodies in clinical use, there are essentially 4 antibodies that have been investigated. Mouse 3F8 was our first-generation murine 3F8, which is the precursor of humanized 3F8 or naxitamab. And then dinutuximab is a chimeric antibody. And then there was another humanized antibody initially developed at Saint Jude's, which is not in current clinical use. So if you look at the profile of all these antibodies, you can see that they're not quite the same. For example, humanized mouse antibody is a very strong activator of complement leading to complement-mediated cytotoxicity, whereas dinutuximab does not activate the complement that well. Then if you look at affinity of GD2 to the antibodies, both humanized 3F8 and mouse 3F8 have a very high affinity to GD2. And there -- they have a long half-life in patients, at least naxitamab has a much longer half-life when compared to murine 3F8. So I consider these as essentially different drugs with different kinetics and even different dynamics. Therefore, there is certainly a role for considering both dinutuximab and naxitamab in the therapy of patients with neuroblastoma. So next slide, please. So the chemoimmunotherapy regimen that we devised has certain differences between the currently used combination with dinutuximab. We have always used higher dose of temozolomide. So we use a dose of 150 milligrams per meter square per day rather than 100 milligrams per meter square per day. The dose of antibody which we use is much higher than that of dinutuximab, although these are different drugs, one being chimeric and one humanized. And we give naxitamab or humanized 3F8 even after completing chemotherapy, and we have preliminary data which suggests that there is a rationale for doing this. Humanized 3F8 or naxitamab is infused over 30 to 60 minutes as opposed to 10 to 20 hours, and it's given outpatient rather than inpatient or the ICU. So there are several differences in between these 2 antibodies. Next slide, please. So in the current Phase II study, all patients had to have evaluable disease. And they were classified as either primary refractory, that means patients who have received chemotherapy but had not achieved remission after upfront treatment; or relapsed for progressive disease, that is patients who had responded in issue to chemotherapy but then relapsed. And it's important to make a note of this because the natural history of both of these types of neuroblastoma is different. As opposed to the dinutuximab study, we allowed treatment with antibody and/or irinotecan before being -- before coming on to study. If they had been exposed to previous antibodies, their HAHA, or human antihuman antibody, test had to be negative. And we did enroll many of our patients who are relatively myelosuppressed, the platelet count needed of only 30,000. Next slide, please. Initially, we were -- we looked at it as a pilot study. And then after we saw favorable responses in the first 7 patients, we expanded into a formal Phase II study in which we defined a favorable response rate of 35% after 4 cycles. We measured response by standard INRC criteria. And Dr. Mora in Barcelona at the Hospital of Sant Joan de Deu has enrolled patients in a parallel manner on a compassionate basis study. So this presentation now has 2 groups of patients combined to 1, although I've differentiated them as we go along. And in this report, we are basically looking at response after 2 cycles and after 4 cycles. And as I've mentioned before, our formal Phase II trial is about to complete. We will have accrued about 50 patients, and Dr. Mora has also treated at least as many patients in Barcelona. Next slide, please. So as you all know, DANYELZA or naxitamab was approved in November. And now this allows us to investigate this agent in novel ways in combination with chemotherapy, which we are considering along with Dr. Mora as we go along. So next slide, please. So the mechanism of chemoimmunotherapy at first glance is counterintuitive. So if you give chemotherapy prior to giving patients antibody, one could hypothesize that the chemotherapy was to knock out the effector cells, which are needed to utilize a antibody. However, we do see pretty good responses. And our hypothesis is, and again, there is some very preliminary data suggesting that this is indeed the case. The hypothesis is that chemotherapy leads to an inflammatory state that leads to enhanced effector function rather than inhibitor effector function. And it leads to the release of cytokines, which then recruit NK cells, neutrophils and macrophage and in larger numbers and more effectively. So that's kind of the hypothesis, and we are gathering samples to support or disprove this. Our preliminary data suggests that indeed, chemotherapy does lead to the release of cytokines, although those data are not quite ready yet. Next slide, please. So here is the initial report as of last year. There were 65 patients treated, both at MSK and Barcelona. And 257 total cycles were given. Because most of these patients had refractory or relapsed disease or most of them were -- had [indiscernible] nonamplified disease because the patient with [indiscernible] amplified disease either have a good -- very good response or have a very aggressive progression. But the point I wanted to make here was that patients had pretty -- these were very heavily pretreated patients with a median number of prior relapses of 2, that is patients who had already relapsed 2 times and now are on their third line treatment. And most of these patients were patients who had relapsed, not primary refractory patients. In fact, primary refractory patients respond quite well to antibody or naxitamab plus GM-CSF. And so it's worth pointing out that 88% of these patients were what we would call it as an ultrahigh-risk group, again, as compared to the dinutuximab where these data have not been separated out. And if you -- if a majority of patients who are primarily refractory, then one would have expected better responses. All these patients have metastatic disease. This is a typo here, it should be the other way around that almost all patients have metastatic disease. And a majority of patients had already received irinotecan and temozolomide. And again, a large majority of patients had previously received anti-GD2 antibody. So next slide, please. So in this very ultrahigh-risk group of patients, we were able to administer treatment quite safely. Apart from the myelosuppressive toxicities, there were really no major toxicities seen. And the myelosuppressive toxicities were reversible in all patients. We did see some irinotecan-related diarrhea with some electrolyte imbalance, which is, again, typically seen and quite easily reversible. Again, to point out that all these patients were treated outpatient and no patient needed admission for any reason at all. So next slide, please. So after 2 cycles, if we look at the 56 evaluable patients, the CR plus PR rate was 34%, that is 19 out of 56 patients achieved complete or partial response in a very heavily pretreated group of patients, this is a very encouraging response. Again, comparing to dinutuximab, these patients had 2 or more relapses before coming on to this treatment, up to even 8 prior relapses. We saw responses both in soft issue disease, in bone marrow disease and in bony disease. So osteomedullary disease, which means MIBG positive uptake. In the bones, 43% responses; bone marrow, 70% responses; and soft tissue, 27% responses. So again, quite an encouraging response rate. Next cycle -- next slide. And you can see that these response rates were quite robust, impressive. And you can see the response after 2 cycles of chemoimmunotherapy on the MIBG scan on the left side is a patient who's had bony disease in the spine and various bones of the legs and arms as well as the skull and has had a very robust response, which was then very durable. And responses like these are -- in the era prior to antibody would be unheard of. Next slide, please. Now if you look at the subgroup responses, these responses were seen in all patients, including [indiscernible] amplified disease, those with primary refractory disease, those with relapsed disease, those had have previously received antibody or not and even in those patients who have previously received the same chemotherapy that forms part of this chemoimmunotherapy regimen. So again, responses were seen in all of these subgroups. Next slide, please. And then these responses, as you recall from the previous slide, was -- the response after 2 cycles was 34%. But then further patients had responses after 2 further cycles, leading to a response rate of 40% after -- or 39% after 4 cycles. So these responses generally were durable. And many of these patients, we continued chemoimmunotherapy. Those patients who had complete responses, we were -- the plan was then to switch to antibody alone without continuing with chemotherapy. So next slide, please. So the durability of response is shown here. Those patients who had initial response -- had initial complete response went on to maintain their complete response after 4 cycles. Those patients who had partial response, again, continue to have a response after 4 cycles. And those patients who had incomplete responses, 2 out of 7 -- after 2 cycle and then a further 2 patients had responses after 2 more cycles. So again, suggesting that these responses are quite durable. Next slide, please. So if we look at -- compare this to the initial study, which was a Phase I study, you can see that our patients were a much higher-risk group, 39% of patients had more than one relapse, and 71% of patients had prior irinotecan, temozolomide compared to none of the patients who had more than one relapse or previously had irinotecan and temozolomide. So response rates are kind of similar because the follow-up study of ANBL-1221b suggest that the response rates are more like ours, about 40% in a less highly resistant group of patients. So next slide, please. Again, very preliminary data. If you look at why this is happening, the first time point was cytokines were measured before starting chemotherapy. Second time point is after the first day of chemotherapy, you can see that many cytokine levels are increased, which is probably why you see effector cells, which are directed by antibody, utilizing these cytokines and causing anti-neuroblastoma effect. And then as expected, over time, these cytokines would diminish. So all the action is happening really in the first week or so. Next slide, please. So in summary, chemoimmunotherapy on the HITS protocol is associated with major responses, both in soft tissue and osteomedullary disease. We see responses in patients who are even previously received components of -- each of the components of this regimen. It was tolerated quite well, outpatient. And even in this group of patients who have had multiple chemotherapy regimens in the past, we were able to give this outpatient and with a relatively low incidence of fever and neutropenia, and these responses were quite durable. The immediate plans are to complete the Phase II. We are looking at combining with other chemotherapy regimens. And both us and other investigators are thinking of using this chemoimmunotherapy cassette upfront in patients. Next slide, please. So I think that's all I had to say, and I'm open to questions, if any. Thank you.

Yes. Thank you very much, Dr. Modak. I think, Sarah, you will now run the Q&A -- short Q&A session. We'll limit it to 5 minutes for Dr. Modak, if anyone has any questions. Thank you.

Yes. Thank you, Thomas. So at this time, we are going to open it up for the first Q&A session. [Operator Instructions] The first question comes from Boris Peaker at Cowen.

Can you hear me?

Yes.

Fantastic. I guess, 2 questions on my end. One is on dinutuxim. I mean, obviously, the drug has been for a while now. With naxitamab now finally approved, how do you dinutuxim being potentially displaced by naxitamab? And second, you mentioned a frontline study ongoing. Can you comment on the time line and what we should anticipate from that frontline study?

No. We don't -- so Dr. Mora is going to talk about the front line study. We have not introduced immunotherapy into our frontline chemotherapy. So Children's Oncology Group is doing a study where they are adding dinutuximab after the second cycle of chemotherapy as a pilot study. We are somewhat reluctant to do that because we feel that this approach would be better when the disease burden has been reduced with chemotherapy and surgery. In the short term, we are not planning to do -- come -- adding antibody with induction chemotherapy. But what Dr. Mora will talk about is after patients have completed induction upfront in frontline patients, the use of naxitamab. And we ourselves have treated, I would say, more than 100 patients with this approach, but that study hasn't been completed or hasn't been published yet. The other question was, how do I see it replacing dinutuximab? I think that is a market question about how these 2 antibodies will compete or coexist. One advantage of the naxitamab is that it's given outpatient over a short period of time. It will probably lead to cost benefits for hospitals and less pressure on beds. And I would say that many families or most families would prefer to have treatment outpatient rather than inpatient. Staying inpatient for 5 days versus coming to clinic 3 days a week because naxitamab is given typically on Monday, Wednesday and Friday in the clinic, I would say that most patients would prefer to to come to clinic. Now the label, of course, is -- for naxitamab is for relapsed/refractory disease. The label for dinutuximab is for post-transplant in upfront. So I think there will need to be some education and culture change before these antibodies are -- respectively enter the entire neuroblastoma therapeutic journey.

Just holding to see if we have any more questions. If not, I'll turn it back to Thomas for the rest of the presentations.

Okay. Thank you, Sarah.

There is a question about whether Dr. Moda could comment on the complement-mediated neuropathic pain.

Yes. So after all these years, I don't -- we don't subscribe to this pain being complement mediated. Because if you look at the St. Jude's antibody, where the complement activation was completely abrogated, the grade 2 pain was seen in all their patients. So I don't think this is complement mediated. So St. Jude's antibody, murine 3F8 and naxitamab and dinutuximab, all with varying complement activations continue to cause pain. I don't think there is a way out of pain yet, and that is certainly distressing to see. But dinutuximab is associated with pain that might sometimes be prolonged because of the prolonged infusion, but naxitamab is also associated with severe pain. And we have to manage the pain, and we have well-established programs in place whereby we can manage pain outpatient and then discharge the patient home after 2 to 3 hours in clinic.

And one last question from Walid Abdul Nabi from Barclays.

This is Peter Lawson from Barclays. I guess the question I have just for Dr. Modak is just how many of these patients would you want to switch over to naxitamab based upon the...

I mean that I don't -- that question is kind of irrelevant to me because I've been using naxitamab for 20 years, more than that. We never used dinutuximab because we developed naxitamab here and we -- and previous to that, there was the mouse 3F8, murine 3F8. So again, that question remains to be answered. Now my own personal experience is that patients who don't respond to dinutuximab might respond to naxitamab and even vice versa. So I think there is a role to play. And in fact, we get many patients now and before who had not responded to dinutuximab and then we treated them with naxitamab. And again, certainly patients who don't respond to naxitamab, you could -- physicians could try dinutuximab. And I don't think these are identical antibodies. They are very different in terms of their pharmacokinetics, pharmacodynamics and toxicity profile. So as people are more educated about using naxitamab, I think there will be more people looking at how to use both of these antibodies in patients because even in the best of settings, cure rates for neuroblastoma in the modern era are still below 50% if you start the clock on day 1. So I think since this is now FDA approved, it will give people the opportunity to work with these for their individual patients and see what sort of responses they get.

Thank you, Dr. Modak. And we'll have time for one quick question from Alec Stranahan at Bank of America.

Dr. Modak, can you hear me okay?

Yes.

Perfect. I have one quick question actually on the pain with DANYELZA. How quickly do patients in your care sort of recover from the grade 3 or 4 pain? Are they back on their feet pretty much right after the infusion or does it take a little while? Particularly since we saw on the label that the incidence of grade 3, 4 pain is maybe slightly higher than dinutuximab.

Pain is very subjective and grade 3 and grade 3 is hard to define. The pain score -- the CTC version of the pain scoring is far from optimal. But what happens in the real life is we can treat as many as 10 patients a day, outpatient. In fact, we routinely used to, in the pre-COVID times, treat 10 patients per day in the clinic, every day. So patients come in, they get pre-meded, they get the naxitamab. And typically, over the second half of that infusion is when the pain kicks in, then we give them pain medicines and -- narcotic pain medicines, which cause them to sleep mostly. And then once their vitals have stabilized, they are sent home. That period of time is between 2 to 3 hours. Very rarely or almost never do I have a patient come in at night with excruciating pain that requires IV pain medicine. Usually, if they do have pain at night, it's taken care of with oral pain medicines. Now the next day, it's still -- some -- many patients will have achyness, but again, not needing IV pain meds. And then when I see patients on the next antibody day, if -- most of them would have recovered to -- a large majority, 90% of them, would have recovered to baseline. So we have kind of mastered this art of giving it in the clinic. And so I would say what I described is kind of what families experience. And over the weekend after the antibody, the naxitamab is done, I would say, what you call baseline would be another -- by Monday or so most patients are at baseline. So both Dr. Mora and I have treated thousands of patients either with naxitamab or its precursor. And the incidence of admission to hospital, I would take a guess, would be less than 1% to 2%. Yes, does that answer your question? Hopefully.

So I think we'll turn it back to Thomas now to introduce Dr. Mora.

Yes. Thank you so much, Dr. Modak, and we'll now turn it over to Dr. Mora, who is speaking to us from Barcelona, Spain, where it's about to be lunchtime. So pleased to introduce you, Dr. Mora. Thank you for being here today.

Well, thanks, Thomas. It's about dinner time here actually. Anyhow, it is a great pleasure for me to once again participate in this meeting. And also, I need to thank Y-mAbs for the opportunity that has given to our group to be part of this revolution in the management of high-risk neuroblastoma. This is an ongoing historical revolution that I'm so proud to be part of it, and this is mainly through the contributions of Dr. Cheung's lab and Memorial Group team and then through Y-mAbs company. So today, I'd like to share with you our experience stemming from the various first infusion of naxitamab in the world, now DANYELZA, which happens to be -- happened to be in our center in June 12, 2017. We were honored to be the very first group to infuse naxitamab, now DANYELZA, from Y-mAbs. And through Y-mAbs as well, we were offered the opportunity to treat patients under a compassionate use format, monitored and sponsored by Y-mAbs for patients who were in complete remission. And that is because at that time and even now today, majority of children with high-risk neuroblastoma in the world have no access to dinutuximab family of antibodies, which are approved both in the U.S. and Western Europe. But majority of children with neuroblastoma in the world live outside of these 2 isolated islands. So the need for treatment, it is huge. And hundreds of families have flown from everywhere in the world to access these novel opportunity, novel treatment. So this is the summary now of this experience. Next slide, please. So stepping back and for the general audience here today, I want to emphasize high-risk -- what is high-risk neuroblastoma. We're talking about usually child in between 18 months of age and around 5 to 6 years of age. That's the majority of what we understand as high-risk neuroblastoma, usually presenting -- majority of them presenting with disseminated disease, like you can see here in this MIBG scan, showing the bone desalinated disease as well the bone marrow as shown here with this raccoon type of eyes presenting because of the invasion of the school basis, bone marrow and the children, which is the bone marrow is fully replacing the whole bone marrow on all the skeleton of children as compared to adults. Or subtle presentations like these, proptosis, their eye bulging from from the eye socket outside. So these -- there's very -- a huge variety of presentations for high-risk neuroblastoma, but certainly, very sick kids when they show up in the clinic. Next. So what -- how can we manage these patients and the whole -- the community has already come up with a consensus on multi-modality management for these patients. Basically, this is -- in the beginning, we started off with chemotherapy and surgery, which is called the induction phase with the goal of eradicate the -- all the detectable disease, meaning that after chemotherapy and surgery, we perform an evaluation. And ideally, patients should get into complete remission, meaning all the MIBG test, bone marrow test, MRI test, everything that was positive in the beginning should become negative. That's the ideal world after induction. And then it comes the consolidation phase, where the goal is to eradicate what we call the minimal residual disease, and I'm going to talk about this in a moment, this concept. And this is basically radiation therapy and anti-GD2 immunotherapy that is what everybody agrees upon. Next. So the concept of minimal residual disease is a general concept in oncology, and we need to make this very thing -- this concept clear to everybody. So once the patient presents in the clinic with any tumor and have a clinically detectable disease, if you sum up all the masses in the bodies, you can count at least of 10 centimeter mass and above. And that turns out to be 10 to the 12th billions of cells -- 1 billion of cells in their body, at least, to be clinically detectable. So the patient undergoes induction treatment, all your chemotherapy and surgery, all the management that you can imagine to eradicate this detectable disease. And then you use all your tests, even your imaging the best imaging test like MRI, CTs, whatever you have, and you come up with these very tiny minute nodules of 0.5 centimeters nodule. So that nodule, it is estimated to still remain 10 to the 7th, 10 to the 8th. So close to 100 million of cells in that tiny nodule that is hardly detectable even with the best imaging technology. But in some compartments, you can even use the bone marrow, for instance, you can use your [indiscernible], you look at the -- under the microscope. And you can even check whether you detect any detectable disease, neuroblastoma cells, for instance, among all these normal bone marrow cells. And you can go all the way down to 10 to the 5th one tumor cell out to the 10 to the 5 or 10 to the 6th at maximum. But even in this compartment, you can use molecular testing that has been well-developed by different groups. You can use micro testing and you can actually go further down to your detectable level, down to 10 to the to the 3rd. But still, you will never ever get a test whereby you can assure that there is no detectable disease at all. So the 0 level, it's impossible. There is always a threshold but below which, you are not sure whether there is any residual disease. And this is what we call actually minimum residual disease, and that applies to every single oncological entity. Next. So in the past, high-risk neuroblastoma has been managed by the competitive groups, both in the U.S. and in Europe, Japan and Germany and other corporate groups, like, for instance, this is the regimen used by the CIO group in Europe. Here, you can delineated all the comobility regimens for the induction for treatment of high-risk neuroblastoma. Next. That's the schema that you would use if you were in Germany by the German oncology group, different chemotherapy cycles and then randomization to high-dose chemotherapy versus maintenance chemotherapy and then you would go on to immunotherapy. That's another schema. Next. Old pioneering group by MSK. That's their schema on 5 cycles of chemotherapy, well established with early surgery after 3 cycles and then move on to radiation and further down with antibody. Next. Those are standard combinations. But here, you see, for instance, the recent results reported by the U.K. group, highlighting the results and the long-term results and outcome for patients in neuroblastoma treated in the 1990s with this regimen, well described. And as you can see, the overall survival, it's about 30% to 40% at best at 5 to 10 years. So still very difficult to cure high-risk neuroblastoma patients with old pre-immunotherapy standards. Next. Similarly, for the German group experiences in the 1990s, early 2000s with the overall outcome not much higher than 40% even in the best group of high-risk neuroblastoma stage 4. Next. And even more recently, the GPOH Group, the German group, has published their most recent trial from 2004 all the way to 2016 with experimental and standard chemotherapy with no use of antibodies. And as you can see, long-term survival at 10 years less than 50%. So this is the standard and well-established outcomes for patients with high-risk neuroblastoma in the era before immunotherapy has been established. Next. So the question is why we fail to cure more patients? Well, certainly, when we use induction chemotherapy, surgery and radiation, with the goal of getting patients into the complete remission state, we are certainly mostly successful nowadays with the majority of regimens, majority of patients getting into complete remission, at least in a very good partial response. So the gross disease, we are taking good care of it. The problem is that we don't take good care of this minimal residual disease because later on, further down the line, patients would eventually relapse. And once these patients relapse, in the past, it was almost incurable. Next. So that was the experience reported by the MSK group, always the pioneers in this field. They were reporting subsequently studies showing that the addition of murine 3F8, the precursor murine antibody, the precursor of naxitamab, when they added to the standard chemo surgery radiation therapies schema, they reported -- their initial studies from the 1990s with a 10-year cure rate, long-term cure rates of 40%. Then when they moved -- they added the GM-CSF to -- with the antibody, along with the same schema, the backbone schema of standard treatment, they increased cure rates 10 years out of treatment of 60%. That was never heard of before. And even more so when they only switch from IV to subcu GM-CSF with the same backbone of treatment, they reach 80% 5-year overall survival rate, which that had never been heard of in the literature before. Next. So then a landmark study by the COG, which was -- is well-known today. The study that prompted the approval by FDA and then EMA of dinutuximab. Patients at complete remission -- remember patients at complete remission that achieve complete remission, not all the patients, but only those patients who achieve complete remission after induction management and bone marrow transplant. We will get into this point later in my talk. Then those patients will be randomized to receive the triple immunotherapy, meaning anti-GD2 antibody; dinutuximab, now called dinutuxin; GM-CSF and interleukin-2. And those patients in the randomized study showed a 2-year overall survival of 84% and event-free survival of 63%, clearly statistically significant compared to those patients randomized not to receive immunotherapy. That was a landmark study, certainly 10 years of a randomized study, well performed by the COG that started off the anti-GD2 antibody to become the standard of therapy for these patients. Next. So what can we do? What have we done in Barcelona. Thanks to Y-mAbs for these patients that had achieved complete remission in their local institutions, and they would come to our place and then we would screen them for whether there is any residual disease of bone marrow refractory disease, screen for the 201 trial. And then it just happened to be in complete remission. Those patients would be treated through the compassionate use, and this is what I'm going to report today, the first time ever to be reported. Next. So again, patients would have received induction treatment at their local institutions. As far from China all the way to Russia and New Zealand, anywhere, they would come to our institution, they would be evaluated, thoroughly evaluated. And then if they were in complete remission, no evidence of disease, minimal residual disease status, then they would go on to compassionate use. If they had a partial response, but there were any refractory disease in bone marrow compartment, then they would be treated on the 201 trial, and those patients would have been included in the trial that prompted the recent approval by the FDA of naxitamab. Next. So the eligibility criteria from the study that I'm presenting you today was, as I mentioned, no evidence of disease by a thorough study, including bone marrow studies for [indiscernible] and 2 biopsies, meaning even molecular testing. Everything had to be clear, at least under the microscope, which is the standard MIBG scan and/or FDG PET scan and a whole body MRI. So no evidences of soft tissue, brain disease or bone -- and bone marrow studies. Since very first -- June 12, 2017, the very first patient, now cured, who was -- and actually -- and a patient on complete remission after induction and [indiscernible] amplified, now completely cured. Since that very first infusion up to December this year, 73 patients have been treated in complete remission, including 55 in first complete remission, 18 in second complete remission, meaning patients had a history of prior relapse and would have achieved a second CR and then they would go on to receive naxitamab in this same program. This distinction is very important as you will see. Next. As mentioned by Dr. Modak, prior -- the treatment is outpatient. The schema is well-known today since the approval by the FDA. That means it's a backbone of 10 days of subcutaneous GM-CSF, given by the family, subcutaneous injection. And then 3 doses of naxitamab, they are usually Monday, Wednesday and Fridays within the same week. And that's 10 days cycle. And those cycles will be repeated every 21 days, approximately 1 every month. And for a total of 5 cycles, if the patient remains -- remained in complete remission. So now I'm going to show you the outcome of these patients. Next. So out of these 73 patients, 7 patients, as I said, had prior relapse isolated in the CNS, 1 had CNS and systemic relapse and 11 had exclusive systemic relapses. So those are the 18 patients that had a prior history of relapse before getting into a second CR. 10 out of the 55 patients in first CR and 12 of the 18 in second CR had received prior autologous stem cell transplant in their local institutions. We don't perform transplants in our institution. So this is a subgroup of cases that had either received transplant or not received transplant that we will be able to compare their outcomes, and I'm going to show you also the results. Since June 12, 2017, our landmark historical day, a total of 365 naxitamab cycles have been administered in SIA patients in our institution. Next. 22% of the patients have not completed the 5 plan cycle, 16 out of the 73. Why? Well, 5 because of grade for toxicity, and I'm showing you the relevant grade 4s. 2 because of apnea-related infusions. Patients would not tolerate, and they would stop briefing immediately after very a few drops of naxitamab. 1 patient because on our opioid-related test [indiscernible] syndrome, which was not able to be rescued at that time. And one patient who developed a stroke that we don't think it was related to the naxitamab, but because of the importance -- medical importance -- relevance of the side effect, it was taken off study. 1 patient could not complete the cycle because of the HAHAs development blocking antibodies. And 10 patients, a total of 13, because they had relapsed during -- before completing treatment. 6 out of 55 in first complete remission and 4 out of the 18 in second complete remission. Next. So this is the survival outcome, the couple of [indiscernible] curves. On the right side, overall survival; and left side, event-free survival for the whole group, the 73 patients total. So it's a 2-year overall survival of 90% and a 3-year overall survival of 82%. And I'm pointing out here the 2-year and the 3-year because we're going to be comparing this 2-year survival outcome with what was reported at the COG study. Next. So when we did the multivariate analysis for all the variables that had been reported in the past to be relevant for the outcome of patients treated with anti-GD2 antibodies, the only -- so -- and [indiscernible] number of chemotherapy cycles, whether they had received bone marrow transplant or not, whether they had received radiation prior to the antibody or not, whether they had minimal residual disease detectable by molecular techniques or not, the age of diagnosis, the age of treatment initiation, all these variables were not significant either for event-free survival or overall survival, except for whether in the event-free survival outcome, only the history of prior relapse was clearly significant regarding event-free survival, meaning that patients who had a prior history of relapse had a much, much higher probability to relapse again as compared to patients with -- on first CR. Next. So here is what I'm showing, the 2-year event-free survival for patients in first CR, it's 74% as compared to 2-year event-free survival for patients in second or more CR, it's 38%, and that's significant -- statistically significant. Not for overall survival, however, which is a good -- it's also a very important point. But the prior history of relapse makes this patient in a very high likelihood of relapsing again. Next. So this is the overall survival, 3 years for first complete remission. As I said, 91% at 3 years for patients in first CR, they are alive after 3 years of treatment. And 3 years of 66% for patients in previous -- with the history of previous relapse. Next. And then if we look at the historical comparison with the landmark study by COG, as I told you, remember, that was patients after transplant and complete remission. They showed a 2-year 84% overall survival and 63% of event-free survival for only first CR patients. So if we compare naxitamab patients treated in our institution without bone marrow transplant prior, then you can see 2-year overall survival of 90%, which is comparable. Of course, we're talking here about 55 patients compared to 200 plus. So that is something to be taken into account. But the numbers are holding up year-by-year even when we're increasing the numbers in our institution. And a 2-year event-free survival of 74% also very comparable. So basically, here, we're showing that patients in first complete remission without the need of previous transplant, we can offer very similar survival outcomes as previously reported with dinutuximab by COG. Next. So again, when we did the multivariate analysis, once again, only the prior history of relapse prior would come up with significance for event-free survival, not for overall survival, meaning, those patients can relapse again and again, but they would not die. So our overall survival would be very similar. Next. So in conclusion, for first CR patients and if we compare naxitamab experience in our institution in first patients compared to the dinutuximab reported by COG, we certainly can say there's no need for bone marrow transplant to achieve similar outcomes. Patients are treated, as I said, very shortly as in outpatient setting with very significant improvement in the quality of life. Patients that we had treated prior with dinutuximab, unituxin in our institution prior, the same patient relapsing later. When we compared and we asked the families and the patient whether they would prefer the inpatient setting or the outpatient setting, absolutely everybody would prefer to the naxitamab regimen because of the quality of life required. And also, when we compared the same patient treated prior with dinutuximab and the same patient treated with naxitamab later on, the amount of opioids required for pain management management is 7x less for each patient on the naxitamab regimen. Different profiles of toxicity, significant toxicity. We reported transverse myelitis for dinutuximab and compared to never seen naxitamab such toxicity. But also more common hypertension empress for naxitamab as compared dinutuximab. The price and availability is still pending in the worldwide by naxitamab, where we know now the price is certainly unaffordable for more children in the world for dinutuximab. And certainly, availability is a big, major issue for majority of children worldwide for dinutuximab. Next. So finally, just to mention the issue of bone marrow transplant. Well, as you know, most competitive groups would use autologous bone marrow transfer or stem cell rescue after induction treatment for patients with or without residual disease. So the Memorial group had already questioned the need of this very toxic regimen, very costly regimen in patients treated and managed in an era of anti-GD2 immunotherapy. Next. So we were able -- we just published our own experience using either dinutuximab or naxitamab most recently in 2 consecutive studies, and we just published our results in our institution for patients with or without having received prior stem cell transplant. Next. And the results reproduced exactly what the Memorial group had said several years ago that overall survival and event-free survival is exactly the same for patients having received or not autologous stem cell transplant. Next. And this is the results from today's study. Only patients on naxitamab study, as I showed you, they show exactly the same outcome, overall survival and event-free survival, having received or not stem cell transplant. Therefore, in our experience and that of the Memorial group, stem cell transplant is certainly not needed if patients can access to effective anti-GD2 immunotherapy in the current era. So that is a major impact in the cost of management of these patients and also in the long-term toxicity in the short and long-term toxicity for these patients. So this is a major change, in my opinion, in the management -- in the overall management of these patients. Next. So in my final slide, just to highlight how naxitamab and GM-CSF represents a very potent combination that can be administered outpatient with a clear quality of life improvement for patients and families. This is important to strength for everybody involved in these developments. Naxitamab and GM-CSF provides high chances of long-term survival for first CR patients without bone marrow transplant consolidation, and that is another major impact in our results, reproducing exactly what the Memorial group had said many years ago already. And further enhancing the immunotherapeutic response after antibody with vaccine type of strategies, which we haven't talked today yet, should be explored certainly to improve the cure rates of patients with a history of prior relapse because certainly, patients that had already relapsed have a much, much higher chances of relapsing again, which doesn't mean that they should die, but certainly need a much further improvement in what we can offer today. Next. Thanks for your attention, and happy to answer any questions, if any.

Thank you very much, Dr. Mora. It's a fantastic presentation. So I'll let Sara go ahead with Q&A.

Thank you, Thomas. So we're -- now we're at our second Q&A session. [Operator Instructions] It looks like there's no questions in the queue right now, Thomas. So I'll turn it back to you, and we'll open it up for questions again at the very end.

All right. Thank you. Again, thank you, Dr. Mora. And now, yes, I'm pleased to introduce Dr. Santich, who worked with Dr. Cheung since 2013 and actually was the inventor on the SADA platform. So we look forward to hearing from you. Thank you very much, Brian.

Thank you, Thomas. I am Brian. And as mentioned, I recently joined Y-mAbs, but previously worked in the Chung lab and Memorial Sloan Kettering, where I helped develop the SADA technology platform. And today, I'll be presenting to you an overview of the development of SADA drug delivery platform that I believe strongly changed the way that physicians can use radiation to treat cancer. Next slide. In much of medicine, physicians need to administer treatments while trying to maximize the effectiveness -- the therapeutic effectiveness, minimize any and all side effects that they may cause. In oncology, however, doctors frequently need to use highly toxic drugs and some of them even mentioned today, things like chemotherapy or radiation. Next slide. In an ideal world, all types of drugs could be used effectively with minimal side effects or toxicities to the patient. All the toxic effects of the drug would be restricted to the cancer cells and none of it would impact any healthy cells around it. Next slide. However, instead, often, the opposite can be true. Many cancer therapeutics can cause side effects that are so severe, they will require limiting the dose administered to the patient, which we call dose-limiting toxicities. And in many cases, lowering the administered dose to subtherapeutic quantities makes the treatment less effective and can lead to relapses or sub-optimal responses. Next slide. Part of this problem comes down to the specificity of cancer drugs. Conventional monoclonal antibodies, like the one shown on your left, are considered to be one of the most specific therapeutics possible, even once considered to be a silver bullet for oncology because of their intrinsic ability to hone straight to their target. All you needed was a good cancer target and the thought was an antibody could deliver a drug straight to it to destroy it. However, even with their incredible position, selectivity can be suboptimal and toxicities for many antibodies are unavoidable. Next slide. And the problem here is due to another important property of antibodies, their persistence in the bloodstream. When an antibody is injected into a patient, it begins to circulate through the blood, as represented here in red. Next slide. But over time, it will also accumulate in the tumor, as shown in blue, and where it exerts its anti-tumor effect. However, because of this persistence in the blood, antibodies can also cost a significant and unwanted drug exposure in toxicity throughout the body. Next slide. Now if we measure the relative drug exposure between the tumor and the blood or another tissue, we can determine a ratio called therapeutic index, which represents the relative selectivity of a given drug. Next slide. If this ratio is higher, we can achieve effective tumor responses with minimal toxicity. Next slide. But if this value is too low, the side effects become more serious and then dose-limiting toxicities will lead to suboptimal treatment outcomes. Next slide. Now one of the most powerful anti-cancer drugs that we can attach to the antibody is radiation. And when we couple radioisotopes to an antibody to deliver radiation to tumors, we call it radioimmunotherapy, and it can be an effective way to treat metastatic or micrometastatic disease in ways that cannot be done surgically, just as Dr. Mora was mentioning with MRD. However, radiation is also very potent and the side effects can be quite serious. Next slide. For most drugs, the most problematic toxicities of those that affect the liver and the kidneys that filter and break down many drugs or the bone marrow that maintains the blood integrity as well as the immune system. And in the case of radiation, bone marrow is almost always considered the dose-limiting organ, and therefore, it's the one we must try to minimize exposure to. Next slide. So just how much selectivity do we need to best utilize radioimmunotherapy? To treat some of the most aggressive solid tumors, you're going to need to deliver as much as 100 grays of radiation to a tumor, which is approximately the equivalent of about 10,000 chest X-rays. Yet the bone marrow can only tolerate a very small fraction of that of, 1 to 2 grays, which means in order to treat these cancers, you're going to need to achieve therapeutic index at least -- of at least 50. Otherwise, dose-limiting toxicities are going to prevent you from providing enough radiation to the tumor. Next slide. Unfortunately, conventional radioimmunotherapy may only be able to achieve a therapeutic index of 5, meaning that even with the best tumor markers, you might only be able to treat a tumor with up to 10% of the dose needed to treat to completely ablate it before you hit a dose-limiting toxicity. Next slide. Now part of this problem can be solved by uncoupling the antibody and the radioisotope and delivering them separately, which is a concept called pretargeted radioimmunotherapy or PRET. And basically, you are delivering a cold nonradioactive antibody first or pretargeting it to the tumor, as shown in the gray. And then after a certain amount of time, you're going to -- after the antibody level in the blood has dropped, you're going to administer the radioactive component, usually in the form of a small, rapidly clearing radio metal or radioisotopic like lutetium that's been caged in a small molecule like DOTA. And importantly, these small radioisotopes either bind to an antibody through some form of engineering or chemical modification or quickly remove from the blood due to their small size. Next slide. But since these 2 drugs are delivered separately, it does improve the therapeutic index but perhaps not enough. Even if we wait several days, we can get an improvement in therapeutic index, but there's still going to be substantial amounts of antibody in the blood when you administer the radioisotope. and this will inevitably lead to unwanted bone marrow exposure and eventually bone marrow damage. So how can we bring therapeutic index above 50? Next slide. We reengineer antibodies so that they can clear themselves in circulation within a short period of time. And that way, we can safely and consistently deliver high doses of radioisotope without fear damage to the bone marrow or other organs. Next slide. And in this way, we're going to be able to basically achieve high therapeutic effectiveness with minimal side effects. Next slide. And this need is what led to the creation of SADA technology. We began with a basic design, basically 2 antibody fragments linked together to form a bispecific antibody molecule with one end, represented here in blue, targeting the tumor; and another end, represented here in orange, targeting radioisotopes, in our case, lutetium and DOTA and -- which is the same isotope used in the recently approved LUTATHERA. And instead of a conventional Fc, as you would see in an antibody, we design, what is represented here by the small purple section, which is the SADA domain. And the SADA domain allowed these individual bispecific antibody molecules to self-assemble or disassemble, hence SADA, depending on their concentration. If we manufacture -- when we manufacture the SADA adding bodies, the concentration is high and the SADA domains self-assemble each of these bispecific molecules into complexes of 4 or tetramers. And as tetramers, they had enhanced binding the tumors and they had slower elimination from the blood. Next slide. However, when the concentration of SADA antibodies drops below certain thresholds, such as in the blood after extended circulation, the same SADA domains disassemble and the tetramers go back into the individual antibody molecules, which are called monomers. And unlike the original 4-armed tetramers, each of these monomers was 3x smaller than a normal antibody, and therefore, small enough to be rapidly filtered out of the blood through kidneys and into the urine, a process that only takes several hours. Next slide. And because of this low therapeutic -- because of this low blood concentration and high tumor uptake, we should be able to achieve a very favorable therapeutic index. Next slide. So what is the actual SADA blood clearance look like? So for reference, here in purple, I represented a conventional antibody with slow clearance in the blood of a mouse over a 2- day period. And as you can see, over 48 hours, only a small fraction of the antibodies are moved out of the blood. Next slide. When we measured the clearance of the GD-2 of GD-2 targeting SADA antibody using the same -- which is the same target as DANYELZA that's been discussed today, we see a very different blood clearance profile. Some persistence in the early hours allowing for tumor uptake, but then dropping to essentially nothing over the 48-hour period, which limits the unwanted circulation and an eventual radiation exposure. Next slide. And importantly, this closely matched the idealized example we had -- I had presented before. Based on our estimates, we figured a 48-hour window between the first step, the administration of SADA; and the second step, the administration of our radioisotope with TCM DOTA would be optimal to maximize tumor uptake and minimize background exposure. Next slide. Now one of the more unexpected consequences of the unique clearance profile of SADA technology, however, came in a follow-up study using an animal experiment that measured drug immunogenicity, which represents the tendency of a drug to develop an immune response against itself, similar to how a vaccine works. However, unlike a vaccine where we would like to have these immune response to protect us from infection, antidrug immune responses can substantially reduce drug effectiveness and complicate clinical translation. And although there are many ways around it, immunogenicity can be a problem, as discussed by Dr. Mora, with patients that are disqualified from trials because of HAHA, another measurement of drug immunogenicity. And it is particularly problematic for drugs that require multiple doses, which is common in oncology. Using this model, we measure the drug immunogenicity of our lead GD2 SADA antibody, as shown in red, and compared it to a conventional antibody, which is represented in blue. And as you can see, the SADA antibody surprisingly showed almost no antidrug immunity in these treated mice, which contrasted the higher response we saw in the -- with the mice treated with conventional antibodies. And while we don't fully understand this phenomenon, it is likely related to the unique clearance profile of SADA and suggests that patients treated with SADA may be less likely to develop these unwanted drug immune responses. Next slide. Now graphs and figures, they're great for research, but what really demonstrates the potential for SADA technology are images. So for reference here are the 2 representations I've shown before. On the left is the preconventional pretargeted radio immunotherapies and a conventional antibody in the first step and then a radioisotope in the second step. And on the right, we have a representation of the SADA pretargeted red immunotherapy, which a SADA antibodies administered first; and a second one, a radioisotope is administered second. Next slide. And this first image represents a mouse treated with the conventional antibody and a radioisotope used for imaging or PET and administered with the general pretargeting approach. And what you can immediately see is the impact of low therapeutic index. Lots of radioisotope, all throughout the body of the mouse, the liver, the blood. And by contrast, not very clear uptake in the tumor. And if this were a therapeutic isotope, this mouse would have been quite sick. Next slide. In contrast, on the right, is a mouse bearing the same exact type of tumor dose, the same amount of SADA antibody and the same amount of isotopes was administered on the mouse in the left. What you can see, obviously, is just how much more precision you achieve when you use a drug that has very high therapeutic index. You have substantial uptake of the tumor, which is noted by the orange arrow; and you have almost little to no signal in the blood or the body throughout the rest of the mouse. An image like this is exactly what you would want from a drug. Next slide. However, imaging is only part -- is only the beginning for SADA. SADA -- we were able to measure through dosimetry studies that we could achieve a therapeutic index when looking at the bone marrow of 150, meaning that we could deliver 150 grays to a tumor before we would reach the 1 gray limit to the bone marrow, which surpassed our threshold of 100 grays that I had mentioned before. And meant that we could treat most tumors without fear of dose-limiting toxicities to the marrow, at least. Next slide. And this is a nice image of one of the first therapy studies that we performed at MSK. The first image on the left is a mouse shown with a large tumor on its right side, a neuroblastoma tumor. That was just prior to treatment with the GD2 SADA and lutetium data that I've been describing before. And on the right side, the second image, shows the same mouse 9 days after treatment, where the tumor has been nearly eliminated, highlighted by that red box. And this shows that SADA technology could not only target tumors with precision, but also could actually deliver substantial doses of therapeutic levels of radiation to completely ablate blade an established tumor, and it shows you how powerful radiation can be when used appropriately. Next slide. But of course, treating a single mouse is not enough. And here, we have a mouse model of neuroblastoma, where mice bearing palpable solid tumors were treated with G2 SADA and lutetium DOTA. In this model, we decided on a 3-cycle treatment regimen, where each cycle consisted of a single dose of G2 SADA and a single dose of lutetium DOTA separated by 2 days, our 48-hour window that we looked at before. And each cycle was given once per week for 3 weeks. And as you can see, we went beyond just shrinking tumors. We actually cured some of them. And cure is a word that shouldn't be taken lightly even in animal experiments. These mice were followed up to as long as 200 days after treatment and only 3 of them ended up developing relapses. Next slide. But even more importantly, when these mice were analyzed by veterinary pathologists, they reported no toxicity to the liver, none to the kidneys, none to the blood and none to the bone marrow, meaning that not only can we treat these cancers, we could also cure some of them, and we could do it while avoiding some of the most problematic toxicities typically faced in the clinic, confirming the estimates of our therapeutic index of being high enough to deliver curative doses of radiation without damaging to bone marrow. Next slide. However, tumors grown up from cell lines, like the ones I just showed before, may not always be representative of the complexity of tumors in actual patients. And so to address this, we performed an additional study using patient-derived neuroblastoma tumors, which are literal pieces of tumors taken from patients treated at MSK. In short, these tumor fragments can be grown up in mice, and then allows us to treat them just as if they were cell line tumors like the ones before. And in this case, using exactly the same 3-cycle regimen described in the previous slides, we could show that GD2 SADA could not only shrink these tumors but also provide long-term responses without relapse. Next slide. And just like before, we can achieve this without any kidney, liver or bore marrow toxicity of any kind as confirmed by veterinary pathologists. SADA technology was able to deliver curative doses of radiation to establish patient-derived neuroblastoma tumors and shrink them durably without dose-limiting toxicities. Next slide. And lastly, we moved beyond pediatric tumors into a highly aggressive adult tumor model, small cell lung cancer. Another GD2 expressing tumor, but one with a very, very poor outcome. Small cell lung cancer is one of the lease survival of cancer diagnosis with over 90% of patients succumbing to the disease within 5 years. And in collaboration with Dr. Ruden at MSK, we treated a number of mice bearing patient-derived lung cancer tumors obtained from actual lung cancer patients. And just as before, we could demonstrate that GD2 SADA in a 3-cycle regimen with lutetium DOTA was able to shrink these tumors and provide very long-term durable responses. Next slide. And of course, GD2 is really just the beginning for SADA technology. An important thing to highlight is that the way the SADA technology was designed, it was made to be purposely flexible. It was -- allows -- it only needs a few key parts found in almost every antibody available. And consequently, SADA can easily be adapted to go after practically any type of cancer where antibody therapy has a relevant target. And here at Y-mAbs, we are already exploring many new targets in both solid tumors and hematological malignancies. Next slide. Furthermore, SADA technology is more than just a therapeutic. It can also be used as a diagnostic, a combination usually referred to as theranostics. And this means in addition to treating tumors, it can be used to image tumors using technology like PET or spect that are already established in many health care centers and allows us to see how a patient is responding to a treatment. Next slide. So in conclusion, SADA technology represents an important step forward in the treatment of cancer. It has a high therapeutic index, allowing for physicians to finally harness the full potential of radiation to treat patients with widespread metastatic disease in a way that's not only effective but safe. With GD2 SADA, we demonstrated effectiveness against 2 aggressive solid tumors, pediatric neuroblastoma and small cell lung cancer, and cured many of these mice without any clinical or histological signs of liver, kidney or bone marrow toxicity. In addition, SADA proved to be less immunogenic or prone to less antidrug immune responses than conventional antibody therapy. SADA is also highly modular. And while today, I only showed you how it can be applied to GD2 expressing tumors with lutetium-177, many other tumor targets are in development and even other types of radiation forms are being explored. And lastly, SADA's precision makes it a great theranostic, demonstrating not only therapeutic effectiveness, but great images that can be used to identify masses and measure their responses to therapy. Next slide. And finally, although this project was started by only a few of us at MSK at the time, it is important to acknowledge the totality of what I presented to you today was only possible with the help of many incredibly talented and supportive team members at MSK and collaborators outside, including physicians and many members, especially of the Larson and Chung labs as well as our collaborators in compare pathology and Y-mAbs Therapeutics. And with that, I'd like -- I hope to take questions. Thank you.

Great. Thank you, Brian. Yes. Let's move straight to Q&A.

Great. So our first question comes from Alec Stranahan.

Brian, thanks for the comprehensive overview of the SADA platform, very interesting technology. I had one question, and you sort of alluded to this at the end. But could you sort of frame use cases for different radioisotope partners with the SADA program? Like how would you sort of balance the tumor specificity with the penetration that you would require and any residual effects as it's excreted?

Sure. Sure. Sure, of course. So I mean, obviously, therapeutic -- isotopes can be kind of divided into either imaging isotopes or therapeutic isotopes. But then obviously within that, you have quite a bit of variation. And on the therapeutic side at least, a major consideration would be, as you've kind of alluded to already, you can either look at kind of the energy level, which kind of corresponds to how potent it is, and then maybe the penetration of the radiation. And obviously, kind of maybe not speaking for Y-mAbs but speaking for just kind of radiobiology in general, the thought is that lutetium-177 would have kind of a larger penetration. It would be better at targeting masses maybe that are more heterogeneous, whereas something with a much smaller path length would be going after kind of much more microscopic disease or individual cells where you would maybe be more concerned about kind of going beyond the tumor margin. And so that could be a consideration for developing other isotopes.

Thank you. So the next question comes from [indiscernible] at B. Riley.

This is [indiscernible]. I wonder, did you guys observe different PK profile with SADA at higher concentration of doses? And also [indiscernible], is the concentration high enough to have SADA as a tetramer as you have shown?

Yes. Sorry -- yes, I mean, that's a great question. The study is looking at the kind of differential PK across different concentrations are still in the works. But we have observed that if we sampled the SADA in the blood at certain time points, we will observe it as a tetramer still. And as it's broken down, it very quickly [ will leave ] the blood.

Great. So the next question comes from Peter Lawson at Barclays.

Just what other competing technologies do you see that could enhance the therapeutic index of toxins or radioligands? Just interested in your kind of overview there.

Sorry, could you read that again? There's a little bit of noise in my end.

Just what other competing technologies do you see that can enhance the therapeutic index of toxins and various radioligands?

Yes. Yes. I mean, in general, I think pretargeted radioimmunotherapy is kind of a widely used technology as a way to do this. I think it's pretty much really the only successful way that people have looked at and researched, and there are many different approaches to pretargeted radioimmunotherapy. The issue with most of them really being either they require a third step, a third novel clearing agent in order to achieve these high therapeutic indexes, which while it works kind of on a research level I think has kind of complication issues. Or they really just simply wait until their antibody is dropped below a certain level and they just accept a certain amount of circulating antibody. And that can be problematic for tumor markers that may not be stable for multiple days. But in general, separating the actual active toxin or isotope from the antibody from the targeting part is really kind of the fundamental basis for any improvement in therapeutic index.

Thank you. So the next question comes from Etzer Darout from Guggenheim.

Can you hear me?

Yes.

Just a couple for me. Just wondered quickly, can you help me understand sort of the clearance mechanism of the make it sort of radioisotope and sort of compartments? And just trying to understand how sort of that impacts sort of the just general toxicity of the radioisotope itself in terms of its PK mechanism. And the second one, just wondered, in larger human compartments versus rodents, how do you solve for the entropy issue that you would sort of expect with sort of assembly/disassembly?

Sure. Sure. Sure. So in terms of the first part, I mean, DOTA itself, either with lutetium or with other metals like gadolinium, have been quite well characterized. And they generally have a very, very short half-life in blood because essentially, they're so small they can -- they basically pass through the kind of the filters that exist at the kidneys. And they just leave the blood kind of in a permanent one-way exit, out through the kidneys and into the urine. And in that way, SADA can take advantage of the same mechanism but kind of existing at this size threshold so that it is at times above and other times eventually below the threshold. So in general, DOTA itself has very, very low uptake throughout the body. So essentially, it isn't 100% through the kidneys. There are obviously other contributing components maybe through the liver or through the gut. But the vast majority goes to the kidney, and really you don't see any nonspecific uptake outside of, like, say, a bispecific antibody or a chemically modified one. And obviously, I mean, when we're -- all of this data so far is in mice, and obviously there's a lot of considerations when you're translating into humans. But I think -- I mean, from my standpoint at least, it's kind of speculation as to how the PK profiles would change. But we think that the -- at least on the basis of concentration, you should be able to achieve kind of comparable concentration levels and hopefully kind of, consequently, similar PK kinetics in patients.

The next question comes from [ Simon Reed ].

I had a couple of questions. First was around immunogenicity, and it sounded like the way you at least narrated the story that you were quite surprised about the lack of immunogenicity. Do you feel that, that is a reflection that you haven't really explored in higher species like primates, for example? And the second question was more of a CMC question. Is there any specific issues with handling these types of molecules? Are they -- or should we expect them to be handled similarly to monoclonal antibodies?

Yes. Yes. So regarding your first question, the immunogenicity, I mean, I think any type -- I think immunogenicity is a very difficult thing to predict especially in humans. And so we're working with humanized antibodies that will be to some extent more immunogenic in a mouse than they would be in a patient hopefully. But I think the relative difference between them is still going to be relevant because we're using, essentially, the same backbones at least for the targeting antibodies in this initial comparison. So I mean it is something we see, in the mice at least, a lot like the problem of any drug immune responses. And so I suppose it wasn't surprising that we developed them in the antibody case, but I felt that -- I was -- we were surprised that the difference was kind of so dramatic. We kind of anticipated that there would be more of an effect from SADA, maybe even an enhancement because it cleared in a different way, but that just didn't seem to be the case. And in regards to CMC, so far, I mean, we don't anticipate any significant issues. I mean you can purify these proteins in a very similar way. It is obviously a little bit different because they're not exactly the same as monoclonal, but you can practically go through the same process for most of them. And in terms of stability, we've seen generally very, very comparable stability in storage as would be needed for monoclonal antibodies.

Thank you, Dr. Santich. So we have 2 questions from [ Pascal Sansone ]. The first one is regarding SADA. Which current validated approaches can be deployed with the SADA technology?

I assume that, I mean, that's in terms of targets?

He didn't specify.

Okay. I mean -- yes, so I mean, obviously the GD2 SADA with lutetium is the lead candidate. And others in development, I'm not sure if maybe Claus might be able to kind of discuss the priority among the next-generation ones. But that one is the lead one for, hopefully, entering development late next year.

This is Claus. That's correct. We plan to have our first SADA construct, the G2 SADA, in the clinic already for clinical treatment in the fourth quarter next year. We are working very diligently and fast towards [ doing a tox ] program right now and the cGMP manufacturing and getting ready for a pre-IND meeting. We have the B7-H3-binding SADA construct based on a humanized B7-H3 antibody. Also moving fast forward, we also have the HER2-binding SADA and GPA for colorectal -- GPA33 for colorectal cancer. And as Brian also correctly mentioned, we have a number of hematological targets that we are working on SADA constructs for. And I would definitely hope that our first hematological construct would be ready for clinical testing in 2022 where we would have at least one additional solid tumor candidate for SADA also available. So this is having a very high priority for the company. And as Brian alluded to, we believe this could be a complete game changer for how we see cancer treatment with radiolabeled constructs, and therefore, we also determined liquid radiation. Thank you.

Thank you, Claus. One more question from [ Pascal ] on SADA. From a PK point of view, will these bulky tetramers be able to infiltrate high-volume diseases?

So that's actually an interesting question. And I mean we think that the tetramer itself is only marginally larger than kind of a monoclonal or even if you have kind of a modified bispecific antibody. So it should at least have comparable penetration to an antibody. And at least from the tumor models we've done, quite large tumors, quite small tumors, in the preclinical setting, there seem to be no issue with distribution. That being said, I mean, there is the possibility that it can actually also separate into either the monomers or kind of an intermediate dimer state where it's just 2 molecules. And theoretically, that may allow it to have kind of transiently better penetration into certain masses and then be able to potentially reform at the tumor site when multiple of them kind of come together at the target. But we don't foresee any significant issues.

And one question from [ Paul Chenoweth ]. He's asking if payload is different [ lutetium ] versus actinium.

Right. Yes. So I mean actinium is another obvious major isotope that could be used. And as kind of alluded to earlier, the primary difference between them if you kind of look at the complexity of manufacturing and put that aside is really the difference between the path length, basically the distance that the energy can travel or the actual amount of energy that each isotope releases. And so actinium has a much more potency kind of per actinium isotope. It can kill cells very, very effectively, but it has a very short path length. So it's really only going to hit the cells that's on the antibody that it is attached to. Versus lutetium, it has moderately lower energy, but it can penetrate much deeper into a tumor. And so in these situations where maybe you don't target every tumor with the antibody, you're still able to hit them as kind of a bystander effect with lutetium.

Thank you. And one last question from [ Sebastian Vanderzei ]. So the question is could you maybe elaborate on how the size of the antibody tetramer will impact tumor penetration? Could that be problematic once you go into the human setting with larger, more bulky tumors than in the animal setting?

Yes. And as, I mean, previously alluded to, the dynamic nature of SADA may actually be able to provide an advancement there. I mean where we see breakdown of the SADA over time, if the smaller sizes, as it goes from tetramer to kind of an intermediate state where it's just 2 molecules and then down to the monomer, if at any point that actually enhances the penetration to a tumor that SADA will preferentially go through, which wouldn't be the case for an antibody. So while we kind of achieved a comparable range of size as an antibody of the tetramer size, we also can take advantage of these smaller sizes that may enhance penetration. But that's something that, I mean, really hasn't been explored to date on the preclinical side at least.

Thank you. So I'll now turn the conversation back to Thomas for the next presentation.

Yes. Thank you so much, Brian, for a comprehensive presentation. It's all very exciting with the new platform. And with that, I'll give the word over to Dr. Claus Møller. Thank you. Claus?

Thank you. So we need to move on with the slide and the next slide. And initially, I'm just going to give you an overview of where we are with the iodine-131 omburtamab where we have already filed a BLA once. We got a refuse to file and a request for some additional information from the FDA. So I'm going to give you an update status on this. And if we go to the next slide, so the omburtamab BLA and also the European marketing authorization application time lines is right now that Y-mAbs is in close discussions with the FDA. We have had a Type A meeting with the FDA after the refuse to file. We -- the final agreement on content of the BLA package that will enable filing is anticipated in early January 2021. We estimate submission of the file shortly after reaching an agreement with the FDA. For EMA, we have a PIP agreement, pediatric investigational plan, for the product in the CNS neuroblastoma and has agreed and validated by the PDCO. Furthermore, Y-mAbs has had a promising and informative meeting with the EMA in November 2020. And it's our intent to file the marketing application authorization in early March 2021. So we go to the next slide. The results of the multicenter Trial 101, we have previously alluded to the fact that the multicenter Trial 101 is seeming to having a very comparable overall survival development to the 03-133, the biggest study in history ever done in these patients where we have 107 patients in the study. And you can see the Kaplan-Meier curve for now almost with 2 years almost follow-up for the first patients is still on the top of the original MSK study. Next slide. The FDA also asked us to do for the refiling what they call the propensity score analysis of the 03-133 study versus the historical data set from the Central German Cancer Register in Cologne in Germany. And to do this, you match the different groups, so you get the subjects to be more comparable. And therefore, instead of having 107 subjects, we are down to 54 subjects in each of the 2 groups to have the best matched patients to compare with. And lo and behold, big surprise, we have still a highly significant difference in overall survival. And the overall survival of the patients from the 03-133 is still at the same level of about 50% cure rate for the omburtamab and CSI, craniospinal irradiation, treated patients versus the patients from the Central German Cancer Registry. So here, we are very nicely addressing the FDA's request for a propensity score analysis on those 2 patient cohorts. The other thing the FDA asked us for, you will see on the next slide, omburtamab-independent radiographic evaluation of tumor responses from the patients. What we have is 24 patients, and among those 24 patients, we found 10 patients that had measurable disease where we had the investigators doing these response evaluations. And in other 14 patients, 13 of these 14 patients simply didn't have any measurable disease. One patient did not have sufficient amount of scans at the time point for us to be able to evaluate the disease. So of the 10 patients where the independent radiographic evaluation was done, we saw an overall response rate of 40%. 20% or 2 of the 10 patients had complete responses, and 2 patients had partial responses. Even more interesting, of those patients considered to have measurable disease, 5 of them showed stable disease. And if you have a tumor in your brain, it's going to continue to grow. And interestingly enough, 9 of the 10, all the patients that had either stable disease or response, at week 26, half a year later, we're in disease control. Meaning that the stable diseases does not necessarily mean that it's actual tumor, but it could be scar tissues after surgery or after the cancer there being killed by either the radiation or the chemotherapy that patients received prior to entering our protocol. So 9 out of the 10 patients still in disease control at week 26. Now we do not know whether this will be sufficient to address the FDA's interest whether we are actually having a direct antitumor effect. But it's definitely, in our opinion, very promising. And we are continuing to enroll patients in this study. We have more than 30 patients enrolled now, and we will continue to evaluate tumor responses on patients that has measurable disease. Next slide. So before we go into naxitamab and our osteosarcoma study, let me also just finalizing of the omburtamab. We're reminding you that we initiated 2 new protocols under 2 separate INDs with omburtamab DTPA lutetium-177 in the last couple of months, meaning we got both IND approved. One of them is for medulloblastoma and should start recruiting patients early in the new year, a pediatric indication with a devastating cancer in these patients. And the other one is for adult patients with B7-H3-positive CNS leptomeningeal metastasis from solid tumors other places in the body, and that study has also been approved. The IND is open, and we expect to start enrolling patients in that adult indication for omburtamab in the new year. And finally, I also want to remind you that we have a program also for diffuse intrinsic pontine glioma, DIPG, that has been ongoing at MSK for a number of years now. And we have just recently finalized the protocol that we hope to be able to open for patient recruitment in the first half of next year in a multicenter setting. And we are getting a tremendous amount of interest from all over the U.S. to participate in this study for DIPG patients since there is no treatment and this is the only treatment that shows some kind of improvement in the outcome of this devastating disease where all patients seems to be dying within the first 5 years and 90% within the first 3 years. Let's turn back to naxitamab and osteosarcoma. We have been talking about this program for a long time now. The study has been ongoing [ indeed ] relatively slowly at MSK for a number of reasons. But it's a Phase II study of humanized antibody in the treatment of recurrent osteosarcoma. So these are patients that have relapsed after being in remission in frontline, and then they typically relapse in the lung or at the original bone site. And more than half of the patients we are looking at in this study is relapsing in the lung. Then they have surgery. The doc takes out that part of their lung or their bone, and then they basically are in complete remission. But what we also know is that 1-year event-free survival for these patients is not more than 20%, 25% because they still have microscopic disease. So the idea is to give 5 cycles of naxitamab and see if we can prevent micrometastasis from presenting as new solid tumors. Like Dr. Mora explained in his presentation, the minimal residual disease, get rid of that with the antibody. Next slide. So there's quite a bit of interest, and the study is not fully recruited yet. We are targeting 39, and we are -- pending that it still looks promising, we would go for additional patients in an expansion of the study. MD Anderson and Children's Hospital Los Angeles have just gotten IRB approvals and have been initiated and should both be ready to enroll patients in January. So we expect to have all 39 patients shortly. If you go to the next slide, you can see here that [ very ] draft and this is very preliminary, but it's pretty clear to us that there is clearly an indication that we can do better than the 20%, 25% EFS for these patients and the OS follows this very nicely also. And this is based on the first 31 patients that's in our database. Next slide. Just to remind you that it's not without any side effects to treat with naxitamab. So of course, in these patients, because they are much bigger -- and the average patients with neuroblastoma is about 20 kilo, whereas the average patient here is about 80 kilos, so they're getting a substantially higher dose. The total dose is reduced 20%. So we give not 9 mg per kilo during a week, but only 7.2 mg per kilo divided into 3 doses. Nevertheless, grade 3 and 4 events are the same as we saw with neuroblastoma in kids, pain, hypotension and hypertension. But this is, in my opinion, the only thing in osteosarcoma right now that looks promising. Next slide. So I also promised to give an update today on our bispecific GD2-CD3 nivatrotamab. And there has been a study ongoing at MSK that opened in February almost 2 years ago, a dose escalation study. It's a Phase I/II study of the 3F8 bispecific antibody in patients with relapsed/refractory neuroblastoma, osteosarcoma and other GD2-positive tumors. So I'll go to the next slide. The clinical experience on this protocol, so far, is the 10 patients has been administered at 6 dose levels of nivatrotamab, ranging from 0.0045 micrograms per kilo per dose up to 8 micrograms per kilo per dose and then via intravenous administration. And then in addition to the first dose, so we give one dose at day 1 and one dose at day 8. So that adds to the 9.3 microgram per kilo per cycle, with each cycle consisting of the 2 doses. The priming dose has been now set to 1.3 microgram per dose -- per kilo per dose. And we have seen dose-limiting toxicities at dose levels 1 to 5, where a total of 7 patients were exposed. But when we came to dose level 6, we have actually had 2 patients experiencing dose-limiting toxicities. And we have now modified on the steroid premedication. And we have also had to replace the [ dropped ] product that we are using here. The initial product that was used in this study was manufactured by MSK. And now we have switched to a product that we have large-scale production of the CTMP conditions by Y-mAbs, and we have introduced this under the IND. And so with that, we have agreed to go to cohort 4 again and start dose escalating again at this level, with a modified premedication and increased steroid dosing of the patients. So there's currently no reports of CR and PR at these very low dose levels, which does not -- does encourage us from continuing developing this. If you go to the next slide. We definitely are planning to introduce this in our small cell lung cancer study 402, the safety and clinical activity of nivatrotamab in relapse or recurrent metastatic small cell lung cancer. Next slide. Just to remind you, lung cancer is probably one of the most -- the small cell lung cancer is the most devastating part of lung cancers at all. And if you follow the prognosis for small cell lung cancer, it's dismal, right? It's not been improving over the last 25 years. Without treatment, small cell lung cancer is the most aggressive pulmonary tumor type with a median survival from diagnoses of only 2 to 4 months, and the survival at 5 years is 5% to 10%. So these patients are in need for new treatments. Next slide. So where did the whole idea arise from? Well, again, a lot of fantastic research has been done at MSK through the years. And with an antibody that is the predecessor of naxitamab, the GD2 antibody, the murine 3F8 antibody, which is the same binding side of the antibody that is on naxitamab is also the same binding side that is on the bispecific GD2-CD3 antibody. And this antibody, they took back in the [ mid-'90s ] and they took 10 patients with small cell lung cancer. And they looked at GD2 expression in these patients, both in the original cancer and also in liver metastasis -- including liver metastasis. And almost everywhere, except from when it was metastasizing to the brain and there was a single sample also from the left iliac crest, where they could not [ sustain ] over the SPET scan with a radiolabeled 3F8 antibody binding to the GD2 on the cancer. And you see this very nicely illustrated on the panel to the right. And the CT scan imaging, and you see the liver with a big tumor on the bottom of the liver, and you see this nicely images by the SPET scan illustrated after the binding with the radioactive GD2 antibody. And if we go to the next slide. So just to remind you also that our commitment to these types of antibodies, the BiClone types, come from our direct comparison of traditional heterodimeric bispecific antibodies. Compared to the bite -- the single chain -- 2 single chain [ of these ] bispecifics and to our BiClone constructs, where we see significantly higher potency of our BiClone constructs and no T-cell activations in the absence of the tumor. Next slide. So we have chosen to change the dose route after our first-in-human experiences from the first study we did, the 401 that we just talked about. So to be able to see if we can even further enhance the safety and tolerability of dosing, we have changed to subcutaneous administration and slower onboarding and with the Cmax estimated to be 2 to 5 days after dosing. And the MSK study is limited to 2 doses per cycle on a monthly basis, so we are trying to change the cycle durations also to further increase the ability to get more bispecific antibody. And then in the premedication, further increased the use of methyl prednisolone and dexamethasone or equivalent. So next slide. So we have 6 sites that have committed to participate in the study. The 3 first sites where we have final acceptance is listed here. And the Y-mAbs IND submission for this study is going to the FDA this month, and we expect to enroll the first patients in the first to second quarter next year. And next slide. So the patient population for this is primary metastatic Stage IV or relapsed patients with small cell lung cancer, regardless of platinum sensitivity. And in the Phase II, it will be the same patient population of this study. And next slide. So this finalize my part of this presentation today. But also reminding you that our commitment to this bispecific constructs remains, and we are planning also in the first half of next year 2021 to file our IND for our bispecific CD33-CD3, same construct as the GD2-GD3 for pediatric AML. Thank you very much.

Great. Thank you, Claus. We will -- I guess, we'll go straight to Q&A from here, Sara. Thank you.

Thank you, Thomas. So we'll now enter our last question-and-answer session. [Operator Instructions] So the first question is from Peter Lawson at Barclays.

I may have missed this, but how long were the patients on treatment for the GD2 bispecific?

They were dosed on day 1 and day 8. If they were still on protocol and did not progress, after 1 month, they could have another dose at day 1 and day 8 and so forth.

Got you. And was there any evidence of CRs?

There's definitely in the higher dose cohorts, including cohort 6, indications of CRs, yes, definitely. As I said, one of the issues was to handle the premedication with dexamethasone and the on-study dexamethasone dosing. So -- but we seem to be able to handle that now continuing with the protocol.

The next question is from Alec Stranahan at Bank of America.

I've got a couple on omburtamab. And I understand the discussions are still ongoing. But my first question, did you get a sense of whether regulators are looking for a certain level of response?

If they are, I would guess, a 20% response rate in a brain tumor where you also have survival benefit should be sufficient. So I think if we had been down to like 10%, 15% or something like that, they would have probably been a little more shaky. But the key thing here is that, as the FDA have said a couple of times to us, that we believe you are doing something. We really have a problem not seeing a direct antitumor effect. We would really love to see that. And we've had that discussion since they gave us breakthrough designation, which is why we introduced in this protocol to have independent tumor response evaluation according to the RANO criteria. So it's done the right way. It's done as we have agreed with the FDA. Why they changed their opinion about asking for this as a part of our BLA filing and not originally saying that -- I mean they never said they wouldn't need it. They just said -- they never requested it as a part of our original BLA filing. And at the pre-BLA meeting, they were not alluding to that they would need this. But that's how life is sometimes. And we have the data now. And whether it will be enough, the tumor responses from these 10 patients or they say, no, you need to give me another 5 patients and -- but you can do it at 120-day safety update or whatever they say, I don't know for sure yet. But we have an ongoing dialogue with the FDA, and they're looking at our data. And we'll come to an agreement with them. And the whole CMC issue that was raised, that whole package is ready for submission.

Okay. That makes sense. And then my second question, do you think there's a chance that the FDA could potentially limit EFS or OS on the label to just the population of patients and the tumor response cohort? Or was this really more just to know like their understanding of the drug's activity?

They just wanted to see that there's a direct antitumor effect, so they can safely argue that the reason why we see this dramatically increased survival is because microscopic disease that we cannot see on scans are being killed by these treatments. I think -- I'm certain -- absolutely certain based on our discussions.

Great. So the next question is from David Lebowitz at Morgan Stanley.

Just jumping back to DANYELZA. When looking at the label, the response data from Study 201 is different than what was presented at SIOP. Can you just run us through how the FDA looked at the data and how they, I guess, adjusted the data to put in the label?

Well, we have 3 sets of data out from that study. We have the investigators' response evaluation, which shows about 79% overall response. We have the independent tumor response evaluation, where we have 2 independent radiologists and 2 independent pathologists looking at bone marrows and scans from the patients and concluding that 68% of the patients is responding. And the same data set was sent to the FDA, and their decision was that they excluded a number of our responders for various kinds of reasons. And I could have spent the next 3 months discussing whether it was fair and reasonable and added additional information on data. I felt it was more important to get the treatment out to the patient than having that discussion that the FDA wanted to remove a number of our responders out of the first 24 patients. Remember that we have a post-marketing commitment from that study, where we now have -- this is based on the first 24 patients. We now have more than 40 patients in that study. And we have a commitment to come with data from the first 80 patients in that study as a post-marketing commitment and providing additional tumor response data and additional event-free survival and oral survival data. So I felt it was more important than continuing discussing this to simply get the product approved and live with the FDA's interpretation of the data versus the investigators. Because what the pediatric oncologist is going to experience when he treats these patients is the same as the investigators. 4 out of 5 kids will be determined as a responder after treatment with naxitamab. And that's the important part. That's what's happening in real clinical life.

When looking at the frontline data, is there going to be, I guess, an attempt to, I guess, maybe alter how the responders are adjudicated to try to maybe make the responder analysis come in line somewhat?

In the frontline data? I'm not sure I understand.

So when you're evaluating frontline patients, if you're going to bring that data to the FDA?

Yes. Well, I mean, we have -- in addition to Dr. Mora's investigator response study, we also have a study ongoing at MSK that is supposed to enroll 59 patients, and it's almost completely enrolled. And then we are planning a multi-center frontline study also. And we will have a Type B meeting with the FDA in the beginning of next year to discuss what is needed for expanding our first indication to also include frontline data based on what we have available from the 2 studies at MSK and Dr. Mora's side, and also what else could be investigated in a Phase, you can say, II/III protocol in frontline. So we will discuss that with the FDA to see if we can get a label expansion into the frontline.

So the next question comes from over the web from Tessa Romero and Anupam Rama from JPMorgan. So the question is in 2 parts only. So let me start with the first one. "Can you please remind us if you have in hand all of the clinical data to be included in the BLA and MAA filings at this point for omburtamab?"

Yes, we believe we have that. But until the FDA agrees with me -- I mean, for the EMA, we are quite comfortable after the discussion we had in November. So we have a filing date schedule there for the beginning of March. The FDA, as I said, I haven't gotten a feedback on whether what we are offering in terms of tumor response data will be sufficient. But we will know that very soon.

And then the second part is, "For the osteosarcoma trial for naxi, anything in baseline characteristics worth noting that is predictive of positive outcomes with naxi so far? And does the company have plans to present further details at any medical meetings?"

The last one first, yes, definitely, we would work with the MSK investigators and the new investigators participating in this and hopefully find a suitable venue in 2021 to present the complete data set when we have the 39 patients and remaining 6 patients included in the study. So right now, as I said, this was just to give a preliminary update, and we felt that after this study has been ongoing for more than 5 years, that we were obligated to give a status for it. And so therefore, it's very limited, what we have released today. But as I said, it's definitely our intention to give more detailed information later this year. This could be the first change in prognosis for these kids or young adults that are relapsing with an osteosarcoma. I've not seen anything in the last 25 years that have increased the survival probability for this patient cohort before.

Thanks, Claus. So the next question comes from Arlinda Lee at Canaccord. So the first part of the question is, "Do you have plans on monetizing PRV or using yourself?"

We definitely will monetize those -- the one we received from naxitamab, and I'm quite certain that, that will happen within the near future. And I cannot foresee that this is going to take months and months before -- so definitely monetizing it. And the second one, that we should receive when omburtamab gets approved, would definitely also be monetized.

And the second part of the question is on pain management. "Drs. Modak and Mora discussed what the standard protocol is for naxitamab. Could you also talk about what the dinutuximab protocol [ data pays off ] and how they differ?

I'm not sure I understand the question. How what differs?

Yes, how they differ from dinutuximab.

What -- naxitamab and what?

Dinutuximab.

I don't understand the question.

If you look on the Q&A, you can see it.

Maybe I can jump in, Claus. I think they were asking whether the pain management protocol between naxitamab and dinutuximab, whether that differs any significantly. All I can say is that -- well, yes, it certainly changes because we are talking about a very acute and short time lapse of pain for naxitamab, whereas for dinutuximab, it certainly is 10 to 20 hours infusion, and that pain is lingering longer and longer. So the pain management protocol is clearly different. We can talk about the details, but the answer is, yes, it is clearly different.

Thank you very much, Dr. Mora. You're definitely the right one to answer since you have treated numerous patients with both products. So thanks for that.

And the next question is from [ Sebastian Vanderzeil ]. So the question is, "The data on osteosarcoma looks very promising. What is your view on the continued development after Phase II? With an additional confirmatory study be likely?"

I think there is a likelihood that the FDA may require an additional set of data. But I think when we have the first 39 patients, the idea would be to take the data from this study and go and discuss with the agency and find out what would be needed in terms of a Fast Track approval for a construct like this -- sorry, accelerated approval, meaning a post-marketing commitment could also be a solution. If the FDA agrees that this is of significant importance for osteosarcoma patients that -- then they may be willing to approve based on a more limited study. But since we are now expanding and making it [ more than single ] study, we should address one of the normal primary concerns of the agency.

Great. So that concludes the question-and-answer session. I'll turn it back to Thomas or Claus for closing remarks.

Thomas, please go ahead.

Thank you so much, Claus, and thank you so much, everyone, for participating today. As you can see in here, we are very excited about our pipeline, but also very excited about our -- being a commercial stage company right now and continuing to optimize the neuroblastoma portfolio as we move forward. So again, thank you very much. Thank you, Dr. Modak, Dr. Mora, Dr. Santich, [ Dr. Mora ] and everyone else who's listening in, and have a great day.

Thank you. Bye.

Bye.

This concludes the call. You may disconnect your lines.