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

Good afternoon, and welcome to the Y-mAbs Therapeutics Virtual R&D Day. [Operator Instructions] I'd now like to turn the call over to Thomas Gad, President and Founder of Y-mAbs Therapeutics. Please go ahead, Thomas.

Thank you, Sarah, and thank you, everyone, for joining us today at our third annual R&D Day. We have a very exciting lineup of speakers today, starting with Dr. Oesterheld from Levine in North Carolina, who's going to present on the current treatment landscape of DANYELZA today, followed by Dr. Mora from Barcelona, who's going to show us some exciting those in experience with DANYELZA on patients with high-risk neuroblastoma. We will hear from Dr. Rajah, who is our Chief Medical Officer, how that new dosing experience plays into our strategy with DANYELZA going forward. And we will hear from Dr. Steen Lisby, our Chief Scientific Officer, on an update on our very exciting platform, SADA; and Claus Moller, our CEO, will give us a general company update after that, and we'll have Q&A out for each presenter. Thank you very much.

Thank you for the opportunity to present high-risk neuroblastoma in the use of naxitamab. As mentioned, my name is Javier Oesterheld, and I'm the division chief here at Levine Children's Hospital for cancer and blood disorders program. Next. So our indication for naxitamab is indicated in combination with GM-CSF for the treatment of pediatric patients 1 year of age and older, and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow, who've demonstrated a partial response, minor response, or stable disease to prior therapy. And it is approved under accelerated approval based on overall response rate and duration of response, and then obviously, doing our confirmatory trials for that. Next. And before we kind of get into it, naxitamab and its safety information as seen here, there are serious infusion-related reactions and neurotoxicity. It can cause serious infusion reactions, and I'm not going to go through all of these, but the most common is pain and infusion reactions, which we will manage with either reducing the rate, interrupting infusion or discontinuing it. The neurotoxicity includes neuropathic pain, which we premedicate with. And then if that is too severe, then we will need to discontinue the medication. Next. So our experience here at Levine Children's Hospital with this agent really is kind of important to do patient selection. It's probably the most important part of the process to make sure the drug is appropriate. We have a large solid tumor team with multiple physicians, multiple advanced practice providers who go through the goals of care, what the appropriate therapy should be and the patient characteristics. Not every patient is the right patient for naxitamab. Assess the patient profile for the treatment of the patient. And then many of the patients, unfortunately, have lots of comorbidities and have been heavily pretreated. So evaluating organ function and how they're going to do is crucial. Next. So we are the home of the Beat Childhood Cancer Research Consortium. This is a consortium that is international with sites in the U.S., Canada, Lebanon and more being added. And so we're seeing patients internationally come for this, and it's a great option to have for those -- for that patient population. For those who have failed previous treatments as part of the relapsed therapy, and then for those patients who have persistent marrow and bone disease, this has become a really crucial agent for us. And the refractory patients always incredibly difficult because a lot of these patients won't respond to what we consider conventional chemotherapy or cytotoxic. And so naxitamab allows a different type of therapy and in addition to our choices that we have. Next. I think it's always important to hear a patient example of how we've selected a patient and the kind of patients that we are seeing at Levine Children's. And so we have a young patient who was treated with no response upfront therapy, which is approximately 20% of the patients that we see with high-risk neuroblastoma, failed chemotherapy and had incredibly frank progression of a facial mass actually breaking through her oropharynx and then required emergent radiation, but had no response at all to that radiation. We discussed here with multiple colleagues at our institution, and we thought that naxitamab and a transfer to our institution was the next appropriate decision tree. And so she, unfortunately, at that time, we did get chemotherapy prior to moving her on to naxitamab and she had no clinical response as well. Next. And so here, as you noted, she had all of marrow and bone disease as well as some sub tissue disease, and she got quite sick on us and a decision was made to put in a tracheostomy tube to protect her airway because of the mass. And we decided to treat her with naxitamab. I'm really happy to say that she had a clinical response. And after the 2 cycles of this, all of her oral tumor had sloughed off, her MIBG improved, her bone and marrow disease also improved. And then patient at this point continues on therapy. I think it's just a great example of using this agent and having a response, which this patient specifically have been resistant to everything that have been tried prior. Next. And so we've been fairly busy administering naxitamab here, as mentioned by being the BCC anchor institution. We've treated many patients and administrated successfully. A lot of help from the company in the sense of trying to educate our nursing staff and everything else, utilizing our premedications with a good algorithm, and then management of adverse events and using guidelines for that. Next. So, AE management are really the most important part of taking care of patients receiving naxitamab. And so we received extensive education from Y-mAbs virtually because of COVID, but really got our nursing staff up and our supervisors, our clinical supervisors making sure that we knew exactly what to expect. We worked as a pretty big team rapidly over about 4 to 6 weeks, which, as you can see there, included nursing, pharmacy, our pediatric ICU, our respiratory therapy and then our blood and cancer medical team. We actually have a local algorithm utilizing the management from the company as well as some of the internal discussions, which really includes fluid essential pain management, blood pressure management and then having kind of a path to other issues that could arise based on experience here, and then experience from the company. We are blessed to be able to have our good response available from our PICU if needed, and they are here within about 3 minutes if called. Next. Preparation, preparation and preparation, I think that's the key to administering this agent. You really do have to be ready, drugs pulled out, make sure that you understand exactly what your patient has done before and is -- has had a prior tolerance to other antibodies is really important. Like I mentioned, having medications at the bedside to not scrambling to make the doses and everything else is really important for quick interventions. And then the most difficult component is the nursing requirements to perform this safely. It is important to have one nurse in the room, one nurse charting -- one nurse in the room and one nurse to be able to pull things up. And I think with that concept or adverse events and how we've done it been very manageable. Next. So as is indicated, you can give us an outpatient. We did do it outpatient, but attached to a day hospital for the first few, just out of concern that we wanted to make sure we were doing it right. And so we gave it a bunch of times, probably around 6 to 9x to make sure that we were ready and understanding kind of how the adverse events were going to play out in real time, not just from an education but just with our patients and different types of patients. So as I mentioned, it was in the day hospital with our outpatient inpatient staff, so we would have an inpatient nurse and an outpatient nurse to train both staff to 2:1 nursing. So it's 2 nurses for each patient, which is fairly staff heavy. And then as you get more comfortable with the adverse events, we actually have a select group of people nursing staff that are actually trained for this agent and some of our other high acuity medications. And so I think a dedicated nursing staff is really important. Next. So as noted, our most common adverse event is pain, and that is very, very expected and it's managed with a combination of narcotics, benzodiazepines and other interventions. We are lucky enough here to have an integrated oncology team. And so it's actually that support of medicine has been really great, using Reiki, or music therapy from our younger patients to our older patients, depending on what they like. It has been a real help in lessening the amount of narcotics and other pain medications we need to give. We have definitely seen a lot more hypertension on days 3 and 5 than day 1. And so I've had to adjust our algorithm a little bit to give higher doses and antihypertensive. Day 5 is definitely for us, at least so far, has been the day where they're above [indiscernible] and spiked a little bit more than expected. Our average time of our visit is about 5 hours from start to finish. We have a complete naxitamab schedule here where it is blocked off every afternoon from 12 to 5, Monday, Wednesday, Friday. And so we observed them for 2 hours as is indicated, and then that just needs to be considered depending on the hours of your clinic and how that works. And it really varies depending on the patient's treatment experience. I think the first cycle is always a little longer, second cycle seems to be a little less time. Next slide. That was it. And so I think statement is, we really have utilized naxitamab a lot. It's a really great option for our patients. I'd be happy to answer some questions.

[Operator Instructions] So our first question comes from Joseph Thome from Cowen.

So the first one, I know you mentioned that the first part is sort of understanding which patients would be most applicable and could benefit from therapy. Could you maybe just, at a high level, tell us what goes into that decision, which patients maybe are immediately screened now? And which ones do you say immediately, these will be good candidates for treatment? And then second, you mentioned potentially 2 nurses for one patient. Is this something that you think most centers would be able to accommodate?

Yes, great questions. I think -- to answer your first question, I think it's those patients that have lingering bone and bone marrow and have had been fairly refractory. I think those are fairly easy to guess that you can use this agent and it will work since it's a little bit different than obviously conventional chemo. The patients that have had some stable soft tissue disease are definitely in there. And I think patients that are having at times frank progression, just depending on kind of what we want to do with the family goals are. I don't think we exclude anyone right off the bat, but there are patients just from organ toxicity and things like that that are probably not going to be a great choices and those that are allergic to some of the narcotics are a little bit more difficult to manage. Some situations of using ketamine and things like that, we do not use those agents here, and sedation for these patients. So if we have to do that, then those patients, unfortunately, we can't do here yet. And then second is the 2:1. It's rigorous. I will be honest, I think, especially in the time of a nursing shortage, it's a big challenge. I think you have to have some dedicated staff and really be incredibly aware of your schedule in the clinic to be able to make it work. And so it's a little bit of a juggling act. But yes, to your point, I think it is doable. I think you definitely need to have quick availability for cardiopulmonary resuscitation in your clinic to be able to do it the right way.

I'll now turn it over to Tim McCarthy to read any questions that may have come over the webcast.

We have one question. What drives the choice of naxitamab versus the treatment protocol outlined in ANBL1221?

I can answer that. At our institution is a -- most patients have had to fail 1221 before we would consider naxitamab, or a patient cannot receive the immunotherapy agent in their home country.

Thank you. The next question is what is your clinical experience of DANYELZA versus that of Unituxin?

I've been -- I have a lot of experience in dinutuximab, happen to just be at the Phase 1 site or one of the Phase 1 sites that started dinutuximab, and so I've had a lot of experience with it. And then my experience with naxitamab has been since the beginning of the year, we have administered almost every week since February. And so we have fairly got comfortable with it, definitely a little bit of a learning curve in the beginning. But we probably administer dinutuximab quite often as well as, as naxitamab now.

Okay. Thank you. The last question for this session. You mentioned hypertension was higher than you expected. Were there other side effects that were lower than expected?

Yes. It's interesting. I know that we've discussed it with other groups who had a lot of either not anaphylactic reactions, but a lot of hives and a lot of rashes, a lot of this and have had to stop the infusions. We actually haven't had to stop the infusion very much. We've chuck through pretty well. Angioedema has popped up in a couple of our patients, some hives that are easily managed with Benadryl. I would say, honestly, due to the fact that we have integrated oncology with every patient, which I know not every center can, those distraction techniques in some of those younger patients allow us to give less narcotic. And so we obviously give a lot if you have to, but that's been a surprise that we haven't had to give as much as we thought we would.

Okay. Thank you. That concludes the Q&A for this session.

Thank you very much, and I'm happy now to introduce Dr. Mora, who will be talking about [indiscernible] indemnification of institution of naxitamab and his experience from his side in Barcelona and Spain. Dr. Mora, welcome.

Thanks, Claus, and thanks, Y-mAbs for the invitation to share with you the -- our most recent investigations on how to improve naxitamab infusion reactions. Actually, my previous colleague and speaker in this session today has set us well the context whereby reactions are really -- could be really intense. So we've been working on how to improve such, and I'm going to share with you our findings next. So this presentation is basically a product of our own research in Barcelona, and has not yet been approved by health authorities. So it needs further collaboration and foundation. Next. These are my disclosures, consulting fees from Y-mAbs. Next. So we're talking about anti-GD2 antibodies like naxitamab. And this is what we are really talking about, high expression of GD2 in the surface membrane of neuromuscular cells -- showing up here in green by this products and immuno products and test, which is something that we need to remind everyone on where we are going to be talking next. So GD2 is ganglio lipid, which is among all the lipid that make up the membrane of the neuroblastoma cell. And it has many different functions, and it's something that we need to remind -- remember, because it just regulates the contract -- self-contracts as well as modulate some of the proteins, which are the major players in the immunology of the majority of the cells. So here, we're talking about this glycosphingolipids, which generates those antibodies that we are going to be using and using for our -- in the clinic. Next. So what is GD2? The normal function, we sort of spoke already. But we have to remember also that GD2 is broadly expressed in the [indiscernible] patients. And the pre-perennial resistant, which I'm going to be talking more in detail, also some granulocyte with [indiscernible] derived cells, lymphocytes, some lymphocytes also, which might be of interest and more importantly, mesenchymal stem cells, that's why tumor derived from these mesenchymal stem cells like some sarcoma do also express, G2, which also might be a target for our therapy. So in the central nervous system, certainly GD2 is -- while expressed in humans, so it would not be a good idea really to use anti GD2 antibodies for these central nervous system diseases. Next, however, in the peripheral nervous system, it was a long time ago, already shown that GD2 is expressed not in the actions, in the nerves, actually, but in the cells that surround those nerves, which are called the stone cells, and those stone cells do express the GD2 at very low levels that they do express. And this is the reason why we see some of these reactions. Next. So in malignant tissues, as I said, the most highly expressing tumor is neuroblastoma, but also many other neuroblastomas like melanoma. There are many sarcomas that we mentioned, the Ewing's sarcoma as well as osteosarcoma, some small cell lung cancers. Those are all neuroblastomas or a stem cell -- mesenchymal stem cell direct tumors, retinoblastoma also. Many of these tumors that might be of interest for our target therapies, that most highly expressing tumors 5 million to 10 million of GD2 molecules per cell are the neuroblastoma, nonetheless. And this is what has provided the most important evidence for antitumor. So this is what we're talking about, neuroblastoma, highly expressing GD2 and uniformly, which is very unique and quite different from other tumor test, and that might also explain some efficacy issues on our planning therapies. Next. So here are on target, on tumor effects that are well described from our antigenic therapy, which will be relying upon the immune system killing the tumor cells. But we are also seeing on-target off-tumor effects which give up the consequences that we see in our patients during infusions like pain, the cardiovascular reactions, allergic type of reactions, airway and gastrointestinal reactions. All these are also on target, off tumor side effects. Next. The metrics behind each of these effects are quite different. Immune system is -- gets activated to kill the tumor cells, which is good. This is what we're looking for. But for the on-target off-tumor, the immune system is not engaged, thankfully, Otherwise, we will be killing the immune system. And this is something that has not properly been investigated and we've been looking at in a little more detail. Next. So here, it's all well described, and we've been talking about this, how do we kill the neuroblastoma tumor cells or any GD2 expressing tumor cells by different ways of engaging the immune system. This is not the focus of my cup today. Next. Whereas the on-target off-tumor effects has not -- have not well been described, the mechanism behind it. So our hypothesis of being that there is actually an activation of the autonomic nervous system without -- again, without we engaging the immune system into the action. Next. So how can we prove that? Well, first of all, clinically, these are the Grade 3, Grade 4 side effects that we have -- that have been described, not only for naxitamab, but for many -- for all the anti-GD2 antibodies that are in clinical use. Hypertension is fairly common. Pain is almost universal, as you know, urticaria, pyrexia, but also bronchus on Cytocardia highlighted here. The Grade 3s, Grade 4s that were described and reported in the 201 study by naxitamab. So what if I can tell you that we can get rid of all these -- almost all the Grade 3s Grade 4s of all these highlighted reactions. That wouldn't be great. Well, this is what we aim for. And those are related to actually the activation of the autonomic nervous system, which is a system that is not really well listed and have much less investigated. Next. So my pain, when you explain these antibodies to our doctor in medical oncologist -- I mean, nobody really exactly knows why this antibody is called pain. But certainly, the clinic -- in the clinic, it all suggests that there is an activation of this autonomic nervous system that we're not going to have a very -- enough time to get into detail, but this is what we suspected all along. Next. So this is the treatment regimen for naxitamab, which I'm going to be using as the baseline. We all know very well, it's a -- the backbone of subcutaneous GM-CSF for 10 and 3 doses of 3 days, on day 1, day 3 and day 5. So what we call Mondays, -- usually Monday, Wednesday and Friday infusion. And this schedule is going to be important for the regimen I'm going to be explained next. So this is the test that we've been using that we have started actually from the diabetes management clinic, because those patients in the adult clinics, they have this autonomic nervous system dullness from the diabetes. So they have already set up this testing. It's a noninvasive way of measuring the conduction of these autonomic nervous system. And you can actually measure this quite easily in your patients noninvasively. So we adapted that to our patients receiving naxitamab. Next. So this is a patient coming in for the infusion on day 1 of the cycle of the naxitamab antibody. At baseline, you can see when they stimulate the nerve, you see the wave and normal wave with a normal amplitude and normal latency. By the time you start the infusion by minutes 2 to 4, there is a massive increase of the conduction in velocity with a short-term latency and the lower amplitude becoming right evident, right after the infusion starts. But progressively, when you go through the infusion time, you see progressive decrease until complete disappearance of all the weight and the conduction of the nerves. So the nerves becomes completely unreactive. Next. That was really surprising. Also, we knew from the clinic that there was -- this concept of tachyphylaxis that is well described for drugs or different systems, whereby the effect winds off over time after repeating dosing. And we know that this is what happens in the clinic, meaning the side effects on the Monday are always worse than those in -- for the temptation on the Wednesdays and Fridays. Next. So that concept of tachyphylaxis also was expected in our patients. So that same patient on the Friday infusion, you can see the wave of that sudomotor test was already of a lower amplitude to begin with before the infusion starts. But not only that, but after the infusion got started, the patient lost the weight much more faster. So the nerves were already partially depolarized, and that's the reason why we see -- we don't see as much reactions as the -- [indiscernible] of infusion. Next. So this is a tachyphylaxis concept applied to the depolarization of the nerves. And what we're seeing here is that nerves get depolarized, and by the time they depolarize, they get into this at the depolarization or refractory period, whereby there's no response whatsoever to the any of the steam line, no matter how much antibody you provide at that particular time, there's no reaction coming out of those nerves that get depolarized. Next. So based on the previous observations of different antibodies, dinutuximab and nuances and so on, there was no clear relationship between the amount of pain and the dosing that you were providing on any of your antibodies. The pain intensity was independent of the infusion time as well. So those kind of observations were really partnering and nobody has really understood and the coalition between the opioid adversely doses with the dosing of the monoclonal antibody was not linear. So there was something missing here in our understanding of how to manage the pain. Next. So based on all these findings in the pharmacokinetic data that was available and the neurophysiological data that we have access, we came up with a mathematical modeling of pharmacokinetic infusion of naxitamab. Next, in order to prevent the major side effect. So this is what we're doing when we plot the rate of infusion. This is the 3 milligram per kg per hour, which is the constant rate that is the usual way of providing the antibodies currently with all these wild side effects that are well described. Whereby, we are using a very low rate of infusion for the first 75 minutes, we get on to this depolarization phase of all the autonomic nervous system. And after this system is completely depolarized, then we can increase the rate to reach our goal by the next 45 minutes for the day 1 of the infusions. That's the hyper-polarizing phase and whereby the reactions are much, much less intense. Next. So if we're using this way, we are predicting that we are going to be decreasing at least most of our Grade 3, Grade 4 toxicities for our patients during infusions. Next. So if you plot the cumulative dose that is being given in these different models, so for a constant rate, you can see the flat rate of -- from 0 to 3 milligrams per kg total dose. And this is where we're standard in using whereas by -- on this stepping up protocol, what we're using is only 8% of the dose is given on the first 75 minutes very slowly. And afterwards, we can provide all the target dose up to 3 milligrams per kg in the very fast 45 minutes later on, up to a total of 2 hours infusion for the very first day of the infusion. Next. So if we apply the tachyphylaxis concept to this protocol, so we can devise of a day 1 protocol and a day 2 and -- of day 2 and day 5 protocol of infusion. Next. So this is exactly what we did. And this is for the day 2 and day 3 of naxitamab infusion. We can go higher and faster in the depolarizing phase. So in a way that we can complete the whole infusion by 19 minutes on these day 2 and day 3. Next. So that's the cumulative dose also achieved for those subsequent days according to this modeling. Next. So if that's true, then what we did was really to test this setting a protocol in 20 high-risk neuroblastoma patients in our center since May this year, for a total of 53 cycles and drove up to 159 infusions. And we were pleased to see that 3 patients only out of those 20 presented some Grade 3 or Grade 4 adverse events in the hypertension apnea and pain, which were very classically described for this antibody. Most importantly, next, and it was really the observation that those while [ swing in ] the heart rate or blood pressure, respiration problems really disappeared in during the stepping up infusions. So much so that there's no longer a need for having us, an MD at the bed side because the nurses are running all the show basically to say because the grades -- the toxicity grade have decreased so much. And we are also very pleased to say that we are managing now almost our patients without the use of many opioid rescues and we have switched over to almost the new protocol base, whereby we are taking off all the opioids. So now we are coming to a phase where we are going to be quantifying this -- the impact -- the clinical impact of this new infusion protocol and hoping to be able to show more definitive data in the near future. Next. So, and finally, I want to thank my research team in Barcelona and who has made the major contributions and observations to come up with this very most easily present tolerable protocol that we hope that it's going to be implemented in many centers, so to make naxitamab much easily tolerate. Thanks for your attention.

Thank you, Dr. Mora. We will now be conducting our second question-and-answer Session. Our first question comes from Sebastiaan van der Schoot from Kempen.

I was wondering, you just mentioned that you only have 3 patients, 15% of the 20 patients you currently treated with step up those in protocol. Can you mention how was the Grade 1 and Grade 2 events were reduced with the step up dosing, and compare that to the normal step up you usually use.

I don't see -- I don't really I understood well your first question. You said there was only 3 patients. No. 3 patients out of the 20 presented this Grade 3/4 reactions. That's what I said. And if I understood well, what you would say is whether we have changed the Grade 1 and 2 profile of toxicities. Is that what you have asked?

Yes. So my question is Mora, how does the [ 15% ] compared to the conventional treatment regimen on the administration, so not the step up dosing. And do you also see an effect on the Grade 1, Grade 2 events by using step-up dosing instead of the conventional treating regimen where you don't use step-up dosing?

Well, basically, the profile of toxicity hasn't changed. It is basically we are modulating the effects. So the way we are measuring toxicity, this is based on grading, which is an international accepted protocol that is being regularly updated. And we're using the same grading for the standard protocol management or the stepping up protocol. So we are grading those reactions in a similar way. And all we see is that basically, our patients are now having the same profile of reactions. I'm not saying that they are going through uneventfully. But certainly, those reactions, the intensity of the reactions have dropped significantly down to Grade 1s and Grade 2s. That's all we could say as of -- up until now.

Our next question comes from Joseph Thome from Cowen.

Just a quick question on those patients that did end up having the Grade 3, Grade 4 AEs. Was there anything different about their fitness or anything about their, I guess, disease profile that made them more amenable to maybe these AEs? And is this kind of easily addressed if you were to slow down the rate of administration? Or how do you typically handle these AEs to bring those down?

Well, thanks for the question. First of all, I have to point out all these patients were treated in complete remission and on the compassionate use because I'm not able to treat patients on trial with this new protocol. So all the patients were in complete remission. So all had very similar profile of nonevidence of disease. So there's no way I can predict whom are going to be responding or not responding to these infusion protocol. So I guess, we all made this different and people, autonomic nervous system reacts quite differently from one to the other. So it's not 100%. It's significantly down from 60-plus percent reported Grade 3s and Grade 4s in the 201 protocol. I'm hoping that we're going to be lowering down to 10% to 15%. So it's a significant decrease, but it's not 0, of course. And that's probably the heterogeneity among individuals. But certainly, it has nothing to do with the profile of the back of the disease we're talking about. This is all based on the autonomic nervous systems and the expression levels of GD2 and autonomic nervous system for each individual.

Our next question comes from Alec Stranahan from Bank of America.

Perfect. Thanks, Dr. Mora for the presentation, definitely encouraging data on the side effect profile and a great sort of scientific rationale for the improvement. I actually had a question for Claus. I see he's also on the line. I guess in the DANYELZA launch to date, how big a pushback has the side effect profile been on whether treatment centers decide to use it or not? And I guess with this information in hand, how are you guys empowered for your sales force? Or would you need to actually run a small study to get this included on the label first?

I think it's a little too early to say what would be needed in terms of getting it added to the label. But there's no doubt that the resources, as Dr. Mora also mentioned in terms of how much staff you need to have available bedside when infusing the product with the existing regimen seems to be reducing -- and reduced. And I think what -- so -- and that sometimes, of course, can be a capacity issue, but also, as Dr. Mora mentioned that total time the patient needs to stay in the hospital is relatively limited. So that's the, of course, the advantage of how naxitamab used in the outpatient setting. So I think it's still a balance, but it's just that having the staff available. I would not say that the side effects have been an obstacle for patients actually being -- coming on the treatment, but it's definitely certain that a number of patients has been taken off treatment again because of side effects. And especially if you're not very used to having the side effects, then you are more kind of prone to take the patient off the treatment rather than being able to continue the infusion and getting to the day 2 and day 3 whether they are Friday where the side effects typically are less predominant than they are on the first day. So I think if those data can be validated, that Dr. Mora has presented today, it's definitely making it a lot easier for first comers to use naxitamab in the outpatient setting and would also potentially allow for dosing in -- with larger dose of antibody and potential add-on indications. So we are very encouraged by the findings that we have seen here. And also that we now have a scientific rationale that we can use to provide the background for why we are seeing this. And I think Dr. Mora stated on the extortion of the automatic nervous system is very elegantly presenting what is actually happening and why we are seeing these system-based side effects at hypotension, hypertension, the respiratory depression and other types of similar technicality are also in these patients. So I know it was a little elaborated answer, but hope I gave some clarity.

This concludes this portion of our Q&A session. Claus?

I don't know if there's, Sarah, any more questions?

No. That's it. We can move on to the next presentation.

Tara?

This concludes our question-and-answer Session. We can move on to the next presentation.

Thank you very much, Sarah. So we'll be moving on with Vignesh, our Chief Manager Officer, who will give you an update on our strategy and development trends. Go ahead.

Thank you very much, Claus. Good afternoon, everyone. I'm Vignesh Rajah, Chief Medical Officer in Y-mAbs. It's a real pleasure to be here today to share with you some key updates on the strategy and development plans relating to DANYELZA, and a short update on a couple of our early-stage pipeline assets to 177-lutetium, omburtamab and nivatrotamab. Next slide. That's a disclaimer. Next slide. I'll begin with just a few words on what is important to us in Y-mAbs. This is actually an exciting period for us because we are embarking upon an ambitious R&D program. We're building our success by doing some really great signs in creating a platform of industry technologies. And this is underpinned by a strong belief that if we do this right, we will bring transformative medicines to address the outpatient needs in difficult-to-treat cancers, such as those listed here. And the fact that we've had a few breakthrough designations in the orphan drug and rare pediatric disease designations in many of these rare cancers is testament to this belief. And the progress we've made is only achieved, of course, through strong partnerships and collaborations, which we are taking about with the research network groups, expert counter centers, alliance partners and of course, our patients and families are all vital cog in this wheel. This is what's important to us in Y-mAbs. Next slide. So let me begin with DANYELZA, naxitamab, which is our GD2 targeting humanized monoclonal antibody. Next slide. As we know, the GD2 antigen has limited expression in normal tissues, that is overexpressed across a wide range of tumors. That was an ideal target for cancer therapy. And this led to the development of successful FDA approval of DANYELZA in relapsed/refractory high-risk neuroblastoma. But as you can see here, GD2 is also expressed -- highly expressed in other cancers such as, osteosarcomas, soft-tissue sarcomas and to a variable degree in breast cancer and melanomas. And just to prove this latter point, our own analysis in melanoma tumor samples are actually showing closer to 100% expression. So it's only logical, therefore, that we will consider further investigation and clinical development given these new indications when feasible to fully realize the potential value of naxitamab in both pediatric and adult tumor indications. Next slide. If we take a closer look at the addressable or treatable patient population in the U.S. pediatric, you get a better sense of the patient impact in terms of the number of patients that could potentially benefit from new treatments in these indications. They are relatively small numbers in the relapsed/recurrent osteosarcoma, about 200 a year. But in the adult tumors, even in the second and third line setting, the number of treatable patients is quite significant and thousands. Next slide. So before we embark upon investigating DANYELZA in these new indications, there are a few form factors for consideration and assessment when transitioning from pediatrics to adults. And these include the safety profile and tolerance in the adult setting, potential differences in PK and effective dosing adults. And as you heard from Dr. Mora's presentation on his clinical experience in Barcelona, these observations are very promising indeed from a safety perspective. So we are actively looking into this, and we'll be testing these new schedules in some of our ongoing and planned trials to define this further to determine the optimal dosing administration schedule. It has the potential to enable and accelerate the clinical development of DANYELZA in adult indications, as Claus said, which will be a significant step forward. Next slide. So what does that look like if we project that in terms of anticipated time line for study initiation? I mean this diagram shows -- was already ongoing with DANYELZA and what we are filing with new indications as we scope out the trial program. As you can see here, we are probably have the ongoing study in relapsed/refractory high-risk neuroblastoma. There's also an important ongoing MSK trial in osteosarcoma, the 15-096, which forms the randomized controlled trial, which we are planning to initiate towards the end of next year or early 2023, as shown on the slide, and I'll come back to this a bit later. Then there are the 2 recently initiated studies, one in frontline and the other is a chemo combination study in high-risk neuroblastoma. Regarding the last 3 tumor indications on the bottom right-hand corner shown here, we have an ambition to get these started in 2023, which is very exciting indeed. And the details of the study designs, patient populations, dosing schedules, et cetera, will be worked through and defined further earlier in the new year. Next slide. This slide just gives a bit more granularity on those studies that I referred to previously. So for the pediatric population, we have the 201 study with DANYELZA. Here, the latest as we 73 patients recruited so far. We also have our 202 the frontline study of a 203 chemo combination study with DANYELZA, both initiated in quarter 4 this year. For the 202, an additional arm is being considered to assess the new infusion schedule, as outlined by Dr. Mora's presentation. And for the 203, we are considering additional arm to assess a novel combination of PD-1 blockade. There are some studies and proof of principles showing there are synergies with PD-1 blockade in combination with anti-GD2 treatment. And for the osteosarcoma and soft-tissue sarcoma study, the only added point to mention here is that we're considering Phase 2 studies to consider the combination of naxitamab with CD47 blockade in IDO or both of these tumors. And this was, again, a recent presentation of the sarcomas, showed us very interesting results from Stanford University showing the potential synergy in combining anti-GD2 with CD47 blockade. And the last 2 study in metastatic breast cancer and melanoma, I've already mentioned, we're in the planning phase, so more details to follow next year. There's certainly a scientific rationale for exploring both these tumors, metastatic breast cancer and expressed GD2 ranging from 35% to up to 50%, 60% expression, and GD2 is considered a prognostic and predictive marker. And similarly, for melanoma, there have been some small-scale studies showing anti-GD2 activity in these tumor cell tissues, but nothing really substantial in terms of studies going forward. So there is a rationale for us to look into this in more detail. Next slide. In addition to the Y-mAbs-sponsored studies, as I mentioned earlier on about importance of collaboration, we are very active in collaborating with a number of academia and independent researchers to support continued data generation to investigate sponsored studies. And some of these partnerships are highlighted here as examples. So such as, for example, on the left-hand side, you see naxitamab in induction treatment, and studies looking at combination with checkpoint inhibitors such as PD-1 or CD47 blockade in sarcomas, and also an in-vitro and in-vivo preclinical study assessing the activity of naxitamab in triple-negative breast cancer. We're very excited that these data are very important for us because they build our knowledge and evidence base, and provide proof of concept that could be taken forward for future clinical studies and potential label extensions. Next slide. So a great example of this collaboration is in actually osteosarcoma program. So you may be aware from previous presentations, this is an ongoing MSK study, 15-096, which is a single-arm Phase 2 study running 3 centers in the U.S., MSK, MD Anderson and CHLA. Looking at the combination of naxitamab plus GM-CSF in the treatment of recurrent osteosarcoma. The study is getting close to completing its recruitment with 39 patients enrolled so far at a planned 46, and is anticipated to complete accrual quarter 1 and quarter 2 next year. As a reminder, this study is looking at patients with recurrent osteosarcoma. Those in second or more complete remission, and patients between 1 and 40 years of range. The primary endpoint is 12 months event-free survival in patients with pulmonary recurrence. And the second endpoint to give time to recurrence 12-month EFS in patients with extra time to recurrence close to survival and safety. The study is hard to show a 12-month EFS with a maximum of 50% compared to historical controls, the AOST0221 study, which are closer to around 20%. This is high expectation indeed. And if we were to show this incremental benefit, it would be groundbreaking in the context of this disease and its prognosis. So we anticipate data to be available next year when approval is completed. And based on these results, we will then move forward with our own pivotal study. Next slide. So the Y-mAbs pivotal study will be a randomized controlled trial comparing naxitamab to GM-CSF versus standard therapy in patients with recurrent osteosarcoma similar to the injury criteria to the MSK study, because we believe this will probably be the fastest route to potential BLA submission. It'll be a multinational study. We're participating in from U.S., Europe and China. We'll seek advice from the FDA around May next year and aim for an IND submission in July next year. And if all goes to plan, we expect first patient enrollment before the end of next year, potentially quarter 1, 2023. Next slide. So I'm going to shift gears now and give a very short update on the development plan for 177 lutetium omburtamab, which is B7-H3 targeting radioimmunotherapy. Next slide. Just to give some context, B7-H3, as you all know, is an antigen expressed on the surface of many solid tumors and is associated with poor prognosis. And the table on the right-hand side shows the degree of antigen expression seen in some of the cell lines from various tumors. It is highly expressed in tumors such as medulloblastoma and neuroblastoma, and reasonably high also in other tumors, where there's a bit more variable expression that is breast cancer, melanoma and non-small cell lung cancer. Omburtamab is a B7-H3 targeting new line monoclonal IgG antibody that may be combined with either 131-iodine or 177-lutetium to deliver radioimmunotherapy. The products, the lutetium DTPA Omburtamab binds selectively to B7-H3 expressed on tumor cell surface and delivers a targeted radiation dose on sensitive tumor cells. And lutetium-177 is ideal for delivering this tumor targeting radiation to small volumes, including minimal residual disease for surgery, micrometastatic disease and tumor cell [indiscernible] as well as reducing the risk of normal tissue toxicity. Next slide. So we have 2 ongoing studies currently in Phase I to study the effect of Lutetium Omburtamab in some of these tumor groups. And the first is a 301 study medulloblastoma, which has just recruited its first patient. And the second study is a 302 study, which is for patients with CNS or leptomeningeal metastases from B7-H3 expressing tumors, namely breast cancer and melanoma and non-small cell lung cancer. And this study is expected to enroll its first patient imminently, probably in the first quarter of next year. Next slide. This is just a little bit more detail on the design of the Phase I/II studies for the 301 study. And as you can see, the primary objective of the Phase I, which is the dose escalation phase is to explore the tolerability of up to 2 cycles of intracerebroventricular Lutetium Omburtamab in pediatric and adolescent patients with recurrent or refractory medulloblastoma. The maximum tolerated dose handled or recommended Phase II dose for part will be determined. And for the Phase II part, this will be an open-label, parallel group multicenter randomized controlled trial, which we hope will be a pivotal study, and we will randomize patients between those who will receive Lutetium Omburtamab and those with no treatment. The primary point will be progression for survival with secondary endpoints of overall response rates and duration response overall survival and safety. Efficacy evaluation incorporated into criteria. So that's with central review and verification after 4 weeks. And in case of progression after randomization, patients will be allowed to receive additional treatment, including Lutetium Omburtamab in the control arm. Next slide. The 302 study is also a Phase I/II open-label safety and efficacy trial in adult patients with leptomeningeal metastases from solid tumors. Now if you're aware of the limited expression of B7-H3 on normal brain tissue, combined with a broad expression on a wide range of solid tumors makes B7-H3 an ideal target for antibody therapy of leptomeningeal metastases in various types of solid tumors. And leptomeningeal metastases maybe diagnosed in as much as 10% of patients with metastatic cancer and can occur with virtually all malignant tumors. This particular study includes patients above 18 years of age with primary level of breast cancer, non-small cell lung cancer or malignant tumor, which are amongst the most common causes of leptomeningeal metastases. The Phase I will be a dose escalation phase. The patients will receive a maximum 5 lots of 5-week cycles of treatment with intracerebroventricular Lutetium Omburtamab. And the Phase II part contribute a cohort expansion phase in which patients will receive treatment with lutetium omburtamab at the [indiscernible] Phase II dose. Treatment will continue until confirmed leptomeningeal progression, unacceptable toxicity or death, whichever comes first. And key exclusions are progressive systemic extra leptomeningeal disease, and where small-diameter or the metastatic tissue is more than half a centimeter. Next slide. Finally a short update on nivatrotamab, our GD2 bispecific antibody. Next slide. So our clinical program consists of 2 studies at the moment, the ongoing MSK study 18-034, in patients with relapsed/refractory neuroblastoma and osteosarcoma. And the Y-mAbs 402 study in small cell lung cancer, which, as we know, is a cancer with a high doses of GD2 expression, studies indicating in excess of 90%. Next slide. This slide gives a bit of disease context. There are about, as you can see here, about 30,000 new cases of small cell lung cancer every year in the U.S. and roughly 1/3 of them are classified as limited stage disease and the remaining 2/3 of extensive stage disease. And the most patients receive chemotherapy first, second or third line for the prognosis and outcomes. As you can see here, in small cell lungs vary for 5-year survival between 5% to 10%, median survivals within 9 to 10 months for extensive stage disease. So there aren't really that many options for these patients. And in fact, many of these patients are frail and choose alternative treatments instead. These are 6 patients with low-performance status, who do not do well and therefore, there is a higher net need for effective treatments. Next slide. So we hope nivatrotamab could be one of them. This is our 402 study, which opened recruitment this year, quarter 3 2021 and has a number of U.S. sites involved, as listed here. It is a Phase I study followed by a dose expansion phase. The patient population for the Phase 1 will consist of primary metastatic Stage IV or relapsed patients with small cell lung cancer regardless of platinum sensitivity. Patients will be eligible after failing the first-line platinum-containing treatment or after progressing on both second- and third-line treatments. And in the Phase II part, it's the same patient population, but the patients will be stratified into 2 groups, based on whether they are platinum sensitive or resistant disease. Now unlike the 18-034 study, the dose here will be every 2 weeks, not monthly. The route of administration will be subcutaneous, not IV, because subcutaneous dose is known to reduce cytokine release syndrome with markedly slower onboarding from the Cmax estimated between day 2 and 5. And we're also giving premedication steroids. And regarding the dosing schedule, you'll see that the cycle length is every 2 weeks. And on cycle 1, they have that dose on day 1 and day 8 and in cycles 2 to 13, they have dosed on day 1 only. And the primary and second points are as listed on the slide here. So we're very happy that the study started recruiting, and we're looking forward to getting more patients on this trial and updating you on the results when they are available. Next slide. So I'll stop here. And thank you for listening. Happy to take any questions. Thank you.

[Operator Instructions] So our next question will come from Tessa Romero from JPMorgan. She's joining. So Tim, can you go to the written question while she's joining?

Sure. We have one written question at the time. Any updates when the neuroblastoma vaccine will be available in Europe?

Well, we are working on initiating the study next year. So we're working through developing a validated IP product. So we are also in discussion with corporate groups as well to see how we can make this a collaborative study. So we aim to -- once all this be resolved, we aim to start the study as early as the end of next year. This will be a multinational study, including the U.S., Europe and potentially other centers as well. This will be a truly multinational multicenter study. Our goal is to accelerate access to the vaccine as quickly as possible. Clearly, there is a huge demand from patients and patients and families for this product alone, more than any other products we have, not surprisingly. But we're also looking at how we can incorporate the GD2 and GD3 vaccine in potentially other studies as well, potentially involving studies where we have naxitamab ongoing as well. So further details to follow.

Sarah, back to you.

Great. Our next question will come from Tessa Romero from JPMorgan.

Specifically on the frontline setting, you have talked about an additional arm being considered to assess the new infusion schedule that Dr. Mora presented earlier in the presentation. My first question is how important could a more favorable safety profile be in the frontline setting, say, versus Unituxin? And my second question is, you've talked about the MSK Phase II study in the frontline being ongoing. What is the latest on where and when those results could be presented? And as I think we had thought we might see those results today.

Okay. The first half relating to the benefit, if I understood your question. I think this will potentially have a significant benefit from a safety point of view. As you mentioned, as was mentioned by our previous speakers, one of the limiting steps in accelerating the development of DANYELZA in adult indications, has been the potential tolerability issues relating to higher dose and in the adult setting well. We do have limited data available. So I think we are excited to actually validate what we have seen with Dr. Mora's center by incorporating patients in our 202 frontline study even if we have a cohort of 10, 15 patients, in addition to potentially the nonosteosarcoma study, we are ensuring that the patients can be included with that new schedule, as well as, of course, looking further to detail into compassionate program that's already been used by Dr. Mora. We'll take all of these into account as we design our studies in metastatic breast cancer, melanoma and soft-tissue sarcomas. So yes, I think these are the key factors that are taken into account in also designing these studies. And in terms of second question, were you relating to osteosarcoma study? The 202 study? The question related to that was…

[indiscernible].

We hope to see that next year, there's the review of the data being looked at, at the moment. We're working with MSK or looking into potential publication next year. I don't have any defined dates yet, but they're working on doing that sometime next year.

Our next question comes from Sebastiaan van der Schoot from Kempen.

Yes, 2 questions for me. The first one is regarding the frontline study in the naxitamab in neuroblastoma and then the multicenter study. Is that study necessary for later approval? And when do you expect that we can see the full data? Can you remind us on how that study will be and how many patients will be enrolled? And then the second question is on Osteosarcoma. Can you remind us of the EPS that you have shown earlier this year?

The line is not clear. So maybe you can ask it…

Yes, your line is very unclear. I'm barely able to hear the question. Maybe you can type it in or…

Can you her me now?

Yes.

So my first question was on the osteosarcoma study. Can you remind us of the interim data that you have briefly shown and what the EPS rate was there? And then the second question is on naxitamab in neuroblastoma. Can you remind us of how the 202 trial is designed and when we can expect the first data?

Okay. So the osteosarcoma, the MSK, there hasn't been a planned interim analysis. So there, they may have seen previously related to safety as well as the design of the study. We don't have any latest data in terms of survival or response at the moment. We hope to share that once accrual is completed. So we don't have any more data to share on that study at the moment. Regarding the 202 study, we have initiated that trial. The recruitments will be open now, ongoing. The design of this is for patients to receive a single arm study, a multicenter study, enroll in the U.S. and European sites. These are patients who are receiving irinotecan/temozolomide, patients who are in maintenance treatment in frontline, single arm only. And we anticipate the data to come on the patients or the patient sample size and the recruitment, we anticipate to be completed probably 2023. Again, this is to be determined.

I'll now turn it back over to Tim to read the written questions.

We do not have a question at this time.

Great. Back to you, Claus, for the next presentation.

Yes. So our next presentation will be from our Chief Scientific Officer, Dr. Steen Lisby. And we are looking very much forward to hear your presentation on the update on the SADA Tech.

Thank you, Claus. So I will give you a short update on the SADA Technology Platform today, where we are and how we envision it going forward. Next slide, please. So the SADA Technology Platform likely represent a highly versatile and pre-targeting approach to -- with radio activity to treat cancer. It has the potential to be adapted to target a wide variety of tumor markets. And also, it can be adapted to deliver an area of different isotopes for imaging as well as therapy. Already now, we do have nonclinical data in both beta and alpha emitters as well as for imaging purposes. We believe this platform to be safe and effective and a potential to target tumors with a high precision. And due to the 2-step approach, it has a potential for a much higher therapeutic index as compared to radio antibody controls. Also, this technology be used for theranostic purposes. And already now, we have data, monthly data demonstrating that tumor can be improved by PET scanning using an interim based approach as well as specificity expansion, which I will come back to later. Next slide, please. So with SADA molecule designed using 2 single [indiscernible]. You can see in the box at left. The first couple of fragments targeted to, which is the [indiscernible]. The second one is the anti-dose, where we can add the payload [indiscernible] of the SADA molecule. This is a [indiscernible] peptide. If you look at the bottom left, a higher concentration peptide results in SADA molecules [indiscernible], which results in a very strong tumor binding capacity. And at lower concentration, that's an [indiscernible] concentration, the SADA molecule is a sample and the molecule goes into monomer state from 60 to 70 [indiscernible] that gradually can be cleared from assimilation. And at the bottom of the slide, you will see [indiscernible] photometry analysis, where we had a higher concentration [indiscernible] have the majority of the molecule into the next stage. And on the right side, you can see the lower concentration of the vast majority of the SADA in the monomer state, which is first of [indiscernible]. It's important to stress that this is a 2-step targeting radio monotherapy. So in the first stage, we [indiscernible] pre-target SADA molecules. This is COVID protein. So we do not anticipate major side effects related to that and no off-target radio activity as it is COVID molecule. Step 2, the next slide, please. We come with a payload at the time where the majority of the free SADA is cleared from the circulation. And the payload is complex to the molecule that only combines to the SADA molecules as depicted in the green at the upper right of the slide. This results in a much lower systemic expression and a higher specific targeting of the radioactive compound to the tumor target as compared to normal IgG approach. Next slide, please. To demonstrate this, where we have looked for the 2-step approach either using an IgG approach using a bispecific antibody with a tumor target as compared to the SADA molecule. As you can see on the left, the conventional antibody and the half-life is roughly between 5 and 7 days and the SADA molecules have been optimized with a half-life of only 8 hours, meaning that when we come with the reactive second payload at 48 hours, the vast majority of the SADA molecules is cleared from the circulation, and this is in contrast to an IgG-based approach. On the right, you see the 2-step IgG-based approach, where we do see tumor targeting using PET imaging on the right side, but also significant of tumor targeting 24 hours after administration of the radioactivity. Next slide, please. And this is what it looks like when we change the IgG-based approach to the SADA approach, where we can see a highly specific and selective uptake of radioactivity in the tumor only. Next slide, please. So this is specificity scanning of the GD2 SADA in the GD2 in vivo module. We have given the protein with 48-hour spacing to 177 lutetium, which is a payload that we move towards the clinical development. And as you can see here, you have highly selective uptake in the tumor only, and these pictures are 24 hours after administration of radioactive compound. We do believe that the SADA molecule is unique and that the determinations have a high importance for this very high and selective uptake. Next slide, please. So we have done some nonclinical testing where we compare the SADA molecule as seen on the left curve, to compare with obligate monomers, so we had the same molecule [indiscernible]. So we do have both in vitro data that support a marked high affinity and cell binding using the SADA molecule as compared to the monomeric version and also, as we can see here on these graphics, a significant enhanced tumor uptake by the SADA molecule, again as compared to the monomeric version of the molecule. So we cannot take any monomer infuse and have the same high uptake on the tumors. So this is really supporting the concept that the domain of the SADA molecule plays an important role. Next slide, please. We also have seen biodistribution, which is one of the main concern of radio monotherapy. And because of this 2-step procedure where we only apply the radioactive compound with the vast majority of the protein is cleared from the circulation, we have a quite unique and very low uptake in normal tissues. We can see here on the curve that the significant signal in the bladder, which is in accordance with urine. And also, we can see very low uptake and fast clearance from other tissues, including the frame, which represent the red marrow and also the heart that represent the [indiscernible]. Next slide. Efficacy models, we're also seeing effect of the SADA molecule when coupled to beta emitter, in this case here, again, 177 lutetium, both in neuroblastoma PDX models, but also as you can see on the right side on small cell lung cancer PDX models. Next slide, please. So we are quite encouraged of this data. And also, there's a lot of possibilities going forward with this platform technology, both the theranostic approaches, as you see on the left, where we have very much imaging, very high precise imaging done by PET scanning using iterative 86 [ covered ] to the delta. And on the right side, we also have each data using an alpha emitter. So [indiscernible], where we have a differentiated linger and have higher efficacy in neuroblastoma PDX model. Next slide, please. This brings us that we want to bring this into clinical testing, and we are quite advanced and the clinical Phase I trial is expected to be conducted both in U.S. and EU, and we are still on-track of submitting the IND in this year. This study will have a theranostic approach in both tumor imaging as well as through predict intent. And you see specificity -- we can actually identify tumor targeting already after the first few patients, verifying that SADA is doing what is supposed to do to the tumor and adding radioactive exposure to tumors. This Phase I study, we have 3 parts. First, we will dose optimize the protein part of this construct and the spacing between the SADA and the payload. The second part, we will dose optimate the payload. And in the first half, we will have a cohort-specific dose expansion both for lung cancer and sarcomas in order to see the safety for repeated dosing. Next slide, please. So the lead program is GD2-SADA. We will have the Phase I clinical development done in patients with GD2-positumors, including small cell lung cancer, sarcomas as well as melanoma. And also, we are considering pediatric development, which will seem relevant for both sarcomas as well as neuroblastoma. Then, as discussed, to submit the IND this year. We have more ongoing nonclinical programs, including for CD 276 under consideration for patients with B7-H3 positive tumors, including castration-resistant prostate cancer as well as non-small cell lung cancer. And also, we have an advanced nonclinical program with a target within hematology. And we do work on more programs, both within the solid and liquid tumor space, including GPA33. It's a colon cancer target, and there was an initial data presented at AACR earlier this year as well as referred to. Last slide, please. So in summary, this technology has the potential to be developed both as a therapeutic and as well as theranostic. It has the potential to target tumors with a high precision and spare normal tissue, in particular the bone and bone marrow as well as the blood. We also think and hope that we can administer a high amount of the payload due to 2-step approach. This platform technology is highly modular. The SADA domain is critical for the tumor binding and the outcome, which has the potential to be adapted to address a wide variety of tumor markets, including within solid tumors as well as hematologic malignancies. It also has the potential to be adapted to deliver a wide area of different isotopes into both alpha and beta emitters and I showed you a nonclinical data for both earlier in this presentation. So we think this platform is very interesting and also it will exceed our therapeutic intent, also has the potential to be used as a theranostic, and we already have shown data by both PET emitter as well as spec emitter in a nonclinical setting and those can be used to identify remaining tumors as well as tumor uptake and/or measure the responses. Thank you.

Thank you, Steen. We will now be conducting our next question-and-answer session. [Operator Instructions] Our first question comes from Joseph Thome from Cowen.

So first one, just in terms of the first SADA study here. I know you outlined the different segments, the Part A, Part B. How are you thinking about disclosing data from the study as this comes in? I know you indicated you can maybe be able to seek target engagement pretty early after administration. Is that something that's meaningful that you would disclose or what would, I guess, represent a good amount of data that you want to disclose from the study? And then second, as we're thinking about potential toxicities, what are sort of the key ones that you will be looking out for? I know you do get rapid clearance from the kidney, but it looked a little bit higher than the other tissues. Is kidney toxin an issue here? Or maybe why not?

So you're correct. Using the theranostic approach, we will be able to seek tumor targeting already in the first few patients. Of course, dosing of the protein as well as the radio activity, we will have increase in signals, but we do expect to see tumor targeting from the first cohorts already. We do plan to submit, as I said, the IND in this year. So we will have mid-end next year some clinical data that we might be able to share with you. Regarding the toxicity, liver toxicity as well as kidney toxicity are the 2 main focus areas for us. Having said that, we haven't seen any major signals from the tox programs we have run so far. But definitely, that's something we look forward to follow. And we have mitigated plans in the clinical protocol if adverse event was to occur. We do know that a protein gets cleared from the blood stream in the animal model. So we have a lot of nonhuman nonclinical data. We also do know that some of the proteins get into the liver as well as the kidney. But when we come in the payload, at least in the animal models, we do not see any significant uptick there. But you're right, the delivery and the kidney would be 2 major organs that we are taking care of in the clinical program.

Our next question comes from Alec Stranahan from Bank of America.

Just one question for you guys on sort of how you prioritize assets with SADA pipeline. You have the GPA33 data as well. If you were to see early ins of activity with the GD2, would you accelerate things on your own? Or is the plan really to partner beyond that just to help reduce the strain on the pipeline?

Yes. I think we have said before that it is clearly one of our objectives to find partners to work with. Not necessarily just one partner, but a number of partners, even partners that may come to us with their own cancer targets, where they would like to know us constructing with our SADA tech, a SADA construct targeting that particular target. And in terms of your question on the priority of the targets that we're working on, obviously, when we took all these programs from MIC and from MSK, the most advanced one was the GD2 SADA, which is the first one to enter clinical development. But giving priorities for a number of reasons, we ended up giving the B7-H3 a high priority, and I can also see other people are seeing increased interest in the targeting of B7-H3 antibodies, even with toxin conjugate. So I think we have picked a good one as the next solid tumoral target. And then we also, based on -- a lot of us having had long past in another company called -- work with hematological targets has decided to move forward a couple of some very interesting hematological targets addressing -- significant unmet medical needs. We haven't disclosed the targets yet. But again, also in terms of how quickly we can do this, there's a limit to how many programs that we can push forward at the same time and also get CGMP manufacturing slots available for. And that's really some of the limiting steps that's in this, I suppose, being able to run more than 3 programs at the same time as probably to the DX. We can do that in the early clinical research development, but putting them to a formalized preclinical development with [indiscernible] programs and CGMP manufacturing. We have a GD2 SADA and we have 2 more that we are pushing and hopefully get ready for clinical development and IND filing within the next 12 to 14 months. So -- but that again underlines why we are so interested in finding partners we can work with that have the additional resources and strengths to be able to push even more of these programs fast, because they can really be the game changers of how we treat cancer in the future with these highly selective treatments and without having the normal side effects of both radiation and chemotherapy. So it is extremely exciting. And with that, I think I give time to respond to other questions.

We also have one written question here. From my pulp from Mike Ulz from Morgan Stanley. Considering you have tested both beta and alpha emitters in the preclinical setting, do you have a preference for one or the other? And for the GD2 SADA you are taking to the clinic, are you using the beta emitter?

So the most advanced payload is beta emitter. So one 177 lutetium data would be the payload we use for the SADA program. We have initial also some research data on the alpha emitter to Lutetium. I showed you one graphics with the tumor responses, but the most advanced is the beta emitter that we will be using for the first program, but we are working very hard on also having the possibility to add in an alpha emitter as a payload. And the good part with the SADA construct is that you can actually accommodate both alpha emitter and beta emitter as well as imaging agents in that platform technology, which we are working on.

That's it for the questions for this session. Claus?

Thank you. And then let me finish off by giving a more general company update here on our R&D Day, December 2021. So go to the next slide, please. It's our big prior disclaimer. I'm sure you're all familiar with it. So let's take the next one. And here, I want to emphasize that although we are starting a number of clinical development in the adult setting also, Y-mAbs mission and commitment is to become the world leader in developing better and safer antibody-based oncology products, addressing clear unmet pediatric, and then we have added and adult medical needs. But we have a very strong DNA towards getting new pediatric oncology programs to help mitigate. There is a number of unmet medical needs in the pediatric oncology setting. And that's clearly one of our priorities to make sure that we continue to be truthful to that original DNA backbone of the company. But it also underlines, as I just mentioned before, also our need for the adult indication that is potential for some of our products to find partners, where we can develop these in collaboration for those constructs. So going to the next slide. So you can see we have a very diversified platform. We have 2 technology platforms, the Y-BiClone platform and the SADA platform. We have the DANYELZA and in combination with the GD2-GD3 vaccine, a very nice and strong program targeting the -- potentially also teenagers and young adults with osteosarcomas. We have our omburtamab platform, and I will get back to where we are on the resubmission of the BLA to the omburtamab. And as Vignesh also went through with the omburtamab, we are not only developing it with the [indiscernible], but we also have the lutetium construct with medulloblastoma and for the B7-H3 tumors in the adults. And then our BiClone platform that we are still very excited about where we have our 2 bispecifics that are in the clinic, the GD2 targeting bispecific and that Vignesh also gave you an update on the status of both small cell lung cancer study. And then our most recent bispecific, where we have filed the IND, our CD33 for tumor leukemia in pediatrics. And I've been very, very grateful to see how positive this asset has been received by the hematology clinics under the COG. Very quickly, we had 17 sites joining us to participate in our CD33/CD3 study, and we start opening clinics most likely during first quarter of 2022 and look forward to start testing our second bispecific in patients also. And so that takes us to the SADA platform. I think Steen made a fantastic overview, but that's our fourth core of this overview of our company. So go to the next slide. Here, you can see the overview of our clinical studies and status for our lead candidate, the DANYELZA. Vignesh also gave you an update on the clinical trials for that. We have also just summarized the Iodine-131 omburtamab. We are planning to resubmit the BLA in the first quarter of 2022. And as I said, I'll get back to that shortly. There was also questions about our vaccine program. And as Vignesh explained, we are planning to start 2 studies in the vaccine program setting, both in first complete remission patients with neuroblastoma, but also in those that are second remission or eventually later, where most of the data has been generated today. And as Vignesh also alluded to, we are planning to do this in collaboration with the organizations that are both -- and are expressing significant interest in working with us on these 2 -- this program with the vaccine. And the 2 bispecific programs I just mentioned, we're very excited about these to see them going forward. And the other early stage, we have just been going through with Vignesh and Steen. So that'll take you to the next slide. And then the regulatory path to U.S. approval. I mean, we have had a series of meetings with the FDA, and we have filed and submitted the pre-BLA meeting target. So we have a pre-BLA meeting coming up shortly in January. And after that meeting, we expect to get a green light and hope and cross our fingers and all the things we can do. We have had a very detailed dialogue with the FDA with several meetings and interactions with the agency since we got refused to file our first BLA filing. And I think we have put together a very strong package that should satisfy the concerns the FDA raised at the refused file and that they have also raised during our discussions. So we, of course, have a Skype meeting prior to the request for the pre-BLA meeting during which we presented to the agency what we plan to be able to include in a pre-BLA meeting package. And they signed off and said that would be sufficient, so we could go ahead and request the pre-BLA meeting. And they have now granted us a pre-BLA meeting taking place in January. If that goes positive, which we, of course, hope and expect, then we should be able to complete a new resubmission of the omburtamab BLA in the U.S. in the first quarter of '22, not '21, which is mistakenly said here on the slide. So we're looking very much forward to that, and we are having very high expectations. We'll go to the next slide. I can allude to what's changed. This is what was basically available by the end of last year that overall data from the study 03-133 at MSK is, of course, the same. The Central German Cancer registered data is, of course, also the same. And those are the key historical control data. What we have done since we had the discussion and during discussions with the FDA is that we have, based on the Central German Cancer registered patients created a kind of artificial synthetic control arm to compare to a similarly mass group of patients that will not include all 107 patients from the MSK study. And then we have done 4 different analysis, comparing these to show the survival potential benefit in that. So that's the part of the package, and those data will -- after we have submitted the package and gone it with FDA, we present it at a suitable event. In terms of the Study 101, which is a supportive study, we, in that study, originally had agreed with the FDA to include a total of 32 patients, and that's what it was supposed to be our post-marketing commitment to control with tumor response data and overall survival, progression-free survival data from that study for the 32 patients. Now we are, because of their additional time that has gone by in a situation where with the filing package for the resubmission, we have all 32 patients in the study. We have more than 2 years of overall survival follow-up from the first patient entering the study. Of those 32 patients, and again, this was a part of the FDA primary concern when we filed that they didn't see any direct antitumor effect. The data you're seeing here was from the first batch of patients where we presented that, radiographically evaluated. We had 2 and 2 partial responses and 5 patients with same disease. Now we have a set of 16 patients in the 10 patients where we have been able to evaluate tumor responses. And those data will also be presented later on. But I can just say that I'm seeing nothing in the data that would kind of disqualify the positive impressions we got from the first analysis. So we are very comfortable with the data that we are using. And of course, on the safety side, nothing seems to have changed. So next slide. So let me finalize this short company overview with the financial summary. Next slide. So by the end of third quarter, the company had about $215 million in cash and cash equivalents. And we have previously said that we expected or market expects us to have between $180 million and $190 million in cash by the end of this year, and I see no reason why that would not still be the case. And since we are only 2 weeks from the end of the year, I'm probably pretty right. So having said that, we are in a financially very strong position. We have one product in the market. And although we all would have wished that it was penetrating market even faster than has done. I think we initially for the first 2 quarters saw significantly better sales than anyone at all, then it was flat in the third quarter. But I think there's no doubt in my mind that any DANYELZA will be a very important product and will take a very significant share of the neuroblastoma market as we continue to work with clinical trials, work with our collaboration partners in the pediatric oncology environment. So we are very comfortable. We are in a strong cash position, and we have a lot of exciting stuff coming towards us in 2022. Thank you very much.

Thanks, Claus. We'll now be conducting our final question-and-answer Session. [Operator Instructions] Our first question comes from Arlinda Lee from Canaccord.

I had maybe a follow-up on omburtamab and then on maybe the broader picture as well. On omburtamab, can you provide an update of what the evaluable response rate might be looking like? And then maybe more broadly, with your multiple platforms and interest in potential biz dev, I was wondering how you're thinking about target and what you might think about for yourselves going forward or collaborative projects or just full out licensure of certain targets or how you're kind -- how should we be thinking about these things?

Yes. Well, I mean, I alluded to that we have evaluated all 16 available patients out of the 32, that's in the 101 study, but we have not disclosed the data. But as I also said, we are not discouraged with the continued support of direct antitumor effect and response rates, i.e., it's not come down from what we have seen. And so there's no -- none of the initial responders that have disappeared. So -- but we will be presenting the data when we are also presenting other data from the BLA package after we have agreed with the FDA that we can file and have accepted the file. In terms of which programs that we may decide to pursue ourselves, again, as I said, we have a very strong commitment to pediatric oncology. And obviously, although we are starting the GD2 SADA in adult indications, there's also a need for this to get into pediatric oncology and neuroblastoma -setting potentially also in the osteosarcoma setting and other GD2 pediatric indications. And for our next one, the B7-H3, that would definitely also be indications in the pediatric setting that we would like to pursue ourselves. But going into non-small cell lung cancer full-fledge development in parallel with castration-resistant prostate cancer, which is also a huge indication and while also developing pediatric indication. That's clearly places where we would need collaboration partners for that. And the same for the hematology indications that our SADA is targeting, hematology is addressing. And again, also for the SADA in gastric and breast cancer would obviously also be nice to have a big pharma partnership in place before we get to find into development of those constructs.

I'll now turn it over to Tim for any questions that may have come over the webcast.

Yes, we have one from the webcast. Again, as a follow-up from Mike Ulz with Morgan Stanley. The initial GD2 SADA, given the broad potential, can you talk about the indications you're considering? And is there new plans to prioritize at this point?

So as I alluded to, we are mentioning 3 separate indications, small cell lung cancer, we have a significant unmet medical need. In Europe, second line; in U.S., more third line. Sarcomas, there's a huge unmet need also in murine sarcoma as well as soft-tissue sarcoma. Osteosarcoma is less radio sensitive but high GD2 expression. So those patients will be included and as well as the melanoma. I think the unmet medical need in small cell lung cancer volumes have really -- look at this population, in particular, if we can have it in the patient refractory population. But data will show, and this is a good part that we have experienced for those indications during the Phase I of the study, and we have expansion cohorts in the large part, Phase I. So we will know there what would be the most appropriate indication to pursue based on data.

Thank you. At this time, I'll turn it back to Claus for closing remarks.

Well, thank you very much, everybody, for participating today and listening to this R&D update from Y-mAbs. It's really been a pleasure and -- as always, to have a chance to chat and also we see good questions from the audience. So I hope you also enjoyed it. And in particular, special thanks to our external presenters, Dr. Mora and Dr. Oesterheld. So enjoy the rest of your day. Thank you very much.