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

Welcome, everybody, to the 2022 Y-mAbs R&D Day. We will have the presentations by management over the next 1.5 hours, and we're very excited to share their plans. Please note the disclaimer here and forward-looking statements, and you can read them and check the website and the SEC filings. At this point, I'd like to invite Thomas Gad, Founder, Interim CEO, Head of Business Development and Strategy and overall inspirational guy [ to move into the slides ].

Thanks, [ Sanjay ]. Thanks. Good morning, everyone, and thank you for being here today and spending time with Y-mAbs. We are in an exciting period of time, a little bit overshadowed by our ODAC vote, but we will manage through that as well. So I'll start with a short update, company update. Then we'll hear from Steen Lisby, our Chief Scientific Officer, who will focus on our exciting SADA development. And after that, we will hear from Vignesh, who will -- our Chief Medical Officer, who will focus on mainly DANYELZA. So just to address omburtamab, which I think it was obviously a big disappointment for the company. But after having the ODAC meeting, October 28, I don't think anyone was surprised to receiving a CRL Letter. So the next steps that the company is doing is we are, as we speak, preparing a response book for a Type A meeting. We plan to submit that in next week or end this week actually in order to have a turnaround time of 30 days. So we will have a Type A meeting mid late January. And I think we will explore what else can be done. I think the company is in a position where we have done everything you can do in this indication, but we will update everyone about the outcome of that Type A meeting and what will happen with omburtamab program after that meeting. So unfortunately, we can't share any more insights on omburtamab at this point in time. Y-mAbs is – we're refining our focus and we are continuing to develop the DANYELZA franchise. And we have a single-center study at MSKCC that has fully recruited, which we're waiting for that study to read out in frontline high-risk neuroblastoma. And we also have a second-line recurrent pulmonary disease only osteosarcoma trial that is almost fully recruited at MSKCC. And we are also anticipating that eventually to read out as a second indication from neuroblastoma. We have this year, as you saw, we got an approval in China. We got an approval in Israel with Takeda, and we filed a BLA in Brazil with Adium or also Tecnofarma. And so I think we are really looking at expanding DANYELZA's international footprint quite nicely. We got a $15 million milestone triggered at the China approval. And they have a dedicated sales team of 15 people and we're going into 40-plus hospitals next year. So we're very excited about that launch as well. And then we have made tremendous advancements on our SADA tech platform that we licensed in only in April 2020. And it is obviously a completely novel radiopharmaceutical tech platform. It's highly differentiated to any other radiopharmaceuticals out there at this point in time. So we are very excited to give you an update today on that platform as well. Finally, we had $115 million in cash on hand in -- at our third quarter. I think it's important to mention that omburtamab revenues and PRV was never part of the company's guidance. I understand when we didn't get an approval, we lost the opportunity for monetization of a PRV, which would have brought in non-diluted capital around maybe $60 million to the company. But our task is to turn around, make it an opportunity and manage through that. And I think we are comfortable being conservative and extending our cash runway into 2025, but we'll come back to that a bit later. So just to quickly refresh ourselves about the opportunity of DANYELZA that has been -- it was approved in November 2021 -- no, November 2020, launched in February 2021. And today, we guided $45 million to $50 million U.S. national sales. I think we are quite excited about -- we kind of relaunched a product in 2022. Sue Smith, who was hired in, in January, implemented a fair amount of new strategies, and I think we are seeing them translating into more prescribers. And so this is a slide to show you what we really can do with the product. Just to address the adult indications, we will address those through [ ISSS ]. We will not spend budget on these indications ourselves. We will do it through ISSS proof-of-concept and then that should lead to partnerships. But we are not throwing budget at these larger indications. So we are going for neuroblastoma second-line. We are hoping, we are waiting to see how the frontline MSK study reads out and the osteosarcoma second-line study at MSK reads out. We're well underway with our ex U.S. sales, expanding that footprint. And then we are looking at ISSS to create proof-of-concept for the larger indications. So this slide, I guess, [ I mean happened ]. So just an update on what really Q3, I think was quite an important quarter for DANYELZA. I mean those -- we are heavily focused on some key accounts, and we have identified 63 key accounts, and they stand for more than 75% of the overall GD2 market. So that's what we are addressing. We are seeing some very nice trends out of the third quarter. We are seeing sites that are treating 2 or more patients growing outside of MSK. 7 out of the 11 new patients were started at large academic centers. It's a very nice trend as well. And the percentage of patients actually receiving 5 cycles or more is also increasing. So that tells you we are coming more down towards our label instead of being used in third-line, and you obviously don't want your drug to be used in third-line because you have efficacy dilution and less duration of cycles. So a very good trend. I think it was the first time we'd actually took market share, which we used to expand the market. And this time, we actually took 12% of the overall GD2 market in the U.S. So that's a very positive trend as well. And I just spoke about China, but I just had another bullet on it here. We are very excited about that launch next year. And we haven't disclosed the economics of that partnership, but it's a very healthy partnership and pricing is healthy, and it's a -- we see it as a significant opportunity for the company. SADA, SADA, we have invested a significant amount of money into CMC and derisk that platform over the last 2 years. We've shown some very nice data, where we can target tumors with high payload exposures without exceeding acceptable normal tissue uptake. I think the AACR poster was very, very nice, where we showed that why we need a tetramer versus a monomer. I'll let Steen talk more about that, but it just was very superior in all the different areas you look at tumor uptake, avidity, time on target and the anti-tumor responses seen in the animal models. So very exciting. And the SADA platform is -- the nice thing about that, it's potentially we can derisk that platform very early on because of imaging data. I'll let Steen talk more about that. But it's -- these programs, you infuse the protein, you infuse an imaging dose, you see if the protein lights up, but then only then you move the patient over to a therapeutic dose. So early on, you can derisk your programs and validate the mechanism of action. First site, I'm already behind here. First site was opened. I think actually the second site was opened. So we are running fast. We are planning a total of 4 to 6 sites in Q1, and then we're adding more sites later this year. What we are hoping to do is validate this program early on in order to that will lead to -- what we want to do with the platform is third-party target optimization failed Phase III assays and then also looking at our larger indication assays to license those out and keep the pediatric indications for ourselves to build up a rare pediatric disease portfolio. So that's the overall strategy with SADA. So depending on what happens with the FDA, I think the company, we are very well focused and we know exactly where to focus and throw budget. And this is just a summary of what happened this year. And I can't really tell you what more is going to happen until we have more clarity from the FDA about omburtamab. But omburtamab was really the Priority Review Voucher initially, monetization of that, and that is not happening anytime soon. So we'll see what happens with these programs. And if we get a clear pathway with the FDA and if not, we'll manage that as well. So if we look at the company and what is Y-mAbs, I try to kind of make this focus of what will generate value, where will the revenue come from? And eventually, SADA will or should overtake everything in terms of partnerships, revenue and royalties. Initially, we are working down in this circle. We're adding our ex U.S. partners. We are looking at ISSS to see if we can get proof-of-concept to move DANYELZA into larger indications, but that would be a completely new dose studies because you would need to dose it differently than you do it today, you need to dose day 1 or day 8 or day 1 or day 16. So we'll do that with partners instead of spending money on that and then we get into SADA. So that's where we are today. And overall, omburtamab have overshadowed a little bit of what's going on in the company, but I think we are comfortable in moving this forward and excited about doing it. And with that, I'll give the word to Steen.

Thank you. Thank you, Thomas. My name is Steen Lisby, I'm the Chief Scientific Officer here at Y-mAbs. Today, I will share with you where we are with our pipeline, in particular, with the SADA programs. And today also, I will reveal the second SADA program that we'll be working with and we are going public with today. It's very important to understand why SADA is unique. And I think I'll step [ one ] to go one step back and repeat something that was actually disclosed a year ago. But it's very important for you to understand this is a unique platform. So the aim with SADA is to develop what you call a 2-step radioimmunotherapy platform. And also to develop a platform that could be used for targets, more targets as well as more payloads. It's very important for us to have a platform that differentiate from what's out there. And due to the molecular structure, we have the probability for this molecule to disassemble and also allow for PK optimization that allows for a subsequent payload. So this is ideal for a 2-step procedure. What we've seen so far is that in the nonclinical research that most SADA protein actually can be removed from the circulation and normal tissue before we come with the radioactive payload. And this results in a much less normal tissue exposure and better safety profile in nonclinical assays. So this is really a benefit risk. It's an upside for the SADA that you don't have the payload circulating attached to protein. And what we've seen so far is a very high tumor to tissue [ radio ], both compared to blood but also tissues including the bone marrow. And the 2-step approach potential will allow also the protein administration to be separated from the handling of the radioactive payload, which is good not only for the research setting, but also later for a potential commercial setting. So this is how the molecule looks like. It consists of 3 segments. The first segment is a tumor-targeting segment. It's derived from a normal IgG-based antibody where we take the scFv parts of it and link it to DOTA binding sequences. And why we're using DOTA binding sequences, this is because we use DOTA as a key [ loader ] for the payload. This means that when we come with a payload later on, the only place the payload can bind into humans, that is actually on the segment here of the SADA molecule, it means that all it binds to the SADA molecule or it will be removed from the circulation immediately. And lastly, the third part is unique for the SADA is a SADA molecule part. It is a domain from the TP53 molecule that has what we call a tetramerization peptide. And this means that at higher concentrations, it will actually form a tetrameric structure around 260 kilodalton, but at lower concentrations, it will automatically and predictably disassemble. All of this we have discussed before, but that is the basis for this platform. So the first step is a cold step, meaning that when we give the protein, it is in circulation, there is no radioactive payload attached. And first, when the -- after the binding and removal of the protein from the circulation, we add the hot radioactive payload. And this, according to our nonclinical data, will give much less non-specific binding. This is how it looks like in animal models. We've shown this before also and as we published in 2020. If we compare, let me see here, if you compare with a normal IgG-based antibody with 6 days to 8 days half-life with a PK optimized SADA protein with roughly 8 hours to 10 hours half-life, you can see that if -- when we come with the administration of secondary payload like for the 8 hours after, the vast majority is removed from circulation. Here on the left, we see a 2-step procedure with a IgG-based approach and the IgG circulates longer and it's not cleared when we add the payload and you see huge unsignificant -- unspecific binding. And here to the right, you see what happens if you use a 2-step SADA approach. All the circulating non-bound SADA have been cleared from circulation when we come with radioactive payload, and we have a very specific and intense uptake in the tumor only. This is why we are so excited by this platform, and this is why we are moving this towards clinic [ reversion ]. What we have been able to do in at Y-mAbs, even though we are a small company, is to have a really good interaction between our CMC Group and our nonclinical development. So we very early on can get material and start the nonclinical development. This means that even though we don't even have the master cell bank established at this time point, we can start as a development, we can start pharmacology, we can start to touch pure lead programs. This allows Y-mAbs actually from a lead to have a regulatory submission package that we do this within 2 years. And I think this is a huge advantage for us that we can turn around new molecules at speed when you have the lead candidate selected. This is what we've been working with the last 2.5 years, as Thomas was alluding to, we got the license from MSK in April 2020. We have early on looked for several targets in the earlier assessment. And here today, I will present you the second SADA molecule that going into clinic, hopefully, in next year. This is a CD38 targeting SADA molecule. The first SADA molecule we developed was the GD2-SADA. This has been -- that's been not clinical presentation, and as Thomas was alluding to, we also presented here at AACR earlier this year, where we really showed the importance of the tumor sharing as compared to only a BiTE on monomeric version. We have the lead candidate selected. We have submitted a full IND package that has been approved by the FDA, and we have an [ open IND ], and I'll come back to where we are with the clinical sites just after these slides here. The second SADA actually is a fast follower. We have been working with this now for more than almost 2 years for now. We have the lead candidate selected. We are in the process of finalizing IND regulatory submission package with a goal that we can have the data ready for Q1 next year and submission first half of next year. On top of that, we work on other molecules in the early assessment, including the B7H3-SADA, but also targets like GPA33, which is the colorectal cancer target and HER2, of course, breast cancer and gastric cancer targets, we are looking actively at the early part of the development. So GD2-SADA, the first SADA that Y-mAbs has produced and the first SADA that is entering clinic. The first study is called 1001 and it's open for enrollment. What is GD2? We have talked about before also with DANYELZA. It's a sugar molecule. It's a carbohydrate antigen. It's a valid target that have been approved by the FDA for IgG-based antibodies. We know that there's limited tissue expression by GD2, but there is expression of peripheral neurons and also on pain fibers. And we are looking into that as a part of the early development. And also we'll try to see whether we find and luckily enough, we see very little binding with the GD2 SADA to those structures. We know this molecule is highly expressed in neuroendocrine tumors, including neuroblastoma, but also in sarcomas, melanoma and small cell lung cancer. So in adult indications that are the target for the first clinical trial for the SADA according to the FDA guidelines. And the development we start with, of course, will be in the relapsed/refractory setting in a Phase I controlled setting. So the status is that we have a fully developed CMC package and an approved IND CMC package. We have also fully FDA nonclinical IND package and have had a discussion with them for approval of our first-in-human Phase I protocol. Here again, first site was opened yesterday, actually site #2 was opened, and the trial is listed on ClinicalTrials.gov. This is just a few data here showing the nonclinical efficacy, not only in neuroblastoma patient-derived xenograft models, but also in small cell lung cancer data. This is what it looks like in time course. This is a biodistribution study we did with tumor-bearing mice. What we see very early on is that there is few hours after it, still something in the liver, we can see the -- vastly around in the body, and then we have a quite high intensity in the tumor and in this case, here also in the bladder. But we can see very quickly already 24 hours after and 48 hours and even 5 days after, we have specific and only uptake in the tumor, and it stays on up to 5 days, which was the longest time when we spotted the study. It meaning that the normal tissue exposure, even though, of course, there will be a normal tissue exposure as we injected in the bloodstream, it's very brief. We've also seen that on the biodistribution studies here, and this is a non-tumor-bearing animals, the same urine vitals we are using here. We see an eternal spike in the bladder. This is expected. This is the way you excrete your radioactive payload and then very rapidly clear from the bladder. But also very importantly, when we look for other organs, including the liver because many proteins goes to the liver of degradation, it doesn't matter with a 2-step procedure because the protein goes there in internalizing liver cells, but when we come to the radioactive payload, it cannot bind anymore because it's not on the surface. Also if you look for the femur, which represent the red marrow and the heart that represent the bloodstream, there's very, very little exposure, meaning that the unwanted non-target specific binding is very low with this structure here, and we can actually, by doing -- by looking at these data, dose very high at the tumor. And this means that if you look for both red marrow, kidney and liver, 3 of the major organs for antibody, we want to look for, we can easily, with the started design we've done now, dose up high maybe even up to [ 1 clearly ], if we need to do that without exceeding even 5% of the organ toxicity limits, mean that there's a very large window between what we have administered to the patients and the safety tolerability for the normal tissues in the patients. So there are, of course, many questions we want to address in such a first-in-human clinical trial. And what we have discussed with the FDA and agreed to the FDA is that we have a 3-step procedures in the Phase I, exposing roughly 60 patients. In the first part of the study, we will expose the protein dose escalation, but also importantly, the distance in humans between the SADA protein and the payload to be delivered, because we know very well what happens in the nonclinical setting. This is the first time ever we dose humans. As Thomas was alluding to, we have a theranostic approach, meaning that we give an imaging dose of the radioactive payload first. And we use 177 Lutetium-DOTA, and the good part with 177 Lutetium is that you can visualize it by SPECT/CT scanning. So before we dose higher in these patients, we actually have an imaging performed on the patient and in patients where we can see tumor uptake, we are allowed already on the very first patient to give 200 millicurie of therapeutic dose to the patients. It means that we quite quickly can dose escalate and potentially see positive outcome in the patients. And please remember, this is a Phase I study that we are allowed to do this in. In the second part, we dose escalate from the starting radioactive payload up to -- and keeping both the protein, amount of protein and the spacing intact from defined here in Part 1. This we use in Part 2, what we call, Part B, where we dose escalate on the radioactive payload. And also, actually, we were allowed to have repeated dosing as what we call a Part C, where you can see long-term safety as well as outcome, and all of this we can achieve in the very first clinical trial. Where are we with this trial? We plan, as Thomas was alluding to have a limited number of trials open because this is a Phase I scenario. We plan to actually have 6 to 8 clinical trial activated here in the U.S. 2 of them already now are opened is [indiscernible] and also [indiscernible]. Both of them are now active and starting to screen for patients. For now, we have at least 2 patients lined up that we are looking for. And hopefully, we will include those patients early next year. If we're very lucky, we can have the first one included before Christmas, but that's to be hopeful. We have the study lead, it's the University of Pittsburgh, Dr. [indiscernible], who is a lung cancer specialist. Also, we have specialists within the sarcoma field as well as melanoma field. And this leads me to the next SADA because the GD2 SADA is addressing solid tumor platform. We also want to explore the SADA in hematological indications, so in liquid tumors. And to do that, we have developed what we call a new SADA for liquid tumors called CD38-SADA. CD38 is a well-characterized membrane associated target. It's again a valid target. We have monoclonal antibodies developed and approved by the FDA for that target. What we do know about the target is that it's highly expressed in major lymphoma indications, both B-cell and T-cell origin. It's also in plasmacytomas as well as myeloma. We do know this target is -- can internalize. And this, of course, has been part of the selection or deselection early on in the nonclinical development to have the lead candidate selected. This is potentially a new way of addressing CD38 positive tumors. It's addition to the toolbox for the physicians, in particular for the relapsed/refractory setting. What we do know also from other antibodies is, is that CD38 antibodies normally do not cross-track the standard animal species. So in order for us to build our nonclinical package, we actually accessed a commercially available CD38 human transgene mouse. And this we obtained from a commercial breeder. What we have done is that we have validated this mouse model. We have validated it. So we know that the expression both in peripheral blood cells as well as tissue, there was sufficient overlap between what we saw in our model and what we know from the humans. And based on both the normal phenotype and all the relevant tissue binding assays we did perform, this model was considered to be suitable model for assessing both PK toxicity as well as biodistribution for us to go into clinical development in humans. Where are we with this second SADA molecule. We are aiming to finalize the whole nonclinical package early next year. So Q1 next year. We'll submission of the full regulatory package to the FDA in the first half. This is the intent, and we are getting the very large data in now. So if they are not disappointing us, I think this is a time line that we are striving to reach. The protocol which in the future will be called the 1201 clinical protocol is a basket trial. And it will assess safety and also outcome in adult patients in hematological indications known to express the CD38. This would be a stand-alone protocol to establish proof-of-concept in these indications and can be followed then within the each indications that we're seeing positive signals for. This is just some of the data that we have done so far. What we see here is a very, very limited uptake in normal tissues. We will expect in the urine bladder because this is the way you excrete it. And again, as we've seen here, as we saw for the GD2-SADA, we have an initial uptake in the bladder but very quickly this exposure is disappearing. Also this is an non-binding tumor setting. So some of the animals even had it in the bladder fluid. Also we see minor signals only in the kidneys, but again, this is a route where you excrete the protein, so this is expected. This has no major uptake, and this is very positive, not even in the liver and not in the red marrow, which you can see here. So very little uptake in those organs that we think would be the critical organ and dose-limiting. We have done tumor models. We know that it binds a lot of different tumor cell lines, both here in the Burkitt's lymphoma cells but also mantle lymphoma cells. And we have done -- we are seeing dose responses in some of our tumor models here. This is a Burkitt's [ lymphoma cell ], where you can see we can eradicate tumor in the highest doses with only 2 exposures. So to summarize our SADA [indiscernible], we now have one SADA program in the clinical with an open IND. The project is open and the first patient expected to be included, hopefully, just before Christmas or at latest Q1 next year. The second SADA program, we are almost finalizing the nonclinical development. We are on track for Q4 or Q1 '23 regulatory submission to be submitted. And the IND is currently scheduled to be submitted first half next year. On top of this, we're also looking for the framework, can we optimize it further. We are also looking for, can we put other payloads on top of Lutetium. There's a lot of work ongoing for alpha emitters. And this is, I mean, we're not the only one looking for alpha emitters as well. And we do have a special linker called Proteus 1, that is designed better to capture alpha emitters as compared to beta emitters. Also, we are looking for Yttrium as a PET emitter, so we can use both for imaging as well as for therapeutic purposes. So I think that was the status for the SADA program. Thank you. I'll hand over to Vignesh to talk about the clinical DANYELZA.

Thank you, Steen. Good morning, everyone. It's great to see you all. I'm Vignesh Rajah, Chief Medical Officer. It's a pleasure -- it's a real pleasure to be here today to share with you some key updates on specific programs relating to DANYELZA. So this will be a slight change of tack from what Steen's presentation focusing on early-stage development. There's a couple of programs that I'd like to share with you today. Firstly is our pivotal randomized controlled trial in osteosarcoma, which we are very excited about, and I'll share with you a few more slides around the design and the status of the study. And the second study you can see here is an investigator-led study, looking at the use of DANYELZA as part of induction treatment. This is frontline use of DANYELZA in high-risk neuroblastoma patients. So you've seen this kind of slide before. This is just as a background, as you're aware, DANYELZA is a humanized monoclonal antibody targeting the GD2 antigen. It's although this GD2 antigen has limited expression in normal tissues, we know it's over-expressed in a number of cancers as listed here. And this was a rationale for development and ultimately, approval of DANYELZA in high-risk relapsed/refractory neuroblastoma. Equally, as you can see, there's high degree of expression in other cancers of interest, notably here osteosarcoma, which we are going to push on, and we are going to start our randomized Phase III trial, which will hopefully lead to regulatory approval. The other studies in the adult indications, as Thomas alluded to earlier, our strategy right now is to support investigator-sponsored requests for now. But really, if you want to stimulate a clinical development program, we'll be looking -- hopefully looking for partners to collaborate with us in these indications. This includes indications such as soft tissue sarcoma, triple-negative breast cancer as well as melanoma. So why investigate -- why are we interested in osteosarcoma apart from the fact it is highly expressing GD2 antigen. We all know it's an area of high unmet need. And as the slide shows here, roughly about 1,000 patients are diagnosed with osteosarcoma each year in the U.S. alone and similar numbers in Europe and in China. And for over 2 or 3 decades now, there's really been nothing that's made any inroads in terms of improving survival in this tumor beyond chemotherapy. So it's still very much the mainstay of treatment now, just combination chemotherapy, which is shown to be superior in terms of survival compared to surgery alone. So this is pretty much the closest we'll get to standard treatment. Although many institutions, both in U.S. and Europe, there isn't a natural consensus, which combination of chemo is used, but there are some official NCCN guidelines and ESMO guidelines, which do highlight the recommended chemotherapy treatments. Of course, chemotherapy is not a cure. Most of these patients will relapse due to micrometastatic disease. And as you can see on the slide here, the survival is pretty poor. I mean the prognosis is dire in these patients. And this is what's tragic about this tumor despite several promising agents coming into development from all sides of places, nothing has really made much of an impact. So there's a huge unmet need for us to look into this indication. This is a kind of a guideline published in the NCCN guidelines and ESMO guidelines, recommended treatment pathways for treatment of osteosarcoma. So generally, most centers will use a combination of what's called a MAP regimen, which is a combination of methotrexate, doxorubicin, and cisplatin or carboplatin as first-line treatment. This is after surgery and some of these patients may also receive neoadjuvant chemotherapy prior to surgery and then followed by further cycles of chemotherapy. As I mentioned earlier, many of these patients will relapse. The commonest site of relapse is the lungs by far, and then they are eligible for second-line treatment. And here the commonly used chemotherapy regimens are combination of the alkylating agent, ifosfamide and etoposide, that's generally accepted second-line treatment. And as you go further to third-line and subsequent relapses, different lines of chemotherapy are used as shown here. So what are the general outcomes we've seen so far, what evidence have we seen out in terms of disease-free survival. This was a study, independent academic study, AOST0221, which is published in 2015, which are the patients who have relapsed first as a first recurrence in the lungs, and they've had complete resection of the pulmonary lesion from their lungs, and these patients were given inhaled GM-CSF as part of treatment at that stage. And the curves you can see here are typical of what we've seen in this, in osteosarcoma. The blue dotted line shows the event-free survival. And you can see here at 1 year stage, typically, it's around 20% 1-year event-free survival, which is pretty poor. There was also another study recently published. This was a study looked at the role of anti-GD2 immunotherapy. So this study looked at the combination of dinutuximab plus interleukin. Again, looking at those patients who had surgery for their pulmonary lesion [indiscernible] relapsing to the lung, and they look to the disease-free survival or disease control rate as well as overall survival. The difference here is they included all relapses, not just first relapse, but also second, third and more relapses. Unfortunately, they failed to meet the primary endpoint. So as you can see here, the overall endpoint of disease control rate 12 months was 30.7%. They were looking for 40% as their endpoint. However, subsequently, when they looked at a subgroup analysis in those patients who just had their first relapse, you can see there on the top right hand corner, they approach the disease control rate of 39%, which is close to 40%. So this is a rationale here that if you choose the right group of patients and you look at those, there is some activity of anti-GD2 in osteosarcoma. And this also provided a good rationale to look at the role of naxitamab in this tumor indication. I just wanted to show you, as you're aware, Thomas mentioned earlier on that MSK are doing a study, MSK-sponsored study called the 15-096 study, looking at recurrent osteosarcoma. relapse in the lung, and they're also following up these patients. And this is a study -- I'll come on to the study in a second. The only caveat, I will say is just to show -- indicate the patient population is being included in the study, ignore the bit where it says second-line chemotherapy treatment, and that's not part of the study protocol. This is a study that MSK is doing. So this is a Phase II study involving 3 centers, MSK, MD Anderson and CHLA. The recruitment status as of beginning of this month showed they reached 42 patients out of a target of 46. 36 of these patients represent only pulmonary-only relapse. And the goal is to achieve at least 39 patients with pulmonary-only relapse. Because as you can see on the top right-hand corner, that's the primary endpoint for the study, which is event-free survival at 12 months in patients with pulmonary early recurrence. Secondary endpoints, also looking at event-free survival for those patients with extra pulmonary recurrence such as soft issue and neighboring regional areas. Secondary endpoints also include overall survival and safety. We anticipate the study will complete accrual, we hope by the end of quarter 1 and 2023, and hopefully, then we'll be in a position -- MSK will be in a position to publish some early efficacy data a year after that. Just on the bottom right-hand corner, you'll see what the ambition of the studies. The way the study was powered was to show a difference of 20% versus 40%. 20% disease-free survival is taken from the previous slide, I showed you where the disease-free survival from the AOST0221 was approximately 20%. So assuming that is the results that we will see, the aim here was to show a disease-free survival of at least 50% with a combination of naxitamab in this. So we're hopefully, we're confident that we'll reach a positive endpoint in this. These are the just the safety results. This study hasn't matured enough to show efficacy results, but these safety results were presented at the SIOP meeting in 2019. And then if you can see this at the back that this was a study where the range of patients enrolled in this range from 8 years, [indiscernible] of age. Majority were male. And as you can see in the bottom left-hand corner, most of these patients had relapse to the lung, either one lung or both lungs, and almost all of them had chemotherapy and surgery. In terms of safety profile, there's really nothing remarkable here. What we saw in terms of immediate short-term and serious adverse events were very similar to what we've seen in the neuroblastoma indication toxicities as in the neuroblastoma indication, pain, hypotension infusion reactions were typically seen in similar proportions and there were no long-term or delayed toxicities seen. As I said, we have no efficacy results to show at this stage, but that will be presented at a later time. So this leads us on to the Y-mAbs-sponsored study. The intent here is to seek regulatory approval for use of naxitamab plus GM-CSF in recurrent osteosarcoma. So the plan was to replicate the MSK study as far as possible, but also in order to seek regulatory approval, we need to do a randomized controlled trial versus standard of care. And we've had discussions with the FDA, the European Medicine Agency and also the regulatory authorities in China. And we've got their input in terms of the study design to maximize the chances of regulatory approval. So as you can see here, our expectation is this will be a global study involving sites, multiple sites in the U.S., in Europe and in China. Our aim is to submit for IND in quarter 1 next year. And hopefully, our first patient will be recruited in this quarter 3 of next year. This is a study design for the study. We aim to recruit 140 subjects with recurrent osteosarcoma, who are in second remission following complete surgical resection of their pulmonary lesions. And these will be randomized 1:1 to receive either chemotherapy alone and the standard chemotherapy for second-line treatment is ifosfamide and etoposide. And this is following input, as I mentioned, from the U.S. Advisory Board, COG, FDA as well as other centers and other authorities in Europe and China. And this will be compared to the same chemotherapy regimen plus naxitamab and GM-CSF. So this is how it's designed. And naxitamab will be given over 5 cycles at similar dose to what we've seen in neuroblastoma, which is 3 milligrams per kilo, day 1, day 3 and day 5 and it will be on a 3-week cycle. Key inclusion criteria, I've already covered this. Age range will be minimum 1 year of age up to 40 years of age. Primary endpoints will be disease-free survival at 1 year. Secondary endpoints, including overall survival, 1-year and 2-year disease-free survival as well as safety. We do -- we have inbuilt 2 interim analysis events. First one after 1/3 of the events. This is an event-driven trial. So the first interim, we anticipate based on a number of events at a certain recruitment rate at quarter 1, quarter 2, 2025. And this will be primarily for futility and early stopping depending on the results that we see at this stage. There will be a second interim and possibility for us to reevaluate study sample size depending on the results we're seeing to ensure we get a positive result, and top line results, we anticipate to see some time in 2026. This study is powered, 80% powered with alpha of 10%. And again, this was input from the regulatory authorities in terms of the statistical consideration. And our aim is to see at least a 20% difference between the standard chemotherapy arm and the chemotherapy plus naxitamab. So it is quite ambitious expectation, but we're very excited and confident that we'll see if the prior trials are anything to go by some positive results, which will really be a breakthrough for a very difficult to treat cancer. These are just the participating sites, as I've alluded to earlier, there will be roughly 1/3 of the patients recruited in the U.S., 1/3 in Europe and 1/3 in China, multiple centers across all of these countries. Changing tact slightly, the last couple of slides. Thomas mentioned about the first-line study from MSK. That study was particularly looking at the use of naxitamab as part of the consolidation treatment, first-line treatment. That study will read out and hope to have a manuscript submitted in the next few weeks. We'll come back to you at a later stage when we have the results of this. This particular study is a very exciting study. This is sponsored by Beat Childhood Cancer, which is a very important network group in the U.S. comprising all up to 50 sites who are affiliated with this group in the U.S. and Canada. And they are looking at the role of naxitamab as part of frontline treatment in the induction protocol to treat patients with newly diagnosed high-risk neuroblastoma. And in that treatment regimen, they will be looking at the use of 5 cycles of naxitamab plus GM-CSF in combination with chemotherapy as part of the induction treatment. The rationale for this is we've seen that the earlier you use immunotherapy, the greater the chances of improving overall survival. We know the disease-free survival, even if you just use immunotherapy and maintenance and consolidation is still not where we would like it to be. So there's a strong rationale if we're going to make any headway into improving disease-free survival as a rationale to move the role of induction, sorry, immunotherapy in the induction phase. So that's really the aim of this. Primary endpoint is looking at VGPR+ rate, which is a combination of very good partial response plus complete response, and they will be comparing this to historical controls. Secondary endpoints includes objective response rate, PFS and overall survival. An inclusion criteria, as I mentioned earlier, will be newly diagnosed, high-risk neuroblastoma and patients with no prior systemic chemotherapy. Up to 50 sites are anticipated to participate in this study. And I'm glad to say this study has started, has opened up, and the first patient was recruited in September this year, targeted to enroll 76 patients. Last slide, this is, again, apologies if it's too small to read at the back, but this is just a study schema to indicate the study design. On the left-hand side shows you the induction chemotherapy protocol. So these patients will get 5 cycles of chemotherapies as part of the induction treatment. These patients will be randomized depending on the ALK mutation. And if they are positive for that mutation, they will receive an ALK inhibitor. But both those arms will receive naxitamab plus GM-CSF. After about 4 cycles, these patients will be eligible for surgery. And then after the 5 cycles, there will be an evaluation for response. If these patients have shown poor response, i.e., partial response, minor response or no response, they are eligible. On the right-hand side, as you can see here, for salvage chemotherapy, which is an additional 3 cycles of naxitamab plus chemotherapy. If they have had a successful response to the induction treatment on the left-hand side, these patients will go on to get standard consolidation treatment, which is combination of radiotherapy, more intense chemotherapy and stem cell transplant and then following that maintenance treatment as per the COG protocol. So this is a study that we're -- it's going to be very important for us, although it is sponsored by Beat Childhood Cancer, I think data that comes out of the study will be yet further evidence and support for use of anti-GD2 further in the -- earlier in the upstream in the lines of treatment of patients with neuroblastoma and hopefully improve outcomes for these patients. So I'll stop there. Thank you for your time. And I'll -- I think we're open to questions. Thank you.

Yes. So -- does this work? Thank you, everyone. I guess we'll go to Q&A now, and we both have online and participants in here. So we'll just start from -- we'll work that way. So first question to Charles.

Charles Zhu from Guggenheim Securities. My first question perhaps on the SADA and perhaps also stepping a little bit into medical physics. But in addition to the initial potential imaging and PK data that you could disclose from your lead GD2 program, will you also potentially be able to share dosimetry data? And similar to that, how are you thinking about from a dosimetry perspective, the level of radiation dose that the tumors in your priority GD2 indications might require for therapeutic effect?

So the dosimetry, of course, have been shared with the FDA during the process and will be shared at the international conferences later. So I cannot share it with you today. But what we've seen so far is that due to the PK optimization of the molecule, and we first add the radioactive payload when more than [ 90% ] of the protein is out of the body. We can dose very high amount, meaning that we can target efficaciously the tumor without hitting too much neither to the bone marrow or to the kidneys. And we've also seen data for the liver. Normally, proteins are degraded in the liver that there's very low uptake in the liver when we have the spacing between the protein administration and the radioactive payload. So in conclusion, we can do it much higher with a 2-step procedure as we would be able to do with a one-step procedure like, for example, on 131-iodine omburtamab.

Got it. Great. And regarding my second question also on SADA, this time on the CD38, I'm kind of wondering how -- what was your thinking? How did you arrive at this target? And how are you thinking perhaps not only about the preclinical scientific and clinical rationale, but also the current commercial landscape for CD38 therapies? And as a related follow-up, as a specific question, does your epitope overlap with that of DARZALEX or some of the other available therapies out there?

Yes. The [ sequencing bind ] is not public yet, but it does not completely all with DARZALEX isotope. So it's not DARZALEX molecule. What we do, we discussed a lot, that indications. And we know for now, there's a lot of activity with the CD38, for the naked antibody approach is predominantly is from multiple myeloma, an indication that's not really rapidly dividing. There's been less success in lymphoma space and also plasmacytomas space for the CD38 antibodies as of now. But I think the SADA has a potential here with a much more powerful payload administration to overcome the challenge for those indications. So we are looking very actively to what is happening in the field, not only for naked antibody, but also antibody drug conjugates and CAR-T cells, of course, and bi-specifics. But we definitely think there's a lot of space for radioimmunotherapy approach in the relapsed/refractory setting. And the good thing here is that despite prior therapy, the CD38 target is not down-regulated significant on the cancer cells, where we can actually repeat exposure to the patients for targeted therapy for CD38 with another payload, and this is what we're aiming for doing with SADA.

Joe Thome from Cowen and Company. Maybe just on osteosarcoma, how do the results, the final results of the MSK Phase II kind of impact your thinking about the 205 study? Do the final results there impact your commitment to that, especially as it relates to that 50% EFS bar that you've set? And then maybe second, on the SADA platform, how far do you want to take some of these assets before you think about partnering and licensing deals?

So maybe I'll -- can you hear me? Yes. So maybe I'll take that first point for -- initially. I think there's obviously enough rationale based on what we've seen from existing studies with dinutuximab and how they narrowly fail to meet the endpoint to indicate that we expect to see a positive impact of naxitamab. We're not able to comment on the MSK efficacy results, and that will read out when it will, but we are optimistic based on the historical results, it will be positive.

And just to address your second question, we are looking for validation in patients. And as I said before, we can derisk these programs very early on. And our strategy is to out-license larger indications, such as small cell lung cancer and keep in-house small indications, niche indications, pediatric indications to build a portfolio of those. So I don't believe we have to take it through a full Phase I because of the derisking, a possibility of these programs early on.

Alec Stranahan from Bank of America. Good to be back in the [ Lotte ] Hotel for another Y-mAbs R&D Day. It's been a few years. But 3 questions actually on SADA. Maybe I'll just go one by one. First is a clarifying question in the study design for the GD2-SADA. You mentioned that the dose escalation for the SADA components in Part A and then the radioisotope is Part B. So could we potentially have a Phase II dose selected after Part A for the SADA component or is that going to be a refinement as the study goes on?

I think we will look at it and refine it as study goes on. But definitely, after Part A, we have a pretty good idea how the molecule performs in humans, how the PK profiles are with different dosings look like in humans as compared to nonclinical animal models. And based on that, we will have a significant better way of predicting a recommend Phase II dose. But the recommend Phase II dose is not a dose, is a dose schedule because it's a combination of 3 things. It's a combination of the protein concentrations, spacing to the payload and the amount of rate activity we can add as a payload to -- within the safety of the patients. So that's why we have this 3-step procedure build in and that we, in a Part C already in the Phase I have been allowed to have repeated dosings in patients. This also allows us there to get a better and first view on the outcomes because I think that you need to dose more than once with this technology to overcome these tumors.

Okay. That's helpful. I mean my second question, you mentioned that the CMC package has been fully developed, FDA approved for SADA. Do you see this actually accelerating time for new assets to enter the clinic? And would this be viewed, I guess, positively for any potential or future partnerships?

I think this is very positive that we have been able, first time ever with this compound to discuss with authorities and agree on quality of the compound to be given to humans. And what I shared with you was also a very close collaboration between different groups within the Y-mAbs. So we within a 2-year period from we have a lead actually can develop not only CMC package, but a full nonclinical package and protocol developing as well.

Okay. Great. And my last question, maybe for Thomas. You mentioned that you'd probably partner in larger indications and maybe look at failed Phase III drugs to roll into the SADA platform. Are these drugs that maybe are against a great target, but didn't have clinical efficacy on their own or are these ADCs or some other radio labeled drugs that have failed? Maybe just some additional color around that?

Yes. I think it's drugs that have been proven safe in humans, but couldn't be dosed up or failed in clinic. We saw TLX with Lilly what they did, I mean it's just along those lines. And I think the platform is so uniquely differentiated also on a commercial level, so we can actually go after targets that most other rate of pharmaceutical companies might not be able to because we use large infusion centers for the protein and then they can send you to academia to get your isotope. So we have a very flexible possibility to do sponsored research agreements on failed targets to do third-party optimizations and outlines our own targets. So I think we're going to go out broad, but the gating factor right now is in human data at this point in time.

Bill Maughan, Canaccord Genuity. So I just -- I think with DANYELZA revenues, it's a lot easier to kind of get a grasp for the U.S. potential, but there's still a lot of conversation about these ex U.S. approvals. So what -- can you give us any more context on how big an opportunity ex U.S. you think DANYELZA could grow to be?

Well, I think you have to look at it in terms of number of patients and pricing power in the different markets. And we haven't disclosed pricing in China, but we look at the Chinese opportunity as a major opportunity for DANYELZA ex U.S. I think LatAm overall with Brazil being the leading country where we already filed a BLA in September. We've actually turned around the first responses to Anvisa right now. So hopefully, that will go well. And if it goes well, it might be before October next year, we get an approval. So I think LatAm and China is the 2 major opportunities, but we are obviously also just looking at providing access to children all over the world, and we're also chasing Japan as we speak and other markets. But I would say, significant opportunity for the company ex U.S.

And you mentioned for SADA data that imaging data could be derisking on a quicker time frame from actual therapeutic data. So can you give us more color on what you'd be looking for in early imaging data that you think would help generate excitement and conviction in the program?

I'll just give the -- you can add to it. But I'll -- what we want to see is we want to see the protein and then the imaging dose light up the protein. So the uptake on the protein and that depends on the time space between those 2. That should be enough to validate the mechanism of action of the entire platform. But I'll let Steen go deeper into details of that, if you want.

Yes. I don't know how much deeper we should go. But I think it's very important to say that this molecule has not been in humans yet. So this is the first time ever we have this 2-step approach. And the good part is that we have a theranostic approach. So we give an imaging dose first, meaning that 24 hours after you administer your radioactive payload, we actually will know whether or not you hit the target. And I think this is really proving the concept if we can have a biodistribution clean and a tumor uptake that we can see on a SPECT/CT scan, I think the principle for SADA has been demonstrated. And then from there on, it's safety and efficacy, we look for in a dose escalation fashion, and that's why we perform a Phase I dose escalation trial.

And then last question for me, in between the omburtamab CRL and the upcoming FDA meeting, has there been -- to what level has there been any back and forth to the point where you can gauge sort of tone or content of the meeting coming up?

Yes. There hasn't been any back and forth.

Fair enough.

It's a CRL Letter with deficiencies and advise on how you -- we can address those deficiencies, and we are preparing a response and then we'll speak to them with the Type A. It's just the process, we'll have to work through that.

Understood.

Jeff Lopatin at Red Hook Asset Management. Just a quick question, just with respect to the BCC trial in frontline high-risk neuroblastoma, do we expect this to be a registrational trial? And how do we think about that in the context of having a historical control arm, given recent FDA actions towards perhaps you guys and others?

Thank you. I'll take that. So yes, this is an investigator-sponsored study, of course. So I think we'll have to come to a decision once we see some initial results coming through. We have had discussions with the BCC who have been kind enough to allow us to use the data for purposes for regulatory approval, if needed, if appropriate. So I think we'll just have to wait until that results come through. Now what are the chances that this will be accepted by the FDA for regulatory approval, I guess it depends on the degree of benefits seen, the quality of the data that they've conducted. And historical control is a thorny issue with the FDA, as we know. I think it will really depend on how comparable the patient population they've selected and if there's substantial evidence seen in this comparison. So I think it's possible. We'll have to see exactly to what extent the benefit has been seen before we judge that.

Also adding -- we're obviously also looking at tumor responses with DANYELZA. So it's a little different. Because you're using it upfront in induction phase, where you get 5 cycles of chemotherapy to shrink the tumor and now we're adding DANYELZA to that. So we actually are seeing the difference between a patient who doesn't get DANYELZA versus a patient who gets DANYELZA and chemotherapy upfront. So we should definitely see tumor responses before surgery. So that helps us with the FDA.

Yes, I mean typically, the responses seen at the induction of around 40% responses, and we're hoping to see in this study up to 60% is what the aim is. So if we get anywhere close to that, this will be a significant persuasive element for this to be adopted as part of induction protocols. Whether or not it will be accepted, the FDA will have to come across that bridge when we come to it.

Robert Burns from H.C. Wainwright. One question on your CD38-SADA. So obviously, outside of multiple myeloma, CD38 expression is significantly lower, like CLL or DLBCL. So I'm sort of curious what you're viewing as the benchmark in that -- in those 2 lymphoma populations and leukemia populations? And then thinking about the multiple myeloma opportunity, considering the data we saw from Takeda's Modakafusp alfa at ASH this year, I'm sort of curious how you're viewing that as a competitor to the GD2 -- to the CD38-SADA and then the CD38 CAR-T agents? And where you see the SADA sort of fitting into that myeloma paradigm?

So I think that the benefit from the CD38-SADA is that it has a powerful payload. And I agree that the lymphoma space do have less expression as compared to a multiple myeloma. But so far, in nonclinical in vivo studies, we are actually able to treat different lymphoma cell lines in a xenograft model. So we are confident that we can see some activity, whether it's not, of course, this is why we do the clinical testing. Plasmacytoma also is an indication that a rather very radio sensitive and would benefit from radioactive payload. Multiple myeloma space is highly crowded for the moment, not only for CAR-T, but CAR-T is very difficult to administer and for the selected patients, but you also have bi-specifics and ADCs, and, of course, you have the naked antibody, [ 2 ] naked antibody approved. So the myeloma space is much crowded. The benefit from the myeloma patient is that is very little chemotherapy they receive. So even though we had 3 or 4 lines of therapy administered, they're still in quite good shape and can benefit from having a fifth line of therapy. And also the benefit of the radioimmunotherapy as compared to naked antibodies, we don't need the patient's immune system to be intact anymore. We just need the target to be there in order for us to deliver the payload. And as such, the relapsed/refractory setting still is where we can gain evidence of efficacy with the molecule, both in lymphoma and most likely also in the myeloma space, that's to be seen.

This is [ Taylor ] from Tessa Romero's team at JPMorgan. I have a quick question. So for both DANYELZA and the SADA platform, you've talked about looking for potential partners to move larger indications forward and in DANYELZA's case supporting investigator-sponsored requests. I was just wondering how much interest have you seen for both DANYELZA and the SADA platform from potential partners here? And are there any characteristics for potential partners that you're specifically looking for, for each of these?

I'll take the first, and then I'll let you talk about ISS. But overall partnerships, initially, we would like to work with people we can leverage. So there's a select handful of great radiopharmaceutical companies out there that we, of course, are talking to. I can't give more details on that. And on DANYELZA, well, I can tell you a gating factor right now for us is in human data, which has also put us in a stronger position once we're able to derisk that. So we're happy we ended up where we are now. DANYELZA, we are not spending budget on these larger indications even though we would like to. So we have chosen to use a strategy of getting some ISS proof-of-concept. DANYELZA was developed as a scientific protocol initially at MSK. And it's dosing Monday, Wednesday, Friday and you would never go into a large adult indication with that kind of schedule. So we'd have to do ISS started where we redose it according to its half-life, maybe day 1, day 8, maybe even day 1, day 16. But our strategy is to do it through on ISS. And I think, Vignesh, you can comment on the interest, which is we see that. Yes.

Yes. And we have seen interest for multiple adult cancers. For example, there are 2 studies in triple-negative breast cancer. One is a preclinical. One is a Phase I clinical in combination with chemo in breast cancer. We've also had a request in the past in melanoma and one also in combination with another targeted agent for use in soft tissue sarcomas. So there is interest out there because of the rationale for GD2 as a target. So where the design makes sense and where it fits with our strategic area we want to go, we're looking to support these studies where we can.

Alec Stranahan from Bank of America again. One question on DANYELZA pricing in China. I appreciate maybe you can't give the details yet. But I wanted to ask how you're sort of approaching market access, whether you would seek to get it added to the NRDL at some point, if that even makes sense in a smaller indication like this? And how you're sort of setting pricing up if that is a consideration?

Yes. That's a good question. So initially, we have a strategy that SciClone has worked out. They've been in the market since 1996 and they have a very established commercial infrastructure. So our strategy is initially, I believe it's 3 years before you seek reimbursement across the board nationally and that will obviously induce a price reduction when you get there. But initially, the first 3 years, I don't think that's in the plans. And then once volume, you reach a certain volume, then you go in.

Okay. And I think you had mentioned previously that there has been sort of some use in China, pre-approval. Could you maybe talk about the sort of the adoption there and the enthusiasm around the drug?

Well, we've treated patients in the pilot zone. So once you have an FDA-approved product, they will allow you to treat patients there. And I think the clinical experience, I actually think, Vignesh, you can maybe give a brief on how successful that has been?

Yes, there's been no shortage of interest in the use of DANYELZA as part of a compassionate use or expanded access in those small selection of hospitals. So we've had patients being recruited for over a year now. There's 30-plus patients in the last 12 months alone that have been enrolled. And we've had a very good experience. I think the early few weeks what we realized is close collaboration with SciClone to educate and inform the physicians about the safe and appropriate use of DANYELZA to minimize any toxicities, et cetera. Once we got over that, we got into a kind of a rhythm because the physicians started to get a lot of expertise, and they were able to train the trainers in other words. So as we've gone over the last 12 months or so, the incidence of adverse events has plateaued or if anything, reduced, they're able to manage the patients better, and they're seeing positive response feedback from the physicians. So I think it's all looking good. Certainly from a clinical point of view, there seems to be a positive feedback from the physicians. And if anything, we're holding back until the launch before it's opened up to other centers. The key for success here is to manage the patient education, physician education in a controlled fashion because of the profile of naxitamab. And when you do that, the experience with the physicians is very positive. And that's the key to success. So we have regular interactions with SciClone, our medical and our safety team with their counterparts, and it's working really, really well. So we're very excited about the potential launch or the launch, I should say, of DANYELZA in China.

Robert Burns from H.C. Wainwright again. Thomas, your predecessor quoted that there are roughly 2,000 newly diagnosed patient -- neuroblastoma patients in China annually. And you said earlier that SciClone is going to target roughly 40 hospitals in 2023 for penetration into that market. So I'm sort of curious about the number of patients with neuroblastoma that are treated in those hospitals? And do you see a similar flow-through rate from the frontline into this line of setting as you do in the U.S. and China?

So I think in China, it's a completely different market than in the U.S. First of all, chemo combination is not highly developed there as it is in the U.S., is a standard in the U.S. Second, I think we have a great advantage being outpatient coming to China to these hospitals. And third, the number of patients, yes, I think that number is right. There is a large number of patients. We've seen [ Cassava ] has been approved there. We've seen the number of patients they have treated. So I think the strategy for us is to go in and add on a 203 study. I don't know if you remember the HITS data that was created for ASCO. That data is not over there. So we are actually planning with SciClone to add 203 study on noncommercial patients in order not to cannibalize that and then get that experience out into physicians in all these hospitals. I think it's fairly -- it's fair to say that it's also centers of excellence. So as the same framework as it is in the U.S., and there's some sites that are communicating with U.S. sites in terms of experience and all the conferences and so forth. But it's a different index than it was for us when we launched in the U.S. very, very different.

Thomas, we...

Okay. So I think we look forward to seeing you at JVM, where we will have a presentation and give an update overall on the company, the companies. We hope to give you some guidance there and give you an update on the overall corporate strategy going forward. And we will have some more things to share with you then. So this was an R&D Day today, and thanks very much for spending time with us. Thank you.