Updated Study Results

Jul 8, 2021

Welcome to the On Purpose Audio Card Press Conference 2021. Throughout the call, all participants will be in listen only mode And afterwards, there will be a question and answer session. Today, I'm pleased to present CEO, Marty J. Dover. Please go ahead. Your line is open. Great. Thank you and good morning, everyone. And pleased to provide today updated results on the OCEAN trial And also a communication of a partial clinical development hold for our lead product, melflupan. So joining me on the call, Slide 2 will be Doctor. Klassbacher, our Chief Medical Officer and also Jacob Lindbergh, Our Chief Scientific Officer. And on Slide 3, we will be making forward looking statements. So I ask that Everyone take a look at our submissions and representations for complete fairness and accuracy that you'll find on on our website and in other filings. So looking at Slide 4. So what are the key takeaways here? And this is mostly associated, of course, with the OCEAN trial. And recall that this is a bold head to head study versus pomalidomide. So 2 very different mechanisms of action in patients with 3rd and fourth line relapsedrefractory multiple myeloma. So we are pleased to report today That the independent review committee has reassessed and the trial now meets its superiority on the primary endpoint A progression free survival across the intent to treat population. We'll provide a little bit more detail on that process and how it came about, but now meeting superiority on the primary endpoint in the intent to treat population. We also see in the trial mixed Overall survival results. So we'll describe to you how that's the case and where those Results do reside. And also, we are targeting a particular meeting, the IMWG meeting in September in Vienna, we'll be submitting a late breaking abstract. We obviously don't control the acceptance of that Abstract, but we just wanted to make everyone aware that that was our target for providing the full data set and full data disclosure. And we're also working very hard on a publication of the OCEAN trial results. So as it relates to clinical development, because of those mixed overall survival results, the trials that we have ongoing, Which are in those early lines of multiple myeloma are now placed on partial hold, and we will describe Some of those trials and the rationale behind that. And please know that we are committed to work with the FDA expeditiously to get these trials back up and running so that we can further study our drug in this important patient population. And finally, I do want to communicate that we our COPAXONE commercialization in the U. S, there is continuation of the marketing based on the Horizon label. So with that, I'll turn it over to Doctor. Klotzbacher. Yes. Thank you, Marty, and good morning, everyone. If we go to Slide 5, just as a short background, the study design Of OCEAN, which is, as Martin stated, a head to head study of melflutant plus dexamethasone against 2 very different drugs from a mechanism of action perspective and a quite unique study In that it is not often that you see 2 drugs against each other where you basically can really identify the strength and weaknesses of both drugs. The primary endpoint was PFS as assessed by the Independent Review Committee, and we'll talk about that more a little bit later, And 2 key secondary endpoints being overall response rate and overall survival. Go to Slide number 6, please. If we look at what happened, The top line results were disclosed on May 25, as you may all remember. Today, On the 8th July, we disclosed the final Independent Review Committee, PFS results. As Mardi stated, in Q3, hopefully, at the INWG, we will present The data to a broader audience at a scientific meeting, and at the same time, we're working on a manuscript. These time lines are all unchanged. So with that, we also still have because we have a superiority trial, we still expect to file for an expected sNDA around year end or early next year. Next slide, please. So the top line results were communicated on May 25. After that, There was a deep dive on the data, and this is normal because you need to prepare data for your clinical study report, the CSR. And also for regulatory interactions, you need to look deeper into the data to prepare your file with the FDA. During that deep dive in the data, we became aware that some of the imaging results were not Provided to the IRC at the time of their assessment. And this is being done by our statistical vendor, Who is actually the responsible body to make sure that all the data from the clinical database It's actually shown in worksheets to the IRC members. So while all the information is there in the clinical database, it's always an extraction of the database that comes in front of the IRC. Note, this is a process completely independent of Oncopeptides. Because of this finding of initially 1 or 2 patients where we could see that imaging had been lacking, We asked the CRO to do a full review of all 4 95 patients to see if there was any discrepancy between what was provided to the IRC and what was in the clinical database. Based on that, we landed on 29 patients Sure, a reassessment had to be performed because of changed data points in the clinical database. Please note that after May 7, the clinical database has never been opened. So this is only about what is extracted from the database and put in front of the IRC members. There were no data points changed, and the database remained locked throughout this process. Also, we made the FDA aware on a very early notice that this was going on and this was happening in the background, And we had an ongoing dialogue with the agency throughout this process. Now what did this lead to? If we go to the next slide, Slide number 8. The primary endpoint, progression free survival, as per IRC, now has a hazard ratio of 0.792 with a confidence interval just below 1, thereby reaching statistical superiority with a p value of 0.0311 with a relative median progression free survival improvement of 39%. You will notice that the relative median progression free survival improvement is actually a little bit less than what was disclosed during the top line results, And this all has to do with changing medians due to the reassessment. The overall response rates stayed the same. This is logical since responses as such did not change, of course, during this reassessment. It was a reassessment of time to event data on the progression free survival. So of note, this number didn't change, but because it's a secondary key endpoint, We actually like to show it here again with 32.5 percent for moflufen and 26.9% for pomalizamide. Very positive results. Next slide, please. The overall survival data. As mentioned, this is a head to head comparison of 2 different treatment modalities. And hence, we saw striking differences Between the performance of both drugs across different patient populations, on the ITP level, the overall survival hazard ratio Was 1.1 in favor of formalidomide for the full population. This is Not statistical significant, but because it is other direction than the progression free survival, this, of course, It leads to further analysis to see what explains this hazard ratio of 1.1. And What we and also the agency have seen is that in pre specified subgroups, there are large differences. So in some patient groups, the Pexto or noflavin does really well from an overall survival perspective. In other subgroups, From a little mic, does particularly well. This all adds up to a hazard ratio of 1.1, but We are currently further investigating this in close cooperation and collaboration with the FDA. This is all ongoing. Now let's go to the next slide, Slide 10. So because of these striking differences in overall survival, with Some patient groups also being in favor of pomalidomide, as is shown by the hazard ratio 1.1. The FDA has requested on cohort peptides to put the program of clinical development and earlier lines of treatment on a partial clinical hold. A partial clinical hold means that we are no longer recruiting patients into our entire study program until we have a better understanding of the overall survival results and as such can determine which patients benefit most from nalpukin. Patients on the study can stay on the study, and this is subject to recontent and assessment by the Relevant investigators, the patients who derive benefit can stay on the drug. This decision It is effective immediately and impacts our Lighthouse study, which is the randomized study of nelpflus and daratumumab dex versus daratumumab The ANCHOR study, which is the basket combination study with daratumumab and bortezomib, it's the PORT study, which looks at central versus peripheral administration. It's the BRIDGE study in patients with renal limb power impairment, The ASCEND study in M and OE doses, and we also put and this is something that we did ourselves, Temporarily suspended the COAST study with OPD5 as this is a very close analog of noflufen. And we first want to be absolutely sure, In cooperation with the agency that we fully understand which patients benefit most from this drug and which patients do not benefit most of this drug. There will be a lot of speculation probably about how long a clinical hold We currently don't know, but it is reasonable to assume that it won't be a couple of weeks, But more in the time frame of months. But beyond that, it would be speculative to talk about time lines. It's just that we have a very active information flow ongoing with the FDA to resolve this issue as fast as possible. Thank you. Marty, back to you. Great. So Slide 11. So kind of in summary then, We see the OCEAN results, very pleased to have met superiority on the primary endpoint of progression free survival and the intent to treat population. As we look at then at the totality of the data, Klas reminded on the objective response rate. In addition, we know the clinical benefit rate, duration of response, So our solid data favoring melflupin, but it's in that overall survival secondary endpoint, important secondary end We look forward to Q3 and the IMWG meeting to present full data. As mentioned, clinical development, we are now on partial hold in those early lines of multiple myeloma treatment, partial clinical hold, And we hope to work and we will work closely with the FDA to resolve those issues as soon as we can. And we continue with the commercialization of COPAXONE in the United States based on the Horizon label. So that wraps up The slide part, now we can move into the Q and A. And for that, I turn it back over to the moderator. Our first question comes from the line of Victor Sandler from ABG Sundal Collier. Please go ahead. Your line is open. Yes. Hi. Thank you for taking my question. So first one on overall survival. So I'm a bit Perplexed, why the FDA is looking at the OS data already since it has to be mature at the moment. Could you give any more clarity into this And also the rationale for the big variations between meloxicam and pomalidomide? Yes. Good question. So it is immature and certainly we'll be following it longer over time. But With that, I'll turn it over to Jacob for comments. Thank you, Markku. This is Jacob Lindbergh, Chief Scientific Officer. I think it just underlines the uniqueness of the result, Victor. This is the first time you have a head to head comparison between 2 different modalities. And as a sponsor here, we have actually failed to find precedence for a successful clinical trial where you have Overpassed ratios in large prespecified subgroups going from around 0.5 to around 1.5. And given the large differences, it is clear and it's also clear to us as a sponsor That hazard ratio of 1.5 signals, for example, that those patients shouldn't be in our trials, and they Should be excluded from any potential label, and there, we are in complete alignment with the FDA. And given these very large OIF differences, It is also clear that there is a very clear patient population that benefits from noplasmic treatment. 0.5, That's around that range. It's a very, very good number in the other end. I understand the agency's need To delineate and understand this data before we can continue with our clinical trial program, both That those patients that can benefit will receive the drug as well as those patients that do not actually receive SPALM. So I think it's important to understand how big the differences are in this material, which is a very unique clinical data set that, of course, from a scientific Point of view is extremely intriguing, but of course, as a sponsor of a study, you would rather have an easier trial result, but it should for sure be discussed in academic Okay. Thank you. And are there any risks that there will be a restriction on the current label That you have in the 4th line plus setting, given this data or is it also related to this difference with pomalidomide? Yes. We don't foresee that at this time. Of course, that's a different patient population under accelerated Approval 5th line plus triple class refractory patients. And a reminder, about 90% of those patients had pomalidomide. Yes. And how many of the 29 reevaluated patients have their results changed when they look at imaging once again? So I'll turn that to Klas for comment. We don't know because We get the data in a blinded way originally. We will look into that to better understand that, but we don't exactly know In what arm the patients were, and we also don't know right now in which directions they have changed. Overall, of course, because the numbers have changed towards superiority. It will be in favor of naflutin, but whether that is based on 10 patients That has been like another result or 15 or 20, that would be speculation this time. We don't have full view of that. Okay. Sure. And was the IRC committee made up of the same condition as in the first data readout? Or Yes. The IRC has been no. The IRC is the same IRC. Okay. Yes. I think I'll jump back in the queue, but thank you for taking my questions. Thanks, Victor. Thank you. Our next question comes from the line of Patrick Lane from BNB Markets. Please go ahead. Your line is open. Thank you. A couple of questions. I mean, when you talk about overall survival Barrowing from 0 with the hazard ratio from 0.5 to 1.5. I mean, do you have a feeling for I mean, You know your subgroups. So do you have a feeling for how large proportion of the Sort of market that the OCEAN trial addresses that seems to be less suitable for Well, flufen versus the ones where you can say that it seems to be more suitable. Yes. Good question, Patrick. And obviously, we've been speculating a little bit there since it's probably Not as straightforward as one might think, but let me turn it over to Jacob for comment. I think we should be very careful in speculating exactly where, for example, the FDA's assessment will end here. But as you can understand, with these differences and a superior PFS result and an ITP overpassive ratio of 1.1, We're talking about significant patient populations on both sides of the fence, so to speak, and then we should have to wait for their assessment. But we're not talking about the minority versus the majority. We're talking about 2 very large groups on different sides of this border. Okay. On the OCEAN trial, we also have a special protocol assessment. And As you communicated about it before, it was primarily based on the primary endpoint of Progression free survival that you needed to reach superiority. You've done that now. So Could you see this analysis from the FDA as some sort of early label discussion really For Ocean, to really find out what's are suitable or not? Yes. Well, certainly, the dialogue is going to be very active and has been. It's been continuous since The first release of the data. And as we've kind of Discussed over the past year or so, looking at inferiority or superiority with some regulatory bodies, it's particularly important for the superiority outcome. So we're pleased that in the intent to treat population in these final IRC results that we have that superiority on progression free survival. But I'll turn it over to Klas as he thinks about some of the regulatory interactions Yes, sure. And please note that the file is still valid. So that means that if you reach superiority, you kind of fulfill the first requirement to sit on the table with the FDA, so to say, to talk about a label expansion. The Point is that overall survival is also considered to be a safety endpoint because ultimately, the overall survival event It's leading. And it is the regulatory body's responsibility before taking any actions On approving a drug in a certain indication in a certain patient population to make sure and to be absolutely sure that there is no harm to patients before you enter that stage. So although the site is still leading, from a regulatory perspective, the first action that always needs to be taken is Around safety and overall survival is such an important endpoint. It's in the end the golden endpoint. And That leads now to this, I would say, interjection by the FDA to actually first understand that better before we move on. But as said before, reaching superiority is very important. We'll gather the seat at the table. We think we may still have a good shot at the label. It's just that we first need to sort out to see which patients do benefit from melfluthen and who do not. And currently, the focus is at least to make sure that we do not Provide Neflutphen who actually do not provide benefit from Neflutphen. So in a way, they are kind of separated from each other, The spa and the superiority and this investigation that is based on safety. I think, Patrick, it's also fair to say and Klotz that OS It's obviously a very, very critical endpoint, as Koss mentioned. In a trial like this In earlier lines of therapy where people where patients will live beyond their 3rd and 4th line, there is a confounding factor of subsequent therapy and all of that needs to be worked out in this analysis as well. Okay. But when it comes to the difference in overall survival, you can based on the analysis that you've done Up until today, you can be sure that it's not due to any unexpected side effects or anything that has And caused to the patient by your drug? Or is there something that comes to the No. I can't thanks for asking that question. The answer is you are correct, and there are no As far as we can see now, there are not unknown adverse events or new safety signals, as we have also Already mentioned in the top line results update, that still stands. We have not identified a new safety signal In terms of toxicological terms, it's only the overall survival that we need to understand. But so far, we haven't identified A classical safety issue, so to say, that is associated with his overall survival. What we really look at is Various layers of efficacy. So one patient group seems to be more benefiting from this drug than other patients and some do benefit really well from melflutant, Some do not really, but this has nothing to do, as far as we can say now, with safety as such. So when I say A safety measure, that's what I mean that the FDA just wants to understand who to expose this drug to from an efficacy perspective, But not because they are concerned about more adverse events here. Okay. Last question. Do you see any Correlation between the variation in overall survival with overall response rate and PFS. Do you see the same type of variations for the same type of subgroups for the other measures? I don't want for some. Yes. Go ahead, Jacob. So for melflutin, there is a very consistent path between increased Response rate increased PFS, increased OS. So the entire surrogate Endpoint system, so to speak, from an efficacy point of view makes perfect sense in the nelsleutin arm. It is much more tricky in the pomalidomide arm, where the PFS is basically very stable across all subgroups, but it always varies Tremendously across the business by subgroups, which makes this analysis a bit tricky. But for Miltleukin, your statement is absolutely true. The efficacy endpoints and the OIBDA endpoint goes hand in hand. Okay, great. Thank you. I'll jump back into the queue. Thanks, Patrick. Thank you. Our next question comes from the line of Christopher Yudy from SEB. Please go ahead. Your line is open. Hi there. Thanks for taking my questions. Okay. So it sounded like maybe I'll just ask this one first Since you sort of alluded to it earlier, but just to be clear, so bearing in mind the OS finding, Would you say your confidence in full approval and or label expansion is increased or decreased Compared to when you first announced top line, and do you see any difference in how you view the FDA and EMA processes? Yes, maybe I'll turn that one. Thanks, Giselle. I'll turn that over to Klas for first comment. Right. And thank you, Christopher. We have, from the beginning, also on the top line results, always have said that based on the totality Well, today, we feel very confident in our interactions with regulatory authorities. The fact that this now has changed to a superiority result have even further increased the chances of regulatory success. So when you speak about full approval, I would say there is a substantial Possibility that it will not be labeled that covers the full ICT population Because if you have a hazard ratio, as Jacob already said, sometimes going to 1.5 On overall survival, and that turns out to be true. It's hard to kind of include these stations in a label. So we are not it's not the base case anymore that we will get a full approval on the full ITP population based on these results. Okay. Thanks very much. That's helpful. Then my next question is So it initially struck me, but I guess your last comment there on related to unexpected side effects, whether there are any Suggest that's public space, but I was immediately thinking of venetoclax initially. Is there so first of all, I guess, is it correct then that infections are not part of the problem here In terms of the OS, let's say, deficit in some subgroups for melflupin? And then And is it anything to do with T1114? Okay. Yes, I can answer that question. This is a completely different situation when compared to venetoclax. Regarding infections, higher in certain subgroups, that is not the case. And we don't see a delineation Across subgroups according to the 1114, what you just mentioned. So it's that is not the case. And we look at a completely different situation than Veneto Clarks here. Jacob, anything to add there? Yes. I would just echo what you said. Actually, when it comes to infections, it favors no Sussan in this study, as will be shown at the future conference. No. I mean we have done a very thorough job at analyzing this. And just like you, Chris, offer, our first thought was that this was And it wasn't. From my interpretation point of view today, this is just a stunning Difference in efficacy between 2 different treatment modalities across different patient populations that we are seeing. So we're seeing true efficacy differences between these two drugs. And once again, from a clinical scientific point of view, I think it's a treasure trove of information. But obviously, this may create a complication for us in the regulatory interactions and to determine exactly how to define these 2 patient groups, those that benefit and those that do not. Okay. That's very helpful. And I guess my last question is just a clarification. You mentioned that the database has been locked throughout since May. Is the OS Change, I guess, due to reappraisal then of the existing data from coming out of the IRC Look again or is it to actually 2 maturing data? So And I'll turn that to Bob. Yes. It's a good question. So the IRC reassessment has nothing to do with overall survival. That was that's such a hard endpoint But you don't need to reassess that. It's from a clinical database perspective, you lock it At a certain date, and then you extract the data. That hasn't changed, and we have not seen other OS data today And that we have seen on the very first day. What we did understand at the first day was that it was very immature, The overall survival endpoint and very difficult to read. So we needed further analysis to better understand what We're seeing at that time. But no, there has been no update in the overall survival results. Okay. Thanks. That's all my questions. Our next question comes from the line of Tito Balfour from Jefferies. Please go ahead. Your line is open. I've got four questions, and perhaps we'll take them in turn. So firstly, Just with regards to the overall survival, again, so I appreciate you said there are no new safety signals. But Can you confirm that this is not related to the existing, for example, hematological toxicity? And it's not the hematological toxicity that It's causing this difference. And equally, that it's not related to duration of therapy because I guess Duration of therapy, obviously, I guess, I'm saying it's not the cumulative effects of those human tox events over time that's leading to this OS difference. Yes. Thanks, Peter. I'll let Claude touch on that one. Yes. Thanks, Peter. And 2 very relevant questions and 2 relatively The short answer is no, we don't see this being related to intox, and it's not due to any differences in duration of treatment. I could just add one thing. It's Jacob here, Peter. You actually, if you look at the OS while on therapy And within 30 days of the last dose, you have a positively trending OS and you have a larger Okay. And then the next the second question is just with regards to disclosing This subgroup, I mean, I guess, you obviously are approved Horizon, for the Horizon indication, and you also have open access programs in Europe. I'm not thinking what is your thinking regarding the time line of disclosing these subgroups. I'm thinking ahead of September even, given presumably, there are potentially Patients who may be later lined, who perhaps should not get the drug anymore based on these subgroups, or am I misinterpreting? Yes. No, I don't think you're misinterpreting. I think our initial look and certainly, of course, The communication with the agency has been that the current label is not impacted. So based on our look, we don't see later lines of therapy being impacted. But of course, analysis will continue, but that's not where we stand today. Maybe I'll turn it to Klas also for comment here. Yes. I think for now, I can only echo what you say, Martin. The patient population of Verizon is so Materially different from Ocean, much later line patients with limited clinical treatment options and The subgroup results that we see, based on the analysis that we have been doing, quite extensive analysis, We don't see a repetition of that in Horizon, so to say. So at this moment in time, we feel With the patients who are currently getting melklufen within the Horizon label, we have no concerns about that. And I do hear you. So we're comfortable with a target of a September disclosure On these subgroups and the full data. Got it. And then the third question is just with regards to the comment that was made on Confidence in approvals, but not for the entire population. I guess I understand the thinking, but if you were to exclude, I guess the patients that have unfavorable OS, I guess how is your confidence then that the PFS benefit It's still going to be meaningful and ideally statistically meaningful if you just take that subgroup of the population Because again, to get approval for just the subgroup would then rely on essentially lowering the end of the study. Yes. I think and I'll turn this to Klas for comment as well. I mean, Jacob made one point about the overall directionality The secondaries of overall response, depth of response, duration of response as it relates to PFS. And Klas made mention of the fact that in the intent to treat population, the PFS Meeting superiority makes this a positive trial. And with the trial being positive, then the analysis of subgroups and the meaningfulness of subgroups Becomes more important. So we kind of see that sequence of events. I would speculate you'll find directionally the numbers to line up. But maybe I'll turn it over to Klas and Jacob for their comments as well. I just want to echo what Jacob mentioned earlier. For melfluthen, It's quite stable, as we say here. And what I mean by that is that when there is a clear PFS benefit, That also translates into an OS benefit and the reverse. When the PFS benefit is not really there, The overall survival is not going into another direction. It's really pomalidomide, which behaves differently here. Going back to your question, we have the firm belief that where we see a benefit on the primary endpoint for nolxluthen, That also translates into a good overall survival result. So we have full confidence that some major So, Bruce, actually, everything goes in the right direction, so to say. So we don't see formoflavin Specific patient populations where the PFS Malinberg doesn't hold in the OS analysis anymore. So that makes us Pretty confident on that level. It's Jakob here. I could just add one layer more. Under the assumption that your endpoints move in the same direction, which I think, Peter, you have heard that they really do in this trial, the formal solution, Then it means that you have proven benefit by reaching your primary endpoint and in this case of superiority on PFS. So what the regulator would do, presumably, and now speculation is, and there is A lot of precedent for this is that you exclude subgroups based on risk. And the bar you need to reach to exclude a subgroup Group based on risk is, of course, much lower than to prove benefits, but you have proven benefit on the ICT level already, which means that the exclusion is based on risk assessment rather than benefit assessment. So there are various precedent for this in multiple The trial is actually this exact way of thinking. So final quick question then is just with regards To the call, I guess, just going back to the start of this, really, just trying to understand what the cause of this was. I mean, it seems as Yes. The IRC had, I guess, and the statistical vendor, they have time to do this since when the study was fully enrolled and then the events occurred and happened. So I guess just curious what the causes of this error? And who's I guess, cut me short, who's to blame for this? Because Clearly, something somewhere, I mean, I've thought this a long time, and it's someone somewhere clearly made a mistake in the analysis of that. I'll turn that to Klas for comment. Yes, sure. As always, it's an addition of individual small things that add up to A result like this. What we can say here is that the process that has been followed here is a Sequential read by the IRC of overall survival results in batches. So when every 3 months, there is a review of the event And the IRC reviews that so that they don't review all 4 95 patients at the same time, which would be an awful lot of work. This is common practice. Now between the last IRC meeting and the database logs where data, Of course, it's cleaned, added, subtracted to make sure that everything is correct. There was not a new IRC meeting after that to look at these changes. The IRC is managed by one of our vendors, but guided by us. So it's a combination of parties who are involved here. But to be this is as transparent as I can be in just that because of the not looking at everything at one Time at the end, but instead looking at it at various time points and then not later on look at patients where things have changed. That's, I would say, The main driver here of the fact that the first IRC read was not complete. Yes. And just for slight clarification, that was on PFS, Peter. We have a follow-up question from Patrick from DNB Markets. Please go ahead. Line is open. Thank you. Just a short question. Do you think that FDA analysis and the partial clinical hold will be over by the time you present the data in September. I think that might be a little tight. I'd be speculating a little bit there, but I'll ask Plas to comment. Yes. I think it's really speculative. So I wouldn't feel comfortable to specifically comment on that. As I said earlier, I think it won't be weeks. And then how many months is really speculative. The only thing I can say is that we work As fast as we can with the agency, and the agency is working very hard here as well to get this resolved ASAP because that is in the interest of patients And all parties involved. So no one benefits from the delay here. So we're just doing everything we can to get This clinical hold lifted as soon as possible. Okay, great. Thank you. Thank you. We have a follow-up question Just following on, I guess, from a couple of your comments. The first one in terms of the bar, to exclude being Much lower than the bar for benefit. Does that it sounds like you're saying I mean, given that you said these are 2 roughly Equal, very large populations. I mean, does that it sounds a little bit like, Are you saying that 50% of the addressable of the what we would have considered the addressable market previously would be Potentially excluded or is it more or less? And also, how Do you see this affecting reimbursement in Europe? Thank you. Yes. So maybe I'll turn it over to Jacob to talk about the first part of that question. I don't want to speculate in exactly because we need to finalize the assessment in collaboration with the agency Regarding the exact delineation here, but as we have stated, we're talking about 2 very material groups, right, and looking at the data, But then it's up to the agency also to make their assessment and exactly where they will come out on that, We don't know. And I just want to highlight that your question about reimbursement will then be linked, of course to what the final data set is in those patients that are selected in a potential label. Okay. Thank you. To add on that, Jacob, I think it's not unreasonable to state that The European payers, in general, do like medicines that are Effective in almost all patients that are part of the group. So when you get approval, And this is highly speculative. If you get approval for a certain patient group where you derive a lot of benefit or who derive a lot of benefit, The bar for reimbursement will be lower than going for full IGT population with not A benefit for all patients. And from a European payer perspective, it's always more interesting to look at a smaller group with higher efficacy. Thanks. Yes. I think that and maybe stepping back, Christopher, and others, as we think about this, I mean, think about an intent to treat population here, 495 patients. And on the primary endpoint, as we've described, meeting superiority on PFS and Generally, across the ICT population, favorable secondaries on overall response rate, clinical benefit rate, things like that. It's The overall survival that's confounding. So what that means is that and as Jacob mentioned, we've got The efficacy results on the nufflutin side across the primaries and secondaries that follow one another. So clearly, there are pockets of very large benefit. Again, getting back to the stunning efficacy differences, I think, is the way it was described. And this really is a treasure trove of information. And tying that back into the point that Klaus is making relative to reimbursement on the European side and really where we're at Today, in oncology and other fields, if we can define the population that benefits, that's the best place we can be, right? The highest priced drug is the one that doesn't work. So the better we can define the population that the drug works in, the better off we are. And of course, our commercialization will be more crisp in having more solid results from a benefit risk perspective in those population. Thanks very much. Thank you. We have a follow-up Question from Victor Zanther from ABG Sandler. Please go ahead. Your line is open. Yes. Hi, and thank you for taking my follow-up question. So going back to the Mottola study that Joachten referred to where you showed that overall survival depended a lot on The lenalidomide III period, is there anything there that's driving any difference in overall survival trends? Of course, that's But for median overall survival, just curious about that point. Yes. I'll turn that to Jacob Enklaas For their comments. We don't want to disclose data today, but the answer is yes, Victor. So you can find A lot of patterns in how extensive the lenalidomide use has been and how that impacts Those patients that have used a lot of lemamyalidomide, those groups, that favor is meloxicillin stronger. Yes. We will most likely disclose this at some point. I'm not sure at IMWG if we get that presentation, but that's a very interesting set of data as well. But as that goes both ways, I guess, that's if you had a longer than an implied free period, you had Better outcome or worse outcome from El Flufender? Yes. It goes bidirectional. No, that's correct. Yes. I mean, if you have a longer period and you lift the lenalidomide before that, it benefits, It favors pomalidomide. If you have a lot of lenalidomide use in short period, it favors no solution. That's correct. Yes. And just a final question. On these subgroups that we are talking about, do you expect to show any statistical significant Yes, benefits of the subgroup? Or will this be Showing trends to the FDA? Or how should we think about that? I'll turn that over to the question, Jacob. I cannot short comment. 1 should be careful by talking about specific significance when you don't you didn't have a null hypothesis around that. But what you can claim is that there's full 95% confidence in the volatility, they're larger than 1 or smaller than 1, right? And I mean those differences already exist in the materials. Okay. Yes, yes. So yes, thank you very much. Thank you. We have no more questions from the line. I will hand it back to our speakers. Okay, great. Well, thank you, everyone, for participating. Again, I think the key points here are, Again, I think the key points here are, as stated, this meeting superiority on the primary endpoint of Progression free survival across the intent to treat population is very important. We see overall directionality Positively in melflupin's favor across the intended treat population as it relates to response rate, clinical benefit rate and others. It's the overall survival results that are mixed. We are actively cooperating with the FDA to understand those results better. And in the meantime, our trials in earlier lines of therapy are on partial clinical hold, while we continue to market COPAXO So in the United States, based on the current Horizon label. We certainly look forward to the IMWG meeting where we're submitting a late breaking abstract and targeting a full disclosure of the And targeting a full disclosure of the ocean datasets, and we look forward to that. So with that, I'll wrap up. Thank you very much, and we'll talk soon. Bye now.