Okay, great. Let's get started. My name is Jason Kantor. I'm Chief Business Officer here at Nurix Therapeutics. I'd like to welcome everyone here who's in the room in San Diego and to all the folks on the webcast. Welcome to Nurix Therapeutics ASH 2023 Analyst Event. We've got a lot of data to share with you tonight. It was a good day here at ASH with the posters for 2127 and 5948. And I'd like to welcome up to the podium, Nurix's President and CEO, Dr. Arthur Sands. Arthur? Thanks, Jason, and I'd also like to add my words of welcome to everyone. It's been a very exciting ASH 2023 for Nurix. We had a couple major presentations at this conference, and we'll be talking about those tonight. Before I get started, I'd like to just remind everyone, we will be making certain forward-looking statements, and we refer you to our filings regarding our risk factors with the SEC. We will be talking about two molecules tonight. Nurix has two exciting targeted protein degraders in the B-cell malignancy space, NX-5948, which is a highly selective, pure BTK degrader, and NX-2127, which is a dual-acting agent, degrading both BTK and IKZF1 and 3, which makes it an immunomodulatory agent at the same time as degrading BTK. Again, we'll have two separate presentations on these. But before we dive into that, I want to share with you some sort of big-picture view of how we see this evolving space. So based on the data we see now, the totality of the data to date, which is still early but very encouraging, we believe BTK degraders have the potential to displace BTK inhibitors in this extremely important market. In addition, how can they do that? Well, we have molecular evidence that's now growing quite strong and clinical evidence that we can overcome with our degraders, resistance mutations that are emerging at a greater and greater rate to the BTK inhibitors. If the degraders can offer this ADVantage over inhibitors, we think this is a strategic ADVantage, it's a clinical ADVantage, this is a big ADVantage for patients. Third, we think the degrader mechanism can actually expand the market opportunity from that of BTK inhibitors currently. And we think the molecular mechanism, the underlying this potential for expansion, is that we're not just inhibiting the kinase activity, we're actually removing the protein and destroying the scaffolding function of the protein, which means we hit the target harder. We expand that functionality associated with removing the target from the cell. This could expand into NHL, and we believe also with the safety profiles that we see so far for NX-5948, into autoimmune diseases as well. So we aim to expand this market opportunity. And of course, these two agents have differentiated profiles, and we'll be delving into that tonight. Even as is, the market opportunity for BTK inhibitors is quite large. And it, they've been very effective agents, and they've really led the way in targeted therapy in CLL and certain NHL indications as well. But what's interesting, if you look in the bar graph to the right, the rightmost bar graph, I know the colors are a little hard to distinguish, but ibrutinib is the darker color, and it owns the lion's share of this market. You see it's starting to go down. The other inhibitors are making inroads into this market, zanubrutinib, acalabrutinib. But what's also interesting, even though that's occurring, is that they really haven't penetrated ibrutinib market that much, if you think about it. And I believe that's because although they're excellent agents as covalent inhibitors, they're not actually that different if you stand back and look at, again, the totality of the data. Now, degraders are different. So this is the way we see the world here. The first generation, next generation covalents, and now the non-covalents are all really interesting and excellent agents, but they're not actually that different from one another. The degraders offer a really step up here. And again, the foothold that we're establishing is in the area of these resistance mutations that are occurring. And so we like to say resistance is futile, which is a bit of a stretch. We understand that because cancer cells are very clever, they all find some way to get around agents we invent. But the point is, you want an agent that is hard to get around, harder to evade, harder to become resistant to. So you get depth of response early in patients, you get prolonged response to agents, and such early and deep responses bode well for patients in terms of their prognosis overall. So this is why you want to avoid resistance mutations, if you can, totally or as long as possible, and we think our degraders can do that. Now, what is the molecular basis and cellular basis for making such a large statement? We rolled this out in ASH 2022, really breaking the story about how degraders can address these mutations. I love this picture, this, this one data picture I'm going to have in my introduction. Let me walk you through it. Every column here, the top, across the top, these are the most commonly occurring resistance mutations that we see in our patients, and people see broadly in their patients as well. We've engineered these into cell lines via CRISPR, so we have each mutation isolated in a uniform cell line background so that we can test all of the inhibitors, and we can profile our degrader against them. We do this, you know, heavy-duty benchmarking against our competition. So in green across the top, you see NX-5948, which is our most potent agent against BTK, the pure BTK degrader. You can see green is the most potent cell killing, and we hit all of these mutations. Then as you look down at the first generation, next generation, and the non-covalents, you see all their liabilities. As the colors go down to red and even blue, these are resistant mutations. These drugs are not efficient against these blocks. So they all have their liabilities, their blind spots. This is why we think the degraders can take over this market. This is the molecular basis. In one image, you can see it, and that is what encourages us, and in fact, we're seeing this in patients now. So keep this in mind as you consider all of our data as we've rolled it out here at ASH. So just what are the major messages that we published today? Actually, it was a great poster session today, a lot of activity at our posters. So first, for NX-5948, we have positive preliminary efficacy data early in phase 1. Across all doses that we've tested, we see responses. That's impressive in a dose-escalation trial. Favorable safety profile today with NX-5948. Very important, this allows us to consider earlier lines of therapy to, again, to compete with the inhibitors. And we believe we have an emerging best-in-class profile with this degrader. We also know that we now have other degrader competition coming in. We have BeiGene, we have AbbVie. We're encouraged by the fact that there is competition in the field, that degraders are gaining interest level across this field, but we believe we have the best-in-class opportunity. For NX-2127, we published today a positive update on our findings, greater numbers of CLL patients, NHL patients, our second CR in a very advanced case, an MCL patient, very impressive, complete response. Deep and durable responses we're seeing. We now have patients, I think one over a year and a half, another over a year on therapy, with complete responses. And this is a dual-acting agent. This is a first-in-class dual-acting agent, which we think will have important impact, especially in NHL, but also we've been very successful in CLL, and we've seen our response rates rise as we've increased our treatment periods. That's my introduction and why we're so excited to have you all here tonight and to be part of this next wave of BTK-targeted degradation and seeing firsthand what it can offer and how it's evolved just in the past year here now at this, our second ASH presentation ever. We're very privileged to have Alexey Danilov, one of our leading sites for both 2127 and 5948. He has the most clinical experience of any investigator that we have with 2127. Alexey has been a very important advisor to us as well, an advisor to his patients. We're very, very grateful for all the patients that are enrolled. We always get to hear these anecdotes from our sites about how our patients are doing. We're very moved by that. We're very grateful for the enrollment, Alexey, and grateful for you to be here tonight, presenting. So he'll present 2127, and then we'll have a separate presentation on 5948 from Paula O'Connor, our head of clinical development. This is the first official clinical presentation of this program ever, so this is very exciting. Without any further ado, I'd like to introduce and call up Alexey, please. Thank you. Thank you very much. Thank you. Thank you so much for inviting me to speak here and help advance the field of BTK degraders. I'm a physician scientist, so I manage an R01 and LLS-funded laboratory. So, I've mostly focused on targeted therapies, and this field, in particular, has been of much interest to me for many years. I actually have collaborated with a chemist where we are still trying to develop a couple of degraders, not with this particular target. But the point of this is to say that I certainly believe in this field, and I do believe that this is an emerging class of agents which will change the landscape of treatment of non-Hodgkin lymphoma and CLL in the future. In fact, I got an email from John Seymour earlier, who asked me for the slides and also said, "Well, you've been saying this long ago, long ago, and finally, the field caught up." So I was very happy to hear that from John. Anyway, so I'll briefly describe the data from a phase 1 trial with NX-2127. As Arthur has already introduced you to this concept of a dual BTK degrader and immune modulator. So you may know the data that, for example, ibrutinib BTK inhibitor has been the combinations with lenalidomide and other IMIDs have been tried, and somehow it hasn't quite worked for various reasons, not from the standpoint of efficacy, but from the standpoint of side effects. So I'm really excited to see this data or show this data, where there is a successful—for the first time, a really successful combination of a BTK-targeting agent and an immunomodulating agent in one molecule. And what you can see here on the left side is degradation of BTK via interaction with the E3 ligase complex, which ultimately results in degradation via proteasome. And as you know, the immunomodulatory part is probably more important in a T-cell setting, although it's also important in a B-cell setting. But more important in a T-cell setting, where modulation of E3 ligase results in generation of new substrates and degradation of Aiolos and Ikaros, which ultimately enhances cytotoxicity against tumor cells. The clinical trial design is presented here. This is a classic dose escalation schema, following a 3-by-3 design, where basically any type of patients could go on the study as long as they have a malignant B-cell. And on the right, there are several cohort expansions with a particular focus on CLL, SLL, mantle cell lymphoma, as well as diffuse large B-cell lymphoma. I will reiterate also that this is an oral agent administered once daily, and I can't stress how important it is for patients to be able to have access to therapy like this, as opposed to IV therapy. You know, when we think of other lymphoma-directed therapies which require frequent infusions, be it loncastuximab, tafasitamab, obinutuzumab, this is a huge deal, actually. And once a day is very important because that means compliance. In general, our patients are fairly compliant, but not when they have to show up in an infusion room every week or have to take a drug three times a day, for example. This is the study population. At this point, there are 54 patients. The median age is 70 years for lymphoma and 74 years for CLL/SLL. So this study is actually fairly unique, and I explained it to a couple of folks who stopped by the poster that in many of our trials, we enroll this younger patient population, which is really not representative of whom we see in the clinic. The median age at, of diagnosis of CLL/SLL is 70-72 years old. By the time they get to therapy like this, they're supposed to be 74, 75, and you can see the range goes to 92, 90. Of course, they say 90 is the new 50, but I, I don't know. Maybe I'll believe it when I get there, but I don't know. Anyway, nevertheless, it's just to make a point that it's a highly representative patient population. And what if you look below, some of these patients received up to 11 lines of therapy. And, you know, I treat CLL every day or almost every day. I do take some time off, but I will struggle to name 11 lines of therapy. But it just tells you that these patients are heavily pretreated. They would have received multiple chemotherapy lines, so that basically increases the genetic complexity of disease and resistance to all therapies that follow. And importantly, patients have also received BCL-2, like, particularly if looking at CLL cohort, 80% of patients received both BTK and BCL-2 inhibitor therapy, so this is really an unmet medical need. Nothing's approved in that space. Well, now pirtobrutinib is approved in that space, but that's it. And some patients, what you can see, 25% of patients received both covalent, non-covalent, and BCL-2, BTK inhibitor and BCL-2 inhibitor, so triple refractory. I guess we can coin this new term here today, and there is really nothing approved in that space. So very heavily pretreated group of patients. On the other hand, on lymphoma side, some patients got CAR T and even NK CAR therapy or bispecific antibody therapy, and still, it's still high median, a high number of prior therapies as well. So of course, the general mechanism of resistance to BTK inhibitors is BTK mutations, and there is some variability as how applicable it is to CLL versus lymphoma. In CLL, it is almost exclusively a driver mechanism of resistance, particularly to covalent BTK inhibitors. The story gets a little bit more complicated with pirtobrutinib. But nevertheless, you see that at least in the patients where we tested, where the results were available, many patients had C481S mutations, as well as kinase dead mutations, for example, L528W, which also confers resistance to pirtobrutinib. There may have been some pirtobrutinib patients. Some patients also had mutations in BCL-2, which we have described in CLL follicular lymphoma as a mechanism of resistance to venetoclax. BTK degradation occurred very rapidly upon treatment with NX-2127. What you can see here is that regardless of the dose used, there was full BTK degradation within a couple of days following NX-2127. So, I guess my interpretation of this, I guess probably if we used 1 milligram and escalated by 5 milligram, maybe we would have, we would have had some additional curves here. But, you know, take it for what it is. Even at the dose that we tested of 100 milligram that can be presented here right now, there is a very effective degradation of BTK, so on target, confirmed ex vivo on target effect, which is very important. And this is the pharmacokinetics shown on the left, and this is Ikaros degradation, which is actually interesting too, you know. So you don't, you do not achieve 100% degradation of Ikaros. I don't know if you want to do that because it does have multiple functions in T-cell biology. So I wouldn't claim that I'm a T-cell immunologist, but at least from what I've read, you know, full disappearance of Ikaros may be associated with some issues in the disruption of immune response. So this may be actually just enough, you know. So I don't know if 100% is absolutely necessary. So the safety profile, of course, safety was the primary endpoint, and the safety profile basically tells us that the drug was really well-tolerated. Fatigue is common in our patients, and as BTK targeting agents do take a couple of weeks to work, fatigue gets reported. Patients come as fatigued, and if they don't mention it at outset, you know, it gets reported later, and we can never attribute fatigue just to disease because you never really know. But overall, I will say that the side effects are fairly consistent with what you see with BTK kinase-type inhibitors. So there is some bruising contusion, some neutropenia, lymphopenia, you know, some infections. But overall, the frequency of grade three ADVerse events is quite low. Hypotension is something which also happened. Again, all of these patients have been treated with BTK inhibitors. Many of them had to stay in a BTK inhibitor right up to the very point, up to the very day of starting NX-1607, you know, wash out, of course, was followed, but wash out is very short there. So it's sometimes even difficult to discern what's due to what. And what's also interesting to see that in many phase 1 trials where we use BTK inhibitors, the frequency of AFib goes up as the trial progresses. So here, the opposite happened. The frequency of AFib was higher last year than it is this year. I think it's a reflection of two factors. Well, A, we are now more comfortable in enrolling patients on the study. You know, it was difficult—it's always difficult to enroll first 5 patients when you don't know what the drug does. So only patients, and the eligibility is very liberal here, eligibility criteria, very liberal. So we did enroll sicker patients, pre-exposed, who had previous AFib on BTK inhibitors. I had actually at least one patient like that. And now that it's expanded to still to sick patients, still to highly, highly refractory patients, but maybe those who also potentially have other trial options, AFib rate goes down. So I think that may be just a function of that, but overall, well-tolerated drug. This is the responses. This is our responses, and the formal response rate by strict criteria—stringent criteria is 40.7% in CLL/SLL. This is obviously the largest cohort of patients, 27 patients here. But, you know, as you can see that many more patients actually derived clinical benefit, and some of them still have not achieved the 50% mark necessary to call partial response. There are also some blood criteria to call partial response, and then the response needs to be confirmed a few months later. And so associated related to that, the objective response rate has increased from last year to this year. And again, this is expected if the drug is effective because patients stay on study longer. We have more time to rescan them, adjust for any issues that might be going on, adjust the dose if necessary, and keep the patient on drug. And so therefore, responses are going on. But, the quality and frequency of response goes up. But, you know, if you look at this whole group, the clinical benefit is very significant. You know, I had patients who stayed on the drug for nine months before they achieved response, but they benefited clinically. They don't care if they're in PR or, you know, near PR or near CR, as long as they can do what they need to do, our patients. In many patients, responses were durable. I still have patients who were enrolled a long time ago when the trial just opened, and they still are on treatment and doing well, just come to the clinic once a month to pick up their bottle. You can see here that basically responses occurred at all those levels. The colors blur a little bit, but overall, 150 milligram doses were highly effective across in the CLL group. And with NHL, as always, it's more complicated. There, it's a, you know, it is more heterogeneous group, so there are DLBCL patients, FL patients, MCL patients, MZL patients. So all of them have variable dependency on BTK pathway. And that is what you see is consistent what you would be expecting to see. There are some patients achieve stable disease, but what's impressive is there were patients who achieved complete response, patients with DLBCL, patients with Follicular Lymphoma achieved PR, but we simply don't have enough to exactly know how these patients are doing. And there were patients with Mantle Cell Lymphoma who achieved responses as well. So there were responses seen across NHL subtypes. And you know, what would be interesting to figure out down the road is how much immune modulation actually contributes to these responses. Oops, sorry. Anyway, and in some patients, responses again were very durable. In heavily pretreated DLBCL patients, you can see that some patients stayed on drug for over a year. This is one particular case: an 84-year-old woman with multiple relapsed ABC DLBCL. ABC DLBCL means that they tends to be more reliant on B-cell receptor signaling. BTK had 4 lines of aggressive therapy, including ibrutinib, lenalidomide, rituximab, chemotherapy. And at first assessment at 2 months, she achieved a CR, and after 15 months of follow-up, she still remains in complete response. You know, 84-year-old woman doesn't have that many other options, honestly. So certainly a life-saving drug for our patients. This is an example of a rapid response in patient with mantle cell lymphoma, who underwent stem cell transplant, chemoimmunotherapy, ibrutinib, and underwent complete response after week 8, confirmed at week 8, confirmed at week 16, and it remains in complete response, having come off therapy by choice after a year and a half. So in conclusion, NX-2127 does have a manageable safety profile. It's overall consistent with what we see with BTK-targeted therapies, maybe also immunomodulatory therapies, but I'd say that it does feel like a BTK inhibitor. I'd say lenalidomide, typically, I see more side effects than what I see with the NX-2127. I will admit the prior disclosures. I don't know what they were before, but yeah, sure. Treatment results in very encouraging and durable responses in a very difficult-to-treat patient population. Unmet medical need, triple resistant, triple refractory, double refractory CLL, as well as non-Hodgkin lymphoma, which has progressed following novel therapies, including CAR-T and bispecific antibodies. Thank you very much. Thank you, Alexey. We're gonna move on to Paula. We're gonna have Q&A at the end of Paula's session, for both topics. So I would like to echo the thanks for your participation this evening and also introduce myself formally for the first time to you as a group. My name is Paula O'Connor. I am a hematologist oncologist with a specialty in B-cell malignancies, and I've now been here at Nurix for a little over a year and a half, and I get the pleasure of working with this team to develop both of these assets, specifically NX-2127 that you've already heard about, and now I get to debut 5948 with you. 5948, NX-5948. I guess I have to press harder. Hmm. Okay, so let's try that again. Pardon me. Okay, there we go. So Alexey's already given you an overview of the mechanism of action for NX-2127, which is our dual degrader, and many of the mainstays of the activity that you see with NX-2127 are maintained in the MOA for NX-5948. So specifically, we once again use a harness and a linker to bring the BTK protein to link that to an E3 ligase, targeting it for degradation. And ultimately, when that protein is degraded, we release the linker so that you can have recurrent activity within the cell. So this catalytic component, this catalytic nature of our degrader, is one of the reasons why you want to use a degrader over an inhibitor, which has a one-to-one interaction. So one degrader molecule can impact many BTK proteins. Too, what we also know is that when you are actually getting rid of that protein, you are also impacting the scaffolding function of the BTK protein, and that is critical because it does, in fact, impact B-cell signaling. So we are beginning to see activity, as you've already seen with NX-2127, and which you will see with NX-5948, that really speaks to activity above and beyond the impact on kinase activity for BTK. We are actually impacting the scaffolding function and thereby impacting B-cell signaling, making your cells more susceptible to cell death. Okay, so I'm a tennis player. I guess my hands are really strong, and that is why these slides are flying. Okay, so here we go. So much like the NX-5948, the NX-2127 program, our NX-5948 program is a phase Ia, phase Ib study. We have, as you can see on the far right-hand side, our typical dose escalation. What you'll notice here is that our doses started a little bit lower than they did with our NX-2127 program, and they extend higher. So our window that we are testing is a little bit larger. What I will also note is that we're currently at dose level three in our CLL cohort, and at dose level six as of last week in our NHL cohort. So this too is another way in which this program differs slightly from the NX-2127 program in that we have two parallel dose escalations taking place. What these two parallel dose escalations allow us to do is to really understand our dosing better across all of the B-cell malignancies that we are assessing by enabling us to enroll more patients. On the right-hand side, you can see the phase 1b expansion cohorts that we plan to open, but I think what's most important for you to see here is, in fact, all of the types of patients that we are enrolling. So just as is the case in NX-2127, we are in fact enrolling CLL patients, patients with DLBCL, that is both ABC and GCB DLBCL. We are enrolling patients with mantle cell, the indolent lymphomas, as you see here, but really importantly, and something that is not typically seen in many of our B-cell malignancy studies, this additional cohort of patients with primary CNS lymphoma. This is certainly a patient population with a clear unmet medical need. In addition to primary CNS lymphoma patients, we are also allowing patients with secondary CNS lymphomas, and this is a known and very common event, if you will, for patients with relapse and refractory lymphomas. So in front of you now, what you are seeing are the baseline demographics and characteristics for the patients that we have enrolled on the study. What I'm going to have you do first and foremost is look at the left-hand column, which gives you an overview of the patients that have CLL. What you can see here is that while the numbers are still relatively small, we, in this study, like the study before, are also enrolling patients who have been double exposed and have the greatest unmet medical need, namely, those who've been exposed to BTKIs and BCL-2 inhibitors. We do also have some patients who have been previously exposed to pirtobrutinib, as you can see here. When we look at our NHL patients, similarly, we are looking at patients who've been exposed to the most active therapies. So we have patients who've been exposed to CAR-Ts and bispecifics amongst other agents. When we look at the mutation status, certainly the numbers of patients with mutations in this study are certainly less than those, but that's a reflection of the number of patients that we've enrolled. By virtue of enrolling these very heavily pretreated patients, who have seen both BTKIs and BCL-2 inhibitors, as well as pirtobrutinib, we know that this number is going to rise over time. As with NX-2127, what we note with our pure BTK degrader is that we're getting rapid, robust, and sustained BTK degradation. So when you look at panel B, what you can see is across all of the dose levels, we are seeing BTK degradation of 90% and more. When we look at our PK, we also see a similar dose-response relationship between our PK assessments and the dose levels that have been assessed. For me, the most striking thing about NX-5948, in addition to the activity data that I'll be sharing in a couple of minutes, is, in fact, its safety profile. And when you look at this slide, I think the thing that should really grab your attention, first and foremost, is the fact that you aren't seeing any sort of cardiac liabilities. To date, we haven't seen any patients with atrial fibrillation or A-flutter, despite the fact that patients have been enrolled with this as a previous condition. And all of our patients, or almost all of our patients, have been previously treated with the BTKI. In addition, you are seeing limited or not any hypertension. So once again, in this patient population who's been previously treated with BTKIs, who is of a certain age, and I may now say that as a woman of a certain age, we all have to worry about hypertension, we are not seeing any hypertension. We do see some purpura and contusion, and what I think is important to note is we know that this is a class effect for all BTK-targeted therapies, and there's nothing that's any worse about the purpura and contusion that we are seeing in this setting. And in fact, what I would say, given the information that we've received from our investigators, is that because patients typically start feeling well so quickly, meaning within a week, they are actually getting out and moving more. So this purpura and contusion that we're seeing, we think is, in fact, a reflection of the fact that they are feeling better and doing more, and then as such, getting a little bit more bruising, if you will. Cytopenias, as you can see, neutropenia and thrombocytopenia are certainly well described with BTKIs. What's most important here is that these are all manageable. They have not been considered related for the most part. We do have some patients, actually, most of our patients have had some form of bone marrow involvement. So seeing neutropenia and thrombocytopenia is something that we expect, and this has not been a major problem. So once again, what I really want to reiterate is that we have not seen any cardiac liabilities, we have not seen any DLTs, and we've not had any treatment-related AE discontinuations at this point in time. This gives you an overview of our safety profile by dose, and I think you can see here very clearly that there is no definitive dose-response relationship between the cytopenias or any of our other ADVerse events that we're seeing. For those of you with experience who have heard us present on 2127 previously, you certainly heard that there had been some confusion, and we had one DLT that was related to a CNS event. We have noted headache here, but we don't believe that this is anything related to the drug. These are grade 1 events, and we're actually following Mini-Mental Status Exams for patients and have not noted any, any cognitive or other CNS issues. So these are the same sorts of headaches that you and I get after 4 days at ASH, wishing that we were at home, someplace else, or having spent 5 hours talking to, I won't say analysts, I'll just say people in general. Oh, sorry. So the slide you see before you now is an overview of our activity. You can see in the far right-hand corner, our CR, PR, SD, and PD rates. You can see that we've had 3 of our 7 patients to date who have had a PR. These are not PRLs, these are PRs. And in addition, you can see that 3 of our patients have stable disease. When you look at the waterfall plot, what is also clearly seen is that we have real reduction in lymph node size, meaning more than 50% in all but two of the patients. What you can also see is that these are occurring at the lowest dose levels that we've utilized to date, so 50 milligrams and 100 milligrams. As I mentioned at the start of the talk, we're now at the 200 milligram dose level and anticipate going to the 300 milligram dose level in the next couple of weeks. This is another depiction of lymph node responses that we've seen in patients, and I love this slide, because I really think it gives you a better sense of the activity that we're seeing in patients. So Alexey used the term previously, "clinical benefit" right? Patients, when they feel better, they feel better. They don't need to have a PR to feel better. They don't need to have a CR to feel better, although they like those. But ultimately, what's impactful is that they have reduction in the volume of their disease. And when you look at the spaghetti plot, what you can see is that all of the patients have some reduction in their volume of disease. And for most patients, that is more than 50% by our first assessment, which is at 8 weeks. And that's irrespective of the dose level that we're using, 50 milligrams, 100 milligrams, and we're looking forward to seeing more for our 200 milligram cohort. When we look at our patients who have been treated for their non-Hodgkin lymphoma, what you can see here is that we've treated a broad panoply of patients, meaning patients with mantle cell, diffuse large B-cell, primary CNS lymphoma, et cetera. And you can see that our results seem to skew in two ways. Perhaps the most important thing for you to see is that while we have patients who see with fairly aggressive disease, who are progressing on the left-hand side, what you can also see is that across another wide variety of subtypes, we are seeing activity for patients with NHL at very low dose levels once again. So we're looking at 50 and 100 milligrams. Now, what is not depicted here and what I know, because I'm actually looking at the data every single day, or maybe not every single day, but frequently, is that we have actually seen more responses as we've increased our dose. So I've already mentioned that we're now enrolling patients at the 600 milligram cohort. And so as we've increased the dose, we've started to see more responses in the NHL, and I think that's a reflection, ultimately, of our getting better tissue penetration and lymph node penetration. What you're seeing right now is our swim lane plot that actually includes patients with both CLL and NHL. Our CLL patients are at the top of the slide, and our NHL patients are at the bottom. We have more NHL patients because, in fact, we've been enrolling in the NHL escalation cohort for a longer period, as reflected by our getting to this dose level of 600 milligrams. When we look at our CLL patients who've only been treated to date at the 50, 100, and now the 200 level, and only one of those patients is represented on this swim lane, what you can see is, once again, that we are getting good responses, PRs, and stable disease. And when we look at our NHL patients, once again, you can see that a large number of our patients are very early in their course of disease. So we anticipate having an update for you regarding our data, certainly by mid-year, targeting a meeting not otherwise specified, because I'll get in trouble if I say too many other things. But suffice it to say, there is more data coming, and we're really encouraged, based upon the data that we have been seeing at lower dose levels, that we will have more responses to share with you. So, in conclusion, I can say that, this is, it's never a great time to have a malignancy, but having been a person who has treated patients with diffuse large B-cell lymphoma 20 years ago and 30 years ago, I can say if you have to have a malignancy like this right now, or CLL, this is the time. You've got lots of treatment options, and I'm certainly hopeful that our drug will be one in the future. Our PK and our PK has shown that we're actually getting the drug in. Our PD shows that we're hitting the target, and most importantly, our activity and our safety profiles show that we are actually providing potential benefit for patients that is durable and maintained. And with that, I will stop. Oh, I actually do have a couple more slides. Excuse me. So thank you. Our vision. So I think I've already sort of hinted that we believe very strongly in this, in these, both of our agents, 2127 and 5948. So in the next couple of minutes, I'm gonna give you a sense of what I believe, what we believe is possible for them. The phase I and II in the next year, we'll be focusing on generating data, specifically for our relapse refractory population in CLL, mantle cell, and Waldenström's. But ultimately, the data that we've generated to date already gives us a sense of what is possible in the CLL arena, and that is, in fact, moving into earlier lines, whether that be in the second line in patients who've already been exposed to either a BTKI or BCL-2 inhibitor, and certainly in the front line, where I do think we have the ability to displace BTKIs and certainly delay/get rid of their potential to develop BTK mutations, which limit the durability of responses that they can see with those agents. We will continue to follow the data, as I've already mentioned, to understand whether we have the ability to move forward in a phase III for a mantle cell, where we know BTKIs and BTK-targeted agents have been extremely successful. I will also note that given the activity that we've seen in DLBCL, that is not limited to, ABC-DLBCLs. We believe that there's a potential opportunity, for us in DLBCL. Certainly, our safety profile suggests that combinations, if not monotherapy, will make that a potential, for the future. My first job in industry, was working at Genentech. I worked on Rituxan. That's not what we're here to talk about, but what I'm here to say is that that has given us a sense of what a B-cell-targeted agent can do. Certainly, what we know, based upon what we've seen in terms of the activity and safety profile for 5948, we believe that there is potential for us to develop this agent in the autoimmune space. This is gonna be another part of our key activities, for 2024 and, and beyond. What I'm showing you right now are two specific models, one for rheumatoid arthritis and one for multiple sclerosis. What's important to note is that when you look at NX-5948, which in these cases are the blue, and the very dark blue, triangles, when you compare the activity of our agent across, compared to a series of other well-validated agents, blockbusters in some cases, what you can see is that this appears to be an incredibly active agent in these models. We believe that this is an area for future exploration. When we think about 2127, Alexey showed you 2 CRs for patients treated with 2127, and he really mentioned and focused upon the fact that we are giving a single pill once a day to these patients. So to be able to affect CRs in patients with multiply relapsed disease, mantle cell or diffuse large cell, is really quite remarkable, especially with a single pill. So certainly, in this upcoming year, we will continue to explore our activity in NHL and really try to set the stage for future development in DLBCL and mantle cell. So this gives you a little bit more of a breakdown in terms of the actual specifics of what we're hoping to do in this next year. As I've said before, we are setting the stage with our phase I programs to really understand the doses that we want to bring forward for NX-5948 in CLL, and for NX-2127 in the NHL space. We will also be looking at the potential for combination, certainly for NX-5948, as we certainly know that combination therapies have been the mainstay for B-cell malignancy treatment in the last decade. Now I'd like to end my presentation, and turn things over to Arthur Sands. Thank you. Thanks, Paula, and could I ask you to come and sit up front here, and Alexey, we're going to—as I close out my remarks, just to get ready for our Q&A session, we do allow questions from the web audience as well. We'll prioritize the room, of course. Just to close out, this is how we see the commercial potential for both these agents. NX-5948 across the top here, our therapeutic goal in these primary BTK-targeted areas or indications is to really and be in a position to displace the inhibitors overall. But in the CLL world, again, we can move to earlier lines of therapy. We believe we can have this whole field bracketed, essentially, with NX-2127, prioritizing NHL with its dual activity. NX-2127 is essentially a combination agent built in. And then also in late-line CLL, offer a real therapeutic alternative for patients. So this is how we see the world evolving with our BTK degraders moving in to offer significant benefit potentially to patients. This is our broader pipeline. I won't go into all, but of course, we focus today on NX-2127 and NX-5948. We're very excited with Gilead to have them license our first IRAK4 program, which is an IRAK4 degrader. We have multiple programs, more programs with Gilead and Sanofi, and we're very excited earlier this year to announce our innovative deal with Seagen to use degraders as payloads in ADCs with this new category of drugs called DAC. So it is part of a much broader story as Nurix evolves. And then just to close out, what you've seen tonight is really the result of a very strong scientific foundation that we've built in targeted protein modulation. We have three wholly owned assets we're moving forward in phase one. We do have world-class drug discovery capabilities. I won't go into all the science that has fueled this, but it's been literally a decade of work to advance not only these clinical programs, but multiple preclinical programs. We have a very solid partnership base, and we think this is very important to be able to fund our programs forward with very strong partners, as well as have our independently owned assets. So with that, we'll open up for Q&A. I'll serve as a bit of a moderator here. Just raise your hands. We have a couple floating mics for questions. So we'll get our mics around. Carrie, thanks for helping us. Go ahead. You have the first mic. Hey, thanks for the question. This is Chris from Leerink Partners. A bit early on 5948 and BeiGene's degrader, but I guess just so far, where do you see key points of differentiation between your two assets and BeiGene's degrader? So, we're not gonna really comment on other people's data recently presented. I think, I'll just take that question and say that, suffice it to say, we, we've looked at the totality of the data presented by our, our future competitors, potentially, in the degrader space, and, and we remain convinced that we will take up a best-in-class position. So this will have to play out as more data evolves. We are actually very encouraged that, now two companies, not just BeiGene, but also ADV, have entered the degrader space, and we think that's very telling, that they realize the potential of the space. So overall competition is good for a space, and we're encouraged. But again, we, we do believe we maintain a profile that is best-in-class potential. Thank you. Peter Lawson from Barclays. Just as you kinda look at the safety profile for your selective molecule versus your dual inhibitor, what's driving that? Is it from that data set, the patients, or is it the molecule, or is it kind of the lack of immunomodulatory effect? Paula, would you like to take that question? So I'd like to say it's predominantly the molecule. Certainly, the patients that have been enrolled in NX-2127 and NX-5948 have far more similarities than any differences. In each case, those patients are heavily pretreated. They are the NX-5948 group is a little bit younger at this point, but with the subsequent patients who've been enrolled, we have enrolled older patients, so I don't think that the patients are the difference. Certainly, you know that immunomodulatory agents, the IMiDs in particular, have a safety profile that does include many of the ADVerse events that we've seen with NX-2127, so most notably the cytopenias, some of the CNS events. So I would probably say that the safety profile for NX-5948 is differentiated by its MOA and its singularity as opposed to NX-2127. I think that's the primary driver. Does that answer your question? Yes. Great. Hi, this is Greg Renza from RBC. Dr. O'Connor, could you perhaps expand a little bit on... I think you talked about the tissue penetration at higher dose for NX-5948, but it seems like the degradation of BTK pretty much complete at 50 mg, and then you not get, I think, higher plasma concentration above 200 mg, at least that was shown. And do you plan to explore the dosage up to 600 mg for both indications? And then secondarily, you talk about the vision of prioritizing the indications for NX-2127 and NX-5948. I'm just curious, when will we start seeing that prioritization? Thank you. Paula? So I like that. Lots of questions. Okay, so, let's sort of, tick down. So the PK profile clearly shows that we're getting the drug in. Now, we know that we are degrading at a very, very high level, so we are incredibly pleased with that. Ultimately, what's happening in the lymph nodes themselves and the actual, tumors, if you will, that remains to be seen, and certainly one part of our program is going to be to continue to collect data across all of our doses so that we really can understand what is happening at the tissue level, as well as what's happening in the blood. As you know, when you're looking at NHLs, you don't always have circulating cells. This is not CLL, where you have circulating cells. So we're actually using PBMCs when we're assessing our BTK degradation, but that doesn't tell me what's happening in the lymph node. So we're gonna be collecting more data, and I anticipate that we'll be presenting on that in the future. Your second question was about how high do we think we're going to go? So certainly what I can say is that we have been really pleased by the fact that we have seen activity in that is measurable in patients even at lower doses. What you might have seen as you were looking at this is that in CLL, and I'll use that as an example, at the 50-milligram dose, we had one PR. At the 100-milligram dose, we had two PRs, and now we're actually going to be going to the... Did I say the 200? I meant the 100 dose, if I said 200. And now we'll see what's happening at the 200 milligram dose. So what we are seeing potentially, and we will continue to look at, is whether we are seeing more responses as we increase the dose and whether those responses are coming earlier. For patients, what we know is that they are feeling better quickly, but certainly the depth of response appears to be really important, and we hope that that will translate ultimately into more durable responses. So we're gonna keep going until we understand the best dose to give. What I will lastly say is that, we've been, I guess, supported in that point of view, in that when we've actually treated our NHL patients at a higher dose, we're actually seeing more responses, which we have not yet shown because this is the ASH data cut. I think that addresses all your questions. Yes? Prioritization. Ah, prioritization. We're getting there. I'll take that, I'll take that one. Exactly. I I give you- We're very data-driven, and we're gonna get there. But you did see Paula outline that we see 5948 as a priority for CLL and with potential to move up in lines of therapy, that's clear. And I think 2127 really has great potential in NHL as a single agent. So again, we think we have the field bracketed with these two agents. We do need more data over time here, and then we will further clarify. Okay, next question, Gil. Gil Blum, Needham and Company. For 2127 in CLL, it looked like there were less incidents of AFib. Is there any reason to maybe revisit a higher dose? Uh, Alexey? Yeah, I would revisit a higher dose. Yeah, I do think it's. And we discussed it at several of our meetings, and the investigators felt were in agreement that revisiting a higher dose would be appropriate. And I think what exact dose was the discussion, right? Whether it's 150 or straight to 200, and I think we ultimately decided on 150. And it's, you know, it's not just AFib. Overall, the safety profile is good. I think there was this mention of some potential neurologic toxicity at 300 mg dose level in a patient with CLL. You know, with this, it's always difficult to determine what they are potentially related to because patients admitted to the hospital, they get multiple drugs, they get this hospital delirium. You know, I have patients who get admitted, before they get anything, they already delirious, right? So it's, these are older folks. So, in my experience, I have to say, I have not seen any neurole-- or any brain neurologic toxicity, in any of my patients, either, NHL or CLL, at any of the dose levels which where we've operated. And I don't remember how many patients we enrolled at our site, but it's certainly over a dozen. You know, some-- I have an 80-year-old who complained, that, "Well, maybe my memory is getting a bit worse. It's not like it used to be a year ago." I'm like: "Okay, well, let's talk about, let's keep talking about it." And two months later, I asked her: "How is your memory?" And she said, "It's great." And I said, "Well, you thought it wasn't so great." And I said, "Well, I don't remember saying that." But, anyway, so my point is, you know, for older folks, you know, 74, 90, 74 median age, so they do have concurrent medications. I would be very comfortable with dose escalating again. Thank you. Eric. Hi. Thank you. Eric Joseph with JP Morgan. So a few questions, all on NX-5948. There were a few grade 3 or greater cytopenias, I guess 3 neutropenia, 1 thrombocytopenia, that were deemed treatment-related so far. Can you just talk about sort of how and when they resolved, and whether there was any sort of dose relationship in the pattern with which they occurred. And then, I'm also curious to get a sense of, you know, given that you've adopted this staggered dose escalation scheme between NHL and CLL, I guess how does the clinical profile that you're observing in NHL kind of inform how might that possibly inform dose selection in CLL as you look to start the phase 1b expansion cohorts? Okay, Paula? Okay. So let's tackle the first one first, neutropenia and thrombocytopenia. When we're looking at patients with these B-cell malignancies, the development of neutropenia and thrombocytopenia in either patients with CLL or NHL is not something that is unusual in any way, shape, or form. And certainly, what's most important is that our trial does allow patients to receive growth factors, and as such, those patients who did, in fact, these isolated number of patients, and they did only have one or two cases of neutropenia per patient, they have been able to stay on study with the utilization of growth factors. Not every patient has had recurrent cycles of neutropenia, and that is also a reflection of the fact, of that bone marrow disease. So this is something that we will continue to follow, but the key message is this is manageable and expected in this patient population. So to your second question about our parallel dose escalations and the impact of the dose that we choose for NHL on CLL, one of the reasons why we're doing the two different escalations is to make sure that we are treating enough patients with CLL and with the multiple different subtypes of NHL to really understand whether there is or is not a difference. And so we are looking at them really individually. That having been said, if in fact it is clear that one dose suffices for both, then we will utilize it. The safety profile at this point in time for the 50-200 mg dose level and the 200+ dose level is not different. So certainly, safety at this point in time is not going to be the differentiating factor. Does that answer your question? It does. Maybe just to put a fine, you know, kind of operational point on it, I suppose, I'm wondering how much additional dose escalation in CLL might be sort of a gating factor to starting the expansion cohorts, if that makes sense. So I want you to know that Arthur asks me the same question quite frequently, and I, I'm gonna give you the same answer that I give him, which is: I would like to see the data, because what I can see thus far is that we're getting greater activity with a maintained safety profile, and I don't want to leave any activity on the table if I don't have to. So, what I can promise everyone here is that we are looking at the data very, very carefully because this, we have a shot here to actually make a real difference. And what we're learning at ASH in general is that the depth of response matters, and so I wanna see how good we can be before I make any promises. So that's, that is what I tell Arthur literally once a week. Okay, thank you, Paula. So go ahead. Eric, did you have another one? Yeah, one more follow-up, if I could. Just acknowledging the fact that this is an increasingly competitive space, hey, can you just talk about any efforts you're undertaking to really enhance the rate of enrollment in your current and planned studies? Anything by way of site expansion. Thank you. So yeah, we're targeting, you know, over 40 to 45 sites to open in 2024, so really massive site expansion, not only in the United States, but also countries in Europe. We're being very aggressive with the NX-5948 in particular. I think, Paula, if I were to reveal more about our one-on-one meetings, that the enrollment is picking up quite a bit as we gain experience with responses. I mean, people get very enthusiastic to get their patients on. They're seeing responses. That is probably the primary way to drive enrollment, is that you're able to benefit your patients, and that's, we're seeing that, and so we expect it to continue to grow and really have some significant numbers through 2024. Next. Okay, go ahead. Joel Beatty from Baird. Dr. Danilov, with several BTK inhibitors and degraders in development that could reach the clinic, how do you think physicians will ultimately choose between them, and how much could personalized medicine play a role, such as a patient-specific tumor burden and mutational status? Yeah, so that's a very good question. I think there are two questions here, and you sort of put them, you sort of mentioned them together, both inhibitors and degraders, right? So those are two different classes of drugs. So, regarding the inhibitors, I think at this point it's pretty clear that we will stay with covalent inhibitors as in the first line.... or whatever, second line, but in initially. And at this point, these are zanubrutinib and acalabrutinib. And as you have seen, the ibrutinib market share is dropping pretty rapidly because of the extensive data which confirms increased safety and potentially efficacy of selective BTK inhibitors. So that's that is I think it's a fairly easy question, and at that point, patients don't have mutations. Then we do have pirtobrutinib. Well, what is interesting there is that I actually see an uptick of pirtobrutinib use in frontline setting, even though there is neither data, nor it is approved. I don't think that's the way to use the agent, but we see that happening in the community already. And I know why this is happening, because to the community, it's a BTK inhibitor, period. I don't think the community physicians differentiate between covalent and non-covalent. So I think it will be interesting to see where this goes. Actually, that's one way, one place where I don't have a crystal ball. Of course, Loxo is fairly active at pushing pirtobrutinib in earlier lines of therapy, so it is possible that we will be choosing between the three BTK inhibitors. And if pirtobrutinib goes into the front line, then we will be stuck with all the mutations which confer resistance to all three, right? So, in that sense, I don't think that means there will necessarily be that much, as much competition between the degraders and pirtobrutinib as we might think, okay? I don't have a crystal ball. I don't know what's gonna happen. But, regardless, even today, even in a very refined setting of a clinical trial, which BRUIN is, the duration of response to pirtobrutinib is underwhelming in mantle cell lymphoma. It's not being developed in other NHL aggressively. It's about two years or less in CLL, so that space will still be open. Regarding differentiation between different degraders, I think Arthur already mentioned that. Well, there is really no data on the AbbVie degrader, so I have no idea whether it works or doesn't. There is some data on the BeiGene degrader, which so far is fewer patients than what we have with Nurix compounds. So I don't think I can answer that question. As a clinician, I'd love to see more than one drug in class approved, ultimately. You know, I use, at this point, acalabrutinib and zanubrutinib interchangeably. I have clinics on Mondays and Wednesdays, and Mondays are acalabrutinib day, Wednesdays are zanubrutinib day. So I'd like to—the same to happen with BTK degraders, but at this point, I can't- Okay, thank you. Yeah. But at this point, I can't differentiate them. But, like I said, NX-2127 is great experience. I have only positive experience so far, and I do think with the potential of IMiD efficacy, it, it is the best in class. Yeah. Well, that's a good ending. Okay. We have a question here, Steve. Yeah, Steve Willey from Stifel. I'm gonna stick to Dr. Danilov just 'cause I think he's, he's primed to give some information here. But, Yeah. So I know it's been said that you haven't seen any AFib or cardiac issues or hypertension with 5948, but what's the usual median time to those events that you see? Is there much variability across the BTK inhibitor class? And I'm just trying to think about this in the context of most of the follow-up data that you have thus far is with the lower 50 and 100 mg doses. And then I have a follow-up. I'm sorry, can you repeat the question again? The question was, what's the typical time to AFib- Oh, I see. or hypertension, and do you see a lot of variability among the BTK inhibitors? Amongst the BTK inhibitors? So no, you're not asking the degrader question, right? Right. Am I right? I'm guessing we don't know what that answer is yet for the degraders, right? Okay, so let's start with BTK inhibitors. It certainly is an easy answer because there's more data there. Most adverse events do happen within the first six months. It is also true for atrial fibrillation, and it is also mostly true for hypertension, if it gets noticed. So, both atrial fibrillation and hypertension is different from many other adverse events in a sense that the risk of AFib and hypertension doesn't necessarily goes away. And, you know, the curve looks like this. It's sort of like a hyperbolic curve, like when there is a lot of adverse events which occur in the first six months, and then while it does plateau, it never quite disappears. So you do see some additional events at 2, 3, 4, 5, 6 years, and that is particularly clear with the ibrutinib, based on the randomized RESONATE-2 study, which has a very long follow-up of 8 years, and eventually, it does peter out. With the degraders, the follow-up is still fairly short, right? So we are talking median follow-up, you know, 9, 10, 12 months. So obviously, the AFib that we do see tends to happen fairly early. I can't... You know, maybe Johannes will remember the median time to onset, but I would suspect it will be similar to what we see with BTK inhibitors. Okay. And then just a last question, and I know that you don't want to talk about competitor compounds, but I think it's kind of an interesting question. So, the pirtobrutinib resistance data that was shown on Saturday, they suggested that they had a similar response rate in a very small number of patients who had kinase-dead mutations at baseline. And so I'm just kind of curious, and I don't know who wants to answer this, but if you think that there's a scaffolding function associated with that drug, kind of that closed conformation hypothesis, or whether or not you just think that it was because those kinase-dead mutations were present at such a low variant allele frequency at baseline? Okay, that's a tough question. Alexey, would you like to tackle that first? Yeah, well, so I do think there is a scaffold function, right? And again, I will remind you that we do, like NX-2127 in particular, does have a dual function with both BTK degradation and IMiD effect. And we actually, I don't know if Arthur will stop me if I'm not supposed to talk about it, but we did study it in the lab, and the IMiD func-- IMiD effect is very clear. So there is clearly enhanced cytotoxicity against both allogeneic and autologous model. There is enhanced immunologic synapse formation. There is enhanced synthesis and secretion of cytotoxic cytokines, such as perforin and granzyme B. There is skewing towards proinflammatory state with enhanced secretion of interferon gamma and TNF-alpha. So there is a very clear IMiD effect with this molecule, which I do think in some settings and don't ask me exactly which, but it may be in all settings, will be very, very important. And in the meantime, so that alone might potentially overcome some of the BTK mutation resistance effect that you see. And then, yes, indeed, scaffold function that has been presented by the University of Miami group, and that effect is very, very is also at this point indisputable and seems to be and is overcome by the BTK degraders. Does it answer your question? I might take the second part of that. Yeah, which- Almost, yeah. The, you know, there wasn't a lot of discussion about scaffolding function last year other than us, as we brought it up, and we have clear evidence via degradation, as Alexey alluded to. So I just find it noteworthy that now inhibitors are talking about scaffolding function. But I haven't seen enough evidence to convince me, other than one PowerPoint slide, that there is some type of scaffolding function cartoon. But I think by removing the protein, we clearly see that we have downstream kinase signaling activity that goes away. We can hit the kinase-dead mutations, which are clearly signaling downstream, and they all—no inhibitor hits that. So, I'm a little bit skeptical about an inhibitor with quote, unquote, scaffolding function. But it is, I think it's just noteworthy that at least it is being acknowledged that it's a real growth signaling pathway, and certainly people want to hit it. But I think this, the degraders are going to be the way to achieve that. That's my view currently. So I think we're getting a little short on time. One more question, perhaps, or? Yeah. Hey, Arthur, Joe Catanzaro from Piper. I think you teed me up a little bit here. My question is about the hypothetical second-line trial for NX-5948, and sort of relates back to the first line setting and whether there's any evidence or data to suggest that the mix of resistance mutations in the second line setting could change depending on the covalent inhibitor that's used. So as more zanubrutinib is used, is there evidence that its resistance mutations are different than ibrutinib, and does that sort of tee up NX-5948 to cover some of those where pirtobrutinib and the non-covalent inhibitors maybe cannot? Very interesting question. I'll just start off on that one, that, you know, part of the advantage of being at ASH and being on the poster floor and mingling and talking with everyone, is that you do hear things and learn things that you wouldn't otherwise learn if you didn't attend the conference. One of those was that, tonight, was that zanubrutinib seems to skew the resistance mutation profile to L528W, which is a kinase-dead profile. And actually, you know, this is hearsay, but that it may be the predominant mutation that occurs in the setting of extended zanubrutinib treatment. If that's the case, then that is a very problematic mutation for pretty much all of the inhibitors. Anyway, I'll pause there and turn to Alexey. You have a lot more experience with... Is L528W to zanubrutinib, or do some inhibitors have a different mutational profile? Certainly, pirtobrutinib does, than the covalents. Yeah. So yes, pirto does. Yeah, and indeed, in a still fairly small number of samples. Well, I mean, it's hundreds, but still fairly small number of samples, it does seem that the kinase-dead mutation signals show up a little bit more with zanubrutinib. This also appeared to be the case in the earlier Blood Advances paper, which only had 20 patients, which identified some of the unusual or non-classical, again, let's call them mutations, with zanubrutinib. So maybe it also, on one hand, maybe it is slightly different drug with a slightly different PD, but it is indeed a concern. And if this trend continues, the question will start coming up whether zanubrutinib should be used as widely as it has been used because it may prevent use of pirtobrutinib in relapsed setting. However, I do think that we need more data on this. I do think it's also, again, important to keep in mind that the degraders that we've shown today do overcome these mutations regardless of what they are. Okay, so I think, with that, we should close. I want to thank everyone for participating again tonight. I know it's late here in San Diego after a very long day, last day, major day at ASH. It's been a great conference overall and certainly, a very significant experience for Nurix. We're very excited to move our agents forward, and we thank you very much for your participation. Good night.