Nurix Therapeutics, Inc. (NRIX) Earnings Call Transcript & Summary

Good evening, everyone. My name is Arthur Sands. I'm President and CEO of Nurix Therapeutics. And I'd like to welcome you to our 2025 Investor and Analyst event broadcasting here from Orlando, Florida after -- well, still in the midst of a terrific ASH, but getting near the end. But a lot of exciting new information at ASH this year, not only for our programs, but many others that are relevant to the incredible opportunities to improve therapies for patients with CLL and many other diseases covered here. So really absolutely terrific meeting. So we're very excited to have you all tonight, and I'll be making a few opening remarks, and then we're going to dive -- do a deep dive into our data that was presented here today. We're very fortunate to have Dr. Alan Carr here from University of Miami, who will be presenting the data, a fantastic expert in the field, one of our key investigators. We're very excited to have you. Thank you, Dr. Alan Carr. And then we'll have our Chief Medical Officer, Paula O'Connor, talk to us about our development program for bexobrutideg, our best-in-class BTK degrader. So let me dive in with our very exciting disclaimer slide, and then we'll move from that to the pipeline. So I know, of course, we're going to focus on bexobrutideg or Bexdeg as we call it for short, NX5948 at the top of the slide. But just a reminder that we have many other terrific programs. And in addition, it was a really, I think, big day for our inflammation portfolio as well. So I would be remiss if I didn't mention the progress today made in the field with one of our colleague companies, Kymera for STAT6, our STAT6 degrader NX391 -- we have partnered with Sanofi that's in IND-enabling studies. I think it's a very exciting time to see degraders expand beyond oncology. So I definitely have to mention that program. And if there are questions tonight, we're happy to talk to those questions as well. But in addition to STAT6, we have our IRAK4 degrader in I&I with Gilead. These are important parts of the Nurix pipeline. We maintain 50-50 options on these programs and then multiple oncology programs as well. And so let's go forward, but just again, a reminder that we have quite an emerging and significant pipeline. As part of my introduction here, I'd like to tee up some of the key points about bexobrutideg that we find most compelling and we think defines its best-in-class status. So it was the first DEG. What do we mean by that? We're very proud of having the suffix -deg approved by international naming authorities for the nonproprietary version of our name. And this really relates to us the unique pharmacology and great potential of degradation as a truly differentiated class of medicine as compared to inhibitors. So a few of these points on the slides I'm going to run through, I think, underscore that. But first and foremost, bexobrutideg is potently -- is highly potent and exquisitely selective degrader of BTK. And what I'm showing on the left here is a global proteomics plot that shows that the only protein we hit and that is degraded is BTK. And anything in the upper left quadrant is very significantly degraded. And you can see it's a long protein there. Very clean drug. And this establishes, I think, the molecular underpinnings for bexobrutideg, having an excellent safety profile, which you'll hear about tonight as well as an excellent efficacy -- emerging efficacy profile. There are molecular reasons for having those profiles, and this graph captures it. Let me back up here. Okay, yes. So the other major point here is we know that we can overcome the resistance mutations, mutations that evolve to the existing BTK inhibitors. And this is a very significant and emerging issue in the CLL space. And what's pictured on the left here is a heat map that shows in green is the most highly potent cell killing of these tumor cells. And across the bottom of this picture, you can see the variety of resistance mutations that we encounter in the clinic. And what's immediately apparent, just looking at the colors is that all the inhibitors, we compared -- so we do an apples-to-apples comparison here with bexobrutideg. We're bright green across the way, which means nanomolar cell killing across all of these resistance mutations. And you can see red indicates a loss of potency of 5,000 fold. And there's a lot of red on the slide for the various inhibitors. and blue is 1,000 fold. So all the inhibitors have their liabilities, and they miss these mutations, whereas the degradation mechanism can hit all of them. It's really quite remarkable, a major differentiator. I think there's a lot of great data today from pirtobrutinib, but you can see pirtobrutinib also has its liabilities. And so we think this is another big advantage for bexobrutideg going forward. Another key aspect that we think is incredibly important is that by degrading BTK, we address the scaffolding function of BTK. And that's pictured here in terms of the protein literally being disassembled there at the bottom of the slide on the left. And so there are 2 major signaling pathways for BTK. There's the kinase function and there's this structural function or scaffolding protein. And we take out both of these. And we see this manifest in the clinic where we have patients who have kinase dead mutations that actually respond to degradation, but fail to respond to pirtobrutinib, for example, because BTK is no longer a kinase, but it's still a signaling protein. So this is a critical advantage of degrading the BTK protein. And I think actually many other oncology target proteins. The next point here is that this process is catalytic. And so that's a word, but let me give you some numbers. So one, BTK -- 1 bexobrutideg drug molecule can degrade 10,000 BTK proteins per hour in the cell. So when we say it's catalytic, we mean it's very catalytic. So imagine 1 drug molecule taking out 10,000 oncology target proteins per hour. This is fundamentally different pharmacology from inhibitors where it's 1:1 and allows -- I think allows our incredible efficacy and potency to take place while maintaining safety because it takes less drug molecule to affect changes within the cell. This is, I think, a really important aspect of bexobrutideg's differentiated profile. We have activity in the CNS. And we not only, of course, have measured drug levels in the CSF for cerebral spinal fluid that are basically equivalent to free drug levels in the plasma, so 1:1. So we know we're in the brain. But what we're showing here across the top is a tumor that was in one of our patients with PCNSL. And then across the bottom, it may be a little hard to appreciate, but basically, it disappears. We have had several complete responses in CNS lymphoma and some dramatic responses in CLL with CNS involvement. So this is a very important aspect of this drug. It creates a protection for the brain over the course of therapy so that it does not become a sanctuary for tumor cells. So I think -- and we're very fortunate, again, with Dr. Alan Carr, who's an expert in this area, I think he's going to be addressing some of the aspects of this tonight. And then lastly, we have demonstrated a very robust clinical activity. I won't go into this 83% response rate, median PFS, which we have finally been able to measure in the Phase Ia, although it's still probably going to evolve and get longer, it's 22.1 months already. And with increased treatment time, et cetera, we expect this number to mature again. This is even including low doses in this calculation. So we're very excited about that, and we'll be looking in detail at the data associated with this tonight. I'll just wind up here on what's -- what we look forward to the future. So what's pictured here is our clinical development plan in a graphic sense, we've launched what we call the DAYBreak series of trials. We love this name DAYBreak. It's really a hopeful name. It's a bright name. It brings hope, I think, to patients that are in the relapsed/refractory state, which is where we're starting at the lower level here, where we've designed a trial, we think, appropriate for accelerated approval. And then we really rapidly plan to move to the second-line setting with our randomized confirmatory trial, which we will call DAYBreak-306. We're still in the process of finalizing the design and launch of that. And then we see a combination trials in our near future. We're already working on designing those. And then really getting this kind of medicine to the front line that I think is going to be part of the future. And then on the lower arrow, we have great results in NHL. and Waldenstrom's. And Dr. Alan Carr will be addressing that tonight as well in the Waldenström. We look forward to future presentations on NHL. We have not even presented all of our NHL patients yet. We have over 100 patients in this categories. And then finally, we also see a future in I&I and other areas and especially neuro-related I&I disease like MS, given what we know about our activity in the brain, so an incredibly bright future for the development of bexobrutideg in multiple clinical settings. This is just acknowledging that even in the second line and the third line, if you look at the major markets, in the U.S. and Canada world and then in the U.S. on the right, these are really significant patient numbers that we can address, and we do believe this will have incredibly high economic value as a drug product as we get approval and market this exciting new agent. So that brings us to our review of the data from these 2 great presentations that were given today, the first one, an oral presentation in a really packed room here at ASH on CLL and some of the latest CLL and then the second on Waldenström's. And so let me just get fast forward here. If I can then we'll dive right into the program. And I'd like to invite Dr. Alan Carr up to review all of our data. And I'm sure there's going to be a lively Q&A session. I'll run that at the end after Paul gets search as to Dr. Alan Carr.

Thank you very much, Arthur. It's really a pleasure to be here to -- it's very exciting to share just review data on these 2 presentations. So the oral presentation on the CLL will be reeling first, and then we'll review the data on Waldenström. So we'll start with the CLL presentation. So as you know, on the 5948 study, we divided it in Phase Ia and Ib. In Ia portion, we were trying to define the right dose of bexobrutideg. And so we'll be focusing initially on the CLL arm, but as you know, we escalated from 50 to 600 milligram. And then after we defined our safety dose, then we had a small randomized Phase Ib study that was related to the project optimal from the FDA, comparing the doses of 200 and 600 milligrams in patients with CLL with previous BTK inhibitor and BCL2 inhibitor exposure. In addition, the Phase Ib, we also have a lot of different cohorts with specific patient characteristics that are evaluating this dose that was defined in the Phase Ia of 600 milligrams. So we'll be viewing a little bit of both today. And then later on, we're going to have the volume to data that we're also going to review is kind of the same idea, the Phase Ia with the escalating Phase I doses from 50 to 600 milligrams and then the expiration cohorts in the Phase Ib. So if you look at the -- let me show you. So if you look at the patient population on the CLL, we have a total of 126 patients. So on the Phase Ia, it's 48 patients. So the 48 patients that went through the dose escalation between 500 and 600 milligrams, all these patients were exposed to the dose, at least the dose. So all of them composed the safety population, and we have 26 patients that remain on treatment. Out of the patients that are no longer on therapy, the 22 remaining patients, we see the majority of them are no longer on therapy because of progression. So we have approximately 14 patients that had either radiologic or clinical progression. So they're no longer on therapy, a very small proportion of patients that are not on therapy due to toxicity, so demonstrating the really the very well with very good tolerability of the drug. And then on the Phase Ib portion, we have 78 patients initially, the 42 patients that were randomized, 21 patients, each arm between 200- and 600-milligram cohorts. Again, all these 42 patients were exposed to drugs and are and compose our safety population. 29 patients remain on therapy. And again, the patients that discontinued therapy mainly discontinued because of progression, very few patients discontinued from due to toxicity. We have the other 36 patients that are also on Phase Ib on those special cohorts or specific cohorts that we talked about. For the Phase Ia, so patients that were treated between the dose of 500 and 600 milligrams, we have obviously a longer time of follow-up. So it's a total a median follow-up of 19 months. For the Phase Ib, all these patients treated or most of these patients treated with 600 milligrams. We have a small proportion with 200 milligrams, but it's a shorter follow-up of 9.8 months. So what we're going to show you today is really the focus on the patients that received our full dose of 600 milligrams. So those are 16 patients that were part of the initial dose escalation and then another 20 patients that were from the randomized cohort and also 35 patients that receive 600 milligrams in the other specific cohorts. So first, we view the entire population, 126 patients between Phase I and Ib and then specifically the population that was treated with 600 milligrams. And we'll also take a peak on the comparison that was done on the randomized cohort between 200 and 600 milligrams. Next slide. So this is the overall population of the study. So all 126 patients treated between doses of 50 and 60 milligrams. So with median age 69, which is the expected median age for CLL. Typically, that's the median age that you see in a CLL study. Obviously, there is a disease of older patients. So you can see sometimes a median age of CLO is in the 70s, but for clinical trials, in general, we're going to be 69. But this is very representative. You see patients up to the age of 88. And one point that I'd like to make about whether this is a representative population, the fact that Arthur mentioned the CMS penetration. So most clinical trials will exclude patients with CNS involvement as part of including criteria. And because of the fact that these are harder patients to treat, these are patients that usually have much more aggressive disease and you don't want to confuse your data. And this is the beauty of bexobrutideg and it's actually one of the main reasons why that drove me to start having a relationship with Nurix and really having this drug available for our patients in our center is the fact that not only has the CNS penetration but really represents the real population that we treat patients relapse refractory B-cell lymphomas as the disease progresses very commonly, will have progression to CNS. So when you have a study that allows CNS involvement, you're really representing the real population that you're treating every day. So these patients with a median age of 69 is a typical CLS the population that is involved in the clinical trial, but it's very important to remember that. And we see more commonly men and women in the study. So from 1/3 and 2/3 male and female, most patients are non-Hispanic. The 5 Hispanic patients are probably my patients from Miami. and most patients are white on this study. Next slide. So when we look at the baseline disease characteristics, this demonstrates the very high-risk complex disease that we're dealing. So if we see and we focus on the column on the middle, the Phase Ia/Ib study. So all patients we see that we have a proportion of them with CNS involvement. And that is typically what you see in this group of patients, approximately 5% of patients will have CNS involvement in this setting. But when you look at previous treatments, most of these patients previously exposed to BTK inhibitors, including nearly or 1/4 of these patients 27% with non-covalent BTK inhibitors. Around 60% of these patients with BTK -- dual BTK and BCL2 inhibitor population. if you see only on the Phase Ia population, the 48 patients, you see that this population gets up to 80%. So 80% with previous exposure to BCL2 and BTK inhibitors. It's a smaller proportion, but you still see very high-risk patients, very complex patients previously treated with bispecifics, CAR T cell therapy. So no patients that have been treated with multiple lines of therapy. The median lines of therapy on all patients was 3, but in the Phase Ia was actually 4 previous lines of therapy. And when you look at these patients, another factor demonstrates how difficult they are to treat is a lot of them would mutations, but also high-risk mutations like TP53, BLC gamma 2 or TP53 mutation. All right. So let's review a little bit of the safety profile. So this is the safety of on the middle column, all the 126 patients that were exposed to the drug. So you see that treatment-related adverse events, any of them are around 75%. But when you start focusing on the high problematic risk mutations and mainly those that are treatment related, you see the numbers are remarkably small. So you see that approximately through the 50% grade 3 or plus on adverse events, but only around 1/4 of them were treatment-related. When you see the series of adverse events you're starting to go to single digits for the adverse events that are treatment related. And there is no grade 5 toxicity. There's no mortality in the study. There's actually no DLTs in the study as well and also reflecting this good tolerability, very few patients having treatment discontinuation because of toxicity. So drug is remarkably well tolerated and therefore, meeting the ration of treatment of 7 months on the Phase Ia/b and 3.6 months with the 600 milligrams. But remember those patients are starting later on, on the study. So they've been exposed to the drug for a shorter period of time just because this dose later on as the study advanced. Next slide. And when you focus on the treatment-related adverse events, what you see is that there are a few very important take-home points. One is that we do not see any new adverse events that are new compared to what we know, what we're used to with BTK targeting. So when you think about BTK inhibitors, which are -- is what we're very comfortable with and what we do generally in the clinic as standard of care. when you add a new agent that is targeting BTK, but in a different method, it is very confident to see that you don't have any new emerging new type of adverse events. So that makes it easier for physicians to just be comfortable with the drug to start where it's easy to drug right away. And when you see this graph, what you see is that on the right, you have all doses on -- I'm sorry, on the left, all doses on the right, only the 600-milligram dose. And what you see is what study is that doesn't seem to be at a dose-related toxicities. So we went up on the dose, and we didn't see worsening toxicity related to the dose. And the great -- most toxicities that are treatment related with Grade 1 and 2, very few grade 3 toxicities. The most common grade 3 toxicity was neutropenia, but it's very important to see that neutropenia, we don't see factors complications, where hematologists were used to dealing with neutropenia, so neutropenia doesn't hold from giving the therapy, especially when you have neutropenia that is easy to manage and neutropenia that doesn't lead to infectious complications and also some cytopenias with thrombocytopenia and anemia. Remember, these are patients with blood disorders, marrow involvement. So typically, these patients had low counts even at presentation at the start of therapy. So again, this is not really something that has held us from using the drug. One thing that I noticed on the study and actually learned as we use the drug over a long period of time, some of cytopenias that we saw in the beginning were related to response. So some of the dose adjustments that I did in the beginning are no longer do. So it happens. But then as these patients are getting exposed for a longer period of time, start really responding these neutropenia is naturally resolved because the disease is better controlled. So we're learning how to deal with this without really impacting leading to treatment discontinuations or complications. But otherwise, most of them are Grade 1 and 2. And very important that not only there was no infectious complications, but another common problem that we see with BTK targeting is the issue with fungal infections. We do not see any fungal infections on this on the CLL population. And this, I think, as a graph that really demonstrates the activity of the drug. So this is the reduction in lymph node size. So this is the lower the bar, the greater the proportion of decrease in size of the lymph nodes. So we see that a great majority of patients had a significant reduction in lymph node size. A lot of them more than 50% reduction lymph node size. The asterisk shows the patients that also had responses even though they had CNS involvement, so central nervous system involvement very aggressive disease. And in addition to the aggression of the disease, the fact that most of these patients had mutations of high risk, so either BTK mutations or at least 1 or very quickly more than 1 high-risk mutations such as TP53, SFTP53, [indiscernible] notch one, some mutations that are associated with a very refractory disease. So despite the presence of 1 or more of these mutations at the same time, we see still see most patients having incredible response. So this represents 83% complete overall response rate. Remember that when you're targeting B-cell malignancies with -- or treating with BTK targeting, the expectation is having partial responses. That is what you expect with these drugs. It's very uncommon to have complete responses. So when you see 83% overall response rate and you even see in this highly refractory resistant population, some complete responses, that is incredibly remarkable. This is something that you do not see every day. But I want to bring attention to the disease control rate, which is 96%. So remember, these are patients that have gone through multiple lines of therapy, very difficult to treat. And a lot of times, just halting the disease progression, permitting some control of disease has an enormous clinical value. It allows you to control the disease to take it to something else, you take it to a car to take or just enough to control the disease and allows some improvement in quality of life. So even though we obviously look for the deeper response, the better, we want CRs, especially in this population, having partial responses, stable disease has an enormous clinical value. So this is the Phase Ia patients with a total of 47 patients, the median follow-up of 19 months, this is representing a duration of response of 20 months. And we see these responses in all subgroups. So this, when you're breaking them down on coding to risk factors. We have to take the caveat that some of these groups are very small numbers. So you have very large confidence intervals. But in all of them, there is no statistical significance on the response. So you see patients with TP53 mutation with BTK mutations that are dual exposed, exposed to previous non-covalent BTK inhibitor, which is obviously in the majority of cases pitubrutinib or patients that were continuing because they progress on a BTK inhibitor, patients with more than 4 lines of therapy. So in all of these subgroups, we see the same benefit from the drug without any statistical significance. And this is the progression-free survival curve for the Phase Ia study across all dose levels. So again, those are patients that were treated between 50- up to 600-milligram dose. the median follow-up of 16 months and median progression-free survival of 22 months, which is again, it's never enough to emphasize how remarkable it is to have this type of curve in such refractory population. And if we take a peak at the cohort that were randomized between 200 and 600 milligrams. So this is a population that was treated later during the study. we don't have as long as a follow-up. So the progression-free survival curve is not mature yet. But we start seeing a difference in objective response rates. So we see more responses with the 600-milligram dose. If you remember, we see this response, but we don't see an increase in toxicity with a higher dose. And we're starting to see a difference in progression-free survival, so really reinforcing that we probably picked the right dose. So the fact that we have a difference in response, very likely difference in progression free survival and as we've seen when we compare the toxicity profile, we don't really see any difference. So we're getting additional benefit of the response without additional toxicity there. So for conclusions for our CLL portion, so this is bexobrutideg. It's a novel BTK degrader that is incredibly well tolerated and really has very remarkable activity, even heavily retreated population with the late refractory CLL. So we were able to define the 600-milligram dose as the recommended Phase II dose. And when we have evaluated the overall population with a follow-up for 19 months, we have a very high overall response rate of 83%, including even some CRs. It's only 4%, but it's something that we do not expect the median duration of response is 20 months and progression for over 22 months with all those levels. Again, we may really see a difference when we start evaluating more carefully in the population that is receiving our recommended Phase II dose of 600 milligrams. And it's never too much to emphasize that we see this high response rates even in this very difficult to treat [indiscernible] subgroups, such as the patients with CNS involvement with multiple high-risk mutations. And when we focus on the Phase Ib portion of the study, that randomized phase -- that randomized portion between 200 and 600 milligrams, which was really as a result of the project optimist from the FDA, we see higher response rate in PFS with a 6-mile or at least a suggestion so far on the curve of a better PFS with a 600-milligram dose, really reinforcing them. We really chose the right dose of fragment of Phase II dose. And as Arthur mentioned, we're certainly looking forward to the upcoming studies that are further exploring bexobrutideg. So before we go to the Waldenström's macroglobulinemia data, I just wanted to give you an example. So I think this is very remarkable. It was very nice to bring it home. When you really have a case of a patient that you had in your hands and treated them in the clinic, and you can really put all these numbers in perspective and really see how the impact that you have every day when you're treating these patients and how much ever presents to their life. So this is a patient with CLL with CNS involvement. And what you can see is that with over time what happens in the response and this graph very nicely shows the different compartments that you have disease involvement. Typically, with CLL, we're going to have different compartments, we have the lymph nodes, the disease circulating the blood, the spleen, the bone marrow in this case, a patient with also disease into CNS. And as you can see, typically, with these drugs is that you have progressive response over time. So as you continuously expose patients with these trials, we have a progressive improvement. So there comes the importance of the tolerability. These drugs need to be well tolerated, so that you'd be able to expose these patients with drugs for a progressive period of time. And what we see in this patient is that over a period of 48 weeks, we have slow clearance of all compartments. Some compartments tend to clear faster than the others. That's why you see some CRs and PRs happening different of these over different times in these boxes, but you see that by 48 weeks, all compartments of the disease have pretty much been cleared, and this patient remains on therapy, tolerating remarkably. So I think it's just a remarkable example, a very difficult to treat patient with very few treatment options having incredible benefit from the drug. So now we will jump to the Waldenström data. So I'm having a [indiscernible]. There we go. So as we had the CLL, SLL cohort, we also had a Waldenström non-Hodgkin lymphoma cohort. And in the Phase Ia structure was very similar. So randomizing from 50 to 600 milligrams. It's very important to emphasize that also non-Hodgkin lymphoma, we also included CNS involvement. So these patients were not excluded from the study. And then we had multiple cohorts on the Phase Ib with safety expansion. And we're going to focus on the Waldenström cohort on this presentation. So those were 31 patients with Waldenström's. And again, showing that this is a population with very high-risk features. So median age is 71. 77% of them were male. And again, some patients with CNS involvement, there is a specific presentation of Waldenström [indiscernible], which is the Waldenström macroglobulinemia presenting with CNS involvement. So we had some patients that were treated on the study with Bing-Neel. Medium lines of therapy was 3. And again, we see that most patients were exposed to BTK inhibitors in reality, all of them were exposed, including 4 patients with previous pirtobrutinib exposure. We have some patients with dual exposure to BCL2 and BTK inhibitors the data of venetoclax on -- which is the main BCL2 inhibitor is not as solid in Waldenström. So that's the reason why it's no surprise they have less patients exposed to BCL2 inhibitors in this group of patients. On the other hand, you see most patients, 90% of these patients previously exposed to chemo immunotherapy because the typical treatment for these patients is a combination of [indiscernible] and rituximab or BTK inhibitors. as standard of care. The mutation status is important. It has a different role in Waldenström but as part of a diagnosis helps us understand the expectations of response. And very frequently, you do not have the mutation status available in all patients. There are many reasons for that. Some next-generation sequencing don't actually capture this very well. So we have just typically request them, the hallmark mutation for Waldenström is 98. So you'll see that a good proportion of these patients has the mutation and it was tested, but not all patients were tested, especially for CXCR4. So this is the population that we have available. There are some patients that were not tested, which is very common in this setting. So this is the safety profile on the Waldenström remarkable population. And what we see here is very similar profile as compared to what I showed you in the CLL. So you see most timing-related adverse events represent more than 10% of the population, most of them being grade 1 and 2. Again, you see cytopenias as the main complication what you see here that you didn't see with CLL as some grade 3 post-procedural hemorrhage. So we know what BTK targeting, you have some issue with platelet dysfunction, probably with some mucosal bleeding specifically in this population was a patient after surgery that had some anti-coagulation and had some bleeding postoperatively was a small sub-zero hemorrhage that was easily controlled. And these were completely resolved. This could be a little bit from the drug, has a lot to do with the disease itself because this is a disease where you have the production of a clonal protein. This clonal protein also impacts protein aggregation and very commonly, these patients with Waldenström will have issues with bleeding. So it's not uncommon to see some of this hemorrhage as we're seeing here. But again, it's a very small proportion of patients that were easily controlled. For example, I had a patient that had with Waldenström's that now is in complete response only disease detectable when we did his bone marrow biopsy and previous exposure to multiple BTK inhibitors and he had a small surgical resection. We held the drug. He had no bleeding complication, the surgeon to me, yes. was a little us. He's probably just from his disease itself. He had held the drug. The drug was not present. We held the drug as we expect a few days before the procedure. And you still had a little bit of using during the surgery. That was easily controlled, which just demonstrates that this is really inherent to the disease. And this is the response assessment. So we have our primary efficacy analysis with 28 patients and an exploratory efficacy analysis with 2 different response assessments that we can talk a little bit about. In 23 patients, we see that your objective response rate is 75% in the primary efficacy analysis and 83% with the exploratory efficacy analysis with a major response rate, which means very good response or partial response or better, about 60% and 70%. One thing that is extremely important to tell in Waldenström's is that in Waldenström macroglobulinemia, you do not see a survival difference between patients that have a partial response or complete response. So having a partial response has the same impact on survival in these patients compared to complete responses. So it's very unusual to see complete responses in this population when you're using BTK targeting alone. So the fact that you have a very refractory population, you're still seeing objective response rate in the 70s, 80s is very remarkable. There we go. And this is the graph demonstrating the responses over time. So we see that a lot of these patients had previous BTK inhibitors. Some of them would be 2 inhibitors, BTK inhibitors. Some of these patients but also previous pirtobrutinib as you can see, a lot of these patients didn't have information on the CXCR4 mutation status, but most of them as expected with [indiscernible] mutation. And you can see in these blots that most of these patients not only have responses but continue to response over time. And we've seen responses even in those big new patients that had CNS involvement at present at baseline. So again, this is our novel BTK integrator with a very important activity even in patients with resistant mutations, very hard to treat patients with Waldenström macroglobulinemia in a shorter median follow-up of 8 months, a lot of patients still on therapy showing progressive responses. So in the safety population, the drug was very well tolerated, no new adverse events. Most adverse events were low grade and easily controlled. There were no DLTs. The treatment-related adverse events led to drug discontinuation with no great fiber diverse events. In this 28 response available patients, we saw durable and deepening responses in this heavily pretreated population. Major response rate of 60% overall response rate of 75%, including some very good PRs and 14 PRs. And some of these responses deeply over time as we expect this class of drugs. Out of the 3 patients with CNS involvement you have responded and so far have not progressed. And 1 data that we did not show, but it's another way that we evaluate Waldenström responses, how the paraprotein change over time and what we see is this progressive drop in IgM levels over time with continued exposure to bexobrutideg. And it's very remarkable to say that 14 patients continue on therapy even after more than 6 months of treatment. And I think this is my last slide. So now I'll hand over to Dr. O'Connor.

So everyone's worst nightmare was tripping in front of an audience. All right. Well, first and foremost, I'm going to move back to the mic so that everyone can hear me. Thank you. I want to echo Arthur's welcome. We all know that you have choices with your time, and so I appreciate you taking the time to even to spend it with us and to review our programs. Before I start, I just want to acknowledge that today has been a really good day for targeted protein degradation. The data that you're seeing presented by Dr. Alan Carr, the presentations earlier for Chimera really point to the fact that targeted protein degradation has a role in the treatment of patients, whether you're looking at oncologic disease or whether you're looking at immunologic disease. So I want to shout out to our Chief Scientific Officer, who is responsible for our platform that has enabled us to develop this drug and other drugs. And we really look forward to bringing them all across the finish line and changing how patients are treated. So this I've already said, has been a big year for us. And so as you can see, the most important thing is we've established the go-forward dose, the recommended Phase II dose for bexobrutideg or Bexdeg as we would like to call it. Equally and importantly, this has been approved by the FDA in accordance with Project Optimus but also approved by the EMA and the MHRA as they have reviewed our data sets. We started our first Phase II trial, our first pivotal trial. This is huge. This is -- we have just moved from an early-stage small company to a real player. And so this is a seminal time for us at Nurix, and we anticipate starting a randomized controlled trial in the first half of next year. We've already talked about the emerging data that we have that helps to differentiate our agent so once again, another shot out to Gwenn and her team for allowing us to develop such a specific degrader in bexobrutideg and then lastly, we've had great data this year, which you've already seen. So Dr. Alan Carr has mentioned our high objective response rate. He's mentioned of 83%. He's talked about the duration of response. So remember, ORR is the ticket to the game. DOR and PFS are what allow you to win. And when you look at the data that we've generated thus far in our Phase Ia across patients treated from anywhere between 500 to 600 milligrams to have this level of activity and durability is remarkable, especially when you start thinking about the context in which we're developing this drug. So this is -- I hate to say, if you have to have CLL, this is a great time to have it because we have a lot of very, very active drugs. And despite that, what we can see even as we compare ourselves to the most recent entrant, which is pirtobrutinib, the objective response rates that we are seeing are better than theirs, meaning in the BRUIN 321 study in the JCO paper, which is the most mature data from that data set, their ORR was 65%, their DOR 13.8 months. There median PFS 14 months in the all-comer population, but 11.2 months in those who were double exposed. And I'll remind you that in our study, in our Phase Ia, 83% of the patients are double exposed. So as you look at the bottom of the slide, what you will see is when you think about the patient population, our patient population is more heavily pretreated. Some of them have already seen a non-covalent BTKi, which was obviously not the case in the BRUIN 321 study, and they've been more heavily exposed to BCL2 inhibitors. And so to see improved relative responses, meaning higher ORR, higher durability of response, higher median PFS, that is a game changer and means that we have something to offer to patients. Many of you know that before I actually went into industry, I used to take care of patients with lymphomas and leukemias. And every day that I look at this data, I think about some of my patients, the patients that I actually didn't have anything to offer. And yes, I wish that they were here now because we now have something to offer them. Our first pivotal trial is a single-arm Phase II that you see here. We will be enrolling triple exposed patients. Those patients will have to have been exposed to either a covalent BTKi, a noncovalent BTKi and BCL-2 inhibitor. This will be a global trial. We will enroll people and treat them at the 600-milligram dose level. We'll be looking at ORR as our primary endpoint, obviously, following for PFS and for safety. This program has already started with patients already being enrolled in Europe, and we hope to open several sites in the U.S. later will actually this month. Okay. It's not just you. Okay. Our randomized controlled trial will begin in the first half of next year. In this case, we'll be focused on patients who've been previously exposed to a BTKi. They may be in as early as the second line setting. We anticipate that a lot of the patients who enrolled in this study just as was the case in the BRUIN 321 study will be double exposed. We will have 400 patients approximately who will be randomized between Bexdeg or our control arm, which is an investigator's choice of pirtobrutinib or chemo immunotherapy. We will follow patients for PFS. For those patients who are on the control arm who do, in fact, progress, they will have the opportunity for crossover that will increase the attractiveness of the study and help with the speed of enrollment. We will obviously follow for our primary endpoint of PFS and then also assess for safety. So this is our confirmatory trial. And then our next trial that we will be initiating in 2026 will be the Phase Ib/II combination study, which will really set the stage for our combination study in the second line plus setting as well as the future frontline study. And so what you see is we will be looking at a series of venetoclax doublets or at least a bexobrutideg venetoclax doublet as well as 2 triplets, one with rituxi, one with obi. Once we've established the dose for these in the second-line plus setting, utilizing a fixed duration therapy, we will then assess the activity of these in the frontline setting, specifically looking at the doublet of Bexdeg and ven and then the Bexdeg ven obi triplet. So we know based upon the data that we've generated in our 301 study that Bexdeg clearly has a role to play in the treatment of patients with CLL and other potential malignancies. And so we will begin first with our monotherapy approaches, utilizing our single-arm Phase II and our randomized controlled trial, the Phase III and then we will set ourselves up to ask the combination question with this Ib/II in anticipation of conducting pivotal trials in combination. So it's a good day to be on the Bexdeg team. We look forward to building on the data that we've already demonstrated where we've seen a high degree of activity as evidenced by the objective response rate of 83% in our Phase Ia and a median PFS of 22.1 months. We've seen similar activity in Waldenström's. So this gives us confidence that there is a potential path forward here as well. And then although I've not presented it here, I will just dangle the plan to present other NHL data mid-year sometime next year, which gives you a view on our other NHL subsets. namely those that you see here, DLBCL mantle cell follicular. And given our conversation already, I want to highlight primary CNS lymphoma as well. So thank you for your attention. I'll turn things back over to Arthur.

Okay. So I think let's open it up for Q&A. What's it? I have a few more slides, but I don't want to show them because I want to get to the Q&A because I think we've seen a lot of slides everybody today, there's some tire conference, nothing but slides. So -- and I know it's been a long day. So if we could, thank you, Gwenn Hansen, our Chief Scientific Officer, coming up for Q&A. And we have microphones in the room. And I think we also have the capacity to get some questions online. So why don't we go ahead and start? He's got a mic there. There you go. Roger. Yes, go ahead.

Great. congrats for a very successful ASH for Eric's team Roger Song, Jefferies. Maybe to the question, related to the doctor earlier comment related to the fungal infection seems so we start to see some differentiation among the degrader. Maybe also the team can give us some either molecular or mechanistic reason why Bexdeg may have lower risk or no risk for the fungal infection?

Yes. Thank you, Roger. I'd like to direct that question to Gwenn Hansen, our Chief Scientific Officer, who has conducted all of the selectivity studies, et cetera. So Gwenn.

Sure. Thank you for the question. I think this is a really important point in the field of degraders. The understanding of how you determine selectivity is something that we have had to really develop appreciation of in the field. And degraders really need to be assessed in global proteomic studies in very sensitive cell types that can really elucidate whether or not your drug is degrading off target. So we have shown some of this data recently in a couple of settings where we compare the selectivity of bexobrutideg to the B1 molecule as well as the AbbVie molecule. And it's very clear to us that there are off targets at clinically relevant doses for both B1 and AbbVie's molecules that we really do not see at those same exposure concentrations that we're using in the clinic. So we really feel that some of the early signals that are being seen in the clinic are related to that, either ability to avoid off-target degradation or not?

Thank you next question right up here. Go ahead. yes.

Congrats on the [indiscernible]. Chris from Lucid Capital Markets. Maybe one for Dr. Alan Carr with this new data that we've gotten, do you have any new thoughts on how bexobrutideg compares to other BTK degraders in development?

That we have what was presented here at ASH with the B1, the greater. I think that's the best 1 that we have to compare we really don't have a lot of information on the AbbVie the greater what it has been, where it is. So we see between both, and that's what was just demonstrated on Saturday is that it seems that bexobrutideg has a little bit of a more not only better, more solid follow-up data, so more solid responses and follow-up, but better tolerability, we see less of these issues of concerns with cytopenias and infectors complications. So the numbers are relatively similar numbers a little bit better with Bexdeg. So that's really the best that we have today. It's really the fact that, yes, the class is extremely important. the plastic that we have is what was presented this weekend. And from the comparison that we have, it seems that there is really advantage that probably reflects what we're just seeing the fact that it's more selective and even more effective and with that, a little bit of a better response rate and less toxicity.

Okay. Let's go to Gil.

Gil Blum, Needham & Company. Another question for Dr. Carr. So in the water storms of cohort, I know these are really small numbers, but it looked like at least a couple of the patients that didn't do as well had more prior lines of agents. Any commentary there?

It's very difficult to say whether it's just a reflection of patients that were more lines of therapy. The more exposure they have, they become harder to treat. What we know is that mechanisms of resistance may change over time with a number of lines of therapy. Some of these may be less dependent on BTK pathway overall. So it's just probably a reflection of an even harder patient to treat, and it is such a small number. I don't think we can make much interpretation on that.

Great, Matt.

Matt Biegler, Opp Co. About a dozen patients post [indiscernible] here, 62% OR. Is that kind of the bar that you're seeing for the DAYBreak 201 trial. And then Dr. Carr, do you see this in the clinic as kind of an emerging unmet need for our patients that have been exposed to the non-covalent and the covalent than and/or maybe obinutuzumab.

I'd like to have Dr. Alan Carr comment, but also Paula, if you could comment on this question. Go ahead, Dr. Alan Carr.

So the truth is that covalent, non-covalent BTK inhibitors today kind of they are seeing very close to each other in the clinic in standard of care. Mainly when you go to community practice, I do a lot of these education sessions. And so they're kind of seen together. And even though there's a clear differentiation, it's still not that very well understood. But yes, you still see patients that very clearly who progressed with covalent BTK and non-covalent BTK inhibitor, and still will require more therapy. They still have venetoclax and you're going to see more and more of these combinations. But I think that the point the two points here is not only that there is clear unmet need because these patients will indeed progress through a covalent non-covalent and venetoclax in used to need options, but also because we're combining these drugs, the mechanism of resistance changes, and this will increase even more than need for additional targeting additional options.

Paula?

And so I'll just put the number 62.5% into context, especially when you've seen an 83% response rate overall. The numbers are small. In that -- on that slide, that represented patients treated at all dose levels. So you have small numbers, but you have the majority of patients being treated at dose levels less than 600. So I don't think we have a full understanding of what we will see in our Phase II study. That having been said, another really important point to note, as Dr. Alan Carr has already alluded to, is that stable disease is not included in your objective response rate. And for these patients, in particular, who have been very heavily pretreated, stable disease actually represents a win as well. So we look forward to providing potentially more data on these subsets at a future meeting midyear.

Great. All right. Let's go right there. Yes.

Yes. This is Sudan Loganathan from Stephens. For the team, for the Nurix team. I wanted to ask, when you stratify responses more by mutational subgroup, cytogenetics and depth of prior BTK inhibitor exposure are you seeing any early signals that particular biological subsets respond with different kinetics either in terms of time to response, depth of response or early PFS separation, particularly in the 600-milligram cohort?

Okay. That is a detailed question. I'm just going to open up to the panel, whoever would like to answer that first. And then we may have more than one answer because I think Gwenn may have an answer and Dr. Alan Carr has an answer to.

We all want to chime in. So I'm going to start with what we are seeing across the mutational profile. We're seeing responses across all types of mutations. That's number one. And there's no significant difference irrespective of the type of mutation that you have. Number two, in terms of the time to response, that is a very difficult thing to tease out with the numbers that we have, recognizing that many of the patients who have non-C481 mutations may have also seen a non-covalent BTKi and/or have multiple mutations at one time. I think the most important thing is whether people respond yes or no, and we are seeing that. And then I'll turn things over to...

Dr. Alan Carr. I think I go ahead.

I'll tell you what I see in the clinic, which I think is one matters the most. And what we see is that responses are very fast so when we're starting patients on the drug to, you'll be feeling better next week. You can look at semi, you're going to see lymph node smaller next week, ongoing changes in our accounts in a week. So we see clinical responses that are very fast. So the clinical benefit happens very fast. What I told you is that you see deepening of response over time. So you start seeing the clinical benefit and then you see this low, progressive response and the continued exposure. So the clinical benefit happens fast. And what we see from the response rate, the great majority of patients will demonstrate clinical benefit almost off back from the very first few weeks of their own therapy. And what we'll see over time is that then you start seeing progressive deeper results. That's why that graph was so nice because you can see that in different compartments, the depth of response happened at a different time point because it's just really how the disease behaves when you have just BTK targeting a single agent if you want to expedite responses, you use combinations and all that. But as a single agent, you see very fast clinical response. And we're seeing this even in patients that are coming to us knowing they had multiple previous lines of therapy known to have mutations so I'm not concerned when I'm putting a patient on the study regardless of the imitation that may be coming to us and what I'm not going to put a patient on stenosis not going to respond because it has X, Y or Z mutation. So those the point that you bring asking about the time frame response is very important because you won't have clinical response. You want to have benefit fast and did you see very clearly.

Wow, I mean that is so meaningful that or a patient having being able to hear that, that reassurance thank you for that. Gwenn?

Yes. The only thing I think I will add to this, and this has already been said tonight, but we should reinforce it here. We haven't treated that many people at 600 milligrams to start, right? We were doing a dose escalation, then we did the randomization. So we are actually not going to really understand the responses across all the different carry types until we get more patients into our 600-milligram optimized dose. We definitely understand that we have longer progression-free survival in 600 milligram. That is because it is covering the target the best compared to all the other doses. So I think it's just important for us to understand that we've seen incredible responses even at low doses, but the high dose is going to be very important.

Over here, Steve.

Yes, Steve Willey from Stifel. That was a good segue for my question, actually. So we know that patients were allowed to be dose escalated on an intra-patient basis and you showed the vignette of the CNS patient who was pushed to 600. So I guess in trying to contextualize the dose escalation PFS data in the context of knowing some of these doses that those patients were receiving were I guess suboptimal, do we know how many patients were eventually pushed to 600 through this intra-patient dose escalation that was allowed?

The protocol. Okay. So Paula, and I don't think the word pushed is correct, but go ahead.

Okay. So the way our protocol is written is that patients who were treated at initial dose levels of 300 milligrams or less had the opportunity to dose escalate. We did not require that these patients dose escalate. And so in addition to that, they only had the opportunity to have 2 dose escalations. So many actually have waited until we got to our recommended Phase II dose, which was in October. So I will be able to answer that question better because many patients have not actually had the opportunity to dose escalate because we had to get to the recommended Phase II dose.

And some patients that have had the opportunity have not done it. So I have patients that we had the option of escalating the dose, but we had absolutely no reason to do so, tolerated remarkably well, excellent response. So we discussed, would you like to increase the dose. And there was really no need to do so. So we're still trying to understand whether there was a need or so. So we just said, okay, let's see if we can just drag it a little bit longer and see if eventually something suggests that we might be losing response. And we need to have a reason to increase the dose and we'll do so. But I have patients at different dose levels and that we have had the option of increasing the dose we haven't had a reason to do. So some of the business are like, oh, I want the best as possible, less escalate. I really want it. And mainly that say, well, I don't expect changes in tolerability. So yes, where it can definitely increase but some patients like, why I need more? I'm happy where I am. So we've had both in the clinic.

Now that you've seen the 600 mg data randomized against the 2, would you?

Yes, we participated in the randomized portion I've been on the study really from the beginning, we're in the very first sites to open in the U.S. So I have really exposed patients from the 50 milligrams I participate in the randomized phase. So we have patients on 600 [indiscernible] very, very well.

And then just a quick curiosity question. So the waterfall plot that shows the mutational status of these patients. The VAT that's being reported is at 5%. And I would imagine the threshold for that is actually much lower in terms of sensitivity. So is that standardized across all trials? Like if I look at B1 protocol, would they be using a 5% threshold for mutational presence or absence?

From an investigator point, I will say there is really, really have no clear answer for that, right? So you can a 5% at is a very reasonable, probably clinically meaningful representative cut off. whether a smaller proportion really has significance is really difficult to tell. There is clonal pressure from different populations and you start really getting very complicated. So whether 1% or 5% is the right cut off, I think all I can tell you is that 5%, I think, is clinically significant. It's meaningful.

Paula or Gwenn, anything to add to that? If that's a scientific question. Okay. Let's go Okay. Back in the back there.

Greg Renza at Truist Securities. Congrats on a great weekend. Maybe another one for Dr. Alan Carr. Just with respect to chatter on the floors with amongst your colleagues around sequencing and how the various agents should be CLL-17, for example. If you want to say that continued therapy is the way to go, fine. It's just as equally effective. And if you want to use finite therapy combined and stuff, fine, just this as well, right? So then it gives you options and then it's just part of a very complex decision process when you're discussing with patients. One thing that I see that tends to happen a lot is that when you go back to the first line today, when you're making a decision on which pathway you're going to follow, yes, you can combine a BCL2 inhibitor with a BTK inhibitor. But in essence, you're choosing between a backbone of BTK inhibition or BCL2 inhibition, right? And then as you go through the many different features that are going to decide, some are molecular features, some are social fishers, some of the patient that wishes that kind of guides you to s one way or the other. And what we're seeing a lot are patients that just follow that path of BTK targeting because patients don't change much, right? So the decision that they made in the first line is the on the same decision they're going to make in second line, right? So the social situations are around the same and their life perspective around the same. So it's very common to see now patients are going to go from covalent, non-covalent to a degrader and then really going to BCL2 inhibition. I had a patient on the study that was exactly that. And actually, she was a very young patient that was treated initially by [indiscernible] with FCR and way back when she progressed. So with ofatumumab and lenalidomide also the study, then she moved to Florida. We start with nibrutinib and then came to me actually for the BRUIN study. Also I also was a main investigator in the BRUIN study, so she received pirto on BRUIN, did remarkably well. And then we could see that at every line of therapy, she was developing more resistance. And then she progressed on BRUIN and shows quote on 5948 and had of incredible response. It was really exploding when she was started on BRUIN. They were really nice -- we even let me put on the study because he was being the verge of not being really a good candidate for the study because she was progressing so fast. She had a lot of electrolyte imbalances, her QTC her interval in the EKG was not that great. We start her on the drug. In a week, she was doing incredibly well. So and she had never seen a BCL2 inhibitor and she still hasn't, right? So -- and you're going to see more and more of this is just you follow that path just because that's patients get used to it. You tell them it's kind of the same toxicity profile, so they're familiar with the class. They're familiar with the drug. So you're going to see more and more of this, especially now with the [indiscernible] indication after just a covalent BTK inhibitor. So going to become more and more of a norm. Venetoclax is an excellent drug with combinations. I'm looking for, I'm going to participate on this because I really want to do this venetoclax requires additional layer of complex and a lot of patient wants to do.

Okay. Right here in front.

Tess Romero, JPMorgan. So specifically for you here, what are the lingering questions that you have at this point about the overall emerging product profile for Bexdeg and CLL? And what you would like to see specifically in next studies?

If you really want to know what I want to know there a chance to give us advice publicly.

So I'll tell you first what I so let me give you a little background. So I focus on the treatment of B-cell lymphomas, especially lymphomas that involve old people. So I treat a lot of CLL, do research of mental cell lymphoma and I have a special interest in CNS lymphoma. I really focus on CNS lymphoma. And so let me give you the answer first for CLL. And I think what is happening with CLL and is something that we're not going to answer today, but it's something that is going to get more and more confusing, it's not only -- there's no question that bexobrutideg. It's incredibly active and is going to be approved and it's going to be used. I have no questions about that. I have been using the drug for more than 2 years now. I have trust in the drug, has worked in my hands, extremely well tolerated. The drug is phenomenal. I have no problem with that. What is going to start getting more and more complicated is how are we going to really target BTK? You're starting to see the data of pirtobrutinib versus ibrutinib, for example, and you see that hint of overall survival benefit with pirtobrutinib compared to ibrutinib. When we were approached for that study, I said, no, I don't want to be precept in the studies I want a dealer's choice. So maybe it wasn't ibrutinib, it's all this choice, maybe the number wouldn't be that incredible but still goes home, right? What is happening here? And I know that [indiscernible] is better tolerated than a [indiscernible] inhibitor. I was part of the study. I know how the drug works. But then what is going to happen, you're going to start seeing more and more pirto before covalent BTK inhibitors. Are we killing a class? What is happening? Then you have Bexdeg which works even better, and it's been better tolerated. And I wouldn't be surprised, it is the same conundrum is going to happen. What is going to happen now and we're going to do this before pirto. Am I killing a class completely? So this is something that this is what we've been discussing in the entire week. This is really what we in the entire weekend. It is what is going to happen is we have this more effective, better tolerated even better targeted drugs, what is going to happen in the class overall. But then comes the next point is that these drugs are remarkably well tolerated and are just primed to be combined. And then it opens an entire new discussion is how do you bear them? How can you really manage intermittent there or finite versus indefinite therapy? How do we integrate newer drugs, bispecific antibodies? We're combining with the venetoclax, but you have second-generation BCL2 inhibitors coming. We're combining with rituximab. Obinutuzumab is certainly better. what would happen if we combine with epcoritamab or vlufitumab. So it gets more and more fascinating and it's just wonderful because we have more and more options to treat patients. And then what ends up happening is what we really need, which is really tailoring what each patient needs based on their social issues, based on their patient personal issues or their molecular features. So then let me tell you a little bit just about CNS lymphoma because I just love CNS lymphoma. So I am incredibly excited about the drug for CNS involvement, not only primary secondary CNS lymphoma because not only the drug is incredibly active, but because so well tolerated and it's just again primed for combinations. CNS is not a typical inform what do you want to use a -- this drug as single agent, so you're expecting to combine. So I'm bugging Arthur every week to let me combine this drug with bispecific antibody, with other very effective agents because it's going to be a home run in CNS involvement.

I'm with you on that. Don't worry. Okay. Yes, Biren.

And maybe, I guess, a question for Dr. Alan Carr. On CNS involvement, what percentage of your CLL patients have CLL CNS involvement? And I think a second question also for you is on, I guess, with your experience, have you seen a dose response correlation to PFS even after program maxes out on BTK inhibition at lower doses? So I guess another way of asking is, is B1 leaving efficacy on the table by moving forward with the 200-milligram dose?

Okay. So the first question as far as CNS lymphoma and CLL. So I see a lot. Just because an expert I can just get a lot of referrals. So a larger proportion of my patients with CLL have CNS involvement. Percentage, is it such a small percentage. The percentage that you see over time is really this 5%, 3% of the patient population overall. I see a lot. So I have patients with CLLs and CNS involvement, they were treated on the study and had responses. So I see more than the average physician in the community. Those physicians when maybe we'll see once the CLL patient was CNS involvement a year in their career because they're not common, but the factors that they are there, and it's certainly an issue, especially in these patients that get more and more treated, they become more and more resistant. It is extremely unusual, extremely to have CLL with CNS involvement at diagnosis. These are typically patients especially fishes that have been treated not a typical CLL patient. The CLL patient that is just monitor and nothing ever happens and they die with the disease, not from the disease. This will happen more with the patients that develop mechanism resistance and have additional mutations and then they have more CNS involvement. All right. And the second question was...

The second question was around the dose response.

So two separate things. You asked me about inhibition. And as I told you, I was part of the drug development of pirtobrutinib as well. And on that study, we saw very similar things that we see here and which is really a fact of the class pretty much to some extent, right? We see differences still like with ibrutinib. We have more difference in dose response dose levels and toxicity. But in pirto for example, you had very good activity even at lower doses to the point that I am the global PI on a study that is evaluating 3 different dose levels of pirtobrutinib, 100 to 160 milligrams. So there's a possibility that in lower doses, you have very good activity and very much the same tolerability. So but what we have the data very clear with Bexdeg is that we're seeing that with the higher doses, we're overcoming these higher-risk mutations. So maybe you have better tissue penetration with a higher dose, maybe you really have better not a better credit because degradation even very, very low dose levels but there's something that allows a better response in the higher dose. So it's not necessarily more is more. But I think that a lot of these features you're not going to have available to you when you're evaluating these patients in the clinic. So my recommendation then is go with the full dose because you're not expecting to have more toxicity and you're going to be overcoming any potential mutation that you might not really be identifying. But the truth is that if you have to adjust doses, there's a very good chance that you're going to if you have to hardly ever happen in the study. You have to adjust those because of toxicity, they were able to safely do so and now lose response. I don't know if I answered your question.

That was really helpful. And maybe a couple of questions for the company.

Sure. I guess I can answer questions. Go ahead.

Great. On the second line plus CLL pivotal study in the control arm, I believe the control arm is either pirtobrutinib or chemo immunotherapy. I think previously the company had defined chemo immunotherapy as IR or BR. Is that still the same definition? That's the first question. And then second question would be I think there was an strict on that trial where the trial design for the control arm is subject to change based on changing standards and regulatory review. So if you could maybe provide additional color on what would justify a change in the control arm for the second-line pivotal?

Sure. I can address that. So yes, very astute to see that asterisk that was added. So the we operate in real time. This field is moving fast. I don't think there could be an ash that defines that more than this one with the approval of pirtobrutinib immediately before ASH kickoff and a lot of new pet data. And so the overarching principle in defining a control arm for a randomized controlled study, is that the control arm should be representative of the standard of care in the U.S., especially the primary area of market area for us and our population. And so we are looking at what is that future standard of care as it evolves. And so I do think that's an active area for review for the company. And this is a very timely question and a time to look at that very closely. We are impressed with the pirto results. We think our drug is going to be superior. And we think that offers an advantage in terms of defining the control. So stay tuned on that question, Biren, but it varies to good question. I'd say there's one more question. Yes, go ahead, Joe.

Joe Catanzaro from Mizuho. Two questions for me. One, maybe slightly boring. Why include rituximab combo in that combination study when obinutuzumab seems to be the preferred CD20? And then second question, when do we start seeing MRD data? I recognize it's irrelevant in the context of relapsed disease, but I ask that because it seems like BTK inhibitor monotherapy is not very good at getting patients into MRD negativity. And so is there any reason to think that degraders might do a better job of getting patients there?

Go ahead, Paula.

So the -- I'm going to go with the last question because I can remember that. So we are, in fact, assessing MRD for our patients. We have not aligned on a time when we would present that data. We certainly want to have because we have sequential data. We're going to want to have a year or 2 years' worth of data before we actually present it. So that's one. Number -- what was your first question? Why retain because I worked on rituximab at Genentech when I joined industry that's not my so certainly, as Arthur has already mentioned, we are trying to set ourselves up to run future pivotal trials. And certainly, VR is a well-defined standard. That's one reason. Another reason is in this world where people are trying to contain costs, some people will actually utilize rituximab or rituximab biosimilar because it is less expensive. And so we want to be able to provide with our clinical development plan, information that is going to inform how everyone treats their patients. So if that is their choice, then we will have data to support that.

So I told you that when I talked to belabor the Pert versus ibrutinib study. I told them, I wouldn't open a study because I don't think that ibrutinib is a fair comparator. And I told them, I would open it if it was a dealer's choice and they decided not to, we didn't open the study. So in this study, I would not have a problem in opening the study if I had that number one, because we have pirtobrutinib as an option and I think it is a more fair comparison for the U.S. for where we are today. But we know that in the global study, there are still many sites that is much more complicated to get obintuzumab. Rituximab at the proper doses, but those adjustment of 500 milligrams meter square. It's still a very reasonable anti-CD20 monoclonal antibody, mainly in the relapse setting. Yes, you have the run the data that is based on rituximab. So when I'm asked what is your monoclonal antibody of choice, you're absolutely correct. the answer is on obinutuzumab, it is a superior antibody when you compare head to hatch rituximab. However, it kind of dilutes a little bit in combinations, and I think it's still a fair option, mainly as you think of a global study.

Yes. So thank you. I think that's all we have time for in terms of questions, I would like to make a few closing remarks. But with regard to this question, we do endeavor to address all the different segments of the patient population we want to help both in the United States and elsewhere with these trial designs. So let me just make a few closing statements here in the last couple of minutes. It's at the end of the year, and I think it's appropriate to take a little look back at 2025. We really have achieved quite a bit at Nurix we're very proud of. Securing the 600-milligram dose, a lot of discussion about that tonight as per project Optimus, I think is a milestone. I think it's going to improve how we can address and treat advanced CLL and really get the best results overall. We have initiated the DAYBreak study. It's a new day, I think, in CLL with DAYBreak. We're excited to see that move forward and enroll. And of course, our presentations here at ASH, I think, have been extremely well received, and we're very, very happy with what we've seen happen here. With regard to our partnerships, we're very active. We believe in the partnership model. Gilead advancing GS-6791. They IRAK4 degrader through the SAD/MAD study. STAT6, going forward with Sanofi, we already mentioned that earlier. And I think that we've also seen a future for bexobrutideg in I&I, and we do have a new formulation, which we're pursuing through SAD/MAD studies as well. We think in all of these I&I indications, we will have significant progress in 2026 and updates to look forward to. We did present our first major updates on our Civil B inhibitor, MX-1607, which look quite intriguing, both at SITC and ESMO. And we've been very fortunate to have a terrific investor base, strengthening our balance sheet recently with a follow-on offering of $250 million, bringing our collective cash base to over $650 million and with the cash runway into 2028, which allows the company to do all of these great things with bexobrutideg and also move forward our pipeline. As we look forward to 2026, just a little preview, we normally will give our bigger update on our 2026 goals at the JPMorgan conference in January, of course. But we do see multiple opportunities for new data in 2026 from cohorts in the Phase Ib. We've only been talking about Cohort 1 so far and then our Waldenström cohorts. But we as I said, we have approximately 100 patients in our NHL cohorts. We look forward to presenting that. bexobrutideg, we'll have the SAD/MAD study readouts in 2026. And then turning to I&I, again, GS-6791 should have potentially Phase I results. We depend on Gilead for the timing of that, but that should be on the horizon. And we do anticipate an IND filing it with the STAT6 program with Sanofi and then also an IND filing for bexobrutideg and I&I so we are executing focused now fully on the pivotal development pathway with bexobrutideg. There may be some evolution of that pathway as we've seen and learned new data here at ASH this year. And we look forward to future updates in that regard. So with that, I'd like to thank everyone for participating tonight. I know it's late here on the East Coast. I'd like to thank all of our investigators, thank Dr. Alan Carr so much. I felt there were so many very insightful answers tonight with learnings from you in the clinic, just incredible. Thank you. Of course, Paula and Gwenn, thank you, our entire executive team here. And most importantly, to our patients. I'd like to thank all of our patients who have been dedicating themselves to our trial and trusting us and our physicians worldwide and trusting us with their patients. So thank you all very, very much, and good night. Thanks.