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. Alvaro Alencar here from the 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. Alencar. 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, NX-5948 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 NX-3911.
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, the 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 non-proprietary version of our name. And this really relates to the unique pharmacology and great potential of degradation as a truly differentiated class of medicine as compared to inhibitors. And 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 a highly potent and exquisitely selective BTK degrader. 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 lone 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 emerging efficacy profile. There are molecular reasons for having those profiles, and this graph captures it. Let me back up here. Okay, yeah. 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've compared, so we're doing 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. 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 was 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 two 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.
That's a word, but let me give you some numbers. One bexobrutideg drug molecule can degrade 10,000 BTK proteins per hour in the cell. When we say it's catalytic, we mean it's very catalytic. Imagine one drug molecule taking out 10,000 oncology target proteins per hour. This is fundamentally different pharmacology from inhibitors, where it's one-to-one 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, cerebrospinal fluid, that are basically equivalent to free drug levels in the plasma, so one-to-one. 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. Alvaro Alencar, 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 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 I-A, although it's still probably going to evolve and get longer. It's 22.1 months already, and with increased treatment time, etc., 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 we look forward to the future. 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 a really hopeful name. It's a bright name.
It brings hope, I think, to patients that are in the relapse 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 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. Alencar will be addressing that tonight as well in the Waldenstrom's. 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 these NHL 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, the 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.
That brings us to our review of the data from these two 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 in CLL, and then the second on Waldenstrom'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. Alvaro Alencar 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 Paula O’Connor gets her chance to. Dr. Alvaro Alencar.
Thank you very much, Arthur. It's really a pleasure to be here. It's very exciting to share and just review the data on these two presentations, so the oral presentation on the CLL we'll be reviewing first, and then we'll review the data on Waldenstrom's. We'll start with the CLL presentation, so as you know, on the 5948 study, we divided in phase I-A and I-B. In the I-A portion, we were trying to define the right dose of BexDeg, and so we'll be focusing initially on the CLL arm, but as you know, we escalated from 50 mg to up to 600 mg.
And then after we defined our safety dose, then we had a small randomized phase I-B study that was related to Project Optimus from the FDA, comparing the doses of 200 mg and 600 mg in patients with CLL with previous BTK inhibitor and BCL2 inhibitor exposure. In addition to phase I-B, we also have a lot of different cohorts with specific patient characteristics that are evaluating this dose that was defined in the phase I-A of 600 mg. So we will be viewing a little bit of both today. And then later on, we're going to have the Waldenstrom's data that we're also going to review. It's kind of the same idea, the phase 1a with the escalating phase I doses from 50 mg to 600 mg, and then the expansion cohorts in the phase I-B . So if you look at the, let me show you.
If you look at the patient population on the CLL, we have a total of 126 patients. On the phase I-A, it's 48 patients. The 48 patients that went through the dose escalation between 50 mg and 600 mg, all these patients were exposed to the dose, at least the dose. All of them composed the safety population. 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. We have approximately 14 patients that had either radiologic or clinical progression. They're no longer on therapy. Very small proportion of patients that are not on therapy due to toxicity, so demonstrating really the very good tolerability of the drug. On the phase I-B portion, we have 78 patients.
Initially, the 42 patients that were randomized, 21 patients each arm between the 200 mg and 600 mg cohorts. Again, all these 42 patients were exposed to drugs and composed our safety population. 29 patients remain on therapy. And again, the patients that discontinued therapy mainly discontinued because of progression. Very few patients discontinued due to toxicity. We have the other 36 patients that are also on phase 1B on those special cohorts or specific cohorts that we talked about. For the phase I-A, so patients that were treated between a dose of 50 mg and 600 mg, we have obviously longer time of follow-up. So it's a median follow-up of 19 months. For the phase I-B, all these patients treated, or most of these patients treated with 600 mg, we have a small proportion with 200 mg, but a shorter follow-up of 9.8 months.
What we're going to show you today is really then focus on the patients that received our full dose of 600 mg. Those are 16 patients that were part of the initial dose escalation, then another 20 patients that were from the randomized cohort, and also 35 patients that received 600 mgs in the other specific cohorts. First, we review the entire population, 126 patients between phase I-A and I-B, and then specifically the population that was treated with 600 mg. We'll also take a peek on the comparison that was done on the randomized cohort between 200 mg and 600 mg. Next slide. This is the overall population of the study. All 126 patients treated between doses of 50 mg and 600 mg. Median age is 69, which is the expected median age for CLL.
Typically, that's the median age that you see in a CLL study. Obviously, this is a disease of older patients, so you can see sometimes a median age of CLL 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 CNS penetration. So most clinical trials will exclude patients with CNS involvement as part of inclusion 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.
This is the beauty of the drug, and it's actually one of the main reasons what drove me to start having a relationship with Nurix and really having this drug available for our patients in our centers. The fact that not only has the CNS penetration, but really represents the real population that we treat today. Patients with relapse refractory B-cell lymphomas, as the disease progresses, very commonly will have progression of the 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 CLL, the population that is involved in a clinical trial, but it's very important to remember that. And we see more commonly men than women in the study, so a third and two-thirds male and female. Most patients are non-Hispanic.
The five Hispanic patients are probably my patients from Miami, and most patients are white on this study. Next slide. All right. 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 I-A, I-B study, so all patients, we see that we have a proportion of them with CNS involvement, and that's 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 a quarter of these patients, 27% with non-covalent BTK inhibitors, around 60% of these patients with dual BTK and BCL2 inhibitor population.
If you see only on the phase I-A 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 three, but in the phase I-A was actually four previous lines of therapy, and when you look at these patients, another factor demonstrates how difficult they are to treat. There's a lot of them with BTK 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.
This is the safety data on the middle column, all the 126 patients that were exposed to the drug. You see that treatment-related adverse events, any of them around 75%. When you start focusing on the high problematic risk mutations, and mainly those that are treatment-related, you see that numbers are remarkably small. You see that approximately 50% Grade 3 or plus adverse events, but only around a quarter of them are treatment-related. When you see the serious adverse events, you're starting to go to single- digits for the adverse events that are treatment-related. There is no Grade 5 toxicity. There is no mortality in this study. There's actually no DLTs in this study as well. Also reflecting this good tolerability, very few patients have treatment discontinuation because of toxicity.
The drug is remarkably well tolerated, and the median duration of treatment is seven months in the phase I-A,B and 3.6 months with the 600 mg. But remember, those patients are starting later on the study, so they've been exposed to the drug for shorter periods of time just because we got this dose later on as the study advanced. Next slide. Oh, sorry. 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.
When you think about BTK inhibitors, which 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 comforting to see that you don't have any new emerging type of adverse events. That makes it easier for physicians to just be comfortable with the drug and start using the drug right away. 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 mg dose. What you see is what we experienced in this study is that there doesn't seem to be really a dose-related toxicity.
So we went up on the dose, and we didn't see worsening toxicity related to the dose. And the vast majority of toxicities that are treatment-related were 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 you see neutropenia, but you don't see any febrile complications. We're hematologists. We're used to dealing with neutropenia. So neutropenia really doesn't hold us from giving the therapy, especially when you have neutropenia that is easy to manage and neutropenia that doesn't lead to infectious complications. We had 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 I learned as we used the drug over a long period of time, some of these cytopenias that we saw in the beginning were related to response. So some of the dose adjustments that I did in the beginning, I no longer do. So it happens, but then as these patients get exposed for a longer period of time, start really responding, these neutropenias naturally resolve 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 were 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 the CLL population.
This, I think, is a graph that really demonstrates the activity of the drug. This is the reduction in lymph node size. This is the lower the bar, the greater the proportion of decrease in size of the lymph nodes. We see that a great majority of patients had a significant reduction in lymph node size, a lot of them more than 50% reduction in 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. 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 one or very frequently more than one high-risk mutation such as TP53, SF3B1, ATM, NOTCH1, so mutations that are associated with very refractory disease.
Despite the presence of one or more of these mutations at the same time, we still see most patients having incredible response. This represents 83% complete overall response rate. Remember that when you're targeting B-cell malignancies with BTK 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. 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. 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, to take it to CAR, to take it to a bispecific, or just enough to control the disease and allow 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 to stable disease has an enormous clinical value. So this is the phase I-A patients, a total of 47 patients, the median follow-up of 19 months. This represents a duration of response of 20 months. And we see these responses in all subgroups.
This, when you're breaking them down according 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. In all of them, there's no statistical significance on the response. 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 pirtobrutinib, or patients that were continuing because they progressed on a BTK inhibitor, patients with more than four lines of therapy. In all these subgroups, we see the same benefit from the drug without any statistical significance. There we go. This is the progression-free survival curve for the phase I-A studies. They're all across all those levels. Again, those are patients that were treated between the 50 mg up to 600 mg dose.
The median follow-up was 16 months. The median progression-free survival was 22 months, which is quite 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 peek at the cohort that were randomized between 200 mg and 600 mg, so this is the population that was treated later during the study, so 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 rate, so we see more responses with the 600 mg dose. If you remember, we see this response, but we don't see an increase in toxicity with the higher dose, and we're starting to see a difference in progression-free survival, so really reinforcing that we probably picked the right dose.
The fact that we have a difference in response, very likely a difference in progression-free survival. And as we've seen, when we compare the toxicity profile, we don't really see any difference. We're getting the additional benefit of the response without additional toxicity. For conclusions for our CLL portion, this is bexobrutideg. It's a novel BTK degrader that is incredibly well tolerated and really has very remarkable activity even in heavily pretreated population with relapse refractory CLL. We were able to define the 600 mg dose as the recommended phase II dose. And when we evaluate the overall population with a follow-up of 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-free survival is 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 mg, and it's never too much to emphasize that we see these high response rates even in these very difficult to treat subgroups, such as the patients with CNS involvement with multiple high-risk mutations.
When we focus on the phase I-B portion of the study, that randomized portion between the 200 mg and 600 mg, which was really as a result of Project Optimus from the FDA, we see a higher response rate in PFS with the 600 mg, or at least a suggestion so far on the curve of a better PFS with a 600 mg dose, really reinforcing that we really chose the right dose of recommended phase II dose. As Arthur mentioned, we are certainly looking forward to the upcoming studies that are further exploring bexobrutideg. Before we go to the Waldenstrom's macroglobulinemia data, I just wanted to give you an example. I think this is very remarkable.
It's 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 it represents to their life. So this is a patient with CLL with CNS involvement. And what you can see is that over time, what happens in the response, and this graph very nicely shows the different compartments that you have disease involvement. Typically, with CLL, you're going to have different compartments. So you have the lymph nodes, the disease circulating the blood, the spleen, the bone marrow. In this case, the patient with also disease in the 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 drugs, you 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 to these drugs for a progressive period of time. And what we see in this patient is that over a period of 48 weeks, we have low clearance of all compartments. Some compartments tend to clear faster than the others. That's why you see some CRs and PRs happening 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 well.
So I think it's just a remarkable example of a very difficult-to-treat patient with very few treatment options having incredible benefit from the drug. So now we will jump to the Waldenstrom data. As we had the CLL, SLL cohort, we also had a Waldenstrom non-Hodgkin lymphoma cohort. And in the phase I-A, the structure was very similar. So randomizing from 50 mg to 600 mg is 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 I-B with safety expansion. And we're going to focus on the Waldenstrom's cohort on this presentation. So those were 31 patients with Waldenstrom's, and again, showing that this is a population with very high-risk features.
Median age is 71. 77% of them were male. Again, some patients with CNS involvement. There is a specific presentation of Waldenstrom's Bing-Neel, which is the Waldenstrom's macroglobulinemia presenting with CNS involvement. We had some patients that were treated on the study with Bing-Neel. The median line of therapy was three. Again, we see that most patients were exposed to BTK inhibitors. In reality, all of them were exposed, including four patients with previous pirtobrutinib exposure. We have some patients with dual exposure to BCL2 and BTK inhibitors. The data with venetoclax, which is the main BCL2 inhibitor, is not as solid in Waldenstrom's. 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 chemoimmunotherapy because the typical treatment for these patients is a combination of bendamustine and rituximab or BTK inhibitors as standard of care. The mutation status is important. It has a different role in Waldenstrom's, but as part of diagnosis, it 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 sequencings don't actually capture this very well, so you have to specifically request them. The hallmark mutation for Waldenstrom's is MYD88, 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 Waldenstrom's macroglobulinemia population. And what we see here is a very similar profile as compared to what I showed you in the CLL. So you see most treatment-related events representing 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 is that you didn't see with CLL as some Grade 3 post-procedural hemorrhage. So we know with BTK targeting, you have some issue with platelet dysfunction, probably with some mucosal bleeding. Specifically, in this population, there was a patient after surgery that had some anticoagulation and had some bleeding postoperatively. It was a small subdural hemorrhage that was easily controlled, and these were completely resolved.
This could be a little bit from the drug. It 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 Waldenstrom's 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. I, for example, had a patient with Waldenstrom'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 to have a small surgical resection. We held the drug. He had no bleeding complications. The surgeon told me, "Yeah, he was a little oozy," which was probably just from his disease itself.
He had held the drug. The drug was not present. We held the drug as we expected a few days before the procedure, and he still had a little bit of oozing during the surgery that was easily controlled, which demonstrates that this is really inherent to the disease. This is the response assessment. We have our primary efficacy analysis with 28 patients and an exploratory efficacy analysis with two different response assessments that we can talk a little bit about in 23 patients. We see that the 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 of 60% and 70%.
One thing that is extremely important to tell in Waldenstrom's is that in Waldenstrom 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 70%-80% is very remarkable. It doesn't like me, Paula. I think we're stuck. There we go. 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 CL2 inhibitors and BTK inhibitors. Some of these patients would also have 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 MYD88 mutation. And you can see in the Swimmer plots that most of these patients not only have responses but continue to respond over time. And we've seen responses even in those Bing-Neel patients that had CNS involvement at present at baseline. So again, this is our novel BTK degrader with very important activity even in patients with resistant mutations, very hard to treat patients with Waldenstrom's macroglobulinemias. In a short to medium follow-up of eight months, a lot of patients are 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 two treatment-related adverse events led to drug discontinuation with no Grade 5 adverse events. In these 28 response-evaluable 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 deepening over time as we expect with this class of drugs. Out of the three patients with CNS involvement, two have responded and so far have not progressed. And one data that we did not show, but it's another way that we evaluate Waldenstrom's responses, how the paraproteins 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 see that 14 patients continue on therapy even after more than six months of treatment.
I think this is my last slide. Now I'll hand over to Dr. O’Connor.
Ooh. Everyone's worst nightmare, tripping in front of an audience. All right. First and foremost, let me, 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 appreciate your taking the time this evening 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. Alencar, the presentations earlier for Kymera, 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 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've started our first phase II trial, our first pivotal trial. This is huge. 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 our 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 shout 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. Alencar 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.
When you look at the data that we've generated thus far in our phase I-A across patients treated from anywhere between 50 mg-600 mg, 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. This is, I hate to say it, if you have to have CLL, this is a great time to have it because we have a lot of very, very active drugs.
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, their median PFS 14 months in the all-comer population, but 11.2 months in those who were double-exposed. I'll remind you that in our study, in our phase I-A, 83% of the patients are double-exposed. 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 noncovalent 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 I wish that they were here now because we now have something to offer them. Our first pivotal trial is a single-arm phase two 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 a BCL2 inhibitor. This will be a global trial. We will enroll people and treat them at the 600 mg dose level. We'll be looking at ORR as our primary endpoint, but obviously following for PFS and for safety. This program is already started with patients already being enrolled in Europe, and we hope to open several sites in the U.S., later, well, actually this month. Okay, it's not just you. Okay. Our randomized control 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 enroll 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 chemoimmunotherapy. 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 this 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 this phase I-B/II combination study, which will really set the stage for our combination study in the second-line + setting, as well as a future front-line study. And so what you see is we will be looking at a series of venetoclax doublets or at least a BexDeg venetoclax doublet, as well as two triplets, one with Rituxan, one with Obi. Once we've established the dose for these in the second-line + setting, utilizing a fixed-duration therapy, we will then assess the activity of these in the front-line setting, specifically looking at the doublet of BexDeg and venetoclax, and then the BexDeg, venetoclax, Obi triplet.
So we know, based upon the data that we have generated in our 101 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 control trial, the phase III. And then we will set ourselves up to ask the combination question with this phase I-B/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 I-A and a median PFS of 22.1 months. We've seen similar activity in Waldenstrom's.
This gives us confidence that there's a potential path forward here as well. 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. Given our conversation already, I want to highlight primary CNS lymphoma as well. Thank you for your attention. I'll turn things back over to Arthur.
In the field, 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. We have shown some of this data recently in a couple of settings where we compare the selectivity of bexobrutideg to the BeiGene molecule as well as the AbbVie molecule. It's very clear to us that there are off-targets at clinically relevant doses for both BeiGene molecule and AbbVie 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 data, and thanks for the question, Chris from Lucid Capital Markets. Maybe one for Dr. Alencar. With this new data that we've gotten, do you have any new thoughts on how bexobrutideg compares to other BTK degraders in development?
So the main data that we have is what was presented here at ASH with the BeiGene degraders. I think that's the best one that we have to compare. We really don't have a lot of information on the AbbVie degrader, what it has done, 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 infectious complications. So the numbers are relatively similar.
The numbers are a little bit better with BexDeg. So that's really the best that we have today, is really the fact that, yes, the class is extremely important. The best data that we have is what was presented this weekend. 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. Alencar. So in the Waldenstrom's 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 BTK-targeted 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 the 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's just such small numbers. I don't think we can make much interpretation on that.
Great. Hey. Go ahead, Matt.
Matt Biegler from Oppenheimer. About a dozen patients post-pirtobrutinib here, 62% ORR. Is that kind of the bar that you're seeing for the DAYBreak 201 trial? And then, Dr. Alencar, do you see this in the clinic as kind of an emerging unmet need for your patients that have been exposed to the noncovalent and the covalent and venetoclax and/or maybe obinutuzumab?
I'd like to have Dr. Alencar comment, but also Paula, if you could comment on this question. Go ahead, Dr. Alencar.
So the truth is that covalent and noncovalent BTK inhibitors today, kind of they are seen very close to each other in the clinic and 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 is a clear differentiation, it's still not that very well understood. But yes, you still see patients that very clearly will progress through a covalent BTK inhibitor, noncovalent BTK inhibitor, and still will require more therapy. They still have venetoclax, and you're going to see more and more in these combinations.
But I think that the two points here is not only that there is a clear unmet need because these patients will indeed progress through a covalent and noncovalent and venetoclax, and you still need options, but also because we're combining these drugs, the mechanism of resistance changes, and this will increase even more the 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 mg. 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. Alencar 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 mid-year.
Great. All right, let's go right there.
Yeah. Good evening. 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 mg cohort?
Okay, that is a detailed question. I'm just going to open up to the panel. Whoever would like to answer that, go ahead first. And then we may have more than one answer because I think Gwenn may have an answer, and Dr. Alencar has an answer too.
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 noncovalent 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. Alencar, I think. Go ahead.
I'll tell you what I see in the clinic, which I think is what matters the most. And what we see is that responses are very fast. So when we're starting patients on the drug, I'll tell you, you'll be feeling better next week. You can look yourself in the mirror, you're going to see your lymph nodes are smaller next week, and you're going to start seeing changes in your counts 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 from the continued exposure. So the clinical benefit happens fast.
And what we see from the response rate is the great majority of patients will demonstrate clinical benefit almost off the bat from the very first few weeks they're on therapy. And what we'll see over time is that then you start seeing progressive deepening of response. 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 that'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.
I'm not concerned when I'm putting a patient on the study, regardless of the mutation that may be coming to us. Oh, no, I'm not going to put this patient on the study. Most likely, it's not going to respond because it has X or Y or Z mutation. The point that you bring asking about the time to response is very important because you want to have clinical response. You want to have benefit fast, and this you see very clearly.
Wow. I mean, that is so meaningful to our patient, being able to hear that, that reassurance. Thank you for that. Gwen?
Yeah, 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 mg to start, right? We were doing a dose escalation, then we did the randomization. So we're actually not going to really understand the responses across all the different karyotypes until we get more patients into our 600 mg optimized dose. We definitely understand that we have longer progression-free survival in 600 mg. 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.
Thank you.
Okay, let's go over here. Yes, Stephen.
Yes, Stephen 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 intrapatient basis, and you showed the vignette of the CNS patient who was pushed to 600 mg. So I guess in trying to contextualize the dose escalation PFS data in the context of knowing that some of these doses that those patients were receiving were, quote-unquote, I guess, suboptimal, do we know how many patients were eventually pushed to 600 mg through this intrapatient dose escalation that was allowed during 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 mg 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 two dose escalations. So many actually have waited until we got to our recommended phase two 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 two 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 decided, 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. We need to have a reason to increase the dose that we'll do so.
I have patients at different dose levels and that we have had the option of increasing the dose, but haven't had a reason to do so. Some of the patients are like, "Oh, I want the best dose possible. Let's escalate. I really want it." And mainly that they say, "Well, I don't expect changes in tolerability. So yes, we can definitely increase." But some patients are like, "Why wouldn't 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 200 mg, would you?
Yes, we participated in the randomized portion. I've been on the study really from the beginning. We're on the very first sites to open in the U.S. So I have really exposed patients from the 50 mg- 600 mg. I participated in the randomized phase. We have patients on 600 mg tolerating very, very well.
Then just a quick curiosity question. The waterfall plot that shows the mutational status of these patients, the VAF that's being reported is at 5%. I would imagine the threshold for that is actually much lower in terms of sensitivity. Is that standardized across all trials? If I looked at the BeiGene protocol, would they be using a 5% threshold for mutational presence or absence? Thanks.
From an investigator point, I will say there is really, really have no clear answer for that, right? A 5% VAF is a very reasonable, probably clinically meaningful representative cutoff. 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 cutoff, I think all I can tell is that 5%, I think, is clinically significant and meaningful.
Paula or Gwenn, anything to add to that? Because that's an okay scientific question. Okay, let's go. Okay, back in the back there.
Greg, good evening. Greg Renza of Truist Securities. Thanks for taking the question. Congrats on a great weekend. Maybe another one for Dr. Alencar. Just with respect to the chatter on the floors amongst your colleagues around sequencing and how the various agents should be slotting, covalent, noncovalent, of course, degraders. Just wanted to ask your latest perspective on that. How do you see that shaking out and what some of the considerations are to be made that maybe are worth highlighting? Thank you.
So I think the data from this weekend just tells us that however way we want to interpret the data can be done, and we'll just reinforce and justify the way we see things in clinic, right? So if you see CLL 17, for example, if you want to say that continued therapy is the way to go, fine. It just says equally effective. And if you want to use finite therapy, combine and stop, fine. It just does 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, they're going to decide some are molecular features, some are social features, some are the patient's wishes. That kind of guides you towards 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 around the same decision they're going to make in the second line, right?
So the social situation's around the same, and their life perspective's around the same. So it's very common to see now patients that are going to go from a covalent to a noncovalent to a degrader, and then really going to see BCL2 inhibition. And I had a patient on the study that was exactly that. And actually, she was a very young patient that was treated initially by Michael Keating at MD Anderson with FCR way back when. She progressed with everolimus and lenalidomide. Also at a study, then she moved to Florida, was started on ibrutinib, and then came to me actually for the BRUIN study. I also was main investigator in the BRUIN study, so she received pirtobrutinib 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 she was put on 5948 and had an incredible response. It was really exploding when she was started on BRUIN. They were really nice to me. They even let me put her on the study because she was really on 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 started her on the drug. In a week, she was doing incredibly well. And she had never seen a BCL2 inhibitor, and she still hasn't, right? And you're going to see more and more of this. It's just you follow that path just because that's the patients get used to it. You tell them, you know, 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 pirtobrutinib indication after just a covalent BTK inhibitor. So it's going to become more and more of a norm. venetoclax is an excellent drug. The combinations I'm looking for, I'm going to participate on this because I really want to do this. But venetoclax requires an additional layer of complexity than a lot of patients want to do.
Okay, right here in front.
Hi, Tessa Romero, JP Morgan. Appreciate the presentation tonight. And Dr. Alencar, thanks for being here as well. 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? Thanks.
If you really want to know what I want to know, then you have 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, the research in mantle 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 it's something that we're not going to answer today, but it's something that is going to get more and more confusing, is not only there's no question that BexDeg is incredibly active and is going to be approved and is going to be used. I have no questions about that.
I have been using the drug for more than two years now. I have trust in the drug. It 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 participating in the studies. I want a dealer's choice." So maybe if it wasn't ibrutinib, if it was all dealer's choice, maybe the number wouldn't be that incredible, but still goes home, right? But it's happening here. And I know that pirtobrutinib is better tolerated than a covalent BTK 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 pirtobrutinib before covalent BTK inhibitors. Are we killing a class? What is happening? Then you have BexDeg, which works even better and is even better tolerated, and I wouldn't be surprised that the same conundrum is going to happen. What is going to happen now? I'm going to do this before pirtobrutinib. Am I killing a class completely? So this is something that this is what we've been discussing the entire weekend. This is really what we've been discussing the entire weekend. It is what is going to happen as 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 BexDeg pair them? How can you really manage intermittent or finite versus indefinite therapy? How do we integrate newer drugs, bispecific antibodies? We're combining with venetoclax, but you have second-generation BCL2 inhibitors coming. We're combining with rituximab, but obinutuzumab is certainly better. What would happen if we combine with epcoritamab or glofitamab? 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 and secondary CNS lymphoma, because not only the drug is incredibly active, but because it's so well tolerated and it's just, again, primed for combinations. CNS is not a typical lymphoma. What do you want to use 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 antibodies, 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.
Yeah, thanks, Nurix team. And maybe, I guess, a question for Dr. Alencar. On CNS involvement, what percentage of your CLL patients have CNS involvement? I think a second question also for you is, I guess, with your experience, have you seen a dose-response correlation to PFS even after a program maxes out on BTK inhibition at lower doses? I guess another way of asking is, is BeiGene leaving efficacy on the table by moving forward with a 200 mg dose?
The first question as far as CNS lymphoma and CLL. I see a lot just because I'm an expert. I can get a lot of referrals. A larger proportion of my patients with CLL have CNS involvement. Percentage is 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. I have patients with CLL and CNS involvement that were treated on the study and had responses.
So I see more than the average physician in the community. Those physicians maybe will see one CLL patient with CNS involvement a year in their career because they're not common, but the fact is that they are there, and it's certainly an issue, especially in these patients that get more and more treated, become more and more resistant. It is extremely unusual, extremely unusual to have CLL with CNS involvement at diagnosis. These are typically patients, especially patients that have been treated, not a typical CLL patient, the CLL patient that is just monitored and nothing ever happens, and they die with the disease, not from the disease.
This will happen more with the patients that develop mechanism of 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 to PFS. 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, which is really a fact of the class pretty much to some extent, right?
We see differences still like with ibrutinib. You have more difference in dose levels and toxicity. But in pirtobrutinib, 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 three different dose levels of pirtobrutinib, 100 mg, 200 mg, 600 mg. So there's a possibility that in lower doses, you have very good activity and very much the same tolerability. 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 degradation, not necessarily better degradation because you see degradation even at very, very low dose levels, but there's something that allows a better response than the higher dose. So it's not necessarily that 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, because it hardly ever happened in the study, they'd have to adjust dose because of toxicity. They were able to safely do so and not lose response. I don't know if I answered your question, but.
That was really helpful. And maybe a couple of questions for the company?
Oh, sure. Yes, 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 chemoimmunotherapy. I think previously the company had defined chemoimmunotherapy as IR or BR. Is that still the same definition? That's the first question. And then the second question would be, I think there was an asterisk 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. Thank you.
Sure. I can address that. So yeah, very astute to see that asterisk that was added. So 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 pirtobrutinib data. And so the overarching principle in defining a control arm for a randomized control study is that the control arm should be representative of the standard of care in the U.S., especially the primary 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 pirtobrutinib 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 a very astute question. I see there's one more question. Yes, go ahead, Joseph.
Thanks, Arthur. Joseph Catanzaro from Mizuho. Two questions for me. One may be 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 relapse 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? Thanks.
Go ahead, Paula.
Okay, so 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 two years' worth of data before we actually present it. So that's one. What was your first question? rituximab. Oh, why rituximab? A, because I worked on rituximab at Genentech when I joined industry. No, that's not why.
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 patient.
So if that is their choice, then we will have data to support that.
So I told you that when I talked to Billy about the pirtobrutinib versus ibrutinib study, I told him I wouldn't open the study because I don't think that Pirto with ibrutinib is a fair comparator. And I told him I would open it if it was dealer's choice. And he decided not to, we didn't open the study. So in this study, I would not have a problem opening the study if I had that number one because we have pirtobrutinib as an option. And I think it's a more fair comparison for the U.S. for where we are today.
But we know that in a global study, there are still many sites that it's much more complicated to get obinutuzumab, rituximab at the proper doses with a dose adjustment of 500 mg per meter squared. It's still a very reasonable anti-CD20 monoclonal antibody, mainly in the relapse setting. Yes, you have the bendamustine 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 obinutuzumab. It is a superior antibody when you compare head-to-head to 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.
Yeah, so thank you. I think that's all that 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 that 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 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 that we're very proud of. Securing the 600 mg 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, the 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 BTK and 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 CBL-B inhibitor, NX-1607, which looked 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 a cash runway into 2028, which allows the company to do all of these great things with BexDeg 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 JP Morgan Conference in January, of course. But we do see multiple opportunities for new data in 2026 from cohorts in the phase I-B. We've only been talking about cohort 1 so far and then our Waldenstrom cohorts. But as I said, we have approximately 100 patients in our NHL cohorts. We look forward to presenting that. BexDeg will have the SAD/MAD study readouts in 2026.
And then, in turning to I&I, again, GS-6791 should have potentially phase 1 results. We depend on Gilead for the timing of that, but that should be on the horizon. And we do anticipate an IND filing with the STAT6 program with Sanofi, and then also an IND filing for BexDeg and I&I. So we are executing, focused now fully on the pivotal development pathway with BexDeg. 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. Alvaro Alencar 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, Paul 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.