Welcome to the Nurix Therapeutics EHA 2025 Investor Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. I would now like to turn the conference over to Nurix President and CEO, Arthur Sands. Arthur, you may begin.
Thanks, Paul. Welcome to our call and our presentation today entitled, "Meeting the Needs of Patients with CLL and Waldenström's , Bexobrutideg which is NX-5948, clinical update," which we are delivering here from the European Hematology Association Conference, or EHA, in Milan, Italy. We will be making certain forward-looking statements today, and so we refer you to our disclaimers. We are very excited to be sharing with you our latest clinical updates from two poster presentations we have here at the conference. The first is focused on our phase I-A trial of Bexobrutideg in patients with CLL, which features those patients in the dose escalation portion of our phase I study who have had the longest duration of therapy on bexdeg, which we call it for short.
Although these patients have been on a wide spectrum of doses, they do represent those cohorts who have had the longest duration of therapy overall to date. The second presentation is based on the combined population of our phase I-A and Ib trials in patients with advanced Waldenström's and difficult-to-treat indolent lymphoma disease state. Both presentations today will be given by Dr. Munir, consulting haematologist at The Leeds Teaching Hospitals and a senior investigator on the Bexobrutideg study. Dr. Munir will then be followed by Dr. Paula O'Connor, Nurix's Chief Medical Officer, who will share her observations on our results to date and review our progress on the regulatory front. Paula will also provide an update on our current plans with respect to the future clinical trials and registrational path.
Lastly, I will provide a pipeline update and describe how we see the BTK targeted therapy market evolving and how our clinical development plans are designed to serve patients with unmet medical needs as we work together to find lasting solutions to the challenges of CLL. With that, I'll turn the call over to Dr. Munir.
Thank you very much, Arthur. Thanks for having me. My job is to just get you through the data for Nurix 5948. Now we've got the names, bexdeg, which I really like, the short form. We're presenting the data on this degrader molecule, which is demonstrating rapid and durable clinical responses in the relapsed refractory CLL. Bexdeg is a small BTK degrader that is addressing the needs of the CLL treatment landscape, especially for the relapsed refractory patients. We know that the standard of care in CLL is now focusing on two key signaling pathways. One is the BTK pathway, and the other one is the BCL2 pathways.
We now know that there is still an unmet need simply because a lot of the drugs, like covalent and non-covalent BTK inhibitors, the patients who are relapsing on these drugs are developing resistance mutations, and that's mainly seen in half of the patients. Some of these mutations are interesting mutations because they maintain the intact B-cell receptor signaling, which is really what you're intending to stop with the BTK inhibitor through this scaffolding function of BTK. As we are moving more and more patients towards BTK inhibitors as well as BCL2 inhibitors in the frontline space, we're seeing more and more refractory patients who are coming through, and hence the need for treating these patients with alternative therapies.
The bexdeg really offers an additional treatment modality for these patients because it has got the ability to overcome the treatment-emergent BTKi resistant mutation and also disrupt the BTK scaffolding function, which is quite important in these patients who are developing resistance. For the Nurix 5948-301 study, it had a dose escalation phase I-A program. The key eligibility criteria was patients who had relapsed refractory disease and should have had more than two prior lines of therapy. You can see that the dose was escalated from 50 mg once a day to up to a dose of 600 mg a day dose. There was a phase I-B dose expansion, which is fully enrolled, and two doses were looked at in that expansion program, which was 200 mg a day and also 600 mg a day.
There are a number phase I-B expansion cohorts where we are testing this molecule in early lines of therapy or patients with other complex CLL problems, just for example, immune hemolytic anemias or CNS involvement in these patients. A number of other expansion cohorts really to look at which are the patients who are going to benefit the most from this drug. This slide illustrates the patient's disposition and demographics. For 48 patients who have escalated the Nurix 5948, you can see that starting from 50 mg, we had three patients, and up to 600 mg, 16 patients went on to that dose. We have got 32 patients still on the treatment at this moment in time. 16 patients have discontinued primarily due to progression. There was only one patient who stopped the drug because of an adverse event, which was a grade 2 event.
The median age of these patients is 68.5, predominantly male and predominantly white. When we look at the baseline disease characteristics, you see that it is a very heavily treated population with multiple lines of therapy. The median was four. CNS involvement was seen in five patients. The kind of therapies that patients had include covalent BTK inhibitors as well as non-covalent BTK inhibitors in about 27% of the patients. The majority of the patients have had venetoclax-based therapy. Some patients also had CAR T-cell therapy, and chemoimmunotherapy was used in 72.9% of the patients. Again, when you look at the mutation status, when patients who are relapsing on BTK inhibitors, you need to look at the BTK binding site mutations, and that's picked up in 38% of the cases.
A reasonable number of patients had PLC gamma 2 mutation, which is a downstream mutation in the B-cell receptor pathway. Some BCL2 mutation there, and nearly 45% of the patients had TP53 aberration as well. In terms of the side effect profile, the drug is tolerated very well in this update. There is no new safety signal that has come through. We normally see some kind of minor bleeding issues in these patients. The most important thing I want to highlight is looking at the grade 3 adverse events or really looking at the SAEs. The only thing that stands out there is the infections, which we know that CLL patients are inherently prone to get infections. I would argue that it is probably inherent to disease rather than the drug effect, which is manifesting itself with the SAEs that we are seeing.
Really very good safety profile at all those levels has been well documented with the drug. In this phase I-A program, it's always nice to see that the patients are responding to therapy. As an investigator, that's the most gratifying thing to see. We're seeing the overall response rate of 80.9%. We've got one CR, which is really good to see that the patients are now starting to get deep responses. The PR is the main response that we're seeing in 78.7% of the patients. Even the patients who have got stable disease are benefiting from the drug. The median follow-up on this study is nine months, and the range is between 1.6 months-26.1 months. Look at this waterfall plot. What you look at is the sum of product of diameter of target lesions.
These are basically the lesions that were picked up right at the beginning, and we want to see whether tumor load is reducing in these patients. What you find is that the majority of the patients are showing more than 50% response, and some patients are starting to show very deep response regardless of which baseline mutation they had. Patients with BTK mutations or PLC gamma 2 mutations, all patients are responding, which is again very gratifying to see. On this, each bar represents an individual patient, and you can see on the left side the BTK or BCL2 mutation data in this bar. What you see is that there are a number of patients where the duration of treatment is more than 18 months, more than 12 months. There are 18 patients in that category now.
Some of the patients have escalated the dose during the treatment, and it was given as an investigator choice to move them to the final therapeutic dose that they thought would be reasonable to put the patient through. The 21 patients have moved up the dose. The good thing is that the median time to first response is very quick. It is a median of 1.9 months, and the median duration is not reached. What we are seeing in this extended follow-up is that the durability of the response is there. As you can see, the star shows the CR patient who is doing well, mainly going up to two and a half years on the drug.
Again, looking at the response to therapy, I would just highlight that the majority of the curves, individual bars, are showing you that there is a 50% decrease in the size of the nodal bulk, and that's being measured through the scans. There's only one patient where the disease progression happened, but that was a patient who was on pirtobrutinib and then stopped the drug to go into the trial, and hence you see the diameters increasing in the first place and had some response to the drug and then relapsed afterwards. To conclude, NX-5948 or Bexobrutideg is a novel small molecule that degrades well-validated CLL target BTK by utilizing the ubiquitin proteasome pathway in the fully enrolled phase I-A CLL portion of the Nurix 5948-301 study as of the 12th of March, 2025 data cut off.
We have got a median follow-up of nine months, and most patients were still on treatment. The drug is very well tolerated, and this is consistent with the overall study population and previous disclosures. The clinical activity is in a population of heavily pretreated patients with advanced CLL, with the patient median lines of therapy being four. Amongst those therapies was covalent BTK inhibitors, non-covalent BTK inhibitors, and BCL2 inhibitors. These patients exhibited a high number of patients had BTK, PLC gamma 2, and BCL2 mutations and high-risk molecular features, and some patients had CNS involvement. What we're seeing is reverse and deepening responses with a high overall response rate of 80.9%. We've now got one CR, but the responses are rapid with a median time to first response of 1.87 months.
There are multiple conversions that are being seen from stable disease to PR and then conversion to CR in one patient from PR. Of the 18 patients treated at more than 12 months of therapy, 17 have remained on study, and one patient is approaching 2.5 years on treatment. The phase I-B dose expansion cohort enrollment is complete, and as I told you, there are additional cohorts in which patients are being enrolled at the moment. There are other pivotal trial initiations planned in 2025. Right. Straight away, move on to the efficacy of this molecule, again showing high clinical activity and tolerable safety in patients with Waldenström's macroglobulinemia.
Again, in terms of the study design, we are now, I told you about the CLL cohort, but there is an NHL Waldenström's macroglobulinemia cohort as well, similar dose escalation planned from 50 mg once a day to 600 mg once a day. As we know, the one-week expansion cohort for CLL has fully enrolled, but we're focusing on the Waldenström's expansion cohort, which has also got a fast-track designation as well. In terms of the demographics of Waldenström's patients, these were 22 patients in this study, median age of 72.5, with a range of 58-86, predominantly male, two patients had CNS involvement, and the median prior lines of therapy was three. All patients had BTK inhibitors, the covalent BTK inhibitors. All patients had non-covalent BTK inhibitors. Some patients had BCL2 inhibitors, and the majority of the patients had chemoimmunotherapy.
In this disease, we look at the MYD88 mutation and CXCR4 mutation, which were prevalent in these patients. Again, going down to the side effect profile, again, I would highlight that you have got any grade toxicity, which is small in number, but very few patients had grade 3 toxicity. The serious adverse events again were limited to infections. There was one subdural hematoma, and I think that was primarily trauma-induced rather than spontaneous. In terms of the overall response rate, which was evaluable for 19 patients, it was 84.2%. There were no CRs at the moment, but we know in this group of patients, it takes a lot to get the patient into CR. There were very good partial responses in two patients, 11 patients had PR, minor response in three patients, and a stable disease in three patients.
There were no progressions at this follow-up in this study. The median follow-up is 3.7 months with the range between 1.9 months-18.9 months. When we look at the responses in this bar chart again, what you find is that all of the patients who are continuing the therapy continue to show deepening of the response, and most of the patients have continued the therapy. Some patients obviously have achieved a very good partial response in this trial now. Five patients escalated the dose. Again, similar as planned in what I showed you in the CLL cohort. The median duration of response is not reached, and it is ranging between 2.89 to not reached months. I think this is an important slide because it shows how quickly these patients respond to the drug. This is the percentage change in the IgM levels with Waldenström's patients.
It's quite important to get their plasma viscosity and IgM levels controlled. In the majority of the patients, 50% reduction in IgM levels happened pretty quickly while they started the drug. Bexobrutideg is a novel small molecule BTK degrader that can overcome treatment-emerging BTK-resistant mutations and disrupt the BTK scaffolding. In the Waldenström portion of the phase I 5948-301 study, as of 12th of March, 2025 data cut off, the median follow-up on this for these patients was 3.7 months, and most patients were still on treatment. In the 22 patients with Waldenström's macroglobulinemia, the drug was very well tolerated, consistent with overall study population and previous disclosures. Mainly the toxicity was low grade, and we saw this as a common toxicity like TK diarrhea, neutropenia, and thrombocytopenia, but there's no atrial fibrillation, which was observed.
There was no drug-limiting toxicity, and two treatment-emerging adverse events led to treatment drug discontinuation. There was no grade 5A. In terms of the response, the 19 disease-evaluable patients, durable and deepening responses were observed in a heavily pretreated population, three median lines of prior lines of therapy, and including the patients who had CNS involvement and mutations in MYD88 and CXCR4. Overall response rate of 84.2% with two responses deepening to VGPR with longer duration of treatment. As I said, there was a steady reduction in IgM levels, which was observed in most patients from first IgM assessment, and it continued to deepen over eight weeks and beyond. Three patients had had 90% reduction in IgM levels, which is impressive. Median duration of response was not reached. I'll stop.
Great. Now I'll turn the call over to Dr. O'Connor.
Thank you, Dr. Munir, for that comprehensive review of the 5948 or Bexobrutideg data. Having heard the presentation from Dr. Munir, you can see that the bexdeg data in relapse refractory CLL remains very encouraging with a stable ORR of 80% and a pattern of deepening responses over time and a very well-tolerated safety profile. These data demonstrate the potential for bexdeg to address the unmet medical needs of patients with relapse refractory CLL by completely disrupting the BCR pathway and providing broad coverage of wild-type BTK and the BTK resistance mutations. The rapidity of responses to bexdeg and the deepening of responses over time with our first bone marrow-confirmed CR and a favorable safety profile as monotherapy in the relapse refractory setting positions bexdeg for development not only in relapse refractory CLL, but also in the earlier lines of CLL.
Following the emerging data for bexdeg, the team at Nurix has pursued interactions with global regulatory agencies to support its broad registration. In 2024, we received fast-track and prime designations. These will support an accelerated pathway for the future registration of bexdeg and speaks to the review, or rather the view of bexdeg by regulatory authorities in that it represents a promising agent to meet the needs of patients with relapse refractory CLL. A type B end-of-phase I meeting in 2024 provided key FDA input on the path toward pivotal trials and the initiation of those trials in 2025. As it relates to Waldenström's, we also make progress or have made progress on a regulatory front, specifically with the achievement of a fast-track designation from the FDA in December of 2024, and then most recently an orphan drug designation from the FDA in March of 2025.
Bexdeg is poised to shape the future standard of care in CLL, beginning with monotherapy in relapsed and refractory CLL, and then moving to expansion and combination with BCL2 inhibitors in the treatment naive setting as well as the relapsed and refractory setting. 2025 has been an important year for Nurix and bexdeg. As you can see on the left-hand side of the slide, we have meaningfully advanced our CLL program, completing the phase I-B dose optimization cohort as per Project Optimus, and have expanded our phase I-B program to enhance our understanding of bexdeg activity in critical CLL populations. The data from these additional cohorts will inform our future plans. These populations include patients with high-risk genetic profiles, patients in the second line who are BTKi naive, BCL2I naive, BTKi naive patients, CLL patients with autoimmune hemolytic anemia, and then CLL patients with CNS involvement, to name a few.
On the right-hand side of the slide, you can see our plans to advance our program for bexdeg. We will begin with the initiation of our single-arm phase II in our fast-track designated population of relapsed refractory CLL patients post-BTK inhibitor and BCL2 inhibitors. This will begin in the second half of this year. We will follow that with our confirmatory study in the second-line plus setting, where bexdeg will be assessed versus comparators supporting a global registration. Finally, we will initiate a combination trial with BCL2 inhibitors versus standard of care to address the emerging standard of combination therapy in first and second lines of therapy for CLL. With this, we are really excited about the future for bexdeg, 5948, Bexobrutideg, all the same. I will now turn things back to Arthur Sands.
Thanks, Paula. And also a big thank you to Dr. Munir. We really appreciate you joining us on the call, and you'll be thanked for the Q&A session too. That's great. We're very highly encouraged by the impressive efficacy results that have been demonstrated with bexdeg, and further by the safety and tolerability of bexdeg across both CLL and NHL. As we advance bexdeg to pivotal studies, it is also important to acknowledge that it's part of a larger pipeline of Nurix-targeted protein degradation drugs in oncology and autoimmune disease. Most notably, I'd like to mention the recently announced advancement of our novel STAT6 degrader, NX-3911, in the lower part of that slide in the immunology section, which has now advanced into IND-enabling studies with our partner, Sanofi. We're focused here on type 2 inflammatory diseases, of course, a very large market opportunity.
NX-3911 has best-in-class potential, achieving complete removal of the STAT6 protein and demonstrating gene knockout-like efficacy in animal models of inflammatory disease. Together with Sanofi, we look forward to providing future updates on NX-3911 as it proceeds through development. At the top of our pipeline chart, in both oncology and the autoimmune categories, is bexdeg. We strongly believe that bexdeg has the potential to be the best-in-class BTK degrader, which motivates us to advance the development of our clinical program as rapidly as possible. We also strongly believe that bexdeg has the potential to shape the future standard of care in CLL. I'd like to take a moment to review a couple of points regarding the CLL market depicted on this slide. First, the CLL opportunity across the major markets is very substantial, the major markets being defined as the U.S., EU, U.K., and Japan.
Currently, BTK inhibitors are the most widely used therapies in CLL, which is presented in their generating over $9 billion in sales in 2024. Furthermore, the BTK targeted therapy market is expected to grow to more than $15 billion by 2028. There's clear recognition that the BTK pathway is the dominant driver of disease progression in CLL. Therefore, the most effective and safe way to target BTK will be the determining factor for future success. bexdeg is designed to deliver on these attributes of the most effective and safe way to target BTK. This will provide the foundation for its substantial market opportunity in the future.
As we explore the CLL market in more detail, greater than 55,000 patients start therapy for the first time or start a new therapy each year, consisting of approximately 30,000 patients initiating therapy in the first line, the left, 16,000 initiating therapy in the second line, and 10,000 patients initiating therapy in the third line or later. Our initial development plans will be in the post-covalent BTK inhibitor population, which represents a very substantial commercial opportunity overall. Specifically, our phase II monotherapy single-arm, indicated in the lower right of the slide, is designed to address the approximately 10,000 patients initiating therapy in the third line setting or later. This is the post-BTK inhibitor, BCL2 inhibitor population for which bexdeg has fast-track status. Notably, approximately 30% of patients we have enrolled in our clinical study so far have also had prior therapy with a non-covalent BTK inhibitor.
Next, we intend to move up a line of therapy to the second line, comprised of approximately 16,000 patients. Our phase III randomized control monotherapy study is designed to offer this substantial population the ability to continue to gain benefit of a BTK targeted therapy through degradation of BTK when covalent inhibition no longer works. Turning to the front-line setting, we also anticipate a combination trial with BCL2 inhibitor, likely venetoclax. We are currently considering potential designs for this study. Overall, we clearly see a substantial commercial opportunity for bexdeg as we progress its development in earlier lines of therapy. As Paula described, we are finalizing our development plans for bexdeg in CLL, which we anticipate being completed in the near term, and we will communicate it accordingly. I will conclude this section by saying we are thrilled to have bexdeg as a Nurix-invented and developed wholly owned asset.
This puts us in a very strong position as we transition to a late-stage development organization and prepare to become a fully integrated commercial stage company. As we conclude the presentation section for today and will enter into Q&A, I think it's important to place the bexdeg opportunity in the context of the greater scheme of developing a whole new category of drugs as pictured on this slide here. This is the category of the degraders, and bexdeg, we're proud to say, is the first degrader in this category. Nurix is proud to play a leading role in this exciting journey. We believe that by bringing our degrader drug discovery innovation to patients, we have the opportunity to shape the future standard of care across many diseases, which will make Nurix a very important and valuable biopharmaceutical company that provides critical new therapies for patients.
As we enter the Q&A session now, we'd like to take this opportunity to thank all of the patients who have participated in our clinical trials to date and all of the physicians who have devoted their time and expertise to the successful development of Bexobrutideg. We can now take your questions.
If you would like to ask a question, please press star one on your telephone keypad now. You will be placed into the queue in the order received. Please be prepared to ask your question when prompted. Once again, if you have a question, please press star one on your phone now. Our first question comes from Eric Joseph of JP Morgan Chase.
Hi guys, congrats on the data. This is Ruan An for Eric. One question that comes up a bit in our discussions with T-Monx about BTK degrader classes, whether they're more effective than pirto in the context of refractory disease. Are you or Dr. Munir able to speak to that a bit on the phase I-A update? Thanks. I'll follow up.
That's a very good question. I think the answer to that question is that we have seen the pirto data now, and it's gone through the phase III relapsed refractory trials as well. What we're finding with pirto is the development of these resistant mutations, like T474 and L528. The PFS data suggests that nearly half of the patients will progress at around 14 months. The durability is the question mark, really, with the pirto data. In terms of the exact data at the moment, obviously, it's a phase I-A study, and the main focus was on the safety of the molecule. The clinical effectiveness is doubtless, really. I think we are seeing very good responses in our patients. Certainly, the patients I have got in my clinic are showing durable responses.
Now, over time, as the data accumulates, we will be able to see if this is really meaningful improvement. Obviously, the team here at Nurix are taking it forward to the phase III program. The phase III program hopefully will reinforce the point that we're seeing reasonable, durable responses in these patients who have got very difficult disease, especially the patients who've had covalent and non-covalent BTK inhibitors. Still, we are able to salvage those patients. If we are going to use degrader at earlier lines of therapy, I think we will see more durable responses, especially when we're seeing reasonably prolonged follow-up going up to a year in these patients. Still, the majority of the patients are showing a response.
Did you have a follow-up question?
Yeah. Does the current ongoing phase I-B trial have potential to serve as the initial monotherapy trial for accelerated approval, or would you need a separate study to pursue that? Thanks.
Paula?
Hello. Thank you for that question. We are planning to move forward with a single-arm study, separate and distinct from our ongoing phase I-B, to enable us to enroll patients in a more global fashion. We have sites that we are planning to open in all corners of the globe.
Our next question comes from Brian Abrahams of RBC Capital.
Hi there. Thanks so much for taking my questions, and congratulations on the updated data. Really, two for me. Just wondering if you could maybe talk a little bit about the potential for further deepening of responses and kind of what you're seeing in terms of the patient who has now converted to a CR. Secondarily, how much follow-up are you hoping to see from this dose escalation study and the phase I-B in order to have comfort selecting a dose to move forward with? How much is that a gating factor, I guess, and what else needs to be sorted out before starting that accelerated approval-geared study? Thanks.
Thank you for the question. I think I'll address your first question, which is about the pattern of deepening responses over time. I'm going to begin with some history just to reflect that BTK targeted agents, BTKi in particular, have demonstrated this pattern of deepening responses. In some cases, when we think about the BTKi, you've seen response deepening as late as two or three years after the initiation of therapy. We have not currently treated our patients that long, but certainly, we can say that our first CR was in one of our earliest patients on study and occurred more than a year into their treatment. We have several other patients who are approaching normal counts and hence are eligible for bone marrow biopsies to confirm their potential complete responses.
Given this, we anticipate that we will continue to see deepening of responses over time, as evidenced not only by the reduction, or rather the decrease in the lymph nodes that was shown by Dr. Munir, and obviously the overarching response. Your second question—I apologize, I have lost your second question. Would you mind repeating that, please?
Yeah, sure. Just wondering, I guess, how much follow-up you're hoping to see from both this study and the phase I-B, looking at 200 and 600, to get enough comfort in what the go-forward dose is going to be and any other kind of gating factors to starting that single-arm phase II accelerated approval-geared study?
As noted in my presentation, we have been interacting with the agency regarding our phase I-A and our phase I-B data and anticipate our ability to move forward in the second half of this year. As it relates to the long-term follow-up for patients, we are committed to these patients. They have given us their time and energy, and we will continue to follow them on therapy as long as they show benefit. Thanks.
Thanks.
Thank you.
Our next question comes from Peter Lawson of Barclays Capital.
Great. Thanks so much. You mentioned kind of pivotal trials in first line, potentially with venetoclax. Just kind of what are the gating factors you're kind of looking for that, looking around that? The responses you saw with patients with other mutations, such as TP53, are there any patterns emerging as regards how well those patients do, if there are any kind of trends within those kind of secondary or tertiary mutations?
Okay. Paula, the first question about gating factors for combination trials.
Based upon the review of the data, I think the first gating factor is the safety and tolerability as well as the activity of bexdeg. What you can see is that the safety profile suggests that there is the ability to combine this with other agents. That is the first gate. Otherwise, we will, in fact, have to demonstrate that it is safe to give the two drugs in combination, and that can be done in a number of different fashions. Your second question, once again, would you please repeat that?
Yeah. It's just around patients that harbor other mutations, TP53, if there's any kind of patterns emerging on kind of how well those patients do on the drug, if there's differences between either PLCG2 or TP53s.
Dr. Munir showed two slides in his presentation. The first was the waterfall plot where we basically showed the reduction in lymph node size relative to patients' previous mutation status. There was no mutation profile that is associated with a lack of response. Second, he showed our swim lane plot where you see the duration of time on treatment by different dose level. What you might have seen on the left-hand slide was an overview of all of the previous therapies that patients had received. We did not actually list the mutation status, but what I will acknowledge is that many of the patients with TP53 mutations or other poor prognostic mutations remain on study up to a year or more.
Thank you for your question. I'll just remind everyone also that we do have the slides from this presentation on our website. As we refer to them, you can click back and forth and see them if you need them. Next question.
Our next question comes from Kripa Devarakonda of Truist Securities.
Thank you, guys. Thanks for taking my question and congrats on the data. Just going back to regulatory discussions, is there any indication that the FDA would like to see more durability data before you can initiate the pivotal trial? Can you elaborate a little bit more on the key factors that are driving the design of your confirmatory trials? Thank you.
Sure. With regard to the first question, really, in terms of choosing dose, it's related to length of time on the phase I-B study, so an adequate time period to evaluate the two doses. It's not really linked to any durability time point per se. It's more of a trial time point, which we're approaching very rapidly. Of course, in general, the FDA would like to see ultimately durability and PFS as the key endpoints for any randomized control trial endpoint, approval endpoint. That's with regard to that question. With regard to the second question, I think I'm a little jet lagged like Paula, so I've forgotten the second question already. Could you repeat that?
I was just wondering what the key factors are that are driving the design of your confirmatory trial.
Okay. Paula, do you want to take that?
All of our programs are being designed to be efficient in terms of the use of their patients, but most importantly, to be meaningful from a global standard. For our randomized confirmatory trial and for our future trials in combination, we are always considering what the standards of care are not only in the United States, but also in the rest of the world, so that we can conduct a study that will be clinically meaningful and support registration broadly.
Thank you for your question.
Thank you so much.
Our next question comes from Gil Blum of Needham & Co.
Hi, everyone. Congrats on the progress. I'll ask my questions in order so we won't forget them. For Dr. Munir, emerging infections are seen both in this study and in the competitor's study, in degraders, and both companies basically mentioned that it doesn't appear to be drug-related. Maybe you can give me some context as it relates to infections in these kind of patients, and then I'll have my follow-up.
Yeah, sure. Thanks for the question. I think the main issue in these patients is that we're dealing with a very heavily pretreated patient population. So 75% of these patients have had chemoimmunotherapy, and that probably has affected their normal B- cells and T- cells as well. They are quite vulnerable patients. They would have had venetoclax-based therapy and covalent and non-covalent BTK inhibitor therapies. By this time, when a patient has reached that time point, a lot of these patients are quite vulnerable to infections anyway. The most important thing that we see in those patients in clinical practice is to control their CLL well. If you do that, the infections actually tend to be minor infections, which are easily treated with antibiotics.
I think the good thing with the data that I've seen up till now, and I'm pretty clear that the other degraders have shown as well, is that most patients with CLL are tolerating these treatments very well. We do not end up seeing a lot of these patients being admitted to the hospitals with severe chest infections. Though minor grade 1-2 infections still appear to be pretty common. That is what I would be saying, that is the background infection rate that we will see in our CLL patients anyway, where they are with their journey of their CLL treatment.
Thank you. Very helpful. As a follow-on, and this is maybe a broader question, assuming patients remain responders for a prolonged period of time, maybe achieving a CR, do you foresee a situation where you discontinue treatment with the agent at that point?
That's a very good question. It's really a research question that I would like to answer. I think the issue really is the depth of remission and how you measure it. When we're saying somebody has achieved a CR, we are saying that the blood counts are completely normal, the scans are normal, and the bone marrow is showing less than 30% lymphocyte burden. That is a very broad category of CR patients. We know that some of the patients will still have some disease at what we call as minimal residual disease level. For that reason, some of the patients may benefit from more continuous therapy. It's useful to hear from the team, the guys here, that the plan includes combinations in future because I think that's what will drive more patients to a very deep remission.
That would be the ultimate goal in the earlier lines of therapy. In all honesty, a lot of patients on BTK inhibitors do not achieve even that CR point as well. It is good to see that some of those patients are achieving that at the moment. Obviously, we need the long-term follow-up. If we have got five or more patients achieving that, then that really will stand out for the drug.
Thank you. Very helpful.
Thank you, Gil.
As a reminder, if you would like to ask a question, please press star one on your phone now. Our next question is from Derek Archila of Wells Fargo.
Hey, good morning. Thanks for taking the questions. Congrats on the update here. First, just a follow-up to Kripa's question earlier. Can you just share what your base case is for the head-to-head confirmatory trial in terms of the comparator in CLL? On a separate topic, just to remind, can you just remind everyone on STAT6 some of the economics that you can opt into now that Sanofi has licensed that asset? What time point and what conditions could that occur under? Thanks.
Sure. Thanks, Derek. I'll take that. On the first part, we're not prepared at this time to discuss details around the comparator arm, but we will in the near future, and we'll let you know when that will be. On the second point, we have quite an excellent option that occurs for us to opt back into the program after human proof of concept is achieved by Sanofi's development plan, which means through phase I and also includes early efficacy studies in patients. As you'll also recall from the deal structure, their recent extension of the license, at that point, they've taken over all costs and development of the NX-3911 STAT6 degrader. They're moving it forward. They're responsible for the costs and the planning and the execution of the IND enabling studies, the phase I studies, and the proof of concept study.
At that point, Nurix will then be able to be supplied with a clinical report on the data to date and that will make our decision about our potential opt-in, which would put us in the category of a 50/50 cost-profit share going forward in the U.S. There is no opt-in fee at that moment in time. All we're responsible for then would be the go-forward 50% cost in the U.S. For the ex-U.S., we would then continue to receive royalties and milestones on ex-U.S. sales, etc. It puts us in a really strong position, and we're very happy with the progress of 3911 and with Sanofi's option.
Got it. Thank you. Very helpful.
Thank you.
Our next question comes from Matt Biegler of Oppenheimer.
Hey, guys. Thanks for the question. Maybe Arthur and team, just a high-level question on positioning relative to BeOne's degrader. Are there angles you think you can leverage in terms of safety or maybe CNS activity in particular? Because I think they exclude patients with CNS lesions in their trials. Or maybe bigger picture, it doesn't even matter given the size of the CLL market, and maybe there's room for multiple entrants. Kind of what are your views? Thanks.
Yeah. Thanks, Matt. At a high level, our view is to be best in class. We believe we've got the science and the scientific evidence ultimately to support that, which will translate to clinical results. That is a high level, and that's our belief and our go-forward stance. As we look at the evolving data, we'll have to see. So far, both drugs look very comparable from an efficacy standpoint. It's early on the safety front to really make any determination. As you point out, it's a big market opportunity with this growth from $9 billion to $15 billion. There are several very successful billion-dollar-plus drugs in these categories, and each will have their own attributes, and physicians and patients will make their choices. I think ultimately, it may not matter that much, to tell you the truth.
Both drugs are being developed in the same time zone. I think in terms of time frame, we're in a very close proximity to one another. It's actually very exciting, I think, to watch both drugs develop. It's helpful to have another company really accentuating the importance of this opportunity of degradation of BTK versus inhibition. It's actually been quite helpful for enrollment and the advancement of the program. I think there's going to be really a significant opportunity for both companies going forward. If your question did have a second part, I can't remember it at this point. Oh, the CNS difference.
I did.
Thank you, Paula. Yeah, the brain. Yeah, I do think it's quite a distinguishing feature for us so far at this time. As you point out, they did exclude patients with CNS involvement, as do most drugs at this stage of development. We had evidence in preclinical models of CNS activity in some really very significant CNS models from UCSF. Dr. Rubenstein and our collaborator there with these PDX models, which are quite elaborate. We knew that we could have this effect and substantiate it with preclinical evidence. Investigators were encouraged to try with their patients. It's been a real benefit, I think, for bexdeg and its development program and for the patients. We've seen some dramatic responses. It's, I think, now approaching over 5%. I think even 10% of patients now, we're getting patients with the CNS involvement.
As we like to point out, it's also important for the other 90% who don't have CNS involvement because they don't want to get it. We do provide coverage of the brain. I think that's important, that the CNS does not become a sanctuary site for these CLL cells. Anyway, thanks for your question. We do think that's a very important distinguishing feature.
Thanks again, guys.
Our next question comes from Biren Amin of Piper Sandler.
Hey, hi, guys. Thanks for taking my questions, and congrats on the update. I guess the first-line plus opportunity, what are your key considerations on timing and design for that opportunity?
Turn that to Paula.
You will note that one of the cohorts that we have initiated in our phase I-B is, in fact, a BTKi naive patient population. That will be amongst the first bits of information to inform our future as regulatory agencies quite frequently like to see some evidence of activity in earlier lines before they support the initiation of a large-scale global program. We have started that, and as such, look forward to our next steps in the front line. As we have already noted, there are opportunities not only in the monotherapy setting but also in the combination setting. As Dr. Munir mentioned, though, most importantly, this combination setting is the emerging standard as it represents perhaps the best way to get the deepest responses for patients. It is being utilized increasingly in the United States as well as the rest of the world.
With that, I will stop.
Maybe just as a follow-up.
Sure. Go ahead.
Maybe just as a follow-up, when can we expect that frontline data to be released from the ongoing study?
I'm sorry, the frontline data? Oh, for that cohort. Go ahead, Paula.
The phase I-B cohort is currently enrolling. I don't think I can give you an exact date, but suffice it to say that that cohort is open.
Perfect. Thank you.
Our next question comes from Steven Wiley of Stifel.
Yeah. Thanks for taking the questions. Just a couple for me. I know a very small number of progression events have been observed here following the achievement of a response. Have you done any molecular profiling of these patients to see what might be driving this progression?
Thanks, Steve. Yes. We have conducted molecular profiling and next-generation sequencing. So far, there's no clear pattern that has emerged as a driver for these events. These patients do have many mutations across the board. We focus in on several that we've highlighted in our presentation, but we don't know all of the things going on in their genomes, even with next-generation sequencing. I think it's just a matter of the constellation of genomic mutational burden that they have and the state of their and the fact they've had prior therapies driving a lot of that. As we get more patients, as we see more progressions, which we don't want to see, we will track them and let you know if we see any pattern.
Got it. Maybe just one quick one for Dr. Munir. I know BTK inhibitor-induced cardiotoxicity usually takes a while to reveal itself. I guess just based upon the totality of the degrader data that you've seen to date, are you convinced at this point that these agents will yield lower rates of cardiotox? If so, how could that independently impact the prescribing appetite for degraders, specifically within earlier lines of therapy? Thanks.
Yeah. Thanks for the question, really. I think that's a very important point. I think it highlights the mechanism of action of these new molecules because they're becoming more and more cleaner. Just going back to the first-generation BTK inhibitors like ibrutinib, we know that it does inhibit BTK, but the side story was the inhibition of ITK and a number of other kinases, some of which were present in the cardiac tissue as well. That story did not manifest itself for a number of years before we started picking up those side effects. That's the same thing happening with the second-generation BTK inhibitors. I think in terms of the degraders, the mechanism of action looks very clean. In terms of other kinases, it's minimal impact on other kinases. Up till now, the data that I've seen, we're not seeing any emergent cardiac toxicity in our patients.
That is heartening to see. That is one of the most important factors that we take into consideration when we are using the combinations now. If the drug has got a very clean cardiac safety profile, then using it in various combinations with other molecules will be easier in future. All I can say is that, yes, we need a bit more longer follow-up to look at the safety. Up till now, I have not seen anything that will stop me putting a patient into a trial who still has got some cardiac issues, if you know what I mean.
Our next question comes from Sudan Loganathan of Stephens Inc.
Hi, Nurix team. Thank you for this update. Congrats on the outcomes. My questions are on the regulatory strategy. This morning, BeOne also provided an update on their BCL2 plus BTK inhibitor in CLL that could have the potential to move up as early line standard of care. Will you plan to capture some of these patients that fail this combination for bexdeg monotherapy and the combination pivotal trials? My second question, to expand to the first line, when do you plan to select that BCL2 inhibitor in combo for the head-to-head trial against standard of care? Will that be based on any new developments or go with the current standard of care right now? Thanks.
Okay. Paula, go ahead.
Okay. Once again, I apologize for my jet lag. I remember your second question. I want to start with what I remember. As it relates to the timing of—okay, actually, the timing—actually, let me stop. I'm going to go back to the first question. Your question about BeOne and specifically whether there are patients who are coming off of their trials who would be eligible for our trials. Patients are eligible for our trials as long as they have not received a previous degrader. Patients who were on a control arm, for example, would be eligible, but certainly no one who had received BeOne's degrader.
I think you asked if they received an inhibitor with some roadblocks.
If, in fact, someone has received a BCL2 inhibitor of any variety, whether it be investigational or approved, they would, in fact, be eligible to participate. In regard to our plans to combine with a BCL2 inhibitor, certainly, we anticipate that we will be starting this trial before venetoclax gets approved. As such, we would be working with an approved agent, of which currently venetoclax is the prime BCL2 inhibitor. Did I get it all?
Yeah, I think so.
Yeah. Thank you. I appreciate it. Sorry for bombarding you with this despite your jet lag, but I appreciate all the time and answering the questions.
Thanks for your question.
Our next question comes from Brian Skorney of Baird.
Hey, good morning, everyone. Thanks for fitting me in here. I guess going back to the molecular profiling question you've had, I'm just wondering if you've looked for or seen any cases of the A428D mutation in patients so far who apparently try to express resistance to both BTK inhibitors and degraders. I was wondering if you could also discuss any cases of amylase or lipase increases that have been seen in treated patients so far, especially in contrast to what we've seen from BGB's 16673.
Oh, okay. Put that up. And you just remembered the second one, Paula. And with regard to the 428W, I mean, 428D, so it's a very rare mutation, 1% or less in patients. We have seen a patient with it. We know that we don't degrade that mutation. It is not clear in that patient if that mutation is a driver mutation or a passenger mutation, as that patient had other mutations as well, and I believe also in BTK in particular. It gets to this, there's no pattern yet, and it is a very rare event. If we see more of it, we may be able to make a story about it. But so far, we don't see it as being clinically significant. With that, then, Paula, the second question?
Yeah. I'll just add a little bit to that first one. The patient that we had had multiple BTK mutations and also had a response to our therapy. I want to acknowledge that. That heightens this comment that Arthur made about the A428D mutation potentially being passengers. We'll follow that story. As it relates to amylase and lipase elevations being seen with bexdeg, we have seen an occasional transient elevation but have not seen anything that rises to the level of a signal, certainly nothing that's occurring in 10% or 15% of the patient population. These single episodes have not been things that have been followed for, when I say not been followed, they have not repeated for long periods of time. They've been a single increase and then resolution.
Thanks for your question.
Our next question comes from Roger Song of Jefferies LLC.
Great. Congrats for the data. Thank you for taking the question. I want to make sure the question is clear and slow. The question is really about dose selection for the pivotal, understanding you probably still need to see the phase II-B data to make the decision, 200 mg versus 600 mg. Maybe just remind us what are the key criteria to make that decision as we may not necessarily see the dose response. I have a follow-up question for the doctors. Thank you.
Sure. Paula, do you want to start with that?
As you know, for Project Optimus, the FDA, and I will also acknowledge other regulatory bodies are also interested in this information, is really interested in confirming that we are not overdosing patients and introducing them to toxicity that is not warranted. In our phase I-B dose optimization cohort, we've looked at two dose levels, 200 and 600, and we've looked at 20 patients each. The focus of this evaluation will be on the safety profile as well as the activity, but the safety profile is critical. Certainly, we are benefited by our previous evaluations, which have demonstrated that the 600 mg dose is as well tolerated as the 200 mg dose. We look forward to establishing that final dose to take forward. Once again, I'll note that we are planning to start our program in the second half of this year.
It is imminent.
Got it. That's clear. Thank you. And then just a quick follow-up question for doctors. Understanding we have first-gen, second-gen, new gen for the covalent BTK inhibitor, and then we also having the non-covalent. Now we have the degrader. Maybe just from the biology, maybe clinical reason, how would you sequence those slightly different modalities for the CLL patient in the future, assuming all of those modalities will be available to you? Thank you.
That's a very good question and a very interesting one. It's just how the history has gone in terms of how these drugs have developed. We moved from covalent to non-covalent BTK inhibitors, and now the BTK degraders. I think the main question really would be when we do the head-to-head phase III trials, we will get an inkling on, are we going to get deeper responses with the degraders?
The mechanism of action of the drug is not dependent on the kinase function. BTK is a very long kinase with multiple domains. Essentially, you would expect that if you use it in earlier lines of therapy, we should see at least the same efficacy, even probably more than that. I think it is going to be the vessel of the clinical trials, really, in terms of head-to-head trials, looking at which combinations are head-to-head with other BTK inhibitors will show us the results. I think one of the important things would be the safety question, which would be very important because we know from the real-world data that a lot of covalent BTK inhibitors get stopped much earlier than what we find in the clinical trial settings. The real-world patients actually are slightly different to what we enroll on the clinical trials.
If the drug has got better tolerability, that probably leads to better efficacy over time, and that's been the theory with the BTK inhibitors, whichever class you're looking at throughout.
Great. Thank you. Great question.
Our next question comes from Faisal Khurshid of Leerink Partners.
Hey, guys. Thank you for taking the question. I just wanted to ask about the development of Bexobrutideg in immunology indications. For example, I saw that BeOne is starting a phase II study in chronic urticaria. I'm just curious if you can update us on your latest thoughts on development outside of CLL and in benign indications. Thanks.
Sure. We have initiated a cohort in CLL patients with warm autoimmune hemolytic anemia as our first look at this opportunity. We are considering those indications that are non-oncology as well in cytopenias such as WHA and potentially ITP. There is certainly rationale for the BTK mechanism, and it has been tried with inhibitors in derm indications and MS, as we all know. There is likely to be a place for a degrader in the setting of autoimmune disease. I think the question is, what is that place, and what is the risk-benefit profile for that indication? There are commercial considerations as well in terms of pricing, etc., to consider. We are looking at that. I think it is a valid thing to study. It is not surprising BeOne is looking as well, and I am sure others will in the future.
Got it. Thank you.
Thank you.
Our next question comes from David Dai of UBS.
Great. Thanks for taking my questions, and congrats on the update. Two from me. One is just on the competitive positioning against BeiGene's or BeOne's degrader. As we were looking at the preclinical data, we did see your Bexobrutideg actually has better potency against resistant mutations, especially for the 416L and T474I. As a result of that, do you feel like as a result of this preclinical data, we could discuss potentially deepening of the response over time?
We do think we're the most potent degrader, and you're very observant to point out that information. We think there'll be additional information on potency and also on selectivity. Our position is that we believe we will be the most selective BTK degrader. That's possible to study preclinically via the most sensitive proteomics that you can do. I think some of these fundamental molecular differences or biochemical differences, cellular differences that we'll see with these agents will translate, ultimately, over the long run to clinical differences. I think that's what we've seen with the inhibitors as well. It takes time, but I do think the elements are there for bexdeg to be a best-in-class degrader as we go forward and as we compete with other degraders.
Got it. And then just to follow up, maybe just a quick clarifying question we had missed during the call. But we did see in your recent update for phase I-A, the number of patients for dose escalation went down to 48 patients. Last time you showed at ASH, it was around 60. So can you just help us understand what did you eliminate? Twelve patients in this update? And also, when we look at the patients who are efficacy evaluable, it is 47 patients now compared to last time, around 49. So just wondering about these changes in the denominator here.
Yeah. When we presented our data at ASH, we were looking at phase I-A and I-B total enrollment, and now we are limiting our discussion to the phase I-A patients. All of the differences that you see are a reflection of that limitation to phase I-A.
Okay. Got it. Thank you so much.
Our next question comes from Jeet Mukherjee of BTIG.
Great. Thanks for taking the question. Two from me. The first one, perhaps for Dr. Munir. For some of the competitor BTK degraders, we've seen hemorrhage, including some grade 3 events. How serious is this? Is this something that's perhaps intrinsic to this patient population, or do you feel that this is an adverse event that's molecule-specific? Thanks.
I think that's a risk that is inherent to BTK anyway. The BTK is expressed by the platelets. The platelets usually have got a certain amount of BTK in them, and that helps to aggregate the platelets. The commonest side effect in any BTK inhibitor trial has been a small amount of confusion or purpura. We need to also remember that we're dealing with a population around the age of 70, and most of these folks would be on other antiplatelet drugs like aspirin and clopidogrel. What happens in these patients is that when you are on one antiplatelet and you use a BTK inhibitor or a degrader, the risk of bleeding would be higher in those patients. That's the pros and cons that you need to look forward to when you're treating these patients. Inherently, I don't think it's specifically molecule-specific.
I think it's class-specific effects because of the BTK expression in the platelets.
Okay. Got it. My second question, perhaps for management. You've talked about having a second-line plus confirmatory study that's reflective of the various geographies that this molecule could be designed and commercialized. Can you just remind us how some standard of care regimens would differ between the U.S. and other geographies?
Paula.
When we think about the two sort of biggest markets, the U.S., and I'll go with the EU, certainly the standard in the U.S. is in the second-line setting for patients who have not already received a BTKi is, in fact, to make sure that they've received a BCL2 inhibitor. We recognize that there's an increasing utilization of the combination of a BTKi and a BCL2 inhibitor in the front-line setting. In the EU, the approach is very similar, with BTKis and BCL2 inhibitors being utilized in the front line and then typically in the second-line setting. Dr. Munir is shaking his head, so at least I feel like I'm saying the right thing here. There is a degree of overlap that is broad that will support our ability to move forward in that setting.
I will also acknowledge that chemotherapy, meaning bendamustine given with RITUXAN or an anti-CD20, are also very commonly used therapies, more so in the EU, but also in the U.S. When I say the EU, I also mean the U.K. Pardon me for not calling out the U.K. specifically. Certainly, as we move forward, we will be positioning our trial to address the broad standards.
Thanks for taking the question.
Thank you.
Our next question comes from Christopher Liu of Lucid Capital Markets.
Hey, guys. Thanks for the question, and congrats on the data. Just one from me. When we take a look at the data we have so far on the 200 mg and the 600 mg, are there any differences you may see in terms of responses, deepness of responses, safety, or tolerability?
We have reported previously on our dose escalation and specifically have acknowledged that the safety profile across all of the cohorts is very, very consistent. We have not reported the activity differences and look forward to reporting that at a future meeting, not otherwise specified at this point in time.
Thanks for your question.
This concludes our question-and-answer session. I would like to turn the conference back over to Arthur Sands for any closing remarks.
Yes. I'd like to thank everyone for participating. I think it's been a great session with a lot of really important questions. We've attempted to answer those which we can. Just to highlight, I think, some of the top-level conclusions. We are moving forward into pivotal trials in the second half. We're in active planning of those trials. We'll keep you updated in terms of the more detailed design aspects of the trial. We got several questions on that. The project is moving forward, and we're really very bullish on it. We look forward to future updates. Thank you all again. It's been quite a session, and we're going to return to our EHA meeting. Thanks. Bye-bye.
This concludes today's conference call. Thank you for attending.