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

Welcome to the Nurix Therapeutics EHA 2025 Investor Call. [Operator Instructions]. I would now like to turn the conference over to Nurix's 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 Waldenstrom'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 2 poster presentations we have here at the conference. The first is focused on our Phase Ia trial of bexobrutideg in patients with CLL, which features those patients in the dose escalation portion of our Phase I study who've had the longest duration of therapy on BEXDEG, which we call it for short. And 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 Ia and Ib trials in patients with advanced Waldenstrom's, a difficult-to-treat indolent lymphoma disease state. Both presentations today will be given by Dr. Munir, consulting hematologist 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. So my job is to just get you through the data for NX-5948, and now we've got the names, BEXDEG, which I really like the shot for. So we're presenting the data on this degrader molecule, which is demonstrating rapid and durable clinical responses in the relapsed/refractory CLL. So BEXDEG is a small BTK degrader that is addressing the needs of CLL treatment landscape, especially for the relapsed/refractory patients. We know that the standard of care in CLL is now focusing on 2 key signaling pathways. One is the BTK pathway and the other one is the BCL2 pathways. But 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. And some of these mutations are interesting mutations because they maintain the intact B-cell receptor signaling, which really what you're intending to stop with the BTK inhibitor through this scaffolding function of BTK. And 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. And 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 NX-5948-301 study, it had a dose escalation Phase Ia program. The key eligibility criteria was patients who had relapsed/refractory disease and should have had more than 2 prior lines of therapy. And you can see that the dose was escalated from 50 milligrams once a day to up to a dose of 600 milligrams a day dose. And then there was a Phase Ib dose expansion, which is fully enrolled and 2 doses were looked at in that of the expansion program, which was 200 milligrams a day and also 600 milligrams a day. And there are a number of Phase Ib 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. So a number of other expansion cohorts really to look at which are the patients who are going to benefit the most from this drug. So this slide illustrates the patient's disposition and demographics. So about 48 patients who escalated the NX-5948. And you can see that starting from 50 milligrams, we had 3 patients and up to 600 milligrams and then 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 patient who stopped the drug because of an adverse event, which was a grade 2 event. The median age of these patients was 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. So the median was 4. CNS enrollment was seen in 5 patients. The kind of therapies that patients had include the covalent BTK inhibitors as well as non-covalent BTK inhibitors in about 27% of the patients. And then 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 picked up in 38% of the cases and 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 are -- we normally see some kind of minor bleeding issues in these patients. And the most important thing I want to highlight is looking at the Grade III adverse events are really looking at the SAEs. And the only thing that stands out there is the infections, which we are -- which we know that CLL patients are inherently prone to get infections. And I would argue that it is probably inherent to disease rather than the drug effect, which is manifesting itself with the SAEs that we see. So really very good safety profile at all dose levels has been well documented with the drug. And in this Phase Ia program, it's always nice to see that the patients are responding to therapy. And as an investigator, that's the most gratifying thing to see. We're seeing the overall response rate of 80.9%. We've got 1 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. And given the patients who have got stable disease are benefiting from the drug. The median follow-up on the study is 9 months, and the range is between 1.6 to 26.1 months. Look at this, waterfall plot and what you look at is the sum of product of diameter of a target lesion. So these are basically the lesions that were picked up right at the beginning, and we want to see where the tumor load is reducing in these patients. And what you find is that 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. So patients with BTK mutations or BLC-gamma 2 mutations, all patients are responding, which is, again, very gratifying to see. And again, on this, this is -- each bar represents 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 -- more than 12 months. So there are 18 patients in that category now. Some of the patients have escalated the dose during the treatment and 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, and so the 21 patients has moved up the dose. And the good thing is that the median time to first response is very quick. It's a median of 1.9 months. And the median duration is not reached. But again, what we're seeing in this extended follow-up that the durability of the response is there. And as you can see, that the star shows the CR patient who is doing well, mainly going up to 2.5 years on the truck. Again, looking at the response to therapy, and I would just highlight that majority of the curves of 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 lapsed afterwards. So to conclude, NX-5948 or bexobrutideg is a novel small molecule that degrades well-validated CLL target BTK by utilizing the ubiquitin pathway in the fully enrolled Phase Ia CLL portion of the Nurix-5948-301 study, as of the 12th of March 2025 data cutoff. We have got a median follow-up of 9 months, and most patients were still on treatment. The drug is very well tolerated, and this is consistent with the overall study population in previous disclosures. The clinical activity is in the population of heavily pretreated patients with advanced CLL. With the patent media lines of therapy being 4, and amongst those therapies was covalent BTK inhibitors, noncovalent BTK inhibitors and BCL2 inhibitors. And these patients exhibited high number of patients had BTK, BLC gamma II and BCL2 mutations and high-risk molecular features and some patients had CNS enrollment. And what we're seeing is robust and deepening responses with a high overall response rate of 80.9%. And we've now got 1 CR, but the responses are rapid with a median time to first response of 1.87 months, and there are multiple conversions that are being seen from stable disease to PR and then conversion to CR in 1 patient from PR. And of the 18 patients treated at more than 12 months of therapy, 17 have remained on study and 1 patient is approaching 2.5 years on treatment. The Phase Ib dose expansion cohort enrollment is complete. And as I told you that there are additional cohorts in which patients are being enrolled at the moment. And then there are other pivotal trial initiation plant in 2025, right? Straight away move on to the efficacy of this molecule, again sharing high clinical electivity and tolerable safety in patients with Waldenstrom's Macroglobulinemia. Again, in terms of the study design, we are now -- as I told you about the CLL cohort, but there is an NHL Waldenstrom Macroglobulinemia cohort as well similar dose escalation plan from 50 milligrams once a day to 600 milligrams once a day, and as we know that the 1b expansion cohort for CLL have fully enrolled, but we're focusing on the Waldenstrom's expansion cohort, which has also got a fast track designation as well. In terms of the demographics of Waldenstrom's patients, these were 22 patients in this study, median age of 72.5. So with a range of 58 to 86, predominantly male, 2 patients had CNS involvement and the prior lines of -- median prior lines of therapy was 3. And all patients had BTK inhibitor, the covalent BTK inhibitors as all patients had non-covalent BTK inhibitors. Some patients had BCL2 inhibitors and majority of the patients had chemoimmunotherapy. In this disease, we look at the MYD88 mutation and CXCR4 mutation, which was -- which were prevalent in these patients. And again, going down to the side effect profiles, again, I would highlight that you have got A grade toxicity, which is small in number, but very few patients had grade 3 toxicity and the serious adverse events, again, were limited to infectious. There was subdural hematoma. And I think that was -- it was primarily trauma-induced rather than response-induced. In terms of the overall response rate for -- 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, that it takes a lot to get the patients in CR, but there were very good partial responses in 2 patients, 11 patients had PR, minor response in 3 patients and a stable disease in 3 patients. There were no progressions at this follow-up in this study. The median follow-up is 3.7 months with a range between 1.9 to 18.9. 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 are continuing 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've shown during the CLL cohort, and the median duration of response has not reached and it is ranging between 2.89 to not reach months. I think this is an important slide because it shows how quickly these patients respond to the drug. So this is the percentage change in the IgM levels with Waldenstrom patients. It's quite important to get their plasma viscosity and IgM levels controlled. And the majority of the patients, 50% in IgM levels happened pretty quickly while they started the drug. So okay, bexobrutideg, a novel small molecule BTK degrader that can overcome treatment-emergent BTKi-resistant mutations and disrupt the BTK scaffolding. In the Waldenstrom portion of the Phase I 5948-01 study, as of 12th of March 2025 data cutoff, the median follow-up of -- on this -- for these patients was 3.7 months, and most patients were still on treatment. In the 22 patients with Waldenstrom Macroglobulinemia, the drug was very well tolerated, consistent with the overall study population and previous disclosures, mainly the toxicity was low grade, and we saw a common toxicity like BTK, diarrhea, neutropenia and thrombocytopenia, but there is no atrial fibrillation, which was observed. There was no drug-limiting toxicity, and 2 treatment-emergent adverse events led to treatment discontinuation. There was no Grade Va. And in terms of the response, the 19 disease evaluable patients, durable and deepening responses were observed in a heavily pretreated population, 3 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 2 responses deepening to VGPR with longer duration of treatment. And as I said, there was a steady reduction in IgM levels, which was observed in most patients from first IgM assessment and continue to deepen off over 8 weeks and beyond. And 3 patients had had 90% reduction in IgM levels is impressive. Medium response, median duration of response was not reached. I will stop?

Great. We'll now turn the call over to Dr. O'Connor.

So 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 relapsed/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 of BEXDEG to address the unmet medical needs of patients with relapsed/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 CRR and a favorable safety profile as monotherapy in the relapsed refractory setting positions BEXDEG for development, not only in relapsed/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 relapsed/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 Waldenstroms, we also made 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. BEXODEG -- or rather 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 in combination with BCL2 inhibitors in the treatment-naive settle as well as the relapse 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 Ib dose optimization cohort as per project optimist and have expanded our Phase Ib program to enhance our understanding of BEXDEG activity in critical CLL population. These -- 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. BTK -- I'm sorry, 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-BTKi 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. And 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. And so with this, we are really excited about the future for BEXDEG, 5948 bexobrutideg, all the same. And 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 staying for the Q&A session, too. So that's great. We're very highly encouraged by the impressive efficacy results that have been demonstrated with BEXDEG and then further by the safety and tolerability effects of BEXDEG across both CLL and NHL. As we advance BEXDEG to pivotal studies, it is also important to acknowledge that as 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 of 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 with 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 has resulted and they're 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 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 a substantial market opportunity in the future. As we explore the CLL market in more detail, greater than 55,000 patients started therapy for the first time or started 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 the line of therapy to the second line comprised of approximately 16,000 patients. Our Phase III randomized control monotherapy study designed to offer this substantial population and 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 frontline 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 -- in the earlier lines of therapy. As Paula described, we are finalizing our development plans for BEXDEG in CLL, which we will anticipate -- 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 assets. 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 we'll enter into Q&A, I think it's important to place BEXDEG -- 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'll probably say is the first Deg in this category. And 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 therapy 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 the physicians who have devoted their time and expertise to the successful development of bexobrutideg. We can now take your questions.

[Operator Instructions] And our first question comes from Eric Joseph of JPMorgan Chase.

Congrats on the data. This is Ron on for Eric. One question that comes up a bit in our discussions with heme/oncs about BTK degrader classes, whether they're more effective than pirto in the context of refractory disease. Are you a doctor when you're able to speak that a bit on the Phase I update? And I have a follow-up.

So that's a very good question. And 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. And what we're finding with pirto is the development of these resistant mutations with like T474 and L528. And the data -- the PFS data suggests that maybe half of the patients will progress at around 14 months. So the durability is the question mark really with the pirto data. In terms of the BEXDEG data at the moment, obviously, the Phase Ia study and the main focus was on the safety of the molecule, but the clinical effectiveness is doubtless really. I think we are seeing very good responses in our patients. And certainly, the patients I have got in my clinic are showing durable responses. Now, over time, as the data accumulate, we will be able to see if this is really meaningful improvement. But obviously, the team here at Nurix are taking it forward to the Phase III program and the Phase III program, hopefully will reimpose the point that we're seeing reasonable durable responses in these patients who have got very typical disease, especially the patients who've had covalent and noncovalent BTK inhibitors. And still, we are able to salvage those patients. And if they 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 and still, majority of the patients are showing the response.

And did you have a follow-up question?

Yes. Does the current ongoing Phase Ib trial have potential to serve the initial monotherapy trial for accelerated approval? Or would you need a separate study to pursue that?

Paula?

So thank you for that question. We are planning to forward with a single-arm study, separate and distinct from our ongoing Phase Ib 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.

And our next question comes from Brian Abrams of RBC Capital.

Congratulations on the updated data. Really 2 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 have now converted to a CR? And then secondarily, how much follow-up are you hoping to see from this dose escalation study and the Phase Ib 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?

So thank you for the question. I think I'll address your first question, which is about the pattern of deepening responses over time. So 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. And in some cases, when we think about the BTKi you've seen response deepening as late as 2 or 3 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. So 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 then obviously, the overarching response. And then your second question, I apologize, I have lost your second question. Would you mind repeating that, please?

Yes. Sure. Just wondering, I guess, how much follow-up you're hoping to see from both the study and the Phase Ib looking at 200 and 600 to have -- 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?

So as noted in my presentation, we have been interacting with the agency regarding our Phase Ia and our Phase Ib 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've given us their time and energy, and we will continue to follow them on therapy as long as they show benefit.

Our next question comes from Peter Lawson of Barclays Capital.

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? And then 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 is about gating factors for combination trials.

So 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. And so what you can see is that the safety profile suggests that there is the ability to combine this with other agents. And so that is the first gate. Otherwise, we will, in fact, have to demonstrate that it is safe to give the 2 drugs in combination, and that can be done in a number of different fashions. And then your second question, once again, would you please repeat that?

Yes. It's just around patients that harbor other mutations, TP53, if there's any kind of patents emerging on how well those patients do on the drug if there's differences between PLCG2 or TP53.

So, Dr. Munir showed 2 slides in his presentation. The first was the waterfall plot where we basically showed the reduction in lymph node size relative to patient's previous mutation status. And there is 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. And what you might have seen on the left-hand side 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'd just remind everyone else that we do have the slides from this presentation on our website. So as we refer to them, you can click back and forth and see them as you need.

And our next question comes from Kripa Devarakonda of Truist Securities.

Congrats on the data. So 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? And can you elaborate a little bit more on the key factors that are driving the design of your confirmatory trials?

Sure. So with regard -- I'll take that. With regard to the first question, really the -- in terms of choosing dose, it's related to length of time on the Phase Ib study. So an adequate time period to evaluate the 2 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. And of course, in general, the FDA would like to see, ultimately, durability and PFS as the key endpoints for any randomized controlled trial endpoint, approval endpoint. And -- so that's with regard to that question. With regard to the second question, I think I'm a little jet lagged like Paula, sorry, I've forgotten the second question already. So could you repeat that?

I was just wondering what the key factors are that driving the design of your confirmatory trial.

Okay. So Paula, do you want to take that?

So 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. And so 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.

Our next question comes from Gil Blum of Needham & Co.

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 the competitor's study and 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.

Yes, 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, and they are quite vulnerable patients. And then they would have had venetoclax-based therapy and covalent and non-covalent BTKi inhibitors. But by this time, when a patient reached has reached that time point, a lot of these patients are quite vulnerable to infections anyway. And the most important thing that we see in those patients in clinical practices to control their CLL world. And 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 until now, and I'm pretty clear that the other degraders have churn as well is that most patients with CLL are tolerating these treatments very well. And we don't end up seeing a lot of these patients being admitted to the hospitals with severe chest infections, through minor grade 1/2 infections still appears to be not pretty common. So -- and that would -- what I would be saying that's the background infection rate that we will see in our CLO patients anyway where they are with their journey of their CLL treatment.

Very helpful. And as a follow-on, and this is maybe a broader question. Assuming patients remain responders for a prolonged period of time may be 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. And I think the issue really is the depth of remission and how you measure it. When we're saying somebody has achieved the 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. And that is a very broad category of CR patients. But we know that some of the patients will still have some disease that what we call as minimal residual disease level. And for that reason, some of the patients may benefit from more continuous therapy. And 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 provide more patients to a very deep remission and that would be the ultimate goal in the earlier lines of therapy. But in all honesty, a lot of patients on BTK inhibitors don't achieve that, even that CR point as well. And it's good to see that some of those patients are achieving that at the moment. Obviously, you need a long-term follow-up. And if we have got 5 or more patients achieving that, then that really will stand out for the drug.

[Operator Instructions] And our next question is from Derek Archila of Wells Fargo.

Congrats on the updates here. So 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? And then 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?

Sure. So 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. So as you'll also recall from the deal structure, the recent extension of the license. At that point, they've taken over all costs and development of the NX-3911 STAT6 degrader. So they're moving it forward. They're responsible for the cost and the planning and the execution of the IND-enabling studies, the Phase I studies and the proof-of-concept study. And at that point, Nurix will then be able to be supplied with a clinical report on the data to date and that 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 United States. There is no opt-in fee at that moment in time, all we're responsible for them would be the go forward of 50% cost in the United States. And for the ex-U.S., we would then continue to receive royalties and milestones on ex-U.S. sales, et cetera. So it puts us in a really strong position, and we're very happy with the progress of 3911 and with Sanofi's option.

And our next question comes from Matt Biegler of Oppenheimer.

Maybe Arthur and team, just like a high-level question on positioning relative to B1's degrader, like 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 and 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?

Yes. So thanks, Matt. At a high level, our view is to be best-in-class. And we believe we've got the science and the scientific evidence ultimately to support that, which will translate to clinical results. But 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, but then as you point out, it's a big market opportunity with this growth from $9 billion to $15 billion, and 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. So I think ultimately, it may not matter that much, but it's true. Both drugs are being developed in the same time zone. So 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, and 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 our enrollment and the advancement of the program. And so 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. But all the CNS did.

I did.

Thank you, Paula. So -- good brain. So, yes, I do think it's quite a distinguishing feature for us so far at this time. And as you point out, they did exclude patients with CNS involvement, as do most drugs at this stage of development. But we had evidence in preclinical models of CNS activity in some really very significant CNS models from the UCSF. Dr. Rubenstein, our collaborator there with these PDX models, which are quite elaborate, and we knew that we could have this effect and substantiate it with preclinical evidence. So investigators were encouraged to try with their patients and it's been a real benefit, I think, for this -- for BEXDEG and its development program and for the patients, we've seen some dramatic responses. And it's, I think, now approaching over 5%, I think even 10% of patients now we're getting patients with the CNS involvement. And 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. And we do provide coverage of the brain. And I think that's important that the CNS does not become a sanctuary site for these CLL cells. So anyway, thanks for your question, and we do think that's a very important distinguishing feature.

And our next question comes from Biren Amin of Piper Sandler.

Congrats on the update. I guess the first line plus opportunity, what are your key considerations on timing and design for that opportunity?

I'll turn that to Paula.

So you will note that one of the cohorts that we have initiated in our Phase Ib is in fact, a BTKi naive patient population. And 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. And so we have started that, and as such, look forward to our next steps in the front line. As we've already noted, there are opportunities not only in the monotherapy setting, but also in the combination settings. 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, and it's being utilized increasingly in the United States as well as the rest of world. And with that, I will stop.

And maybe just as a follow-up, when can we expect that frontline data to be released from the ongoing study?

The -- I'm sorry, the frontline data -- oh, for that color. Go ahead, Paula.

So the Phase Ib 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.

And our next question comes from Stephen Willey of Stifel.

Just a couple for me. So I know a very small number of progression events have been observed here following the achievement of response, but 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 next-generation sequencing. And 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-gen sequencing. So I think it's just a matter of the constellation of genomic mutational burden that they have and the state that they are -- and the fact, they have prior therapy driving a lot of that. But as we get more patients, as we see more progressions, which we don't want to see, but we will track them and let you know if we've seen a pattern.

Got it. And then maybe just one quick one for Dr. Munir. So I know BTK inhibitor induced cardiac toxicity usually takes a while to reveal itself. But I guess just based upon the totality of the degrader data that you've seen to date, are you convinced that these points -- at this point that these agents will yield lower rates of cardiotox? And I guess, if so, how could that independently impact the prescribing appetite for degraders, specifically within earlier lines of therapy?

Yes. Thanks for the question, really. I think that's a very important point. And I think that it highlights the mechanism of action of these new molecules because they're becoming more and more cleaner. So 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. And that story didn't manifest itself for a number of few years before we start picking up those side effects. And that's the same thing happening with the second-generation BTKi inhibitors, I think in terms of the degraders, the mechanism of action looks very clean in terms of other kinases, its minimal impact on other kinases. And up till now, the data that I've seen, we're not seeing any emergent cardiac toxicity in our patients. And that's heartening to see. And that's one of the most important factors that is -- we take into consideration when we're using the combinations now. And if the drug has got very clean cardiac safety profile, then using it in various combinations with other molecules will be easier in the future. So all I can say is that, yes, we need a bit more longer follow-up to look at the safety. But up until now, I haven't 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.

And our next question comes from Sudan Loganathan of Stephens, Inc.

Congrats on the outcomes. My questions are on the regulatory strategy. This morning, B1 Medicines also provided an update on the BCL2 plus BTK inhibitor in CLL that could have the potential to move up as earlier line standard of care. Will you plan to capture some of these patients that failed this combination for BEXDEG monotherapy and the combination pivotal trials? And then second question, to expand on -- 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? And will that be based on any new developments or go with the current standard of care right now?

Okay. Paula, do you want to add?

Okay. So once again, I apologize for my jet lag. So your -- I remember your second question. Let me start with what I -- which is -- I remember. So 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. So your question about B1 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. So patients who were on a control arm, for example, would be eligible, but certainly no one who had received B1s degrader.

And I think you asked that we received inhibitor with some [indiscernible].

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. And in regard to our plans to combine with a BCL2 inhibitor, certainly we anticipate that we will be starting this trial before sonrotoclax gets approved and as such, would be working with an approved agent, of which currently venetoclax is the prime BCL2 inhibitor. Did I get it all?

Our next question comes from Brian Skorney of Baird.

I guess going back to the molecular profiling question you've had. I'm just wondering if you look for seeing any cases of the A4280D mutation in patients so, far apparently resistance to both BTK inhibitor and degraders? And 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-16673?

Okay. Put that up. And you just remember the second one, Paula. And with regard to the 428W, I mean, 428D, the -- so it's 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 is 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. So that -- it gets to this -- there's no pattern yet, and it is a very rare event. So if it does -- 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. So with that, then, Paula, the second question?

Yes. And I'll just add a little bit to that first one. So the patients that we had had multiple BTK mutations, sort of and also have a response to our therapies. I want to acknowledge that. So that sort of heightens this comment that Arthur made about the A428D mutation potentially being passengers. So 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. So 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 that then a single increase and then resolution.

And our next question comes from Roger Song of Jefferies LLC.

Great. Congrats for the data. And I make sure the question is clear and is slow. So the question really about the dose selection for the pivotal understanding you probably still need to see the Phase IIb data to make the decision 200 milligram versus 600 milligram. Maybe just remind us what are the key criteria to make that decision as we may not necessarily see the dose response? And I have a follow-up question for the doctors.

Sure. Paula, do you want to start with that?

So 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. And so in our Phase Ib dose optimization cohort, we've looked at 2 dose levels, 200 and 600, and we've boosted 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. And certainly, we are benefited by our previous evaluations, which have demonstrated that the 600-milligram dose is as well tolerated as the 200-milligram dose. And so we look forward to establishing that final dose to take forward. And once again, I'll note that we are planning to start our program in the second half of this year. So it is imminent.

Got it. That's clear. And then just a quick follow-up or a question for doctors. Understanding we have first gen, second gen, new gen for the covalent BTK inhibitor and then we also potential -- having the non-covalent, now we have the degrader. Maybe just from the biology, maybe clinical reason how would you sequence those different -- slightly different modality for the CRA patient in the future, assuming all of those modalities will be available to you?

That's a very good question and very interestingly. It's just how the history is -- with in terms of how these drugs have developed. So 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 them in claimed on is it -- are we going to get deeper responses with the degraders. The mechanism of action of the drug is not dependent on the kinase function. So BTK is a very long kinase with multiple domains. So essentially, you would expect that if you use it in earlier lines of therapy, we should see at least the same as the case even probably more than that. So I think it's 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, but 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 and the real-world patients actually are slightly different to what we enroll on the clinical trials. So if the drug has got better tolerability, that probably leads to better efficacy over time with -- and that's been the theory with the BTK inhibitors, whichever class you're looking at throughout.

Our next question comes from Faisal Khurshid of Leerink Partners.

I just wanted to ask about development of bexobrutideg in immunology indications. Like, for example, I saw that B1 is starting a Phase II study in chronic urticaria. Just curious if you can update us on your latest thoughts on development outside of CLL and in benign indications.

Sure. So we've initiated a cohort in CLL patients with warm autoimmune hemolytic anemia as our first look at this opportunity. We're considering those indications that are non-oncology as well in cytopenia, such as WAHA and potentially ITP. And then also, there is certainly a rationale for the BTK mechanism and it has been tried with inhibitors in derm indications and MS, as we all know. So there's likely to be a place for a degrader in the setting of autoimmune disease. And I think the question is, what is that place and what's the risk benefit profile for that indication? And then also, frankly, there are commercial considerations as well in terms of pricing, et cetera, to consider. So we are looking at that. I think it's a valid thing to study. It's not surprising B1 is looking as well and I'm sure others will in the future.

Our next question comes from David Dai of UBS.

Great. Congrats on the update. Two for me. One is just on the competitive positioning against BeiGene's or B1's degraders. As we were looking at the preclinical data, we did see your excellent food intake has -- actually has better potency against these mutations, especially for the 416L and T474I. So as a result of that, do you feel like -- as a result of this preclinical data, we could see potentially deepening of response over time?

Well, 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 selectivity. Our position isader. And that's possible to study preclinically via the most sensitive proteomics that you can do. So 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. And I think that's what we've seen with the inhibitors as well. So 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 a follow-up, maybe just a quick clarifying question, I missed it during the call. But we did see your recent update for Phase Ia, the number of patients for dose escalation went down to 48 patients, last time you showed at ASH was around 60. So can you just help us understand what was -- why did you eliminate 12 patients in this update? And also when you look at the patients who are efficacy valuable, it's 48 -- 47 patients now compared to last time around 49. So just wondering about these changes in the denominator here.

Yes. So when we presented our data at ASH, we were looking at Phase Ia and Ib total enrollment. And now we are limiting our discussion to the Phase Ia patients. So all of the differences that you see are a reflection of that limitation to Phase Ia.

Our next question comes from Jeet Mukherjee of BTIG.

Great. Two from me. And 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?

I think that's a risk that is inherent to BTK anyway. So the BTK is expressed by the platelets. So the platelets usually have got certain amount of BTK in them and that helps to aggregate the platelets. So the common side effects in any BTK inhibitor trial has been small amount of confusion of [indiscernible]. We need to also remember that we're dealing with the population around the age of 70. And most of these folks would be on other anti-platelet drugs like aspirins and clopidogrel. So what happens in these patients is that when you are on one anti-platelet and you use a BTK inhibitor or a degrader, the risk of bleeding would be higher in those patients. But that's the pros and cons that you need to look forward to when you're treating these patients. So inherently, I don't think it's specifically molecule-specific. I think it's class-specific effect because of the BTK expression by the -- in the platelets.

Okay. Got it. And 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. So can you just remind us how some standard of care regimens would differ between the U.S. and other geographies?

Paula?

So when we think about the 2 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. And then we recognize that there's an increasing utilization of the combination of a BTKi and a BCL2 inhibitor in the flatline settings. 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. And Dr. Munir is shaking his head. So at least I feel like I'm saying the right thing here. And so 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. And when I say the EU, I also mean the U.K., so pardon me for not calling up U.K. specifically. So certainly, as we move forward, we will be positioning our trial to address the broad standards.

Our next question comes from Christopher Liu of Lucid Capital Markets.

Congrats on the data. Just 1 for me. And when we take a look at the data we have so far on the 200-milligram and the 600-milligram, are there any differences you may see in terms of responses, deepness of responses, safety or tolerability?

So we've reported previously on our dose escalation and specifically have acknowledged that the safety profile across all of the cohorts is very, very consistent. So we will -- 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.

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 if 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've got several questions on that, but the project is moving forward, and we're really very bullish on it, and we look forward to future updates. So thank you all again. It has 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.