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

Good morning, and welcome to the Nurix Therapeutics Conference Call. I'm Arthur Sands, President and CEO. And I'm joined today on this call by Gwenn Hansen, our Chief Scientific Officer; Paula O'Connor, our Chief Medical Officer; and Hans Van Houte, our Chief Financial Officer. These are our disclaimers. At Nurix, we're advancing a pipeline of innovative targeted protein degrader drugs in oncology and inflammation and immunology or I&I, each with best-in-class potential. The majority of today's call will be focused on an important update on our lead program in CLL, bexobrutideg, or NX-5948 or Bexdeg for short. This will include our pivotal clinical development plans and some important new data supporting differentiation and Bexdeg dose selection for registrational trials. Next, with respect to our partnered I&I pipeline, we are able to share with you today some new preclinical data from both STAT6 and the IRAK4 programs. Our STAT6 program is partnered with Sanofi, and this is the first public disclosure of preclinical data profiling some key characteristics of NX-3911. The exciting clinical candidate that is now in IND-enabling studies. We will also describe for the first time, some key differentiation data from our IRAK4 program with Gilead, GS-6791, that is currently in Phase I healthy volunteer study. Importantly, Nurix maintains the potential to opt into these 2 partnered programs and a 50-50 co-development co-commercialization structure in the United States. This is an option that will be available after our partners have obtained human clinical data. Although we won't be discussing the exciting potential for Bexdeg in I&I indications today, I would like to mention that we continue to move a new tablet formulation through multiple ascending dose studies in healthy volunteers. This is a formulation that is ultimately intended for use in an autoimmune setting as a distinct product. Overall, we believe the emerging best-in-class drug profiles of our BTK, STAT6 and IRAK4 degraders are no coincidence, but rather the consequence of Nurix's rigorous science focused on the discovery and development of targeted protein degradation drugs. At the end of the call, we'll take questions on any topic including our recent ESMO poster presentation on NX-1607, our first-in-class CBL-B inhibitor, a novel immuno-oncology agent that has demonstrated some very encouraging single-agent activity in solid tumors. The poster is available in the resource library on our website. Now before we go through our very thorough update, I do think it's important to take a moment to step back and place Nurix in the context of a much larger evolution of drug discovery that is taking place, literally before our eyes. We believe targeted protein degradation is poised to take the stage as the next major modality in medicine, probably on the scale of antibodies and potentially even larger since we can address a much larger target class. It is indeed inspiring to recognize the potential for such drugs with Nurix's pipeline truly on the cutting edge of this evolution. So the headline for today's call is that we have announced the achievement of a significant milestone in the development of our lead program, the initiation of our pivotal trials in CLL. This advancement has been enabled by obtaining regulatory alignment on dose selection for registrational purposes with the FDA under project Optimus. Importantly, we also have alignment with global regulatory authorities, including the MHRA in the U.K. and the EMA in Europe to begin our global registrational program. As a reminder, Bexdeg also has fast-track status in the U.S. and prime designation in the EU. The dose of Bexdeg we are taking forward into registrational trials is 600 milligrams once per day. This is the highest dose we tested in our Phase I studies to date in which we encountered no dose-limiting toxicities. This dose selection was based primarily on data from the Phase Ib portion of our study that included randomized cohorts of 200 milligram once daily and 600 milligrams once daily, according to the guidelines of project Optimus. We are very pleased that the 600-milligram dose group showed a favorable safety profile that was comparable to that of the [ 200-milligram ] dose group. By selecting 600 milligrams, therefore, we are able to maximize for efficacy while maintaining safety. We believe this represents a strategic advantage of our competing molecules, both BTK degraders and inhibitors. The selection of the 600-milligram dose has enabled the initiation of our first pivotal trial, which has been named the DAYBreak study, a single-arm Phase II study in approximately 100 patients with relapsed/refractory CLL for potential accelerated approval, addressing a population of high unmet medical need. Today, we are also announcing that this global clinical trial has initiated. In addition to [ DAYBreak ] CLL-201, we are actively planning the implementation of the Phase III randomized confirmatory trial in CLL in the second-line setting, moving Bexdeg up in the CLL treatment paradigm. Paula O'Connor will be describing our core CLL clinical development plan in this call. Turning to the fifth and sixth checkmarked items on this slide. A key question we will endeavor to answer this morning is, what are some of the clinical and preclinical data that support differentiation of Bexdeg and the selection of the 600-milligram dose. Elements of this answer to this question can be found in some of our latest data that we will share today, which will be presented by Gwenn Hansen. Data that distinguishes Bexdeg from both BTK inhibitors and also the competing BTK degraders from B1 and AbbVie. We believe these data clearly support a best-in-class profile for Bexdeg. As we turn to details on the Bexdeg update, I would first like to briefly highlight the overarching advantages of the degradation mechanism of action and of Bexdeg in particular. First, Bexdeg is active against not only wild-type BTK, but also the entire range of clinically relevant BTK mutations that render current BTK inhibitors ineffective. Second, Bexdeg addresses the scaffolding function of BTK, a function that promotes tumor cell growth and B-cell receptor signaling and a function that is neglected by inhibitors. Third, Bexdeg, like all bifunctional degrader acts catalytically, which means very low drug levels can deliver incredible potency. So what do we mean by that? Remarkably, we have measured in cells that 1 Bexdeg drug molecule can degrade between 10,000 to 20,000 BTK proteins per hour. This fundamental difference in PK/PD from inhibitors is what allowed us to justify recognition from the USAN drug naming authority that bexobrutideg deserved the new suffix, deg, which indicates an entirely new category of drugs, the degraders. And Bexdeg is indeed the first deg in this category. It's a real landmark. Fourth, Bexdeg crosses the blood-brain barrier and has demonstrated significant clinical activity in the CNS of patients with advanced brain involvement. And fifth, we have demonstrated robust clinical activity in multiple difficult-to-treat B-cell malignancies across the board in CLL and NHL. And last but certainly not least, we believe that Bexdeg, that are degraders for IRAK4 and STAT6 will bring their mechanistic advantages to autoimmune disease by addressing the scaffolding function of these targets, and by delivering the powerful catalytic activity of targeted protein degradation. In some, we believe the best-in-class drug profiles of Bexdeg, NX-3911 and GS-6791 are no coincidence. So they are a consequence, once again, of Nurix's rigorous science focused on the discovery and development of targeted protein degradation drugs. So now I would like to turn the call over to Paula O'Connor, our Chief Medical Officer, to provide a brief review of our previously presented Bexdeg data that was featured at EHA earlier this year and then an overview of our pivotal clinical development plan in CLL. So I will be changing the slides for you, Paula. And if you could prompt me by saying next slide, I would appreciate that.

I certainly will, thank you, Arthur. So next slide. Okay. So good morning. I'm Paula O'Connor, the Chief Medical Officer here at Nurix. I'm thrilled to be working here at Nurix as we advance the next wave of innovation on the BTK pathway with our best-in-class molecule bexobrutideg, as Arthur has already said. We have confirmed our 600-milligram dose with the FDA, MHRA and the EMA and are moving forward at full speed on our pivotal programs. I'll review these in more detail in just a moment. But just to summarize, as you can see here, our Phase II trial, DAYBreak, the potential -- with the potential for accelerated approval is now underway with our first site activated earlier this month. Our key start-up initiatives are also underway for our confirmatory Phase III study. This study will begin in the first half of 2026. The entire company is laser-focused on the initiation and conduct of these 2 critical programs. As Arthur has already noted, we have also had many positive interactions with the major health authorities regarding bexobrutideg. And as previously disclosed, we have received fast track designation with the FDA and prime designation with the EMA. These will be critical for us as we review our evolving data in our path toward registration. Our interactions have not only set -- have set the stage for our development of these agents, and it clearly informed our pivotal trial designs and our registration plans. Next slide. In the next few slides, I will summarize the efficacy and safety data share for bexobrutideg most recently at EHA and Lugano. Every time we share this data, it reinforces the potential of this asset and the power of protein degradation. As you look at the slide, I'm going to direct your eye to the left, where you see the over -- the objective response rate in patients in the fourth line setting of CLL. As you can see here, the ORR of 80.9% has occurred in patients in whom 75% are double exposed and more than half has TP53 and/or BTK mutations, representing a group of patients with the highest unmet medical need. On the right, you see the waterfall plot and the genetic profile of our enrolled patients, showing meaningful reduction in their lymph nodes over the course of therapy, irrespective of high-risk clinical and genetic features, including CNS involvement and the mutations I previously mentioned. Next slide. The swim lane plot provided on this slide shows the speed, durability and depth of the responses we've seen with Bexdeg across dose levels. The median time to response is fast, less than 2 months. The treatment effect is durable with 17 of the 18 patients reaching a year on therapy continuing treatment. You can also see the pattern of deepening responses over time, evidenced by our first complete response being documented after 18 months of treatment and the first patient that is represented on this swim lane. Next slide. The safety profile for Bexdeg depicted here remains consistent with our earlier reports, even in the setting of longer follow-up and increased numbers. There are no new signals, cardiac, infectious or otherwise. In the next couple of minutes, I will turn to our clinical development programs that we have for Bexdeg. I'm pleased to share with you our 3 pillars for the development strategy for Bexdeg. They are, first, speed to market; second, addressing the needs of relapsed and refractory CLL patients as early as the second line; and third, utilizing combination therapy to further improve patient outcomes in the relapsed setting and potentially to move us to the front line. Before delving into these pillars and how they address the needs of our patients, I will take a moment to give an overview of the CLL market. Across the major markets in the U.S., EU, China and Japan, there are approximately 120,000 patients initiating new treatment each year. 50% of these are in the second line plus setting. In the U.S. specifically, there are 38,000 new patient treatment starts each year, 19,000 of which are in the relapse setting. Our clinical development plan is competitive and is designed to address the needs of CLL patients across the global marketplace. Next slide. This is a schema for our DAYBreak study. This, as we've already noted, has the potential for accelerated approval and started earlier this month. The study addresses the first pillar of our development strategy, namely speed to market. Utilizing this study, we hope to bring Bexdeg to physicians and their patients as quickly as possible. This single-arm Phase II study is designed with registration intent and has the potential for an accelerated approval. We plan to enroll approximately 100 patients with Bexdeg at our 600-milligram dose. The enrolled patient population will consist of triple exposed CLL patients, who have been previously treated with a covalent BTKI, a non-covalent BTKI and a BCL2 inhibitor. These patients have a clear and unmet medical need. The primary endpoint for this study is objective response rate as assessed by an independent review committee and will be further supported by duration of response data. We are thrilled that this important study has started, and the team is working diligently to enroll it. Next slide, please. The second pillar of our development strategy is to address the needs of patients with relapsed and refractory CLL as early as the second line, thereby helping a broader set of patients. This is the schema for our confirmatory Phase III study. We plan to enroll approximately 400 patients. They will be randomized to either 600 milligrams of Bexdeg given once daily by mouth or 1 of the 3 treatment options in the physician's choice control arm. These options include the globally relevant regimens of pirtobrutinib, idela and RITUXAN or bendamustine and RITUXAN. The primary endpoint of this study is progression-free survival, and we plan to initiate this study in the first half of 2026. Next slide, please. The third pillar of our development strategy in CLL is utilizing Bexdeg in combination with other active agents in CLL to improve patient outcomes. The schema on this slide is for our combination basket study. The combination data generated in this study may support future registration studies in the second line or even the first line. The study is designed to establish the go-forward dose for Bexdeg in combination with venetoclax, venetoclax and Rituxan, venetoclax and obinutuzumab in both the second and first line patients. We will enroll approximately 20 patients in each cohort. The dose that we identify in these cohorts may be used in our subsequent studies. This study, like the confirmatory Phase III we discussed earlier is slated to begin in the first half of 2026. The data sets generated in this study will inform future potential pivotal studies in CLL and may inform future development more broadly. Next slide. So having reviewed our immediate plans in CLL with you, I will close this section out of our presentation by saying that we are mobilized as a company to enroll the studies I've just reviewed to support the rapid registration of Bexdeg in CLL in patients with relapsed disease, triple exposed disease, in particular as it relates to the Phase II and to address the medical needs of relapsed and refractory CLL patients as monotherapy or in combination. We look forward to sharing our emerging data with more patients and longer follow-up with you at the ASH meeting in December. And so with this, I'm going to close this section and turn things over to Gwenn Hansen, who will give you more information on how we are differentiating Bexdeg from the other BTK directed therapies, as well as speak to our other pipeline agents. Gwenn?

Thank you, Paula, and good morning, everyone. So my name is Gwenn Hansen. I am the Chief Scientific Officer at Nurix. And today, I'm pleased to be able to share with you some new preclinical and translational data that we think underpin bexobrutideg's potential best-in-class profile. Next slide. I will describe in the next few slides, several key points of differentiation for bexobrutideg including potency, mutational coverage and selectivity, particularly in comparison to key competitors in this space. This data, along with bexobrutideg's ability to cross the blood-brain barrier and show activity in patients with CNS disease, as well as today's disclosure of having reached alignment with regulatory authorities to use the highest dose tested of 600 milligrams as our go-forward dose for our pivotal and confirmatory studies, give us confidence that bexobrutideg represents a potentially best-in-class BTK degrader for the treatment of B-cell malignancies. Next slide. First, in terms of potency, bexobrutideg demonstrates picomolar potency in primary human B cells, showing 20-fold more potency and fivefold more potency than B1 and AbbVie's degraders, respectively. Next slide. Next, in terms of mutation coverage, bexobrutideg exhibits a pan-mutant profile, wholly distinct from known -- all known inhibitors of BTK, each of which showed 2 or more liabilities across this growing list of clinically impactful resistance mutations, that arise in the active side of the BTK protein and then in some cases, actually render the kinase inactive while still allowing it to drive cell growth and disease. This illustrates a scaffolding function that was otherwise unappreciated for BTK and ultimately, is not addressed by the numerous small molecule inhibitors that have been developed to date. Next slide. Degraders in contrast are ideally suited to address scaffolding function, but also inhibitor driven resistance. Comparing Bexdeg's ability to kill the same DLBCL cells engineered to express again, the same set of BTK inhibitor resistance mutations, Bexdeg shows consistent levels of cell killing across wild type in all mutant forms of BTK, where both B1 and AbbVie's compound show liabilities against T474i and maybe slightly more severely V416L. So all these observed potency differentials between wild-type mutant forms of BTK, ranging from as little as fivefold to as much as 50-fold, might not prevent a degrader from obtaining clinical response in patients harboring these mutations the ability for a drug to provide a long duration of benefit to patients harboring cells with these mutations will require dosing that drug at exposure levels that far exceed that would be otherwise needed to fully degrade wild-type BTK and safely achieving such levels requires exquisite to greater selectivity. Next slide. Looking closely at the dose and corresponding exposure levels observed in patients during Phase Ia or b of our trials, you see that our optimized dose of 600 milligrams shows steady-state clinical PK exposures that easily cover not only wild-type BTK that is shown here on the bottom of the PK plot with that dotted line, but also all of the previously mentioned oncogenic forms of BTK marked according to the free drug exposures necessary to completely degrade more than 95% of each protein form. The ability to effectively degrade all or nearly all of the BTK protein found in circulating lymphocytes is something that we've been observing consistently in our translational data and is shown on the right-hand side of this slide, where we directly measure BTK protein levels following once a day oral dosing with bexobrutideg. This data shows that regardless of the dose that we have been using, we consistently eliminate BTK signal in the disease setting across baseline mutation profiles. However, with approval to proceed using a 600-milligram dose, we are assured that we can address the totality of relapsed or refractory disease that is otherwise amplified through the use of inhibitors that fail to fully control BTK function. Next slide. Speaking directly to not only our motivation for exploring the 600-milligram dose during project Optimus, but maybe more importantly to why we obtained approval to move forward with our highest dose tested. This slide addresses our selectivity profile. Using a very high sensitivity mass spectrometry-based global proteomic approach, we have attempted to directly compare bexobrutideg to our competitor degraders and show here that we have an exquisitely selective profile that identifies BTK as the only target degraded at doses exceeding that required for near complete coverage of wild-type BTK. This superior selectivity profile allows us to safely dose bexobrutideg in our patients at exposures that meet or exceed what is necessary to completely eliminate malignant cells. Next slide. Based on these data, we explored a more detailed dose response experiments to show selectivity over critical kinase targets, starting with targets that are well known to be off targets for BTK targeted agents. This slide shows those experiments using K562 cells, confirming that bexobrutideg displays a superior selectivity profile with respect to the tech protein kinase, which has been associated with bleeding and cardiac cyst safety effects across the spectrum of BTK targeted drugs. Next slide. Further, profiling additional targets such as LCK, CSK and ADK in more detailed dose response studies in their respective cell types of relevance, we confirm the data that I just showed you from the global proteomic study, namely that Bexdeg has a superior selectivity profile. So in sum, we hope this data helps you appreciate our enthusiasm for what we think is a potentially best-in-class BTK degrader, bexobrutideg. Next slide. Moving on from oncology to discuss our growing I&I pipeline. Next slide. I would like to highlight 2 programs that we have developed in partnership with Sanofi and Gilead and that are advancing through IND-enabling studies or through early Phase I clinical trials in I&I. Next slide. First, through our long-standing collaboration with Sanofi that culminated in a licensing event earlier this year, we discovered and are now developing a highly potent and selective degrader of STAT6 that was derived from our [ delta ] degrader discovery platform. STAT6 is a transcription factor that plays a central role in mediating type 2 immune responses, which are implicated in a wide range of inflammatory and allergic diseases. Eliminating STAT6 using targeted protein degradation offers the promise of controlling allergic and inflammatory diseases with high efficacy and fewer side effects than broader immunosuppressive therapies, while providing the convenience of a once-a-day oral dose afforded with small molecule therapies like degraders. Next slide. Our compound, NX-3911 shows picomolar potency of degradation in human primary B cells in both the resting and stimulated states, suggesting that NX-3911 has a high catalytic activity and confidence to control the inflamed disease state in a cellular setting. Next slide. Similar to the profile shown for Bexdeg, NX-3911 displays exquisite selectivity. Here assessed using global proteomics and measured across multiple human donors where we were able to quantitatively measure the protein levels of over 9,500 unique proteins. In this study, you see that STAT6 is the only protein that is modulated by this drug. Next slide. This highly potent and selective compound also shows profound efficacy in preclinical models of both atopic dermatitis and asthma using either prophylactic or therapeutic dosing regimes, and assessed by measurements of serum IgE levels following 20 or 24 days of dosing, respectively. Importantly, in these studies, NX-3911 restored inflamed levels of IgE triggered by disease induction back down to levels found in naive animals, and that can be seen in the pink bar and the pink dotted line. In our experience, this level of disease prevention or control has only been possible in the context of genetic knockouts, emphasizing to us the promise of this new class of induced proximity drugs. Next slide. Our second I&I program highlight comes from the first license development candidate emerging from our collaboration with Gilead. NX-0479 or now known GS-6791 is a highly potent degrader of the scaffolding protein IRAK4 that is an essential component of the mitosome that mediates [ toll-like ] receptor signaling pathway control. Next slide. Several updates from this program have been communicated at recent conferences, including ACR and more recently at EADV in Paris. Here, we are showing just 1 vignette that speaks to the differentiation of our IRAK4 degrader in comparison to a competitor degrader from Chimera Therapeutics. In this slide, we are showing degradation in control of cytokine signaling in human basal keratinocytes, following treatment with either GS-6791 or KT-474. This data reveals our superior cellular potency, target coverage and control of inflammation in both basal keratinocytes in isolation as well as a model of reconstructed human epidermis. These data highlight the importance of the detailed cellular and in vivo disease cell profiling for this emerging class of induced proximity drugs. GS-6791 has now entered the clinic, and we look forward to seeing how this agent performs in the clinical setting and ultimately having an opportunity to opt in, in the development of this potentially first-in-class I&I drug. Thank you for your attention. And now I will pass the presentation back to Dr. Arthur Sands.

Thank you, Gwenn, and thanks, Paula, that was terrific. I'm going to just make a few summary -- statements here, and then we'll go to Q&A. So I think you'll appreciate that Bexdeg has indeed the potential to produce incredible value for our pipeline over the course of its life cycle. We're looking at CLL. We're also interested in Waldenstrom's and NHL and of course, potentially I&I indications. You've seen and heard today that we have advanced bexobrutideg one step closer to registration and commercialization. The 600-milligram dose is selected as per project Optimus. We have regulatory alignment -- global regulatory alignment and our pivotal Phase II is initiated and the confirmatory Phase III planning is underway, and we anticipate launching that in the first half of 2026. Indeed, there is definitely best-in-class potential emerging for bexobrutideg as well as our other pipeline programs, as Gwenn outlined. These partnered programs, STAT6 and IRAK4 have the potential for significant milestones in the future as well as data events anticipated in 2026 and 2027. Regarding our cash balance and economic position, we're in a very strong position, having completed our registered direct offering. Our pro forma cash is anticipated to be $678 million, which can provide us expected runway into 2028. And during the Q&A, we will also be joined by Hans Van Houte, our Chief Financial Officer. So 2025 here in Q4, we've really accomplished quite a bit as indicated by the check marks along the left-hand side of this slide, and we've discussed today. What we have remaining, we are presenting at ASH coming up in December. We have accepted abstracts at ASH, and we look forward to being there. And as usual, we'll plan an investor event as well. In 2026, there's a number of very exciting milestones that we believe will be important. We have -- we'll have our Phase I a/b results in NHL, we've yet to disclose a significant NHL results. Those cohorts have proceeded quite well and had some impressive results as with our CLL cohorts. We have multiple cohorts in CLL in the Phase Ib portion of the study in very important patient populations, and we look forward to sharing those results with you as well. As I mentioned, we do intend to initiate a confirmatory Phase III in the first half of 2026 as well as the combination study in CLL that Paula has outlined. With regard to I&I, I think it will be a very exciting year in 2026. We will have our potential GS-6791 opt-in potential in 2026 based on Gilead's Phase I results, which is -- which are currently ongoing. And bexobrutideg, its own SAD/MAD study, which is currently ongoing. Also, we anticipate data for that in 2026. And again, this is intended to enable an I&I indication. And then finally, the potential for the NX-3911-STAT6 degrader is really quite substantial, and we can anticipate an IND filed by Sanofi in 2026 as well. So with that, we'll turn to the Q&A section, and I'm going to stop sharing, because I continue to run these slides. And we've got, I think, all members of our team on for the Q&A.

Let me see if I can see all the participants. [Operator Instructions] So I'd like to start, I think, with Roger Song, Roger?

Congrats for the start of the pivotal and then sharing with us a lot of the new data today. So my question is really related to the detail of the pivotal study design. Given your -- the Phase II is a single arm. So what is the stat assumption for the 100 patient for this post covalent non-covalent BCL2. And a similar question for the second line -- second plus line randomized confirmatory study. You have a dealer's choice, multiple compared arms. So how should we think about the strategic assumption on the primary endpoint? And then maybe more specific any caps for all of those comparator arm you will be enrolling in order to power the study?

Okay. Thanks, Roger. So Paula, I hope you got all that. Do you want to answer that question, please?

So Roger, thank you so much for your question. So addressing your first question, what are the statistical assumptions underpinning both of our studies? Certainly, you know that -- the -- each of our programs has been discussed with the agency. So while we're not going to go into all of the details that you would like, what I can certainly say is that we have alignment with the agency on the plans, specifically for the single-arm Phase II, and for the Phase III. We've touched upon the primary endpoint for the single-arm Phase II being the objective response rate with duration of response data as part of the supporting information. So typically, as you know, the agency looks at the agents that are available and assesses to those patients and then looks at your results in comparison. So I think that's all I'm going to say there. And then as it relates to our confirmatory Phase III once again, we have reviewed our program with the agency and are aligned on its design and the primary end point moving forward. So we feel really good about this. And as you will see with our emerging data at ASH, the data that we're generating really supports our ability to establish benchmarks in each of these studies that should support registration.

Next, we'll turn to Derek Archila.

Arthur, congrats on the update here. Just 2 questions from us. I mean, first, on the combo trial that you guys are talking about, I guess, maybe more discussion around the 450 mg dose. And I guess what you think could be the differences between 450 mg and 600 mg? And then also, just given the additional cash with the financing today, is there any plan to kind of expedite Bexdeg's opportunities in I&I?

Great. Paula take the first part, and I'll take the second.

Sure. As you know, Derek, it's very common to initiate a dose-finding study at 1 dose level minus or 1 dose level below your monotherapy dose. And so we're utilizing this approach as we start therapy. It is our hope and our plan that we will be able to advance that dose to 600 milligrams once we've demonstrated the safety and tolerability of the -- of the combination at 450. Arthur?

Yes. And Derek, regarding the second part of your question, the answer is yes. With the really successful -- extremely successful completion of this offering, we now are in a position to accelerate bexobrutideg's entry into I&I. And so I think that is really going to be a strategic value creation occurrence for us. So we're really interested in doing that. So thank you for your question, Derek. Next, we'll turn to Brian Skorney.

Congrats on all the updates today. I guess maybe my question is on the confirmatory trial design. Just wanted to get sort of early thoughts on the control arm. You're not sure based on the proposed enrollment criteria. There's any studies you would specifically point to, to reference for what you might expect the control PFS to be -- just looking at like the benda RITUX, idela RITUX second-line studies, I think they're about 20-month PFS. Do you think is that a reasonable assumption to go on? Or are there -- since these studies were done kind of prior to BTK and BCL2 usage, are there reasons to think that the control arm would come in at less than 20 months or more than 20 months? Just any thoughts you had on those considerations?

Thanks, Brian. Paula, go ahead.

Thank you, Brian, for your question. So I think that your best analogs right now for BR and IR in the second-line plus setting are going to be based upon the BRUEN data, BRUEN-321. And while it is true that, that population is mixed with both BTKI and BCL2 inhibitor exposed patients, 50% of the patients did not have BCL2 inhibitor exposure and 50% did. And so your estimates there for the control arm in the 321 study with BR and IR is about 9 months, and the estimates for pirtobrutinib in that setting are 14 months. And so we anticipate truth being someplace between that in our ongoing study.

Well, let's turn to Gil Blum. Gil?

A couple of quick ones. I'm not sure I saw this, but how is the trial protocol and a pivotal study addressing the patients with potential CNS involvement? I have a follow-up.

Right, Paula?

So neither of our pivotal trials, the Phase II or the Phase III will enroll patients with CNS disease. However, we continue to re-roll those patients in our ongoing 301 trial. So we have a cohort designed specifically for patients with CNS involvement, and we'll have the opportunity to share that information in a future update.

And is there a difference as it relates to the intellectual property in regards to your competitors. Is there a -- we haven't seen any too much going on there, but are there similarities? Or is there anything you can comment on there?

Well, actually, no. I don't think we're going to comment on IP of our competitors at this point. We're in good shape with our intellectual property around bexobrutideg, so I think that's all we can say on that.

And as the last one as it relates to competition. It looked like your drug had a higher potency and molecular assays. But the overall doses that you guys are using, like the total dose is actually a little higher than what they're using. Maybe you can help us understand the differences in pharmacokinetics there?

Sure. Gwenn, would you like to take that question?

Sure, I will. So the dose ultimately really relates to bioavailability, so there are differences between degraders and bioavailability. But ultimately, our drug and our free drug levels in vivo are actually required to be lower in accordance with the potency to cover target protein. So I think in the end, it's better to compare the free drug levels when you're thinking about total drug needed. So that improvement in potency allows us to stay closer in line to the wild-type protein level target coverage than maybe other drugs that have differential potency of BTK.

We'll go to Matt Biegler.

Thanks so much for this update, guys, exciting news. So Arthur, can you tell me about the motivation for going after triplet exposed. I mean, ostensibly, you guys see pirto and the other non-covalent as kind of their own entity and the continuum of care. So I'm just -- I'm interested to know what went into that decision? And I guess more importantly, what do you think the bar is for success in pirto exposed population because I don't think we really have a lot of data on that. So I'm just kind of interested to hear your thoughts?

Yes. Thank you. So when we look at the emerging landscape in treatment of CLL, we believe that the non covalence will gain approval, full approval, pirtobrutinib in particular. And so looking at also the definition of unmet medical need, it is according to accelerated approval guidelines. We need to address a population that does not have any treatment alternatives. And so that would be this post triple exposed patient population. And so our goal there is to be eligible, ultimately for accelerated approval in the time frame of completion of the trial, and we think that's going to be the best positioning. With regard to where is the bar and what kind of response rate we might see in this population? I think I'll hand that to Paula because we're talking about patient populations in the fourth or fifth line. Paula?

Yes. So Matthew, thanks again for your question. As you've accurately denoted, there is no -- or there are no great studies that speak to the activity of agents in this specific patient population. That having been said, if you look at monotherapy data for chemo or immunotherapy, so RITUXAN-based regimens or bendamustine or even chlorambucil, et cetera, in this fourth-line setting, you can see rates as in the 30% up to if we think about pirtobrutinib up to as much as 65%. Ultimately, those are not specifically in this patient population. So we know the truth is going to be someplace between this 30% and 60% range. But that will occur or rather that assessment will occur at the time that the agency is reviewing the data. So that gives you a sense of what exists, but there are no perfect analogs.

Next, turn to Joe Catanzaro.

Maybe actually somewhat related to the last question. When you look at your data set, like and consider these triple refractory patients, what kind of efficacy are you -- can you say you're observing there relative to the broader relapsed/refractory CLL population that you've enrolled? Have you seen a notable difference or it's sort of similar behavior?

Paula, do you want to take that?

So thank you for the question. As you know, in our Phase Ia, we've enrolled patients from dose -- at dose levels from 50 milligrams to 600 milligrams in the 48 patients that we certainly discussed today, you might imagine that while we've treated patients who are triple exposed, they have not all been treated at the 600-milligram dose level. So what I can say definitively is that we've clearly seen responses, deep responses, including PRs, but it is hard for me to give you an exact number on what to expect at the 600-milligram dose level just because we don't have a lot of patients at that dose level. That having been said, what we have seen is still consistent with our overarching data, which shows that our response rate is in the high 70s to 80s.

If I could squeeze a follow-up in maybe this 200 milligrams versus 600 milligrams, I think the Phase Ia was complicated a little bit for dose response because of intra-patient dose escalation at least from the outside looking in. In the dose optimization, 200 milligram versus 600 milligrams, was there an obvious dose response as it relates to efficacy? Did it come in response rate? Is it trending more towards durability is a little bit of both?

Thanks, Paula, any comments?

Well, you see me smiling or maybe you don't see me smiling, but know that I am smiling. So first and foremost, when the agency is looking at your data as it relates to this dose optimization, they are looking not only at safety, which is their primary objective and improved and a tolerable safety profile, but they're also looking at efficacy. And so suffice it to say that the balance of data, both safety as well as efficacy supported the use or the choice of 600 milligrams, not only by us but obviously by the agency. So we're really thrilled with that. And I look forward to seeing what we will show in our pivotal trials.

We'll turn next to Brian Abrahams.

Congrats on all the progress. Maybe just sort of how the overall landscape in CLL might play out. You spoke a lot about some of the preclinical advantages versus other degraders. I guess I'm curious how you see those playing out in the clinic if you're seeing any hints so far as you kind of look at others data? And then I guess I'm also wondering how you would expect the initial commercial market and used to look here have -- potentially having 2 degraders available that might have different labels based on different accelerated approval trial designs, but having the potential for Bexdeg to have greater efficacy across more mutations, which may be relevant in a refractory population?

Thanks, a 2-part question. Gwenn, we'll give you the first part, which was about the differentiation, I think?

Yes, I think speaking to the differentiation, I think we see several key points that really speak to the ability of bexobrutideg to outperform the competitor agent. So first, really, it is the selectivity. We have observed such a safe profile across all of our doses. I think that really speaks to that distinction that I was showing you in all the preclinical data, particularly the proteomics that really just allows us to press on this target pathway. So we're -- that high dose is really there because we have safety, which means we can control more of that signaling pathway than would otherwise be possible. And I think that really is -- the important point, I mean, the potency is supportive as well, of course, and the mutation coverage is obviously an advantage. So I'll pass it back to you, Arthur or Paula, for the clinical interpretation of that.