Welcome to the Nurix Therapeutics NX-5948 Clinical Update C all. All participants will be in a listen-only mode. Should you need assistance, please email conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star and one on your telephone keypads. To withdraw your questions, you may press star and two. Please also note today's event is being recorded. At this time, I'd like to turn the floor over to Nurix's CEO, Dr. Arthur Sands. Please go ahead. Thank you, and welcome to our call from the European Hematology Association Congress in Madrid. Today, we will be discussing the latest results from our clinical trial of NX-5948 in B-cell malignancies. We will be making certain forward-looking statements on today's call, and we refer you to our filings with the SEC regarding our disclaimers and the risk factors that face our business. I am joined on today's call by Dr. Kim Linton from the University of Manchester and The Christie NHS Foundation Trust, and by Dr. Paula O'Connor, Nurix's Chief Medical Officer, and by Dr. Gwenn Hansen, Nurix's Chief Scientific Officer. The agenda for today's call is as shown on slide number 3. After my brief introduction, we will move directly to Dr. Linton, who will review the latest results from the NX-5948 clinical trial with a primary focus on CLL. We will then turn to Dr. O'Connor, who will provide additional insights into some of the profound effects of NX-5948 treatment, as illustrated by two new case studies of patients in our trial. Dr. O'Connor will also discuss our anticipated next steps for the further clinical development of NX-5948 in CLL. We'll then open the call to your questions. On this next slide, I'd like to place the development of NX-5948 in the context of Nurix's large and growing pipeline. Starting from the bottom of the slide, one can appreciate that Nurix's inflammation and immunology pipeline is now quite substantial, including our IRAK4 development candidate with Gilead, which is currently in IND-enabling studies, and our recently disclosed STAT6 program with Sanofi, which is in lead optimization. In addition, we have NX-5948, which is on track for potential autoimmune IND in the future. Listed above the I&I portfolio, we have our very robust oncology pipeline. With the latest additions, our degrader antibody conjugates, or DACs, that are being developed in collaboration with Pfizer. This is a very exciting new application of Nurix's targeted protein degrader platform. In addition, we have multiple targeted protein degrader programs with Sanofi and Gilead, and at the top of the slide is Nurix's wholly owned oncology pipeline. You may notice that NX-5948 has now moved into the top position on this slide, reflecting the acceleration of its clinical development program, which is fueled by the very exciting data we are about to review. I'd like to complete my introductory remarks with some of the key points we believe are supported by the data we are about to present. First, the results are indeed very positive, with an objective response rate of 69.2% based on 26 evaluable, heavily pretreated CLL patients to date, including patients with BTK resistance mutation. Next, the clinical responses obtained were rapid and deepening with longer time on treatment. Importantly, NX-5948 has been well tolerated with extended treatment durations in many patients. Third, with an amazing and emerging amazing best-in-class profile, Nurix is expanding the NX-5948 trial into phase I-B in CLL, and we are formulating plans to initiate pivotal development in 2025. With that, I would like to turn the call over to Dr. Linton, Senior Lecturer and Honorary Consultant in Medical Oncology at The Christie, and a leading investigator on the NX-5948 clinical trial. Dr. Linton. Thank you very much. So yes, absolute pleasure to be invited to join you all on this call. And as you've already heard, I'm a Clinical Senior Lecturer at the University of Manchester, which is in the North of England, and I lead the program of research at my center, including this NX-5948 clinical trial. So what I'm going to do over the next 10 minutes or so is just walk you through the presentation that I've just given here at the EHA meeting earlier on today. Apologies. I'm a technophobe. There we go. So these are the latest results from this ongoing first-in-human phase I-A/B clinical trial of NX-5948, which, as I'm sure you well know, is a selective BTK degrader. And this program is evaluating the activity in patients with relapsed and refractory CLL and other B-cell malignancies. In CLL, the current treatment is focused on two key pathways, the BCL-2 and the BTK pathways. This has become the standard of care that really has changed the landscape of people in the first and the relapsed refractory setting. The majority of people will develop resistance, particularly to BTK, and this limits the utility of currently available options. The BTK mutations particularly confer resistance to both the covalent and the non-covalent BTK inhibitors. Even those kinase dead and kinase overactive mutations, in the presence of those, you still have activation of the B-cell receptor through the scaffolding function of BTK. This is, of course, where it's engaging with other proteins that will activate the B-cell receptor signaling pathway. There is a real need for a new treatment modality that can target both the resistance mutations as well as this BTK scaffolding activity. This is where the BTK degraders come into their own. NX-5948 is a novel orally administered BTK degrader, and it works by binding very transiently to a binding site close to the same binding site for the BTK covalent and non-covalent inhibitors, but except it does it to target for ubiquitination via the E3 ligase complex. Effectively, what it's doing is it's tagging that protein for destruction. The protein is eliminated from the cell, and the drug remains in the cell to go to the next BTK molecule to do the same thing. You have constant activity within the cell, which is thereby overcoming the resistance mutations because of the different binding site and the transient binding, and also because it's eliminating BTK from the cell, it's actually addressing that BTK scaffolding function. So this is, as you know, a really promising and emerging level of activity in a variety of B-cell malignancies, with the potential to replace BTK inhibitors in the clinic. And that's what I'm particularly excited about. Those patients, either with pre-existing mutations or with treatment emergent mutations following covalent or non-covalent BTK inhibitors, actually have an opportunity to do well with a BTK degrader. So we are overcoming resistance mutations and improving prognosis. So the NX-5948 clinical trial, as described, is a phase I-A/B ongoing clinical study. It's there to address the safety, tolerability, and efficacy of this drug in both CLL and non-Hodgkin lymphoma. There are 2 parallel cohorts. The phase I-A dose escalation part, which is currently ongoing, is enrolling adult patients with relapsed and refractory disease and at least 2 prior lines of therapy. There is a PCNSL cohort as well. They are allowed to have one or more prior lines of therapy. Patients have to have a reasonably good performance status with an ECOG of 0 to 1, relaxed to 0 to 2 for those with PCNSL. And in the left-hand box, you can see the step-up dosing schedule, the 3+3 dose design, which is fairly standard. On the right-hand side is the potential phase I-B dose expansion study, which will enroll both CLL and a non-Hodgkin lymphoma, a variety of malignancies, and currently, the eligibility for these different indications is being worked out. This is the patient disposition. You can see that there are 79 patients enrolled across the whole study, both in the CLL and the non-Hodgkin lymphoma cohort. Now, if I focus you to the left-hand side of the slide, the blue boxes, you can see 31 patients enrolled in the CLL cohort. Right at the bottom, 27 of those are still on treatment at the time of data, up on the 17th of April. Just 4 patients have come off study thus far, and that's mainly due to disease progression. I'm going to focus some of the activity data on the CLL part, but I will present some safety data across both NHL and CLL. This is the demographics for the whole population of 79 patients. Just to focus you on the fact that this is an elderly population with a median age of 67 years, and that's the heavily pretreated population, the median of 4 prior lines of therapy. 15% of the patients in this cohort had previous CNS involvement, and that's a poor prognostic feature. Looking at the third gray box down, you can see the different types of treatments that these people have received. They're fairly standard. They're BTK inhibitors, BCL-2 inhibitors, PI3 kinase inhibitors, and a variety of chemoimmunotherapies. I think almost 80% of the population having been exposed to both a BTK and a BCL-2 inhibitor, so effectively gone through the standards of care for this disease. Then draw your attention to the far left bottom of the blue box for the patients with CLL. You can see that the vast majority of people in this cohort had a mutation, so either a TP53 mutation, which is a very poor prognostic mutation, leading to lower response rates and lower duration of response. Almost 45% having a BTK mutation, which, of course, means that they no longer respond to the covalent and non-covalent BTK inhibitors, and then other mutations, which we'll talk a little bit more about in some of the later slides. So heavily pretreated, highly mutated, poor prognostic elderly group of patients. So looking at the safety of the drug first, and again, this is across the whole cohort, headline figures, this is a really well-tolerated drug. The most common treatment emergent adverse events are purpura, which is bruising, thrombocytopenia, which is a low platelet count, and neutropenia, which is a low neutrophil count that predisposes to infection. But the key thing about this is many of the patients had these pre-existing features at registration with the study, and none of these characteristics led to dose reductions, delays, or discontinuations. This is all very well tolerated. And with the higher doses that we've been through in the 3+3 design, we've not seen any new safety signals, and in particular, we've not seen any new cardiac signals, which is an important toxicity linked to the BTK class of drugs. No real difference either between the CLL and the overall population. And just to focus on the far right box, just to describe some other additional features, we've had one dose-limiting toxicity. That was a patient with a grade 2 rash who came off study for a 7-day or longer than 7-day period. So that was a non-protocol mandated DLT. We had two treatment emergent adverse events, and this was infections in the patients, two of the patients in the non-Hodgkin lymphoma cohort that led to drug discontinuation. We had one related serious adverse event or SAE. This was a case of laboratory tumor lysis syndrome, which was resolved with fluids. And then one Grade 5 adverse event, so Grade 5 meaning a death in study, and that was a pulmonary embolism not deemed to be related to NX-5948. So moving on now to the clinical activity of this drug, and this is something called a waterfall plot, and basically the bars going down suggest that the tumor is reducing in its size. And so you can already appreciate visually that this drug is reducing tumor burden. And the objective response rate associated with that was 69.2%, as you've already heard, with the patients in that group either achieving a partial response or a partial response with rebound lymphocytosis, which is talking to the mechanism of action of this drug. And the little green arrows at the bottom indicate the patients on study who are still receiving treatment. So that's all but two of the patients in the cohort, which is very impressive. Looking at the little hashes at the top, this is indicating the people with CNS involvement, so central nervous system involvement at baseline. As I mentioned earlier, that's a poor prognostic feature. So the fact that we're seeing partial responses in this group of patients is extremely encouraging. So that is very important to note. So now moving on, this is called a Swimmer's plot, and it's giving you some slightly similar information, but a little bit more granularity. So you can see the little triangles in green are indicating where the partial responses have occurred. And you can see that these are occurring early, so generally at the time of the first response assessment scan. And then the longer the Swimmer's line goes, it means the longer the time the person's been on treatment. So you can see you've got your axis at the bottom, which is indicating the cycles in days. So you've got people out there who are achieving very durable remissions. In fact, five of the partial responders in this study have achieved 10 or more cycles of treatment. That's a very specific group. The other consideration is the fact that they're very heavily pretreated. Those are the gray bars on the far left. So despite heavy pretreatment, we're seeing BTK degradation and objective responses in this group. And then on the far right, you can see the assigned dose levels. So these are all different colors of blue, and you're not seeing any appreciable difference in terms of the doses. So across all dose levels, this drug is working. And within the study, nine patients have dose escalated. That means that they've gone up a dose level or two, and that could be associated with a deepening response and duration of response. So this is a single case. So this is a patient with CLL and CNS involvement, so central nervous system involvement. Here, just to illustrate the typical pattern of response to BTK targeting. So the little orange line represents the lymphocyte count. These are the white cells in the circulation. And as you know, this drug starts off by increasing the lymphocyte count, so you get an initial rise, but then you very quickly start seeing that orange line dropping down. So that's indicating that you're clearing those malignant lymphocytes or white cells in the bloodstream. And corresponding with that, this patient with CNS involvement had a reduction in their malignant cells within the CSF, that's the cerebrospinal fluid, and that compartment was cleared. Similarly, the cytopenias, which is low blood counts at the start of treatment, that was cleared with the drug. In other words, the blood counts returned to normal or near normal levels. The spleen, which was a site of involvement for this individual, the spleen was enlarged at baseline, that responded. Across the board, you're seeing an improvement as a result of the activity of this phenomenal drug. Now looking at the BTK and other mutation status. I mentioned at the beginning that a significant proportion, over 40%, have got a mutation of BTK, which means that the binding site that the covalent and non-covalent inhibitors bind to is no longer there. Despite the presence of multiple different BTK mutations shown in different colors in the graph on the right, you can see that BTK is being degraded. There's no single mutation that is either associated with response or indeed resistance to this drug. That's very important, overcoming the resistance associated with these mutations. This is further graphically illustrating some of these mutations. So each of the little colors in orange and some kind of blue in the bottom are referring to treatment resistance mutations or poor prognosis mutations. They're spread out across the cohort. But you can see the corresponding reduction in the tumor burden in the blue bar on the top, indicating that there is no single genotypic profile linked to intrinsic NX-5948 resistance. We're seeing activity across the spectrum. And this is just drilling down into those BTK mutations, which is those binding site mutations. Again, you're seeing that across the spectrum with no particular signal emerging. So if I can just wrap up in conclusion, these are extremely positive results from this ongoing phase I study. I'm a clinician that treats a lot of patients first in human and from phase I studies. To see this kind of signal this early on gets us excited. This is a well-tolerated drug in patients with both non-Hodgkin lymphoma and CLL, with no increasing safety signals at higher doses. We're seeing deep and durable responses in a really difficult-to-treat CLL population. That includes people that are heavily pretreated, receive very unfavorable genetic mutations, and a poor prognosis. We're seeing robust clinical activity demonstrated by the objective response rate of 69.2%, and the majority of these people ongoing at the time of data cutoff, achieving very rapid responses and no patient profile associated with any intrinsic resistance. So I am of the opinion that these data strongly support the continuing development of NX-5948, certainly in the development of CLL, where, as you've heard, there's a phase I-B dose expansion plan. But of course, this is also being evaluated in non-Hodgkin lymphoma and WM, and we are looking forward to getting some more data later in the year. So I am now going to hand over to Paula O'Connor, who's going to talk you through the next section of this presentation. Thank you. All right. So hello, everyone. Thank you for joining us at this early hour. My name is Paula O'Connor, as you have heard. As Dr. Linton has already mentioned, I am the CMO of Nurix Therapeutics. Like her, I am a clinician and a drug developer. In the next couple of minutes, I will try to communicate what makes us so excited beyond the data that she has already presented. I will start with two case studies. At the top of Dr. Linton's presentation, she gave you a sense of how heavily pretreated our patients have been. The case that I will present now gives you greater detail around one patient's course, but specifically addresses our patient population in that you can see that we are treating patients who have received multiple lines of therapy, in some cases as many as 14. What's also incredibly important is to understand the breadth of the types of therapies that they have received. So while individuals may have been exposed to both a BTKI and a BCL-2 inhibitor, several patients, many patients have been exposed to liso-cel or PI3 kinases in addition to the more traditional therapies. In the case that you see in front of you right now, we have a patient who's treated at the 200 mg dose level, which is one of the dose levels that we anticipate assessing in our phase I-B expansion. As you can see here, they have achieved a partial response. When you look at their molecular cytogenetics and other baseline features, what you can see is that this, once again, is a patient who is at very high risk on the basis of their traditional cytogenetic profile. In addition, you can see that this patient does have a BTK mutation and bulky disease of splenomegaly. So this is a patient with very bulky advanced stage disease. On the right-hand side of the slide, you can see the prior systemic therapies that they have received. On the slide in front of you, what you are seeing is a depiction of the course, very much like the case presented during the EHA presentation. On the far left-hand side of the slide, you see the baseline characteristics of this patient, namely that they had large bulky disease with large lymph node diameter. They had splenic enlargement as well as cytopenias and constitutional symptoms. We see, as we look at the blue line, which represents their lymphocyte count, that they did have a transient lymphocytosis associated with or described well for BTK targeted therapy. But most importantly, what you can see is that early on, by 8 weeks, we have a partial response in this patient who's symptomatic at the time of presentation, and that for the patient, their symptoms had in fact resolved. That is critically important because when patients feel better, they stay on your drug because we're actually taking care of the primary problem. By 16 weeks, what we can see is that although they had already received a partial response or achieved a partial response by 8 weeks, that in fact, their disease burden is continuing to improve. So as you follow them out, you can also see that their ALC continues to respond, approaching the normal range. So this is something that we've been seeing in many of our patients. On our next slide, I'm going to present the case of a second patient also treated at the 200 mg dose level. As I've already mentioned, this is one of the dose levels that we intend to move forward with. You can see here, too, that this patient has had several very active prior systemic therapies and has poor prognostic features, as denoted by their IGHV mutated status, their TP53 mutation status, and most importantly, their PLCG2 mutation status. So like the patient on the slide previous, they represent among the sickest of the sick patients with multiple poor prognostic features. What you can also see here is that, like the patient previously discussed, they too have bulky disease and splenomegaly. This patient's course is notable for a reduction in their volume of disease that is almost immediate. So you can see by 8 weeks that they too have achieved a partial response and that their response has deepened over time. It is our anticipation that for many of our patients, that we will see improved responses. So even those patients who've achieved a stable disease at the time of the cutoff for our EHA presentation, they will be followed as will our partial response patients for subsequent changes or improvements in their disease burden. And we look forward to presenting that data in the second half of this year. So having gone through some of the clinical data with Dr. Linton and then giving you an increased flavor of the activity that we're seeing with these two case studies, what I'd like to now do is tell you what our next steps are. Ultimately, and I'll just direct you to the most important part, which is the initiation of our pivotal trials, we do anticipate initiating pivotal trials in the next 18 months. That having been said, what we can also say is that we are looking at both monotherapy and combination approaches as a path to approval. Our pivotal trial in the third line setting is going to be in keeping with our fast-track designation patient population, namely those patients who've been exposed to a BTKI and a BCL-2 inhibitor. Given the data that we have already shown you, the depth of response, and the fact that these responses are continuing to improve over time, we believe that there is also an opportunity for this drug in the front line setting and in the second line setting as monotherapy. And so do anticipate a pivotal trial in that arena as well. Recognizing that the safety profile is such that we are not seeing any sort of treatment discontinuation and that patients have been able to tolerate the drug for multiple months, certainly up to 18 months, which is our longest treated CLL patient at this point in time, we do also anticipate doing trials in combination with other agents in a hope of really minimizing the disease that patients have. Now, in order to do all of that, we will in fact need to, and I'm going to have you move to the left-hand side of the slide, we will need to expand our ongoing phase I-A/B. So we are going into our phase I-B cohort expansion imminently. And as you can see here, we anticipate enrolling up to 150 patients in that phase I-B program. In addition, we will continue to enroll our fast-track designation population, but we'll also be paying special attention to those patients with BTK mutations and other high-risk features given the data that we've demonstrated that already shows that we're highly active in this patient population. In order to support our move into a combination front line or second line trial, we will also be doing combination basket studies specifically with the agents that are demonstrated on the slide, but not limited to those agents as we think about the broad development of this agent. We are incredibly excited about this and look forward to what's going to come next in the next 18 months. So as you can see here in the two presentations that you've received from me and from Dr. Linton, we clearly have an active drug with an ORR in the third-line CLL population of approximately 70%. We are planning for multiple parallel programs so that we can fully understand the activity of this drug in CLL. And at the same time, recognizing that we have not presented any of our NHL data here, we have seen deep responses across all patients and all subtypes of NHL, indolent as well as aggressive. And as such, we are also planning to expand into phase I-B in specific NHL cohorts in the next six months. We certainly anticipate presenting data on these NHL patients to you and others obviously in the second half of this year. And with that, I'm now going to turn things back over to our CEO. Thank you, Paula. And thank you, Dr. Linton. While you're formulating your questions, I will make just a few concluding remarks, and then we'll be ready to open the Q&A session. First off, I have to say I'm always just so moved and impressed when I see the case study reports presented. I think that they really do humanize the entire data set, if you will, especially case study number one, that patient which has been basically on every available BTK inhibitor as well as the chemotherapies and all of the others. It's just very heartwarming to be able to bring benefit to such patients. So my formal concluding remark before the Q&A, so we truly do believe, based on our emerging data, that we have a best-in-class drug in our hands, and this will offer patients very important treatment options ultimately upon approval. We have a great team in place, and we're poised to successfully accelerate the development of NX-5948 to pivotal trials in 2025. And as Paula pointed out, there are multiple pivotal trials to be planned. So it's going to be definitely more than one. Third, we do have a very robust and growing pipeline of oncology drugs at the company, including our I&I portfolio, and we look forward to telling you more about that as the year progresses as well. And finally, I just want to really be sure to express our sincere appreciation to all the support from our investors, from our investigators now across the world, and most importantly, appreciation to our patients and their families for dedicating themselves to the development of this drug. So with that, we can now open the call to questions. I'll turn it over to the operator. Go ahead. Ladies and gentlemen, at this time, we'll begin that question and answer session. To ask a question, you may press star and one on a touchscreen telephone. If you are using a speakerphone, we do ask that you please pick up your handset prior to pressing the keys. At any time your question has been addressed, you would like to withdraw your question, you may press star and two. Once again, that is star and then one to join the question queue. We'll pause momentarily to assemble the roster. Our first question today comes from Gil Blum from Needham & Company. Please go ahead with your question. Hi. Good morning and good afternoon to everyone. A couple from us. Maybe for Dr. Linton first, just to put in context, what are the potential benefits of achieving complete responses in CLL patients? So look, complete response in CLL is not that common. And as Dr. O’Connor already explained with the two cases that she presented, just achieving disease control with a reduction in the cytopenias, the reduction in organomegaly, improves patients' quality of life substantially. So complete responses will happen, I suspect, when we've treated more patients. But I don't think that that's something that you need to be concerned about because what's very clear from the people that have achieved a partial response in this study is that they are deriving considerable clinical benefit. And I can give you many anecdotes from my own clinical practice of individuals who have literally turned their lives around and are currently living their best lives and they're in partial response. So don't be too concerned about that. Okay. Very helpful. Maybe another question here. Given we see activity across many dose cohorts, how do you guys think of adjudicating the go-forward dose, also given consideration to FDA requests for two doses sometimes? So I'll hop in and answer that question. This is Paula O’Connor. So first and foremost, what is clear is that with the 200 mg dose, we clearly have a dose that we are taking forward. As Dr. Linton mentioned at the top of her comments, we've just completed our dose escalation to the 600 mg dose level in CLL patients, and we continue to await that data before we make a decision on our higher dose level that we will take into our dose expansion. Certainly, as we choose that dose, the factors that will go into that include tolerability, first and foremost, activity as well, and then obviously, we will look at durability of responses also. So all three of those will factor into our decision. I think what's really most is best about the data profile that we have seen to date is that certainly we don't think safety is going to play a major role here in that our safety profile has been very, very consistent across the doses. So we are heartened by that information. Okay. Very helpful. And just to verify, were there no dose reduction delays or discontinuations in the CLL cohort? So we have had very few dose reductions because the drug has been incredibly well tolerated. We had two inadvertent dose reductions in the CLL cohort that had nothing to do with a physician decision or patient toxicity, but actually a minor error at the site. Otherwise, we have not had any dose reductions for cause in the CLL patients. So this is really, really tremendous. Right. So we have had dose escalations. The dose escalations have occurred in patients, as you know, who were initially treated at 50 mg and then moved on to subsequent doses. So we're expanding our understanding of the safety profile for patients treated at higher dose levels, 450 mg and 600 mg included. Okay. That's also very helpful. In the waterfall plot, there's a single patient who has progressive disease, but he's still on therapy. Any details there? I'm just going to note that that patient does not have progressive disease. What they do have is stable disease. With stable disease, you can see increases in lymphadenopathy at times. What this patient also has, which is not fully reflected, is an improvement in their symptoms, an improvement in their blood count. Given that, that patient remains on study. They will obviously continue to be followed. I will add, I'm going to turn things over to Dr. Linton so that she can add. Yeah. Thank you. Just about that particular patient, that patient had progressive disease on entering the study, and the timing of their scan wasn't quite the right time for us to be absolutely certain. They stayed on drug for a little longer because they were deriving considerable clinical benefit, and the subsequent scan showed stable disease. But even though that bar chart is going up, it's stable disease by radiological criteria. That patient is still benefiting. Okay. Again, very helpful. And a last one, I promise. Will further studies continue to include patients with CNS involvement, which is different than most studies in this space? So certainly, one of the things that we're most pleased by is, in fact, the evidence that we have CNS penetration without any sort of adverse events associated with that CNS penetration. And recognizing that this is an area of unmet medical need for patients both with CLL in some cases or in rarer cases, but also in patients with NHL, it's a critical component of our development plan. So we will continue to enroll patients with potential CNS involvement in our upcoming study. Thank you, Gi l. Thanks for taking our questions, and congrats on remarkable data. Thank you. Our next question comes from Gregory Renza from RBC Capital Markets. Please go ahead with your question. Great. Good day, Arthur and team. Let me add my congratulations on the excellent updates this weekend, and thanks for taking my questions. Arthur, maybe a question for Dr. Linton. Dr. Linton, you certainly covered some of the attractive attributes of 5948. I'm just curious if you could help us maybe prioritize or stratify some of those characteristics that you find to be maybe most clinically relevant as this could potentially slide in as a treatment option in your armamentarium, especially when it comes to the tolerability, the potential for extended durability, that rapidity of onset, as well as the mutation coverage. That would be great. Thanks so much. Thank you. There's quite a few things, actually, that stand out as making this a very difficult-to-treat group. One is the fact that they've had so many lines of treatment, and that means that they don't necessarily have any further standard of care options remaining. So it would be clinical trials or no further treatment for these individuals without a drug like this. The other is that they're heavily mutated. So in other words, even if they did still have these drugs available, they probably wouldn't respond to them because they've got mutations at the binding site. And it's not just the BTK mutations that are relevant here. It's also things like the TP53 mutations, which I briefly alluded to in my presentation. This is a very common feature of CLL. It's acquired over time, and it just basically means that standard therapies don't work. And this is where drugs like this are really coming into their own. The other factor is that this is such an elderly population. So when you're reaching your late 60s and 70s, you can't tolerate standard chemotherapy. The toxicity profile is too great. So you have to have a drug that's easy to, that you can tolerate, basically. And the safety profile that we've seen with this drug is fantastic. It's better than the first-generation BTK, the covalent BTK inhibitors. It's even better than the second-generation BTK inhibitors. So this has got the potential to, as Paula was saying a moment ago, to get people into remission and to keep them on drug. That's really helpful. Thanks, Dr. Linton. And Arthur, maybe questions just for you, Paula, as well as Dr. Linton, perhaps. Certainly, some nice advancements in BTK degradation occurring in real time. Just curious if you could comment a bit on how you think about the competitive landscape, certainly seeing some data from 16673 as well, and how we should be thinking about the jockeying and the potential for success across the class. Thanks again, and congrats, Arthur and team, on the data this weekend. Thank you very much. Sure. I'll take that up. So yeah, we're very encouraged to see other companies now becoming aware of the true value of the degradation mechanism and its potential, actually, to be superior. So I think we welcome those additions to the clinical trial scene. I think it's improved patients' awareness and investigators' awareness overall. So it's definitely a net positive, no question. Now, as for particular results, etc., we don't comment on other people's drugs. And it's going to take probably months and years to really understand the profile of all these new agents, but I'm sure that it'll become apparent as time goes on. But again, I will say that we are targeting our best-in-class goal, and that's what we think NX-5948 can be. So thank you for your questions. Next question. Our next question comes from Joe Catanzaro from Piper Sandler. Please go ahead with your question. Hey, everybody. Appreciate you taking my questions and congrats on the data here. Maybe one first on dosing. I'm wondering if you think this drug class is associated with a classic dose-response curve. I mean, your data doesn't seem to suggest that. The BeiGene data doesn't seem to suggest that. And I'm wondering if it's maybe more bell-shaped dose-response curve. And maybe for Gwenn, whether mechanistically that actually makes sense here for the degrader mechanism. Thanks. And I have maybe a follow-up. Well, I'll start out, Joe. Thank you. So just with regard to the bell-shaped curves, we have never seen that in vivo. And I think it has to do with the blood concentrations of drug achieved. In vitro, if you go to these absurd concentrations, you can actually generate that, which is really a concentration artifact. I mean, it is a real result, but it does not occur in vivo. But then I think I'll turn it over to Gwenn to talk about some of the blood level differences between a degrader and an inhibitor that we've seen in our analysis and what that can mean in terms of the fundamentally different PK/PD results for these agents. Yeah. So I guess I will start out to say that I don't think you should consider the degraders not to have a dose response. I think just like any drug, there is a dose response in the degraders set, just as there would be in the inhibitor set. But the real fundamental difference is that you need so little of the degrader in the bloodstream to access cells and tissues to essentially cover target. And because it's catalytic in nature, that little bit of drug will remove almost all of the protein, even at very low doses. So what you get at the very lowest dose you start with is very good coverage of the target. But of course, when we're working in the oncology space, very good coverage is okay, but what you really want is the very best of coverage. We are still moving from the lowest dose where we eliminate protein via our measures of detection to higher doses. We do think that we have a bit of a dose response in the speed at which we're getting our PRs. We are seeing them more rapidly as we get to higher doses. We also think that we achieve better tissue penetration and access and maybe even CNS access as we get to higher doses. Underlying, there is a dose response. I think if you look simply at our way to measure protein quantity, it looks like we are covering the protein pretty effectively from the lowest dose. But there's a subtlety in there that is real, and we have not yet in vivo seen any high dose that eliminates that ability to cover the target, even though, as Arthur said, in an in vitro setting, you can dose up high enough to have some repercussions in terms of target coverage. It's really just not something that we expect to see in vivo. Great. And I know, Arthur, you just sort of said you won't comment on other company data, but maybe I could just ask slightly differently. So after the BeiGene presentation, the presenter was asked about the lipase and amylase increases that program was seeing and how that's something that's not observed with BTK inhibitors. If I understood the presenter correctly, they mentioned that preclinically, the program saw macrophage infiltration into the pancreas. So maybe for 5948, can you maybe just speak to preclinically whether you've ever seen any indications of amylase lipase increases, pancreatitis, so on and so forth? Yeah. Easy question to answer. The answer is no. We have not seen that. So I was a little perplexed by the answer that was given today. But no, we have not seen that, and we've gone to very high doses in monkeys and really very thorough preclinical workup. So that's not something we would expect. Okay. Great. Thanks so much for taking my questions. Thank you, Joe. Our next question comes from Joel Beatty from Baird. Please go ahead with your question. Hi. Congrats on the data. First question is for Dr. Linton. Where could a drug like this fit in your treatment algorithm? If the profile holds up, would it ultimately make sense to use it as a later-line BTK therapy, or could it make sense to use it as an earlier line? Obviously, the data currently are in the relapsed and refractory setting where we are seeing remarkable results. So I clearly think it could have a potential place at this later stage. But I think increasingly, we're recognizing the importance of gaining disease control early on. And so I think to try and prevent the emergence of some of these BTK mutations, it makes perfect sense to bring this drug to the frontline setting, either as monotherapy or in combinations. And I would be very excited to see it in that space. Okay. Great. And then in today's presentation, I think there were 31 CLL patients with 26 evaluable. Could someone just clarify the distinction between the five missing patients and the evaluable? Paula? So as you know, when we do a data cutoff, not everyone has reached a point in their treatment course where they have actually had their first assessment, and yet they are counted as being on study. So in fact, two of the patients have not yet reached the point where they would be disease evaluable. We did, in fact, have one patient who progressed rapidly, and the Hodgkin's patient, actually, that patient was evaluable, excuse me, so we have one other patient who progressed rapidly. And then I can't believe I'm blanking on the last two, but suffice it to say that all of the patients that have made it to 8 weeks remain on therapy. And so the 27 of the 31 patients that we've treated to date remain on therapy, and that is remarkable as it represents almost 90% of our patients. Got it. Great. And then last question is, between now and starting a pivotal trial sometime in the next 18 months, could you discuss what the rate-limiting factors are to have that happen? Well, there are many. I think, number one, we plan to expand into I-b and choose our two dose levels. That we anticipate to be occurring shortly. I believe we already have the first dose level selected, as Paula indicated. Shortly, we'll be able to confirm a second. And then collect additional information, of course, interact with the agency, discuss details around pivotal trial plans, and implement those as soon as possible. And I think, as we talked about, 2025 is the goal. I don't think everything's going to wait till the end of 2025. I think there are going to be several that start at different exact time points over that 12-month period. And we anticipate multiple pivotal trials as well as the combination trials. So there's a tremendous amount of clinical trial planning, regulatory interactions, and I think expanding our sites. So all of that's ongoing. It's really about acceleration at this point. Thank you. Thank you for your questions. Our next question comes from Stephen Willey from Stifel. Please go ahead with your question. Yeah. Congrats on the data. Thanks for the update. I guess maybe for Arthur or for Paula, just curious as to whether or not the patients who would be enrolled into the phase I-B, I think you talked about generating an additional 80-150 patients. Could some of that data be leveraged into the registrational study for an accelerated approval purpose? I'm just trying, I guess, maybe to understand the rationale for maybe generating another 150 patients' worth of data without necessarily having that data count towards some kind of regulatory data set as it pertains to accelerated approval. And then I just have a follow-up. So I think first and foremost, while I want to acknowledge that the data that we've shown you to date is quite good, the numbers are still relatively small. And so the purpose of the phase I-B is not only to understand the right dose level to take forward into our subsequent trials, but also to really understand or better understand our activity and our safety profile at that dose level that is chosen. So that data becomes important in that way. It will also inform, to a certain extent, some of our decisions around our pivotal trial design. Lastly, what I will acknowledge is you've certainly seen the development programs for multiple agents utilize their phase I data as part of their registrational package. And so there's nothing that leads me to believe that we will not do the same if we come to that agreement with the agency. But I can't tell you that is something that we can plan because it is not our decision alone. Okay. That's helpful. And then just with respect to the BTK degraders safety that we've seen thus far, and again, I know these are kind of still early days, not a whole lot of follow-up, not a whole lot of patients, but I'm not sure if Paula or if Dr. Linton wants to comment based on her experience with the inhibitors, but it certainly looks like we haven't seen any instances of AFib yet with the degraders in the clinic. And just curious if you think that there may be something unique about the mechanism that perhaps circumvents some of the cardiotoxicities that we've seen with the inhibitors today? Thanks. So I can just come in from the clinical perspective in terms of the safety profile compared to the early-generation BTK inhibitors. So I was involved in developing ibrutinib from the beginning. I've developed zanubrutinib, acalabrutinib, pirtobrutinib, you name it. And one of the key considerations with drugs like ibrutinib is the attrition rate, so the number of people that come off study or drug treatment if they're being treated in standard of care because of toxicity, not because of lack of activity. And that is one of the major disadvantages of the early covalent BTK inhibitors. Now, while the second-generation BTK inhibitors are safer, undoubtedly, and we're seeing less hypertension, atrial fibrillation, and other cardiac events, we are still seeing them. And of course, in this elderly patient group where there's a lot of past medical history of cardiac nature, that's a real consideration. So having been involved in the BTK degrader program with NX-5948, again, from the first-in-human study, I've been very impressed anecdotally that this drug appears to be safer. And then looking at the numbers that we presented today, undoubtedly, we are seeing less toxicity across the board. We're not having to support these patients in the same way that we have to do with the other inhibitor drugs. And I might just ask Paula to talk about whether there's something mechanistically that might explain why you're not seeing as much cardiac toxicity. So I think certainly there have been suppositions when we think about ibrutinib in particular about off-target toxicity that may contribute to the development of the cardiac findings. Certainly, we are not; we don't know anything about our drug to suggest that that is the case. Whether there's any relationship to PK, I don't think that's the case either. I think ultimately the drug is a very specific drug, and as a result, we are not seeing anything. I will note, however, that when you start treating older patients. And remember, all of our patients have seen BTKI in the past. I t is likely that at some point we will see something, but that doesn't mean that it's drug-related. Just like people still get colds when they're on clinical trials or still have headaches, something is going to happen eventually. But we are not seeing anything to suggest that there is a clinical signal that this event or an event is attributed to our drug and our mechanism of action. Okay. Thanks for taking the question. Thanks, Steve. Our next question comes from Eric Joseph from JPMorgan. Please go ahead with your question. Hi. Let me also have my congrats on these data. Just in thinking about the upcoming phase I-B expansion, I wonder if there are any changes to the entry criteria that you're contemplating. It's a very treatment-experienced patient set that you've recruited so far and that you're describing today. I guess, do you expect the median number of prior treatments to be consistent into the phase I-B portion? And whether it's related to median prior lines of therapy or not, what are you anticipating as sort of the pace of enrollment of the phase I-B? Any plans toward site expansion or something to facilitate that effort? Thank you. This is Paula. So as it relates to the patients that we are going to be enrolling, we are certainly interested in enrolling earlier line patients and understanding our activity in patients who have not been as heavily pretreated. I'm going to leave it at that in that regard at this point in time. In addition to facilitate the enrollment of these additional patients, you already heard Dr. Linton mention during her presentation that we were going to be enrolling patients at more sites throughout the world. And so we are increasing our number of sites daily, and that will, in fact, enable us to enroll these additional patients. Certainly, the demonstration of the activity and safety profile that we've seen to date or presented today, I think, will also encourage patients and physicians to be interested in enrolling our program. Certainly, we hope to continue to support that by presenting more data in the second half of this year. Okay. Great. Thanks for taking the question. Thank you, Eric. Our next question comes from Sudan Loganathan from Stephens. Please go ahead with your question. Hi everyone, and congratulations on the progress and the strong data for our 5948 program. So my first question is regarding the response you're seeing in the different CLL pretreatment groups. Can you provide more insight into the response rates for the CLL patients previously treated with the covalent versus non-covalent BTK inhibitors? It seems like there were some PRs achieved with the post-covalent BTK treatment, but not much data for the non-covalent treatment patients. So does one subset stand out as a better response to BTK degradation as post-treatment? And then additionally, there are only 26% of patients with prior non-covalent BTK inhibitor treatment in this cohort. Is that due to the result of a lack of use of non-covalent BTK inhibitors or lack of progression post a non-covalent BTK inhibitor, or just the need for more patients in the trial? So I think both Dr. Linton and I will speak to this a bit. I'm just going to start with the robustness of the data set that we've seen to date. There hasn't been any patient profile, meaning related to poor prognostic features or previous treatment that suggests that we will not have patients who respond. So in other words, we have seen patients who have been exposed to all of the BTKIs, whether covalent or non-covalent. We've seen responses in patients who have been double-exposed, triple-exposed, and who have all of the different mutation subtypes. If I can jump in about the non-covalent pirtobrutinib drug, all of the patients on pirtobrutinib that entered the study had been progressing on pirtobrutinib. No one came off pirto because of intolerance of the drug. And of those individuals, four out of six achieved a partial response. We've seen activity in the non-covalent BTK progressed patients. And the reason that it's just 26% of the population is likely down to access. Pirtobrutinib obviously is a more recent drug, not licensed, not available, certainly not universally available across the treatment centers. And I suspect that's why you're only seeing a quarter of patients having had previous pirto. Got it. Thank you. And my second question was going to be if you thought of a combination trial to lower dose and enhance responses, but obviously you've answered that in the preparatory remarks. But I wanted to dive deeper and wanted to ask if prior treatment and failure to any of the potential combo pairs could disqualify patients to get onto the combination trial that you may be opening. And does this help get BTK degraders to that earlier line of therapy for all B-cell malignancies? Or is this kind of just a strategy specific to CLL? So if I understand your question correctly, we have certainly enrolled patients who've already been exposed to and failed, if you will, or been failed by the BTKIs that they've received. And we have already enrolled patients who have been exposed to BCL-2 inhibitors. That would not be a reason not to enroll them in a combination trial where, in fact, we might see even greater responses because of the additivity and one always hopes for synergy, but the additivity of the two drugs. So given what we have seen to date, we do not anticipate that this is going to be an exclusion criteria, but it, of course, depends on which line we're talking about. So if you're looking at a frontline study, then we will not enroll patients who have been treated before. That situation. But otherwise, no. And I think it depends on the combination. So if you've got somebody who's previously progressed on monotherapy with a BCL-2 inhibitor, it may not be rational to enroll them on a combo study with this drug and a BCL-2 inhibitor. So I think it really depends on the combination. Having said that, if it's a CD20 monoclonal antibody, we previously or we certainly know that individuals can progress on those drugs, but we do recycle CD20 in combination strategies. So that, to my mind, wouldn't be a contraindication. Great. Thank you for answering my questions. And again, congratulations on the progress. Thank you. Our final question today comes from Matthew Biegler from Oppenheimer and Co. Please go ahead with your question. Hey, guys. Thanks for squeezing me in. Congrats from us as well. Dr. Linton, maybe if you could just provide us a little bit more detail on the patient that had the Grade 5 adverse event. I mean, this was new, right? Was this a particularly beaten-up patient? Or did pulmonary embolisms happen quite frequently in this kind of demographic? Just any kind of details that you could provide would be great. Thank you. I might ask Paula to answer that question if you don't mind. So this patient had a previous history of AFib requiring anticoagulation. And so that was, in fact, why they were receiving anticoagulation. They were in the process of transitioning their therapy, meaning the type of anticoagulation that they were using, in that setting and in the setting of having a viral infection develop a pulmonary embolus. So this is likely multifactorial in nature, meaning the potential transition of their medicines, a recent influenza, but certainly nothing else in our profile suggests that there is any increased risk for thrombosis in our patients. And so don't anticipate that this will occur in others, but we have to acknowledge that in any patient with a lymphoid malignancy, there is always the risk for a thrombotic event. That is part of the disease state. Got it. Were any changes? Exactly that. I'm sorry. Go ahead. I was going to say exactly I was going to say exactly that. So patients with lymphoid malignancies that's active, who are heavily pretreated, who've got multiple comorbidities, are at very high risk of developing complications such as this. Even without atrial fibrillation, they're at risk of developing venous thrombotic events, which is why we would routinely prophylax these patients coming into the hospital, for example. So I don't think there's anything concerning there in this particular case. Understood. Were there any changes implemented to the protocol in terms of inclusion, exclusion, or anything else to try to maybe mitigate this going forward? No. There were no changes, and there don't need to be any changes. Great. Thanks a lot. Ladies and gentlemen, with that, we'll be ending today's question- and- answer session. I'd like to turn the floor back over to Dr. Sands for any closing remarks. Yes. Thank you. Well, just very briefly, I'd like to thank all of our presenters today and all of our questioners. A great set of questions. Thank you all for participating across multiple time zones. We look forward to providing future exciting clinical updates on NX-5948 and the rest of our pipeline. Thanks and goodbye.