Welcome to the UBS call. Mr. David Dai, you may begin. Well, thank you so much, operator. Well, welcome to the UBS Targeted Protein Degradation Day. I'm David Dai, I'm one of the biotech analysts here at UBS. It's our great pleasure to welcome Nurix Therapeutics today. With us today, we have Arthur Sands, President and CEO. Arthur, welcome. Thanks, David. Great to be here. Great. So Nurix is a quite interesting story. You are definitely one of the leading players in the protein degradation space, and have programs in both, oncology and I&I. To start things off, could you just give us an overview of Nurix, maybe introduce your targeted protein degradation technology to our audience here, and then what are some key differentiations compared to other protein degradation companies out there? Certainly. So, let me start off by introducing our pipeline, and that'll help me describe our technology, and can you see my pipeline slide right now, David? Yes, perfect. Okay, great. So yes, we have a very large oncology portfolio, which is the top of the slide here. And then we have our I&I portfolio at the bottom. Now, all of these compounds that are in development are developed by Nurix, at Nurix, and we have centered our technology around the E3 ligase system, which is the cellular system that triggers the protein degradation. So we began with targeted protein degradation studying BTK, and that's why NX-5948 is at the top of our pipeline, and also a second BTK degrader, which is a dual degrader of BTK and Ikaros and Aiolos, so it has immunomodulatory activity combined. That's NX-2127. And so I'll talk a little bit about that. So those are targeted protein degraders, but we also have our NX-1607 compound, which is an inhibitor of an E3 ligase. So Nurix started out as an E3 ligase-centric company with science from Berkeley and UCSF around E3 ligase biochemistry and structure, and biologic activity. And so we then embarked on harnessing ligases for targeted protein degradation, as shown here with BTK, and then also our-- we have an ability to inhibit them, as with CBL-B inhibitor that we're developing. So this also allowed us to form multiple partnerships, and if we look back to our pipeline slide, we have deals in place with Gilead, Sanofi, and Pfizer. The Gilead and Sanofi deals are focused on targeted protein degradation in oncology, and then also autoimmune disease. And with Pfizer, which was formerly Seagen, who we originally did the deal with, is focused on using our degrader molecules as payloads on ADCs. So a very broad, portfolio now, and very versatile. So these degraders are extremely potent and very versatile. So I'll, I'll pause there. That's my overview of Nurix, and we can dive into any one of these in much greater detail. Yeah, sure. Sounds good, Arthur. Maybe before we dive in, just, you know, help us understand what are some of the key updates we should be expecting over the next 12 months? So most attention's focused on 5948, and we have and future data disclosures. We've guided to having a next data disclosure in the second half, so within six months, with 5948, focused on CLL and NHL, which is where the trials are enrolling at the current time. I believe that we'll have other disclosures. We've guided to around 1607, and we provide periodic updates with our partners on the partnership programs. Those occur in collaboration with the partners. We have less control of the timing of those, but historically, there's been a certain periodicity to partnership updates as well. But really, I think most attention is moving Nurix to pivotal trials in 2025. That's really a major goal for NX-5948. That's certainly. We'd like that to be within the next 12 months. That'll take us into mid-2025. Our goal, and what we stated, is that 2025 is gonna be a big year for starting pivotal trials for Nurix. That's excellent. Let's, you know, so talk about the lead program, NX-5948, your BTK degrader, targeting multiple myeloma and lymphoma. You recently presented some data at EHA this year. Can you just walk us through the summary of the key data points and where you are currently with this program? Sure. So this shows you the trial design. We're actually. We're focused on chronic lymphocytic leukemia, CLL. I think you may have mentioned multiple myeloma, but we're actually focused on CLL with this. And also, NHL, which covers many different lymphoma categories. But the EHA data was all about CLL, primarily. We shared the patient demographics, and then the initial response rates, which are quite high. But just a word about the patients enrolled in the trial, heavily pre-treated, so, four prior lines of therapy on average. You can see some of those therapies broken down under the previous therapy section here. And then also heavily genetically mutated disease burden in these patients. So over half had, well, approximately half had TP53 mutations, a tumor suppressor gene, about another half had BTK resistance mutations. These are mutations that render patients resistant to the current inhibitors. And so, a heavily pre-treated patient population, we presented data demonstrating the drug was very well tolerated. This is the AE table. You can see really quite an excellent safety profile overall. And then I think, most importantly, we're looking here at lymph node reductions. You can see across the board, the vast majority of patients show lymph node shrinkage and reduction, which is, of course, one of the key elements of clinical response we're looking for. The green arrows indicate those patients that have remained on study. This is indicative of how well tolerated the drug is, so we have great compliance. We've had patients with CNS disease, these two hatch marks here, who have also shown excellent responses. We do know our drug crosses the blood-brain barrier, and we've seen effects there, and this translates to approximately a 70% objective response rate in this advanced patient population. So this is some of the data that we shared that I think has been very intriguing and encouraging for our investors and our patients, our investigators. This is a swim lane plot showing the different dose levels we've gone through, from 50 to 600. We're finishing up the dose escalation at 600 currently, David. And again, the green triangles indicate clinical responses here, here, and here. You can see them all over, and the green arrows show the ongoing patients ongoing on the trial. So, I'll pause there, and then, you know, we have more data. Of course, we can discuss about how we overcome resistance mutations. We also presented data on that, as well as some really interesting patient case studies that really demonstrate how well our drug can work. Yeah, that's excellent. I apologize, I misspoke on the indication. It should be CLL, it's not, not a lot of myeloma. My apologies. No problem. On that front, there looks about 70% OR, looks very interesting. Will you just help us understand what would be considered reasonable benchmark for this particular line of CLL patients? Well, I think the most closely compared drug for us is pirtobrutinib. So that in this patient population, which is this post-BCL-2, post-BTK inhibitor, so where patients where two drugs have failed the patient, then that's a category where I think they reported approximately 70% response rate. Now, So we're in a similar we have Fast Track designation in that same patient population, by the way, so again, that's probably the best comparator. Now, within this study, however, we have about 20% of patients that have also failed pirtobrutinib, that where we have seen responses in such patients as well. So we think we're doing a lot more than your typical inhibitor, and our goal is to show that by removing the BTK protein, by degrading it, you can actually get better efficacy, hopefully improve durability, and you can address the resistance mutations as well. Got it. That's really helpful. And so then just on the CNS front, you know, you've seen some quite interesting data, especially from that case study where, you know, one patient had some CNS benefits. Could you maybe just elaborate on the CNS penetration activities for your drug? Yeah. So here is the patient, you're referring to, the patient journey I'm showing on the screen now, and let me just walk you through this. So first off, yeah, see a CNS involvement, you see the malignant cells in the CSF. So this patient, really presented with central nervous system findings. Very, very sick. You can see the number of prior treatments in the upper right-hand corner here, substantial prior treatments, very challenging mutational profile. And actually developed a CNS involvement while on acalabrutinib. So, on our trial, what you're looking at here to the right, is the absolute lymphocyte count, or ALC, which when a response is happening, the first thing you tend to see is lymphocytosis or elevated, absolute lymphocyte counts, which we're seeing here, and then these counts start to come down. With the decrease in counts, you begin to see the lymph node reduction, which I showed you the waterfall plots before. Reduction in spleen size, a normalization of some of the cytopenias, platelet counts going back to normal, hemoglobin resolving anemia, and then by week 24, you see this malignant cells in CSF being unknown. So there were no cells found in the CSF. This patient has done very well out over six months, and we know, and we've confirmed, because of multiple patients with CNS involvement now, that our drug levels are in the CSF, are comparable to the free drug levels in the plasma. So we're we know drug is there, we're getting biologic effect, and we're seeing clinical response. So it all adds up as a very, very encouraging profile. Got it. Could this be considered one of the key differentiator of this drug versus other BTK inhibitors? I certainly think it could be. The concept is, you know, what percentage of patients have CNS involvement? Well, depending on how you look, it's either 5% or less. But I think it's a broader distinguishing feature than just that subpopulation, because as we saw with this patient, it's an if you have a drug that can keep your CNS compartment protected, so as not to get to CNS involvement, we think that's a very desirable feature. And we think that we do cover and can protect the brain from that kind of involvement of disease, and we intend to continue to pursue that and allow and have enrollment of patients with CNS disease. They're typically such patients are typically excluded from these early phase trials, but we've included them, and we're seeing some good results. Got it. That's really helpful. Then just on the next phase, which is gonna be your development plan for monotherapy and combo pivotal trials, any thoughts on your trial design, and what's the regulatory path so far? So we have just some basic strategic thoughts, which I'm showing here now, which is, let's capitalize on the fact we have Fast Track designation. That's in that same population that pirtobrutinib received accelerated approval recently on. And so that definitely will be something that we would like to pursue as a single-arm trial. One then also simultaneously begins the randomized control trials or the confirmatory trials. These can sometimes be earlier lines of therapy. We find that to be attractive. That's a much larger market opportunity, that second line, and then potentially first line. And then the third category would be the fixed-duration combination trials, and what we're looking at there is venetoclax, obinutuzumab, and potentially rituximab. There's a few agents that are commonly used in the earlier lines of therapy, which can allow for a fixed duration of therapy. So this is sort of the big picture of how we're moving towards pivotal trials, and again, our target is next year. Got it. That, that's really interesting. So on the, moving on to the lymphoma opportunity, so we should be seeing some additional data in NHL patients in the second half this year. Could you perhaps just set some expectations for data readout? What would be a sort of, sort of, like, considered a clinically meaningful benchmark we should be expecting here? Certainly. So yes, we have guided to provide an update. What I'll say is, in terms of clinically meaningful benchmarks, that, and what we said already, is we have seen responses in every category. These are very different disease categories from the more aggressive, DLBCL, and transformed folliculars, to the more indolent, the Waldenström's WM or marginal zone, lymphoma, and then mantle cell, which is kind of has both categories of disease. So I don't think there's any easy, across-the-board benchmarks I can give you right now for responses, 'cause each disease is unique. But we will be sharing where we believe, the single agent can, have the most benefit, 5948, and then, some of the more aggressives are definitely combination therapy, targets. There's no question. That would be more of a combination development plan. Got it. Helpful. And so then, talk a little more about the autoimmune disease for NX-5948. I know you're actually planning to go to the autoimmune for this BTK as well. So any initial thoughts around, you know, indication you're gonna be pursuing for NX-5948 in the autoimmune disease? Well, we have thoughts that we could go in many different directions. What we've guided to is to enable an autoimmune IND. We have not specified yet which areas we would go into. It is an active area of discussion. We have shared preclinical data, which we find to be encouraging. Here, a rheumatoid arthritis model, you can see 5948 in dark blue, being extremely potent at 30 mg per kg, similar to ibrutinib in this model. This is in light blue. It's at 10 mg per kg. Now, this does not mean we're going into RA. It is a general. This is a general model that's commonly used, but with this kind of activity, it definitely confirms that we have an opportunity in autoimmune disease. And then, we confirmed brain activity. In dark blue, you can see NX-5948 compared to FTY720 or Gilenya, which is Novartis's MS drug. This shows us that in preclinical models, we definitely have CNS activity. We now have confirmed that, as I've already discussed, with CNS activity in oncology. But definitely we have a very broad range of indications we, we could go, go into. So that's something that, you know, we look forward to sharing with everyone, when we've made those determinations of, of where the best initial indications are for NX-5948. Got it. And so right now, you are in IND-enabling stage right now, which is it fair to say that you probably can potentially move into clinic sometime in 2025 for this program, for autoimmune? Yeah, I think, I mean, I think that's a fair statement. 2025 is a timing that could be quite reasonable. Got it. That's really helpful. And so let's move on to the second program, which is your 2127, the BTK/IKZF dual degrader program. Maybe just, you know, to start things off, just walk us through some of the potential synergy of targeting both BTK and IKZF, and how do you think that would lead to potentially deeper and durable response in lymphoma? Well, first off, yes, this immunomodulatory activity, mediated by cereblon and the degradation of Ikaros and Aiolos, as pictured here, is a well-established therapeutic regimen in lymphomas via Revlimid and other very successful drugs. That is one of the major growth pathways for white blood cells. BTK is another one, and so the concept of combining them into one molecule, NX-2127, was very attractive to us and as we were in our design phase. In fact, the two independent mechanisms have been combined in DLBCL, and there have been some dramatic results by combining Revlimid with ibrutinib and Rituxan. So as we embarked on this trial, we were very interested in enrolling the aggressive lymphomas. This is the trial design, MCL and DLBCL in particular, although we also had CLL, large CLL cohort. What was apparent very early on, actually, was in DLBCL, this case study that really just a picture is worth a thousand words here. This is a patient, 84-year-old woman with heavy disease burden pictured on the scan. By 16 weeks, had a complete response. In fact, the complete response occurred by 8 weeks of therapy, but this is the 16-week scan. And when you look at the 4 prior lines of aggressive therapy, this is where we see this combination of rituximab, ibrutinib, and lenalidomide being one of the prior lines. But to get this kind of response this quickly really was quite encouraging, and so we're very eager to bring NX-2127 forward into DLBCL. This is an early MCL patient. Again, you can see the lymph node involvements on the left, and then complete resolution, another patient that had over 17 cycles of treatment. So this is the trajectory for 2 27. Pretty simple, straightforward. We're in the midst of initiating our 3+3 design. Again, this is a drug that we now have the commercial production form of the drug, and we're eager to take it forward into the clinic. Excellent. So maybe just set some benchmark again, Arthur, if you don't mind. So I know you're going after DLBCL, especially relapsed refractory setting with multiple prior lines. And so in this population, I would imagine these are very, you know, sick patients. So how should we think about the benchmark in this setting? You know, what's really the bar we should be looking at here? Well, in the kind of patients we're enrolling, there's no approved therapy, so there's really not a bar, unfortunately. And that's, of course, where we started out in CLL with 5948 also. So we're gonna have to define what that bar is, David, and it's something that, you know, is really gonna just be empirically determined, and, you know. But if we're bringing benefit to a significant fraction of patients, I mean, I think, where there is no other approved therapy, that's a pretty attractive bar right there. Got it. That's helpful. And then just to stay on the topic around your commercial product, you know, so recently, you resolved the partial clinical hold of 2127. Can you just talk to me more about, for investors who are new to the story, more or less, what was the kind of the reason behind the partial clinical hold, and then, you know, what was being resolved so far? Yeah. So it was a relatively straightforward chiral center that we were able to fix to create one chiral form versus two of the molecule, and that had to do with the manufacturing process, the chemical process by which we make the molecule. So there was never there was not a safety issue or anything like that. It's a CMC issue, which is resolved, and we've already shipped drug, and we've cleared the partial hold, as you mentioned, and so we're in good shape to restart that trial. Excellent. All right, so now we have about three or four minutes left here. I want to quickly introduce the next program for IO, which is your 1607 program. Maybe just give a quick review, quick overview of the CBL-B program, and then we should be expecting some data update later this year, as you said, Arthur. So maybe set some expectation around what we should be looking for in the update? So this is. I'm showing a mechanistic slide here. CBL-B is an E3 ligase that normally degrades signaling proteins downstream of the T cell receptor, but also operates in dendritic cells and in the tumor microenvironment and NK cells. So our goal for this program is to identify a recommended expansion dose. We have two trial arms going on right now, the monotherapy and the combination with paclitaxel, where it's a basket trial. We're enrolling a range of solid tumors, and our goal, as you said, is to have a clinical update by the end of this year, and to really discuss what the expansion strategy will be, in which indication, and at what dose. So that's really the quick summary for NX-1607, which is captured right here. On this slide, I'm showing you the overall, our overall guidance in terms of, news events for the year that we can expect. Got it. And lastly, just on the collaboration with Gilead and Sanofi for the two I&I programs, your IRAK4 and STAT6 programs, which are, you know, getting a lot of attention nowadays. So maybe just quickly walk us through the programs, where you are currently with these two programs, and what are the milestones we should be expecting over the next, say, 12-24 months? Yeah. So with Gilead, they've exercised their option. They're in IND-enabling studies with the IRAK4 degrader, and so, updates would be coming from Gilead in the next 12 months as to IND filing and then subsequent initiation of the trial. So that'll be important, I think, to keep an eye on. With Sanofi, we recently announced the STAT6 program. These are both these programs we've been working on for about 3-4 years with these companies, so these have been kind of under the radar programs in I&I. But this is a program that's designed to be competitive or superior to Dupixent. The STAT6 target is a transcription factor that controls the Dupixent pathway, if you will, and both are designed to be oral, once-a-day oral molecules. The next step for Sanofi would be, the licensing of this and taking it into IND-enabling studies. And, you know, we've said that when we announced this program, that we're within 12 months of such development candidate identification. So those are the major... And you're right, there's been a lot of attention here. These are very exciting programs, and, and the degradation mechanism has some real advantages. Excellent. Just one last question on the financials. Maybe just help us understand your cash position, your cash runway. Sure. So we have-- we're in a very strong cash position. You can see here, approximately $450 million in cash and investments as of May 31. This is not been augmented recently, you know, with the recent raise we did. But also, you can see our partnerships on the right here, and graphically depicted, have been responsible for augmenting our cash position quite substantially with non-dilutive capital and also building out our pipeline. I should mention, with the Sanofi program, the Gilead program, and Seagen programs, we do maintain opt-in rights for these at for cost profit share in the United States, post human proof of concept. So very exciting partnership programs that also expand our own portfolio. Excellent. With that, we're at the top of the hour. I wanna thank you, Arthur, for taking this time to walk us through the Nurix story. Thank you so much, Arthur. Thank you, David.