All right. Hi, everyone. We'll get started here with our last fireside of the day. My name is Derek Archila. I'm one of the biotech analysts here at Wells. With us, we have Nurix Therapeutics. We have Arthur Sands, President and CEO from the company. Arthur, good to see you. Good to see you, Derek. Thanks for having us again. Of course. Well, maybe to get started, you know, if you wanna just kind of give us, you know, kind of high-level business and state of the business and what you guys are working on, and then we can kind of delve into the more detailed questions. Well, business is excellent. We are moving forward to plan our first pivotal trial in CLL in 2025, so planning is underway for that. That's on the basis of some really excellent data that we presented at EHA, the European Hematology Association meeting, in June in Madrid, on our lead asset, which is NX-5948. That is a pure degrader of BTK, which is, of course, a highly validated target, BTK, but NX-5948 is a new way to target BTK in CLL and other B-cell malignancies. So at that conference, we presented, and I know we'll talk more about all the results- Yeah. But I'll just dive in. Yeah. 70% overall objective response rate in a very advanced patient population, fourth line-plus patients, and we're able to address a number of the issues facing this critical patient population, which include resistance to current BTK inhibitors, so anyway, that's sort of really the keystone event for us midyear, and we're looking forward to updates on NX-5948, and of course, I'm sure you'll ask me about the rest of our pipeline- Yeah. - which I'll hold until we get into it. Yeah. So yeah, maybe let's, you know, go through that, you know, five nine four eight data. So, you know, talking about, you know, the 70%, like, why... Well, first off, like, you know, is there even any comparable data, you know, in that advanced setting, to even comp that data to? Often people will try to compare us to pirtobrutinib at its stage of development in third line plus. Now, the difference is, actually, we're now in fourth line. Yeah. And we're getting these patients that are actually farther advanced, and pirtobrutinib reported around a 70% similar response rate. What's also different, though, is that 23% of our patients coming into our trial are already pirtobrutinib resistant. Right. So we're getting really another wave of resistance, and yet we're still holding up at that 70% objective response rate. And the resistance stems from a number of treatment-emergent resistance mutations to the BTK inhibitors, including Pirtobrutinib, which is kind of introducing a new class of mutations. But the beauty of NX-5948 is that we can address any of those, and we can degrade them with targeted protein degradation, remove those proteins, and actually restore this therapeutic effect to the BTK mechanism. So I think that it is kind of an unprecedented population that we're dealing with, of very advanced patients, and yet we're seeing an excellent response rate. Got it. So again, you, you kind of introduced, you know, you're planning the, the phase III in CLL. I guess, you know, this is gonna be probably late line, you know, potentially, hopefully for, like, an accelerated type of approval. But, like, what, what kind of framework are you using in terms of, like, your thoughts on what that trial could look like, you know, prior to getting it blessed by the FDA? Right. Well, we have Fast Track status- Yeah from the FDA in third line plus CLL, which means patients that have failed a BTK inhibitor, as we've been discussing, but also BCL-2 inhibitor, so that is our Fast Track designation. The design of that trial is, you know, underway. In terms of our approach, certainly an Accelerated Approval strategy could be part of that package. That depends. That's a regulatory question. If it is, then it would be accompanied by a randomized controlled trial, which is the confirmatory trial, that's required to run basically simultaneous with, let's say, a single-arm trial. So that's one design, but we're looking at others. That's the third line plus. We're also looking at second line plus, how to move up already out of third line into second line situation, and so that would be a different trial design. We're basically outlining several scenarios 'cause we think five nine four eight can really offer benefit earlier in lines of therapy as well. So we're not just looking at that first approval, but looking beyond, you know, what is the best market potential for the drug? Why or why not would, you know, like, pirtobrutinib's kind of development, you know, program, why is that, like, a good analog for the kind of third-line plus trial that you might go, you might run? Yeah, I think it's a good analog. I mean, there's a path there that's been proven and successful. The thing is that things change on the development landscape, and so trial designs have to adjust to what, you know, what's coming down the road, not just- Yeah ... you know, what was done, a year or two years ago. But it is informative, and again, we do have Fast Track status, so it's a regulatory question that we hope to answer as we, you know, as we plan to answer, as we prepare for the pivotal in twenty twenty-five. Got it, and I know you're gonna provide some additional data later this year, you know, for the CLL program, but also, I think, non-Hodgkin's, I think, as well. But I just wanted to know for on the CLL, I guess, like, how you know, how much more data are we gonna get in terms of the follow-up? And I guess one of the questions would be, you know, it's very hard to get complete responses with BTK inhibitors, you know, in CLL. So is there an opportunity to see even deepening of responses, you know, with the current patients that are on therapy? ... Definitely, there's an opportunity for deepening of responses, but also, greater patient numbers. Our enrollment's been going at a swift rate, so we'll have more numbers. I think people will be very interested to see our response rate or objective response rate be solid around the 70% number. That'll be important. Longer duration of therapy, so it'll have been about six months since the last report. So we'll see how. We had a lot of patients that were early in their therapy at the June disclosure. So- We'll have a lot of patients progressing over time here in therapy. The longer on therapy, the better chance for getting a deepening of response, and especially in CLL. With regard to CRs, you know, those are rare, and you do need longer duration of therapy for CRs in general. They, you know, are in the 0%-5% range. Also, to truly have a CR confirmed, you need bone marrow confirmation. We have not included that in the phase I-A/I-B as a requirement, so that'll be something we'll be monitoring going forward. But on all the peripheral counts, blood counts, and hemoglobin, hematocrit, and all the key counts that one tracks, lymph node size, we're seeing patients enter this complete response category based on peripheral measures. But again, we need the bone marrow measures for confirmation of that. But, you know, that is what really defines the disease is really the partial response rate, actually, and making the disease, which is a chronic disease, a livable disease and one that can be managed and run and have a normal life, basically. So it's not one of these diseases where you look at CR as the be all, end all. It's really a constellation of things. Having said that, you know, it would be nice to see CRs as a single agent. Sure. I guess, as you think about going earlier, too, so obviously, you know, we've really established, you know, good efficacy, good safety, and I want to talk about the safety bit in a second, but, you know, I guess in terms of the strategy to go earlier in line, I mean, is that something, you know, you would have to partner? Like, if... Are these trials going to get very large as you get to maybe first line, and is that where you want to go? Or do you think there's enough opportunity in maybe second, you know, or third line as well? If you're looking at some of the numbers, third line itself has grown. Now we're talking about there are reports that are at seven thousand or so, seven thousand five hundred patients in third line alone on an annual basis, so that's not a small number. Second line is eleven thousand plus patients, and then first line is, you know, seventeen thousand or more. So you do gain as you go up in lines, but second line and beyond is substantial population alone, and that is a manageable trial for us to do. Okay. as part of our confirmatory, randomized confirmatory trial. So I think that's very manageable, and it's probably a very substantial population. As first line BTK inhibitors like Imbruvica go generic over time, you know, likely that will be a could be a generic first line opportunity. Right. But really, in the first line, I think it's going to be more about combinations. And we're also very interested in combining a degrader with a BCL-2 inhibitor, because in first line, there you can drive a CR rate, a meaningful CR rate for patients, and also get to time, a limited duration therapy. So that's also very desirable for patients, a certain patient population. That's probably the better way to tackle first line. Okay. than really necessarily as a monotherapy, although that is another option. Got it. And how are you thinking about, you know, doing a combo study or, or doing some, you know, or looking at a combo in patients? And I guess, have you looked at the combination preclinically just to establish any sort of safety and efficacy or activity? You know, the preclinical models and combination are not really that informative. Okay. So really, we're poised to start exploring combinations. Venetoclax would be the most obvious, and I think is the one that there's the most data on with inhibitors. I think seeing how our degrader performs with a Venetoclax could be very interesting. That's probably the first place to start. And then there's other combinations, including anti-CD20 antibodies, would be other potential combinations in the first line. Got it. And then maybe just talk about the safety profile of NX-5948, and just how, you know, that's evolved. And also, you know, going back to the combinations, you know, how does it lend to, you know, future combinations because, given, you know, overlapping toxicities and things like that? So the first thing to look at is we have a very low AFib rate. I think we have one case in our trial, entire trial, which for CLL actually was a preexisting condition. Also low hypertension rates very low in an elderly population. So that's been an issue for BTK inhibitors in the past. So we feel very comfortable with our cardiovascular profile. That's sort of first and foremost. Mm-hmm. In this patient population, so that's very important. And then if you get into the other common adverse events, you see the cytopenias, which are largely disease related rather than drug related. In our case, we're seeing cytopenias actually improve on therapy, normalization of hemoglobin, and also the thrombocytopenia. We have patients coming in with grade four cytopenias who improve, so I think that's very favorable. In terms of combination, you know, the issue would be tumor lysis syndrome. We pretreat for that because we also Venetoclax does evoke a very rapid antitumor response, which can create toxicities that's manageable. That's, people, investigators are well aware of that. We manage for that on our drug. We've actually had one case because of a very rapid response, which was managed medically. That's actually, in a way, if you will, a favorable adverse event, if you will, because it does relate to response. So those are the things that one really monitors, and so far so good with NX-5948. It is early, but in total, we've been in now, I think, we reported on over 85 patients from our safety database standpoint, 31 in CLL, and the remainder in NHL, so overall, a really excellent, well-tolerated profile so far. Got it. And so I know we talked a lot about CLL, but maybe, you know, can you just talk to us about the opportunity in non-Hodgkin's? And I guess, you know, I think we're gonna get some updated data. What should we expect? So we have recently expanded our phase I-B into Waldenstrom's disease, into marginal zone lymphoma, and also into follicular lymphoma. So in the indolent lymphoma category, we've expanded as well as, of course, CLL, which we've announced that we've expanded the 200 milligram daily dose and the 600 milligram daily dose. So we think that the indolent lymphomas are real opportunities for BTK degrader. The inhibitors have approvals there, but as in CLL, there's significant unmet medical need, and there's growing resistance of different forms in those diseases. So we think that that's gonna be an expansion opportunity. Got it. Okay. And then obviously, you talked about, you know, CNS penetrance and, you know, also looking at these like, you know, CNS lymphomas. So you have activity in the brain. So I guess, is that something, that obviously is unique to the degrader, but also something that you could apply potentially in, you know, indications outside of oncology? So maybe you can elaborate on that. Yeah, so it may be unique to our molecule. Yeah. Not every degrader gets into the brain. We did, in our optimization of five nine four eight, conduct experiments in CNS disease in animal models, and we looked for molecules that could address specifically CNS lymphoma models, which are very aggressive. Even animal models are very aggressive. So we knew that we had a molecule preclinically that could address disease in the brain. We also saw degradation of BTK in the microglia of intact brains in animal models, microglia being a key mediator of immune activity in the brain, of course. So that was our preclinical information going in. So when we designed the phase I trial, we included patients that had a CNS disease, both in CLL and also primary CNS lymphoma and secondary CNS lymphoma, which is not typically done in phase I-A trials. In fact, usually, these patients who are very ill are excluded, so we included them, and we have seen very encouraging responses there, both in CLL and primary CNS lymphoma, confirming that we do have biologically meaningful, CNS activity. That has also have been accompanied by drug levels in the cerebrospinal fluid that, of course, we can measure in patients, in that disease setting, and those blood levels are basically equivalent to our plasma-free drug levels. So, you know, if you say, your drug gets in the brain, question is: How much does it get in the brain? Is it meaningful, and do you have biologic activity? And we have clinical activity, biologic activity. So it certainly opens up CNS disease for potentially in other areas, too. Interesting. Okay. Gotcha. So yeah, maybe, you know, shifting gears for a sec, in terms of the opportunity, maybe beyond oncology for BTK. Obviously, there's, you know, BTKs that have been studied in a variety of autoimmune diseases, chronic spontaneous urticaria, there's MS, and things like that. So, you know, what do you think the profile lends to, and where... are there opportunities potentially to go with five nine four eight, in autoimmune? It's a ry timely question. Yeah. We've actually, this conference had lots of questions about MS. Because of the tolebrutinib. Yeah, because of the recent Tolebrutinib data from Sanofi, and then also Roche has recently reported. And so that is very encouraging. It seems like those data are proof of concept- Mm-hmm. For the BTK mechanism in MS, but also leaves room for improvement. And we think a degrader could have greater efficacy because we're not only addressing the kinase function of the BTK protein, but also the scaffolding function, which is another whole arm of signaling that is operating in autoimmune disease, just like it's operating in oncology. So that was very encouraging data. I think that those studies are something we're gonna be studying closely. It is an opportunity, you know, potentially for us. We've talked about, you know, declaring our path in I&I in 2025, when we are, you know, fully enabled from an IND standpoint for autoimmune disease. So we've been working on IND-enabling non-clinical studies for autoimmune disease, which are longer non-clinical studies. Mm-hmm. That are required. Those are ongoing. I think we'll have more of an update in 2025, but certainly MS is on our radar. The skin diseases are clearly another area. We think we may have certain advantages in severe skin diseases, so we're also looking at those very closely. Interesting. I guess obviously, to establish proof of concept, probably MS isn't the best place to do it. Potentially, it may be a little bit more challenging, but, I mean, how do you think about, you know, getting rapid proof of concept, with the BTK degrader? You know, again, which indications lend best to that? So those are the two strategies. You know, go for something that you can get a one-month readout and a three-month readout, and we have tox coverage for one month and three months already. So that is one strategy that we're looking at. I think that some of the pemphigus diseases can give you rapid readout. CSU can give a rapid readout. You know, but you have to look at each of those and what the precedents are very carefully. Yeah ... and what the endpoints are, and all of those take capital, right, to run. So the counterargument to that strategy is just, look, you've got brain activity. You're uniquely positioned for NX-5948 in the CNS. You know it works. Yeah. And just go for the larger opportunity and focus your resources, which I think is also a rational strategy. Anyway, this is an active area of discussion, debate. It's in the category of great problem to have. Sure. You know, if you look at the big companies that are developing their own, they do all this. They do several indications at once. Sure. And that's not something that, you know, we are gonna do. We have to focus. Gotcha. Gotcha. I mean, is there anything between, you know, like, kind of in the tox studies that you're doing or, you know, for the IND, like anything that you could get hung up on? I mean, you already have characterized the safety of this molecule pretty well. So I'm just curious, is it really just kind of more routine and there's really no risk kind of ahead of the IND filing and getting into the clinic? I mean, keep in mind, we've been in patients for over eighteen months. Right ... already in oncology setting and in a very challenging patient population with lots of issues. So I think we've got a good feeling about how this drug will perform in humans. So I don't think the non-clinical will provide any hang-ups. I do think that, you know, we are a new mechanism of action- Mm-hmm ... degradation, so there's less experience with that overall. We have not seen any mechanism-specific safety concern. Yeah. We have seen BTK-related safety issues- Okay ... which are associated with all BTK inhibitors, but that means we're hitting the target. So I don't see anything but, you know, we are focused on severe autoimmune indications, I would say ... where the risk-benefit ratio could absorb- Yeah ... any potential safety issues. Understood. You know, there's a couple other BTK degraders out there. I guess, how are you... You know, do we have enough data out there to understand, you know, how these molecules might be different from each other? And I guess, I don't know if there's any comparative data that you can share on efficacy or safety that, you know, kind of drives that conclusion. So the two are... You're referring to, one is from BeiGene- ... which is at a similar stage of development, as we are. And their data so far has been very comparable- ...... I'd say, to ours, from an efficacy standpoint. So that's really great, actually, validation. Mm-hmm. And that's actually been very helpful for us as a relatively small, you know, new player here, to have BeiGene talking about their degrader in a very positive way, which they are, and they should. AbbVie has also entered with a degrader. We have less data, like essentially no data so far from the AbbVie molecule. So I think overall, it's terrific that these larger companies with well-established inhibitors are seeing the value of a degrader to enter the space. With regard to differentiation, we're gonna have to wait and see- ... because there just aren't enough patients yet. And usually these molecules will differentiate in some way- Yeah ... over time, but you need to start to look at hundreds of patients. Gotcha. All right, maybe shifting gears to NX-1607 for a bit, just on the Cbl-b. Kind of just give us a status update with that program and, you know, what we expect, you know, for the rest of the year in terms of any date updates. So Cbl-b is an E3 ligase that really is a target itself. So everything we've been talking about so far has harnessed an E3 ligase to degrade a particular target such as BTK. In the case of Cbl-b, if you inhibit that ligase, you elevate protein levels in T cells and dendritic cells. You elevate signaling in those cells, as well as other cells in the immune response. So it's an IO target. It stimulates the immune system. We've been in the clinic in dose escalation for some time. As an IO target, first-in-class agent, it's been very steady and methodical dose exploration. These kinds of targets have a narrow, more therapeutic window, and that's what we've been you know exploring. And we do believe we've reached drug levels and shown and published that accomplish-... biomarker activation for the Cbl-b pathway. It is a very exciting pathway pre-clinically. It's been known for over a decade, validated genetically, but no one's been able to drug it yet. So we are a first-in-class agent. First-in-class agents, first in mechanism, do tend to go slower, and that has been the course with NX-1607. So by the end of the year, we hope to have an update as to our recommended phase two dose. Are we achieving dose levels that hit the biomarkers we want to hit? We think we're in that zone already, but we'll have to see with greater patient numbers. And then where do we go from here? What would be the- Mm-hmm. expansion indication? So that will be an end of the year update on Cbl-b. Got it. And what biomarkers are most relevant, you know, what should we be looking for? So there's a proximal biomarker that we have developed and identified, very proximal to Cbl-b inhibition, and that's phospho-HS1. It's not a well-known biomarker to other mechanisms, but actually if you do look at it in immune-stimulating situations, it is elevated. So we're looking for elevation of protein levels of phospho-HS1, and we have published on this. But then aside from that, there are cytokines where you want to see actually appropriate level of cytokine elevation. Yeah. And that's important. The word appropriate is important. You don't want them to be too high, because then you're going way on the other end. Right. And so that's the therapeutic window issue with any IO agent. Now, what we have with Cbl-b is a strong IO target, where we have seen single agent activity consistently in animal models. We are looking for some signs of single agent activity in patients. And again, the genetics testify to this being a very potent target. Got it. Understood, and then maybe, you know, with the remaining time, just talk about your kind of discovery platform and leveraging that for collaborations, which you've, you've named a few more recently, but maybe just give us some status updates on those and, and the appetite for more. Yeah. So we have very exciting drug discovery collaborations, each progressing in their own timeframe. STAT6 degrader with Sanofi, I think, has gotten probably the lion's share of attention recently. Clearly a very interesting target directly on the Dupixent- Mm-hmm pathway. The design goal for the STAT6 degrader was to create a small molecule, once a day oral, equivalent of Dupixent or better than. I mean, that was the design goal. I worked very closely with Sanofi on this project. It's gone very, very well. We did announce that, identified the target about three or four months ago. Actually, we've been working on this target for over three years, but we've just disclosed it. So this is not a new program. This has actually been a very mature program now. The goal being to get to a development candidate in twenty twenty-five, in the first half. If that candidate is then optioned by Sanofi, and by the way, they funded the whole discovery program as well. So Yeah ... there's an additional option payment, and then they would be responsible for IND-enabling studies and proof-of-concept studies. Nurix would retain a re-opt-in or an opt-in right post-human proof of concept, for fifty-fifty in the United States. So we have, we see it as a potential future part of our pipeline from a proprietary products standpoint. So that's the STAT6 program. IRAK4 degrader is a program with Gilead. They have already optioned that program. That was, again, part of the original discovery alliance with them, which is about four years old. And we only recently disclosed IRAK4 upon the option payment. So they have taken over IND-enabling studies. The target there is for an IND in the first half of twenty twenty-five. So again, first half of twenty twenty-five, very busy time zone for us in terms of our I&I portfolio, including five nine four eight plans, as we already mentioned. And then lastly is our DAC program, which stands for Degrader Antibody Conjugate program, where we're designing payloads to attach to antibodies. So a next generation ADC concept, where the degrader, hyper potent degraders, are the payload. And so less toxic, improved therapeutic window. Been working on this, originally with Seagen, and then with Pfizer now. And then, of course, Pfizer was part of that whole evolution of the deal. So Pfizer's very enthusiastic about this program, as are we. And so we're really interested in seeing that progress. Again, highly targeted sort of antibodies with highly targeted degrader payloads. Incidentally, there is a DAC conference here in Boston next week. It's an ADC conference, but DAC will be part of it. They're an emerging part of the story, and it's a really exciting new area. It's great to have these three partnerships. It's really provided funding. I think we have had over $400 million in funding just through the early phases of discovery, which is really kind of remarkable for drug discovery deals, and preserve these opt-in rights in each of those deals. That's really a great part of our pipeline, too. In just internal pipeline, too, and your discovery efforts, so like, I guess, you know, I think I've talked to you in the past, and you kind of telling us the split of like, you know, a lot of your, you know, discovery dollars are going, you know, X% of I&I targets versus oncology. So like, I guess, how does that continue to evolve? And, you know, you're obviously very strong, you know, and nice franchises, five, nine, forty. But should we expect more oncology or more, you know, I&I, I guess, in the future as you guys develop, you know, announce new candidates out of the internal pipeline? It's about 50/50- Okay. -between oncology and IO. And, so I think that we'll talk-- going forward, we'll talk about both. We internally time those, you know, carefully. We'd like to be at a development candidate or, you know, beyond, before we start talking about a program. The, an exception there has been our childhood cancer program in collaboration with Children's Hospital of Philadelphia and also now the U.K. team for that program. That was a special grant, and we participated in that. This is addressing fusion proteins in childhood cancers, where degraders could be uniquely situated to take out those fusion proteins. That's actually an area that, you know, it's been kind of a sleeper area. Some of those fusion proteins are active in adult cancers, and so that's an area too that maybe we'll be able to shed greater light on as we go forward. And it's something that, again, we have not talked about a lot to date. Gotcha. And then maybe last question. So, and I've been asking this of many of the degrader companies today, is just, you know, a couple of years ago, there was a lot of focus on the platforms and technologies and, you know, trying to draw some differences between, or differentiation between these degrader platforms. So I guess, where are we today? Now, I mean, I feel like I'm not gonna answer for you 'cause I wanna hear what you have to say, 'cause the other guys have basically said the same thing. But, like, where do you... Do we think we're, you know, the, the platforms are differentiated or, you know, and if they are, like, where, where do you think yours is? The core of targeted protein degradation is the E3 ligase system. Yeah. We were originally founded as an E3 ligase-centric company, and I believe we built up the science and targeting of E3 ligase is probably better than anyone. Yeah. We have more ligases for which we found ligands, which you can then harness, I think, than anyone. It's hard to compare directly because everyone has different approaches to the ligase portfolio, but we have over ninety ligases that we've been working on. Of course, there are six hundred ligases in the human genome, so the opportunity is very large. So I think we're unique there. Our implementation of DNA-encoded libraries, combined with machine learning, AI, has been unique, and I think we'll probably talk more about that and more about our platform in twenty twenty-five. We have a lot of requests to do a research day. We haven't done one for a while- Yeah ... to really elaborate the platform in the early-stage pipeline. But I think between DEL and artificial intelligence to find new ligands to ligases. Yeah I'd say that's what differentiates the Nurix platform. We've used those in our drug discovery deals. I mean, that's where the STAT6 degrader came from. It started as a DEL screen. Got it. Okay. Yeah, you had a better answer than others. Oh, good. Everyone was shifting to, "Oh, it's all about target selection." It's like, "Yeah, well, we know that." But, but yeah, maybe we'll leave it there, Arthur. That was great. Okay. Thank you so much. Thanks, Derek. Thank you. You'll see you.