All right. I'm Stephen Willey, one of the Senior Biotech Analysts here at Stifel, and glad to have with us to wrap up day one. Okay. We brought you in for the finale. Oh, thank you. CEO of Nurix Therapeutics, Arthur Sands. I know we've done this a bunch of times before, but just any comments you want to make before we jump into Q&A? Sure. First off, Steve, thanks for having us, and thanks to the entire Stifel team. Thanks for the slot before the happy hour. We're... I think we brought you a pool table. Okay. Yeah. Well, let's go ahead and get this out of the way, and then we can go on. But so no, we're very excited here now at the end of 2024. This is a very important time. We have ASH coming up. I'm sure we'll talk quite a bit about that. We have two oral presentations and a poster presentation, most of the focus on NX-5948, our BTK degrader in CLL and B-cell malignancies. So that is in phase I-B, getting ready for our first pivotal trial in 2025. So a lot of work and planning around getting ready for pivotals. That's sort of the focal point. But Nurix, for those of you who may not know us, we're based in the Bay Area, based on science out of UCSF and Berkeley, all around creating small molecule drugs that can harness E3 ligases, which are an important class of targets in the cell that control protein levels. And so we have focused on targeted protein degradation. That is, small molecules that are, these are oral agents that can harness E3 ligases and then direct their ligation of ubiquitin and proteasomal degradation of any target. So basically, any protein can be directed to the proteasome for destruction in a highly specific manner. And the BTK program, NX-5948, I was first referring to, is the lead hematopoietic target in that new class of drug. So very exciting technology and platform underneath our growing pipeline. All right. Maybe we can jump right into the upcoming ASH update. So I know the abstract was published a few weeks ago. Not a ton of meaningfully incremental information there, but can you maybe just set the stage for what we should expect in terms of additional responses of evaluable patients at ASH, what the incremental duration of follow-up relative to the June EHA presentation might be? And then what would you point to investors as something that they should be specifically focused on in that presentation? Yeah. So I think the ASH presentation itself, oral, will be an important update with significant more data than EHA in June. As you point out, the abstract itself, you know, you file those pretty early after EHA, so it's incremental data. Directionally, quite positive, though, if you noticed, roughly mid-70s, 76% response rate, overall objective response rate. So I think that we'll have basically around double the number of patients we had at EHA. So that's a meaningful number, taking us from 26 to roughly 50 evaluable patients. And so those are, those kind of numbers enable you to really solidify your response rate. So number one, what investors are paying attention to is, does this 70+% response rate in this fourth-line population of CLL, does that hold up? Is that solidified? Is that backed up when you're talking about 50-some-odd patients? So I think that's a very important data point. And then what do we learn about duration of response? That's also a key parameter in CLL. That's going to be described a little bit by duration of treatment because in order to, you know, our patients are staying on this trial, thankfully, long-term. We're getting long durations of therapy. So we won't have an estimate of duration of response, but we'll have an increasing estimate of duration of therapy. And that's been very positive at the EHA update. So I think duration, you know, indicators around duration would be the second key thing. And then, you know, we've seen our degraders are very active against NX-5948 against the inhibitor resistance mutations to BTK inhibitors. So all the patients entering our trial basically have failed, or BTK inhibitors have failed them. And there's elements of resistance. How does that story evolve? We can address these mutations, and seeing that evolve, I think, will be important. There's other threads of evidence that will be important at ASH, but it's going to be a meaningful update. We also plan to have a corporate event that the evening of that presentation will provide a broader corporate update and sort of what are the next steps for NX-5948 in CLL. Okay. So I know that there's been a lot of, you know, juxtaposing your data against the BeiGene degrader data, BGB-16673. You know, you guys have kind of had matching data updates at ASH last year, EHA this year. You're headed for another one at ASH this year. How do you think about, you know, what the early competitive differentiation of 5948 might be relative to that drug, either on safety, on efficacy, or do you think it's just too early to know at this point? It is early for both programs. But first off, I'd say that, you know, it is great to have another major company enter the degrader space in BTK. I mean, I think it's incredibly validating. BeiGene's been very successful with zanubrutinib, a great inhibitor molecule. I think they, like others, have seen the limitations of inhibitors probably early on, as we've seen. So I do think it's very validating. I think having two companies promoting these molecules going forward in clinical trials has really expanded the awareness of how a degrader can enter the space. So, you know, having, you know, competition is good. And I think that there's more, there's room for more than one, you know, molecule in this space. It's a huge field. So those are all, you know, really, I think, positive things. We're actually, I think, in the same session again presenting. So it's kind of this horse race they're trying to set up. But the field is very interested in seeing how these degraders are sizing up. I mean, these are the first new small molecules to come into this whole B-cell malignancy class since the inhibitors did. So it's really quite exciting. And we get a huge amount of investigator interest. Enrollment is up. So it's very positive. You know, how these molecules differentiate going forward from an efficacy standpoint, they do look similar at this stage of the game. And, you know, how molecules generally differentiate is generally on safety or other nuances that only come out through time, you know, with greater patient numbers. And so we'll be eager to see how that. Our official approach to development of NX-5948 is to be best in class. That's our official policy approach. We want to see that translate out into results. Okay. Maybe another question that's still too early to answer, but I think there's been a suggestion of this as you kind of look across the collective data that you yourself have generated and BeiGene has generated. The question is, do you think that degraders, for whatever reason, are somehow mitigating some of the legacy cardiotoxicity that has been associated with the inhibitor class? Yeah, I do. I think that there's a sound theoretical reason why degraders may be more specific than inhibitors. Very sound, maybe a couple lines of reasoning. The first is that the degraders catalyze a protein-protein interaction between the E3 ligase, in this case, cereblon, and the target protein. And so that requires this ternary complex to form another level of binding specificity between the proteins. So you get the specificity of the small molecule. Then you have the proteins touching in a particular way. And you also pick up binding energy of the protein-protein interaction. So I do believe that that contributes to a higher level of specificity. You have two binding interactions between the ligase and the target that have to work, and then the protein-protein. So you're talking about layers of specificity of binding. I think that's number one of why you could be safer, okay, more specific in general. The second is if you look at the blood levels of our drug, I mean, I know the data on our drug, that our blood levels at therapeutic doses are between 5,000-fold and 100-fold lower than the non-covalent inhibitors or the covalent. So a degrader works at very, very low drug levels. So again, 5,000-fold lower than pirtobrutinib, 100-fold lower than ibrutinib with NX-5948. And yet we're getting this 70-plus response rate, and we're getting complete degradation of BTK. So why is that? Essentially, trace amounts of drug of a degrader can really act catalytically in the cell. So one, what does that mean? One drug molecule, one degrader molecule can degrade hundreds or thousands of target proteins or signal it for degradation and then recycle. Whereas an inhibitor is one-to-one, has to bind as one-to-one. So you have to have thousands of fold more molecule. That leads to more molecules in the system, potential for off-target tox goes up, all of those things. So those are a couple of reasons that these could be much safer molecules, and they're fundamentally different PK/PD. And I think we could be seeing that play out, you know, in these molecules. Okay. You mentioned resistance mutations. I know that there was a novel resistance mutation that was recently described for the BeiGene degrader. I think it's the A4286, right? A428 is all I know. I don't know the. Anyway, but that was recently described in the literature for the BeiGene degrader. I know it led to a fairly rapid relapse, I think, in a patient in the CLL study. Is that something that you've looked at at all preclinically? And I think it was suggested, you know, that 2127, which is your bifunctional degrader, and the BeiGene degrader share the same binding site, right, in terms of where you're targeting BTK. Have you said anything about whether or not the binding site on BTK between 5948 and 2127 are similar? The binding are different between those two molecules, but they are in the vicinity of the active site, but let me just give a more general level answer to the question, so I think that any drug class will have mechanisms of resistance. Okay, there will be mechanisms of resistance that evolve for any drug in oncology. The question is, are they clinically meaningful? At what rate do they occur? How long does it take and you want your drug to be more difficult to become resistant to, you know, over time and I don't think you're going to find a drug that's impossible to become resistant to, so with regard to this particular mutation, we have not seen patients come into the study with this mutation, so it's likely a very rare event. The bulk of mutations we've seen are probably comprised of about 43% of our patient base are all really active site and kinase- dead mutations. So we'll have to see if this becomes a clinically meaningful, you know, resistance mutation. There's other theoretical ways degraders could become resistant, and they would involve the ubiquitin-proteasome system or some mutations in the ligase, cereblon. We haven't seen those either. Okay, you can force these things to occur in vitro, but so I think the question is, is it clinically meaningful, and will our duration of therapy prove that, you know, look, it's a better mechanism to degrade? Okay. Maybe we can talk CLL development plans because I think this will become kind of an interesting part of the Nurix narrative over the course of the next 12 months. I know you've guided to an accelerated approval strategy in double refractory patients. I know Loxo/Lilly tells us that there's a clear path there. They're running their confirmatory phase III trial, I think, in just a BTK inhibitor exposed population, not requiring prior venetoclax, right? So presumably, if they get a full approval from that study, that doesn't impact your ability to get an accelerated approval. But I know as kind of a precursor to that accelerated approval strategy, you're backing off, you know, the 200-mg and the 600-mg doses right now in kind of a randomized way. Have you said, you know, how much patient exposure data that you want to generate at each of those doses before you make a firm decision on selecting, I guess, a recommended phase II dose to pursue that accelerated approval strategy? So to answer the last question first, so our general expansion cohort at the 200 and 600 are 20 patients each. That's sort of our general rule of thumb number. Sometimes you tend to overshoot that. But we do think that's a meaningful number. Plus, we have a large number from the phase I-A that are both at the 200 and 600 too, because we've been backfilling as we go. So I think we'll have plenty of coverage at these doses to satisfy Project Optimus. And so then, yes, we'll make a decision about which dose. By the way, the safety looks similar at the 600 and 200. So that's very good. There's some meaningful spread in PK, which you need for Project Optimus. So we have that at the 200 and 600. Then, you know, we have the mutation data we're going to be studying very closely too, as we just discussed. I think we'll have all the elements to really implement a very smart accelerated approval, you know, single-arm pathway. Now, we have to discuss all that with the agency and then also define the randomized control trial, as you said. I think all of that is open in this double exposed population, which means people that have failed BTK inhibitors and BCL-2 inhibitors. And basically, in the trial and these response rates I've been citing, 80% or 80-plus% of our patients are in that category. We're already having a first look at that response rate. I think we'll be well positioned there. As you indicated, pirtobrutinib and all the inhibitors really launch a suite of phase III studies and addressing different segments of the patient population. We definitely think monotherapy is a big patient population segment. We're seeing great activity in monotherapy. A lot of patients really prefer monotherapy. You take one pill a day. In our case, it's once-a-day dosing. It's very attractive. We're talking about an elderly frail population that will do quite well with that regimen. Then the combination arm. That's also going to be part of our plan with venetoclax likely. Okay, and so you referenced those other suites of phase IIIs that have been launched, and right, those have been launched by BeiGene, Lilly, AstraZeneca. I'm guessing you might need to be a little bit maybe more focused in your development strategy. It's just a presumption. Correct me if I'm wrong, but as you think about those opportunities in the front-line setting, second-line setting, what do you think are the most commercially impactful studies that you could design and execute on to highlight the differentiation of your drug? I think there's two categories. First is success in this fast-track population that we have because it's a challenging population, and that will raise the, you know, reasons to believe level. I mean, if that looks good, you have to prove that for physicians to become excited about, then the earlier line, so the second category is moving up in line of therapy and going head-to-head with inhibitors, and so the central thesis of removing the bad actor protein is that that's fundamentally better than just blocking it, and so we'd like to prove that in some way. Now, you know, what is the trial design? What's the comparator? It ends up being some kind of head-to-head trial where you can really look at how these two very important MOAs compare, and I think that's going to be medically very important, not just for B-cell malignancies, but actually broader. And so I do think we're going to have a, that's going to be a fascinating trial when we get to it. And I think it's going to get a lot of attention from general oncology medicine. Okay. And I guess if I go back and I look at, you know, the studies that were conducted in the BTK space, the labels that were issued as a function of those studies, and then the commercial inflections that were realized, right? It seems like it seems like that head-to-head study versus an entrenched BTK inhibitor is really kind of what has driven a lot of share gains in the CLL space. And so, you know, what's your appetite for a second-line monotherapy trial that looks at 5948 head-to-head versus physician's choice BTK? I would just generally, my appetite is high for that. So I think, you know, what's the actual design, the devil's in the details. But I do think that that's a critical trial, again, to answer some very important medical questions, offer patients more opportunity to choose. You know, if you look at the head-to-heads that have been done within the inhibitor space, you know, they're not that differentiated really that terribly much. I mean, there's better safety if you look at zanubrutinib versus acalabrutinib versus ibrutinib. But, you know, efficacy kind of looks similar. And so because they're all inhibitors. And so I think the degrader has a chance to really differentiate on several fronts. So we shall see. Definitely something there will be in our suite of studies. Okay. And then maybe just quickly, outside of CLL, I know you just showed some 5948 data in Waldenström. So you have expansion cohorts in a couple of indolent non-Hodgkin subtypes. Are you pursuing registrational plans over the near term for non-Hodgkin's in addition to CLL? I definitely would think that would be part of the plan. We haven't outlined those yet. But the Waldenström's response rate was similar to CLL. So that was very nice and confirmatory. You're talking about 75+% again in Waldenström's very advanced patients too. So that was very, again, confirmatory already. But those were low numbers of patients. We want to expand that and see if there is an accelerated approval path there. That has been a pathway that other BTK inhibitors have been successful in MCL or some of the other non-Hodgkin's before CLL, just by virtue of the indication size and the timing. So I think we've got a lot of opportunities and the pathways are there. Okay. Outside of oncology, I know that you're very interested in looking at 5948 in autoimmune disease. I know it's something that we get a lot of questions about. You just showed some additional preclinical data at ACR. I guess anything incremental from that presentation that you think kind of specifically warrants a mention? Yes. So we had a really nice poster at ACR. It was really well attended. There were tons of people at that poster all the entire time. The interest level is very high. There's several good panels of data on the poster, but one of the, I think, best ones is looking at B-cell signaling that is blocked by 5948 compared to remibrutinib and rilzabrutinib and acalabrutinib. And we really did. So it's, you know, kind of head-to-head on cells with IgM signaling. And we have two panels. And you see that the degrader is 10- to 100-fold more potent on wild-type BTK signaling, BCR signaling than the inhibitors. I mean, once you start to look at 10- 100x changes and things, you pay attention. You know, 2x, 3x, who knows? But this was significant. I think that that reflects the scaffolding function of taking out that whole protein. So for those who don't know, the scaffolding, there's the kinase function, which is what all the inhibitors go after, but there's a whole another function, which is the structure of the protein that's conducting the node and other pathways through it. I think that that function we've shown is important in oncology. I think the same function is very important for efficacy in autoimmune disease. The theory is, and we believe that the inhibitors are showing promise in autoimmune disease, but they don't seem to quite be there yet. Like there's something missing. I think it's they're not hitting the scaffolding function. I think those two panels are kind of showing you that if you really look at it. Okay. Interesting. You've got into an IND submission in autoimmune disease, I think next year? No, actually we haven't, but it's a good idea, but what we've said is we said we'd complete IND enabling studies this year. We haven't gotten to next year yet, although it already feels like next year, you know, but that is a lot of questions around that, and so yes, in the next, you know, several weeks, we should outline our strategy, having done a lot of fundamental legwork for an autoimmune IND, which is a little more involved than the oncology IND, so we can get ready to share that kind of information. So if and when that IND submission happens, you know, what are some of the kind of pushes and pulls that you're considering as you think about where you'd like to focus some initial resources and generate some proof of concept data? Like are there some specific indications that you think you can just get a rapid answer? It makes the most sense. I'll say there's some specific criteria that can lead you to the indication choice and strategy. The first is, is there a strong rationale for BTK as a target in that indication and have the inhibitors sort of shown promise there? Because there's been a test already done in several of these, right? This is a valid test. That's number one is BTK a relevant mechanism and has there been evidence to that effect? I'd say secondly, how fast can you get a readout to get to proof of concept? That involves the biology. Can you do it in a 12-week study or is it a six-month study? You know, that's important when you're going for proof of concept. We'd look at indications where you can get a relatively rapid POC. The third is what is the POC? Is it quantitative or is it this subjective stuff that, you know, really is hard to understand? And we like quantitative readouts for biomarkers that really do speak to clinical efficacy. So that's another criteria. The fourth would be what's the market? You know, does it, you know, does it mesh with oncology pricing and such? And what's the dose? How would we sort that out? How would these two indications, you know, or three or four live together? So, you know, the markets for these are all fairly large. So I put a little lower there. These are all big markets. And so you can use those strategies to then look at all these different autoimmune indications and then actually kind of rank them and put them in order. And so that's something that we'd like to talk about in the next, you know, weeks and months. Okay. The bifunctional degrader 2127, I know it's back in the clinic now. Yes. Has your perspective of that program at all changed just given the breadth of the 5948 data that you've seen today? NX-2127 is a very different drug. So my perspective hasn't changed. It looks great in aggressive lymphomas. It is a combination drug built into one molecule. So it's like having an IMiD or a Revlimid molecule plus a BTK degrader in one molecule. And so that makes it very attractive. And we've seen in aggressive lymphomas like DLBCL and aggressive follicular, where we've seen these signals in the initial trial of the chimeric mixture even, we've seen complete responses that are durable. And we want to see, okay, at what rate does that occur with now our chirally pure form of the molecule, which we now have and is in the clinic and enrollment is ongoing. We have investigators that are very excited about that across the United States. And we are really going to pursue that. It'll define its own trajectory that'll be different from NX-5948. Okay, and so you've reinitiated dose escalation with that new formulation? Yes. We are enrolling, and we've reinitiated, and we have patients. Okay. I know you've also guided to having an update for the NX-1607 inhibitor before the end of this year. What does that update look like? Is that just a qualitative update about where you are with that program? Or is there going to be some granular safety and/or efficacy data that gets disclosed? It'll be part of our corporate update. It's not the right forum for a real, you know, granular safety. That should be published at a major medical conference in 2025. Okay. I think it's going to, you know, it's going to have a lot of information in it. But I do think it's worthy of a corporate update at the end of the year for the program. I think you've had that asset and dose escalation now for maybe three years. I know it's really novel, complicated biology. I think you've been kind of triangulating around these PD biomarkers to guide dosing. But I guess, is the time that it's taken to kind of define a go forward dose and/or a schedule, is that somehow an indictment of the TI that you have available here? Is this a pretty narrow therapeutic index? So I think an IO agent, by definition, any IO agent has a narrow therapeutic index. I mean, at their therapeutic doses, they have something like a 60% adverse event rate associated with autoimmune side effects. I mean, so you want to find where that area is. But they are by nature narrow therapy. So you have to dose escalate and carefully. I mean, that's the bottom line. And so that is really what it's been. You know, we've had to start out 10x to 50x lower than where you would normally start a program. And so that takes time. And that's really what's happened here. The biology is playing out. The biomarkers are playing out. We're on target. We are the first in the world to bring this mechanism of action, the small molecule CBL-B inhibitor into the clinic. And so when you're, you know, really defining and breaking this new ground, it does take longer. Very different than the BTK program, which, you know, really had a much smoother runway. And you can see all the data we've had very quickly. But this addresses a huge market. I mean, basically all solid tumors potentially. We have 11 different indications. We've been testing this in. Yes, it's a phase I-A, but these really are more like phase II scale studies in the end. So in the end, we will have a lot of information and know where to go with this program. And it's a very exciting program. Maybe last question. You presented some preclinical data recently on a pan-mutant BRAF degrader. Is this now kind of a formal DC within the Nurix pipeline? It's not a formal development candidate yet, but it is a pan-BRAF degrader. What the industry, I think what the field really needs is to be able to hit the class one, the class two, and the class three mutants. There's really no molecule that does that effectively and cross the blood-brain barrier. The molecule that we did disclose does have those attributes. Is it the ultimate development candidate? We'll find out. It really is a pan-BRAF, which is the RAS pathway as we know, and is quite an exciting opportunity for genetically defined solid tumors, including melanoma, metastatic melanoma to the brain. That was a big development hurdle. I really, we're very excited about that program. It is still not development stage, which is why it's not on our official pipeline slide yet, but we'll see. Okay. And I know we didn't even get to your collaborations with Gilead, Sanofi, Pfizer, et cetera, but I've almost eaten up three minutes of your happy hour time. So we're going to let you go. I just want to say one word. Go right ahead. STAT6. STAT6. One target. Really cool. Okay. So yeah. I know that's with. Thank you. So that's with Sanofi? Yes. And then IRAK4. So you expect to hear about an IND on the STAT6 side? That's our goal for the first half of 2025. A lot of attention to that target. Very interesting biology. IRAK4 should be on schedule for an IND with Gilead. That timing is up to them, but we're working very closely with them on those, so a big, you know, first half for NX-2127 plus our own 5948 strategy. All right. Very interesting. Arthur, thank you as always. Thank you, everyone. And I'll let you go. Great. Thanks, Steve. Thank you.