Thanks so much for everybody to join us here. It's the second day of the Piper Sandler Annual Healthcare Conference. I'm Joe Catanzaro, one of the Piper biotech analysts. Great honor to kick off this next session here with Nurix Therapeutics. We have Arthur Sands, CEO of Nurix. A lot of topics to cover here, but maybe, Arthur, I could give you, like, a minute or two, you could sort of introduce Nurix, tell us what you guys have been up to, and what we can look forward to. Yes. Thank you, Joe. So at Nurix, we have three drugs in clinical trials currently, all in oncology. two are in leukemia and lymphoma. These are targeted protein degrader small molecules, so it's a very unique new mechanism of action in heme/onc, the degradation of a BTK, a known driver for leukemia and lymphomas. And then also, a CBL-B inhibitor, which is an E3 ligase, which we block and creates an upregulation of the immune system, so it's a novel IO target. The central theme for all of The molecules we make, is targeted protein modulation, and that is using small molecules to alter target protein levels within the cell by harnessing or otherwise, inhibiting the ubiquitin-proteasome system, and that is a system running on E3 ligases, which are the natural regulatory mechanism of protein levels in all cells. Those are the kinds of molecules we make, and happy to update you on our clinical trials, too. Yeah. I want to obviously tick through some of the BTK programs and 1607, but maybe first, just you know, overarching question on the degrader space. I think something I maybe ask you on an annual basis here, but you know, at this point, with clinical data you guys have generated and the space has generated, what are some clear knowns about degraders, and what they offer and can do clinically, and what are some maybe remaining unknowns that we still need to figure out? So I'll start with the clear knowns. Clearly, not only with our molecules in the clinic, but now other companies have all demonstrated that targeted protein degradation works. It's very efficient. We can create oral molecules that can knock down protein levels very rapidly and very thoroughly. So as compared to, say, the nucleic acid-based therapies that would knock down RNA to get at protein levels, this is a new small molecule-based modality that has now proven itself in several different therapeutic settings, including oncology, inflammation, and also in other areas. So we know that we can make small molecule degraders that can harness ligases for very efficient degradation. They can be oral agents. We know in our case, with BTK degradation, that these agents can degrade the protein BTK, even in the setting of resistance mutations, where resistance mutations have occurred in response to being treated with BTK inhibitors. So this can elicit a mutagenic event in BTK that renders the patient vulnerable again to the lymphoma or leukemia growth, and our degraders can actually degrade those mutations. So that's a new piece of information we now know, and we've shown that very effectively at our previous American Society of Hematology or ASH presentations. In terms of other knowns, now, we know that these target proteins, kinases, BTK in our case, has not only enzymatic function, but a scaffolding signaling function that degraders can remove. So by removing the protein, you hit the target harder, much harder than an inhibitor. So I think what we're demonstrating, what we know now, is that degraders can offer several advantages over inhibitors, especially in the case of kinases, where we have the most information. And I think that those are all very important findings, and really only in the last 18 months, as we have really disclosed all of this. In terms of unknowns, you know, no one has an approved targeted protein degrader yet, so that is an unknown. But, there really are no... We haven't seen any class effects that would cause concern from a safety standpoint. Safety is always kind of an unknown until you have larger patient numbers, so I'd have to say that is technically an unknown still. Yeah. Maybe another sort of high-level question, you know, as we think about the degrader space, it for the most part, I think the class has gone after well-validated targets. At what point do you potentially start taking on more target risk from the degrader side of things? And maybe this is a good sort of connect the dots, how does this recent collaboration with Seagen and these degrader antibody conjugates maybe offer that opportunity to go after more novel targets? So I think now is the time to go after more novel targets and expand the potential, you know, basket of drugs that can be made. So the Seagen collaboration, to which you referred, is an example of that. Not only going after novel targets via an antibody targeting a particular cell type, but these are not your typical antibody drug conjugates. These are called degrader antibody conjugates, and we build a degrader molecule that is the payload on the antibody. So not only does that open up another target class and cell target class, but it also is a new MOA for a compound, and I think can greatly expand the ADC space. So again, we call these DACs or D-A-Cs. So that's one good example. In terms of novel undruggable targets, we have several in our drug discovery pipeline. Most of those are undisclosed at this point. We have five programs with Sanofi, five programs with Gilead, and now several with Seagen. And most of those targets we have not disclosed, but they include several very novel heretofore undruggable targets. And so as those progress towards the clinic, towards development candidate, we will disclose them, and we will talk about them. Great. And maybe now we could shift to the BTK programs that you have. I think a question that I often get is, you know, what's the optimal level of BTK degradation that you want to achieve? How do the inhibitors inform that, and how does the clinical data you've generated to date inform, you know, where you think the optimal window is, in terms of how far down you degrade BTK? So in general, more is better in terms of degradation. We start to see therapeutic activity that is clear anti-tumor activity in patients at about 80% degradation. Now, as compared to inhibitors, the conventional sort of wisdom would be, you want 95% inhibition of the enzyme. And I think the fact that we see clinical activity at 80% degradation, approximately, means that we are doing more than just inhibiting the kinase activity by removing the protein. We're getting that scaffolding effect. So I think we get additional effects. Now, in the case of 2127, our dual ACT degrader, we can push that with dosing up beyond 90%, and we have. And in the case of 5948, the pure BTK degrader, we're clearly north of 95%, protein removal. In fact, we're at the floor of the assay, so we really can't actually measure 100% accurately, but the protein by Western blot is essentially gone. Maybe sort of segueing to ASH, but before we get to your program, you guys are obviously opportunity to be first-in-class for BTK degrader. There are some programs bubbling up. We'll get some initial data for another BTK degrader program. Any insights into what that program is maybe seeing, how it's designed relative to NX-2127 and NX-5948? So, yes, you're referring, I think, to... There are two programs now that we are able to track that are now in the clinic. BeiGene has a program that started in phase I. Very little data has been released from BeiGene so far, and we do look forward to seeing that. The same for AbbVie. I don't think any clinical data yet, but, at any rate, all the programs are in B-cell malignancies broadly. They're all in dose escalation. We are now entered into dose expansion cohorts in CLL and also in DLBCL and MCL. But all the programs are starting across a broad range of B-cell malignancies and doses. So, it should be interesting to start to compare them through time. But the numbers are low, the patient numbers are low, so comparisons are very challenging and always tricky between trials. But ultimately, when we get the numbers up, I think we believe we have the best-in-class agent. We've done a lot of profiling preclinically of compounds we know that could be competitive. So we think we're best in class. We have been the first mover in the space, so we've had a lot of defining work to do, so. But it is an area that's heating up. Yeah. So maybe now we could shift to ASH and some of the data updates that we'll get there, maybe starting with 5948. Maybe you could just help frame up sort of the data set we should expect to see there and what you see as maybe some important takeaways that we'll get after looking at the phase Ia data. Well, it's a very exciting time for us. It's the first time we will have presented clinical data on NX-5948 in terms of patient responses. We have previously demonstrated the biomarker response that is very thorough degradation of BTK. So we'll expand on that, but we'll have clinical data not only in NHL patients, but also CLL across a range of doses. And so it'll start to become, I think, apparent that we have an agent that has broad range of activity and has a very favorable safety profile. But all of that will be wrapped up in a poster presentation that we have, and then we're also having an investor event where we'll be having one of our lead investigators give a presentation on BTK degraders. How much should we think about NX-5948 not being limited in its dose relative to what you saw with NX-2127 and some of the IMiD activity you saw in neutropenia? You know, like, how much further can you go? And it sounds like there's a... You know, if you're using BTK degradation, you're kind of at this maybe ceiling of level of degradation. So I think 5948 will have a very broad dose range, capability, and also, a broad disease sort of scope that it could treat. So CLL is clearly the primary, I think, target, disease target for 5948, where pure BTK mechanism of action drugs have proven very successful. That's where the inhibitors are currently dominating. We think 5948 has the potential to displace the inhibitors from that market and then also broaden the market because it is, again, hitting the target harder with the scaffolding effect and the removal of the protein, broaden the market into NHL as well. We also see 5948 with great capacity to combine with other agents.... One of the great hopes, for example, in CLL, is to get to complete responses rather than partial responses, which is really the standard current target for inhibitors. So I think it has a lot of potential. There's also the ability to consider autoimmune disease with a compound like NX-5948. And so we are very interested in enabling that pathway. That would likely be a much lower dose than required in oncology, where the disease burden varies, and it can be quite large, actually. So a lot of potential for NX-5948. So, you mentioned it here, and I've heard you say it a couple of times, the opportunity for NX-5948 to maybe compete directly against the inhibitor class. Ultimately, what kind of profile do you think is needed to sort of justify that argument that it can be used in place of a BTK inhibitor? So, rapid response, number 1, and we see a very rapid degradation of BTK within the first 2 hours of dosing. So rapid response. Deep clinical response is another way to distinguish from inhibitors, and highly durable without the emergence of resistance mutations. We'd have to prove all this, of course. We think that the inhibitors will end up, over time, propagating these resistance mutations. We think by removing the protein, that is less likely to happen. And so I think if you add those things up, plus a very excellent safety profile, I think you have the ability to displace inhibitors. I mean, why go on an inhibitor and foster resistance, if you can avoid resistance and you can get a deep durable response rapidly? All of those things correlate with much better clinical outcomes in the long run as well. So if you can hit the target hard, get a deep durable response early, that bodes well for the patient's prognosis over the longer run. The other thing I think you said is that, excuse me, NX-5948 should be readily combinable. What's the rationale strategy to combine in CLL? And at what point do you take that step to start to explore clinically some potential combination strategies? So as soon as we establish what we think is a recommended phase II dose or pivotal dose, I think it's time to start combinations early trials, like, right away. And I think that's important because the goal would be to get to complete responses in CLL, for example, and to do so in a non-chemo-based regimen, and to avoid the chemotherapy regimens altogether and really replace that with targeted therapy. So I think that really is the goal clinically. I think it's achievable with combination therapy, certainly. And Rituxan would be an obvious combination, but also venetoclax could be another obvious combination for 5948 in CLL. In DLBCL, there's other approaches that could be taken. The other thing you mentioned was the opportunity in autoimmune. I know this has always been on the table, I think, for NX-5948, going back a couple of years. It seemed like you guys maybe paused that strategy a little bit, but maybe now you're shifting back to pursuing that. Maybe talk about how you think about that and when and where you start to explore on autoimmune. Yeah. So 5948 always looked very good in the autoimmune animal models, arthritis models, multiple sclerosis models. It crosses the blood-brain barrier in animals. We can measure BTK degradation in microglia in the brain, which are, of course, key for the inflammatory response in the brain. But we didn't start there because starting in oncology offered a better risk-benefit profile, especially when we were the first degrader ever to go into a heme indication. Now, having established what we have with not only 5948, but 2127, we have a much higher confidence level about the therapeutic index for these, for the degrader modality in general. And I think that that kind of data from oncology will tee us up very well to consider autoimmune indications. Maybe we could jump to NX-2127, also expected to get an update at ASH. Maybe first, any updates you can provide on the partial clinical hold that has been placed on NX-2027 and NX-2127, and sort of steps needed to resolve that? Sure. So, this is a CMC issue. We developed a new manufacturing process for NX-2127. These are relatively large, small molecules that are complicated to actually manufacture. And we developed a process that was able to control one of the chiral centers of the molecule, so we could have a chirally controlled, commercializable form of the compound. So that it turns out to be, I think, a real advantage as you march towards commercialization. So we're implementing that. We're on partial hold in terms of enrolling new patients into the mixture form, the initial phase I form. But patients who are on can stay on, 'cause they are deriving clinical benefit. And then, so to remove the partial hold, we need to submit the new process to the FDA for review, which we've actually already done, and then also develop the bridging study design and just have agreement on those two main issues. Those are really the key things. Great. So maybe looking towards ASH now and the data we'll get there, maybe similarly as I asked on 5948, sort of frame up the type of data set we'll see there. And I guess most of us are interested in what's the next steps for this program, and where do you take it, and will we get any insights there? On 21 27? Yeah. Yeah. So NX-2127 is the dual-acting molecule, which degrades BTK, but also has immunomodulatory activity via degradation of IKZF1 and IKZF3, which are key transcription factors. Those are the same targets that are degraded by Revlimid and the immunomodulatory IMiD class of agents from BMS, very effective agents. So we built that into one molecule. So it is essentially a combination therapy in one molecule with this dual activity. This makes it a very powerful agent. And so we've seen. We've reported already on our first complete response in DLBCL. This is a fourth line plus patient, been on R-CHOP, had R-CHOP, R-ICE, had antibody therapy, other experimental therapy regimens, and got a complete response within eight weeks on the drug as an oral agent, and very durable now beyond a year of therapy. Very strong anecdotal response. We wanna build on that at ASH. We have more NHL patients. We want to enroll more at the 300 mg dose and really see what kind of rate do we see there in terms of complete responses. So that is really a goal for the program. We think that could tee it up for being very important in DLBCL and potentially also MCL. One thing I've tried to figure out and understand is why in CLL for 2127, sort of 100-200 was kind of the tolerated dose, and in NHL, you've been able to go up to 300 mg. Any sense of why you're able to do that? You know, the disease burden does vary. CLL, being a liquid tumor, primarily, is more accessible, I think, to the drug in the bloodstream. The solid tumors with DLBCL can actually be quite bulky. You have to penetrate the tumor mass itself with the compound, so it probably does require more drug. And we're seeing responses, you know, at those higher doses. Even with BTK inhibitors, there are different doses approved in the different histologies. So there's a lot of variability across these histologies, and we label them DLBCL, and MCL, and CLL, but there's a lot of heterogeneity, even within one. And so you've got to get to a dose level for each that covers most of that heterogeneity. I'm talking about genetic heterogeneity, 'cause they're usually mixed populations of cells with different mutational burdens, and you've got to cover all those. It really just has to be determined empirically, and in the clinic is really the place to determine that. So you mentioned in NHL, you know, next steps, more patients at 300 mg, fully sort of flush out the clinical profile in that setting. What about CLL? Are you at the point where you have enough data at 100 mgs to sort of make a decision on where to go with the program within CLL? I think in terms of 2127 and CLL. It really was a very powerful proof of concept of the whole mechanism and gave us the whole mutational degradation story. But we think with 5948, that profile really has potential to go in earlier lines of therapy, being a pure BTK degrader, better tolerated, doesn't have the dual activity. But if we can move 5948 up earlier in lines of therapy and really compete head-to-head with the inhibitors, those, those are very large markets and would probably be the better overall investment. However, for, you know, third line plus, the dual mechanism of 2127 is very attractive. It's just, can we develop both in one indication at the same time? Probably not. Probably need to pick, you know, where is our best foot forward for each of these very different molecules. So maybe these last couple of minutes, we could touch on 1607, the CBL-B inhibitor. You guys have established the PD effect with that molecule. So what's the next learnings that we get from the phase Ia study? Yeah. So the CBL-B is an inhibitor of the ligase, CBL-B. We've shown, as you mentioned, upregulation of a key biomarker that is on the CBL-B pathway, which is just downstream of the T-cell receptor. This is where we are. And we know that that biomarker elevates when you block CBL-B. That is because we're blocking the degradation of CBL-B by blocking this ligase. We've also seen other biomarkers move that correlate with activation of the immune system. So mechanistically, we, we definitely are in the zone with our inhibitor. The next question is really, what's the dose to start to get clinical responses? And what is that therapeutic index for this novel IO agent? We are the first-in-class agent in the clinic, and being an IO agent, you know, you do have to dose very carefully and very slowly, and you have to consider different dosing regimens. So determining this optimal dose is always been challenging for an IO agent, and I think that's really going to be a 2024 goal. Yeah, so maybe my follow-up, and maybe you just answered, was that, you know, I think expectations or have the next update before the end of this year. It's now early next year. Is that simply a consequence of, you know, identifying what the right dose is, just taking a little bit longer than maybe you expected? Yes, and it's also a desire to focus on the BTK program towards the end of the year. We have so much going on with both those agents. Really, this allows us to pay attention, close attention to, to those agents first and then continue to gather dosing data, for a 2024 disclosure on 1607. So keeping with NX-1607 in the last 30 seconds we have here, I think often we've seen companies take novel IO agents and start to combine with PD-1. You guys have chosen a paclitaxel combination as the first combination to explore. What's the rationale there? Why did that make sense to be the first combination? Well, it's been one of the more successful combinations with the PD-1s, is with chemo-based co-combinations that trigger immune-mediated cell death. And so that clearly is attractive to us. We're also, though, keen on seeing single-agent activity, which has been a distinguishing factor for successful IO agents, can't just rely on combinations. So we'd really like to take a look at both settings to make a determination about efficacy. Perfect. With that, we are out of time, so I wanna thank Arthur for your time and thoughts. Thanks, everybody, for joining us. Take care. Enjoy the rest of your day here. Thank you. Thanks.