Afternoon to, you know, go through and review the pipeline of degraders in immunology. I know that you know, the lead focus with your degrader platform is on the oncology side of things, but you do have several pipeline programs across STAT6, IRAK4, BTK that could potentially address the immunology side of things. Maybe just, you know, at a high level, you know, I guess, what would be the advantages of targeting inflammatory diseases with a degrader approach versus a small molecule inhibitor approach? Sure. Well, first off, thanks for having us, Biren. I appreciate being included because I do think that our emerging I&I pipeline is sometimes somewhat overlooked, given the Phase 3 progression of our oncology pipeline. But the immunology pipeline at Nurix is very robust, as you point out, with three major targets. I think three of the best targets in the industry, currently novel targets for small molecules: BTK, IRAK4, and STAT6, as you summarized. So to start off directly on your question, what is the advantage of a degrader modality against these targets? So there are several levels of advantage. First off, the degrader mechanism takes out the totality of the protein, and that means the totality of the protein's function. So in the case of the kinases, like IRAK4 and BTK, you know, these are thought of as enzymatic targets, kind of traditional enzymatic targets. You block the active site, you block the function. Well, it turns out that's not entirely true. In fact, there's another whole set of signaling functions, plural, that go through the structural nature of the protein and the structural node in which that protein sits in the cytoplasm. This is called the scaffolding function, and so this function is not blocked by inhibitors, enzymatic inhibitors, like the current BTK inhibitors or the first-generation IRAK4 inhibitors. In fact, this function, we, in some of our assays, can account for, you know, perhaps up to 50% of the signaling going through this node in certain situations. We've learned that directly in our oncology trials with patients that have mutations in the kinase function. So the BTK, in this case, is no longer a kinase, and yet it's signaling tumor growth rapidly. That was the first way that we knew, and we published this in Science a couple of years ago with our Memorial Sloan Kettering colleagues, and this was a big finding because it was clinical proof that the signaling function, the scaffolding function not only exists, but is clinically relevant and could actually drive tumorigenesis. So that's how strong it can be in that setting, and we think it plays a big role in autoimmune disease just the same. Even in a wild type, if you will, a non-malignant condition of the immune cell, the scaffolding function is still there, and providing signal, and so the degraders can take that out. And that's a major, you know, advantage. And we have many assays where we go head-to-head with degraders in cell-based assays, and we show our degrader gets deeper response in cells compared to the inhibitors. Of course, our BTK inhibitor, bexobrutideg, shows clinical response in CLL, in oncology, when the inhibitors stop working. And so that's another proof that we're hitting another function of BTK. So that's the scaffolding function. The second point I'd make, a big advantage for degraders, is that we can target virtually any protein. So STAT6 is a transcription factor and does not have any, you know, traditional active site of an enzyme, and transcription factors have traditionally been challenging, very challenging to target with small molecules. But we have extremely, potent compounds against STAT6 because all we have to do is bind to it somewhere. We don't even need an active site, right? So we just bind to the protein somewhere, trigger degradation through the ubiquitin-proteasome system, and then we have these really, incredible therapeutic effects, which, of course, we've seen in animal models, and now we're eager to get into humans with Sanofi. That program is a Sanofi program, as you know, and is in IND-enabling studies. But so that, that's, perhaps a little bit of a long-winded answer, but it, it is a, I think, a very important point of why degraders are so advantageous as compared to inhibitors, and in I & I, in particular. You know, you mentioned, with the STAT6, the NX-3911 program, it is partnered with Sanofi, and Sanofi is taking the lead in terms of, clinical development, and they are gonna be filing IND, this year. You know, what, what do timelines look like for the IND, and what, you know, gating items are, still need to be completed before the IND is filed? If you can share some of those details. Well, all I can say is that, Sanofi licensed the compound or extended their license to take it into IND-enabling compounds last year, in the first half. And so with industry standard timelines for IND- enabling studies, one would anticipate those should be completed, this year, you know, potentially in the first half. But that is under the Sanofi now, administration of the program, the way that deal works. So, so we don't know more than that at this stage. It'll be, of course, up to them to, make announcements regarding this program's progression. So we do think that'll be an important milestone potentially this year. That, just for context, the way that program worked, we started working with Sanofi in 2019 on the STAT6 program under a drug discovery alliance, which was a major alliance that contained multiple targets. STAT6 was one of the first and one of the most exciting. So this has been a multi-year program. Nurix drove all the discovery efforts there with our technology and our platform for degraders, including our DNA-encoded library technology, which is how we found the STAT6 binder in the first place. And then, now as we got to a development candidate last year, that was Sanofi's trigger point to extend their option and then take control for IND-enabling studies and proof of concept studies in humans, which they fund that whole section. Then they're responsible for that result. At the end of that, Nurix then returns to the program with an option to opt in for a 50/50 co-development, co-commercialization deal in the United States. And so that's how that whole deal works. So we consider this program a very important part of the Nurix pipeline as well. You mentioned, you know, that STAT6 is a transcription factor. It doesn't have an active site. So from a traditional drug development standpoint, could be difficult to target. Is that the reason why STAT6 has been difficult to drug until now? Yes, it is, and I think that it's true, and it's a generalizable statement for transcription factors. It doesn't mean you can't find inhibitors of them, you know, but it's just generally more difficult. And then the question is, how exactly do they work, those inhibitors? What do they really block? Because there is no, you know, traditional active site. And so that creates a number of drug discovery and development complications. Whereas with degraders, again, we just remove the protein. So our goal is to imitate the gene knockout, which we do. And in fact, we use the STAT6 gene knockout as a control for all of our experiments in the development of a compound. So we want the compound to look like the gene knockout, basically, right? Because... That's a very desirable phenotype, by the way. The STAT6 knockout, you know, is really a great phenotype. It's, you know, healthy animals, but they lack, you know, the IL-4, IL-13 signaling pathway, like, completely. So they lack this type 2 inflammatory response, otherwise intact immune systems. So it's, it's the kind of target that is, you know, excellent to just remove, if you can remove it with the degrader technology. And it seems like, you know, from some of the published literature and the biology that's been described, it seems phospho-STAT6 homodimer dimerizes with or through the SH2 domain, pY peptide, which then translocates to the nucleus. And I think the SH2 domain has been, you know, used as a target for degradation. Is that the modality that NX-3911 is targeting, or is it a different area within the STAT6 pathway, which, which is where you would potentially degrade? So we have not disclosed where exactly we bind. This is a novel ligand that was discovered by Nurix again through our DEL screening technology, which basically allows us to probe the entire protein for binders across the entire protein surfaces, all the surfaces at once, which is the power of DEL. And that's a library that's proprietary to Nurix. It's a 5 billion compound library. So we think that's a real advantage, and that's not disclosed. How selective is the degrader to STAT6 versus STAT5A and STAT5B? Well, this is something that I believe we have shared with Sanofi's blessing in terms of describing NX-3911, the development candidate that, as we mentioned, is now in IND-enabling studies or hopefully completing them. But at any rate, we've shown, we've shared in the past, a proteomics plots, where we do this very in-depth, the highest resolution global proteomic study that you can, which is the state-of-the-art methodology, to find proteins that are degraded by a degrader or proteins that move. And when we treat human immune cells, normal human immune cells, STAT6 is the only protein we see degraded at clinically relevant concentrations. And that goes for all the other STAT families. You can see them on this proteomics volcano plot, as it's called. You can see all the other STAT family members just sitting there right around the mean because they don't shift. And I think that for people who want to find that data, we have published it. It should be on our website in our resources section in one of our presentations. For NX-3911, what's the cell permeability? I think that's one of the characteristics that is required for a degrader. How quickly does 3911 degrade STAT6? ... It's very rapid. We've shown some degradation curves in cells, both that have been stimulated and unstimulated cells. So, and we get the same very rapid degradation in cells. I mean, it's literally within minutes. So, this is extremely rapid, and it demonstrating we get cell permeability. And of course, not only on cells, but we've done an extensive preclinical development workup with Sanofi on this compound before selecting NX-3911. So not only in cells, but basically in every species of animal, and we've, through oral dosing, shown very rapid and potent and complete degradation of STAT6 in multiple species, you know, through primates. The parts we've shown, the data we've actually disclosed has been in mouse models of inflammation, type 2 inflammation. There again, you see rapid decrease of STAT6, as well as moving all of the inflammatory response actually below knockout levels or 2, 2 knockout levels and below unchallenged mice. So actually, it's a complete removal of the pathway in these animal models. With regards to the animal model data with NX-3911, were you able to compare that to, you know, Kymera compound, where I think they're developing KT-621, also against the same target? How do the two compounds compare and contrast in terms of properties? We have not been able to do a direct head-to-head comparison. We don't have their molecule. We certainly didn't have it at the time of development. What we compared to was other industry benchmarks of approved agents in terms of blocking the pathway and these animal models. Those are obviously the clinically and market-relevant comparators today. And our degrader performed extremely well against those benchmarks. And of course, it's oral, so that's an advantage. In terms of future comparisons, I'm sure people will do those comparisons with the Kymera compound when all these structures actually are published, and it'll be interesting to see. I think obviously the most important will be what are the clinical data comparisons that can be made when that time comes. So, I mean, you raise a good point. I mean, I'm sure you compared it to dupilumab in animal models with NX-3911. Actually, that was something left up to Sanofi to- Oh. ... to engineer. There are certain limitations in terms of what they, what compounds they wanted us to work with, as you could imagine. So, but you'd have to ask them. Okay, that's fair. Well, I mean, from a positioning standpoint, how do you think NX-3911 would fit, given you know, dupilumab has been approved since, I think, 2017, and, you know, initially in atopic dermatitis, but now they've got many more indications across skin inflammatory as well as respiratory inflammatory diseases. So just your thoughts there in terms of NX-3911's positioning to what, you know, has been you know, very successful drug so far in dupilumab. Right. Well, I think this is one that, one area in terms of describing that, this is one area where Kymera has done an excellent job. I think, you know, they had recent disclosures of their phase one data, I believe, their early data of about 22 patients. And, you know, Nello, the CEO, he did a great job of describing the opportunity, and it's extremely large. So, you know, one of the main advantages, it's being an oral agent, safe, with a profile that basically is like dupi or perhaps even better than dupi, we have to see. And again, this is one area where I think I really... Well, it's probably more than one area that I agree with Kymera on, but I think that they, they did a great job describing the opportunity. It's a multibillion-dollar billion-dollar opportunity, can reach, you know, tens of millions of patients, that, you know, don't wanna deal with it, an injectable, and, and where perhaps you could get even, as I said, potentially even better efficacy. So it's a huge market opportunity. There'll be multiple drugs in the space, well, would be my guess. So it's, it's not like a winner-take-all approach here. And there's so many different segments and diseases, as you point out. Each one, you know, is a development program and has to be done exquisitely. So, there's gonna be a lot of opportunity. Yeah, I'm sure. I mean, it's quite a big patient population and total addressable market. So really looking forward, you know, to you know, that program advancing into the clinic. But I did also want to talk about some of the other pipeline- Sure ... programs. So the BTK degrader, so with bexobrutideg, you know, currently, you know, being developed in hematologic malignancies, but you're also developing it on the autoimmune side. I think there's an indication called autoimmune hemolytic anemia. What was the rationale for devel- you know, evaluating bexobrutideg in this indication, you know, for, on the immunology side? So that was just the rationale was an early proof of concept look. You know, not necessarily, this is not necessarily a commercial indication for us, and because we were looking in CLL patients who had wAIHA or the warm autoimmune hemolytic anemia at the same time. So a small number of patients, just sort of a first look. So it's not really, you know, a commercial indication because it's really under the CLL umbrella. Now, but you can't extrapolate from that, and I think, you know, when we started that cohort of patients, that was important. However, now there's so much data from the inhibitors in the space with wAIHA and ITP and all the, you know, pure heme, non-malignant heme, autoimmune indications, like, again, ITP and wAIHA, and they've, you know, seen great results. So I think proof of concept is established there by the inhibitors, and so I think it's a matter of, can bexobrutideg, the degrader, be better than that? And we think it can. So I think the heme autoimmune indications are one area of high interest. Derm, also, we've seen remibrutinib get approved in CSU. So that's another one where I think there's great opportunity, and then we've just seen recent positive results from venetoclax from Roche in MS. So the neuro applications are all, I think, of high interest to us, also for bexobrutideg. So, again, the wAIHA, you know, initial POC look, I think now it's just sort of been overwhelmed by real POC from the inhibitors in the space. So I think there's clearly a big opportunity there. The proof of concept has been established for the BTK mechanism, and again, the advantage of the degrader that we have in oncology, and we think we can bring that to inflammation, also. I think you know, when you move it into these areas like CSU or MS, I believe right now you're working on a tablet formulation. Can you maybe just talk about the status of that, and why you would need that, in terms of developing it for, you know, these indications like CSU or MS? So that's right. We, you know, have a tablet formulation that is in healthy volunteers. It's in, we're in the MAD study portion of the study now, doing all the correct pharmacologic workup to get ready for a potential Phase 2 program in I and I applications. The tablet formulation, we believe, may have certain advantages over the capsule formulation, which is in oncology. And that could include enabling a wider range of low doses, actually, that we think may be util- you know, important or utilized in the I and I setting. So we don't think we're gonna need as much drug. We think we could maybe improve some of the pharmacologic properties of it with the tablet, maybe convenience. We're still sorting out exactly, you know, what would... But it'll definitely be a different product profile, is the way it's gonna end up. And so that enables us to, you know, address differences in the market, pricing differences, dose differences. So it gives us a lot more clinical development and ultimately commercial flexibility. Arthur, when can we expect to see some of the Phase 1 data, you know, with the trial that's currently ongoing? You know, our goal is this year. And that'll be important data to tee up, you know, how we approach the studies that will take place in patients then. Yeah, so this year would be the goal. These are healthy volunteers, so, you know, one shouldn't likely expect, you know, like a PD, you know, parameter or endpoint. But I think, you know, other companies have done ex vivo blood assays to kind of mimic what an immunology patient would potentially look like. Is that something that we could expect with the, you know, Phase 1 SAD, MAD, healthy volunteer data? Well, I'd prefer not to comment right now on all the types of data that we hope to get out of it. Obviously, we'd like to do as much as we possibly can in the healthy volunteer study that it would read to patients. You know, but I can't comment on all the assays we've done, and we've done a ton of in vitro assays as well as in vivo assays. And it's very thorough healthy volunteer study. That's all I can say at this point. But don't forget, we've also learned a hell of a lot from all of our patients in CLL. We've been in over, I think it's about 300 patients in B-cell malignancies. So we have a lot of patient data from the fundamental molecule. Now, not this formulation, of course, we're gonna translate over, but we do have a lot of basic information from those studies as well. And you also have an IRAK4 degrader. Can you talk about this target and its relevance in some of the immunology indications? Yeah, so, IRAK4 is another one of these important kinase nodes in the cell, like BTK in many ways, but it's a different pathway, and it has different attributes. So we're partnered with Gilead here, so similar deal structure to what I talked about for Sanofi, so I won't repeat that. But, you know, we embarked on that as part of the drug discovery collaboration with Gilead, I think in 2019. They had a IRAK4 inhibitor in the clinic at the time, so they knew a lot about IRAK4. They knew it was a great target. It's another really important one that's illustrative of this advantage of the degrader over the inhibitor, because they had an inhibitor in the clinic, and they could see they're running up against certain limitations, and not only Gilead, but others had. The target itself was, is a great target, but it, it really needed to be removed. So, when we developed the degrader, this is an area where they allowed us to use their inhibitor, and they have more than one inhibitor as a control to show superiority. We had to prove to them superiority of the degrader mechanism, you know, as compared to their own inhibitor, which in vitro, as we're developing this, of course, which we did. So it's pretty impressive. They're very excited about the program. It's completing the MAD portion of the healthy volunteer studies under their administration now. And we're very excited about that target, and again, removing IRAK4, you really do get the, the right, the right efficacy out of it. Can you talk about some of the key learnings? Because there was a competitor degrader program that Sanofi was developing through their relationship with Kymera. I think it's KT-474. They initially, I think, presented Phase 1 data showing IRAK4 knockdown, you know, north of like 80%-85% across various doses, and then moved it into Phase 2 in atopic derm as well as HS. And but then, you know, last year, I think they announced that they were gonna pivot to a backup. Maybe I know they didn't really provide much more than that, but anything to kind of any key learnings that you take away from their development program? Sure, a lot, and that was one area where they were out in front, which was great, and we were able to make their molecule, so we actually directly profiled it against our candidate. And we've shown and publicly shown that we have better tissue penetration, significantly improved. So you can degrade in the blood rather easily, but then you got to look at the target tissue, and so we've been very adamant in the workup of looking at skin. We penetrate the skin down to, like, near total degradation of IRAK4, whereas the Kymera compound didn't. It was only about 50% levels. That's number one. Number two is that the safety profile. I think there were some safety issues around QT issues with the Kymera compound. We did never saw those, don't have them. You know, we actually did, and Gilead did. This is sort of, you know, a Rolls-Royce of studies in animals around cardiac safety with regard to our clinical candidate. So we're, we think we've got a safe profile. You know, obviously, it's in humans now. So safety, efficacy, you know, this is... So, you know, one area where degraders are similar to small molecules, you know, not all degraders are created equal, right? Just like small molecules, right? And so you, you've got to get all the parameters just right in order to really have a successful drug. And I think, anyway, those are some of the major issues there. Great. I think we're about out of time. Really appreciate you, you know, joining and sharing the immunology side of the story. I'm sure... A lot of focus on the oncology side, so really appreciate that, and, looking forward to a lot of the early-stage readouts later this year as well as next year. Well, thanks, Biren, and we really appreciate being included in this, you know, group of companies that you cover in this field. Because I think it's gonna be a big year for Nurix in 2026 here with our immunology pipeline. Great. Thank you. Thanks, everyone, for joining. Thanks.