Hey, good morning, everyone. Good afternoon at this point. Thanks for joining the OpCo conference. Excited for our next fireside, which is with Nurix Therapeutics. We've got Arthur Sands, CEO. Arthur, how's it going? Great. You know, I guess we'll start with NX-5948. Probably the most topical thing right now, pipeline in a drug. Clearly working through at this point. Thanks for joining the OpCo conference. That's very stressed. For our next fireside, which is Nurix Therapeutics. I'm right there. Is that better? What's going on here? Oops. Hear me? Hello? Oh, geez. What happened there? All right, we're back. The joys of virtual fireside. Let's try again, Matt. Let's try again. Yeah, let's try again. Okay, so NX-5948, ASH, I think you showed what everyone wanted to see, right? At least in blood cancers. It's clearly a drug, deepening of responses, clean safety. What are the main pushbacks that you're still getting from investors? Not many. I think most people are basically wanting to know, you know, how are we going to push forward the development program into phase III to approval? So that's really not a pushback, it's sort of a push forward, right? So we're getting a lot of great feedback as to what we should do to get this drug approved. And of course, we're working wholly on that. That's our number one corporate goal for 2025, is start our pivotal trials. As you probably know, we anticipate an accelerated approval pathway for this with the results we have. But obviously, we will initiate that trial this year. Single arm, probably be 100+ patients. And that's the main goal. And then at the same time, or in close proximity, start the randomized confirmatory trial, which is required as well. So that's our full focus on NX-5948 this year. So that strategy kind of looks like pirtobrutinib with BRUIN? We'll see. You know, they started a few years ago, so you have to treat the current landscape, you know, in terms of the trial design. That's an active, you know, area of discussion where we're working on that. Yeah. I think the main pushback that I still get is that the duration of responses is still kind of an unknown. I mean, they're clearly shaping up very well, but you've really only got like four to five months on average duration. You're not getting many relapses, but I think pirto has something like a 12-month median DOR, right? Can you kind of, yeah, do you want to just frame that for us, kind of what your expectations are internally? Yeah. So first off, we have not reached our duration of response, right? If we had by now, it would not be a good thing. I mean, our duration of response is not calculable yet. We can't calculate it because people are still on the study and they're staying on. I think we talked about duration of treatment, which is just how long people have been on, you know, a median. And so that's very different. That is going well. But the duration of response is a key factor. I think pirto, yeah, is hovering or seems to be around 12 months or with a PFS of maybe 14 months at their last presentation at ASH. So it'll be interesting to see. The non-covalent in general, which pirto is a non-covalent binder of BTK, you know, we think degrading BTK and removing it will be a stronger overall effect, which should translate to a superior duration of response. So it's, you know, we're fundamentally different than a non-covalent inhibitor and also fundamentally different than a covalent, you know, by removing the protein. So we think we're going to have better responses for longer. That's the goal. Why are we not seeing the typical BTK class effects here on the safety side? We're not really seeing a lot of AFib, flutter, the CV risks, thrombocytopenia, the bleeding risks. We're not really seeing much of that. Kind of like, what do you think is unique about your degrader versus acalabrutinib, zanubrutinib, and the others? Yeah, so I can tell you that the degradation mechanism requires much less drug to be effective, and when I say much less, like our blood levels are 5,000-fold lower than pirto, about 100-fold lower than ibrutinib, and I think it's several hundred below acal and the others, so in order to trigger the degradation mechanism, which is a catalytic mechanism, you need very small, almost trace amounts of molecule to get inside the cell, and one drug molecule can knock out, we don't even know, 1,000 targets itself, so it's not one-to-one stoichiometry. The inhibitors are one-to-one. Why does that potentially lead to a better safety profile, well, because the high, you know, high blood levels of any compound are going to have more off-target effects. It's almost by definition, and that's how inhibitors work. They have to saturate their target, and they have to saturate it like 24/7. A degrader molecule, you need one molecule can, again, take out hundreds or thousands of target molecules, target proteins, BTK. So anyway, that's, I think that's one of the main reasons that we appear so far to be safer. Yeah. Yeah. Yeah. Speaking of another degrader out there, people often compare you to BeiGene's degrader. I think some of the pushback I get is as a huge conglomerate, they have more resources than you do to run a phase III. They already have an established sales force. How do you think you can compete with BeiGene? So we're focused, we're nimble, we're a wholly focused biotech that have been developing degrader molecules for the last 10 years. So I think our focus is an advantage. And certainly BeiGene is a great company. And I do think that they've actually lent a lot of credibility to the degrader concept, actually. So we've actually seen, I'd say, an uptick of awareness because BeiGene is in the space. And they certainly know inhibitors. Well, zanubrutinib is a really great drug, but they're shifting to degraders. And I think that tells you something. And so, you know, we're right there with them. Yeah. What do you think about their strategy of, I mean, it sounds like they're planning a head-to-head against pirtobrutinib. That sounds like a pretty high bar, right? I mean, obviously they don't want to cannibalize zani in the front line. So maybe they're in kind of a tricky position. I don't know. Does what they do affect what you do or how you're planning? I mean, I can only talk about what we are doing and what we do, but we think that our degrader NX-5948 has the potential to be a best-in-class drug, degrader, the first that actually entered HemOnc, and as such, we believe we can displace or maybe even replace inhibitors in general. So that would be, you know, the covalent as well as the non-covalent. So I think the real strategic play here is, can degraders, can removing the protein be better as a therapeutic option than blocking any target, whether that be BTK or other oncology targets or I&I targets? And we think by removing the target, you'll have a superior drug. And I think that'll play out over time. So it's not just about, you know, us versus BeiGene or what they're doing; it's about degraders versus inhibitors, actually. Yeah. Well, I mean, speaking of scaffolding function, you're clearly showing activity in patients that basically have like kinase null mutations. So there's certainly an angle for this drug in kind of a later line setting. But I agree, it will be interesting to see how this shapes out on a potency versus potency basis against like the zanis and the acals in front line. And I think ultimately, as we think about the share price of this stock, where it is right now, none of these earlier line settings are priced into shares, I don't think. No. I mean, I think that people will start to see this as a superior therapy and modality in general. You know, and of course, BTK is our lead program, but we have about 10 other degrader programs running, as you know, several with partners as well as our fully owned. Yeah. And we'll get into some of those a bit later. Just to finish up on the oncology front, recaps or catalysts for this year. I have pick a dose for dose expansion. I have get regulatory alignment on the path forward for accelerated approval. And then I have more mature duration of response data around ASH. Should we expect the usual cadence of data at EHA and then ASH this year? I think so. I mean, enrollment's going well, you know, actually, you know, kind of ahead of schedule, and so, you know, we are on a pretty vigorous reporting schedule, which is twice a year. Obviously, we have a big following in Europe. We have a number of European investigators, and we're open in basically almost all countries now in Europe, so EHA is a great venue for us no matter what. Of course, you have to submit abstracts and have them approved, so we don't know that yet, but that's definitely on our radar, and then ASH, similarly, so those two meetings are key for us. Yep. Yep. All right. Switching to I&I for NX-5948. Again, like honing in on this pipeline in a drug. I mean, there's so many different places that you could take this thing, right? Remibrutinib has shown its activity in both HS and CSU. Tolebrutinib recently in a certain form of the kind of the more smoldering form of MS, which is a huge underserved market, I think. You know, you guys have penetrance of the blood-brain barrier, which I think is unique to you relative to other degraders. What are you thinking? I know you've shared some early thinkings about the I&I strategy, hemolytic anemia being one that's come up as maybe having a good biomarker and obviously bridges like that. You know, you're already in hemolytic, you know, oncology and heme indications. So kind of, yeah, just like run through the I&I strategy as it's evolving right now. We want to be the first BTK degrader in I&I. And, you know, as a B cell mechanism, it's very translatable to many different indications, as you point out, as it's a fundamental B cell mechanism, as rituximab is, for example, anti-CD20. But as a small molecule, we think we have that kind of potential. Now, the question is how do you get there? And so it's a stepwise approach that we've outlined, starting with hemolytic anemia, so autoimmune hemolytic anemia, which exists in CLL patients as well as non-oncology patients. And this is the warm autoimmune hemolytic anemia indication to start with. And that does carry with it several advantages, very, you know, rapid readouts, objective readouts. And we can see our activity and our benefit, clinical benefit for patients. So we rank that very highly. We've already opened a cohort in CLL with autoimmune hemolytic anemia. Then we'll also be pursuing the non-oncology indications as well. Now, in terms of, you know, rank order, dermatology is clearly a whole, you know, obviously huge field. I think MS is a very important one for us, given our brain activity in patients with CNS lymphoma, which is obviously one of the most serious aspects of lymphoma that there is, and that we've seen great results there, which tells us, I think we work in the brain and we could offer benefit there. Do you think there might be a biomarker in MS that you could use? There's been some studies about these paramagnetic lesions and kind of more smoldering disease. It makes sense to me that a BTK inhibitor like yours as a chronic therapy could work for kind of some more of these chronic type phenotype patients. I just wonder, you know, really kind of where's your thinking around MS right now? Is that really an indication you think you could go after? I mean, I think it is. You know, now the question is timing and, you know, we have to get there in a logical sequence. But, you know, so our theory, and which I think is backed up with our oncology findings so far, is that the scaffolding function of BTK is just as important in autoimmune disease as it is in cancer and in what we're seeing in oncology. So you pointed out that, you know, our degrader works even in kinase-dead mutations. These are patients that have a BTK mutation where there is no kinase activity. So it's just a, it's a scaffolding protein. It's a signaling protein, part of the structural fabric of the cell. What's also interesting in our oncology results is that over half of the patients have wild-type BTK, actually. So, they're not. It's not even mutant, but they fail to respond to inhibitors. So why is it that they respond to our drug by removing the protein? Again, I think it's that other signaling function of BTK, which is the scaffolding function, is sitting there in front of us. So we think that's a play in autoimmune disease too. So that by, again, removing the protein with a novel mechanism, we anticipate getting better efficacy and a better safety profile. And that we think all the BTK inhibitors, although they've shown promising results, as you point out, there's definitely, they're leaving room for, they're leaving stuff on the table there. So it's definitely room for improvement. Do you think that's because the therapeutic window, like on a molar level, like they just can't hit the target hard enough without seeing the safety side effects? Obviously, as you know, when you're not dealing with cancer, safety is much more paramount, especially with chronic type therapies. You know, what I really think is that there's two mechanisms going on. There's the kinase mechanism and there's a scaffolding mechanism. I think they're about 50-50. I think the kinase inhibitor, I think you're taking out about half of the function. Even taking out half of the function is good. You'll see therapeutic effects, you know, but if you can take out all of it, which the genetics fit, I mean, there are, you know, humans lacking BTK who basically have a, you know, immunocompromised phenotype that is significant, but tolerable. They're viable. You can remove this protein and affect the immune system, you know, singularly. I don't think the inhibitors are doing that as effectively as a degrader can do. Got it. We've seen also from the preclinical studies, you've got pretty good penetration into skin tissue. So I wonder if this opens up for you, like indications like HS and CSU, if you're thinking there? It definitely opens it up. The question is that, you know, as bullish as we are on the novel mechanism, it is still a novel mechanism, so you know, we believe that the right way to start is in truly, truly life-threatening conditions. I see. Because it is novel and we're learning as we go. Now, everything we've learned so far is great, but, you know, you've got to be cautious. First, do no harm, right? Yeah. You know, so we're seeing a safe profile with great efficacy, but we need to start in life-threatening conditions. Okay. So that is something like a hemolytic anemia then, like the warm autoimmune hemolytic anemia. Definitely life-threatening. There's no approved agents. Steroids are used, Rituxan's used. Clearly, there's evidence for the B cell component. We do have some evidence from BTK inhibitors in the space. But also, yeah, I would put MS in, you know, that is a life-threatening condition. Got it. And so when do you think we'll get more granularity on your autoimmune aspirations later this year? It'll be later this year. You know, it's running already in the autoimmune hemolytic anemia condition in CLL right now. So it's running. But, you know, what we're focused on is opening up the phase II/III program in CLL also. So we got to get all of this running this year. Makes sense. We'll switch to the partnered programs now quickly. IRAK4 and STAT6. I think IRAK4 was with Gilead, STAT6 was Sanofi, right? How are these partnerships looking at this point to the extent you can share? They've been terrific partnerships. You know, we've been running these for now 4+ years, four to five years. We started on STAT6 and IRAK4 at the very beginning. Both of those relationships started within the same year, was about 2019. This has been, these have been longstanding drug discovery programs that are now, you know, bearing fruit. With Gilead, with IRAK4 degrader, that's on track for an IND filing in the first half. Gilead is responsible for that filing, although we are playing a big role in aiding them in the filing, of course. And then, and they'll develop that through human proof of concept in patients. And then we have an option to opt in 50-50 in the United States, similar structure with STAT6 with Sanofi. Now that program is about a year or so behind the IRAK4. So that will be, we believe, a development candidate licensing event in the first half. That's our schedule for that program with Sanofi. But that, if that occurs on schedule, then that would enter IND- enabling studies, which they prosecute and fund, as well as human proof of concept studies. So those are two really substantial I&I programs. And we consider them part of our future pipeline too. I have to imagine you're paying attention to Kymera STAT6, which is probably coming out the first half of this year. Do you think there's any real differences between you and that degrader that you can speak of based on the preclinical data that you've seen? Hard to say at this point. But, you know, I think it's fantastic that they're out in front. This is a huge market opportunity. So there's obviously room for more than one compound. You know, we've worked very closely with Sanofi over the past five years, the goal being to create an oral Dupixent. You know, obviously they know this market extremely well and they know the science. They've been terrific partners to develop this molecule. Our goal is to have a best-in-class molecule. But, you know, we have to see all that play out in the clinic. Yeah. Makes sense. Maybe just in the time we have remaining, first, maybe if you just want to talk about any other pipeline programs that you're particularly excited about. I know you have this DAC kind of approach, which is a bit, you know, out of left field for sure, but you also have a bunch of other degraders that you're kind of working on behind the scenes. So are there any that are really exciting to you? Yeah. So you mentioned the DACs, which are degrader antibody conjugates or DACs, which is a, you know, a whole new generation of ADCs, is basically antibody drug conjugate, but with a degrader. I think this is one of the biggest new areas for us and extremely exciting based on the data we've seen. We've been working originally with Seagen and now, you know, Pfizer, of course, great alliance. The whole concept is really shockingly effective so far, which is, you know, you put a degrader on an antibody and, you know, use the antibody to give you cell-specific delivery, highly potent, highly specific targeted therapy. So unlike ADCs, which have been basically toxins, you know, generic kind of linked, we're talking about targeted therapy on top of targeted therapy. And I just think this whole field is about to just be blown wide open with new opportunities. And, you know, not just in cancer, by the way. So I think this is something big to watch. And, you know, I love having a front row seat with the Pfizer Alliance, Pfizer Seagen. It's great. Yeah, it's pretty cool. Just want to run through the catalysts for this year and then we'll wrap up. Sure. So we're, you know, we're going to have NX-5948 on stage. We anticipate at, you know, mid-year EHA. There's a Lugano meeting also. EHA this year is in Milan. And then Lugano is every two years, which is a CLL-focused meeting. We're also planning to participate there. And then we have ASH, you know, which is of course a big event for us. I think what's, those are 5948-centric, you know, events. But really the launch of our I&I platform with the progression of our Gilead Alliance and our Sanofi Alliance, I think in the first half, there's probably more going on there than people realize. So I think that's going to be important, like very important for us. And then we'll, you know, of course we're invited to any number of conferences where we participate, scientific as well as investor. We're going to be very active this year communicating our advances. Nice. Sounds like a lot of fun. It's always a pleasure, Arthur. Thank you so much for the time. Thanks, Matt, and I'm glad the technology held up. That's right. That's right. Thanks to everyone for joining. All right. See you.