Welcome everyone, and thanks for joining us for our first afternoon session of Baird's Global Healthcare Conference. I'm really pleased to have with us today, Nurix Therapeutics and CEO, Arthur Sands. Arthur, thanks so much for joining us today. Thank you. We're happy to be here. Great! So I think to begin, would you provide an overview of Nurix? Absolutely. So as Nurix, we're focused on targeted protein modulation, which is creating small molecules to move protein levels either up or down. In terms of decreasing protein levels, that's known as targeted protein degradation or TPD. We have several programs in the clinic around TPD or advancing to the clinic. And then in terms of elevating protein levels, we have a program that inhibits a particular E3 ligase, and the entire system is centered on E3 ligases, which is at the center of the slide. And this is an enzyme system that regulates protein levels normally in the cells. So there's over 600 E3 ligases encoded by the human genome, and it represents a whole new target class that allows us to manipulate protein levels, again, either decreasing or increasing protein levels. We've built our pipeline around this. Here's our pipeline slide. We have three programs in the clinic now. The first two are centered on the degradation of BTK, the removal of this important B-cell malignancy driver of malignancy. I'm sure we'll be talking a lot more about NX-2127 and NX-5948, and how they're differentiated. Then we have NX-1607, which is an inhibitor of the E3 ligase CBL-B, which elevates the immune system, and this is a novel oral immuno-oncology agent. All of the three agents are oral agents focused on once-a-day dosing, and those are all wholly owned programs for Nurix. We recently announced an option was taken to our collaborative program with Gilead Sciences for an IRAK4 degrader, and they are moving that forward through IND-enabling studies towards the clinic. So we're very excited about that. That's they're going to be developing that in rheumatoid arthritis. We have five programs where we have not disclosed those targets that are also wholly owned oncology and autoimmune disease programs. And we have four more programs with Gilead Sciences and five with Sanofi, so we have a very robust pipeline. And then most recently, we announced a major new deal with Seagen, focused on the use of targeted protein degraders to create a new category of cancer drugs known as degrader antibody conjugates or DACs. So this is a really exciting new deal. This was just announced last week, and we received $60 million upfront to initiate this deal. It anticipates multiple product opportunities that are DACs, and that could produce up to $3.4 billion in milestones, as well as our eligibility for royalties. And then importantly, out of this product portfolio that will be created, Nurix has two options to opt in for a profit sharing and co-promotion opportunity with Seagen. So we can talk a lot more about this, but that gives you an overview. It's a very robust clinical pipeline and preclinical pipeline with some truly novel approaches to creating now this next generation of biologics, these degrader antibody conjugates. Terrific. I'll stop there and we can go to questions. Awesome, and that's a great framework for the rest of our conversation today. Maybe starting with the BTK degraders, NX-2127 and NX-5948, talk about how they're differentiated, but maybe more so, what the implications of that differentiation are for where they could fit into, you know, what part of B-cell malignancies they could go after? Yes. So, NX-2127 is what we call a dual degrader mechanism. It degrades BTK, but also it has, the immunomodulatory activity similar to, Revlimid, and that's how we designed it to have both activities. And it does so by achieving degradation of the, transcription factor family, IKZF family of transcription factors, which is how, Revlimid or lenalidomide work as well. So by combining these two activities, we see, have seen now, and reported our first complete response in diffuse large B-cell malignancies, where we think this dual mechanism will have a particularly, powerful impact, and that, that's a once-a-day oral, treatment. In addition, we've reported on its use in third-line CLL patients, chronic lymphocytic leukemia, and we report a response rate on that. We reported that at last, last year's ASH. So that's NX-2127, and we can talk more about it. NX-5948 is a pure BTK degrader, i.e., it does not have that dual activity designed to only degrade BTK. It's extremely potent. We're developing that. It's now in dose escalation across B-cell malignancies. We see that its primary role ultimately in CLL given the great success of BTK inhibitors. But the real advantage of degraders here is that we have seen that degraders work in a setting where the patients are harboring specific resistance mutations to the inhibitors. So this is a growing issue of resistance to basically the entire class of BTK inhibitors, which is now an $8 billion a year plus market. Half of the patients we see enrolling in our trials have mutations in BTK, which render the inhibitors ineffective. And we have also identified that our degraders confer another anti-growth mechanism via removal of the protein, which is known as the scaffolding effect of proteins. Which means that BTK is not only a kinase, but it serves as a scaffolding for other signaling pathways, and by removing the protein completely, we're getting a sort of a double approach to the anti-growth effects of hitting the BTK pathway. So NX-2127, the dual acting agent, where we see aggressive lymphomas, the diffuse large B-cell lymphoma activity is being very intriguing. And then NX-5948, more towards the CLL end of the spectrum, the chronic lymphocytic leukemia end. Great. So maybe for NX-2127, there should be additional data by the end of the year, I believe. Could you help frame maybe kind of what additional data could add beyond what we saw, previously? So we'll have more patients, greater numbers in CLL at the expansion cohort of 100 mg once a day. And then also, we have expanded and announced our expansion in the aggressive lymphomas, diffuse large B-cells. So it would be. Hopefully, we'll have updates on where we are with that, those indications. So that's NX-2127. NX-5948, we did disclose the first data around degradation of BTK, which is the mechanism of action, and we see degradation in 100% of the patients treated. We also see an accompanying biologic effect associated with that degradation, and so we hope to have a clinical update by the end of the year as well for NX-5948. Great. And for these two updates, how much of an opportunity will there be in the data to assess efficacy against the resistance mutations? It'll be a growing data set because we continue to get patients with those mutations. I think that'll just further substantiate what we've already published, which is again that ability to degrade these and to have confer some clinical benefit to patients. So it'll be an emerging, continuing emerging story, and I think it's one that's unfortunately very, very important for the field because it is a growing medical problem. Got it. And what, what could be the next clinical directions for these agents, you know, between now and eventual approval? Well, I think the next big step for both... Well, all three of our programs, is identifying doses to use in the next stage of development. So under Project Optimus guidance from the FDA, the general approach is to expand at two dose levels and pick those doses with being very well-informed on biomarker activity, safety, and clinical effect. So expanding at two doses for each of our programs, I think would be an important next step that'll enable dose selection for a pivotal trial. So we're at a stage where we're ready to do that kind of planning and to take that next step with these programs. You know, we've established some really fundamental things already, such as PK/PD, that we see degradation, as I said, very efficiently. We've established an initial safety profile, and we've shown that the mechanism of degradation can provide significant clinical benefit. So now it's refining that, pick the dose levels, and then prepare for the pivotal studies. That makes sense. And I guess in thinking ahead to pivotal studies, especially for NX-2127, I think part of that is regulatory discussions. Could you kind of tell us where you're at in those, and how to think about the, you know, what pathways could make the most sense for NX-2127? So I think for both our programs, the pathways or the indications towards approval that make the most sense are where we see the greatest clinical benefit and the highest unmet medical need. So to position the programs for potential accelerated approval would be one of the primary, I think, goals for regulatory interactions. And that would be, you know, I think, a next step from a regulatory standpoint, and we have guided to provide some regulatory guidance feedback by the end of the year. Got it. What and endpoints are most important to assess in thinking about the readiness for moving ahead to a pivotal program? Well, you know, I think the key aspect would be proper dose selection under Project Optimus. Mm-hmm ... to move forward. Because, of course, having the right dose and having that justified and having alignment with the FDA on that is critical for effective pivotal study. Again, we've already established the fact that we see clinical responses, we see clinical benefit, we have a safety profile that enables us to move forward, and now it's all about dose and building the right trial. And that's again, for all three agents, not just NX-2127. I think it's important, you know, to remind everyone that we do have three agents. I know two and two seven gets most of the attention because it's farther along, but the other two are actually moving very rapidly towards their expansion doses as well. I would imagine then it'll be interesting to see which of the three actually advance fastest based on their potential for accelerated approval pathway. Yeah, great. So yeah, I guess with that in mind, the one agent of those three that we haven't really talked about as much yet is a CBL-B inhibitor, NX-1607. Can you tell us about kind of frame what data we have so far and what could be coming next for that agent? So, NX-1607 is a first-in-class CBL-B inhibitor. CBL-B is an E3 ligase that has been, I think, on a lot of people's most wanted list in terms of targets because it downregulates the immune system across T cells, NK cells, and dendritic cells. And so with our inhibitor that we've developed, again, a first-in-class small molecule, we can elevate the immune response in the setting of tumorigenesis. And we've demonstrated preclinically that effect. We've been in the clinic and have published on moving the biomarkers in the right direction. So with this novel mechanism of action, it's of course important to demonstrate we're hitting the target, we're getting the biologic effect we expect via biomarkers, and we've done that. So, I think now it's again a matter of getting the dose right and getting the optimal dose, and then we can look for clinical benefit. Got it. More recently, there's also, I believe, been a study of combination of NX-1607 with paclitaxel. Could you kind of discuss that study and physician interest in that? Yeah. So that's our first combination with NX-1607 was, is, with paclitaxel. Obviously, a widely used, anti-cancer agent that, that causes immunological-based cell death and anti-tumor effects. And so, a number of the IO agents have been successful when combining with paclitaxel and chemo. It's been one of the most productive, ways to combine an, an IO agent, and so it's a very logical, next step, with a broad patient population potential and multiple indications. In addition, we expect there to be non-overlapping, tox profile between paclitaxel and then an IO agent. So a lot of, a lot of strong medical rationale for that combination to start. We've, we've just lifted off with that, so it's early for me to talk about any kind of results, but it is a good sign that we've been able to embark on that combination cohort. Terrific, and, well, I guess that cohort is underway? Yes. Great. So for all three of these agents, is there a role for patient selection and, you know, thinking about developing the agents going ahead? So these agents actually have the potential to work in many of the subpopulations of each of these tumor histologies. So these will be, if successful, very broadly used agents, I would say. And there's not a direct way to select a subpopulation, you know, nor should we have to via these mechanisms. So we're really able to enroll broadly across B-cell malignancies in the case of degraders, which we've seen patients in every tissue type of disease, and the same for NX-1607. We have 11 different histologies that we're enrolling, so it's quite a spectrum of tumor that we can potentially treat. Terrific. So maybe I've been seeing the Seagen slide up there, and I think, with such recent news, it would certainly be good to dive into that more. Could you provide maybe, I guess, more of a overview of kind of the financial terms of that arrangement and what the next steps are for, you know, Nurix, as well as, in this case, Seagen, to deliver for the collaboration? Certainly. So, as indicated on the slide, the upfront payment is substantial and indicates the level of dedication to this new technology that Seagen has and that we have as well. So, we have some significant cash up front that's actually... Based on the financials here, we've increased our cash runway guidance to going into Q2 of 2025. This is without counting any of the research-based milestones that we also achieve or anticipate to achieve in this alliance, as well as the Gilead and Sanofi alliance. So, we're in a strong cash position, which is, of course, always very important. And then in addition, the milestones built in are substantial, up to $3.4 billion, as indicated here. This is, we're working to form degraders that will be conjugated to their antibodies, and what why that's important is that one degrader molecule that Nurix makes could be conjugated to several antibodies. And so this particular alliance has really a modular approach to building these future DAC drugs, and that allows the products portfolio that would arise from this to be a potentially quite substantial, again, because of this modular approach. And Nurix would gain milestones based on the products arising, all the products arising through this, under this collaboration, as well as royalties as indicated there. Importantly, on the non-financial side, the pipeline building slide, Nurix has two options to opt in to a cost profit share agreement with Seagen, so on two products. This would expand Nurix's pipeline potential into the area of biologics and indeed this new class of biologics, the degrader antibody conjugates. So the advantages of DACs, we've gotten a lot of really great questions at this conference on this alliance and a number of good articles that are written in the industry press about it. Obviously, ADCs have been very successful, and Seagen being the leader is the perfect partner for Nurix. But the limitations of the ADCs have been the payloads. So the payloads tend to be and have been toxins, so very toxic molecules that can generically kill cells and sometimes too generically. So in this case, the payload is a very targeted drug molecule, the targeted protein degrader. And so these are the bifunctional molecules. I've been speaking about the BTK molecule we've discussed quite a bit, the BTK degraders. These would be different targets. These are novel targets selected in collaboration with Seagen. But they're all targeted therapies, so these molecules will specifically degrade a selected target within the cancer cell, and they'll be selectively delivered to the cancer cell via the antibody. So this molecule enters the cell via the specific antibody binding, goes into the cytoplasm. The TPD molecule is then released. The degrader is released within the cytoplasm of the cell, hits its target and achieves the anti-tumor effect. That's the design of this. And so we have two layers of selectivity here. We have the antibody layer, and we have the degrader layer. And so that provides, we hope, will provide a larger therapeutic index and highly potent anti-cancer agents as well. Now, this has not been achieved with other inhibitor molecules. It's difficult to have a potent enough molecule added to an antibody to achieve cell death, tumor cell killing. The beauty of the degrader is that they're catalytic in nature. Once inside the cell, one molecule, the degrader, can destroy many target proteins via the E3 ligase system, and the proteasome; it sends it to the proteasome. So, the delivery, you really need to deliver very few molecules of a degrader to get a very strong anti-tumor effect. In addition, given that it's so targeted, the degrader, we think that the therapeutic index will be large. We know via the BTK program that it is a fairly wide therapeutic index we're seeing. Here in that program, of course, that's just an oral agent, a bare degrader, and it's well-tolerated. So we think these very specific agents being delivered via antibody should offer up a new concept and therapeutic window for anti-cancer agents. Terrific. So I guess in thinking about the degrader you use in here, I mean, is there a balance to think through in terms of does it need to have to be somewhat targeted to that cancer, or is the antibody doing the work of targeting that cancer? And then for a degrader, you can use something that might be lethal in healthy cells, but since it's being directed at the cancer, you know, that's good enough. Yeah. So there's, I think, that category would be very attractive. So where we hit some of these oncogene targets that, you know, the fields have known about, the field has known about for decades, some of these oncogene targets. But since they also operate in healthy cells, they've been very difficult to hit with a bare small molecule. So here, I think we could actually target some of, you know, the favorite types of targets to kill tumor cells and deliver them specifically, and but still being a targeted therapy, so again, not just a toxin that would kill, you know, any cell. So that I think would be important. But we could also layer on another level of specificity that I didn't really talk about yet, which is the ligase binder that we engage. The E3 ligase that gets engaged to degrade the target could also be tissue-specific. You could layer in two layers of specificity, which would allow you to hit very toxic targets, but only in those cells that you want to do so. Great. So with all these unique components to the DACs, could you kind of go through what is exclusive to this Seagen, Nurix collaboration? Is it the molecules as a whole or the antibodies or the degraders? Well, you get at a very important point. As you can imagine, this is a very well-fortified type of molecule from an intellectual property standpoint because it does incorporate very proprietary technologies on both sides, the payload and the antibody. And so what's exclusive under this alliance are the targets that we degrade. So we identify specific targets for degradation, and those are exclusive, and those are limited to that target set. And we have not disclosed which targets yet or how many are under the alliance, but that focuses the alliance, and it enables us to potentially do other deals in this emerging DAC space as well on different targets. And so that, that's really how the deal is set up. It's exclusive around on a per target basis. Terrific, um- And all the intellectual property associated with that. So, for example- Mm. I got a question from one investor: Well, what if the degrader molecule itself is a drug without the antibody? Okay, well, that would be under the alliance. So we—there could be multiple products anticipated under this alliance to that particular target. That makes sense. Mm. So maybe switching to another collaboration with Gilead earlier this year, you announced IRAK4 agent. What's the status of development of that agent, and how does it fit in the collaborative competitive landscape with other agents in development for IRAK4? So Gilead has been and continues to be a terrific partner. That was one of the earliest targeted protein degrader collaborations we entered into. And of course, they have tremendous small molecule chemistry expertise within the company, so it's really been a great partnership for us. And they had been working on IRAK4 inhibitors, and so they have a whole set of inhibitors. They've actually moved them into clinical development. And the central question on the IRAK4 program then was, could a degrader be better than our inhibitors that we have? And so we're very pleased that they selected the first IRAK4 degrader, and that it's been heavily profiled against inhibitors. So we think it does offer a differentiated potentially superior profile to IRAK4 inhibitors. There are more than just the Gilead IRAK4 inhibitors out there. So the competitive landscape is, has mainly been inhibitors. Kymera does have a degrader program for IRAK4 as well. And so it is an area that is clearly recognized as a desirable anti-inflammatory target. Great, you know, in thinking about these collaborations, and especially the most recent one with Seagen, kind of shows that you're still kind of active in this space. And I guess I'm curious to ask, what, how do you explain Nurix to a potential collaborator? You know, there's other protein degradation companies in the space. You know, why collaborate with Nurix? So Nurix has built a platform, which we call the DELigase platform, that I think is really differentiating. And what that is, it's DEL stands for DNA Encoded Libraries, and we have built now what is over 5 billion compounds, which is a combinatorial library tagged by DNA, that enables us to find uniquely a new chemical matter. And so that's what's really been holding the whole degradation space back is, can you find the chemical matter to build these ligase binders? And we have, you know, over 50 ligases now that we've put through our discovery process and expand this universe of ligase-mediated protein degradation. That's really been the rate-limiting step. I think when partners evaluate us and do diligence on us, which Seagen did quite a bit, they see that our libraries and our chemical repertoire that we can bring to bear to build these very challenging DAC molecules is quite substantial. So I think that's really been a great investment that we made years ago in that DELigase platform. It continues to pay off, and the opportunity is quite large in this space. Great. Well, I see we've almost reached our time here, so I guess, Arthur, just as our last question, I'll leave it to you. Any closing remarks? Yeah. I think it's, it's great to envision, you know, a new world where degraders, really not only compete, but maybe replace a large number of inhibitor molecules that have been the mainstay of medicine, really, are mostly inhibitors. And if we can hit those targets harder, better, with a degrader, it's really an exciting future. We get questions about, you know, how big is this opportunity, you know, to, to be a new class of drugs? And I, I used to say, "Well, it, it could be as big as antibodies," okay? And I still say that, except now we've actually joined with antibodies, so we've got to be bigger than, we've got to be at least as big as antibodies if, if this degrader antibody conjugate concept, comes to fruition. So I think I'll leave it at that. It's a very exciting time in the field in general, and especially for Nurix, I think that these degrader moieties are really gonna be very important novel medicines. So I'll stop there. Thank you. Terrific. Yeah. Thank you, Arthur. Thank you.