All right, I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to be joined with, by Nurix, with Nurix Therapeutics, for this next session. Joining us, we have Jason Kantor, who is the Chief Business Officer, and Hans van Houte, who is the Chief Financial Officer. Either of you want to make any opening statements before we jump into Q&A at all? Sure, Steve. Thank you very much for inviting us. Appreciate being invited, as always, to discuss Nurix and our programs. Yeah, I guess I'll start off with that we had some great announcements last week, which were received very enthusiastically by our investors. Both the announcement of our extension with Sanofi for our STAT6 program that we were working on for a number of years now, which is getting closer to a development candidate. And the CNS penetrant data that Gwenn Hansen, our Chief Scientific Officer, showed at AACR. You know, as probably investors are aware, we decided to pursue a follow-on offering last week of our common stock. The proceeds, in particular, to accelerate the enrollment of our oncology trials for NX-5948, which is a heightened degree of interest from our investigators coming off of ASH 2023, and most recently, AACR last week. So we plan on using the proceeds to accelerate our oncology trials for NX-5948. I realize this is an oncology-focused event, but in addition to oncology, another goal for NX-5948 and use of proceeds is to enable an autoimmune IND later in 2024, and put Nurix in a position to start clinical trial in 2025. So we're very excited about the reception we're getting from investors and our outlook for 2024. Steve? Very good. Yeah. I guess we will try to keep things on theme with respect to oncology, but I know it's getting harder to talk about Nurix and not bring in the I&I piece. So, I think we do an I&I day, so we'll have you back for that as well. So I think, you know, Hans, you mentioned some of the AACR updates that were provided last week, and then maybe we can start with the clinical evidence of CNS penetration, that you provided for those couple of patients. I know that this molecule wasn't predicted to be CNS penetrant, you know, per a lot of the historical medicinal chemistry rules that usually govern these things, but was this just a serendipitous finding? Was this something that you stumbled upon in preclinical testing? Would just be kind of curious to kind of hear the evolution of the CNS exposure story here. Well, I can jump in there. So, thank you, Steve, for including us in this, in this investor event. So just to backtrack a little to the data that we showed at AACR. So we had previously shown that NX-5948 was brain penetrant in models, in both rat and mouse, both fully intact and in disease models. But what we showed for the first time was that we get brain penetration and activity in the brain of patients. Now, we're the only trial in the space that's admitting these patients. They're excluded from all the other phase one trials. And so, we reported that we had six patients with CNS involvement as of January, and we had CSF samples from five of those patients, and all five showed nearly equivalent CSF drug levels as to the free fraction in the plasma. So this is a really good evidence, and the first evidence of a degrader penetrating into the CSF. And on top of that, we showed two patient case studies, one in primary CNS lymphoma and the other in CLL with CNS involvement, both showing a very dramatic activity of the drug in the brain of both of these patients. And so, we're very excited about this. This was not entirely serendipitous, as you describe it. We, these are rule-breaking molecules, but we are in the process of writing the rules. We, Gwenn showed in her presentation that we tested over 12,000 degraders, and, you know, we take all of the degraders that are oral and test those for brain penetration. So we are learning how to make these brain penetrant. And again, you know, I think we're teaching the field how to do this. Very good. So I know the epidemiology of CNS lymphoma that occurs as, I guess, either primary disease or secondary DLBCL is pretty rare, but do you think that there's an opportunity to leverage the signal that you're seeing to potentially pursue an accelerated approval? And, you know, I'm guessing that you probably wouldn't need more than 75-100 patients worth of exposures, and you could presumably design an expansion cohort that could have registrational intent. Is that something that you guys are considering at all? Yeah. So to speak to the epidemiology a little bit, primary CNS lymphoma is about 4%-5% of all primary CNS tumors and about the same percentage of extranodal lymphomas. So, you know, it's on the rare side, but it's definitely a real indication. For CLL, CNS involvement is a little less well understood, so we don't have good numbers there. In terms of an approval pathway, there are drugs that are in development for primary CNS lymphoma that could be, you know, a possible path for us as well. We haven't specified that at the moment, but in primary CNS lymphoma, that would likely be a combination approach just because single agent therapy there is quite challenging. Durability is key, and although we know we have very strong activity, you know, we'd want to put our best foot forward if we were to move forward in Primary CNS Lymphoma. Okay. And Hans, I know you mentioned the IND filing you're targeting for autoimmune. I guess, is it safe to say that MS is kind of the obvious application here, just kind of given some of the prior art that's been established by some of the other BTK inhibitors that are out there? And I guess, just given the dose escalation work you guys have done thus far, do you think you'd have to step through healthies, or could you go directly into patients? We're working through that. I mean, I think we have – we do have a healthy volunteer study plan for 2024 to, you know, further, you know, do our preclinical work and clinical work on oncology. We're in the process of looking at indications. I think MS is not safe to assume we would go there, but safe to assume we'll look at it hard in conjunction with other autoimmune indications. But we have a panel of experts right now that we've convened to kind of work through that as we complete our kind of preclinical work on enabling an autoimmune IND. Got it. I'm having some camera issues. Apologies. So I guess on the safety tolerability front, Mm-hmm ... we have kind of yet to see any instances of atrial fibrillation or hypertension associated with NX-5948. I know it's, again, small patient numbers with a limited duration of follow-up. But we've also seen, you know, a lack of these AEs recapitulated at least thus far with the BeiGene degrader. Again, small patient numbers, short duration of follow-up. But do you think that there's, you know, something about kind of purely degrading BTK that is somehow mechanistically or circumventing these adverse events? Well, we know that BTK, as a target, is really one of the cleanest, best targets out there in heme onc. I mean, there's just a ton of data showing good long-term safety and efficacy of BTK inhibitors. On the degrader side, you know, we're very encouraged by the safety profile that's emerging for NX-5948. You mentioned, I think two of the important safety signals that have been seen, particularly with ibrutinib, which is the atrial fibrillation and hypertension, which we haven't seen with NX-5948. And so, you know, we're very encouraged, and it's part of the reason that we're moving forward aggressively with this program. We think it's got a product profile that, you know, we would put up against any of the inhibitors and certainly any of the degraders. And the free plasma exposure data that you showed for NX-5948, you know, was really orders of magnitude lower than what we've seen with the inhibitors thus far. And I guess I'm curious, does the NX-2127 free plasma exposure data look comparable to NX-5948? Yeah, I don't think that we've presented that, but what you know, what you're referring to, some of the data we had at AACR, where NX-5948, the free unbound fraction in the plasma is really quite low. And we think that this is important, you know, because many of the inhibitors need to maintain very high free drug levels in order to maintain inhibition of the target. And this could lead to additional off-target toxicities, and we have seen some for some of the inhibitors, particularly some of the newer inhibitors that have run into liver tox signals. We think the fact that our degrader can operate at such a low free plasma level and, you know, an equivalent level in the CSF is a very good aspect of the drug, and it relates to the catalytic activity and the removal of the target protein. Okay. So I know that you're now guiding to providing a broad update of NX-5948 later this year. I think mid-2024 is the guidance. Can you just speak, I guess, to the magnitude of dose escalation data that you'll hope to have in hand at that point and, you know, whether or not you'll be in a position to declare, you know, a dose or doses to move forward into expansion? Yeah, certainly. We're really excited to be guiding to a mid-year update. We're also guiding to an expansion of the trial in CLL and potentially in other NHL indications as well. Those two events may not coincide directly. They may or they may not, so we'll be making the decision on the expansion independent of when we're actually presenting the data. The data update will be meaningful. So our last data was at ASH, which was based on an October data cut. This data cut will be about six months later, will include significantly more patients with both CLL and NHL, will cover the whole range of doses in the trial. We'll have about six months longer follow-up. We'll have additional data on mutations at baseline, and you know, we're hopeful that this data set will at least directionally provide some indication of how the therapy is shaping up, both from an overall response rate and a duration of therapy. Okay. Any expansion of the CLL trial, can you just remind us what that entails specifically? Yeah. So on clinicaltrials.gov, we list two CLL expansion cohorts at two different doses. So this is going to be how we approach it, you know, to keep up with Project Optimist. We'll be looking, you know, essentially at two different doses in CLL before choosing, you know, a dose to move forward into pivotal studies. Okay. And so we know that you're, you know, dose escalating in both CLL and then kind of various NHL subtypes in parallel. Presumably, you know, there's a higher disease burden in NHL that may require a higher dose. But I guess in terms of, in terms of where you need to be from a dosing perspective in CLL, do you know, I guess, you know, what those levels look like that allow you to effectively cover all of the resistance mutations? Yeah. So we're like I said, we are exploring all the dose levels for CLL as well. And, you know, we're going to choose our dose based on, you know, a mixture of very standard, you know, efficacy and safety measures, as well as PK and PD measures. So, we'll be looking at all of that in order to make those determinations as to which which dose to take forward. But yes, we are covering the mutations at the doses, you know, that we're testing. Okay. I know in addition to expansion, right? That's being expanded, I believe, in these double refractory patients still. Is that correct? Yeah, I think the focus for the expansion will be in patients who have failed both BTKI and BCL-2, which is where we have our Fast Track designation. Mm-hmm. And can that expansion effort be designed in kind of a seamless way that would then allow you to start pursuing a path to registration in that double refractory patient population? You mean to expand the phase 1 to become a registrational study? Yeah, correct. So you kinda, you kinda have a seamless phase 1b expansion slash to the registrational- Well, I think that's sort of what Lilly Loxo did. I think they ultimately enrolled, like, 800 patients in their phase 1 study. You know, I don't know if that's the exact way we would approach that, but certainly all the patients that were... that we have in this study, you know, go towards, you know, whatever eventual approval- Mm-hmm Path will happen in CLL, whether that's an extension of this trial or an expansion into, you know, a newly named trial. I think, ultimately, what we're gonna look for in CLL is very broad development strategy. Our aim is to get this into second line and then ultimately, potentially in the first line. We think that degraders have the potential to displace inhibitors in the marketplace. Certainly, in the second line setting, you know, our view is if you failed one inhibitor, you're gonna wanna move on to something which has a new MOA and can address all the emergent mutations, and that's why, you know, a second-line degrader would be the way to go. But if that data holds up, you know, we think that there's no reason not to start with a degrader. We think hitting the target hard is a proven mechanism in cancer. We think preventing mutations is a great strategy, and so ultimately, we're gonna look to, you know, to do the big studies, to get this in the right position in CLL. We may pursue accelerated pathways outside of CLL. That could be, as you mentioned already, in a CNS lymphoma, that could be in a Waldenström's or mantle cell, or another indication as well. Okay. This progression into second line, maybe even front line, I guess, have you guys internally thought about how you would want that trial to look like in an effort to try to maximize competitive differentiation? Would you... So for instance, in second line, would you be interested in pursuing, you know, a combo approach with venetoclax? Are you interested in fixed-duration therapy, which is something that we've seen from some of the BTK inhibitors? And I guess if you do push into earlier lines of therapy, do you think that that is something that Nurix can pursue independently? So have we thought about these trials? Absolutely. So our head of clinical, Paula O'Connor, is quite an expert in this area. We've mapped out potential trial designs. We're not ready to share those publicly at the moment, but they will involve, you know, head-to-head trials. We will be looking at combinations with drugs such as Venetoclax or with anti-CD20 antibodies as part of a long-term strategy to get into the front line. We would definitely be interested in looking at fixed-duration therapies. Again, anywhere that a BTK inhibitor is going, we think a BTK degrader could do it better. Obviously, we have to let the data play out. It's still early, but these are aspirational goals. In terms of can we do it ourselves? Well, we're in a better position this week than we were even last week, having just raised a significant amount of capital. But ultimately, we do think a partnership makes a lot of sense for this asset. This is a big market, big trials... and we think, you know, it would make sense. We have a history of doing good deals. Most of our deals involve 50/50 rights, and so we think we can maintain significant ownership in this program and still potentially look to partner it in the future. Okay. Maybe just shifting gears quickly to 21, 27. I know the partial clinical hold was just lifted. Maybe you can just kind of remind us what the next steps for this program are, and when we might be able to see an incremental update. So we haven't guided for an update this year. Our only guidance was to get off clinical hold. Now, we did that in very short order, and we're working to introduce the new, chirally controlled drug form into the clinic. We need to get IRB sign-off and get the new protocol, you know, approved. But from a regulatory perspective, we're all good to go. We will be doing dose escalation with the new form just to make sure we get the right dose matched to what we have in the clinic currently. Patients continue on therapy on the old drug form, who are continuing to benefit. You know, the goal is really to essentially finish up the phase 1b for DLBCL and mantle cell so that we can get a, you know, a response rate. Just to remind you, we've seen some really remarkable, durable, complete responses on single agent NX-2127. This is highly differentiated. You know, we had a DLBCL patient, I think was out 15 months at the last update, and that was last September, and ongoing in CR. And we had a mantle cell patient, who, after 17 cycles of therapy and a CR, just decided to come off therapy because they were feeling so much better and just was lost to follow-up as a result. But, you know, these are remarkable responses, and we wanna make sure that we, you know, chase this signal down, because if we do have a real response rate with these types of responses and these indications, I think it's meaningful, and we'll pursue it. Okay. Maybe we can just talk quickly about NX-1607, which is your CBL-B inhibitor. I think you are guiding to having some clinical efficacy data here before the end of the year. I know we've talked a lot about, you know, the therapeutic index of this molecule, kind of whether or not you'd be able to circumvent any on- and off-target toxicities. I guess, as you've dose escalated, you know, both as single agent and in combination with chemo, you know, has your confidence in the safety tolerability profile, and I guess the potential to demonstrate single agent activity, has that changed at all? I wouldn't say that it's changed. We are taking it slowly. We've been, you know, in sort of a dose escalation, dose exploration for a little while now. We are tracking both proprietary biomarkers as well as more standard IO biomarkers, as well as clinical activity. But again, you know, as a novel IO agent, and especially because we're in, you know, a dozen different solid tumor indications, you know, it is a lot of work to really characterize it. Our guidance is to provide a clinical update this year, and that will be, you know, largely focused on you know our ability to select a dose and an indication to move forward with. I think, to really assess the drug on its best, you know, from its best perspective, will be when we're able to, you know, select an indication or indications and, you know, a go-forward dose or doses that we think are have the best probability of having that, you know, single agent activity that you're talking about. Okay. Maybe in the last few minutes, we can just kind of touch upon some of the collaborations. I know you've referenced this has been a kind of an important part of the Nurix story. Seems to be an underappreciated part of the Nurix story. I know the targets we've learned about, the Sanofi, Gilead, or the targets under the Sanofi, Gilead collaborations to date have been I&I focused. But can you just speak to, you know, how oncology occupies the bandwidth of the remaining targets that are available under each of those collaborative umbrellas? Yeah, sure. I'll just remind folks, we signed these deals back in 2019. Each of them are five-target deals. And those are all for the development of oral degraders. The targets were undisclosed initially. We've disclosed now through the announcement last year that Gilead took a license to the IRAK4 program. That was a $20 million dollar license, and they're working to move that into the clinic. Sanofi, we just announced that they extended their research term to for STAT6 programs, so this was newly disclosed. So these programs are really important, not only because they're bringing in non-dilutive funding throughout the partnership, but also because it helps build our pipeline. For each of these collaborations, we have options to 50/50 co-promote, co-develop in the US, two programs. And that's also the case for our third collaboration with Seagen Pfizer. But to answer your question, we do have programs in the oncology space in both of these, but we also do have other INI programs. I think if you look at our pipeline chart, we mentioned that there's another INI program with Sanofi that's that we're working on. But I'd say the majority of what's undisclosed in these programs is in the oncology space. Okay. And then I guess in addition to some of the early stage collaborative efforts, I know you've talked previously about having kind of your own wholly owned internal efforts in the degrader space. And, you know, when you think about those candidates, you know, how do you characterize the novelty of the targets that you're now interested, right? Are these, are these BTK like in terms of biological certainty, or are you now kind of comfortable taking a bit more biological risk, given the progress that you've made on the platform and on the medicinal chemistry fronts? Yeah, our pipeline is highly diversified from the perspective of, you know, druggability. So like you said, on one end, the BTK, you know, very known druggable target, but then on the other end, STAT6 as a, you know, a transcription factor with, at the time, no known ligands. This is a very undruggable target. So, the pipeline spans that whole range. We've also talked about working on, oncogenic fusion proteins, another difficult area, and new for degrader. So, you know, the pipeline is exciting. We have, put a lot of energy into our partnerships, and, and that's because these-- we do have these options, you know, moving a STAT6 degrader forward quickly, hugely valuable for, for the company. We do have our own internal pipeline, and we'll be talking more about that, to come. We have guided to a clinical candidate this year, which could be from our pipeline or from our partner's pipeline. Okay. And then maybe, Hans, just in the last second here, you mentioned the financing last week. Congratulations. Have you given any formal cash runway guidance? Yeah, we've updated our guidance. We originally had, at the beginning of the year, cash in the second half of 2025. Now we're talking about cash in the second half of 2026. And that includes, you know, additional investment in our NX-5948 oncology trial in particular. Okay. Very good. We are out of time. Jason, Hans, appreciate it. Hey, thanks a lot. Thanks for having us, Steve. Have a great day. Thanks for listening, everyone. Take care.