No, it's really been driven by our lead asset, NX-5948, which is a targeted degrader for BTK, and that looks to be showing up quite well in the clinic. So I think that's gotten a lot of interest from our current investors. Yeah, that's great. And maybe for the audience here, let me just do a quick intro of Nurix. What is your key technologies? Maybe just a quick overview of what Nurix is all about. Sure. We were founded about 10 years ago out of work that was done on E3 ligases at UC Berkeley and UC and UCSF. And really, Nurix started out as an E3 ligase-centric company. So most of the programs we had at the time were focused on E3 ligases. We had about a dozen that we were looking to find chemical moieties to bind to them because we knew they would be involved in disease. And fast forward, now we're fully integrated R&D. We've got three partners. We've got three wholly owned clinical assets. 5948 is leading the charge. We've guided towards pivotal trials for oncology next year, and we're well funded to prosecute them. Excellent. So I know you guys have a very interesting degrader platform called DELigase, which is what you referred to, Hans, earlier. Maybe just tell me more about, give us an overview of what exactly is this platform and how are you able to identify novel targets and ligases using the platform? Yeah, well, DELigase, DEL and ligase. Ligases are kind of what we were founded on exploring. And DEL stands for DNA-encoded libraries. This was in response to the industry's need for more chemical inventories to basically screen against. When I first started out in the industry at Vertex, we had maybe we do screens against 300,000 compounds, right? And we thought that was a huge number of compounds. Now we're talking about billions of compounds that we screen against. And you can screen targets like BTK against them. You can screen ligases like Cbl-b against them. You can screen all sorts of different things against them to find binders to these targets. And we're developing now more AI and machine learning to actually consolidate those hits more rapidly and be able to resynthesize them. But the DNA-encoded libraries is core to our foundation. We think we have the industry-leading platform that involves DNA-encoded libraries, and we got three partnerships that are discovery that were based upon our ability to discover new entities for development in the clinic, so I think the partnerships are validation of that platform. Yeah, and you mentioned the two lead programs, which are your NX-5948 and NX-2127. Can you tell us about how did you identify those two compounds through your unbiased screening using AI machine learning or using kind of novel ligases? How did you identify those two compounds? Jason, do you want to take that one? Yeah, so just by way of background, so NX-5948 is an orally bioavailable BTK selective degrader that's in the clinic. It's in a phase I-B clinical trial for B-cell malignancies, and with the lead indication being CLL. NX-2127 is also an oral BTK degrader, but it's a dual degrader. It also hits the IKZF1/3 target, which are the targets of the immune. So it's really a dual-acting drug. It's in a phase I trial as well for B-cell malignancies. And both of these were designed in-house and rationally built, one to have that extra immune activity and the other to be pure orally bioavailable and CNS penetrant BTK degrader. Very interesting. Actually, we definitely want to spend some more time talking about both programs. So maybe let's talk about the lead program for 5948. So we've had an early look at the ASH abstracts, where we saw that the ORR increased to 77% with about four more patients evaluable compared to the last update at EHA. So maybe just share some expectations heading into ASH in the next month. How many more patients should we be expecting, and how should we think about the durability of this therapy? Yeah, so thank you. The last major data update was at the European Hematology Association, meaning EHA, back in June. And at that point, we had presented data on 31 CLL patients with an overall response rate of 69.2%. As you mentioned in our abstract that we're just released for ASH with about two months more follow-up and four additional evaluable patients, we're now at 76.7% ORR. And what that's indicating is a deepening of response over time. What we saw at EHA was what we think is a very robust overall response rate, a very favorable safety profile, and to the extent that we could show it at that time, very durable responses. None of the patients who had responded subsequently relapsed. What we're going to see at ASH is approximately six months more follow-up. So all of the patients from EHA, if they've remained on study, will have had six months more duration of treatment. We will have almost a doubling of the number of patients. So we were 31 at EHA. It'll be somewhere in the 50s for ASH. So a substantial update. We think we've already kind of cleared the efficacy hurdle. So again, what we'd like to continue to show is that efficacy holds up, that we see patients staying on therapy throughout, and that the safety profile remains in this very tolerable range that we've seen today. That's excellent. And so we know that the BTK space is extremely crowded. You have the first generation ibrutinib, the second generation zanubrutinib, as well as acalabrutinib, and then you have the third generation pirtobrutinib. So I'm just curious, how are you thinking about positioning NX-5948 in terms of in the whole BTK space overall? Yeah, so for those who may not be as familiar, this is a major blockbuster drug class. Annual sales are approaching $9 billion. It's a very dynamic market. So the first product in the space is a drug called ibrutinib. It's being supplanted by next generation drugs, acalabrutinib and zanubrutinib. And one of the two things that I think are really important is this is a market of long duration therapy, primarily monotherapy. So patients are on oral once a day therapy for a long time. And the major market is chronic lymphocytic leukemia. And these are older patients. And tolerability and ease of medication is really critical. What we know is that it's a dynamic market, meaning new agents that are better are replacing old agents that have liabilities. And we think that degraders have the potential to supplant the inhibitor class. And the reason for that is that NX-5948 overcomes treatment resistance mutations that are driven by all of the inhibitors. And we've shown this both preclinically and clinically. It also addresses the scaffolding function of BTK, which is this unique signaling activity that's not addressed by the inhibitors. And it's been very well tolerated. So our goal is ultimately to replace the inhibitor class. Would you say that the first thing you're trying to do is just to supplant pirtobrutinib? Pirtobrutinib is the most recently launched BTK inhibitor from Eli Lilly. It's approved in the third line setting, post-BTKi, post-BCL2 inhibitors. And that will be the first indication that we go after in the CLL space. So we have fast track designation. And as Hans mentioned, we're planning to initiate pivotal studies next year. What should we be looking for if you were to supplant pirtobrutinib in terms of efficacy and safety? Just maybe help understand what would be the bar that we should be looking for here. Sure. Well, pirtobrutinib is a very good drug. It's got good high overall response rate, and it's very well tolerated. The duration of therapy is relatively short in the third line plus setting. It's about a 12-month duration of response. And we think we can do better than that. And ultimately, we think just mechanistically, when a patient has failed one BTK inhibitor, I think physicians and doctors would prefer potentially to treat with a new MOA against the same target. So rather than going inhibitor to inhibitor, the idea of going from an inhibitor to a degrader to really tackle this protein in a more comprehensive manner, I think this has a lot of appeal. Got it. Okay. That makes sense there. So you mentioned something about overcoming immune resistance mutations. Maybe just talk a little bit more about that. What are some of the features that really allow it to overcome those resistance mutations? Yeah, so degraders work differently than inhibitors. So for an inhibitor to work, you have a small molecule. It binds within an active site of an enzyme, and it really has to stay there. It only works while it's occupying the active site. So we call this occupancy-driven pharmacology. But with a degrader, the way a degrader works is it brings the E3 ligase in proximity to the protein and causes that protein to be tagged and then ultimately destroyed. And we call this event-driven pharmacology. So one drug molecule can catalyze this degradation and then go on to catalyze it again and again and again. And so each molecule may take out thousands of BTK molecules. And this allows a very potent, very selective, very durable degradation. It also allows for a certain loss of binding affinity because that degrader doesn't need to stay bound to the target as long, and so for an inhibitor, one small mutation may completely abrogate the activity, but for a degrader, you can lose a little bit of affinity and still be a very, very potent degrader. Got it. Got it. That's really helpful. So another thing you mentioned was the CNS penetration. So maybe help us understand how is that going to be helpful for patients who are resistant to pirtobrutinib or could be a better feature compared to pirtobrutinib or any other BTK inhibitors? Sure, so let me lead with an example and then think a little bit bigger picture. So we had a patient in the study that we presented at EHA, and this is a patient who had failed three different rounds of therapy. The patient was on acalabrutinib and developed symptoms of CNS disease. Upon assessment of their spinal fluid, they found CLL cells in the CSF. This is a very bad outcome for this patient, and this patient would not have been eligible for really any other clinical trials because patients with CNS disease are typically excluded. We actually include patients with CNS disease in our trial, which is unique, and it's something we did because we knew that our drug preclinically got into the brain and was active. So this patient came on to our study, responded to therapy, had a confirmed partial response, but most importantly, cleared CLL cells from their CSF and went on to continue on therapy for quite some time. So this is really a big success. Bigger picture, if you think about next generation drugs, the thing that drives next generation drugs to be widely adopted typically in cancer is that they're safe, they address mutational resistance, and they're able to address disease in privileged organ systems such as the brain. And so to be able to have all of those things, we think this really sets us up for success in the market. Got it. That's really helpful. And so you mentioned that you are recently starting a single-arm pivotal trial for NX-5948 in 2025. So maybe just help us understand sort of the clinical efficacy bar we should be looking for in that single-arm trial? Yeah, I think with the efficacy where we are now in the 70% range, I think this is clearly hitting that bar. I couldn't tell you where FDA is going to come out in terms of the lower limit of what they would need to see. But I think with the number of patients that we have in the study so far, we can be fairly confident that we are there. The other aspect is that we're approximately 25% of our patients in the study are post-pirtobrutinib. So these are patients who have failed all available therapies. And there is really no benchmark in those patients. And we do quite well there as well. So I think that if we can show that these responses are durable, which we hope to provide some evidence of at ASH, that this bodes really well for the profile of the drug. What about the safety? We know that pirtobrutinib has some bleeding, some AFib, some of those kind of AEs. How should we think about safety for BTK degraders like 5948? Yeah, that's a great question. I mean, we say it's well tolerated, but this is still a medicine. It's still a medicine for oncology patients. But these are very generally elderly patients. And the profile is actually quite good for the BTK class. Most of the BTK inhibitors have bruising as a side effect. And that's something that we see as well. You see some cytopenias. That's part of that is probably related to the disease. But you mentioned atrial fibrillation. This was, I think, probably the most concerning side effect of ibrutinib. And with subsequently more selective BTK inhibitors, we've seen less and less atrial fibrillation. Importantly, for NX-5948, we seem to be more comparable to the new generation of BTK inhibitors. And we're not seeing new onset atrial fibrillation as well as hypertension. So the cardiovascular side effects of our drug look very clean. That's great, so for the audience here, maybe just tell them more about the market potential of 5948 in the last line they're going after, and then as you move into earlier line, how much market potential are we talking about here? Yeah, so as I mentioned before, the market for BTK inhibitors is currently about $9 billion, and it's growing. The majority of that is in CLL. That third line plus market is by patient numbers per year in terms of new starts. It's probably about 20% of the market in terms of patient numbers. But of course, the front line setting is more valuable because patients stay on therapy longer. So it's really, although it would be exciting to be approved in that third line plus setting, it's very important to move into the second and the first line. And we will be outlining a strategy for introducing the drug across all lines of therapy, both as a monotherapy and potentially in combination with other drugs like venetoclax, which are making inroads in that early line setting as well. Got it. And what about the competitor landscape? We've seen a few BTK degraders came into the clinical trials. Recently, the data from BeiGene's BGB-16673 released some abstracts. And it seems to be quite interesting with 78% ORR with two CRs including. So what do you think about that data? And then how should we think about the features of 5948 versus BeiGene's or any other BTK degraders out there? Yeah, so the competition in the space has been quite welcome. If we were talking a year or two years ago, the biggest question we have is, why do you need a BTK degrader? There's so many inhibitors out there. And so this was a real hurdle for us to convince investors of this. We now have two of the leading BTK companies, BeiGene and AbbVie, which have taken BTK degraders into the clinic. And as you mentioned, BeiGene has been showing very robust efficacy just as we have. And what this has done is created a lot of excitement in the field that, in fact, this is the next generation of drug to take on this very large market. And that this has also generated a lot of enthusiasm with investigators, which has led to an increase in enrollment across our BTK degrader portfolio. So we think their data is very encouraging. And I think, again, it speaks to the drug class being very, very exciting. And we're going to move as quickly as we can. And our intention is to be first to market. Maybe just tell a little bit more about some of the features there. Because I think I've seen some preclinical data where you showed that your degrader can overcome resistant mutations better than other BTK degraders. Maybe just tell me more about what are some of the preclinical data that show that your BTK degrader is a little more superior, at least from a resistant mutation point of view. Yeah, so what we had shown preclinically was that NX-5948 was able to degrade BTK regardless of these various clinically emergent mutations that we had seen. And we developed cell lines where we could test this and show that 5948 was able to kill tumor cells that were dependent on BTK that harbored these various mutations. And we asked ourselves, well, is this a feature that applies to the degrader mechanism, or is 5948 special? And what we did was we synthesized degraders that we had seen in the literature and that we had seen in other people's patents. And what we found is not all degraders are made the same. Now, none of the degraders that we made can we claim were anyone else's clinical candidates. We don't know the structure of their clinical candidates. But we just wanted to ask the question, is this a degrader-specific phenomenon? And what we found was that 5948 was fairly unique among the degraders that we synthesized in that it really did address all of those clinically emergent mutations that we were able to assess, whereas others had various liabilities. So we think we have a really good drug. That's great. So for the next 12 months for 5948, maybe just outline a few key catalysts that we should be watching for your next updates for 5948. Yeah, so our next update is going to be at ASH in December. As you said, we have an abstract that's been accepted. It's going to be an oral presentation. We'll be hosting an event at ASH on the Monday evening. So that's something we've done the last two years as well. So that's going to be an important update for CLL primarily. And then as we look into next year, we have guided to that we will initiate pivotal studies in CLL. We'll clearly, between now and then, give a lot more guidance in terms of how those trials are going to be designed. We also, outside of CLL, have shown very positive data in Waldenstrom's macroglobulinemia, which is another B-cell malignancy where we've shown 78% response rate. That’s a data set that we will continue to update and provide some discussion around where we might go with that. We’re also working to develop NX-5948 in autoimmune and inflammation. BTK inhibitors as a class have shown very intriguing activity across a range of indications in allergy and in dermatology and neurology. We had guided this year to complete the preclinical data that would be necessary to enable an IND. We will be giving more guidance into next year in terms of what to expect with that program. Got it. Great. All right. Now we can switch gears and talk about your second program, which also is a pretty exciting program. It's a dual BTK and IKZF inhibitor degrader. So for that program 2127, you are starting the dose escalation trial again using the updated manufacturing process to produce this currently controlled substance. Maybe just share about the progress of your trial enrollment so far and maybe just help us understand some of the data expectations heading into 2025. Right. So NX-2127 is our dual degrader that I mentioned earlier. It started in the clinic before NX-5948, but it's a little bit behind. And that's because we had to take a pause in enrollment as we made a change in the manufacturing of the drug. The original drug that went into the clinic was an approximate 50-50 mixture of two different chiral forms of the drug. And we subsequently developed a manufacturing process to develop a pure form, which we think is a commercially viable, regulatorily viable version of the drug. And so, as you mentioned, we've reinitiated enrollment with that new drug product, which is now in a dose escalation. So we want to reestablish our dose. The reason that we're excited about this drug is we tested in CLL and NHL. And particularly in the aggressive lymphomas like DLBCL and mantle cell, we have seen some very remarkable responses. So we report this one DLBCL patient who had very extensive disease, I think failed four prior lines of therapy, and came on our drug single agent once daily, had a complete response. All the tumor was gone by PET scan at eight weeks. And that patient remained in complete response for 15 cycles of therapy at the last time we looked at the data, which was in the fourth quarter of 2023. So this patient had a very long response and a complete response. We saw a similar response with mantle cell. So we think there may be something very special about combining these two activities in a single pill. And so we're excited to continue to develop that. And we're likely to see data from that program sometime next year. We haven't given specific guidance. Got it. Just one thing, just from looking at some of the data last year that you presented at ASH, we did see some really good efficacy data, especially in DLBCL. We also see a little bit of drug-related toxicity, especially in cases of patients with some AEs, severe AEs. Could you just share about what are some of the thoughts around what causes these toxicities and how you plan to mitigate these toxicities going forward? Yeah, so relative to NX-5948, NX-2127 definitely has more toxicities associated with the drug. I think the primary toxicity that we saw that was dose-related was the neutropenia. This is, we believe, directly related to that second activity, which is the immune modulatory activity. So that is a known side effect of the IMiD class of drugs like Revlimid and Pomalyst. And so this is to be expected for that drug class and also not particularly difficult to manage by hematologists. There were some other side effects that we saw, a few cases of confusion at the higher doses that we think may also have been related to the IMiD activity. And so ultimately, we chose a lower dose to take into our expansion cohorts. But we think the drug is very well tolerated compared to CAR-T, compared to multi-drug chemoimmunotherapy. I mean, you have to think in DLBCL, what are these patients getting? They're getting very, very harsh, sometimes requiring hospitalization therapy, and this is a once-a-day oral pill, so the safety profile, in our view, is very well tolerated for the types of patients that we're looking to treat. In CLL, we think 5948 is the better drug. Got it. And do you think that actually the safety toxicity that we see could be caused by this chiral mixture from the manufacturing point of view? Yeah, we're very certain that it's not. All of our tox workup preclinically was done with the mixture. We know what each of the forms is contributing. They're both active. We don't really see very significant difference in the activity of one versus the other. The only reason to switch to a chirally pure is that regulators require that you have a chirally pure drug if you can manufacture it. And so in order for us to take this forward, it was important for us to introduce that new form into the clinic. And because they're not chemically exactly the same, they're chiral versions of each other, it was required that we would do a dose escalation. But we don't expect the activity to be significantly different between the two drugs. Got it. And so then just to help us understand the market potential of this drug in DLBCL as well as Mantle cell lymphoma, how should we think about the TAM for this market? Yeah, I think it's too early to say that. Like I said, we saw some very interesting clinical signals. We are following up on those clinical signals. And until we really have a view of exactly where this is going to fit in, I think it's difficult to assign a particular patient number. DLBCL is a large market. It's a crowded market and a fragmented market. Mantle cell, not as big. But we haven't really decided where we're going with the drug yet. So I think it's a little too early. What about sort of just position thinking about the clinical and meaningful efficacy here? Is it too early to say what will be the sort of bar we're looking at here? I think it's fair to say that what we would like to see is whether or not the experiences that we had in terms of these long-term complete responses is replicable. If those were one-off examples and they're not things that we see frequently, then maybe it's less interesting. if we're able to see any kind of consistency in those types of responses, then it becomes very, very interesting. it's not a big part of our spend at the moment. It's not where most of our activity is in terms of the opportunity cost is really quite low. for us, we really want to answer that question and then figure out what to do. Right now, the entire organization is very much focused on getting 5948 into pivotal studies next year. We are very much on track for that. Got it. Okay. Great. And we do want to spend some time talking about the last program, the last clinical program, which is NX-1607, which is a quite interesting degrader. It's more like it's called degrading enhancer, which I thought was quite interesting. It's targeting a target called Cbl-b. Maybe just give us a quick overview of what exactly is this degrading enhancer and what are some unique features about this program. Yeah, so Cbl-b is an E3 ligase. And this is an inhibitor of the E3 ligase. So E3 ligases are, again, the proteins that are involved in tagging proteins for destruction. And there are hundreds of E3 ligases in the genome. And as it turns out, each one is involved in regulating a very discrete set of proteins. So Cbl-b is involved in regulating proteins that are involved in immune reactions and immune signaling. And by tagging these proteins for destruction, they lower the protein levels of these key signaling proteins. And so when you inhibit Cbl-b, those immune signaling proteins, their levels come up and you see enhanced immune activity. So these are not immune activators. They're immune potentiators. So it's very much like a PD-1 or PD-L1 type of effect. So it's an IO agent. We're developing this drug as an oral IO agent. It's in a phase 1 study. It's being tested in 11 different tumor types. It is a very broad phase 1 study. We're looking at multiple doses and multiple different regimens, both monotherapy in combination with taxane. We've got it to provide an update on this program this year. We will certainly have a lot more clinical data next year on the program. Excellent. And so just to help us understand a bit more about this, what are some of the biomarker strategies you're thinking of implementing into the clinical trials to identify the right solid tumors to go after? so there are two different kinds of biomarkers. There is like a selection biomarker, like what patient to do. And then there is a pharmacological biomarker, so are we hitting our target? So we have developed our own proprietary biomarker, Phospho-HS1, which is a direct downstream protein from Cbl-b. And we can measure how well we are hitting our target in the clinic, in patients. So that is going to help us decide what dose to take forward. You can also look at downstream biomarkers like cytokine production and other inflammation markers to say, not only are we hitting our target, but we are having the desired biologic effect. In terms of patient selection at this point, rather than looking at a biomarker, we are really trying to assess which tumor type would be most amenable. And then once we're able to do an expansion cohort in a certain tumor type, then maybe I think we can dive deeper into which subset of those patients would be most amenable to therapy. Got it. Now we have one and one and a half minutes left. And I want to ask you a very interesting question. So I know you guys are probably going to be here next year. So if you were to look, if next year we wouldn't sit together again, what are the three things that you were to do this year that you wish to achieve next year? By next year, you wish that we can actually achieve it. Is there any maybe helps to understand that? How would you guys accountable for that? Yeah. I think first of all, as Jason said, we're going to be in pivotal studies for NX-5948. So I think the market will appreciate the fact that we've gotten there. Second of all, we'll have laid out our IND strategy better with respect to not only our collaborations, which we haven't really talked about. We have an IRAK4 degrader with Gilead and a STAT6 degrader that we're working on with Sanofi. And Jason mentioned our NX-5948 program, which crosses the blood-brain barrier. So that could be very interesting. We've got it towards enabling IND this year, more to come on that next year. And I think just having developed a number of building blocks and multiple programs that are kind of at the same stage as NX-5948 is to just show a real appreciation of value at the same time next year. Okay. Great. We'll hold you accountable for those three things. All right. Excellent. Thank you so much, guys. I think we're okay in here. Thank you. Thank you very much for inviting us. Thanks, David.