Morning, everyone. Thank you for joining our next session. I'm Brian Squarney. I'm one of Baird's Senior Biotech Analysts. I'm very happy to have with us presenting Nurix Therapeutics. It's a company that I cover. I'm very excited about the working in the protein degradation space. They have a lead asset hitting BTK degradation and a number of partner programs behind that. Thank you so much for joining us today. Maybe to start, you can give us a bit of a brief intro into yourself, Nurix Therapeutics, the company's history, and the core competencies as you see it. Thank you for having us. Happy to give you an introduction. These are our disclaimers. Targeted protein degradation is a new field still, although we've been at it for over 10 years. We're based in San Francisco in the Bay Area, based on science out of UCSF and UC Berkeley. What's pictured on the slide is this evolution of new therapeutic modalities. We are in targeted protein degradation, which focuses on the removal of proteins that are disease-causing proteins from the cell. We put it in context of a number of major breakthroughs that have taken place in drug development as far back as antibodies and also nucleic acid-based therapies. Targeted protein degraders are small molecules taken orally that can remove proteins from cells. One of the goals of all therapeutics has been to target particular disease-causing proteins. What we can do now with targeted protein degradation is to harness the machinery of the cell to remove particular proteins that are causing disease. At the top of our pipeline list is Bexobrutideg, which is a degrader of BTK, which is a driver of B-cell malignancies, specifically CLL and other major, the most common leukemias in adults is CLL. That's where we're focused to start with. We have a whole pipeline coming in addition to Bexobrutideg that are all modulating protein levels within the cell. Oncology is our primary focus, but inflammation immunology is our next emerging pipeline area. STAT6 is a very interesting transcription factor, which we've embarked on with Sanofi S.A. That's a type 2 inflammation degrader that we're focused on for atopic dermatitis. This is a transcription factor that we can remove selectively from the cell. IRAK4 is also with a partner, Gilead Sciences. Each of these, we have 50/50 in the United States in terms of ultimate co-commercialization. Let me focus on Bexobrutideg, which is the first degrader in the area of B-cell malignancies. We remove BTK selectively from the cell. We can address not only wild-type BTK, which is the normal BTK protein, but also areas of BTK that have been mutated or selected for by BTK inhibitors, which is a significant current market. We remove those proteins that stop the lymphocytes from developing and growing. In the case of CLL, this is, of course, the major target. Not only do we address the resistance mutations of BTK, but also the scaffolding function of BTK, which is another signaling moiety through which BTK signals growth within the cell. There is some early data on the right-hand side. I'm showing you the areas of resistance mutations that we see in the clinic. Those are labeled by virtue of their mutation within the BTK protein. Bexobrutideg (NX-5948) can degrade and remove all of those mutations. That's the green, the most potent cell killing. Here, we're comparing ourselves to the current inhibitors of BTK, the covalent inhibitors and the non-covalent inhibitors. What you're looking at in the different colors, blue indicates a loss of potency of 1,000-fold, red, 5,000-fold loss in potency. This resistance to these inhibitors emerges with treatment of the current BTK inhibitors. The significant marketplace is over $10 billion currently. The degraders, our degrader, can address all of those. On the left-hand portion of the slide, you're looking at the actual removal of BTK from the blood circulation from our patients. By day two, we see significant degradation of BTK, and all the way through the first 30 days, we get to essentially complete elimination of the BTK protein. This translates to a significant clinical benefit. What you're looking at here on this slide is the reduction in lymph node size in patients with CLL. You can see the overwhelming response is positive in terms of reduction of lymph node size. Each bar represents a patient. The light blue bars include patients that have CNS involvement, so CNS lymphoma and leukemias. On the bottom across the slide, we're seeing the different mutations that exist in each of these patients. Regardless of the mutational spectrum, we have a very significant clinical effect in each of these patients. We are very encouraged by this data, and it shows us that BTK degradation can really address a wide spectrum of genetic burden in these patients. It translates to an overall response rate of 80% across the patient population, which includes fourth-line plus patients. These are patients that have seen chemoimmunotherapy, they've seen BTK inhibitors, they've seen, in some cases, CAR-T therapy, and when they come to us in this trial, we are able to achieve a response rate that is actually quite remarkable at 80% with a very well-tolerated safety profile. Here on this slide, I'm outlining our phase three plans, our registrational plans, which include an opportunity for accelerated approval. That's number one, which is a phase two trial, approximately 100 patients, which we're currently initiating. Number two, to be followed by a randomized control trial with a global standard of care control arm, including pertubrutinib, Eli Lilly drug, which is a non-covalent BTK inhibitor, and then chemoimmunotherapy agents as well. This will be about 400 to 500 patients. The third trial we're initiating as well is a combination trial with venetoclax, a BCL2 inhibitor. This offers the opportunity not only in the second line, but also first-line opportunity. There's a little more detail on the trial design for the phase three trial. We are addressing rather large markets, starting on the left, which is the third-line plus opportunity within CLL, $1 billion to $2.5 billion forecast growth. In the second line, which is our phase three trial we'll address, is another major market, 16,000 patients or greater. Ultimately, the first line, we see Bexobrutideg being able to address that population and combination. I won't go through the trial design in detail. On blue is the CLL trial. We're also exploring non-Hodgkin's lymphoma, in yellow on the bottom, and marginal zone lymphoma, as well as Waldenstrom's and the other categories of NHL. I'm just going to highlight the objective response rate in Waldenstrom's at 84%, very significant, again, response rate in a heavily pretreated patient population. We're at a number of scientific and medical conferences coming up. We have a tremendous, I think, news flow in the second half of this year. Happy to talk about any of this in detail. Oh, great. That was a comprehensive intro. Yeah. Maybe to just go back high level and just think about the sort of theoretical advantages. You had some empirical slides highlighting what those potential advantages are of targeted protein degradation versus the more classical mode of inhibiting covalently or non-covalently tyrosine kinases or other proteins. The central advantage is removal of the bad actor protein in the cell and to do that efficiently. The only way you could do that really before targeted protein degradation was by CRISPR or genetic removal, so actually knocking out the gene. In this case, we harness the E3 ligase machinery of the cell, which is the natural enzyme system within the cell, to remove proteins. We can do that in a very targeted fashion. When you remove the protein that is actually causing growth, in the case of cancer, you get a more comprehensive shutdown of that pathway, that signaling pathway. That's the fundamental advantage to this technology. Of course, being a small molecule, being orally bioavailable, makes it a therapeutic that can be widely available. This is the major advantage of targeted protein degradation. When you think about BTK degradation, it's funny. I remember, that must be 15 years ago, talking with the J&J BD team, who ultimately, a couple of years later, licensed ibrutinib for ex-U.S. Covalent inhibition, there were a lot of questions whether actually permanently inhibiting the protein was safe. There were concerns. Now, obviously, we've seen a lot more utilization of covalent. As you look at target identification for degradation, how do you consider the puts and takes of completely eliminating the protein? Are you generally looking at something where complete knockout models are safe? How do you determine what's trying? The guide that we use is genetics. If you look at human genetics and mouse genetics and look at loss or removal of a gene, and when you see a desirable outcome from blocking that gene or removing it, that opens the window to removing the protein via a chemical means like targeted protein degradation. Covalent inhibition was, I'd say, the next best thing to this, where a compound would bind permanently or covalently to a target and basically take it out of action. The problem with covalent inhibition is that there are many binding sites that have a cysteine, which you have to bind to to cause this permanent binding, many binding sites in other proteins. Off-target was the big concern. If you could make a drug that was specific enough, then you'd have a success story. Ibrutinib was the poster child for that in chronic lymphocytic leukemia (CLL). It's a multi-billion dollar drug still today. With targeted protein degradation, we can really avoid the need to bind to a cysteine, which is a common binding site, and engineer a specific binding site that then can trigger this degradation machinery. That allows us to target any protein, basically. We don't need the cysteine binding site of a covalent binder. We have targeted not only enzymes such as BTK, but also transcription factors, and STAT6 being, I think, the best example of that in terms of regulating immunology. We can be very specific, very targeted, and again, orally bioavailable. Great. When we talk about BTK degradation, obviously, we've had great success with covalent BTK inhibitors and now some non-covalent BTK inhibitors. There's sort of the resistance profiling, maybe selectivity that are options. How do you think about developing Bexobrutideg to kind of specifically show the advantages over covalent and non-covalent? What liabilities do you think you can overcome? We started in the third-line plus patient population. These are patients that have become resistant to the current therapies. When you have success there, you can translate that forward into earlier lines of therapy, specifically with regard to the resistance mutations that have occurred in these patients. That is how we first proven that targeted protein degradation has an advantage. If you can really overcome resistance to current therapeutics, it's pretty black and white. We expanded to show that not only these resistance mutations are vulnerable to our drug, we can tackle those, but also even the normal protein. We take out the entire protein and we get an efficacy advantage. 40% of our patients have the resistance mutations, but 60% have the normal protein. This 60% of patients have also not, they've progressed in their disease on the current inhibitors. When we can treat both the wild type or normal protein and the resistance mutation proteins, we're showing that targeted protein degradation has a real advantage therapeutically in the broader population. Our clinical development strategy is to move up in lines of therapy from treating the worst cases, if you will, to then treating the earlier onset disease patients. That becomes a very important opportunity for us. In terms of the safety profile, I mean, maybe you guys are in a better position than anyone else to understand what is specifically BTK-mediated versus some of the other targets that maybe ibrutinib or the other BTK inhibitors are hitting. What are you seeing clinically? What could you kind of say is definitively a BTK-mediated? The beauty of targeted protein degradation is that you really are, from a safety standpoint, seeing only on-target safety issues, which is the target you're trying to hit anyway. In the blood system, BTK is responsible for the acceleration of proliferation of lymphocytes. We obviously reduce lymphocyte numbers primarily, which is the key factor in a B-cell malignancy. BTK inhibitors have also been associated with other blood system side effects, including bleeding and bruising. We do see bruising. We don't see any frank bleeding. We do not have that severity on the clotting system. We also do not see cytopenias. In fact, we see improvement in the white blood cell counts when you treat the fundamental disease state. Neutropenia and hemoglobin levels come up. We see improvement of the cytopenias. With regard to cardiac side effects of the inhibitors, we basically do not have that. From a cardiovascular standpoint, we think a safer profile overall compared to the inhibitors. OK, great. In terms of the resistance profile, I know you sort of stated that for anything over time, you'll see resistance to it. I guess mechanistically, how could you even envision what would BTK degrader resistance look like? Can you select for it in preclinical assays? Has it been seen clinically? Is there any sort of genetic underpinning that would render BTK resistance? Preclinically, people have modeled essentially resistance to a degradation machinery. It usually involves loss of function of the E3 ligase machinery of the cell, which is extremely rare and has not been seen clinically. You can actually engineer it in the laboratory, but it does not appear to be a clinically relevant event. We think that targeted protein degradation will be somewhat inherently harder to become resistant to. There will still be mechanisms of resistance that evolve to any cancer therapy. What you want is something that will be more difficult to get around, and that appears to be what targeted protein degradation represents. In terms of the modeling, if you sort of break the E3 ligase system, does it do anything to those cells in terms of their survivability? I mean, it would seem like it's such a big break in a system that those cells couldn't plausibly survive. Yeah. Actually, it is very hard to lose that machinery. That's part of the advantage that we have. There are over 600 E3 ligases encoded by the human genome. There is some redundancy in the system as well. It seems to be a system that is very robust. It must be in order for the cell to survive. By taking advantage of it and harnessing it, we see this therapeutic window being quite large, actually. Theoretically, you can lose any one of the ligases and still survive. In the case of Bexobrutideg, we are harnessing cereblon, which is a particular ligase, very active in the hematopoietic system, and has been used by other drug categories, Revlimid being the most significant one. It is a robust system that can be harnessed and can be used to a therapeutic advantage, really without too much worry about losing that capability. Got it. Maybe looking ahead to the pivotal programs that you're planning on starting here, starting with the single-arm study, are there specific characteristics beyond sort of post-BTKI and post-BCL2 inhibition that are part of the enrollment criteria? Like, are you specifically looking at resistance profiling for inclusion and exclusion criteria? Is it important that you have a substantial number of patients with C481S or other BTK resistant mutations? Are you looking at underlying genetics to enrich, like 17p? Does that matter anymore in a post-BCL2 BTK world? Yeah, it's a great question. In the early days, we were very intent on getting these particular genetic profiles. When we've seen Bexobrutideg work across the spectrum, we have loosened the enrollment criteria. We don't have any of those enrollment criteria that selects for a particular genetic mutation. We take all comers. These are patients that have been on, in general, three to four lines of therapy. Technically, for the phase two, it'll be third-line plus patients. Many of them have been on at least eight lines of prior therapy, and we're still seeing this 80% response rate. We just take all comers into the phase two trial, third-line plus. The phase three will be second line. All we require there is that they have already been treated with a BTK inhibitor. We want to prove that we can rescue these patients who have been on a BTK inhibitor, but their disease has progressed. Got it. In terms of the rate limiting steps, I think you've said that the last step is sort of agreement with the FDA on the dosing for this study. I know in the phase one, you've looked at cohorts across 50 to 600 mg QD, expansion cohorts at 2 and 6. I guess one of the questions I have looking at the data is how can you tell apart any efficacy signal difference? It almost looks that response and safety is pretty consistent across doses. I guess you obviously have much more data than I do. What informs dose selection to go forward? You know. It's a big question. The FDA under Project Optimus is trying to determine this. In the era of targeted protein therapy, how do you pick the best dose when even low doses work? We've had responses at 50 milligrams. We've tested 10x that, and we see a very similar safety profile across 10x of dosing. That's really encouraging from a therapeutic perspective, obviously, because the therapeutic window is very large. It makes picking a dose difficult, right, because all the doses look pretty good and they look fairly similar. We're in the midst of it, discussing with the FDA, the EMA, and the MHRA in the United Kingdom. It ends up being a medical judgment call about how to pick the best dose of a drug that really is so highly effective across all doses. We'll keep you posted on that. OK, great. The second line phase three study you're planning is physician’s choice with either a pertubrutinib-based regimen or an idelalisib-based regimen. I was kind of surprised to see that idelalisib even is used anymore. Do people still use that drug? How do you think of what to expect the PFS to be in the second line? Would the underlying assumption be that it would be around 19.5 months, which I think was the PFS for both perto and idelalisib? Were there other considerations to think about in the trial design around that expectation? There are many considerations to launch a single globally relevant phase three. You have to have a control arm that is used across the globe, and treatment variation is significant. In the United States, idelalisib plus rituximab is not used very much. Pertubrutinib is coming up, so we've included pertubrutinib, the most, I'd say, relevant non-covalent BTK inhibitor as a control. We think we will beat that. We think degradation is going to be superior to non-covalent inhibition. Idelalisib R or IR is used in Europe, actually, quite a bit. BR, bendamustine plus rituximab, is still given to 50% to 60% of patients globally. It is a very common therapy, both in the first line and the second line and even the third line. We've chosen a globally relevant control arm that will really give meaning to our results, really, in whatever country we're in. We'll probably be in 20 to 30 countries with this trial. Got it. How do you kind of think about the commercial step-ups going from sort of late-stage setting to second line, and then ultimately aspirations for front line? Yeah, so I think on one of these slides, I did have that step-up. If you start on the left, that's third line plus, about 10,000 patients. It's still a blockbuster opportunity even there, which is where we've seen this 80% response rate. We know, essentially, we believe we will be successful there, certainly. Moving to the second line, what you generally see if you move up in lines of therapy is an even higher response rate to an effective therapy. We're looking forward to initiating the phase three, which will be in that second line setting that addresses about 16,000 patients in the U.S. alone. I'm showing U.S. numbers here. This is a very significant market, currently about $10 billion in sales of BTK inhibitor drugs. We think the degrader can capture a very significant fraction of that in order to be really a significant enterprise. Great. In the last couple of minutes, I just wanted to touch on your partner programs and understand there's a limitation as to what you can say on STAT6 and IRAK4. Just kind of high-level thoughts on those programs. Obviously, there's a lot of enthusiasm around STAT6 now. IRAK4 seems to come and go in terms of enthusiasm. It's going to come back, IRAK4. These are new targets in autoimmune disease. The goal is to be more targeted, to be safer, and to be highly effective. STAT6, which we've been working on with Sanofi S.A. for about five years now, is entering IND-enabling studies. It's a highly specific degrader of this transcription factor, STAT6. If you genetically knock out STAT6, you have an animal that is healthy but basically does not have an autoimmune capability, does not have autoimmune disease. It's a very clean target. It's really quite a remarkable target. It has not been druggable until targeted protein degradation. We're very excited to move that forward with Sanofi S.A. Of course, they're having Dupixent. That is a major franchise for them in type 2 inflammation, atopic dermatitis, and many other autoimmune diseases. IRAK4 is similar in terms of hitting the immune system in a very specific way. It has not been successfully drugged before. We started working with Gilead Sciences on that about five years ago as well. They had IRAK4 inhibitors that were not getting the kind of efficacy required. With a degrader, we can overcome the limitations of the inhibitors they actually had in phase two at the time. We think both of those opportunities are very significant in autoimmune disease, addressing, again, multi-billion dollar markets. Great. In the last two minutes here, is there anything we didn't discuss today I didn't ask that you think is particularly important for investors in Nurix to know? If you look at our upcoming events, I do want to just highlight ESMO in Berlin. We will be presenting on NX-1607, which is an inhibitor of an E3 ligase. We're blocking degradation in this case, and this stimulates T cell development and autoimmunity in terms of cancer. It's an immuno-oncology target. NX-1607 is the first inhibitor of SIBLB. This SIBLB is the ligase that we block. We'll be presenting that for the first time. It's our phase one results in Berlin. We'll follow that up with CITSI in Maryland, another international conference. I think 1607 is kind of a sleeper agent to keep an eye on. Most people have been focused on Bexobrutideg. We are presenting that also at a number of settings in Europe. ASH is a big event for us coming up in December, as usual, which again, we'll present an update on Bexobrutideg. Great. Art, thank you so much for the time today. Thank you in the audience for being here. Thank you. Appreciate it.