Good morning, everyone, and thank you for joining the H.C. Wainwright 26th Annual Global Investment Conference. My name is Daniel Smith, and I'm an H.C. Wainwright Equity Research Associate in Biotechnology. With that said, let me introduce our presenter for the session. I'd like to welcome Dr. Arthur Sands, President and CEO of Nurix Therapeutics, who are developing protein degraders and degrader antibody conjugates for oncological and immuno-oncological indications. Nurix is traded on the Nasdaq under the ticker NRIX. The floor is yours.
Thank you, Daniel, and I'd like to thank Robert also, and the entire H.C. Wainwright team for inviting us to participate today. I will be making certain forward-looking statements, so we refer you to our filings with the SEC regarding risk factors that affect our business, so today, in just a few minutes this morning, I'd like to focus on our lead program, NX-5948, which is a pure BTK degrader. The target, Bruton tyrosine kinase, is highly validated in CLL, but we were the first to enter with the concept of removing this important protein in B-cell malignancies, so I'll spend most of my time today on NX-5948, describing its progress in the clinic.
We are in full swing on this program to set up for pivotal trials in 2025, so we're moving very swiftly in that direction, but I'd also like to mention our other programs on this slide, so let me go through some of these, and then we'll dive into 5948 more deeply, so first off, you can see we have several very important alliances with Gilead, Sanofi, and Pfizer, formerly Seagen, and I think I'll start out with mentioning Sanofi and Gilead. If you focus on the lower half of this slide, we have a significant number of programs in the I&I space, so in autoimmune disease. The first, furthest advance is an IRAK4 degrader with Gilead, which is currently in IND-enabling studies.
Earlier in the year, they exercised their option on this program. This was part of a larger discovery alliance that we have with Gilead, encompassing multiple targets. This is the first to go into IND-enabling studies, and this is targeted for rheumatoid arthritis. The goal is to have an IND filed in 2025 with Gilead. Now, Gilead has responsibility for IND-enabling and Phase I studies. Nurix has an option to opt back in and co-cost-profit share in the United States structure after seeing human proof of concept data. The second is STAT6, which is with Sanofi. This target has attracted a lot of attention. It's a very exciting transcription factor target, formerly undruggable target. It's on the Dupixent pathway, and this is why this has high interest level for Sanofi.
We developed this degrader in concert and working closely with Sanofi. Both this project and IRAK4, we've been working on for about four years, and now they're approaching their development candidate timing and entry into the clinic. STAT6, we benchmarked our STAT6 degrader against Dupixent. That is, the design goal is to have an oral molecule that could be competitive or perhaps superior to Dupixent in these Type II inflammatory diseases. This is a very important target, and this program has progressed very nicely. We're also interested in taking a look at NX-5948, our BTK degrader in inflammatory diseases. I may have time to address a little bit of that later.
If you then return to the top part of this slide in our oncology program, we have multiple undisclosed targets with our partners, but let's dive into NX-5948 and the BTK program, with regard to degrading BTK. So first off, why do we need BTK degraders when there's a whole host of inhibitors to BTK? The first point there is that there's also a host of emerging resistance mutations to the current inhibitors. So these are point mutations of BTK that render the inhibitors useless, and our degraders can overcome those, and I'll show you data related to that. The second point is that BTK, although a kinase, actually has structural function, which is called scaffolding function.
There's a whole signaling pathway through BTK, by virtue of its complex within the cytoplasm, that inhibitors don't really hit, and by degrading it or removing BTK, you can actually hit this whole other signaling function, boosting efficacy, so that's why that's important. It actually relates to efficacy of these agents, and of course, we have activity in a wide spectrum of B-cell malignancies, and that last point on the slide, I think from a strategic perspective, we think we can potentially replace BTK inhibitors, which is currently a $9 billion-plus market just in B-cell malignancies. This slide is a historical in vitro data where we first observed NX-5948 in green across the top there.
The green indicates highly potent nanomolar-level degradation and cell killing of these cells that contain a variety of resistance mutations, and those are across the top there, C481S, V416L, and so forth, and L528W, which is an important mutation. Then, as you can see, all the inhibitors are along the X-axis below there, and the different colors indicate their loss and potency against those inhibitors. The blue color there indicates a thousand-fold loss or decrease in potency as compared to wild type with ibrutinib, which is how C481S was first identified. In red, it's a five-thousand-fold loss of potency. Across the board, all the inhibitors have various liabilities with regard to their inability to kill cells once they acquire these mutations, whereas our degrader, 5948 , across the top, looks quite good.
So this was the first cellular molecular basis for thinking that a degrader could be superior to inhibitors. As I mentioned already, this is a big market, so if we can really replace these with degraders, and have this be really the best-in-class agent, we think we could have a really high-value drug here. So NX-5948, how does it work? A little diagram on the left. It's a bifunctional molecule. At the top, you have the brown piece, which is the E3 ligase binder, and then a light blue, which is the target binder, binds to BTK. And these are molecules linked with a linker in between. They are relatively larger small molecules, about 750 molecular weight. Typical small molecules will be sub 500, but they are oral.
They get into the cell, and as I'll show you, they actually get into the brain, and they can affect degradation of BTK by bringing BTK in proximity to the E3 ligase, pictured in yellow there, which triggers ubiquitination or ligation, hence the term ligase, of a ubiquitin protein tag onto BTK, and then multiple tags are applied that signals BTK tags BTK for degradation in the proteasome. So this is a catalytic event. It's event-driven pharmacology, which means that our molecule can cycle, and one molecule, one drug molecule can degrade many, many target proteins. That's fundamentally different than inhibitors, where it's a one-to-one stoichiometry. The inhibitor has to stick to BTK forever and stay there if it can, to inhibit that kinase function. We remove the protein; our molecule can recycle.
So I'll show you some data now on CLL, which is in the light blue. We're in dose escalation. We actually completed our dose escalation. We're now in dose expansion, Phase 1b in CLL. We're also in NHL, non-Hodgkin's lymphoma. I won't have time to talk about that today, but we will be having disclosures later in the year in the NHL cohorts. This is the disease characteristics. We presented this data most recently at the European Hematology Association, or EHA, meeting in Madrid. So let's focus on the light blue column on the left. This is an elderly population. If you look in the middle of the slide, median prior lines of therapy are four, actually two to 14, so heavily pretreated patient population. You can see the prior therapies listed there.
Everybody has failed a BTK inhibitor, or rather, the BTK inhibitor has failed these patients, and also BCL-2 inhibitors, but also a host of other therapies, and at the bottom, multiple types of resistance mutations in these patients. I'm just gonna highlight this. It's a well-tolerated drug. We've had really an excellent safety profile, and patients have remained on therapy, as indicated on this slide. With green arrows at the bottom there, these are all patients that continue on therapy. That's a reflection of how well-tolerated the drug is. What you're looking at is right away you can see lymph node decrease, so the y-axis here is measurement of lymph nodes, and you can see basically almost all patients show decrease in their lymph node size, which is impressive.
Overall, by the IWCLL criteria, it comes to about a 70% response rate, but also significant numbers, 23% in stable disease. With ongoing therapy, we believe a number of those stable disease patients can actually get a better response and become responding patients as well. This is the swim lane plot. You can see patients, how they progress on the trial. On the left are the prior therapies, and grayed out, you can see most of them have had... well, basically almost all of them have failed. They've had BTK inhibitors that have failed them, or whether covalent or non-covalent, and then also the BCL-2 inhibitors. Again, the green arrows indicate ongoing therapy of patients, and then the green triangles show those that have hit the response criteria.
The open circles are those that are at stable disease. You can see some of the open circles do convert to triangles, which is very important, as they stay on therapy, so this was again presented in June. We're anticipating presenting at ASH, coming up with another six months of data on these patients, and hopefully, you'll see these lines go off to the right, and we'll see a greater number of green triangles appearing with an increased responses, so this is a single-patient case study that I think is very important with CNS CLL involvement, and what you're looking at at the left is when the patient entered, had significant CNS disease, and the absolute lymphocyte count is what's tracked here in the orange line.
When therapy started, you see an increase in absolute lymphocyte counts, so your white blood cell counts actually go up. This is characteristic of a response occurring. And then with increasing time on therapy, you see the absolute lymphocyte counts come down very nicely. And then if you look at the malignant cells in the CSF, which is the last line in each of these boxes, you can see by 24 weeks, that middle box, there are no malignant cells in the CSF of this patient. This patient has done very, very well. The prior treatments are interesting. In the upper right-hand, this patient was on acalabrutinib, a BTK inhibitor, when he developed CNS involvement. So a number of these inhibitors do not cover the brain, and we think this is another important distinguishing feature of NX-5948....
This is a second case study patient, very interesting. Focus on the right side, the prior therapies. This patient had basically every BTK inhibitor available: ibrutinib, acalabrutinib, Zanu, pirtobrutinib, and as well as combination therapies with chemo, R-CHOP and lomustine. Actually, this patient also had cell therapy, had CAR T, and all those did not produce sufficient responses in the patient. This patient's journey, very similar to the last, that characteristic first uptick in absolute lymphocyte counts, and then the response to the degrader, 5948 , kicks in, and you see a really nice decrease in absolute lymphocyte counts. Then, again, this patient was on 11 prior therapies, none of which worked. So this is really a truly important case study for us and tells us we've got a great agent here.
On the right, I'm just showing you degradation of BTK, you know, based on patients grouped in the different colors that have different resistance mutations to inhibitors, and you can say, regardless of what inhibitor resistance mutation they have, we can degrade that BTK, and the blood draw from day zero, when you get out to day eight, actually, they're all basically at the floor of the assay, so we can remove BTK from these cells that harbor these resistance mutations. This is another way to look at the mutation story. You can see this is the same waterfall plot I showed you with lymph node decrease, but now every tick mark there is a different patient, and we've called out the mutations that they have in their disease, so it's a heavily mutationally burdened population.
The BTK mutations are the first listed there. In light blue, they can have multiple BTK mutations, but then also p53 mutations, other poor prognostic mutations. Regardless of the mutation burden, we actually have not seen any genotypic profile that's linked to intrinsic resistance to NX-5948. So that's very encouraging. We can really take on all of these resistance mutations. So just to summarize briefly with 5948 , we're looking at about a 70% response rate overall in this heavily pretreated population. We are in the midst of planning, as I mentioned, for the pivotal trials to start in 2025. Very eager to gain additional data through this year in the fall here and present that additional data at the end of the year on 5948 .
And again, we'll give an update on the non-Hodgkin lymphoma, NHL, in the second half here of this year as well. This is a preview of what we're planning. So we do have fast track status from the FDA in the third line plus population, that is, patients that are post-BTK inhibitor, post-BCL2 inhibitor, and so we're actively planning that study as we speak. We're also interested in then a randomized trial in the second line to move this drug up in lines of therapy. That would put us in a randomized controlled trial there. The patient populations are significant, about 11,400 per year in the second line plus population. Even the third line is 7,600 patients, so this is a significant patient population.
Ultimately, we think NX-5948 can move to the front line, and that would be, of course, a larger number of patients. What's not captured here is there's over 200,000 patients with CLL in the United States in this pool of patients that are cycling through these various therapies. So patients really do need alternatives like a BTK degrader that can really address all sorts of issues that are faced with advancing disease. I will have a few minutes here to hit on NX-2127, which is our dual degrader of not only BTK on the left, but also IKZF1 and IKZF3 on the right. This molecule is designed to hit both pathways, which are strong growth pathways in lymphoma.
The pathway IKZF1 and IKZF3 on the right is what's hit by Revlimid and the IMiD drugs, which have been very successful agents. We're able to build this into one molecule, NX-2127. Just a few highlights. This has been in a dose-escalation trial in CLL, but also MCL, and diffuse large B-cell lymphoma, very aggressive lymphomas, DLBCL, and I just wanna highlight a couple patients here, and then we can take some questions. The swim lane plot has progressed in this trial, but really, let's look at these two patients. This is a patient, eighty-four-year-old at the time, she's now eighty-six, happily. A very heavy disease burden on the left. You can see the scan there, very large lymph node burden, failed four prior lines of therapy, including R-CHOP and others.
At 16-week scan, you can see the disease is basically gone. This is a complete response. Actually, her 8-week scan looked like this as well, and she's been able to stay on therapy and done very, very well. This is a dramatic response, encourages us in this diffuse large B-cell, very aggressive lymphoma, where we think the dual combination activity is critical. This is an MCL patient where we also saw a complete response. You can see on the left, the circles are the lymph nodes that are enlarged, and then on the right, the 8-week scan, basically complete response, the lymph nodes are gone. Again, this is an oral therapy, single therapy, single oral treatment, monotherapy, so very encouraging.
We look forward to bringing NX-2127 into a dose-escalation trial, focusing mainly on MCL and DLBCL. And that's pictured here. So, with that, I think I'll pause here and leave a couple of minutes for questions. Daniel, if you have any questions, I know you have a medicinal chemistry background. I invite you to ask questions or anyone else in the audience. Yes? Did you repeat the question to-
Do you see a sign-
... Okay. Yeah, the question is, what about side effects with regard to this MOA, this mechanism with the catalytic activity of these bifunctional molecules? The answer is no. And that was an early concern, that is there some mechanistic, specific side effect that all these degraders might share? And we really haven't seen that. So the side effects that we've seen with NX-5948 are really BTK target-specific, which would be expected from hitting the target. But there's no degrader mechanism general. Highly specific, NX-5948, and we studied this by proteomic analysis, where you can see what other proteins you might be hitting. But no, we're not hitting anything else. And the catalytic activity. Well, let me give you an example of how powerful this is.
So, pirtobrutinib, which is an inhibitor, our blood levels for 5948 are five thousand fold below pirtobrutinib. So, you a lot less drug is required on board. It's, which could lead to a safer profile than what you need with an inhibitor. So, sure.
Study to see how much, how much are you funding it, and how much is it?
Yeah, so the question was about the RA study in IRAK4 , and that it is an expensive study in rheumatoid arthritis. The beauty of this deal is that they are funding the clinical activity here, clinical studies, from all the way from development candidate selection through IND-enabling studies and Phase 1. What happens at the end of Phase 1 then, we get to look at the data from the patients and decide if we, Nurix, can opt in into a cost-profit share. If we opt in, it actually, the option itself doesn't cost us anything, which is good, but then we'll be co-funding under a structure of cost-profit share, yes, going forward. So Gilead would be in charge of the global trial. There'd be a joint steering committee, and this is the same with Sanofi. Sanofi, it's the same kind of structure.
And then, yeah, we would proceed basically fifty-fifty in the U.S. They have ex-U.S. Yeah. Yes?
... molecule. What's the next cadence of patient data that we're gonna see?
The question is, what's the next cadence of patient data that we'll see with NX-2127? So, we have not disclosed yet our plans for talking about 2127. You know, a good goal would be to have something to present at ASH, but I'm not sure enrollment will give us enough data to make that presentation, so we'll have to see. The end of the year is really gonna be focused on NX-5948, where we are enrolling large numbers of patients, and we will have data by the end of the year. So if we don't have data for 2127, it'd be a 2025 disclosure. Yes?
What are your financials like?
Oh, yes, I should mention that. I didn't mention our DAC deal either, which is a very exciting deal. By the way, just pitching here, using these degraders as payloads on antibodies. We are presenting in Boston, actually, I think tomorrow. We had a press release on this. Oh, and I don't have the financials, but we have over $450 million in the bank as our last disclosure, and that gives us cash runway into the second half of 2026. Yes. One last question, perhaps, I think, unless I'm out of time, but go ahead.
difference.
So the degrader approach, we think, and we're interested in it, for not only IRAK4 and STAT6, but, basically, you take out the scaffolding function as well in autoimmune disease, and there's a big signaling function going on in autoimmune disease, just like there is in cancer. And so we think it's gonna translate to better efficacy with the degrader approach in autoimmune. So I think. Am I over time? Right on time. Okay. Well, thank you. Thanks a lot.