Hi. Welcome, everyone, to Day 3, Jefferies London Healthcare Conference 2024. My name is Roger Song, one of the senior analysts covering small/mid cap in the US. It's my pleasure to introduce our next presenting company, Nurix. And then welcome, Arthur. And then Arthur will give us a brief company overview, and then he may join me for the Q&A session. Arthur.
Well, thank you, Roger. And we'd like to thank the entire Jefferies team for inviting us. These are my disclaimers. So I will spend a little time here upfront on 5948, and I think leave time for the Q&A around our pure BTK degrader, which is now in phase I-B. We will be presenting a clinical update on this program at ASH here in the next few weeks, early December in San Diego. But we have quite a robust pipeline. So a few comments on that, and then we'll dive a little deeper into 5948. NX-2127 is a dual BTK degrader and IKZF1 and IKZF3 degrader, which means it combines immunomodulatory activity with BTK degradation. 2127 is in dose escalation in aggressive B-cell malignancies, so DLBCL and MCL primarily. Whereas NX-5948 is really being developed primarily in CLL and the other indolent lymphomas.
There's a distinction between those two agents. NX-1607 is our CBL-B inhibitor. CBL-B is an E3 ligase that downregulates T cells and other immune cells. We developed an intramolecular glue in NX-1607 that locks CBL-B in a closed conformation, and it is in dose escalation in multiple solid tumors. We have a number of other undisclosed targets that we're developing both on our own and with our key partners, Gilead, Sanofi, and Pfizer. At the end, I'll mention a little bit about our degrader antibody conjugate, or DAC, technology with Pfizer. We have a growing I&I portfolio as well. This feature is really the IRAK4 degrader, which is being developed in partnership with Gilead, and also our STAT6 degrader being developed in partnership with Sanofi.
Now, with all of our deals, we have built-in cost profit share options for Nurix to come back into these programs after human proof of concept has been achieved. These allow for Nurix to exercise an option for 50/50 cost profit sharing in the United States. We consider all of our partnership programs to be integral parts of the Nurix pipeline overall, in addition to our wholly owned pipeline. We're focused on our small molecule pipeline, which is targeted protein degrader oriented. Why do we need targeted protein degraders for targets like BTK, STAT6, and others? In the case of BTK, we know that from our data, we can overcome the emerging BTK resistance mutations to current BTK inhibitors, which is a $9 billion-a-year market. This is a very large unmet medical need that's growing in nature.
They also have revealed that BTK, although a well-known clinically validated kinase, has what was heretofore relatively unknown scaffolding function, which is a whole nother growth signaling cascade function that BTK has, which is not addressed by the inhibitor, so with a degrader, we can remove that function as well and drive what we believe is deeper efficacy and have shown such efficacy in the setting of BTK inhibitor failures of patients that have progressed on BTK inhibitors, and so we know we have activity along this line. I'll show you a little bit of that, and then we'll get into our Q&A, but just one bit of early cellular data to illustrate what I just described. Across the top, you can see this incredible potency of NX-5948 across a variety of BTK inhibitor mutations, resistance mutations that we've seen in the clinic.
Green is sub-nanomolar potency and cell killing against all of these. We compared ourselves to all the inhibitors, both covalent, ibrutinib, acalabrutinib, and zanabrutinib, and then the next generation non-covalent. You can see each of them designated by colors, blue losing 1,000-fold potency, red would be 5,000-fold loss in potency against these targets. All the inhibitors have these significant liabilities against these resistance mutations, whereas by degrading the protein and removing it from the cell, we can actually address all of those. I already mentioned it's a very large market opportunity. Just want to give you a few highlights from this trial that's ongoing and that we'll be expanding information on at ASH here. If we focus first on the dose escalation trial in CLL, and then I'll just comment on Waldenstrom's a little bit at the end.
So first off, very well tolerated. NX-5948 has a really well-tolerated safety profile across dose levels, actually. And so we're very pleased with this. We do see some cytopenias, which are primarily associated with the disease state itself. These actually improve over time with therapy. This is data we showed at European Hematology Association, EHA, in Madrid in June. Right off, you can see significant lymph node shrinkage on this lymph node waterfall plot pretty much across the board. This totaled into a 70% objective response rate with significant patients benefiting really across the line. And a couple of those hatchmark patients are indicated. There are patients with CNS disease. We also crossed the blood-brain barrier. We're able to address this, and we've seen some really excellent responses in CNS disease. This is the swim lane plot just to highlight that this is an ongoing trial.
All the green arrows indicating that, again, the drug is well tolerated. Patients are able to stay on this therapy. And then off to the left, you can see this is a heavily pretreated population. Essentially, all patients have seen a prior BTK inhibitor and progressed on those drugs, as well as BCL-2 inhibitors. And also, we have about 22% of patients that have also progressed on the non-covalent inhibitors, mainly pirtobrutinib. And yeah, we're seeing this excellent response rate. Just to highlight a case study, this is a patient with CNS involvement in CLL. This patient had multiple prior lines of therapy, as indicated on the right, the most recent being acalabrutinib, which is, of course, a very effective non-covalent inhibitor of BTK. But on acalabrutinib, this patient developed CNS disease and then came onto our study. This is the patient's journey.
If you start off to the left there, initiation of dosing at cycle one, you see this uptick in absolute lymphocyte count, the orange line. This is characteristic of a patient that is actually responding to a BTK mechanism where the tumor cells are dying and coming out of the lymph nodes into the bloodstream, and then you see this white blood cell count come down nicely over time. In addition, at every time point of measurement, we're showing how platelets have recovered, hemoglobin has recovered, spleen size being reduced, lymph node reduction size, but really, remarkably, by cycle seven, week 24, there were no longer malignant cells in the patient's cerebrospinal fluid or CSF, so we actually cleared the CSF. This is really a very remarkable finding, and I think speaks to the power of the degrader technology and NX-5948.
With regard to the resistance mutations, again, these are the most common ones. What I'm showing you on the right side is a degradation of BTK. So we take a blood draw at day zero as baseline and then two, eight, and the first 29 days. And you can see, regardless of the BTK mutation status, we're able to completely degrade the protein. And so this is really a very important result. And we can track this biomarker very easily in all of our patients. This is the same waterfall plot, but underneath it, I'm showing you all the different mutations these patients have. So this heavily burdened mutation population, not just in BTK, which is the top line, but also p53 and a number of other poor prognosis mutations. And yet, the degrader can overcome a lot of this genetic burden. Just a word on Waldenstrom's.
This is early data we presented in Prague at the International Waldenstrom's Congress recently. Small initial subset of patients, but again, you see the 70-plus% response rate, 77.8%, and these responses continue to persist over time. And importantly, we're seeing reductions in IgM levels, which is, of course, characteristic of Waldenstrom's, which is gross overproduction of IgM from these tumor lymphoma cells. So again, seeing almost everyone showing response here, again, late-stage patients. So with that, we're very enthusiastic about our responses to date in CLL and also Waldenstrom's. We're planning on our pivotal trials in 2025. So next year, we're in very active work on planning these. We do think there's a single-arm accelerated approval path available in this high unmet medical need population of post-BTK inhibitor, post-BCL-2 inhibitor, and we have Fast Track status there.
Very happy to just announce yesterday that we got PRIME status from the EMA, giving us, again, more accessibility and perhaps an accelerated path in Europe as well. But we have ambitions to go up in lines of therapy to the second line and first line. We think these degraders actually have the potential to ultimately replace BTK inhibitors as a superior potential agent. That's our goal. That's our ambition, and we'd love to see this evolve in that direction. So with that, Roger, I think I'll pause, and I think I left enough time for some Q&A.
Sounds good. Do you want to join or you want to?
Yeah. Well, maybe I'll.
Yeah. Okay.
Talk quicker so I can keep showing things.
Yeah. Maybe we stick on the upcoming event for the ASH. So understanding this is another data cut from the EHA. So how much data we should expect from there in terms of the patient number, and then what exactly you're looking for to share with us in terms of the data, the category, what is the expectation there? Thank you.
Yeah. So since our last disclosure at EHA, we had there about 26 patients that were evaluable. We anticipated ASH to essentially double that number of patients and also have five to six months more duration of treatment. So I think people will be looking for, do we solidify that response rate of 70-plus%? Is that solid with now 50-plus patients? And then also, what is the duration of treatment? Can we make forecasts about duration of response? Probably not. It's still early in the trial. So I think those would be the main elements, as well as this ongoing evolving resistance mutation story. Do we maintain activity as we've seen in the past?
Okay, so given you already gave us some early data cut from ASH, any new data category you potentially will share with us at ASH? I think you shared with us the resistance, CNS. Any other data category you may share with us for the first time?
I think that we'll try to talk a little bit about where we are in Non-Hodgkin's lymphoma and continue to evolve the story on Waldenstrom's. But mainly with NX-5948, we'll be focused on CLL and the expansion of that story. That's an oral presentation, and then we'll do a corporate event afterwards on the Monday of ASH. But we do have an oral presentation from another investigator on NX-2127 looking at the dual activity of that molecule. So I think that's going to be an interesting, largely mechanistic-based oral presentation. And then there's a poster that's going to be presented by our collaborator at UCSF, James Rubenstein, on the CNS activity and crossing the blood-brain barrier with NX-5948 and I believe 2127 as well, which is fascinating because these are relatively large small molecules as degraders or bifunctional degraders.
And we're not supposed to cross the blood-brain barrier and have this kind of activity, at least according to conventional medicinal chemistry wisdom. But in fact, we're seeing this activity. So that'll be another expose on that.
Interesting. Okay. Great. So we're going to look forward to the ASH presentation. And then you will host the investor event during ASH, and then you'll give us some guidance in terms of the next step. So any preview you can share with us today in terms of current thinking about what's the potential? You have the slides here. So the first pivotal study looked like, what's the line of therapy? You think of why you have the confidence they can be an accelerated approval pathway, how much kind of FDA interaction you already have with them?
So I think we can provide a little bit more clarity based on what I'm showing you here at a top level at that time in terms of our regulatory update. But really, most of that will come in 2025, to be honest, when we're closer to launching the pivotal study and we have better clarity from the FDA. We will be prepared then to discuss that in greater detail. But at ASH, I think we'll do our best to focus on the new data, and we'll have one of our lead investigators presenting at our corporate event. We'll also provide a corporate update on 2127 and 1607, our CBL-B inhibitor, and then perhaps discuss a little bit more about our I&I plans too.
Excellent. Understanding you are now enrolling the expansion cohort for the 5948, how did that data going to fit into your pivotal plan with the FDA and the design of the pivotal study?
Yes. We're in the expansion phase I-B, studying the 200 mg once-a-day dose and the 600 mg once-a-day dose. This is designed to address Project Optimus to really adequately test two dose levels that have a PK spread between them and substantiate the selection of doses for the pivotal trial. Those cohorts are underway. We will be putting all the patients together, though, when we look at the total ASH results in terms of we've looked at all dose levels together historically. We are getting close to being able to break out each dose level and then say, okay, what is going on at each dose level and what will contribute to our decision about final dose?
And then just to more drill down in terms of how much data coming from this expansion cohort needed before you can start the pivotal design and the study?
So the phase I-B is enrolling very, very well. In general, our target patient number is about 20 patients per dose level in the phase I-B to get enough to analyze to support the selection for the pivotal. So about 20 patients each dose level. But we also have a fairly large number of patients now that we've backfilled in the phase I-A at various dose levels. So we actually will have, I think, a substantial cohort, but that'll be really analyzed in the first half of 2025, which will then inform the pivotal, the initiation of the pivotal.
We're expecting some additional data in the first half of 2025 from phase I-A and phase I-B, and then you can have the conversation with the FDA for the pivotal second half next year.
Yes. I think 5948 is, we're generating and enrolling at such a rate that, and we're generating data that we think allows for meaningful updates probably on average about twice a year. So a mid-year update and then an end-of-year update as well, especially if it's around decision-making for the program, such as the initiation of the pivotal.
Excellent. I'll have a couple more minutes. So understanding the initial indication is the CLL later line after the first BTK and then maybe BCL2. And then how are you going to move into the earlier line? You say you have the ambition to move into the earlier line, potentially replace the inhibitor. How the pivotal study going to look like, understanding that it's still early in the progress too?
Yeah. So I think some form of head-to-head in the first line setting is really what's required to demonstrate what a degrader can do compared to an inhibitor. And so which inhibitor is likely the covalent, because I think they do dominate the front line. So something along those lines. We have not outlined that yet. But also, in addition to the single-arm third line study, we then would have a randomized control study confirmatory that would likely be one line up in therapy, perhaps second line as the randomized control trial, but that the first line would be more of a head-to-head and would be a label expansion type of trial. That's kind of the direction, but we'll be giving that more detail as we go forward. I do want to mention our DAC program. I forgot to mention that.
Yeah, let's do it.
So this is our degrader antibody conjugate program, and it demonstrates the power of this technology. This is where we're working with Pfizer, formerly Seagen, to create these targeted protein degraders as payloads for antibodies. So I just wanted to mention this program because it's one of the most exciting, I think, scientific programs that we have, and it demonstrates the versatility of this degrader technology. Because these compounds are so potent, it takes very few degrader molecules that can be delivered specifically to a cell to degrade a new target. And I think it's going to greatly expand the ADC field, which has been dominated by toxins as payloads, but this is targeted therapy. So this is something to, I think, keep an eye on in 2025 too.
Yeah, absolutely. So we'll stay on this earlier pipeline. You have 2127 reinitiated, and then you also have 1607. So maybe just give us some of the data cadence. So how much data we're going to see in the coming years, and then how excited are you about those different indications and different assets compared to your lead 5948 in the CLL and the 5948 also in the NHL as well?
So I think we will have clinical updates at medical conferences for all three programs next year. So I think it'll be a busy year in different venues and in different indications. But also our I&I portfolio will evolve, which is on the bottom part of this slide. So our IRAK4 degrader with Gilead, the anticipation is an IND for that with Gilead in 2025 in the first half. And then our STAT6 degrader for type 2 inflammation with Sanofi. The anticipation there would be identification of a development candidate and Sanofi's exercise of an option over that development candidate, take it into the clinic. So as well, we would be defining better NX-5948's utility and development in I&I. So I think in addition to oncology, I&I next year will be a big year for I&I for Nurix as our pipeline evolves.
All of these are really, all of these programs have breakthrough potential. We'll have to see which ones actually do break through, but I mean, they all actually have that potential.
Yeah. BTK in general works pretty well in I&I outside of oncology. IRAK4, STAT6 is definitely a very high-value and high-interest target there. So maybe on the BTK, what's the initial indication going to look like? You're going to follow the previous BTK inhibitor path or something special about the degrader you may be able to differentiate on the initial indication?
So, I can't at this time name particular indications where we'll go first, but I'll specify to the second point of your question, why a degrader in I&I. And so, we believe the same reasons we're seeing the advantage in oncology will apply to I&I and autoimmune disease, namely that BTK has this scaffolding signaling function that inhibitors are not addressing. So, the BTK inhibitors in I&I indications have shown promise and have shown positive results already, but they leave room for improvement. Seems to me perhaps there's more efficacy that you could get out of them, it seems. So, I think that's where a degrader comes in. And by removing the function of this protein, I think you can address very difficult and challenging autoimmune diseases.
With 5948 in particular, I do think MS is an interesting opportunity because we cross the blood-brain barrier, but there are many other opportunities for 5948 because it has such a safe profile already. So we'll be defining that as we go forward here to the end of the year and early 2025 as we work on our strategy here. But the BTK degradation, I think, can beat inhibitors in I&I as well. And of course, for IRAK4, we take out the scaffolding function too, and that's actually what has held back some of the IRAK4 inhibitors. It's not getting that full efficacy that you can get with a degrader. And then in the STAT6 situation, that's a transcription factor. So there really is not an active site, an easy active site to inhibit, and you have to go with degradation there.
I think degradation is going to be a really superior mechanism overall in I&I.
Yeah. Different reason why you want a degrader versus the inhibitor function, protein function, or just difficult to bind to the target binding site in different ways.
Yeah, exactly.
Awesome. And then, just the last minute, and then, what's the cash position, and then, what's the runway look like in supporting the big pipeline here?
Yeah. So we ended our quarter with $457 million in cash. In our recent 10-Q, we did indicate utilizing our ATM recently, which was another $80 million on top of that since the end of that quarter. So we're in a very strong cash position, which enables us to really move aggressively towards the pivotal trials in 5948.
Excellent. Thank you, Arthur.
Thanks a lot, Roger.
Yeah. Thank you, everyone.