All right, we're going to go ahead and get started. I am Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us, presenting in the next session, Arthur Sands, who is the CEO of Nurix Therapeutics. We're going to just do kind of a casual Q&A. If anyone has a question, feel free to raise your hand. Arthur, maybe you can just kind of kick us off with some introductory comments, and then we'll get right at it.
Yeah, so at Nurix, we're focused on targeted protein degradation as a new modality, first in CLL. We're entering pivotal trials in CLL this year. We've actually kicked off our first pivotal trial with Bexobrutideg, formerly NX-5948. We call it Bexdeg for short. The "deg" stands for degradation, which is the new MOA. We target BTK, which is a clinically validated drug target. We degrade BTK, or we remove it from the cell, and that creates a very strong therapeutic effect that we've seen in the clinic so far, with about an 80% response rate in CLL patients who have seen four prior lines of therapy. In addition, the degradation mechanism offers the advantages of addressing resistance mutations that have arisen in the BTK protein after treatment with BTK inhibitors. This degradation modality we see as a fundamentally new way of targeting cancer targets.
Not only cancer, but we are also in inflammation with our STAT6 degrader with Sanofi, which is partnered with Sanofi, as well as our IRAK4 degrader, which is also in I&I indications, which is partnered with Gilead. Very broad therapeutic area potential. I have just mentioned our lead program a little bit, and we can talk in any direction you would like to go.
Yeah, maybe let's start things off with Bexdeg, just because it was the focal point of a pretty voluminous update that you gave last month. You declared the nomination of a go-forward dose. You initiated the registrational phase II program in triple-exposed patients. You kind of gave us an outline of what a confirmatory phase III would look like. Maybe starting with dose, I guess when I look at the clinical data that we've seen today, there really hasn't been a ton of daylight between the 200 mg and 600 mg doses, just from a safety and efficacy perspective. Maybe you can kind of talk about what are the important PK/PD advantages of the 600 mg dose, and how do you expect those advantages to kind of reveal themselves over time and in the context of clinical data?
Yeah, so we're going to be presenting at ASH, number one, coming up here. We will be talking more about this in terms of the actual data behind the 200 and 600 mg doses. Those were the two doses that we took into our randomized phase IB under Project Optimus to really look for safety, which is the number one, having seen efficacy across the board, as you point out. The question is, is there a safe dose where you can actually push the boundaries of efficacy in terms of target coverage? As you point out, the 600 mg dose basically looks like the lower doses in terms of safety, which is great. This allows us to really push for target coverage, which is, of course, a great goal in any cancer therapy.
If you look at the resistance mutations I mentioned earlier, there are slight differences in terms of ability to cover those with our degrader. And with any degrader, there are slight potency differences. At the 600 mg dose, we believe we can get better coverage across the board, across any of the mutations that we've seen in the clinic. This should spell out in terms of better efficacy overall, longer durability, progression-free survival. It's a real advantage if you can push the dose to maximize efficacy, especially in the case of BTK. It's been seen with inhibitors that the efficacy really directly correlates with target coverage. You really have to keep this enzyme suppressed almost completely in order to suppress growth of the cells. That's why the 600 mg dose is really an advantage.
It also, as I said, reflects on the safety of the molecule.
OK. On the accelerated approval trial, you've identified this triple-exposed class of patients. Maybe you can talk a little bit about what that triple-exposed class is. Do we know currently what proportion of CLL patients kind of fall into that triple-exposed bucket? Given pirtobrutinib availability right now, just from a geographic perspective, do you have to primarily enroll in the US to capture all these patients?
Yeah, so triple-exposed, first of all, to define it, these are patients who've been treated with a covalent BTK inhibitor, so zanubrutinib, ibrutinib, or acalabrutinib are the major ones. They've also then been treated with a BCL-2 inhibitor, largely venetoclax. They may have received those at the same time in combination. The third item is a non-covalent, so pirtobrutinib, most likely a non-covalent inhibitor of BTK. Those three drugs, the shorthand is triple-exposed. Unfortunately, patients can sequence through those fairly rapidly. Resistance then crops up. These are the patients that we see as an unmet medical need. Therefore, we believe would qualify under the definition of unmet medical need for accelerated approval purposes. We've seen responses across the board in patients that are in this category and also even beyond. In general, we've treated already fourth-line patients.
Triple-exposed are essentially fourth-line, but we've treated from four to 10th-line patients that have seen all sorts of other therapies as well. That's the category that we're going after here with the accelerated approval single-arm study.
OK. In terms of where you'll have to center your enrollment efforts?
Largely U.S., but also Europe. Those will be the focal point of phase II.
Now, when do you expect to reach, I guess, definitive alignment with FDA on the concept of the appropriateness of this triple-exposed patient population that you just defined for the purposes of accelerated approval? Is that just a pre-NDA issue in terms of when you have that conversation?
Yes, it really is a filing, the time of filing. Yeah.
Do you think that this notion of appropriateness could prove a regulatory issue for one of the other competitor degraders in the space? Do we know if they're specifically looking at these triple-exposed patients, or is it just BTK and BCL-2 exposed?
We know that they are included, I think, in everyone's trial at this stage. I think B1, you're referring to B1. Yeah, we know that they're including triple-exposed patients as well. How many patients, I don't know. We do think that this does qualify for potential accelerated approval. Again, it's a review issue. In general, the whole accelerated approval paradigm is questionable at this point in time. Like with this FDA, what does constitute accelerated approval, et cetera? It's on a case-by-case basis. We'll see. Again, it generally means a category of patients where there's no approved agent. This would be this triple-exposed population.
Yeah, because I was looking through the, I think, the B1 protocol. I know that they're going to be including these patients, but I can't tell if they're pre-specifying for these patients.
Yeah, you'd have to ask them. I don't know.
OK. Do you have any sense from your initial conversations with FDA just with respect to what the duration of follow-up will need to look like at a time of filing from this triple-exposed DAYBreak trial that you're running?
In general, it's about a year. Yeah, I think that would be about the number to target.
OK. Maybe you can talk a little bit about the rationale for the design of the confirmatory phase III trial and maybe specifically speak to your decision to include kind of a pre-specified menu of different control arm options.
Yeah, so our goal with the confirmatory trial was to design a trial that could, a single trial that could address the sort of global formulary for CLL in the second-line+ setting. We’re targeting patients that have received a covalent BTK inhibitor but have progressed on that. That’s the second-line trial. If you look for a global trial, then pirtobrutinib is not approved in many, many regions. One has to select a confirmatory or control arm that can be prescribed in those regions. We’ve included the physician’s choice for bendamustine or rituximab, which is a standard of care in many regions, continues to be prescribed in the United States as well. Also idelalisib, rituximab. Those two combinations as choices. It is a challenge to develop a trial that can enroll globally, a single trial.
That's our attempt at addressing the various geographies in one trial.
OK. Based on your comments, I'm guessing you can navigate site selection in a way that allows you to kind of control for control arm therapy representation within the study itself.
Yes, one can navigate that. I think it, though, is an active area for us to evaluate how best to really create, again, the most attractive control arm. It is something that we're actively dealing with as we set up this trial.
OK. Would you imagine that you would have to, I guess, cap the representation of any one of those control arm options within the study itself?
That's one option. It's not entirely attractive because if you give physicians choice, you really want them to have a choice in terms of what to prescribe. Again, we're currently navigating that and determining the best actual logistics.
I would imagine how you navigate that would also dictate the way you think about powering assumptions as well. I would imagine that there's a different outcome assumption for each of these control arm therapies. Then there is the outcome assumption for Bexdeg in this patient population, which I'm not sure we necessarily know what that is at this point either. Right.
It is a moving target right now. The beauty of Bexdeg is that we do not know our PFS, the progression-free survival number, yet because patients are staying on this drug a long time. That is a, but as our data sets evolve, especially with the phase IA, we hope to learn what will that number be. What is the duration of therapy? So far, it just keeps getting extended out, which is excellent. We need to see a number at some point. That will then allow us to really put a fine point on the design of this trial because we want to design the trial that will win. We want to know what it can do, how it can perform against the control.
As we gain data for our drug and also as we see more data from pirtobrutinib, for example, I think we're going to take all that into consideration. This upcoming ASH is going to be a very important event, I think, for Nurix, but also for the field because we expect to see a lot more data from the non-covalents as well.
OK. Yeah, I definitely want to talk about ASH. Maybe just one more phase III study. I think the initiation of this in terms of it starting in the first half of next year would align with this notion of, OK, you're going to have this DAYBreak trial data that you're going to submit to FDA for accelerated approval. At that point, you need to have sufficient enrollment in the confirmatory phase III. Should we assume that the way that you're rolling enrollment of these two things or staggering them, that then allows you to make sure that the phase III would be "sufficiently enrolled" at your time of an NDA submission?
Yeah, that is definitely the goal, is to make sure that the phase III is sufficiently enrolled. The key word there is sufficiently. That is not well defined. The sooner, the better in terms of getting the phase III up and running. We do want to have as much information as we can when we implement the final design of that phase III trial. It has to be a trial that is globally relevant, is relevant to the marketplace, the future CLL marketplace three years from now. Those are things that we are taking into consideration here over the next few months. Yeah, our goal is to initiate that trial in the first half of 2026.
OK. Moving to ASH, we'll be getting an update of dose expansion escalation. I'm sorry, question in the back, Renex.
I'm sorry. You may have covered this, but this phase III trial, when it's designed, will it be designed to look for a superiority in the standard of care or a non-inferiority?
The question is whether or not the phase III will be designed to look for superiority versus non-inferiority? It will be designed to look for superiority to the control arm, yes.
Just quickly on ASH, I know we're getting an update on the IB, IA dose expansion, dose escalation data. What's kind of the expectation framework that you would like to provide in terms of what we're going to see? Is there anything that you would kind of suggest to investors that they should maybe be paying some attention to?
Certainly. The abstract's published. It was sufficiently vague in order to allow us to present the data that we think is going to be most impactful at the time of the presentation because, of course, you submit these abstracts in August. The presentation's in December. There's a big gap there. There's data cuts that occur. I think what people will be looking for is a duration of response or progression-free survival numbers. How does Bexdeg perform? How long can patients stay on the therapy, which is a critical question? I think that'll be probably number one. I think looking for justification of the dose, data that justifies the 600 versus the 200 milligram dose, I think that's a major important point.
I think those two things, because if you combine those two things, if you look at those and really study the data, then I think it will predict really how the drug will perform in the DAYBreak study, the phase II single arm, but also how it will perform against competing agents. I think those are going to be things to really align on. We expect to have these competing agents presenting a lot of data as well. I think it'll be really interesting. We often end up on the podium together with our competitors. It usually makes for pretty interesting sessions.
This notion of being able to get better visibility into durability, I know at EHA, you presented the dose escalation data only. That kind of is the segment of patients who have been on drug the longest. That allows us to maybe better tease out what that durability might look like. The ASH abstract lumped the two together, dose expansion, dose escalation. Will you somehow be providing kind of another snapshot of that dose escalation cohort for us to maybe better understand durability?
Yes, that's the goal. I mean, to understand durability, you really need to look at the cohorts that have been on the drug the longest. That would be the phase IA. Then the IB section, where we're able to look at a randomization in doses, gives you this picture into the dose question. You can look at, for safety, you can look at the groups together. I think what we're going to try to do at ASH is to really look at the different slices because they'll show you different dimensions of how the drug performs. That's very important to look at those different categories. Of course, the IA data, although you can get durability from it, you have to remember that these are patients that are on all different doses from 50 mg -600 mg.
They're all mixed together in terms of treatment duration. I think the duration you'll see from the IA is not going to be, should be less than the duration you expect from the 600 milligram cohort ultimately once they've been treated a sufficiently long period of time. The snapshot that you'll see at ASH and the IA in terms of duration, I think, should be an underestimate, basically, of what the drug can actually do.
OK. One of the updates you also gave here in conjunction with this overview was this selectivity data. I know that you and I have been kind of qualitatively speaking to this for a little while. I think we finally saw a snapshot of it. I think it looks pretty interesting. Can you kind of just summarize what you think that selectivity data is telling you about Bexdeg relative to some of the other competitor BTK degraders? Do you think this now begins to explain maybe some of the differences that we've seen on the safety tolerability side?
Yes, I think that this is a real differentiating feature for Bexdeg. I think Bexdeg is the most selective drug in the category. We see the selectivity superiority based on proteomics, very in-depth proteomics. When you're working with a degrader, you can actually do the proteomics on cell types of relevance, i.e., B cells. We've done this head-to-head against B1 and against AbbVie's molecule. You can see which proteins are degraded that disappear in the proteomic scan. For us, if you go at 10x the dose level that we treat, which is the way you evaluate these drugs for selectivity, the only protein degraded is BTK. It's a thing of beauty in terms of seeing this proteomic spectrum. If you look at the competing molecules, you see many other proteins degraded.
ABV is actually fairly clean, although TEC kinase is degraded, which is a known off-target associated with cardiovascular disease or cardiovascular side effects, I should say. With the B1 drug too, not only do they hit TEC, but they hit several other kinases that we think are associated with liabilities that are significant. This proteomic scanning is really the latest technology to show this ability. I think before degraders and before the proteomics at this level, you could not tell how clean your drug was. Of course, we have been using proteomics for years. Bexdeg is an extremely clean, selective drug. We think that will translate to safety advantages. People are familiar with the kinome scan to look for selectivity in kinase inhibitors. This takes it to a whole nother level of selectivity. It is pretty impressive technology. We think we are the most selective.
We think we're going to have that that'll translate to the best safety profile. It also has translated to enabling us to dose at the 600 mg dose level to get efficacy, maximize efficacy.
OK. I know you have development aspirations for this drug in I&I. Maybe you can talk a little bit about what's ongoing right now and what we should expect to learn on the I&I front for Bexdeg within the next 12 months or so.
We're currently conducting a multiple ascending dose study in healthy volunteers with our new formulation, which is designed for an I&I indication. In 2026, we expect to share those data. That'll really speak to the dose and also talk about which indication we intend to pursue. This application of BTK in I&I, I think the inhibitors have gone there already. We think the advantage of a degrader will be just as great for I&I as it is in oncology.
Speaking of the inhibitors, I think Roche just announced last week that fenebrutinib won in a couple of different phase III studies in various MS populations. We know the CNS penetrance of Bexdeg is pretty exquisite. Does this now, I think this is kind of like the second confirmatory signal that we've seen from an inhibitor within the context of MS, maybe more cleaner than the first one in terms of ambiguity. Where does MS sit on the hierarchy of things that you're interested in?
Given Roche's results, which I think are fantastic, on top of Sanofi's result, I think it puts MS very high in terms of the target list for indications for a degrader. The central thesis there is that they can inhibit the microglia, BTK in the microglia of the brain. That'll shut down the neuronal-based attack on neurons, basically. What's impressive with Bexdeg is we've done all those experiments in animal models. In rats, especially, we've seen near 100% degradation of BTK in microglia in the brains. Of course, we get drug levels that equal plasma levels. Free drug level in the plasma is equivalent to CSF levels. In addition, in our patients currently with CLL, with brain involvement as well as primary CNS lymphoma, we've had some dramatic responses to our drug in clearing tumor cells from the brain.
We have little doubt that we have activity that's profound in the brain. We think that this can translate to a real advantage potentially in MS. The microglia are really the target. It's really an exciting advancement of the field. The advantage of a degrader versus an inhibitor is that one Bexdeg molecule can degrade 10,000 BTK-20,000 BTK target proteins per hour. This is how the degradation is catalytic, how powerful it is. It really will be able to deliver, we think, a much greater therapeutic effect than any inhibitor in the I&I setting.
OK. Before we jump into a couple of the other things that are I&I related, maybe real quickly on CBL-B. We just saw data at ESMO. Maybe talk about what are next steps. Are you confident that you've established proof of concept here?
We are confident that we've established mechanistic proof of concept by inhibiting CBL-B, which is an E3 ligase. We are activating the human immune system with anti-tumor effects. We published that at ESMO. Now, again, at SITC, another dimension that we published. The signal was strongest in colorectal cancer and prostate cancer, so cancers that are normally cold, cold tumors in terms of their response to anti-PD-1 antibodies. We are very encouraged by that. The biggest indicator for a potential successful IO agent is to see monotherapy activity. We think we're seeing strong signals of monotherapy activity. The next step then would be to expand that and confirm those signals. In an IB study to expand cohorts as monotherapy and look for monotherapy activity against the tumors.
OK. And then maybe just on 2127, which is another version of a BTK degrader that has preserved some of the Revlimid or the imid-like activity of the E3 ligase itself.
It is a combination drug in one pill, in one molecule. It does deliver Revlimid-like activity along with BTK degradation. That tees it up for really use in non-Hodgkin's lymphomas, diffuse large B cell, and mantle cell, where we've seen some dramatic, again, complete responses. That is currently in dose escalation. We want to finish that in 2026 and then determine the next steps for that molecule.
OK. Your I&I collaborations with Gilead and Sanofi, I know you're kind of limited as to what you can say about each of these things. Maybe you can just qualitatively speak to how you view the opportunity for competitive differentiation kind of relative to some of the first-gen molecules that we've seen out there thus far. Maybe the first-gen 1.0 version of an IRAK4 degrader from Chimera, and now kind of the STAT6 degrader from Chimera. Where do you think there's opportunity to differentiate? I guess in the case of STAT6, just given the magnitude of the opportunity, does that differentiation matter?
Starting with STAT6, it probably doesn't matter. There will be room for more than one successful molecule in the type 2 inflammation space, which is, of course, the Dupixent market, but probably greater than the Dupixent market, given that these are oral. I think there's going to be more than one winner in the STAT6 space. It's a fantastic target. Having said that, you're talking about really having to create a highly, highly selective compound that's very clean. The risk-benefit equation in type 2 inflammation is different than in cancer. You have very low tolerability for any safety issues. That's what happened to the first IRAK4 degrader. It ran into some types of safety issues, which was then canceled with Sanofi and Chimera. Ours is in MAD studies right now, healthy volunteers with Gilead.
We think that we have a very clean molecule, our IRAK4 degrader. We think we'll proceed nicely into the clinic. We work extremely hard to make that exquisitely selective and safe. It looks quite good. We apply the same standards to our STAT6 degrader, which, again, you have to set an incredibly high bar for selectivity. This is where this proteomics analysis comes in again. We really throw the book at these molecules, making sure that we find the cleanest molecule that degrades just one protein. STAT6, it's clearly the sole protein we degrade. I think that we're in a good position there. Sanofi has taken that molecule, which is NX-3911, into IND enabling studies. In 2026, we should see it go into healthy volunteers.
OK. What are you expecting from the IRAK4 degrader that Gilead currently has in clinical development? I guess, do you have any freedom to communicate around progress that is made with that drug under the umbrella of that collaboration? Is that just something that will go through healthy volunteers, phase I, SAD, MAD, and we'll never see anything?
I don't know. I suspect we will see data from the healthy volunteer data. I mean, it's in Gilead's interest too, because you need to cultivate interest with investigators to get enrollment and to show that these agents are safe and they hit the target. They've been very good to collaborate with in terms of publication. They've published too. They presented this fall, September. They did a whole poster on GS-6791, is the Gilead number now. We were allowed to show some data recently in our investor meetings with regard to our penetrance of keratinocytes, of our IRAK4 degrader getting into keratinocytes and degrading IRAK4. They're interested in atopic dermatitis, of course, and other, there's, of course, a whole host. I think we'll be seeing data from, I certainly hope so, from the IRAK4 degrader.
OK. Last question, unless there's any more from the room. Maybe just talk a little bit about the balance sheet. I know that you guys just strengthened it, cash runway, and just what that now allows you to achieve.
Yeah. So we have over $650 million in cash currently. This gives us runway through the end of 2027 into 2028. This was strengthened recently. We're very fortunate to have a great investor base with an offering we did of $250 million recently. That put us in a really strong position to launch our pivotal programs, which is the primary use of proceeds, but also move our entire pipeline forward, including, of course, our participation with STAT6 and IRAK4. We're in strong financial shape. We're going to have a lot of data readouts over the next several months here, starting with ASH in the next week.
Starting with ASH in the next week or next month. Sunny Orlando.
Yeah, Orlando is wonderful.
Maybe you can meet at Applebee's for a beer or something.
Yeah, that'll be great. Or go to Disney World.
Thank you, Arthur.
All right.
Always appreciate the time.
Thanks, Steve.