All right, good morning everyone. I'm Stephen Willey, one of the Senior Biotech Analysts here at Stifel, and glad to have with us, as part of the next session of day two for the I&I Summit, the CEO of Nurix Therapeutics, Arthur Sands. Arthur, thank you so much for your time today.
Yeah, I'm happy to be here.
We're glad to have you. I know we spend a lot of our discussions talking about, you know, bexodeg and the CLL landscape, and those are obviously relevant topics based upon some of the news that you announced earlier this week or last week. Just wanted to stick with the theme here and really kind of focus on Nurix's, your efforts in the I&I space. I guess if maybe there's some time at the end, we could hit a few oncology-related questions, but sure, would like to keep this I&I focused. Maybe we can start with bexodeg, right? You've talked about having development aspirations for this drug in autoimmune disease. We've seen the development history of BTK inhibitors in this space kind of wax and wane over the past decade or so. There's been some recent phase III successes that have kind of reignited interest.
What makes BTK a good autoimmune disease target? Just given that this is broadly expressed on other immune cell subsets besides B cells, is the biology that you're specifically looking to target dependent upon the disease state itself?
BTK touches many different immune cells, as you point out, and different subsets are more amplified in certain diseases. It can have utility across many diseases based on its versatile sort of nature. It ends up being disease specific because, again, certain subsets are amplified or, you know, out of equilibrium. BTK not only functions in B cells, which is where most people associate, of course, its primary function, but actually it's also in mast cells, basophils, monocytes, macrophages, and also in the brain, in microglial cells. It's a versatile target. What also makes it very attractive is if you look at the genetics, which are longstanding and well known, that one can completely delete BTK and still have a functioning mammal. In fact, there are humans lacking BTK who have immune system function.
They are more susceptible to infections, but they basically have a suppression of the B- cell axis in essentially a very safe manner. Although it is a strong target in terms of its effect on the immune system.
Okay. I think I've been previously characterized as a functioning mammal. Anyway, how do you think about the competitive differentiation of this drug, just relevant to the covalent inhibitors that have been at the center of some of this recent phase III success? Rilzabrutinib from Sanofi, remibrutinib from Novartis. Maybe just tackle that question first. I just have a follow-up.
Yeah, so first off, from a real structural level, the BTK degradation with bexobrutideg, which is highly specific and highly potent, removes the entire function of the protein. The compounds you named, remibrutinib and rilza, they are kinase inhibitors, so they block the enzymatic function. What we've uncovered through our degradation work in BTK, and we were really the first to reveal this, is that there's a whole other function of BTK, which is the scaffolding function. That is the structural function. BTK forms a node, a physical node, in the cytoplasm. When one removes BTK, that entire signaling node falls apart, and there are several other kinases associated with it.
We uncovered this via our work in CLL and cancer, where we discovered with our collaborators at Memorial Sloan Kettering that even though they could completely inhibit a BTK kinase function, there was still signaling going through that node, that physical node within the cell. Downstream targets were phosphorylated. This was a Science article about two years ago. It was clearly, even though the kinase function was mutated, these were kinase-dead BTK mutations that were studied from patients who had active cancer, there was still a strong growth signal coming through a kinase-dead BTK. How could that be? That was the first evidence of a structural function and the signal coming through it.
There's other evidence that we've accumulated since then, where not only do we have responses in our CLL patients that have kinase-dead BTK mutations and they're resistant to inhibitors, but there's also wild-type BTK patients, about 60% of them, who have become resistant to kinase inhibitors, the BTK inhibitors. Yet our degradation mechanism works. We get responses in these patients with wild-type BTK that have stopped responding to inhibitors. How can that be? Why do they still respond to BTK degradation? We think it's because we're removing the structural function of BTK. I know I've talked a lot about CLL, but we think the same mechanism is an advantage in autoimmune disease. Inhibitors are only really hitting that kinase function, but they're leaving efficacy on the table by not being able to hit the scaffolding function. I can add one more piece of evidence.
When you look at normal cells, not CLL cells, normal immune cells, and we've published this too, our degrader is 10 to 100- fold more potent in blocking the IL-8 pathway and other pathways, B cell activation measures, however you measure them. So 10 to 100- fold more potent than rilzabrutinib or remibrutinib. Even with achieving complete kinase inhibition, you see this shift in potency and a deeper response. Again, we think that's evidence of hitting the scaffolding function by degradation.
Okay. You're now in the process of generating some clinical proof-of-concept data under the existing IND by enrolling CLL patients with this underlying autoimmune hemolytic anemia. Can you talk about how much patient data you're looking to generate, the magnitude of benefit you're hoping to show, and maybe when we might expect to see some of this initial data?
Yeah, the good thing about looking at wAIHA or autoimmune hemolytic anemia, which overlays, can occur in CLL, and it's estimated that maybe 20% of CLL patients will develop the severe anemia as well via an autoimmune overlay of autoimmune disease. Hemoglobin measures, seeing hemoglobin come back up, gives you a direct quantitative measure of efficacy. We hope in 2026 to have enough patients to report on in that cohort of CLL. We think that would have direct read-through to wAIHA in a non-oncology setting and other hematologic autoimmune diseases. Those in general are still relatively small opportunities compared to looking at other opportunities that bexdeg, as we call it, bexobrutideg or bexdeg for short, could have. That is a first look, if you will, but that won't be till 2026.
Okay. I know you had previously mentioned about conducting some dose-finding work with a new formulation in healthy volunteers. I think there was some discussion of potentially opening up a separate IND in non-malignant hanging. You know, what's the current status of those efforts and plans right now?
Yeah, so we're in the midst of the multiple ascending dose study with the new formulation, which is designed to give us a broader dose range, if you will. It's a tablet versus a capsule, so there are some patient-friendly aspects, more friendly aspects to the formulation. It also would enable very easily us to do placebo-controlled trials across a wide spectrum of indications if we so choose. It also defines a different product category because it does have different characteristics in terms of PK and PD, which we think may provide some advantages in a broader autoimmune disease setting, which may be a much larger market setting than CLL. At any rate, we're in the midst of studying that formulation. The single- ascending dose portion is completed. Again, we're in the multiple- ascending dose portion to really understand the new formulation.
Plus, combined with everything we've learned from the capsule formulation in oncology, we should be in a strong position to file an IND in an autoimmune indication in 2026.
Okay. As you think longer term about maybe having a presence with Bexabritadeg in a larger autoimmune setting, do things like IRA and then maybe the potential need for a partner within some of these larger indications you might pursue, does that imply that any real dedicated development effort here would require a new molecular entity?
First off, on the IRA , it kind of falls in the category of good problems to have, right? If you get there with a very, you know, large blockbuster drug. In terms of requiring a partner for full development, it certainly would help on the financing front, but it's not required. I think we can approach this in a stepwise fashion and continue to maintain control of the program. Although we do have several interested parties, this is obviously a very interesting product opportunity with multi-billion dollar potential. Who wouldn't be interested in it? We are right now prosecuting it on our own, and we're well funded to do so. Depending on how large the program gets, it may be a future consideration, certainly.
Okay. If you were in the process, or if you were to develop a new molecular entity as an alternative to bexo, are there certain properties that you would look to enhance if you were developing a BTK degrader specifically for autoimmune disease?
I think, I don't know if that was part of your previous question. I didn't quite hear that correctly. I thought you were talking about partnerships in the previous question.
Yeah, no, the prior question was partnerships, and I guess this is just more of a question of if there were to be a new molecular entity, would there be certain product properties that you would like to either enhance or dial in relative to what you have with bexo, with the understanding that this would be an autoimmune disease new molecular entity specifically?
There's always room for improvement, although it's difficult to do that for bexobrutideg because it's actually quite an amazing molecule. There's always room for improvement on molecules, and we do have investigative programs to come up with new molecules that would degrade BTK, perhaps with slightly different profiles. What you work on always is even better selectivity, even better potency, even better PK, and we have a great benchmark to try to improve upon. Having said that, the selectivity of bexobrutideg is so exquisite, it's kind of difficult. Even if you just came up with another molecule that looked like, you know, had all the attributes that bexobrutideg has, but was a different molecular entity, that would, of course, define clearly a different product and would allow it a different, totally separate development path, which would take place in healthy volunteers and then autoimmune disease patients.
It would also allow for very different pricing opportunities. In some of the derm indications where pricing is very different than oncology, that might be attractive.
Okay. Maybe we can shift gears to the collaborative I&I pipeline. You've got a clinical stage IRAK4 degrader, which is part of what Gilead, a preclinical STAT6 degrader part with Sanofi. I guess maybe before we talk about each of those, how do you think about the biology of these two targets intersecting and potentially overlapping, just given that IRAK4 has also been implicated in some of these more classical type II pathologies like atopic dermatitis?
Yeah, definitely. I mean, I think there is room for overlap. The markets are significant. In general, while there may be some overlaps in the biology of IRAK4 and STAT6, when you do hit a different target, you are going to see different biology, different pharmacology, certainly, ultimately in the clinic. These things are sometimes very subtle, but they will show up in the clinic and in different indications. These diseases are different from one another, and that's where the pharmacology will reveal itself. What you see happening, of course, is that companies will have multiple clinical trials going with these different mechanisms and look for the winner, what works the best. You almost have to do it empirically at that point. Both STAT6 and IRAK4 will have differences, and they have biologic differences that we can see in vitro. Then we'll see that, I think, manifest in the clinic.
Okay. In terms of each collaboration in terms of the structure, should we assume that indication selection for the purposes of generating the clinical proof-of-concept data that then triggers your opt-in decision under each, is that indication selection a process driven exclusively by your partner, either Gilead or Sanofi ?
Yes, it is. The way these deals work is, you know, we were responsible for the full discovery program. I think in each of those deals, we've received over $125 million each through the discovery process, which was a multi-year process. We've been working, collaborating with Gilead and Sanofi . for quite some time. When we reach development- candidate stage, they have an option, with the associated payments, to opt in, take control of the program for the preclinical and the phase I and proof-of-concept development. They fund all of that themselves. At that point, at which they conclude that human experimental phase of studies, then we have our option. We get a data report of all the patient data to date. Then we have an option to opt in for 50/50 cost-profit share in the United States. They retain rest of world operations and commercialization.
We will receive royalties and milestones on ex-U.S. sales. That's the way they work. Along the way, they make choices about the indication to get to your question specifically. There will be multiple indications, but I think we'll make our decision based on some of the early human data so that we can participate in multiple indications with them.
Okay. I know you're quite limited in terms of what you can say about each of these molecules, but I guess maybe you can qualitatively speak to how you see the opportunity for competitive differentiation with the IRAK4 degrader, relative to what we've seen from the first-gen molecule from Kymera and Sanofi. I know that there seemed to be a suggestion for some room for improvement on the safety side. I guess anything kind of on the selectivity, maybe potency fronts that you can qualitatively speak to.
Yeah, so apparently they did have some safety issues that came up and that it has to be, I would imagine, off-target. It usually speaks to a selectivity issue of the molecule, which you can in general screen out, counter-screen out your off-target effects. I imagine that's what happened in terms of the discovery process for that first-generation IRAK4. In our case with Gilead , working on our IRAK4 degrader, we really worked side by side with them over five years. They had an IRAK4- inhibitor program, so they knew a lot about IRAK4, had all the assays and all the off-targets to look out for, and we built that into our optimization process.
We also, being aware that there was some QT signal that Kymera had revealed, we really did throw the book at our molecule to make sure there was nothing at all that would hint at that in our animal models. We really were striving for an exceptionally selective and clean IRAK4 degrader, and I think we achieved that. It had to pass not only muster with Nurix , but also with Gilead and their rigorous optimization process as well. Of course, we tested our degrader with their inhibitors and could see the advantages of degrading IRAK4, the scaffolding function of IRAK4 being functional there as well. In the case of STAT6 degrader, a very similar story, working for five years with Sanofi from scratch on that degrader program.
Obviously, I think one of the best partners in the world understands the Dupixent pathways, IL, the interleukin-4 and 13 pathways and interleukin-1. We had all sorts of assays we used to optimize that. Also, the most sophisticated proteomics to get rid of any off-target effects. I think we have really a fantastic, clean STAT6 degrader as well. A lot of work has to go into optimizing these to make sure that they're the most selective they can possibly be. These autoimmune indications, really, the risk-benefit ratio is different, really must have extremely safe molecules to have broad potential in the marketplaces.
Okay. I would think in terms of the competitive profiling of your STAT6 degrader, you have constructed the Kymera STAT6 degrader in-house and probably have a pretty good understanding of how your program profiles.
I think there, you know, really it takes a little time to know exactly what the clinical candidate of another company is. The patent's published, but there's lots of molecules you can look at. I don't know where we are in that exact profiling. Now, we have, since the bexdeg program is more mature, done that with the other BTK degraders now, where we think we certainly know the B1 molecule and the AB molecule, but we don't have that advantage, I don't think, with the Kymera STAT6 degrader at this point. At some point, they will all become public and people will profile these molecules preclinically against each other. Certainly, that's going to happen.
Okay. It looks like Gilead is going to be presenting some preclinical data here for the IRAK4 degrader at the EADV conference, I think later this week. Is there anything you can say about the presentation? Should we learn anything incremental about that program?
I think it's going to be one of the first more fulsome disclosures of the preclinical profile of the compound, of the drug that's in the multiple ascending dose studies right now in healthy volunteers. It's an important publication, and I think it really will set the stage and give the profile of our molecule, again, preclinically. Clinical information probably would be in next year's 2026 timeframe.
Okay. You mentioned the opt-in decisions earlier. How do you think about these decisions to co-promote each of these assets, just given the fact that these are likely to require fairly significant resource-intensive development programs? I would think these decisions converge with your effort to push bexodeg kind of to registration in CLL. I'm not sure if there's a question in there, but maybe you could just kind of speak to how you think about the convergence of those two things occurring in lockstep and where that puts you from just kind of a strategic perspective in terms of needing to make that choice.
It puts us in a very strong position because we'll have great opportunities. We'll have human clinical data before we have to make any decisions, and we know that the IRAK4 decision point will come at least a year to a year and a half, probably earlier than the Sanofi decision point. There is also time to gain the full understanding of the opportunity. It is basically a great investment opportunity for us, both of those molecules.
Okay. Maybe just in the last minute here, drug-antibody conjugates. I know you have the collaboration with Pfizer. How should we think about this mechanism as it pertains to autoimmune disease? I guess, are there applications that you...
Yeah, there are applications in autoimmune disease. It offers the ability to be even more specific and selective and safer. The risk-benefit profile of these molecules, I think, could be made very, very attractive in autoimmune disease. The first place for proving their efficacy is going to be in oncology. Those programs with Pfizer are oncology programs. We do think there's opportunities in autoimmune disease as well.
Okay. Maybe just lastly, you can just kind of give us a snapshot of the balance sheet. I know you have a busy second half of the year coming up in terms of various pipeline disclosures. Maybe you can just recap those as well.
Yeah, so we had ended the last quarter with $485 million in cash, which is plenty to take us through to the mid-2027. The disclosures we have coming up, you mentioned the Gilead disclosure coming up here in Paris, tomorrow and the next day. Then we have ESMO, where we're going to be publishing on NX-1607, the phase I study results, I-A study results, which I think will be very important. Also at SITSI, we'll be there in early November, and then at ASH, which is a big, big event for us with bexobrutideg, the latest on that clinical trial. A lot going on. We're launching into pivotal studies with bexobrutideg, as well, as you know, we outlined the clinical plans. I know we don't have time to talk about all that, but we will be a phase III company in 2026.
That's an important transition, as well as, of course, our I&I portfolio moving forward.
All right. Very good. Arthur, always appreciate the time. Thank you very much.
Thanks, Steve.
Thanks, everyone, for listening.
Great seeing you. Thanks.