All right. Thank you, everyone. I'd like to welcome everyone to the Piper Sandler Healthcare Conference, and introduce our next company. We have Nurix Therapeutics and their CEO, Arthur Sands. Welcome, Arthur.
Thanks. Thank you, Biren. Thanks for having us.
And maybe to start off, for those on webcast and in the audience that you know, haven't dug into the pipeline, maybe you could talk a little bit about your focus. You have clearly a platform on, a degrader platform that you've deployed to develop a, you know, wholly owned internal pipeline. So if you could maybe just give us an overview.
Yeah. Sure. So Nurix Therapeutics, we're based in the Bay Area. We've been developing targeted protein degrader drugs for over a decade, well over a decade now. Originally based out of science from UCSF and Berkeley in terms of the foundation of the company. We have developed a pipeline focused in oncology and autoimmune disease, are the two major therapeutic categories. Our lead program is a targeted protein degrader of BTK, known as Bexovibart, formerly NX-5948. And that is being developed. It is now in pivotal studies for CLL. And we're planning our Phase 3 randomized confirmatory trial to start in the first half of 2026. Bexovibart is a very clean, exquisitely selective compound, targeted degrader, and very, very potent.
What we've learned of the safety profile, now in over 200 patients in oncology and CLL primarily, but also NHL, is that we think it has applications in autoimmune disease also because of its safety profile and its potency. So we are developing a second product profile for autoimmune disease with its own formulation. And that's ongoing in a Phase 1 study currently in a multiple ascending dose study to test that new formulation and determine dose for potential autoimmune indication in 2026. So far I've just talked about one drug in our pipeline. We have many others we can cover. Since I was just mentioning autoimmune disease, I'll also mention we have a STAT6 degrader, which we're developing with Sanofi. That is a product of a multi-year collaboration to develop that program that is now in IND- enabling studies.
They are currently managing that, and they will also fund and manage the initial clinical development of the STAT6 degrader. That's NX-1607. We have an IRAK-4 degrader also in autoimmune disease, which is being developed with Gilead. That is currently in Phase 1. They are managing the clinical aspect. We did all the discovery with them over this multi-year collaboration. The beauty of those collaborations is that we have also opt-in rights after human proof of concept, so we can opt back into the program for 50/50 co-development, co-commercialization, in the United States. We consider that an integral part of our IND pipeline. Both those programs have great potential. We have multiple other oncologies skipping back up to that, but I'll pause there because I know you've got a lot of other questions you want me to ask too.
Yeah. You know, with Bexovibart , clearly targeting the BTK path.
Yeah.
You know, a lot of success there, with other agents. You know, I think initially with Ibrutinib, but now we've had many more advances since then. Can you talk about where Bexovibart potentially differentiates versus, you know, some of the newer BTK inhibitors or degraders that are in development?
Sure. So, BTK is obviously a fantastic target that was discovered genetically originally by virtue of being a complete knockout in certain patients, humans, that do not make certain forms of antibodies, cannot mature their B cells. Otherwise, very actually safe phenotype. And so that really turned BTK into a potential drug target. So the inhibitors were the first wave of compounds to block the kinase activity. However, what they do not do is they don't remove the total protein activity. They don't imitate the genetics, in other words. In other words, so with targeted protein degradation, we completely remove the protein. And that's important because there's not only a kinase function in BTK, but there's what's called a scaffolding function, which is a very strong structural function of the protein through which growth signals transmit.
So the inhibitors are only blocking one aspect of the function, and they do have significant activity, but they're leaving activity on the table. The other, sort of blind spot for inhibitors is there's multiple mutations that have now arisen in patients that are resistant BTK mutations that render them resistant to the inhibitors. And these are all mutations within the kinase domain, and they can lead to constitutive activity of the kinase. So the kinase is stuck on, and the compounds can't block it. Or interestingly, kinase dead BTK mutants that actually transmit growth, again, via this scaffolding function. And kinase dead mutations are interesting ones. That's one of the discoveries we made originally with our collaborators at Memorial Sloan Kettering from our patients in the trial. So the Bexovibart has a number of advantages, taking out the total protein and all its functions.
So we get more efficacy. We can drive efficacy. And then also addressing the resistance mutations. And we can get into other aspects of the pharmacology, including selectivity and drug levels, which are very, very low, but there's many, many other advantages to the catalytic degradation.
You, I think the company recently presented mass spec data, you know, characterizing off-target hits with Bexovibart compared to, you know, BeiGene's BTK degrader, as well as AbbVie' s compound. Can you talk about, you know, some of that data that have been shared recently?
Sure. So, we can use proteomics, highly sensitive mass spec proteomics, to identify any potential off-targets of a degrader. So you can see the proteome and see which proteins are disappearing, and you want only one protein to disappear. You want, in this case, BTK to disappear. And that's what we saw with our compound. Very, very clean, proteomic profile. When we look at some of the competitive, competitor compounds, you mentioned BeiGene and AbbVie , we have identified more off-targets that we think will, can contribute to safety issues in the long run. The analogy is to the kinome scans that people are quite familiar with, with kinase inhibitors. Those kinome scans you can see, are you hitting many kinases? That's not a good thing. You wanna have a very clean profile, and that'll lead to better safety ultimately in the clinic.
And you can also then push on potency because, if you have a clean compound. And that's the kind of profile we see with Bexovibart . So we're very excited about those data. And then we also did compare mutational coverage of the different degraders. So like inhibitors, degraders can have a different spectrum of mutational coverage as well. And what we found is that Bexovibart does have the most consistent mutational coverage across all the BTK mutations compared to, again, BeiGene or the AbbVie compound. And we think that's very important, so there are advantages that we think we've identified preclinically.
Got it. And then, I think, one of the data sets around this disclosure was the fact that Bexovibart is selective against TEC, whereas, the BeiGene compound degrades TEC. What's the significance of TEC?
TEC is the closest homolog. It's a kinase. It's the closest homolog to BTK. TEC has been associated with cardiovascular side effects, cardiovascular detriment, including AFib and hypertension and, potentially also platelet function. TEC has been a known off-target for the inhibitors also, and everyone's tried to steer away from it. I think one of the most selective inhibitors is about six, 24-fold selective by our measurements, and that's Acalabrutinib. Zanubrutinib is actually only seven-fold more selective over TEC. It does hit TEC, and Bexovibart is 64-fold. We have a 64-fold window. I think in that same panel, as I recall, the BeiGene compound was something like threefold. We have a much larger safety window over TEC. But there's other kinases that we've identified to watch out for that include LCK, which regulates T cells.
You don't wanna turn down T cells. You really, we just wanna hit the B cell malignancy, and then CDK, which is another cardiac off-target, and then I think another one was ADK, which is a liver off-target, so proteomics is really allowing people in the targeted protein degradation world to make cleaner drugs, superior drugs, not only against, you know, compared to other degraders, but to inhibitors, and so those are some of the off-targets.
Got it. Got it. I think in a few days, at the ASH meeting, the company is gonna have some data sets. Can you maybe talk about why and provide a preview of what we could expect there?
I can provide a framework, but not the preview. We're gonna have a great, great podium presentation on Saturday morning coming up here in a session on CLL with Bexovibart , and then we have a poster presentation on Bexovibart and Waldenström. The oral presentation on Saturday is CLL. We also have another poster of Memorial Sloan Kettering addressing all this mutation questioning, which is going to be another interesting presentation. In terms of our presentation on CLL, I think most you know to frame that up, looking at duration of effect is gonna be key 'cause now we have patients on over two years of therapy in the Phase 1a. We'll look at a duration of effect.
We'll look at progression-free survival in these more mature cohorts now. Another big topic is choosing our dose for the pivotal studies, which we've done under Project Optimus. We've chosen the 600 mg once daily dose. Another topic for ASH will be why we chose that and how it looks compared to the comparator dose, which was a randomized cohort in the Phase 1b study. We've never presented data on that before. 200 versus 600 and supporting our dose selection. I think those are probably two of the most important topics.
Got it. Got it. And then I guess, will there be any subgroup analysis beyond that?
Yes. For the first time, we are going to present on some subgroup analyses. We're talking about a, so far about 100 patients, I think, in this presentation. So when you start to break down the subgroups, the numbers do get low, especially looking in the subgroups of the mutations. But we're gonna take a first look at it. Those numbers will probably change through time. So looking at mutational subgroups, looking at pretreatment subgroups, like those patients that have been pretreated with a covalent BTK inhibitor and a BCL-2 inhibitor, how do they perform versus those patients that have had all, also had a non-covalent? Looking at a group of patients that progressed, all the patients that progressed on an inhibitor, did they behave differently than the total population? So, we're gonna break it down.
Good. So I guess we'll get a lot of insights in terms of different patient groups, different doses, and also longer follow-ups.
Yes. It'll provide the foundational data set for our pivotal studies.
And so with the pivotal studies, you know, clearly there are two that the company has disclosed that they're moving forward with. The first is a study in the third-line plus, you know, relapse-refractory setting. It's a single-arm study. The second is, you know, second-line plus study where, you know, there's a control arm, investigator's choice of three different regimens. I guess on the single-arm strategy, what kind of informed that, you know, is it the data set that evolved in the Phase 2 and the confidence to, you know, design the single-arm?
Yeah. So the data set that really inspired the Phase 2 and moving into this third line plus, really fourth line setting is that what we've seen already in the phase Phase 1a are fourth line patients, fourth line plus actually. And so this is where we've seen an 80% response rate. So we see a very high, you know, response rate. We've essentially almost already done the experiment, if you will, in that subgroup of patients. And so we think we thought that would make for a potential accelerated approval strategy where there's no currently approved therapy. There'll be about 100 patients, as you point out, at 600 mgs dose. That trial has started, has commenced, has started enrolling already. And so we're really looking forward, hopefully, for that to enroll rapidly. Investigators are very enthusiastic about it because they've seen our Phase 1a data.
and we're gonna reinforce that again on Saturday.
Great. And, I know you probably haven't provided guidance on timelines for enrolling, the third line plus study, but are there any historical metrics that we could look at to say, at the point to where you could say, okay, this is study where, you know, they've taken this long to enroll, you know, 100 patients?
Yeah. Well, we don't have formal guidance on the enrollment data, but I mean, I think a goal would be to enroll rapidly and try to fully enroll the trial within a year to 18 months. It is a global trial where in Europe, in the U.K., and U.S. And so we'll have a large enough number of sites that we should be able to accomplish that.
The Phase 3 second line, plus trial that starts in the first half of 2026, what kinda needs to happen between now and then in order to initiate patient enrollment?
So, that trial design is still under construction. I mean, you did indicate the general approach here. We see the comparator arm evolving. So Pirtobrutinib will be included, chemotherapy, chemoimmunotherapy should be included. We wanna do a single trial that where a control arm can be, can fit the prescription habits of many regions, so up to 15 countries or 20 countries. So we're working on that. And so what has to happen between now and the initiation is getting full regulatory alignment across these geographies so that we can implement that trial and have the right design.
Got it. So, I guess meeting with other regulatory authorities and getting their alignment, and then you would potentially initiate the study.
Yes. Exactly, and of course we have alignment on the Phase 2 , the single arm trial across those same geographies, so regulatory authorities are very familiar with this compound already, but to then set that up in a proper, randomized control trial is another level of complexity.
How do you think about the second line market opportunity in CLL, patient numbers and, you know, the potential opportunity that you're pursuing there?
In the U.S., in the second line, I think. I believe it's something like 10,000 new patient prescriptions or starts a year. Then I think in the third line, it's on the order of 6,000 or so the third line plus. And then, you know, you can almost double that globally, so it's a substantial. It's a multi-billion-dollar market. I mean, I think the total CLL marketplace right now is $9.5 billion per year for BTK targeted agents. This is a very large market segment. And second line is still really split up. There's a lot of opportunity. We think a degrader as a monotherapy could be very competitive there. We're also starting combination trials 'cause we do think that can also be an important segment of patients.
The combination data, could we see some of that by second half next year?
Second half of ne. I'm not that far.
Okay.
I can't go there.
Oh, all right. That's fair. That's fair. I mean, I guess on the front line.
Yeah.
You know, that's a very significant market. You know, what are the plans to investigate in newly diagnosed patients?
It is a significant market. I think it's about 16,000 patients per year or so in the U.S. And the issue there is that the BTK covalent inhibitors, even though I talked about their flaws, they actually are very good drugs and they do have a significant progression-free survival time. But to do a head-to-head in the front line is a very challenging and very long study. Now, there are certain subpopulations in the front line where you could get faster readouts. These with p53 mutations or del(17p) mutations, high-risk populations could be an approach to the front line. Also, combination is another approach to the front line. We have a lot of reason to believe that combining the degrader with things like the BCL-2 inhibitor or an anti-CD20 could have really profound, deep, and durable responses.
So those are some of the things we're thinking about on the front line, but we haven't designed those yet.
That's perfect. And I think you know, with the BTK inhibitors, there seems to be emerging data sets in the autoimmune side of things. And I think the company's disclosed that, it's potentially looking at, you know, an indication, in this setting. What are the plans there? And what are plans going outside of the non-heme autoimmune, indication?
So we're. I think I mentioned in my intro, we are developing a new formulation. We want to see the results of our MAD studies in order to really fully characterize this form. And that'll help us determine our dosing regimen. In terms of the indications, we have not selected one, although I've spoken before about we are intrigued by MS as a potential. There's been some really interesting data recently from Sanofi and Roche with their BTK inhibitors and MS that look promising. And yet we think there's room for improvement because again, they're not addressing the scaffolding function. And we know that Bexovibart has activity in the brain. We cross the blood-brain barrier. We've had patients with CNS lymphoma who have had complete responses, which is remarkable.
Also, patients with CLL with brain involvement who have also had complete responses, clearing of the CSF of tumor cells. So we know we have a lot of data there. We've also demonstrated degradation of BTK in the microglia of rat brains, which is very important 'cause the microglia hypothesis in terms of inflammation. These are the macrophages of the brain, if you will. They are implicated in brain inflammatory disorders. Specifically, MS is one of the theories of why a small molecule would be better than an anti-CD20 in MS. Those are some of the things we're thinking about. It does take a lot to prepare for such indication expansion. We're well underway with the new form, new formulation.
Great. So more, I guess more to come, down the line.
In 2026.
For sure, and then, you know, or you mentioned the collaboration with Sanofi and the STAT6, clearly a high focus for investors given, you know, there's a competitor program with Kymera that's in Phase 1b studies. Can you talk a little bit about your program, the potency against STAT6 versus the Kymera compound?
Well, not versus their compound 'cause we did not test it against it yet. We didn't have it. But we're picomolar potent. We've released with Sanofi a little preclinical data on this. Clearly, it's in IND-enabling studies. They will be responsible for presenting data sets, you know, going forward. We have shown that in animal models, one of the things we released was our STAT6 degrader. We can actually reduce inflammation in atopic dermatitis models and asthma models down below the zero or control level, in terms of the inflammatory response. So, we get comparable results to the unchallenged animals. So it's really quite thorough in shutting down the IL-4, IL-13 pathways. STAT6 is another target that has terrific genetics. You can knock it out and you just specifically knock out IL-4, IL-13 pathways. So it's designed to be this small molecule equivalent of Dupixent.
We've designed it for oral once-a-day dosing and also to be a best-in-class agent.
Given Sanofi's responsible for the program, have they guided to IND filing timelines?
They have not guided to IND filing timelines. We know that they are in IND- enabling studies and we know when they started, and if you project for them, it should be in 2026.
You know, given the interest in the target, where does it fit in? You know, you talked about data in atopic dermatitis and asthma. Clearly, there are other biologics, Dupixent, you know, standard of care, in both indications. So, maybe if you could talk about where this would fit in with other biologics.
It would be designed to be safer and to be oral and to be equally, if not more effective. So, I mean, I think in terms of these large markets like atopic dermatitis and others, having an effective, safe oral medication, I think would just be a home run. You know, a lot of the patients, you know, these injectables, although the injectable pens have become easier, it's still an injection and it's still an awkward long-term dosing regimen.
You mentioned that the company actually has an opt-in into the program. When would that potentially occur?
So, under the contract, I can tell you it occurs after human proof of concept has been demonstrated. And then Sanofi would deliver a data package to us, a clinical data package. So I don't know when that would happen, in terms of calendar, but that's the structure.
That's the sequence of events. Okay. And then, lastly, I guess IRAK-4, this is a program that's partnered with Gilead. When can we start to expect data from that program?
I hope that Gilead would consider releasing phase 1 data in 2026, but we don't control that. We know they are in phase 1. It's the program's progressing. This is a compound that, again, exquisitely selective, designed to be best in class. No QTc issues seen in preclinical development. So we think we've really achieved something here that could be a superior IRAK-4 targeted agent.
Great. I mean, we didn't get to some of the other programs like the Cbl-b program and your Pfizer collaboration on the degrader antibody conjugate. So a lot clearly going on.
Yeah.
I know we're out of time, but you know, looking forward to further conversations and more dialogue and more data.
Great. You'll have to have me back then, so.
Definitely.
Okay.
Look forward to seeing you down in Orlando.
Yes. Yes. Thank you.