Nurix Therapeutics, Inc. ($NRIX)

So let's get started. Good afternoon, everyone. Welcome back from lunch. I'm Brian Abrahams, senior biotech analyst here at RBC Capital Markets. We're really pleased to have our next featured company, Nurix Therapeutics, represented by their CEO, Arthur Sands and their CBO, Jason Kantor.

Great. Good to be here. Thanks, Brian.

Thanks for being here. So maybe let's start a little bit bigger picture on your lead program, Bexdeg. Tell us what your latest view is on the potential advantages that BTK degraders can have in the CLL space relative to the currently available inhibitors, what's out there today? And what's been your view as to the strongest preclinical and clinical evidence and data to date that's really helped support that? And I know the data is continuing to evolve. So I would love to hear your latest views on that.

Yes, excellent question. The advantage of targeted protein degrader in this space in CLL and in BTK, we're seeing advantages expand and grow. So I can tell you where we started and now where we think it is, which is quite exciting. So we started with the concept that by removing the protein, we could address certain BTK inhibitor resistance mutations, which were just emerging, if you go back to the beginning of, let's say, 2020, 2019. So the concept that by degrading the protein through the ubiquitous proteasome system, we could address this emerging problem of resistance was, I think, well-recognized potential. As that evolved, it turned out that we could not only degrade what was then the first identified resistance mutation, the C481S mutation, but we could degrade all of them, like all the resistance mutations that were starting to show up in the clinic. So the degrader mechanism started to be recognized as a much more powerful way to address cancer -- current cancer therapy resistance. And we could illustrate that very well in CLL because we have the advantage of being able to essentially biopsy of the patient's tumor through a blood draw like repetitively and do gene sequencing and watch what's happening to the genetic profile of the patient. So -- and we've seen high response rates in these patients. So we're talking about 80-plus percent, 83% overall objective response rate, which is very, very high, and these are patients that have a heavy genetic burden. The next thing that happened in the field was really fascinating was that some of the mutations we could address were actually kinase dead mutations. So the Bruton tyrosine kinase or BTK had mutated and was no longer a kinase. And yet it signaled growth and was a driver mutation in those patients. And the biggest one was the L528W mutation that illustrated this. And then we ended up publishing this with Memorial Sloan Kettering in the Journal of Science. And it demonstrated that, a, kinases were not -- are not just kinases and specifically BTK and that it argued for a scaffolding function or a structural function, the scaffolding function of BTK and likely other kinases by extrapolation, perhaps all kinases. And so there's a whole another signaling mechanism that kinase inhibitors could not touch. So that was sort of the next major step of realizing the advantage of degrading a protein. By removing it, we take out all that function, structural scaffolding and enzymatic kinase function. So that was the next sort of major, I'd say, advance for the field and demonstrating an advantage. And I think the most recent one has been now having patients on therapy 2 years, 3 years is the duration of effect is very long. So we're seeing our progression-free survival in these very advanced patients of 22.1 months, which is very long. These are patients that have been on multiple lines -- prior lines of therapy. Many of them rotated through all the BTK inhibitors and so I think that's the third advantage that this is a durable type of therapy. We can address the resistance mutations that are occurring. We can address this other major scaffolding function. So the advantages are mounting. And I should also mention the safety profile. At the same time, we're doing this with a really great safety profile.

Great. And then I know we're going to be coming up on another data cut at EHA. Can you help frame expectations on the breadth and scope of the Bexdeg data that we're going to see updated in June at EHA and the degree to which we should expect follow-up, PFS response rates to evolve versus your EHA abstract?

Sure. So I'll let Jason comment on the upcoming meeting less than 3 weeks.

Yes. So thank you. So we'll be at the European Hematology Association meeting in Stockholm, like you mentioned, the abstract to publish. It's an oral presentation, which we think is meaningful because this is maybe the fourth oral presentation we've had from this trial. It just speaks to the excitement in the field around BTK degradation as a new modality and sort of the hunger out there for investigators to see the latest data. So every time we've presented, we presented on an expanding best set of patients. And I think what we're really focusing on here at EHA is the consistency of the data. So we continue to see very high objective response rates even as we add new cohorts and those responses continue to be durable with a very favorable safety profile. So one of the focuses of the presentation at EHA is going to be around these new Phase Ib cohorts, cohorts named [ Cohort 5 ] and 15, which are in earlier lines of patients, so patients who are either BTK naive or BCL-2 naive. The BTK naive patient group also contains patients who are fully treatment naive, so first-line patients. And this is really to show that, that activity continues to hold up in the earlier lines, which is really important because ultimately, we do see [ beexibrutinig ] as a potential first-line agent. And I think it's amazing that people are even enrolling first-line patients in a Phase I study. I think it speaks to the excitement for this new modality. So in terms of what additional data you'll see, obviously, we just gave very limited top line. We're going to have very detailed data behind all of that at EHA.

Excellent. Look forward to that. When you think about the competitive landscape, what do you think is the -- are the key areas of differentiation for Bexdeg versus other degraders in similar stages of development? And I guess, how much does it matter? I mean do you get the sense that KOLs just sort of lump the inhibitors together or lump the degraders together? Or are there learnings from the way they view the different inhibitors and the way they use them today that could translate to where the degraders ultimately get that fit in relative to one another and relative to the inhibitors?

Right. Well, actually, so investigators and physicians are very discriminating in the field. They don't lump. They look at every drug individually, look at the profile, look at safety, look at the efficacy and come to their own conclusions then about how do they want to sequence treatment in CLL. And what we're seeing is that within the degrader space, there's really only been a couple of other BTK degraders. So it's not a huge space to compare to. But most people look at B1, formerly BeiGene [ as their ] degrader, which is in development. And then AbbVie has a degrader as well. So these are both very obviously experienced and well-recognized companies in B-cell malignancy. So number one, the fact that they see the value in developing a degrader, we take is a real positive. And then -- and it's expanded the awareness of the field, and we present right next to these companies at these major conferences. And -- but then people drill into the data for each molecule. And I think what's emerging, and we believe that is emerging is that we have a best-in-class profile for [ beexibrutodeg ] or Bexdeg for short, formerly [ NX5948 ]. And that's substantiated by not only the tremendous response rate Jason was citing in multiple lines of patients, but then also the safety profile. And I think that our drug is starting to distinguish itself as having that best-in-class, best efficacy, best safety. We published some data showing how we're the most selective. So we think by global proteomics, we're highly selective, the most selective, and that translates potentially to long-term safety benefits. And then also, we're the most potent. We're about 10 to 24 more potent, which can translate to deeper efficacy. So -- and then if you compare it to the inhibitors, you're -- again, you're then looking at the fact that we overcome resistance, we have durable responses in late-line settings. We have potential in earlier line settings that we're now demonstrating and seeing. So I think big picture is, I mean, we believe degraders will have the potential to displace inhibitors actually and be generally recognized as a better way to hit a cancer target, remove the cancer protein, the driver protein rather than try to just block it.

You guys are currently running a Phase II study for Bexdeg in CLL. Can you talk a little bit about how that is going overall and maybe the key elements you've put in place to optimize study conduct?

Yes. So we've started last year our Phase II potentially pivotal single-arm study in late-line patients. So this is patients who have failed on a covalent BTK inhibitor, a BCL-2 inhibitor and a non-covalent BTK inhibitor. And so those patients, we're targeting about 100 patients to enroll. We believe that defines an unmet medical need population that could qualify for accelerated approval consideration. And we're opening that study primarily in the United States and Europe. It is open in the United States and Europe already. As I mentioned, we started enrolling last year. So we're -- our intention is to complete enrollment this year and then look for the data in the following year and then potential filing for that accelerated approval opportunity. At the same time now, we're in the midst of initiating the Phase III program, which is we call the DAYBreak trial. So the first one was DAYBreak-201, the Phase II, and now the DAYBreak-306 will start.

And this will be head-to-head versus...

Head-to-head versus [ PEO ], and that's going to be in second-line patients, so patients that have seen a prior BTK covalent agent. And they may have seen other agents, but the minimum is that they have taken the covalent BTK inhibitor. So that's kicking off midyear this year.

Okay. What are the remaining gating steps to get that study kicked off? And can you talk a little bit about the design, the decision to choose [ Perto ] as the control arm? And should we imagine this will be primarily in the U.S.? Or I guess how should we think about the next steps to get that study going and the overall execution?

Yes. So it's really an execution series of events, getting regulatory clearance in the United States and Europe. We feel very assured that we will be starting in the United States, as we said, the target is midyear, so that's right around the corner. And then Europe will follow that. So there's a number of regulatory regions that we are getting approval. That's really what's rate limiting at this point is just execution of that. And then, of course, site activation and sort of at a global -- on a global scale. We will ultimately be in 20-plus countries, approaching approximately 200 sites. So those are the execution things we're tackling right now. And then let's see, the second part of your question?

Well I it's just overall conduct. And do you have any specific goals for what the time lines could be? Obviously, it's a competitive space in terms of running trials in that particular setting, but there are a lot of patients and the data so far has been, I'm sure.

Yes. And you asked about the comparator arm, too.

Yes.

So we chose pirtobrutinib, and this relates to the competitive nature of the field. So pirtobrutinib was recently approved. It's the most recently approved new CLL agent, a non-covalent BTK inhibitor from Eli Lilly. So this is a very attractive drug, has a great profile. So we're using that as a comparator arm in a head-to-head. Number one, that will position [ bexibrutideig ] as really ultimately being superior to BTK inhibitors because it is a superiority trial that is our endpoint. And we're taking on the latest approved drug. So patients, we think it's a competitive trial because patients will in either arm, receive a great agent, right? pirtobrutinib is a great agent. And so that's attractive for patients to enroll because it is a randomized trial. And so we think we'll enroll rapidly around the world. And we -- as I said, we're going to kick that off midyear. So we're going to refrain from giving our time line forecast until we actually start the trial. So then we'll have to come back and tell you about that.

Makes sense. Good. Let's talk a little bit of -- let's shift from CLL and oncology to I&I. You guys just in the last week or 2, presented initial Phase I healthy volunteer data, SAD/MAD data at the Society for Investigational Dermatology. What were some of the key learnings there, just what you saw in terms of BTK degradation in the blood and skin? And where do you guys think about potentially going and taking this in I&I? I think you've talked about MS, CSU, HS. I think your competitor just made a decision to move forward with the Phase II in CSU, given some of the data that they're seeing emerge. So I'm just curious if you could maybe tell us a little more about what you're seeing in the early days from this I&I specific formulation of Bexdeg and what you see for the future?

Right. So it is a new formulation that we've developed for autoimmune disease for Bexdeg. We think that it has expansive opportunity in I&I. There are probably at least 3 main indication areas, derm, dermatologic being one, CSU being a very logical one. And we did recently publish in Chicago and present the data -- preclinical data substantiating Bexdeg's activity in CSU models as well as the healthy volunteer data where we're testing the new formulation. So the really exciting thing that I think we've presented and seen is that we get complete BTK degradation in the skin of healthy volunteers. We take skin biopsies through these studies. And you can see BTK is wiped out in the skin, not only which, of course, is the target tissue for CSU and HS. But also in the bloodstream, we have [ basophil ] data as well as [ mast ] cell BTK degradation data. So all the key cell types that are responsible for this allergic dermatologic condition. So we think that's a very logical place to go. We are -- we have said that we're intending an IND to be filed in autoimmune indications in the second half of this year. We have not yet specified CSU, but clearly, this is our first presentation in the space, and that, I think, directionally makes sense. The other one is multiple sclerosis, so MS -- and this is very interesting to us because we have brain activity. We cross the blood-brain barrier. We've seen activity in our CLL patients and our CNS lymphoma patients with Bexdeg. So that's quite some dramatic responses. So we know that we could.

I mean now the BTK inhibitors work in MS other than they just have the toxicity, but you guys shouldn't have the liver issue, I guess.

Right. We've not done any liver tox issue. So we think we can bring our safe profile there. We also think -- yes, and the inhibitors like [ eneubrutinib, palbrutinib ] have shown efficacy, essentially proof of concept established for the BTK mechanism. But we think we can enhance efficacy also because, again, we're taking out not just the kinase function, but the scaffolding function, which we believe is operating in autoimmune disease, just like it is in cancer actually. So we can deepen efficacy by degrading the target by removing the protein, and we think we're going to bring our excellent safety profile over too.

These are pretty large spaces we're talking about, right, with CLL, MS. What's your appetite for taking Bexdeg yourselves to the finish line and commercializing it independently versus potentially partnering? And what are some of the considerations around that? And would you consider partnership by indication, regionally? Is there sort of an optimal profile for a potential partner that you would think about if that's something you're interested in?

Yes. So we have the advantage of having our Chief Business Officer here. So Jason, go ahead.

Yes. I mean, first, I'd like to say it's a privilege to be able to invest in Bexdeg. It's not often that you have a drug that is -- has such a well-established mechanism of action in terms of the target, but it's also at the forefront of a new modality, has best-in-class profile and the potential to address multiple multibillion-dollar markets and really, at the end of the day, help patients. And so -- but in order to achieve that fully, partnership is something that we are considering, but it would definitely be in the setting of a partnership that could enhance the therapeutic and commercial reach of the drug. So a partner that had a vision to take this not only into early line CLL, but also potentially NHL and a variety of other I&I or neurology indications. So we're very much open to that as a potential. But again, this is not a situation where Nurix is looking to monetize this asset. We see ourselves becoming a commercial company. We have a lot of opportunity in our pipeline and the best way to fund that is through product revenue. And so ultimately, we're going to become a product company, and we think Bexdeg is the product to get us there.

Excellent. I know we only have a few minutes left. We spent a lot of time on Bexdeg. I'd love to touch on some of the other partner -- the other pipeline programs. Maybe for the IRAK4, just can you talk about your expectations for the Phase I healthy volunteer study? And what would you want to see with regards to differentiation for [ 479 ] versus other prior IRAK4 degrader approaches that others have done?

Yes. So our IRAK4 degrader is being developed with Gilead in partnership with Gilead, and it was discovered and developed by Nurix under that alliance. So it should be completing the Phase I trials this year. So the SAD/MAD studies, healthy volunteers and Gilead, we expect will be hopefully sharing data with that. They're in control of data releases. But the goal would be for completion of the Phase I and then to outline the Phase II plans, which would be in autoimmune disease. Previously, Gilead has mentioned RA as one of the indications. There could be more. This is another program where we have preserved an option, a 50-50 option post Phase I. We have the potential for that. And then I think I'm sure your next question is about STAT6.

You read my mind. A little bit more about...

We only have a minute left.

What are your latest thoughts? How do you differentiate in the competitive space? And just -- I know there's a lot of degraders and there's some inhibitors and some degraders now in early to mid-stage development in atopic derm? Just what atopic derm...

Yes STAT6 is a very exciting new target in atopic derm. The way we differentiate is we have a scientific and corporate policy to create best-in-class agents. So that's our official approach to discovery and optimizing these agents. And so we expect our agent will ultimately define itself as best-in-class. Of course, it has to enter the clinic first. So it's on the verge of doing that with -- and this is under Sanofi, our partner, long-standing partner on the development of the STAT6 degrader NX-3911. And so that's on track, should be on track for starting in the clinic this year. Sanofi is now responsible for that. They've been responsible for the IND-enabling studies. They will be for the Phase I and proof of concept. And then we have our opt-in, again, we can opt-in at a 50-50 co-co structure in the United States. So we see that as a really great growth opportunity, another growth opportunity in I&I.

Excellent. We're just about out of time. Arthur, Jason, great to see you and hear your perspectives. Thanks so much.

Great. Thanks, everyone.