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. Thanks for having me.
Thanks for having us. Good to be here. Thanks, Brian.
Well, thanks for being here. Maybe let's start a little bit bigger picture on your lead program, bexobrutideg. 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? I know the data's continuing to evolve, so would love to hear your latest views on that.
Yeah, excellent question. The advantage of targeted protein degrader in the space in CLL and in BTK, we're seeing advantages expand and grow. I can tell you where we started and now where we think it is, which is quite exciting. 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.
The concept that by degrading the protein through the ubiquitin-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 resistant 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.
The degrader mechanism started to be recognized as a much more powerful way to address current cancer therapy resistance. We could illustrate that very well in CLL because we had the advantage of being able to essentially biopsy the patient's tumor through a blood draw, repetitively, and do gene sequencing and watch what's happening to the genetic profile of the patient.
We've seen a high response rate in these patients, so we're talking about 80+%, 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.
The Bruton's 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. The biggest one was the L528W mutation that illustrated this, and then we ended up publishing this with Memorial Sloan Kettering in the journal "Science."
It demonstrated that, A, kinases 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, but by extrapolation, perhaps all kinases. There's a whole other signaling mechanism that kinase inhibitors could not touch.
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.
Right.
Structural scaffolding and the enzymatic kinase function. That was the next sort of major, I'd say, advance for the field in demonstrating an advantage. I think the most recent one has been now having patients on therapy two years, three years, is the duration of effect is very long. 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. 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. 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. 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 bexobrutideg 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. I'll let Jason comment on the upcoming meeting. That's in three weeks, right?
Yeah. Thank you. We'll be at the European Hematology Association meeting in Stockholm. Like you mentioned, the abstracts have published. It's an oral presentation, which we think is meaningful because this is maybe the fourth oral presentation we've had from-
Yeah
this trial. It just speaks to the excitement in the field around BTK degradation as a new modality and the hunger out there for investigators to see the latest data. Every time we've presented, we've presented on an expanding set of patients, and I think that what we're really focusing on here at EHA is the consistency of the data.
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. One of the focuses of the presentation at EHA is going to be around these new phase Ib cohorts, cohort 5 and 15, which are in earlier lines of patients, so patients who are either BTK naive or BCL2 naive. The BTK naive patient group also contains patients who are fully treatment naive, so first-line patients.
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 bexobrutideg as a potential first-line agent. I think it's amazing that people are even enrolling first-line patients in a phase I study.
Yeah.
I think it speaks to the excitement for this new modality. 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 are the key areas of differentiation for bexdeg versus other degraders in similar stages of development? And I guess, how much does it matter?
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 fit in relative to one another and relative to the inhibitors?
Right. Well, actually, investigators and physicians are very discriminating in the field.
Yeah.
They don't lump stuff together.
Okay. Yeah.
They look at every drug individually, look at the profile, look at the safety, look at the efficacy, and come to their own conclusions then about how do they want to sequence treatment in CLL. What we're seeing is that within the degrader space, there's really only been two other BTK degraders, so it's not a huge space to compare to.
Yeah.
Most people look at BeiGene, formerly Beijing, at their degrader.
Which is in development. AbbVie has a degrader as well. These are both very obviously experienced and well-recognized companies in B-cell malignancy. Number one, the fact that they see the value in developing a degrader we take as a real positive.
Yeah.
It's expanded the awareness of the field. We present right next to these companies at these major conferences. 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 bexobrutideg or bexdeg for short, formerly NX-5948. That's substantiated by not only the tremendous response rate Jason was citing in multiple lines of patients, but then also the safety profile.
Yeah.
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.
Selective, yeah.
We think by global proteomics, we're highly selective, the most selective, and that translates potentially to long-term safety benefits. Also, we're the most potent. We're about 10- 24 more potent.
Yeah.
which can translate to deeper efficacy. Then if you compare us to the inhibitors, 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. I think, big picture is, 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.
Yeah
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?
We've started last year, our phase II, potentially pivotal, single-arm study in late-line patients. This is patients who have failed on a covalent BTK inhibitor, a BCL-2 inhibitor, and a non-covalent BTK inhibitor. 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. We're opening that study primarily in the U.S. and Europe.
It is open in the U.S. and Europe already. As I mentioned, we started enrolling last year. 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.
Yeah.
Which is we call the DAYBreak trial. The first one was DAYBreak CLL-201, the phase II, and now the DAYBreak CLL-306 will start.
This will be head-to-head versus pirtobrutinib.
Head-to-head versus pirtobrutinib, that's going to be in second-line patients. Patients that have seen a prior BTK covalent agent. They may have seen other agents, but the minimum is that they have had taken the covalent BTK inhibitor. That's kicking off mid-year this year.
Okay. What are the remaining gating steps to get that study kicked off? Can you talk a little bit about the design, the decision to choose pirtobrutinib as the control arm? Should we imagine this will be primarily in the U.S., or just how should we think about the next steps to get that study going and the overall execution?
Yeah. 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's mid-year, so that's right around the corner. Europe will follow that. There's a number of regulatory regions that we are getting approval.
Okay.
What's rate limiting at this point?
Okay.
Execution of that. Of course, site activation and sort of on a global scale. We'll ultimately be in 20+ countries, approaching approximately 200 sites. Those are the execution things we're tackling right now. Let's see, the second part of your question?
Well, I guess just overall conduct. Do you have any specific goals for what the timelines 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-
Right.
The data so far has been, I'm sure, attractive.
Yeah, you asked about the comparator arm, too.
Yes.
We chose pirtobrutinib, and this relates to the competitive nature of this field. Pirtobrutinib was recently approved. It's the most recently approved new CLL agent, a non-covalent BTK inhibitor from Eli Lilly. This is a very attractive drug, has a great profile. We're using that as a comparator arm in a head-to-head. Number one, that'll position bexobrutideg as really ultimately being superior to BTK inhibitors because it is a superiority trial.
That is our endpoint. We're taking on the latest approved drug. Patients, we think it's a competitive trial because patients will, in either arm, receive a great agent. Pirtobrutinib is a great agent. That's attractive for patients to enroll because it is a randomized trial. We think we'll enroll rapidly around the world, and as I said, we're going to kick that off mid-year.
We're going to refrain from giving our timeline forecast until we actually start the trial.
Sure.
We'll have to come back and tell you about that.
Makes sense. Good. Let's shift from CLL and oncology to I&I. You guys just, in the last week or two, 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? 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 a phase II and CSU, given some of the data that they're seeing emerge. 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. It is a new formulation that we've developed for autoimmune disease for bexobrutideg. We think that it has expansive opportunity in I&I. There are probably at least three main indication areas, derm, dermatologic being one, CSU being a very logical one. We did recently publish in Chicago and present the preclinical data substantiating bexobrutideg's activity in CSU models, as well as the healthy volunteer data where we're testing the new formulation.
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. 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, all the key cell types that are responsible for this allergic dermatologic condition. We think that's a very logical place to go. 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 was our first presentation in the space, and that, I think, directionally makes sense. The other one is multiple sclerosis. MS. This is very interesting to us because we have brain activity. We crossed the blood-brain barrier. We've seen activity in our CLL patients and our CNS lymphoma patients with bexobrutideg. That's quite some dramatic responses.
We know the BTK inhibitors work in MS other than they just have the toxicities, but you guys shouldn't have the liver issue, I guess. Is that?
Right. We've not seen any liver t ox issue, so we think we can bring our safe profile there. We also think, yes, the inhibitors like fenebrutinib and tolebrutinib have shown efficacy. There's essentially proof of concept established for the BTK mechanism.
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. 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 bexobrutideg yourselves to the finish line and commercializing it independently versus potentially partnering?
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?
Yeah. We have the advantage of having our Chief Business Officer here. Jason, go ahead.
Yeah. First I'd like to say it's a privilege to be able to invest in bexobrutideg. It's not often that you have a drug that has such a well-established mechanism of action in terms of the target, but is also at the forefront of a new modality, has best-in-class profile.
Yeah.
The potential to address multiple multi-billion dollar markets and really, at the end of the day, help patients. 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.
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. Yeah, 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.
Right.
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. Ultimately, we're going to become a product company, and we think bexobrutideg is the product to get us there.
Excellent. I know we only have a few minutes left. We spent a lot of time on bexobrutideg. We'd love to touch on some of 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 NX-0479 versus other prior IRAK4 degrader approaches that others have done?
Our IRAK4 degrader is being developed with Gilead, in partnership with Gilead, and it was discovered and developed by Nurix under that alliance. It should be completing the phase I trials this year. The SAD, MAD studies, healthy volunteers, and Gilead we expect will be hopefully sharing data with that. They're in control of data releases.
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. I think, I'm sure your next question is about STAT6.
You read my mind. Can you tell us a little bit more?
Well, we only have a minute left.
your latest thoughts. How do you differentiate in a 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.
Atopic derm.
What do you differentiate? Yeah.
yeah, 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. That's our official approach to discovery and optimizing these agents. We expect our agent will ultimately define itself as best in class. Of course, it has to enter the clinic first. It's on the verge of doing that.
This is under Sanofi, our partner, our long-standing partner on the development of the STAT6 degrader. This is NX-3911. 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. We see that as a really great growth opportunity, another growth opportunity in I&I.
Excellent.
Yeah.
Well, we're just about out of time.
Yes.
Arthur, Jason.
Thank you.
Really great to see you and hear your perspectives. Thanks so much.
Great.
Very much.
Thanks, everyone.