Nurix Therapeutics Inc Aktie

All right. Great. Good morning, everybody. Thanks for joining us. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. I'm very pleased to be hosting Nurix this morning. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

If you have any questions, please reach out to your Morgan Stanley sales representative. Joining us from the company this morning is Arthur Sands, the company's President and CEO. Thanks so much, Arthur, for taking the time. Really appreciate it.

Thank you, Terence.

Bright and early in the middle of Times Square.

Yes, it is early.

Well, I thought maybe to kick us off, we talk about the Roche collaboration now that that's closed. Congratulations there. Maybe just talk to us a little bit about the strategic rationale for partnering Bexdeg, which is your lead pipeline asset.

Yes. So that deal we announced in June. It did just close in August. It's a landmark deal, I think, for the field of targeted protein degradation and in B-cell malignancies and autoimmune disease, 2 therapeutic area deal, that's number one.

So that was one of the strategic considerations as we were embarking on a partnership process, which was a competitive process. We wanted a partner that really could span both oncology and immunology because those are the 2 major areas for Nurix in terms of creating drugs and value. And Roche was really perfect for that.

They have, of course, I think, the preeminent drug portfolio in B-cell malignancies, CLL and NHL and then also in autoimmune disease with their multiple sclerosis expertise and of course, their Xolair franchise. And so these are areas of great importance to us for Bexdeg. And so this deal really maximizes the clinical development program for Bexdeg and thereby maximizing the market potential of the drug and also gives us a global footprint, of course, with Roche. So those are some of the strategic considerations. Plus they're great people to work with and terrific scientists.

Great. Maybe talk about the milestone structure in terms of any more clarity you can provide there in terms of some of the maybe near-term milestones and then how to think about some of those. But again, I think it's about $2.3 billion all in.

Yes, in total cash payments and most significantly, the upfront payment of $700 million, which I think signifies the level of importance of this deal and again, the breadth of the clinical development plan. And then an additional $1.6 billion in clinical development, regulatory and sales milestones pretty much evenly distributed among those 3 categories. So this is very accessible future cash, the $1.6 billion for the company.

In addition, I think, and probably most importantly, long term, is we have -- it's a 50-50 cost profit share co-development, co-commercialization in the United States. Roche will commercialize ex U.S. for which we receive significant milestones and royalties. So it's really, again, maximizes the global footprint, play to each other's strengths as 2 companies, and it's a terrific deal.

Yes. What -- and then how do you think about capital deployment in terms of what that upfront can do for the rest of your portfolio now in terms of maybe additional investments or other areas that you could potentially accelerate as a result of that upfront? I'm sure it gives you some more flexibility now.

Well, the main area for acceleration right away is the autoimmune opportunity for Bexdeg because within the deal and defined in the clinical development plan upfront is a CSU trial, so chronic spontaneous urticaria, which we're in the midst of planning with Roche and their Xolair team, which they've got such expertise in this whole allergy area. And then also MS.

So that right away, we get an acceleration there. Of course, the funding, we can use -- we are using that for our share. Now the cost portion is 40% Nurix, 60% of Roche. So the offsets in the costs are significant. So if you look at all of the cash financials of this deal, really, it is essentially a self-funding deal, if you look at it that way within oncology and the current clinical development plan.

Now it can expand beyond that clinical development plan. Both parties would need to agree to future -- such future expansions. I think there will be expansions because Bexdeg can go so far -- very far further in autoimmune disease or so many indications. We are covering essentially the waterfront of CLL and NHL. So I think that's already fully baked.

Yes. What would that talk about NHL, CLL in a bit, but what would the time frame for that indication expansion on the immunology side? Like are we talking months? Are you talking quarters?

We were talking months. Our goal is to file the IND for CSU this year, which would put us right into a Phase II trial, basically. We've already completed over 200 healthy volunteers studies with our new formulation designed with certain different profile improvements for autoimmune disease currently. And so that's all ready to go. And then MS would be next year.

Okay. And would MS be gated by CSU initial data? Or are they kind of separate development paths?

They're very separate development paths. No, there's no gating. We'll go right into the planning for that -- the planning has already started. And yes, MS is a big opportunity, as you know, the whole BTK hypothesis is very exciting.

Recent announcements from Novartis with remibrutinib. I think the playbook for remibrutinib is quite intriguing and appears to be very successful so far. So we see -- we think degrading BTK is superior in oncology, and it will be a superior approach in autoimmune disease.

Great. Maybe we'll just go into the lead indication, CLL. So you've already enrolled the first patient in the Phase III 306 trial.

This is versus Lilly's Jaypirca. Maybe just walk us through the design here and how to think about your confidence in showing superiority.

It's a simple design, head-to-head study against pirtobrutinib from Lilly. And really, what we're testing the central hypothesis of degrading BTK, removing BTK is superior to inhibiting the kinase activity and we think it is. Many lines of evidence have pointed us in this direction, not the least of which is the fact that our BTK degradation mechanism can overcome all the resistance mutations that are cropping up after treatment with inhibitors.

And there are a number of these new mutations that have evolved with treatment of -- with zanubrutinib or acalabrutinib. Originally with ibrutinib, the original, it was really just C481S, the covalent cysteine bond, but there's more now. And pirtobrutinib does not cover those. It was designed for C481S, and it does so effectively, but now emerging are about half the mutations are different categories where we cover those. So we think that's a big advantage. In addition...

Are you going to have a prespecified criteria that you're going to have a certain percentage of patients that are going to have these mutations? Or is it just an all-comers?

It's all-comers second line. So they do have to have been treated with a covalent inhibitor, which we'll select for the -- but we just -- that's just the natural process. We're not going to select from an enrollment standpoint. The other major advantage we see is that we remove what's called the scaffolding function of BTK.

So that's a structural signaling function for BTK. And it's actually -- it's quite substantial. So it's really interesting. If you really look at this mutational spectrum of these patients, about half -- really about 40% have some type of BTK mutation driving resistance to inhibitors. But 60% are wild-type. And so that means wild-type BTK is not responding to an inhibitor.

So what's going on here? We think it's that signaling function through the scaffold, the structural function of BTK can go through another kinase mechanism that's part of the physical scaffold. So we remove that via degradation of the proteasome system. So that's actually a very important feature that's, I think, sometimes not -- kind of overlooked.

Okay. Great. And I think the co-primary endpoints, ORR and PFS, have you guys talked at all about what kind of effect size you'd like to see for the trial to be successful?

They're dual primary endpoints. And well, of course, we've scaled the trial according to certain statistical assumptions of superiority. We've not shared what those are.

But it brings us to a patient number around 600, 620 is, I think, the target number. But it's an event-driven trial. So there's opportunities to evaluate earlier based on events. And yes, we think the trial will enroll very rapidly. It will be -- we're going against the latest agent.

So it's very attractive for patients to have 2 really actually excellent drugs to choose from. Well, they don't choose. It's randomization.

Right. So the interim is -- it sounds like there's an interim based on PFS events because ORR is just ORR scans. So again, an interim would be triggered by PFS.

There's some standard ways to look with interim results. I'm not going to go into the details of it here. But yes, it's a fairly typical trial design, like I said, very simple statistical plan, too.

Could you -- if let's say, ORR shows a benefit earlier at some landmark analysis, could you file there? Or you need both ORR and PFS to kind of file on?

So again, I don't want to speculate at this point. There's a lot of -- as we get farther in, we'd probably provide more clarity on the more interim plans.

Okay. And you guys haven't guided the timing yet because it's contingent on enrollment and events, so...

Right. So what we have announced is the first patient, so, let's go from there. And then if we get more, we'll give you some updates.

All right. Fair enough. You also have a single-arm 201 study. So maybe again, similar type question here.

Just remind us kind of design there, that patient population and then what you've said about accelerated approval pathway.

This is a third line plus patient population, if you will. Largely the kind of patients we've already treated in the Phase I. Frankly, I mean there, we were fourth and fifth line, but -- so here, we can take third line plus, which means they need to have seen a BTK inhibitor, covalent, BCL-2 inhibitor, which is standard now would be for second line and then a non-covalent, so likely pirtobrutinib.

So in that patient population, this is about 100 patients for single-arm trial, potential accelerated approval. We have seen excellent results in those patients in the Phase I portion, and we hope to replicate that in this single-arm registrational trial.

And just remind us what your ORR was in kind of a similar patient population from Phase I, just as a benchmark?

So between 65% and 80%, depending on which category of patients you look at exactly. We have multiple cohorts there. Actually, some of the latest cohorts we just reported at EHA were more of the early line patients. But just to tell you about that, those results are very exciting.

They're 85% and 90% response rates, ORR in the earlier line patients. And actually, they haven't even been treated that long. I mean we think they have potential to move up to 95% or 100% ORR. So we'll see. We're continuing to track those early-stage patients. But the later line patients are -- we're in the 70%, 65% range.

And just remind us on the durability, like how much durability data do you guys have? And then again, what's the minimum amount you need for kind of an accelerated approval from the ongoing study?

So we reported a 22.1 or so months of PFS, which is really quite remarkable. Again, these are patients that have failed all available or all available therapies have failed the patient, I should say. And so that we think is -- if we come anywhere in that ballpark, that's really, we think, a significant benefit for patients. Obviously, that's up to the FDA in terms of their judgment calls over what constitutes accelerated approval criteria.

Yes. Okay. Great. The other one on the competitive landscape is B1673 (sic) [ BGB-16673 ] -- that's another BTK degrader. Maybe just talk about high level, again, differentiation of Bexdeg in your view. What are some of the key features here?

So they've been presenting with us basically at every conference. We're going to share the podium with them every 6 months or so at ASH or EHA. And the efficacy data does look similar. So I think between the 2 agents. And I think that's very encouraging. We have external validation, completely different company, different trial coming up with the same results in very difficult to treat patients.

I think I do believe our safety profile looks slightly better. That's sort of my -- our interpretation of data so far. There aren't many patients to make that judgment on. But if you -- I think, read between the lines, I do think there's a safety advantage. We have looked and profiled both compounds cellularly and molecularly, and we do believe we have a selectivity advantage at the cellular and molecular level, certain targets that we see showing up on proteomic analysis with the B1 compound, we do not hit. We do not degrade. So we think we have a more selective compound.

Okay. I guess the -- when we think about the Phase I/II data we're just going through, are we going to see another update at ASH this year? Is that a fair expectation?

That would be a fair expectation. I mean we're at ASH every year in some form or fashion. It depends on getting your abstracts accepted and where will we end up. But yes, we've been giving updates. Basically, the cadence has been about every 6 months.

Okay. I guess the other thing is just frame for us kind of how to think about the initial opportunity before you get to frontline, just how to think about kind of second, third line plus in terms of numbers. I mean, I think Jaypirca so far has had a fairly good ramp, but how are you guys sizing up those kind of later line opportunities?

Well, the later line opportunities are kind of difficult to really get accurate numbers on. But it's not a lot of patients.

The real benefit will be in the second line and any frontline opportunity where you're talking about tens of thousands of patients potentially depending on how competitive our agent will be. So the goal is second line, I think, is the focal point. But if we can start in the third and fourth line and offer benefit and get on the market, that could be an advantage.

Yes. Okay. Great. Maybe talk to us just what is the frontline strategy? I know in frontline, there have been a number of moving pieces. Like you said, there's been ibrutinib was the standard of care, but now there's Calquence, some other drugs that are moving there. And then you also have the notion of kind of combination therapy, fixed duration.

So it seems like there's a lot of different directions that you guys could go in that frontline setting. And so what's right now the current thinking in terms of kind of how you guys with Roche would approach that?

So it's an active area of discussion with Roche, what is the best strategy. And it's true that fortunately, patients have a lot of options now in the frontline. So -- but they do boil down to monotherapy or some type of combination.

And really, I believe the majority of patients are still in the monotherapy sort of camp and investigators, if you go to academic centers and more of the tertiary care centers, they really favor the combinations and getting a deeper response, a longer response and even trying to find a combination that could approach a cure-like level for this chronic disease. So it's an active area of debate, and we'll just have to keep you posted on that as we evolve our thinking there.

Any rough time lines? Is that like months, quarters when we might get an update?

I think quarters.

Okay.

Yes, it's important to get going. Yes.

Okay. All right. We'll stay tuned. The other area is just non-Hodgkin's lymphoma. So maybe just, again, similar type question, what data you have there and then how you're thinking about addressing that opportunity and other sub-pool?

Yes. So Waldenström's and then also MCL. We've presented on some of our later-stage patients in Waldenström's with, again, about an 80% plus response rate as monotherapy. So those 2 areas are defined within the clinical development plan of the agreement to be initiated -- that will be largely a Roche-driven trial.

Okay.

2 trials and largely combination approaches. So we haven't specified those yet. Beyond that, we're...

And that later lines, that's going to go frontline? Like any more detail there?

The current discussion is around second line, but also frontline. So we haven't outlined exactly the strategy there. But again, that will be likely a combination approach. And then with regard to the other areas of NHL, that's for future exploration.

Got it. Okay. Maybe just pivoting, we talked about this a little bit at the beginning, but just immunology, neurology, again, molecules can go in a lot of different directions. So maybe just elaborate a little bit more on kind of the multiple sclerosis piece there, kind of biological rationale here, what gives you and Roche confidence to move into MS.

So we've demonstrated brain activity, number one. So we've demonstrated our drug crosses the blood-brain barrier. We can measure it in the CSF free drug levels compared to the plasma level to CSF roughly 1:1. So we know we're at effective concentrations. And most importantly, we have patients with CNS disease in the oncology setting that have responded to the drug, some quite dramatically.

So we have biologic proof of activity in a disease setting. And then in addition, we have all the animal model data for MS, where we have really very potent activity, including demonstration of degradation of BTK in the microglia of brain. So this is central to the whole microglial hypothesis as being the resident immune cells embedded within the neuronal structures that are responsible for the debilitating aspects of MS.

And so if you can shut that down, which the CD20 antibodies don't really do, then you could block this debilitating progression. That's central to the hypothesis. And we've demonstrated that in animal models. So I think that this is a very exciting new dimension to explore. Degraders have a unique, I think, advantage here because the drug levels required are low to achieve basically complete removal of BTK. And I think that gives us a safety advantage.

The other advantage is taking out that scaffolding function because that's every bit as important in autoimmune disease as it is in cancer. And so the inhibitors don't do that. So I think they're leaving some efficacy on the table, and I think it will be very interesting to explore this.

What are you predicting from a dose level versus CLL, for example? You mentioned the potency in CNS. But again, are you going to need potentially a lower dose? Are you going to need to push the dose because of the blood-brain barrier? Like how do you think about dose selection relative to CLL?

That's an excellent question. The devil is in the details with dosing and determining how -- what levels are required for that particular pathology. So the current thinking is -- it will either be a similar dose to the oncology setting or it will be less. It won't be more. So we don't think...

So you don't need to do any more additional like animal tox higher dose, you have all that stuff covered. So it's just a matter of tweaking it.

No, in terms of -- we won't go up. So yes, we've covered in terms of dose levels. It could be as low as 1/3 or 1/4 the amount, but we'll model the best we can, probably test 2 doses. Really, you just have to go with the empirical study in a Phase II.

Right. And you said that's next year. That's next year.

We hope to initiate it next year, yes.

Okay. Got it. And that's -- just remind me because, again, I haven't looked at these MS studies and all, that's just usually like an MRI imaging type Phase II study.

That's...

Typical of lesion, something like that.

Yes, lesion measurement, 12-week, 13-week, that's what's been done. That will definitely be part of the picture. We may do more, but that will be determined when we get to the IND level.

Okay. Okay. Great. You mentioned CSU. Obviously, Roche, a lot of experience here with Xolair. There's been some other targets that have been successful now. So just remind us kind of the paradigm in CSU and then where you think Bexdeg would slot into that current paradigm?

So there's antihistamines. So -- and most -- a lot of patients will progress with serious CSU, which is triggered by this mast cell degranulation of significant allergic response and quite debilitating. So BTK is a driver in mast cells. It's clearly a driver in the allergic response in multiple cell types, which we hit, including basophils, and we can measure in healthy volunteers.

So I think mechanistically, we're spot on. Of course, remibrutinib has demonstrated it clinically is launching quite well in this area. So we anticipate a similar rapid onset of therapeutic activity, which will be an advantage to Xolair is a slower onset, although they do get a very deep response. It is the leading drug, I think, in the area. So I think it would be an important addition to that franchise for Roche and it will be new expansion for us.

But it's clearly a great place to start. It's a rapid initial proof-of-concept trial, so that's attractive. MS is longer. And again, Remi has -- remibrutinib has and Novartis charted a very, very nice successful course.

And where is that -- where is remi used mainly? Is this post-Xolair? Or is it used pre-Xolair?

I don't know how it's actively being prescribed. But I mean they were post-histamine. And then I'm not sure about the post-Xolair or not.

Okay. Got it. All right. Well, maybe just in the last few minutes here because, again, you might be able to answer some of these you might not because they're partner programs. But Sanofi, you guys received a $10 million milestone payment for STAT6 moving into Phase I. So maybe just anything more you can say on that?

And how, I guess, big picture, what a lot of investors are looking to is this upcoming Kymera data as well as like a kind of lateral. So first, just talk about this Phase I trial and then maybe your profile and differentiation versus the Kymera approach?

Yes. So first off, STAT6 is a terrific target for type 2 inflammation broadly. Transcription factor, largely undruggable to date. We started the program in 2019 with Sanofi. It was one of our original drug discovery programs under that alliance.

So we've been working side-by-side with them for quite some time, quarterly joint research committee meetings, really a highly evolved program that has yielded a terrific molecule. Our number was NX-3911. It has started Phase I. And so in terms of its profile, it's exquisitely selective for STAT6, and we've shown that with global proteomics, highly active in animal models of atopic dermatitis as well as asthma. So -- and there's multiple more animal models that we haven't shown. So it really fits the bill.

I think that Kymera is leading the way and has done a great job. I think their characterization of Dupixent in a pill is really the goal. I do believe that there -- as they described, it could open up the market quite substantially. There probably will be significant read-through. I think from looking at their data, their Phase I data looks so good already and their initial patient data. So we look forward to their data, too. And I think it would be -- I anticipate it will be very positive for the STAT6 field.

So I think it's important. It's a huge market. There's room -- it's not a zero-sum game. There's room for many drugs here, likely that will have different profiles. There are inhibitors being pursued by Recludix and Pfizer, they'll probably have different profiles as well with different MOA. But we do prefer the degrader mechanism. We think that's going to be a leading mechanism based on the genetics of the removal of STAT6 gives you a great phenotype. So we're going to reproduce that.

Great. What should we watch just in terms of STAT6 pathway like what should be top of mind in terms of the safety side for this pathway, if anything?

Well, safety, we look at the genetics. And if you look at the mouse knockout of STAT6, they really don't have any phenotype other than blockade of IL-4, IL-13. It's incredibly clean. It's actually cleaner than BTK genetic phenotype.

So from an MOA mechanism on-target standpoint should be quite safe. Then if you look at human genetics, too, there's allelic variation -- patients with some allelic variation of STAT6 have decreased immune -- autoimmune symptomology. So really, it should be good.

So the issue then is off target. And so that's a molecule-by-molecule analysis. And if you clear all the IND enabling the GLP tox studies, which we have and Sanofi has run, by the way. They've been in charge of those and now they're in charge of the Phase I. Our option comes in after that. But if you run all those, it looks quite safe in animal models. And then really, it's the patients.

And this is first, I'm assuming SAD. This is SAD Phase I. But the single ascending dose, the Phase I?

Yes, it is standard SAD/MAD type approach is our understanding. We really haven't disclosed the design of that yet nor Sanofi, but that would be a standard.

Okay. And then -- so again, typical industry time lines, I'm assuming this would wrap up sometime next year. So then the next step would be like a Phase II?

Yes. We would anticipate direct to Phase II dose selection.

And then you guys would get a milestone payment. And then just remind us what the size of that would be and then what economics you'd get downstream if this were approved?

Well, there are milestones along the way. We haven't disclosed the size of those. But I think the important thing is the option exercise, which would be after seeing -- we will get a report, a clinical report, data report on the Phase I, which will also include some patient data.

So it should -- it will be able -- we'll be able to look at an initial cohort of patients as well as the healthy volunteers. And that would trigger our option period, then we'd make a judgment based on the data whether or not to opt into that 50-50 in the United States. And then there are milestones along the way, like I said, but the really important value creation would be the option.

So you will -- the Phase I will include some atopic derm patients ultimately, like when you go to patients that you'll get to review?

Well, so the -- under the agreement, our option is triggered by that, we must see patient data -- we anticipate that, that would represent a smaller cohort, not a full Phase II. But again, Sanofi has not disclosed the design of that study yet.

It's more than healthy volunteer data.

It should be -- it will be more than healthy volunteer data.

Okay. Got it. Okay. I guess the last one I had is just the IRAK4 degrader. Gilead, I think, has talked a little bit about this, not too much. But again, maybe just what can you say about the profile there, kind of similar type question, remind us of your economics.

Well, so it's a similar structure from a deal structure standpoint. IRAK4, they should be finishing Phase I this year.

So we anticipate a Phase II transition there. So -- we've got our Phase I with STAT6, hopefully Phase II transition with IRAK4 and of course, our own Phase III program. So our pipeline is kind of well timed out for, I think, value creation at many levels. The profile, it's a great molecule, again, developed with side-by-side with Gilead. They had an IRAK4 inhibitor team, which worked on the degrader with us since 2019 also.

So very clean, high activity in the skin, very safe profile. We think it's going to have -- we're in the lead now. There were 2 other degrader programs that have fallen away, one from Kymera, one from BeiGene. So we will be the leading degrader there. Scaffolding function is very important for IRAK4. That's why the inhibitors haven't, I think, been as exciting. And some people have gotten a little disappointed with the target, but that's not true. It's really how you hit the target and you have to have the right molecule. The biology is fantastic. Again, the genetics is fantastic.

Yes. And I guess we'll see data from Gilead's inhibitor Phase II, I think, later this year, maybe, right?

I would certainly hope so. They've been very diligent about appropriate publication and timing in international congresses. We've worked with them on certain posters preclinical. So hopefully, yes, there will be future disclosures here.

Okay. All right, Arthur. Well, that's great. Thank you so much for the time this morning. Appreciate it.

Terence, thank you very much.

Thank you.

Great.

Welcome to our next fireside chat. I'm Robert Burns, Managing Director and senior biotech analyst at H.C. Wainwright. I'm joined today by the CEO of Nurix, Arthur Sands. Arthur, thank you for joining us today.

Well, thanks for having us. Very happy to be here.

Awesome. So maybe let's just start from a high level. For investors who may be newer to the Nurix story, can you provide a brief overview of the company, the platform and your pipeline today?

Yes. So we're focused on targeted protein degradation, which is a new small molecule approach to actually removing protein targets, disease targets from the cells via the ubiquitin proteasome system. So removal, targeted removal of the protein, which gets a more thorough hit on the target compared to inhibition.

So our lead program is BTK, a BTK degrader called bexobrutideg, recently just signed a great deal with Roche, which I'm sure we'll talk about for CLL, chronic lymphocytic leukemia and non-Hodgkin's lymphomas, where, again, we're removing the BTK protein, and we get a more thorough and deeper efficacy response, can address resistance mutations to inhibitors. The inhibitor class is $10 billion a year class, but a lot of resistance mutations coming up.

So degradation removes that with Bexdeg, as we call it for short. And then we have a whole inflammation program, partially with Bexdeg, again, with Roche, but also our STAT6 program with Sanofi, which is in Phase I and our IRAK4 degradation program with Gilead, which is completing Phase I. And then we have a host of other undisclosed targeted protein degrader projects. So we're about 12 years old.

We're based in the San Francisco Bay Area -- and had a very successful entry into the clinic with Bexdeg now starting Phase III.

Yes. No, that's perfect. So I guess the major news, as you just alluded to, was that massive Roche collaboration for Bexdeg. So can you talk a little bit about what made Roche the right partner for this asset relative to all the other major pharmas out there, the economics of the deal and more broadly, how the partnership changes the opportunity for Nurix and its shareholders?

Sure. Well, so Roche was the right strategic choice to fully develop this drug across multiple indications in oncology, but also in autoimmune disease, where we've specified CSU or chronic spontaneous urticaria and MS with Roche, again, global experts. So they're the right strategic partner. And I might add, it was a competitive process to get this deal. Because Bexdeg really has such a best-in-class potential for any BTK drug, I'd say, inhibitors or degraders.

But of course, the degrader aspect brings the superiority of efficacy because we remove not only the kinase function but also what's called the scaffolding function of the protein, which is another signaling function at any rate. So Roche, they've been great to work with from the beginning, and they followed this program for actually several years. We signed this deal in June. It was a landmark deal.

As you point out, we're talking about it was $700 million upfront and then another up to $2.3 billion in milestones, development milestones and sales milestones. And that's a significant -- if you look at the economics of that. And then, of course, probably even more significant is that it's 50-50 in the United States.

So we retain product rights in the United States. We get milestones and royalties ex-U.S., which are substantial. And of course, they've got the whole ex-U.S. infrastructure, which we don't have. So we get the strategic expansion just from an operational standpoint. And then they have the best portfolio of B-cell malignancy drugs. So CLL and NHL, they have the best antibody portfolio, the best combination portfolio for our drug to go with.

So when you add it all up, I mean, it's really -- and then scientifically, we're so aligned. And it's just it was an intense deal process, but it really worked well. It worked the way a deal process should work through all the diligence and boy, are they diligent. I might add.

I believe.

So anyway, I wouldn't do it again. I'm glad that deal got done, and it's a great deal. So anyway, that strategically the best fit.

Yes. So one of the things that I noted when I was looking over that press release and the deck that you guys put out was the massive expansion in the development opportunities for Bexdeg, not just within hematological malignancies, but also within I&I, right? So you mentioned Roche's complementary portfolio. Obviously, they got fenebrutinib in MS.

They have a bunch of other bispecifics in B-cell malignancies. So talk to me a little bit about how this expansion or go into detail a little bit more about the expansion opportunities from a clinical dev perspective for Bexdeg?

Yes. So that was really the second part of your first question, too, is like how -- what does this mean for Bexdeg as a drug and for shareholders. So really, it is an unprecedented sort of breadth of development that now we can do with Roche that we could not do.

So this BTK mechanism really is analogous to the CD20 target. So a Rituxan-like molecule or -- so CD20 has so many uses with the right molecule. So Bexdeg, I think, is that versatile. And so with Roche, it can be put to work in all these different settings. Now in the oncology setting, the combinations are critical. Although our monotherapy activity is 80-plus percent overall response rate, 85%, et cetera, in relapsed/refractory patients who have become resistant to inhibitors, BTK inhibitors.

So our monotherapy trial, which is the Phase III against pirto, we're going to -- I believe we're going to see that degradation is superior to inhibition. So this is a big expansion opportunity for the targeted protein degradation in oncology in general. But then you've got all the antibodies with Roche. So the anti-CD20s, Rituxan, obinutuzumab, some of the bispecifics are going to be very interesting.

I completely agree with you there.

And Roche, they were very frank with us. They're like, we don't have an anchor BTK mechanism in oncology. We have fenebrutinib.

But that's just MS.

That's just MS, but we -- that's been missing in our portfolio, and this could -- this is -- and we were not just going to bring another inhibitor into the clinic, but the degradation mechanism is so unique and the profile is so best-in-class like, right, so far.

So at any rate -- then if you go to non-oncology, you look at what's going on with BTK, remibrutinib with Novartis has done very well in CSU, and now they've talked about their MS data. And so there, again, degradation can be superior. In fact, we've shown all of our curves comparing to remi and fenebrutinib and others, we're 10 to 100-fold more potent than any of the inhibitors against -- in terms of B-cell inactivation.

What's more for MS, and I think very important is the microglial hypothesis for MS. Microglia are basically the immune cells of the brain that are driven by BTK, and they're resident -- and they are responsible, it's thought for the neuronal -- chronic neuronal damage that occurs.

Even if you block with an anti-CD20, the peripheral B-cell activity, you're not going to get at those microglia with -- and that's what causes the debilitating progression. And that's what's so exciting about the whole BTK hypothesis.

Now the thing is that, again, degradation hits it better than inhibition. And we've shown we degrade BTK in the microglial cells of animals in the brain, and we have brain activity established in our CLL patients who have brain disease. So we have unequivocal brain activity with this drug. Plus, of course, we see the drug levels in the CSF and the plasma. But the fact that we can remove BTK from the microglia, I think it directly addresses a central hypothesis of MS debilitation. And so that's really what the potential is here for the MS. And then there's many other diseases to go after, too.

Yes. When you -- when you sort of add up the potential commercial opportunity across all these different indications and lines of therapy, what does that sort of look like with Roche now as the partner here?

Well, I think it tells you something, first off, that a company like Roche or again, a competitive process is a large market opportunity.

That's the only thing that's going to be a driver for any of the pharma, right, it's multibillion. I mean, no matter how you model it. Now you can go anywhere from $2 billion a year to $10 billion a year, depending on what you want to model. But I think the very fact that it has that potential is what we need to know right now.

Yes. No, I completely agree with you. So before we get into the updated Bexdeg data that you presented at EHA not too long ago, can you help level set us on the current CLL treatment paradigm and how that treatment typically evolves across the various lines of therapy here?

So typically, CLL is a chronic disease, so disease of the elderly. It's the most common adult leukemia in the world. And in the old school days, it was watch and wait. You wait and see if the disease progressed, if it got worse, then you would get chemotherapy, which was harsh treatment. And that would be bendamustine and it would be any number of other chlorambucil in the early days. A lot of side effects, very toxic. People used to hold that back. Then you have ibrutinib, the BTK inhibitor. And it was relatively nontoxic. And so people started getting treated earlier and better with a BTK inhibitor. It was one of the first targeted therapy stories after Gleevec, I would say, a major story. And so now it really is a standard of care, start with an inhibitor.

Now ibrutinib has sort of fallen away. It was up to over $5 billion, $6 billion a year, but it has off targets. And so then acalabrutinib from AstraZeneca and then zanubrutinib have come up more selective and now they're taking over the market. In total, it's a $10 billion a year BTK inhibitor CLL market. So it's very substantial already. And then -- but after that, after the inhibitors, then you have BCL-2 inhibitors and venetoclax. And they can be given upfront, targeted therapy, a little more toxic, a little bit less tolerable, but really very effective. And the combination seem to be quite good in second line.

So a lot -- most patients will start with one drug in first line an inhibitor. They progress, you add BCL-2. Some people believe you just do the doublet up front, start with both drugs upfront. But then after that, you pretty much had nothing. And so that's where these inhibitors are what's called covalent inhibitors.

And that's where Lilly came along with Loxo originally with the non-covalent pirtobrutinib. So now pirtobrutinib is trying to pick up that second-line position, but also in first line, it looks quite good. But it's an inhibitor and it's non-covalent. And the question is, what is the real lasting power of that drug compared to a degradation mechanism, which again is stronger, deeper. And so we think that's why we're going head-to-head against pirtobrutinib in the second line as our first Phase III.

So that's 620 patients, the trial is up and running. It's an international trial. Roche is going to be driving the ex-U.S. and Asian. We're driving U.S. So anyway, I hope that helps give you the idea of the treatment progression. But after the BCL-2s and such, there's not really much CAR-T mixed bag so far in CLL.

Yes. So now with that as a backdrop, walk us through the data that you presented at EHA for Bexdeg and help frame the expectations around the data update that will be coming later this year for Bexdeg.

So I think at the EHA, the 2 exciting cohorts that we presented for the first time were basically frontline patients. So patients that had naive patients had never been treated. And this is a Phase I trial with 20 patients in each cohort. I didn't think we'd get many treatment-naive patients because there's a lot of treatment options with the inhibitors. We enrolled that very fast. And then we also had patients that had just seen one BTK inhibitor. And so we had our first pure second-line patients, if you will.

So we had treatment naive, we had BTK second line. So early patients basically. And there, we're looking at 85% to 90% response rates, very high. And -- and I think that was very encouraging. Plus it gives us the rationale for moving to the front line because we have basically a frontline cohort, which the FDA will allow you to do in a small number of patients in a Phase I. And as I said, it enrolled really quickly.

Yes. I note that you've got 2 pivotal trials ongoing now, DAYBreak-CLL-201 and then the 306 trial. Maybe walk us through the trial design of each of those trials. And with regard to 201, when do you think that we can anticipate trial results from it? And what is the time line for potential NDA submission here to the FDA for accelerated approval?

Yes. So it's a DAYBreak family of trials that we're starting -- and we've started. DAYBreak-201 is in the third line plus. So it's very advanced, a high unmet medical need. Patient population where there are no agents, no approved agents. And so that's the definition of enabling an accelerated approval, if you will. So we're enrolling.

We're going as fast as we can. Our goal would be to complete enrollment by the end of this year or in the first half. It's only 100 patients. However, there are not many of these patients yet because they're post-pirtobrutinib patients. So you had a covalent, you had the BCL-2 and you have to have had pirtobrutinib. So it's a slower trial to enroll, but it's a very important patient population for potential accelerated approval. I'm not going to give a time frame now because--

Okay.

We have to work on that.

Yeah. No problem.

Plus, I have to collaborate with Roche--

Yeah.

And whatever I say.

Disclosures.

So -- but it's going well. And then 306, DAYBreak 306 is head-to-head against pirto. That's a 600-patient second line, so patient population. So these are patients that failed a covalent, failed a covalent inhibitor and then they need a new treatment. And so it's pirto -- so it's a Lilly drug versus our drug.

Yes. I note that BeOne also presented some data at EHA. They had a 94% objective response rate with that 200-milligram dose and PFS of 24.4 months across all dose levels. So with BeOne planning to file for accelerated approval later this year, how should investors be thinking about the efficacy profile of Bexdeg 600 milligram versus tacabrutideg, which is B1's drug at 200 milligrams. And more broadly, where do you see potential differentiation of Bexdeg relative to Taca?

So if I'm not mistaken, the numbers you're citing are from early parts of their Phase I trial that was 16 patients at 200 milligrams. They dosed up to 500 -- and they went with the 200. And it's not -- when asked -- when the investigator was asked at the podium, why, they said safety issues.

So I think that that's telling because we had no dose-limiting toxicities to 600 milligrams. And then you apply classic oncology development strategies, which is, okay, look, if it's safe, max the dose and you're going to get better efficacy because you got to cover all sorts of tumor burden for these patients.

All these patients are different. They have different mutational burdens, different sizes of tumors, bulk of tumors, more is generally better if it's safe. So our drug is safe, and we can dose up and so that's what we do. So I do think safety will be a differentiating factor between the 2 drugs is kind of what I'm saying indirectly or maybe directly. But people are going to be the judge of the data as they come out in these larger cohorts because they're still small cohorts for both companies.

So that's on the different -- but on the positive -- very positive efficacy side is that both companies are seeing good efficacy, which is very reassuring and completely separate hands, you're seeing this degradation mechanism showing such superiority.

I think it's validating for degradation over inhibition.

That's great. Yes, independent validation.

Yes. Why don't we shift gears now to your -- to 2 other partnering programs, namely IRAK4 and STAT6. Maybe walk us through the economics behind those programs. And what sort of market opportunity those 2 assets hold?

So yes, there are huge market opportunity that starts there. STAT6 is basically considered the small molecule target equivalent for DUPIXENT, right? So safe target, blocking the IL-4/IL-13 pathway. It's a transcription factor.

So no one's really hit it well, hard to target with an inhibitor. Kymera, of course, has got the lead there and is doing extremely well with their STAT6 degrader. And then we're, I think, next in line with our partner, Sanofi. And there, we have 50/50 economic option in the United States. We started that program with them in 2019.

They've invested into the program over $100 million in cash through that time and been with us through the discovery and development of NX-3911, SAR something something 272. They have a lot of numbers. So yes, so it's going well. And then IRAK4 is with Gilead, that's completing Phase I. STAT6 is in Phase I, and we look forward to data hopefully from those over the next 6 to 12 months. 18 months.

Perfect. Obviously, you mentioned the Kymera program. I wanted to touch base on that a little bit. How do you view that asset from a competitive positioning perspective, given the data we've seen released to date and some of it just came out probably this past week or last week, I should say.

It looks quite good. And I think it bodes well for the STAT6 franchise, which is extremely large. I mean, Kymera has their projections, which dwarf DUPIXENT really according to Kymera, which I could see because if you had a safe small molecule, it's going to be a huge opportunity.

So -- which means there's room for more than one drug and more than one player, more than one company. There'll be multiple drugs here. There may be some inhibitors that actually make it too, which would be great. So it's not a zero-sum game here.

Okay. Good. Beyond your clinical stage programs, one of the modalities that you guys are developing, which I'm fascinated with and so is major pharma as well is the DAC class. And those are the degrader antibody conjugates. So given the novelty of the structure, talk about the mechanistic rationale behind it? And what sort of targets do you believe are best suited for DACs?

So degrader antibody conjugates, mechanistically, why they are exciting is that you can attach a degrader to an antibody and the degraders are hyperpotent targeted therapies. Before your ADCs, you would attach a toxin, which was hyper potent toxic therapy. And so you need to have a hyper potent molecule. A plain old inhibitor won't work because it's 1:1 stoichiometry.

So people have tried those, they don't work. The degrader is one drug molecule degrades 10,000 protein targets per hour, 10,000 per hour, 1 molecule versus 1:1 of an inhibitor. So you're enabling now you have a payload that's strong enough, but is also targeted. It's not just generically toxic. So that -- because what happens with ADCs is you don't actually drag many payload molecules into the cell. The numbers are low. And so that's why only the toxins really work, and they have all sorts of fallout effects.

These degraders are potent enough. So now you can add targeted therapy to the cell with targeted therapy within the cell -- and I think it's going to be a whole new generation of ADCs. We renamed it with originally Seagen DACs and then now Pfizer. And those programs are going great. And it's a new technology. It does take 2 companies. They bring the antibody technology, we bring the degrader. It's a great collaboration.

Yes. It's interesting that you mentioned the inhibitors as a payload. But obviously, we saw, I believe, last week, which major pharma, but entered into agreement for KRAS inhibitors used as a warhead on, let's say, an ADC, right? And it doesn't make much sense to me given what you just said with the one-to-one stoichiometry. So you think a KRAS degrader would be better than just a straight-up KRAS inhibitor being attached to the antibody conjugate?

Well, it depends what they mean by inhibitor, too, with the RAS target because -- some of the inhibitors are actually induced proximity agents like degraders. So some of them work like RAS(ON) drug, is an induced proximity drug.

So it depends what they mean by inhibition there. It's a little tricky with RAS, which doesn't have a classic binding site. It's not an enzyme really. So I don't know. I'm not familiar with that program. I can't. But I would surmise that the DAC approach to RAS would actually be kind of interesting.

So when do you think we might get some disclosures with regard to your DAC programs?

Well, not today. So maybe later.

I had to go fishing for it.

I know we work with Pfizer now, so we have to talk to them.

Sounds good. Well, Arthur, thank you for joining us today. I really appreciate it.

Okay. Thank you very much, Robert.

All right, everyone. I think we'll get started here with our next fireside discussion. My name is Derek Archila. I'm one of the senior biotech analysts here at Wells. I'm very excited to have with us Nurix Therapeutics. From the company, we have Jason Kantor, Chief Business Officer. Jason, good to see you.

Good to see you, Derek. Thank you so much for having us.

Yes. I mean maybe just to start off, a lot of things going on at Nurix. You guys announced a big deal on Bexdeg and other things. So maybe give us kind of the state of the business first, and then we can kind of get into more specific questions.

Sure. Terrific. So for those who don't know Nurix well, we are a multiproduct, multi-therapeutic area, biopharma focused on targeted protein degradation. Our lead asset is a degrader of BTK, which is a central node in B-cell signaling as well as other immune cells. It's in pivotal studies for CLL and is moving into Phase II for chronic spontaneous urticaria, CSU, and also multiple sclerosis, MS.

We've got partnerships with Roche, as you mentioned, for Bexdeg, but also discovery partnerships with Gilead, Sanofi and Pfizer. We've got -- our lead programs in those collaborations include a STAT6 degrader with Sanofi and an IRAK4 degrader with Gilead, and I'm very happy to be here. Thank you very much.

Yes. So maybe to start off, just on kind of Bexdeg and what kind of underpins the deal with Roche in terms of like the strength of the data in CLL and kind of the promise in some of these I&I indications?

Yes. It's a great question. What I'll say is last year, as we were thinking about our strategy around this product, one of the things that was really clear was in order to achieve the right kind of value inflection for the program, we wanted to, one, establish the efficacy; two, establish long-term durability. So on the efficacy side, we had 83% response rate in heavily refractory patients. We had 22.1 months median PFS. We wanted to be able to have an established dose to take into pivotal, and we did a randomized study for Project Optimus.

So having the data package in place, and being on the cusp of Phase III, doing the deal at this point is ideal for us because not only does it derisk us financially in terms of our ability to execute, but it expands the indication space we can go into, which increases the total addressable market, and that includes not only the malignant heme, but also I&I and neuro. And Roche is the ideal partner for us in this respect.

So in terms of just kind of the CLL opportunity, so you guys had already started kind of the late-line trial. And then obviously, the Roche partnership opens up kind of early line. But how do you kind of think about the competitive dynamics with kind of the next-gen BTK inhibitors versus kind of a BTK degrader? And then within that kind of class, how do you guys feel like you're differentiated versus kind of the BeiGene or BeOne molecule?

Yes. Fantastic question. I mean the BTK inhibitor space obviously started with ibrutinib and then acalabrutinib, zanubrutinib and then the non-covalent like pirtobrutinib. And so with each of those, it's been the goal of getting better selectivity, better safety and then ultimately to increase the therapeutic footprint into I&I. Degraders bring an entirely new modality to a target that's proven. So in CLL, or the BTK space right now is $13 billion annually. It's growing at close to 15% and the indication space keeps growing.

We are the only -- the BTK degraders are really the first to try to cross both oncology and I&I. So the inhibitors have -- tend to do one or the other. But the BTK degraders, such as bexobrutideg have the advantage of removing the protein, doing it catalytically and being able to address mutations as well as wild type. And so the data has been, I think, remarkable, and we're full steam ahead on all of that.

In terms of differentiation versus our closest competitor, BeOne, it's hard to say. Right now, they're both showing fantastic efficacy in the 80% range, which is remarkable. And I think ultimately, probably where we'll see the differentiation is on the safety side. We think we have a safer molecule. We think we have a more selective molecule, and we'll just have to see that play out over time.

Got you. So I guess when you think about the Roche deal in terms of like the economics to you guys and ultimately kind of the development plans, too, in terms of the cost, can you just walk us through kind of step-wise, like how you kind of go from where we are today and then building out the overall kind of set of CLL opportunities?

Yes, sure. So we announced the deal back in early June, so it was not long ago. It was the largest single degrader deal to date in terms of upfront. So it was a $700 million upfront payment, $2.3 billion total milestone and upfront package. The cost sharing is 40-60 on the development cost, and it's a U.S. 50-50 profit share ex-U.S. royalty.

Now it's -- people have asked, oh, is Roche taking over? And no, this is truly a collaboration. We have equal representation in all the joint governance, and we're working together on a very ambitious CDP. That CDP includes the randomized Phase III study that we talked about, which is head-to-head versus pirtobrutinib, which is the standard of care in this second-line setting. And we are about to kick off a Phase Ib/II study in combination with venetoclax in order to enable the potential for maybe fixed duration, shorter course therapies that could get to very deep and durable responses.

You asked how we're thinking about covering the CLL landscape. Well, Roche is the perfect partner because they have all of the potential combination drugs, including venetoclax, CD20 antibodies and the CD19 bispecifics. We're also looking to expand into Waldenstrom and mantle cell, and that just covers the heme space.

Got you. So maybe we're going to get some updates, I think, later this year. What should we be paying attention to for the Bexdeg kind of additional CLL data and anything else kind of in the heme space?

Yes. So in terms of Bexdeg data, we are also in addition to running -- having the ongoing studies in heme, we are running a healthy volunteer SAD/MAD study with a new tablet formulation, which is designed to initially go into our studies for CSU and MS. And so we will have disclosures around that Phase I data set this year. We're also working towards an IND in CSU as well as MS. CSU would come first, MS to follow.

And then in terms of the cadence of news flow on the clinical side in CLL and NHL, we typically present data at ASH and at EHA. So that's -- the American Society of Hematology is in December and the European Hematology Association is in June, and we'll have updates on our Phase Ib cohorts at that time.

Should we -- I mean, I think we're going to look at some earlier CLL patients in that data set. So I guess what are the benchmarks should we be looking there for those patients?

Yes. So at EHA, we showed data from patients who were BTK inhibitor naive, including people who were treatment naive. We also looked at a cohort of patients who were BCL-2 inhibitor naive. And the response rates were quite high. I think in one of the cohorts, the response rate got just above 90%. So what we'll look at going forward is do we see further deepening of responses? Do some of the stable disease convert to PR? Do any of the PRs convert to CRs over time? This is something we've seen in the later line patients.

And then how does the durability overall look in those patients as well as the safety. I mean, every time we've looked at the data, it continues to look very positive. So my expectation is it's going to continue to look that way.

Got you. And then maybe just to shift gears to the I&I side of the coin. So we know BTK works in a variety of different indications. Remibrutinib is approved in CSU. There's been a variety of different MS trials. So I guess when you think about the best kind of differentiator there, is it more the efficacy play or more the safety play given that there's been kind of a check or pass even in these MS trials about safety. And to be fair, even remi's got some bleeding risk associated with it.

Yes. These are great questions. So the reason that people got very excited about looking at BTK outside of the heme/onc space is because BTK is a central signaling node for not only B cells, but mast cells, basophils, microglia in the case of MS. And so disrupting the signaling has the potential to really shut down a lot of these autoimmune diseases. What was unexpected when the BTK inhibitors went into these spaces was a lot of them suffered from liver tox.

And it's never really been fully explained why many of these ran into liver tox signal. Some of the possible explanations are higher doses that were needed in order to get the proper exposure in the brain in the case of MS. Certainly some sort of off-target because it's not a BTK on-target signal as far as we can tell. In our experience, we have not seen a liver tox signal. And so -- and just in general, we think we are more selective than many of the BTK inhibitors. So we are very encouraged by that, and that's led us to feel good about moving into these indications.

Now in terms of like efficacy, do you think what we've seen in CLL and somewhat translates like full degradation of BTK will confer better efficacy in I&I? And again, is that part of the...

Yes. That was the other part of your question. So we have run a lot of preclinical studies looking at B-cell activation, mast cell, basophil activation. And the -- our BTK degrader is much more potent than all of the inhibitors. So there's a potency. Now potency could just relate to dose, too. So you get away with a smaller dose. But what we've also seen, especially in the B-cell assay, is a deeper suppression. And we think that, that is likely scaffolding driven so that you actually can get more out of the suppression of the target than you can by simply inhibiting it.

So there's work to be done there to prove the sort of scaffolding function in the I&I setting. But biologically, it makes sense, and we think we can get to a deeper suppression. Specifically in CSU, I mean, remi kind of sets the bar. They have shown biologic-like activity, so activity similar to dupi or to Xolair. The activity is actually quicker. It's more rapid, but it's a twice-a-day drug, and there is some rebound of symptoms between doses even on a twice-a-day drug.

We think with a degrader with Bexdeg, we can dose once a day. We think we can have coverage throughout the treatment window. And we think that we could potentially drive that efficacy better. About half the patients are well controlled on each one of those therapies. So that leaves half the patients who aren't. And we think we can probably push the BTK mechanism a little harder than remi does.

Is there any insights? So I know BeOne had a trial with theirs in China, their degrader in CSU. Any insight to like how that performed? And it does sound like they want to move that forward. So what do you think -- I guess, like what would your internal benchmark be to move something forward with kind of an incumbent BTK inhibitor? Like how much better would you need to be? And what differentiation would you want to see to move that forward into a global registration Phase III trial?

I think remi does set a bar, and I think we would look to at least meet that bar. I think there are advantages potentially just being once a day versus twice a day, but we think we can probably do better than that. But I think that bar is pretty well established now in terms of the composite endpoints on itching and hives and swelling that's associated with the disease.

Is there any specific part of the disease, whether it be, again, itching or hives or anything like that, that is more directly driven by the scaffolding function? Or is that just like too nuanced that we don't really know?

It's very nuanced, and we probably don't have all the right information, and I am probably not the right person to be able to answer that. What I can say is the place preclinically where we've seen or in vitro where we've seen the most differentiation is on the B-cell side. So the disease involves both the B-cells in terms of the autoantibodies that are involved, but then also the mast cells and basophils, which are releasing the compounds that are causing the itching and swelling.

So BTK is impacting the disease in 3 different cell types. And we think that certainly at the B-cell side, at least from the data I've seen, we do have good evidence of a deeper suppression of the pathway than you do with remi.

Got you. And then just on the other side in terms of MS. So MS is quite a mature market and fairly crowded. But I guess where do you think BTK should play? Is it more relapse and remitting or progressive, given some of the data sets that we've seen with prior BTKs, where do you want to establish kind of the beachhead?

Yes. It's a crowded market, but it's a big market, and it's a market with still high unmet medical need and a market where new therapies are adopted, new oral therapies are needed. The place where the biggest unmet medical need remains is in -- for drugs that can slow disability progression. I think that's the hope for BTK-targeted therapy, particularly if you can get access to the microglia. So the microglia are immune cells that are resident in the brain that are believed to be involved in some of the demyelination that's critical for the progression of the disease.

So I think mechanistically, a BTK degrader should work across all of the forms of the disease. But I think commercially and clinically, the place where we'd want to see the benefit would be in disability progression.

How do you think about generating proof of concept with Bexdeg there? Would you do kind of Phase II kind of MRI? Or do you want to go into kind of a longer trial? What's kind of the design that you guys would like to do? And now with the kind of the backing of Roche and the help there, you could fund kind of any trial that you'd actually like?

Yes. I mean one of the great advantages of working with Roche is having that collaborative team now that's working on finalizing the trial design for the Phase II. I mean there's no group out there that has more knowledge of, for example, biomarkers in the space, and they've just run a full program for fenebrutinib. And so they are fully aware of how best to run the study.

I think you always, in early trials, want to look at MRI-type endpoints, things that are quantitative. But ultimately, you need to show data on relapse rates or disability progression, but your ability to measure that in smaller studies, you really have to look at both surrogates as well as clinical endpoints.

So we should think more of a standard proof-of-concept MRI imaging-based endpoint study first before kind of going all in on Phase III.

Our thought -- just our general thought, and I'm not going to speak specifically to the trial designs at this point, but our general thought both for CSU and for MS is to run registration enabling -- trials that will enable a registrational study. So something that will provide -- we're not looking for a quick proof of concept. We're looking for a full understanding of the right dose and the right patient population in order to enable a positive registration study to follow.

How do you think about dosing across these I&I indications relative to what you guys have seen in CLL and I mean you have to do some exploration. I don't know if there's some differences in the tablet, but maybe kind of give us a view of like should we be expecting multiple doses? And what sort of PD effect do you need to show to maybe drive efficacy?

Yes. So this is a great question, and it's part of the reason that we run such a robust Phase I program. So not only do we have this big CLL and NHL patient experience to rely on, but we have very well-run Phase I SAD/MAD studies, which includes PK/PD, and that's really going to form the basis of our dose selection for not only the new formulation, but just to be specific for each of these indications.

So we've shown a little bit of data on the activity of the drug in the skin. We see very robust BTK degradation in the skin. We're also looking at PK levels in the CNS which is going to be very important for the MS indication. And so we'll show some of that data later this year, and that should support our dose selection. We will be looking at lower doses than we are looking in oncology.

Got you. I mean do you think that's probably a fair assumption that ultimately, you probably need lower doses in autoimmune or is not -- we just don't know yet?

Yes. I mean when we are dosing in oncology, we are really looking at trying to get to as high a dose as possible within the context of Project Optimus. We're dosing at 600 milligrams once a day. And part of the reason for that is we really want to make sure we're adequately covering all the mutations. That's not really an issue in terms of what you see in I&I and in neuro. In I&I and neuro, it's really more about what is your coverage in the right tissue. So in the skin, how well are you covering BTK? In the CSF, how well are you covering BTK?

And the good news is, again, we're working catalytically. We work at very, very low plasma concentrations. So you only need very little of this drug in its active form to degrade. We've measured the rate of degradation. A single molecule of our drug can degrade 10,000 BTK proteins an hour. So -- and then that has to be resynthesized to come back. So the target coverage is phenomenal and it's very, very different than sort of 1:1 inhibition that you see with an inhibitor. And it's why we think we can get away with lower doses, why we can dose once a day and why we think we can get better target coverage.

Got you. And I know it sounds like the near-term priorities on the I&I side are CSU and MS. But where else could you go with kind of BTK and I&I? And I guess when would that happen? Would it happen more about the time we get proof of concept for these 2 and then kind of start to expand? Or could that even happen sooner?

Yes. So some of the areas that people have shown good data for BTK inhibitors include -- food allergy is one that a lot of people talk about. I mean their safety is really paramount. So I think showing good safety in an I&I indication may be important before embarking on that. But there are a lot of -- there's a long list of I&I indications, including some rare but higher value or higher morbidity diseases that we could consider going after as well.

In terms of when, the governance around the collaboration with Roche has us and Roche really equally represented, and it's really whether the -- each therapeutic area team feels is best. So we are excited to understand where Roche would like to take the drug. We have ideas. Right now, we have a lot on our plate just in terms of executing on what we set out, but it's possible that we would add additional indications.

Got it. Maybe switching gears to STAT6. You guys have a program that you are partnered with Sanofi and your peer out there, Kymera will have data, hopefully, to derisk this target and this class of drug. So maybe just talk about your program, the partnership with Sanofi, and it has just, I think, entered the clinic. So you're hoping to get some maybe data maybe sometime next year. But maybe just give us a little bit of background on where we are in development.

Yes, great. So the program with Sanofi stems from a 2019 5-target discovery deal that we did. STAT6 was one of the initial targets that was put into that collaboration. We generated a degrader to it. We licensed it to them last year at the development candidate stage. And just this past month, we announced that they've initiated the Phase I study for that program. We've shown some preclinical data. It's very potent sub-nanomolar potent. It's probably the most selective degrader that we've made. It's incredibly selective. We think it's a fantastic drug. And Sanofi has disclosed they're in Phase I.

That study is a SAD/MAD healthy volunteer with at least that -- they're also treating patients in that study. That study should inform our option decision. So when that data is -- when that trial is complete, we have an option to go 50-50 co-development, co-promotion profit share with them in the U.S. And yes. So the Kymera data, we're eager to see the -- how that pans out. So far, they've shown biologic-like activity with a relatively clean safety profile as far as we know. And the more derisked this target gets, I think the more value that will accrete to our program.

So do you think -- so you kind of talked about so this Phase I program will include a cohort of patients. Is that -- so should we think about this as a similar type of program that Kymera ran with theirs with like Phase Ib kind of small cohort uncontrolled? Or is it more robust than that?

Yes. I mean, unfortunately, I can't say more about it than that. Sanofi has limited disclosures, and we're only able to speak to what's in the public domain. There is a listing on the European clinical trials site, which states that it includes healthy volunteers and patients. It doesn't denote what type of patients those are or how that cohort is designed. But I look to what Kymera did and it's a similar -- could have been described similarly. So yes, that's really all I can say about it.

Got it. And I guess when you think about STAT6 degradation versus STAT6 inhibitors, there's a few others out there like Recludix and whatnot, also exploring that, Pfizer. Where do you think whether the issues or the challenges lies with inhibitors relative to degraders? And what gets you confident that degradation is the best approach?

Yes. So I have 2 thoughts on that. The first is that the knockout for STAT6 looks really clean. And the degrader mechanism is the closest thing we have to a knockout phenotype and all the preclinical data supports that. And our experience with BTK and other targets suggest that this is a very safe and effective way of really maximally addressing a target.

Now when we talk about comparing -- so there's the second point, we talk about comparing degraders to inhibitors. Classically, you think of an inhibitor as being the less risky modality. We have inhibitors of BTK, we have inhibitors of lots of things. But there has never been an inhibitor of a STAT6 because it's not a catalytic enzyme. It's a transcription factor. So the novelty around inhibitors is actually quite high as it relates to transcription factors and some of the ways that they're trying to do it, whether it's SH2 blockers or other types of blockers, there's a lot of novelty and a lot that's not known about selectivity and off targets and things like that. So -- and target coverage. It's not as easy to measure, I think, as an enzyme. So our view is you want to hit the target, degrade it.

Got you. And so trial is ongoing. And as you said, you'll get a decision point at some point where you will see the data. I mean, should we understand that like because this is a Phase I trial, and Sanofi is probably not going to report out results, but at some point, you'll kind of just pop up and be like, we decided to move forward with the co-development plan? Or like how would that disclosure end up happening? And I'm sure there's some sort of period where you will sit with the data, review it and then come to that decision. But what are -- I guess, maybe high level, what are kind of the mechanics of the decision-making process?

Yes. So our option is triggered by results of a trial that were designed to assess safety, dose and efficacy. So given that last piece, efficacy, that would require at least a pilot Phase Ib in a disease setting. And so it's our assumption that the trial that they're running should be sufficient for that. And we would -- yes, we would get a data package, which we would then have a period of time to make a decision. In the meantime, we're paying $0 for the development. And then if we opt in, we would just pay our share going forward. There's no catch-up payment or nothing like that.

In terms of their disclosure, we're eager to have them say more, I should say, but that's really going to be up to them.

Seemingly an important program for them.

Yes.

And then I guess one of the things I'd love to get your take on. So we cover Kymera, and I think there's differing views on like where the efficacy needs to be for a STAT6 degrader relative to dupi. Do you believe that it needs to kind of mirror the efficacy? Or it could still be 70% to 80% of the efficacy of dupi and still be successful because it's an oral? Like where do you kind of come down on that in terms of like where you think it needs to be benchmarked?

I think you wrote a giant report on this.

I did. Go read it.

Yes. I read it on the plane. It was -- that's fantastic. If you haven't read it, you should read it. I heard the doctors that you interviewed had expressed that you could have a drug that's even a notch down versus the biologics in efficacy and would still be a huge opportunity. And the example, of course, is Otezla, which is not a great drug, and it does a lot because people want to step through an oral and that the biggest opportunity is not to, for example, replace dupi, but to expand the market. There's tons of patients who suffer for a long time either before going on dupi or never go on dupi or something similar. So I think a safe and effective oral truly expands the market. And so yes, I think there's a lot of room for this drug class to be a mega blockbuster.

Yes. And maybe with the last couple of minutes, we were just talking about before we went live here, but kind of the other components to your collaborations and what the overall Nurix platform is like capable of. So we were talking about the DACs and other things that you guys have kind of done deals on. But I guess what is kind of exciting to you guys that you've got a lot of collaborations, but internal pipeline that you guys want to start to develop because now you've got a big cash infusion, you kind of go in direction you want with the early-stage pipeline. So what are you guys thinking in terms of new targets? Is it more oncology, more I&I or other areas? Like where do you want to take it?

Yes, it's a great question. So first of all, we think we have one of the greatest degrader platforms out there. It's been very, very productive. Since our IPO in 2020, we put 6 drugs in the clinic, including 2 in the last 2 years, STAT6 and IRAK4. We have more coming. The -- in terms of where those programs are going to be, we are primarily focused in oncology and immunology. And I think that's where you're going to see the most interest in terms of our late preclinical.

Our most advanced preclinical is a pan-mutant wild-type sparing BRAF degrader, which has the potential to be a mutant selective genetically defined drug in lung, colon or melanoma. It's very much best-in-class potential and something that we could take forward on our own. We also have I&I programs that we haven't disclosed.

Importantly, you mentioned the DACs. That was a deal we did with Seagen, now part of Pfizer. That's moving along very well. We haven't disclosed much from it, but we do have options for 50-50 co-promote profit share on 2 programs. We have options for 2 programs out of the Sanofi, and we have options for 2 programs out of the Gilead collaboration. So our pipeline is not only generating non-dilutive capital from our partners, but also generating product rights and ultimately, drugs for our own portfolio.

I mean do you think the direction is going to be more focused on looking at targets that maybe you're just not appropriately drugged with inhibitors and kind of validated but suboptimal? Or are you guys ready to take even more kind of risk around kind of targets yourself like for internal?

It's a great question. I mean, originally, we went with BTK as a very derisked, easy to monitor target. We saved some of the more difficult targets like STAT6 to be under our collaboration with Sanofi. Going forward, we are disease agnostic to a certain extent, and we're looking at targets that are high value across the proteome. So there's -- stay tuned. There's a lot under the hood.

Got you. And then so maybe just sketch out for us with the last question, like 12 to 18 months, what should we expect from you guys in terms of updates and internal and external partnerships as well?

Yes. It's going to be a busy -- it's been a busy year. It's going to be a busy next year through the end of the year. This year, we're looking at data from the Phase I healthy volunteer study, which is going to enable the IND for CSU and MS. We'll have an update, a clinical update at ASH. Going into next year, we're looking at opt-in for IRAK4 and potentially some visibility on that data. We'll be looking at additional clinical updates at EHA and ASH.

We'll be making sort of go/no-go decisions for next steps for 1607, which is our Cbl-b inhibitor as well as zelebrudomide, which is our dual BTK, IKZF degrader. And ultimately, if you kind of think where we'll be next year, end of the year, we will have visibility on pivotal readouts from our CLL program. We'll be deep into our combination studies as well as Phase II studies for CSU and MS.

Got it. Well, Jason, I think we'll leave it there. Thank you so much.

All right. Thank you.

Welcome to the Nurix Therapeutics, unlocking the full potential of Bexdeg call. [Operator Instructions].

I would now like to turn the conference over to our host, Arthur Sands, President and CEO. Arthur, you may begin.

Thank you very much, and good day, everyone. I'd like to welcome everyone to our call today for a discussion around a very important new collaboration between Nurix and Roche centered on the development and commercialization of bexobrutideg, our potentially best-in-class BTK degrader for B-cell malignancies and autoimmune disease.

We will be making certain forward-looking statements today, so I refer you to our disclaimers and risk factors which we have filed with the SEC. So today, I'm very delighted to be joined by our Chief Financial Officer, Hans Van Houte our Chief Business Officer, Jason Kantor; and our Chief Commercial Officer, John Northcott, on this call. And we prepared a short presentation for you on the strategic underpinnings of this new collaboration as well as some of the details regarding the structure of the partnership and the planned drug development initiative and most importantly, the potential value creation for patients as well as for all Nurix and Roche stakeholders.

After this presentation, we will have time for a question-and-answer session. So first off, I'd like to make a few general statements about the collaboration we're announcing today. It unites 2 companies on a common mission to unlock the full potential of a next-generation BTK targeted therapy, bexobrutideg, or Bexdeg for short.

Bexdeg is a potential best-in-class BTK targeted therapy that specifically and potently removes the BTK protein through targeted protein degradation. Bexdeg has generated robust clinical data in a broad CLL patient population that is chronic lymphocytic leukemia as well as in selected NHL or non-Hodgkin's lymphoma indications and has also generated compelling preclinical data in other therapeutic areas, including chronic spontaneous urticaria or CSU and multiple sclerosis or MS.

The collaboration combines Nurix leading position in targeted protein degradation, with Roche's established leadership position in oncology, immunology and neurology, thereby unlocking opportunities across multiple therapeutic areas. Specifically, Roche's existing portfolio of B-cell targeted therapies creates the potential for synergy with Bexdeg's ultimate therapeutic targets in both CLL and NHL.

Further, Roche's well-established product franchises of Xolair in allergy and immunology and Ocrevus and MS create even broader potential for exploration of Bexdeg's utility in additional major therapeutic areas. Lastly, Roche's global clinical, regulatory and commercial infrastructure can help make a shared ambitious vision for Bexdeg a reality, namely developing Bexdeg as a potential backbone therapy across BTK mediated diseases to be available globally for patients in need.

With that framing, I'd like to turn the call over now to Jason, our Chief Business Officer, who will walk you through the financial structure and strategic rationale of the partnership. Jason?

Great. Thank you, Arthur. It's truly a pleasure to be able to announce this transformative partnership between Nurix and Roche. Today's announcement marks the culmination of a very comprehensive and competitive process, which we believe maximizes the clinical and commercial opportunities for Bexdeg across oncology, immunology and neurology. Importantly, this global partnership provides Nurix with a clear path to achieving its corporate strategic goal to become a fully integrated biopharmaceutical company capable of bringing novel degrader-based medicines to patients in major medical markets.

The deal terms also represent a milestone in the field as it is one of the largest, if not the largest deal of its kind for a degrader drug, which we believe is emblematic of the tremendous potential that Bexdeg and targeted protein degradation in general, hold for medicine.

Following the close of this transaction, Nurix will receive $700 million in upfront cash with total potential payments of up to $2.3 billion, inclusive of the upfront. This includes clinical, regulatory and commercial milestones, both aimed at rewarding success and also time to provide offsetting funding scaled with our robust clinical development plan and its associated costs.

Importantly, additional significant value beyond the $2.3 billion comes from the future retained downstream economics captured in the 50-50 cost-profit share in the U.S. as well as royalties on ex-U.S. sales, which make this deal potentially extremely value-enhancing for Nurix, both in the near term and over the long run.

Nurix and Roche will co-develop Bexdeg globally across indications, leveraging the robust clinical plan already underway at Nurix and expanding our operational footprint with Roche's global development and regulatory capabilities. Development costs will be shared 40-60 with Nurix paying 40% and Roche paying 60% of global development costs.

Beyond the dollars, the structure reflects a true partnership, a shared mission and a vision to maximize the value of Bexdeg across multiple indications with shared U.S. commercialization and Roche taking on operations of ex U.S. commercialization. Driving the significant financials and the chosen structure of the deal are the compelling attributes of Bexdeg a potential best-in-class BTK targeted agent.

First, BTK has proven itself to be a foundational target and a central node in controlling B-cell and other immune cell activity with proven therapeutic utility across a wide range of diseases, including in oncology, immunology and neurology. The potential advantages of Bexdeg are numerous and derived from its unique mechanism of action. Unlike inhibitors, Bexdeg removes BTK from cells, eliminating both the enzymatic and scaffolding functions of BTK, a much more profound blockade of the BTK signaling potential.

Bexdeg acts catalytically. A single Bexdeg molecule can remove approximately 10,000 BTK proteins per hour from the cell, increasing its potency and fundamentally changing the PK/PD relationship of a small molecule drug to its target. Bexdeg has also been engineered to be exquisitely selective, which we believe accounts for its highly favorable safety profile.

In the oncology setting, Bexdeg also has a unique advantage of addressing the widest range of BTK mutations, overcoming treatment resistance and driving deep and durable responses. And finally, Bexdeg has demonstrated clear ability to cross the blood-brain barrier, bringing demonstrated clinical benefit in CLL and lymphoma patients whose disease either originated in or spread to the brain. This demonstrated activity in the brain, we believe, also has the potential to translate into significant clinical benefit for patients with multiple sclerosis.

The mechanistic advantages of Bexdeg have translated to clinical benefit for patients, which became apparent at the earliest stages of clinical development. In fact, we believe the results of our Phase Ia trial are actually quite remarkable. For patients with chronic lymphocytic leukemia, or CLL, Bexdeg provided a robust 83% objective response rate in a patient population that has already received a median of 4 prior lines of therapy.

This high level of clinical activity is observed across patients with high-risk features such as BTK mutations associated with resistance to BTK inhibitors and other high-risk molecular features as well as for patients with CNS involvement. And these responses are quite durable. In our Phase Ia dose escalation experience, the median PFS is 22.1 months, which appears to exceed existing therapies, especially considering the degree of prior treatment that these patients have received and the fact that they have been treated across a range of Bexdeg doses.

For my last slide, I want to share with you my excitement for Roche as a partner. I really can't think of a better partner to maximize the opportunity for Bexdeg to deliver benefit to a wide range of patients. On every axis, scientific, clinical and commercial, Roche is the clear leader and the best partner for Nurix. Roche is an innovator in the area of B-cell biology, not only in oncology but across indications, including immunology and neurology with blockbuster standards of care, including RITUXAN, Gazyva, Ocrevus, Venclexta, Polivy, Xolair and emerging new bispecifics and of course, their BTK inhibitor, fenebrutinib.

We are extremely excited by the shared vision and enthusiasm for bringing Bexdeg to patients across indications and to position Bexdeg as the best-in-category agent across disease setting. When we embarked on this partnering process, we wanted a partner who shared our scientific conviction who had deep disease expertise across oncology, immunology and neurology and who had the infrastructure to take bexobrutideg global. Roche checks every one of those boxes. To tell you more about our development plan, I would like to turn it back to Arthur.

Thanks, Jason. Before I dive into the development plan, I just do want to mention that as exciting as today's announcement is, this collaboration really is ultimately about something much bigger and that is our mission and now our common mission with Roche, which is to establish degrader base medicines at the forefront of patient care. What makes this collaboration so important is that it gives both Nurix and Roche an opportunity to fulfill that mission on a very large scale.

Together, Nurix and Roche have aligned around a shared goal, advancing bexobrutideg into areas of significant unmet medical need where we believe it has the potential to make a meaningful difference for patients. So let's turn to the joint development plan more specifically. So importantly, this is not a collaboration centered on a single indication. It is a comprehensive development strategy designed to explore the full potential of bexobrutideg across oncology, immunology and neurology.

The result is a broad clinical development plan that we believe can maximize the value of Bexdeg while creating multiple opportunities to improve patient outcomes. The breadth of what we are pursuing together across 3 distinct therapeutic areas reflects the potential of the Bexdeg mechanism of action to counter disease biology and the significant unmet medical need that persists in these major disease categories. In CLL, patients continue to develop resistance to current BTK inhibitors as well as to other difficult-to-treat genetic driver...

Do we lose you Arthur?

Arthur?

Operator, did we lose Arthur?

His line is connected, but not hearing any sound. He may need to reconnect.

Okay. Well, I'll just pick up where he left off and Okay. In CLL, patients continue to develop resistance to current BTK inhibitors as well as other difficult-to-treat genetic driver mutations. And once they do, options are limited. In immunology and in neurology, BTK-targeted therapy has initially been explored with BTK inhibitors, leaving the additional benefits of total protein removal untapped.

These are key motivators that fuel the ambition that Nurix and Roche share for this molecule. Let me walk you through an initial outline of the collaboration plan. Our -- overarching strategy is to advance a comprehensive Bexdeg development program across multiple lines of therapy as both monotherapy and in combination settings in B-cell malignancies. The first 3 studies are as Nurix has previously outlined and will continue as per their previously described designs and timelines. These include the DAYBreak CLL-201 study for potential accelerated approval, the Phase III DAYBreak CLL-306 study and the Phase Ib/II basket combination study.

The Phase Ib/II basket combination program is designed to enable not only future planned first-line and/or second-line Phase III studies in CLL, but also potential Phase III combination studies in NHL as indicated by the blue bars below. Specifically in mantle cell lymphoma, or MCL and Waldenstrom macroglobulinemia or WM. We are pursuing both monotherapy approaches for speed to market and combination strategies to enable potential fixed duration regimens with Roche's venetoclax as well as exciting potential for multiple other combinations with Roche's other existing portfolio drugs. Overall, one can easily imagine how this powerful collaboration with Roche can establish bexobrutideg as a future backbone therapy across B-cell malignancies.

I think, Arthur, are you back, Arthur?

I am back. Can you hear me?

Yes.

Yes.

Okay. Great. All right. Well, thanks. Sorry about that, Jason, thanks for picking up. So yes, as we -- I'd love to speak to this next slide here about CSU and MS. And so let me just dive into that. We see these as really representing very significant expansion opportunities. And I would like to spend some time walking through some of the rationale, both scientific and clinical for expanding Bexdeg clinical development into these areas.

So first, the totality of the BTK protein, not just the kinase function plays a key role in autoimmune disease biology, particularly as a critical regulator of the Fc receptor activation mast cells and basophils and controls B-cell inflammatory pathways. Secondly, we have shown that Bexdeg more potently suppresses BTK signaling and activation in mast cells, basophils and B-cells compared to multiple BTK inhibitors in vitro.

And third, we have recently published our findings that Bexdeg achieves rapid, robust and sustained degradation of BTK in both the skin and the blood of healthy volunteers. Therefore, we are actively planning with Roche the initiation of a Phase II clinical trial in chronic spontaneous urticaria to determine the dose of Bexdeg required to deliver the full potential of BTK degradation to treat this disease and enable a Phase III program as rapidly as possible.

Turning to neurology and MS. We know from our current trials that Bexdeg crosses the blood-brain barrier and exhibits therapeutic activity in primary CNS lymphoma and CLL with CNS involvement without signs of liver toxicity in a safety data set of greater than 300 CLL and NHL patients to date. In addition, Bexdeg has demonstrated potent therapeutic activity in preclinical disease models of MS. And perhaps most excitingly, we have shown robust in vivo degradation of BTK in brain-resident microglia in animal models, eliminating both the kinase and scaffolding functions of BTK and thereby providing a mechanistic rationale for potentially enhanced by biologic activity in the brain with direct implications for diseases such as MS.

Based on the above rationale, we are also actively planning with Roche a Phase II clinical trial in MS, and we cannot think of a better partner to be joining forces with to explore the exciting potential of BTK degradation in neurologic disease. So overall, for Nurix, this is a defining moment. This collaboration enables and accelerates our evolution to become a fully integrated biopharmaceutical company, one that combines an industry-leading targeted protein degradation drug discovery engine with the ability to translate innovation into global clinical and commercial impact across multiple therapeutic areas.

We have an innovative oncology pipeline spanning both hematologic and solid tumors, both wholly owned and partnered with significant product sharing rights across multiple indications. In addition, we continue to push the forefront of targeted protein degradation technologies with our degrader antibody conjugate or DAC programs, a truly exciting area to be the subject of future disclosures.

If we turn to our pipeline in immunology and inflammation, we can see that we are now have quite a breadth of platform that beginning to translate across entirely new therapeutic areas, particularly in immunology and neurology. Nurix's opportunity for value creation is poised to continue to grow substantially as both our IRAK4 program with Gilead and our STAT6 program with Sanofi continue to advance in development. These also will be the subject of future important clinical and business updates.

With that, I'd like to hand the call to John Northcott to discuss the commercial implications of today's announcement. John?

Thank you, Arthur. Good morning, everyone. I'm John Northcott, Chief Commercial Officer of Nurix. I will open with saying how thrilled I am that we are announcing our partnership with Roche, the right partner to help us execute an expansive clinical development plan for Bexdeg across CLL, NHL, CSU and multiple sclerosis. Our joint development plan targets these indications, both as a monotherapy and in combination as appropriate to unlock the power of protein degradation and advance the standard of care for patients across a range of therapeutic areas, all of which have very large addressable patient populations.

Each of these therapeutic areas and markets have the potential to generate significant value and represent major blockbuster potential for Bexdeg with a collective total initial addressable market opportunity of approximately $48 billion. We believe this partnership with Roche positions us exceptionally well, bringing proven commercial infrastructure, deep therapeutic area expertise and established market access across every indication we will pursue together.

This is a real competitive advantage, and it means we are in the strongest position to deliver innovative therapies for patients across all of these areas, which is ultimately what drives us. Needless to say, these are all large competitive markets and the established global footprint of Roche will rapidly enhance our ability to deliver Bexdeg to every major market.

First, in terms of expanding our clinical development program into new countries with a greater number of investigative sites and then towards achieving regulatory approvals and launches across the globe. Under the terms of this global agreement, we will build our size of the U.S. commercial capability to support a successful launch of Bexdeg in a stage appropriate fashion with the benefit of Roche's established infrastructure behind us from day 1, giving Nurix a clear path to becoming a commercial stage revenue-generating and ultimately profitable company.

Today marks a new chapter for Bexdeg and Nurix, and I'm confident that together, we will achieve great things for patients and all the stakeholders we serve. Now for a brief look at the high-level financial implications of this strategic collaboration, I will hand the call to Nurix's Chief Financial Officer, Hans Van Houte. Hans?

Thank you, John. Well, as most of you are aware, for more than a decade, we've built one of the industry's leading targeted protein degradation platforms. And we've also used that platform to establish partners with some of the world's leading pharmaceutical companies. These collaborations have generated over $1 billion of non-dilutive cash for Nurix while enabling us to retain meaningful co-development, co-commercialization participation and future success of our programs.

This Roche collaboration represents the most significant example of that strategy to date. It brings a potential best-in-class BTK degrader together with a global leader in oncology, immunology and neurology, expands the development and commercialization and reach of bexobrutideg while preserving substantial long-term economics for Nurix through U.S. profit sharing and ex-U.S. royalties.

Importantly, this transaction also significantly strengthens our balance sheet. Following the receipt of the upfront payment, Nurix will have approximately $1.24 billion in pro forma cash, providing substantial resources to advance bexobrutideg in multiple indications, invest in our wholly owned pipeline and continue to invest in our targeted protein degradation platform.

More broadly, this collaboration reinforces a model that has served us well, leveraging our drug discovery engine to create innovative medicines, partnering strategically where accelerates development and maximizes patient impact and retains meaningful participation in the value we create. Back to you, Arthur.

Great. Thank you, Hans. Before opening the call to your questions, I'd like to briefly summarize some of the key points and implications of today's announcement. So first of all, in collaboration with Roche, we are establishing a multi-indication, multi-therapeutic area clinical development program for bexobrutideg in malignant hematology, immunology and neurology.

Next, within malignant hematology, we are broadening and accelerating Bexdeg's clinical development program, not only as monotherapy, but with combination regimens enabled with Roche's significant portfolio of innovative therapies for B-cell malignancies. Indeed, the initiatives within this collaboration position Bexdeg as a potential backbone therapy across BTK-driven diseases.

Together, Nurix and Roche bring synergistic scientific, clinical and commercial capabilities that are creating a shared economic opportunity across a projected $48 billion addressable market. Enabling all of this is bexobrutideg, a real stallion of a molecule that reflects years of scientific innovation and demonstrates the power of targeted protein degradation to fundamentally change how we intervene on disease biology.

With Roche, we have the right partner, the right resources and the right plan to bring bexobrutideg to patients globally across multiple diseases in multiple geographies. I hope today, we have presented and you can also sense from my overtly positive tone, a more expansive picture of what Nurix is and will be. A multi-asset, multi-indication company with the scientific foundation, financial resources and strategic partnerships to compete and deliver as the highest level of drug development and commercialization.

So with that, we'd like to open the call to questions. So operator, if you could do that, please, we'll stand by.

[Operator Instructions] Our first question comes from Brian Abrahams from RBC Capital.

Congratulations on the partnership. I was wondering if you could maybe elaborate a little bit more around the expected additional expansion of the Bexdeg development plans and as well as some of the specific combos that you may pursue.

And I guess, is there any rationale around potentially further expanding the ongoing and planned CLL studies just given the bolstered resources that the deal brings?

Sure. Thanks. I'll take that. So yes, we have plans to expand. Let me first address the combination portion of the question. We are initiating as planned, our Phase Ib/II study which is a basket study starting with CLL, but also can incorporate NHL indications and anticipates multiple combination drug partners.

One of the primary ones we're starting with there is, of course, venetoclax, which is key for Roche as well. So that would be an all-oral combination. But we are -- we have also outlined cohorts that will allow for anti-CD20 antibodies to be incorporated into cohorts. This will start in second-line patients, but then also can then be upgraded after the initial combination results are obtained into first-line cohorts, which we will then choose combination agents at that time.

In addition, as you can imagine, with Roche's portfolio, this combination basket study could be expanded quite substantially. We've not yet outlined what those studies would be, but they are definitely on our radar. With regard to the monotherapy, we are wholly focused on initiating our Phase III program in the head-to-head study against pirtobrutinib that's DAYbreak-306 CLL. That is a study anticipated to be at approximately 600 patients as we previously outlined.

Nurix alone, we, of course, outlined, I think, many countries involved, primarily Europe, U.K. and U.S. with Roche. We are now actively expanding that geography. We'll have to stay tuned for that, but that's going to be something that I think will definitely accelerate our program overall and establish a truly global footprint, making bexobrutideg, of course, even more of a competitive agent.

So I think with that, I believe I've answered the bulk of your question. So thank you.

Our next question comes from Tess Romero from JPMorgan.

Thanks for all the detail you provided as well. So what color can you give us on how this collaboration came to pass and the process that it seems that you ran? And second question from us, just double-clicking here from a housekeeping purposes. Can you give us a picture of how the upfront cash and future milestones will be accounted for as we are thinking about our models?

Okay. Let's start out with the first part. Jason, would you please take that? And then we'll go to Hans when you're finished.

Yes. Thanks, Tess. So yes, indeed, this was a competitive process. We had many players who had an opportunity to take a look at the asset and in fact, many who have been tracking it for quite some time. The deal itself was driven largely by our ability to show very robust clinical data, not only in terms of ORR, but of course, in terms of PFS, our clearing of the 600-milligram dose through Project Optimus and the differentiation data that we were able to show last October, which I think positions bexobrutideg as a potential best-in-class BTK degrader.

Hans, do you want to talk about the accounting?

Yes, sure. Yes, we're currently evaluating the accounting treatment of the transaction. We'll provide additional detail in future SEC filings and earnings communications. Thank you.

Our next question comes from Gregory Renza from Truist Securities.

Congratulations on the deal. Arthur, you certainly talked about maybe expectation of subjects of future disclosures when it comes to your pipeline. You mentioned DAC and certainly on the I&I. I'm just curious, from here, when it comes to Nurix's wholly owned programs, which ones are you most excited about? Which ones perhaps provide the most opportunity for you? And for investors? And then maybe just one specifically. I'm just curious how you're thinking about the pan-BRAF degrader program from here. You certainly mentioned maybe this and others as future topics.

Sure. Well, thank you. So I believe an investment in Nurix is really an investment in the totality of our pipeline, not necessarily any one program, although I think many investors may have their favorites. And certainly, Bexdeg is our leading asset with one of the greatest potentials. But I say looking at the totality of our pipeline because we have not only our wholly owned assets, but our partnered portfolio, which now includes partnerships with 4 major corporations -- of course, the one we're discussing today is the largest to date.

Each of these partnerships allows for us to participate in cost profit share agreements with each of the partners. Obviously, Bexdeg, we detailed as a 50-50 in the United States, which is quite substantial product right opportunity. And then across the 3 others, we have a total of 6 such option rights. Those are structured as options after human proof of concept for significant cost profit shares as well in a similar fashion.

So you're looking at a diversified portfolio and significant product rights owned by Nurix across multiple drugs, which I think helps derisk the investment thesis as well. Now in addition to that, we have additional wholly owned -- currently wholly owned projects, NX-1607, I personally think is extremely exciting as a new immuno-oncology agent. It's a CBL-B inhibitor, which has been developed through Phase Ia, and we look forward to Phase Ib as the next step for that agent.

We have additional projects. You mentioned our pan-BRAF degrader, which is a new entrant into our pipeline for -- that can address basically any of the BRAF mutant resistant mutant clones. And then we have new agents within our I&I portfolio, which are undisclosed -- and then, of course, our DAC portfolio. So again, I see it as a holistic investment, including not only our wholly owned pipeline, but also these terrific co-co development options across 6 programs -- 7 programs total now. So thank you for your question.

Our next question comes from Terence Flynn from Morgan Stanley.

I guess I had 2. The first is just can you confirm if Roche is aligned with you on the accelerated approval path for Bexdeg in CLL? I assume so, given the prepared remarks, but just wanted to check that.

And then on the immunology side, very interesting to see more on the Phase II plans there. What do you think the earliest is we could see some initial proof-of-concept data from those 2 trials?

Sure. So thank you for your questions. So first, on the first point, yes, we are aligned with Roche on the accelerated approval pathway, that being the DAYBreak-201 study, CLL-201, which is underway. That is in a fourth-line patient population post pirtobrutinib patients. And then to your second point in terms of when we would first see data from these. So I think we need to go stepwise, which is, first, we're committed to initiating the trials.

So we're committed to an IND focused on CSU in the second half of this year. We are actively, as I mentioned, actively working with Roche on the design of that trial and implementation as well as for the MS trial. We've not specified a time frame for initiating that. But I would say that upon initiation and getting those trials underway, then we could make a better forecast with regard to data. So I'd like to defer that part of the answer. Thank you very much.

Our next question comes from Biren Amin from Piper Sandler.

Congratulations on the partnership this morning. Can you maybe just talk about your read-through on Roche's ability to take the fenebrutinib development playbook in CSU and MS and to kind of apply those learnings to the Bexdeg program? So that's the first question.

And then second question, Roche clearly has a significant diagnostics franchise and have novel tests for MRD that suggest higher sensitivity for MRD. Could you maybe talk about how you're planning to pair those diagnostic tests for the CLL and NHL development for Bexdeg?

Thanks, Biren. So yes, I think, first off, on your first part of the question, there's no doubt that Roche's expertise in CSU with their extensive Xolair franchise is really the market leader and their understanding of the underlying disease biology and their general experience overall in allergy and immunology is going to pay dividends for the setup of the Bexdeg Phase II trial in CSU.

So many of the learnings that they have, I'm sure, will be put into play here with this next step. And we've really valued our initial meetings and planning sessions with them on that topic. With regard to fenebrutinib in MS, there's no doubt that Roche has the most relevant recent experience completely in MS. And while inhibitors like fenebrutinib work by temporarily blocking the kinase activity of the BTK protein, I think the fact that bexobrutideg physically eliminates the BTK protein, removing both its kinase functions and scaffolding functions, these 2 distinct mechanisms of action against the same target will -- has a potential to really maximize the ability to address the complex neurologic indications like multiple sclerosis and may ultimately provide more diverse and optimized treatment options for patients with MS.

So there, again, I think -- and of course, it's not just fenebrutinib, but Ocrevus and their entire franchise is really so powerful here. Again, we're going to be in a very strong position to optimize that Phase II trial in MS, and we very much look forward to that. So I gave a little bit of a long-winded answer there. But the second part of your question again, could you remind me?

Yes. Second part of the question was around the diagnostic franchise that Roche has and specifically at AACR earlier this year, they unveiled a new novel MRD test that suggests higher sensitivity in testing. So ways of potentially deploying that into the Bexdeg CLL, NHL development plan?

Yes. So we've had some initial discussions on this biomarker topics in general and Roche's advanced technologies there and their experience base there, not only in CLL but also in MS. So yes, we're very much going to be engaged with them on bringing the absolute latest technology, diagnostic/experimental biomarker technologies into these trials. I think that's going to be a big advantage as well. Thank you for bringing that up. And thanks for your question.

Our next question comes from Roger Song from Jefferies.

This is Nabil on for Roger. Congratulations on all the updates on the partnership. I have 2 questions from us. So one on the -- just a little bit more if you could speak on the differentiation of Bexo in MS where we have seen inhibitors have liver liabilities. And then just that CNS penetration, if you could comment a little bit more on that? And then I had a follow-up.

Sure. So the advantages of Bexdeg in MS are based on some of our observations that we've already seen in the clinic in CLL and primary CNS lymphoma. So they're not just theoretical. So they are, number one, clear access to the brain with biologic activity that has translated to clinical responses for patients with really significant brain disease.

That's, I think, quite important. Then there are the -- also observations of how important both elimination of the kinase function and the scaffolding function are in the CLL setting. And we've demonstrated evidence that those same dual functions are important in autoimmune disease, and we would expect would read through to a potential efficacy advantage in diseases like MS and other autoimmune diseases.

So we're translating -- we expect to translate those advantages of total removal of the protein into potential superior efficacy results in autoimmune disease. The other aspect of this, which I think you alluded to with regard to safety is that on the liver enzyme front, we've seen no signs of liver toxicities in now over 300 patients with CLL or NHL. -- all of whom who have essentially received multiple therapies, including multiple chemotherapies and various prior sources of potential liver insult.

And yet we see a very safe liver safety profile. So we think that's extremely important. And part of that, we believe, may relate to the lower drug levels in the blood that a degrader can operate at. So far lower hundreds to thousands of fold lower blood levels achieving complete removal of the BTK protein. So the total drug burden in the system is lower -- and that may attribute to a much lower reduction of general off-target effects, which some of the inhibitors may suffer from. Of course, bexobrutideg is exquisitely selective in and of its own right via proteomics and all the optimization we've had. So...

I think we may have lost Arthur again. Can we go to the next question, please? You're back, Arthur.

Am I back? Okay. Well, I was finished with my answer anyway -- so next question and jump in, Jason, if I go off again.

Our next question comes from Derek Archila from Wells Fargo.

On the deal. Maybe just one on kind of housekeeping for Hans on the R&D spend. You're running around like $80 million to $90 million a quarter. I presume the majority of that was Bexdeg related. So just kind of any thoughts on go-forward spend now with this deal and kind of the offset now that Roche will be taking on some of the development costs. And then just turning back to some of the questions we already heard around the wholly owned pipeline. But I guess what do you kind of think is the next key updates for the wholly owned pipeline? And anything specific that you would point to over the next 12 to 18 months?

Great. Hans, do you want to...

Yes, I'll take the first half of that. Derek, we're not -- I'm not providing any updated financial guidance today. We'll provide updated financial information and guidance in our regular SEC filings and quarterly earnings communications. But needless to say, this transaction significantly strengthens our financial position and provide substantial resources to advance our strategic priorities.

So combined with the development cost sharing, we believe we're well positioned to execute on all of our planned clinical and research initiatives. Maybe turn that back to Arthur.

Yes. So yes, Derek. So in terms of future updates, so the future updates will continue to be centered on bexobrutideg. But I think also there are updates to be expected on the STAT6 program and IRAK4 program. These are all, of course, under partnerships. And with regard to wholly owned pipeline, then we would expect, I'd say, next updates on NX1607 and 2127 and our BRAF degrader and then any new disclosures around so far undisclosed targets within our pipeline. And I think some of those disclosures we've discussed potentially in the second half of this year, having those if we get -- if we're able to get scheduled a corporate update day, corporate research day, it would likely be in the fall and would cover a greater degree of information around the newer wholly owned programs.

Our next question comes from Stephen Willey from Stifel.

Congrats on the transaction. So I guess maybe just 2 quick questions. So curious if this transaction and the 40% commitment on global development spend now changes at all the decision-making process around some of the other -- the other opt-in decisions that you're presumably going to need to make here on some of these other partnered assets. So I guess that's kind of a bandwidth and resource question. And then just secondly, wondering if the agreement at all contemplates some freedom to operate around your ability to make future disclosures going forward? Or should we expect, I guess, the next 6 to 12 months of Bexdeg-related catalyst to now maybe look a little bit differently post this deal?

Thanks, Steve. So I'll take the first part of the question and then hand the second to Jason. So on the first part of your question with regard to our future options, which would encompass the IRAK4 program with Gilead and the STAT6 program with Sanofi. I do think that our financial resources are expanded at this point under this collaboration, this new collaboration we're announcing today and our financial commitments are bolstered then with our partner, Roche, that does create greater financial flexibility.

But I would say this, we're going to have updates, as I mentioned, in the second half, and we anticipate those around the STAT6 program first likely and then the IRAK4 program. STAT6 is clearly, I think, in terms of future option potential, our top priority program. I think for many reasons, IRAK4 would then be our next priority. So I think we'll just have to stay tuned and see how those evolve and what the exact timing of those options are likely to be. So again, I think I'd like to defer to the second half to give hopefully more clarity on updates on those programs.

And then to the second part, Jason, could you address that?

Yes, sure. So there are a couple of parts to that question. So first on the cadence of disclosures around Bexdeg. I don't think you should expect it to change. We're still on this sort of EHA, ASH, June and December disclosure timeline. In fact, as soon as we get off this call, many of us are getting on planes and going to Stockholm to present the latest Bexdeg data at EHA. That will include an update to both the Phase Ia and Ib, including in patients with earlier lines of therapy with very robust ORR. So that is a new disclosure, which will be happening on Sunday.

And in terms of our ability to provide future updates -- the collaboration has a joint governance, which really has us in a very good position in terms of our ability to continue to advance the program and to be able to continue to provide updates as necessary to investors. So I don't think you should expect any real change. In fact, you'll probably hear more about Bexdeg because now it will not just be us talking about it, but it will be Roche. And you saw this morning, they put out their own press release. I assume that at future medical meetings, this will be a program that's highlighted in their investor decks. And so we think actually the cadence and the volume of disclosure is going to increase as a result of this deal.

Our next question comes from Sudan Loganathan from Stephens.

Yes. Great. Congrats on the news here and great to see this collaboration come through. My first question is on the economics for the other indications outside of CLL. Do you anticipate them to be very similar with Roche? Or will there be on a case-by-case basis there? And then secondly, for John Northcott, just curious on what the commercial strategy is now for Bexdeg. Is it -- if there's been any changes yet or if there will be maybe as the conversations with Roche go on and the Bexdeg program advances?

Great. Jason, do you want to take the front part and then John?

Yes. So this is a Bexdeg deal. And so we are partnered globally across indications and the economics are fixed regardless of the indication. So we will be 50-50 cost profit sharing with Roche across indications as well as 40-60 development cost sharing across the indications. So there is no difference. John?

Great. Thank you, Jason. Yes. So once the deal closes, we will be forming a joint commercialization committee with Roche, where we'll be forming kind of our commercial strategy as well as our tactical and operating plans. This is going to be a wonderful opportunity. Roche will take the lead on the ex U.S., and we'll be working collaboratively here in the U.S. to execute the Bexdeg commercial strategy for the benefit of patients.

Our next question comes from Jeet Mukherjee with BTIG.

Congrats on the partnership. So Roche in their press release noted that they saw Bexdeg as a potential best-in-class BTK degrader. I was just curious if you had any perspective or insight from your discussions, what they saw about Bexdeg's profile that made it a best-in-class degrader in their view? And then as a separate question, with Bexdeg now partnered, does this change what you plan to do or what indications you may want to go forward with when it comes to Zelebrudomide?

Thank you. So for the first part, I mean, I might share the answer with Jason because Jason not only had orchestrated the deal process, but also the incredible diligence process associated with this deal. But I think -- so I'll answer at a high level, I believe that Roche having done their incredibly thorough homework, have seen the efficacy profile and safety profile combined based on all of the clinical data we have to date to define it as this potential best-in-class agent.

So efficacy and safety being, of course, the key parameters anyone would evaluate. And besides that general statement, again, the level of diligence done, what they've seen and they've seen just about everything anybody could see with regard to Bexdeg. But Jason, do you want to elaborate any on this?

Well, again, I think it's really just part of the shared vision that we have. We have been saying we believe we have best-in-class. We've brought some receipts as it relates to some of the preclinical data that supports that claim, not only differentiating us from the inhibitors, but also from other degraders. And like Arthur said, not only were they able to really do a deep dive and scrub our data internally, but we assume they've looked at others as well.

So very excited that they are adopting that position. And yes, and we agree. And then in terms of Zelebrudomide , this is -- this drug is not included in the deal. However, it would not be our intention to compete directly with bexobrutideg with that molecule. So any advancement of that would be in indications other than those where we are moving forward with bexobrutideg, which is our highest priority.

Our next question comes from Brian Skorney from Baird.

Congrats, Jason. This is really a great deal. I couldn't imagine a better partner in the B-cell landscape. You did spend a decent amount of time discussing the MS side of the story, and Roche has some interesting dynamics here, obviously, with the top MS selling drug right now and now submitted BTK in fenebrutinib. So I guess, just given kind of the developments in the class and the liabilities among the covalent, non-covalent inhibitors targeting MS, the companies believe this should be able to drive efficacy across the range of MS patients.

And I guess what I'm really getting at, it's kind of a weird question to have to answer. But what do the company see as the advantage of bexo and MS over your partner's own BTK inhibitor, which, as I said, is under review. And then I don't specifically remember collaborations like this triggering a Hart-Scott-Rodino review, but are there any concerns about the overlap between bexo and fenebrutinib in MS on an antitrust basis? Is there any clearance needed from FTC or DOJ here?

I'll take the first part of that question with regard to fenebrutinib. I think that -- I think Roche and Nurix, we both -- I think by -- we both see advancing both of these compounds. Obviously, they're fenebrutinib, a highly selective inhibitor, but advancing a highly selective inhibitor and a degrader really serves to broaden the Roche portfolio, I believe, from their perspective.

These are 2 distinct mechanisms of action against the same validated target. which will potentially maximize the ability to address very complex neurologic indications like MS, which have multiple stages as you intimated in multiple manifestations in patients. So ultimately, I think they'll have the best MS portfolio across the board, incorporating Ocrevus and potentially fenebrutinib and our drug. And I think it will be a very, very powerful portfolio.

The distinct advantages that degradation brings, I think I've already mentioned, i.e., removing the entire protein. I believe also the fundamentally different PK/PD with low drug levels achieving such great potential efficacy. So there are going to be some clear distinctions that bexobrutideg will have, but it will likely be part of a larger MS armamentarium that is out there.

But from our perspective, Nurix, we think it definitely has the potential to be even a best-in-disease in MS drug. And it's oral, certainly could offer efficacy across multiple stages of the MS disease. We have no reason to believe that it wouldn't. But this will all have to play out in the clinical development plan. So then the HSR question is not really in my league. Jason, any comments there?

Well, we don't want to speak for regulators, and this as all deals has to go through an HSR review, and our anticipation is that the deal will close in the third quarter.

Thanks again. Operator, I see we're at the top of the hour, which I think was one of our goals to be finished by then. So if there are no further questions, operator?

There are no further questions at this time.

Okay. Great. All right. Well, I'd like to thank everyone for their participation. It's a great day for both Roche and Nurix, and we look forward to giving you future updates. Thank you very much.

Bye-bye.

This concludes today's conference call. Thank you for attending.

Welcome, everyone, to Jefferies 2026 Global Healthcare Conference. My name is Roger Song, senior analyst covering SMid-cap biotech. And it's my pleasure to have my next fireside chat with Nurix Therapeutics. We have CEO, Arthur Sands. Welcome, Arthur.

Thank you. Great to be here, Roger.

Awesome. All right. So Nurix is a very exciting time point. You're in the pivotal for your lead program and then also you have a platform supporting a lot of the early pipeline development well across the Oncology and I&I space. Maybe, Arthur, give us the latest about Nurix and then we can dive into the conversation.

Yes. Well, the latest is we're coming upon EHA, European Hematology Association conference essentially next week in Stockholm, we'll have an oral presentation there. It will be a significant, I think, update on bexobrutideg, our lead BTK degrader program in CLL. So in that presentation, -- and the abstracts have been published there, but in the presentation, we'll be giving updates on some of the latest cohorts of patients, new data related to earlier lines of therapy in CLL. So we have some treatment-naive patients who will then -- are now treated with bexobrutideg as their first treatment for CLL. Also patients who have not received a BTK-targeted agent at all yet, so BTK inhibitor-naive, and then they'll be getting our degrader as the first BTK therapy.

And then also patients who have not received a BCL-2 inhibitor, venetoclax, for example, yet. And so these are early stage. Those would be second-line types of patients. So these cohorts of patients will be describing, so that's going to be a significant events for us. Of course, we have a lot of European investigators we're meeting with in Stockholm as well. And so that's coming up. I think that also people have been very interested in the progress on our other fronts in I&I, namely the status of our STAT6 degrader, which is partnered with Sanofi. I'm sure you'll have some questions about that. And also our IRAK4 degrader, which is partnered with Gilead. These are all partnerships where we maintain a 50-50 opt-in structure as well.

So those are progressing. And then bexobrutideg itself, we're very interested in advancing that into autoimmune indications as well. And so that will be a second half sort of events for us.

Excellent. All right. Maybe we can spend a few minutes on the CLL, the lead program for now. I think it's interesting you will start to report some earlier line of the result without -- even without the BCL-2. So I understand you are also trying to do the combination approach to moving to the earlier line. And then where are they in the combo? And then with this, I believe it's the mono data, how this profile will support the combo and then when we're going to start to see the data?

Yes. So we're intending to start our first combination trial, Phase Ib/II program with bexobrutideg in combination with a number of agents. So venetoclax, the BCL-2 inhibitor was one of the primary combinable drugs, and that is -- would enable a frontline approach as well. What's exciting there is that people -- this would be the first degrader combined -- BTK degrader combined with venetoclax in the clinic. And investigators and I think patients are very interested in the potential for fixed duration therapy. So therapies that would last a year or 2 years, likely 2 years on the combination regimen and then have basically drug holiday or no drug period. So that's one potential.

In addition, anti-CD20 antibodies are of high interest in combination. So RITUXAN being a mainstay, of course, but then obinutuzumab as well. And then there's multiple other combination potentials built into that protocol. It's a Phase Ib/II protocol. So that's poised to start midyear. Of course, data would then take a year or more after that. So that is -- that's sort of next step for a trial start. But at the same time, we're starting our big Phase III program in CLL monotherapy. So that's in second line. So these are patients that have received a BTK covalent inhibitor, but have progressed. And so that trial will be starting midyear as well. That's about a 600-patient trial and is -- will be in over 20 countries.

So we're very busy in terms of trial initiations and trial execution. You mentioned the pivotal trial is running. That's a Phase II trial, about 100 patients. That's in a later-line CLL patient population. So yes, all of that is moving forward. So very busy midyear for us.

Excellent. As you mentioned, you are doing the mono pivotal as third-plus line triple exposed, I believe that's the population you are doing initially. And then we also know another BTK degrader is running a slightly different setting, but also later line. They may have data earlier, than you will have data next year. So when we see the data, what you are looking for in terms of the ORR, PFS, maybe some of the safety signal, tolerability dose? So what will be considered as a good scenario for Nurix to be able to maybe even benchmarking and then also the beating there.

So you're talking about in the later line patients, so these are third line, fourth line. We've had 6 lines -- patients with 6 lines of prior therapy, actually up to 10 lines. And so what we've seen so far in those patients is around 70% to 80% response rate. The response rates do go down the later lines of therapy that patients have had. So -- but I think if you look at fourth-line plus in general, anything between 50% to 60%, 65% is an excellent overall response rate in those really late-line patients. Now you contrast that with some of the early line patients, we're seeing 85% or greater response rates with the BTK degrader. And I think that's -- those are quite strong.

But as you go across the lines of therapy, obviously, we want to position bexobrutideg to be able to serve patients at every line of therapy, wherever they are in their CLL journey. And then also NHL, we're also interested in expanding in NHL indications as well. So yes, those are the data to sort of look for.

And also compare and contrast other BTK degrader, they're also in the pivotal right now. And then how do you think Bex can differentiate in the later line STAR and then early line probably a bit too early to compare.

Well, our goal is to be best-in-class in the degrader class. There really are only 2 degraders really that are up front and center now in drug development. We think we have the highest selectivity profile. We certainly have the highest potency compared to any other degrader molecule. And that should translate into higher efficacy and better safety. I mean that's really the profile we're looking for. And that's so far what we've seen play out. We've now been in over 150 CLL patients at various lines of therapy, as we discussed. And the profile is remarkably consistent, high ORR, excellent safety profile, relatively low infection risk compared to other agents, no major bleeding risk, which is also a distinguishing feature compared to BTK inhibitors. We have a very -- we have an excellent liver safety profile. We've not seen any elevation of liver enzymes. That's also been a bit of a hex on the BTK inhibitor class in general.

So I think the degrader class and specifically bexobrutideg has great potential to be this best-in-class profile. A lot of mechanistic reasons for that, Roger, some of which I'll just mention. I know you know them, but the catalytic nature of degradation. So one drug molecule of bexobrutideg, I'll call it bexdeg for short, can degrade 10,000 BTK proteins per hour in the cell. So one drug molecule removing 10,000 drug-target proteins per hour. This is fundamentally different PK/PD compared to inhibitors where it's 1:1. You need one drug molecule for every BTK protein. So you really have to swamp the system with drug, and that's how inhibitors work. But degraders work catalytically because they harness this incredible -- incredibly efficient proteasomal machinery in the cell. That's how we work.

So we're fundamentally different. We think we're going to have a fundamentally better safety profile. And the big picture is we're talking about BTK, but this technology has the potential to replace many inhibitors because of these attributes. So...

Yes. Yes, makes sense. And then one of the other discussion I've been having with investors and then also with you is the sequence of use all kinds of different BTK. We have a covalent, we have non-covalent and then now we're about to have a degrader coming to the line. So what's the biological or clinical rationale to use which modality first at the first line, maybe second line and then save to the later line, which makes the most sense?

Well, the clinical rationale is that the better result -- initial result a patient gets from a drug, the better their prognosis is overall. So there's a strong rationale in cancer therapy in general to start with the best regimen, start with the best drug, get the best result, the deepest response, the longest lasting response that you can get in your initial treatment, you will live longer than your progression-free survival, overall survival is all improved. So that's the clinical rationale to start with the best agent up front.

And that's what we've seen going on in CLL. There -- this whole targeted therapy started with ibrutinib, which was a very great advance, but then has been displaced by acalabrutinib and zanubrutinib, better safety profile, better adherence to the drug regimen and better prognosis. So those agents have become frontline. We think that can happen with degraders. Degrader is clearly superior in terms of hitting the target, and we think going to be superior in terms of efficacy and ultimately safety because of some of the reasons I mentioned already. So if you have the best result upfront, the patient will do better and live a longer, healthier life. So that's the rationale to start with your best foot forward and the degrader would be the best foot forward, I think, in the future for BTK-targeted therapy.

Yes, it's a cancer patient, right? Best foot forward is probably a lot of the logical choice. The only thing is people thinking about degrader is powerful, right? When you knock down the entire protein, would you develop some resistant mutation maybe no other therapy can address versus covalent -- non-covalent can address the covalent mutation and then non-covalent mutation can be addressed by the degrader. So that's the sequencing potential logic as well. So how do you respond to that?

Well, what we know so far is that the BTK inhibitors basically select for resistance mutations that are coming up in now over 50% of patients. Once you have a resistance mutation, you then have to try to overcome it with another therapy, either combination or in the case of degraders, we can overcome all of those resistance mutations. So that sounds like a logic to start with an inhibitor and then you have a degrader in the second line. But why ever develop the resistance mutations in the first place if you don't need to and so that is why you should start with the best drug upfront that doesn't even allow for resistance or at least has -- is harder to become resistant to is what we're seeing in the clinic. So the degrader is harder to get around.

Now cancer can always get around drugs. And so there will be resistance mutations that will occur. But you want that to be a low-frequency event, right? And that's why a degrader would be superior. Now in terms of what are the mechanisms of resistance to degraders? Well, there's one mutation that's been identified it happens to be also a mutation that inhibitors don't work on. And that is the A42AD mutation. So basically, none of the BTK targeted agents work against that. It's a very rare mutation. Fortunately, it is also what's called an unfit mutation. The cells actually don't even grow very well because the BTK is such -- so mutated, it does not work well. And by the way, it responds to combination agents very easily.

So that mutation is not really a big threat. So anyway, I hope I've answered the sort of the rationale to start with the best drug upfront. We think that's going to be a degrader eventually.

Yes. And then you do have a solution at the combination called beyond the BTK if you develop something not necessarily addressed by the BTK approach, right?

Yes. I think with venetoclax and a BTK degrader, you're basically going to take out anything. So yes, and we're focused on BTK, but there are a lot of other mutations that take place in these patients, unfortunately, p53 and other really bad-actor mutations. So those all need to be dealt with as well. So combination -- that's why combination agents will be necessary.

Yes. I think Nurix is well capitalized to run the ongoing Phase II as the monotherapy and then also fund the Phase III for the mono or mono in the second plus line. How do you think about the earlier line strategy at the corporate level, you want to do this stand-alone or you think it's better to find a partnership?

I think the frontline strategy, partnership makes a lot of sense. Number one, you're going to be combining with an agent. Again, our lead choice would be venetoclax. These are agents that are expensive to run in combination trials. So great to have a clinical trial partner of some type. There's also all the antibody agents, bispecifics. There's a lot of combinations that almost becomes kind of an endless opportunity. And to do that solo is challenging.

So yes, we do favor partnership model in general. We've done several very successful partnerships with Sanofi, Gilead, Pfizer currently, all of them involve options for Nurix to go 50-50 in the United States and co-co. So we'd like those kind of structures. But there's a lot of opportunity for partnership in the CLL space. And that's not even to bring up yet the autoimmune area where that's another huge market opportunity.

Yes. We'll talk about the I&I. So before that is, I think you've been running the trial in NHL for a while, and then we haven't seen much data from there. So -- but you plan to release some data this year? And how should we -- what should we kind of expect from the NHL cohort?

Yes. So our data release periodicity tends to be every 6 months, so EHA and ASH. We are talking about potentially NHL cohort data at ASH. We haven't settled on what we'll submit, but we have seen some really dramatic responses in every category of NHL. We've seen some complete responses in every category. We've included patients with primary CNS lymphoma. We're talking about DLBCL and MCL, marginal cell lymphoma and Waldenström's, where we have shown some data. There, again, seeing this 85% response rate. So yes, I do think NHL will be an area for us in the future to have more disclosure, more publication. It's also another area for combination therapies, too.

Yes. Okay. Good. I&I is a very interesting thought thinking about the degrader approach because the scaffold function, et cetera. So I think recently, CSU, some of the early data by other degrader and then you're also thinking about developing into different indications. And then right now, what's the thought about the indication selection? What's the area you want to go first and then proof of concept for the degrader?

Yes. So I think that the advantage of a degrader in I&I is actually somewhat similar to what we've seen in Oncology. And you hit on it, which is that we're addressing both the kinase function of BTK in this case, but also the scaffolding function or the structural signaling function. So there's another whole signaling pathway going on with BTK that kinase inhibitors don't touch, and that's operating in autoimmune disease also. And so we're excited by what we can do there from a theoretical standpoint. And so what we've done so far is conduct a very significant healthy volunteer study with our new formulation designed for autoimmune disease.

And we did have a little bit of data come out at our -- at an oral presentation in Chicago at the dermatologic meeting recently, where we show complete degradation of BTK in the skin of healthy volunteers at low doses, and this is once-a-day dosing. So I think we'd like to see the rest of the data from our healthy volunteer data set. And then our goal is to file an IND in the second half of this year. I think CSU is a very logical place to start. It has proven successful for Novartis with remibrutinib, data look quite good. And I think the uptake has been very positive for that drug. That's a twice-a-day drug, I think, and also an inhibitor class drug. So again, we think we can improve on that.

Yes. Awesome. So it seems that skin makes a lot of sense. And any other therapeutic area for I&I potential?

Well, the other one that we're very interested in is multiple sclerosis, so MS. We have activity in the brain. We know this from our patients with CLL and primary CNS lymphoma who have responded to Bexdeg quite well, which is quite remarkable. And we know our CSF levels are basically equivalent to our serum levels. And so we know the drug has brain activity. We know we can hit BTK in the resident microglia cells, which is really where the next, I think, frontier for getting really great responses in MS are is to hit the microglia. And we've seen some preliminary positive results, not so preliminary actually Phase III results from fenebrutinib with Roche, which look quite encouraging. So I think MS is another area for Nurix to consider.

Got it. And then you did mention earlier line of CLL makes a lot of sense for partnership. And then also I&I is a big area if you want to pursue multiple indications later on the NHL. So how do you think about those different therapeutic area for Bexdeg in terms of the overall corporate strategy for the partnership?

So we see this Bexdeg as a foundational therapy. So I think it could have the potential to be like an anti-CD20, like a RITUXAN, lots of applications. Now with the degrader capability, one can actually take advantage. It's more versatile than an antibody, right? I mean, so we've developed different formulations, different doses. Really, we'll have different products that actually are developed ultimately across not only CLL and NHL, but also the autoimmune indications. So in terms of corporate strategy, then it really lends itself to partnership as well.

But it would have to be a very unique partnership really that has the vision of this broad vision for Bexdeg being a foundational therapy across indications. So multi-indication drug development program with a global partner that has the kind of capabilities that would be required. That's sort of the corporate strategy standpoint. But we're well positioned to move this forward ourselves. We're well funded, as you said, we have a great investor base. We're moving forward into Phase III, full on with CLL. And I think we can definitely initiate the I&I platform as well. So we're in a great position.

Yes. So as you said, you also have a tablet formulation maybe better for the I&I already. So it's a different product. But overall, it's a degrader, but you can have a different presentation for the pipeline.

Yes. So we have the tablet formulation. It's new. This has been now in over 200 healthy volunteers as we've developed it ready for the autoimmune indications. So it will definitely be different presentation, different doses, and it's well positioned for that. The CLL current tablet capsule formulation is moving forward, of course, into Phase III. So that's all good. We have the manufacturing all down. We're really in good shape there. So this is -- it's all kind of a green light for us right now.

Awesome. All right. Maybe last couple of minutes, talk about the partnership with Sanofi and Gilead. STAT6 got a lot of the airtime within the I&I space. So I know preclinically, you show comparable, if not better than the current degrader. And then what should we expect to see? And then the more interesting thing, you do have the opt-in option and then potential co-co decision later. So what will make you to make that decision opt-in? And then if you make that decision, how are you going to fund those program if you move forward?

Right. So STAT6 is a transcription factor. It's a very exciting transcription factor. Clearly is a small molecule target basically competitive with DUPIXENT is the ultimate goal there. So it's a very large opportunity in autoimmune disease. We have been developing a degrader to STAT6 with Sanofi since 2019. So this is quite a mature project. This is something that scientific teams have been working on together for many years. Sanofi exercised their option to take that forward into clinical development about a little over a year ago. They initiated the IND-enabling studies, which should be coming to completion this year. And then if on schedule, should start Phase I. And Sanofi is responsible for that clinical development period up through human proof of concept, at which point Nurix has this opt-in that you referred to.

So we could opt in 50-50 in a co-co in the United States. And this is a high-priority project for us. So I mean, this would clearly be something that we would be very interested in exercising our option on. So that program is, I think, a high visibility program. And the next steps would be in Sanofi's court in order to move this program forward.

Okay. Similar thing for IRAK. I think IRAK is a little bit ahead of time, ahead of STAT6 and we may have some data this year. Is that still the expectation?

IRAK4 should -- degrader should be completing Phase I this year. And that is a similar structure as the Sanofi deal, but with Gilead. Gilead then will control the disclosures around that and the next steps. It's a great program. I think it's probably now the leading IRAK4 degrader program. A number -- a couple of others have fallen away. So we're out in front with this degrader program. I think we've got a great partner. And yes, hopefully, they'll disclose data this year, and we'll see that march into Phase II at some point.

Awesome. Alright. Okay. Just the last minute or 2. Anything else from the pipeline? We do have the IO program and then maybe some of the other earlier you want to tell people.

Yes. So NX-1607, our immuno-oncology program is an inhibitor of CBL-B ligase that could be transitioning into Phase Ib in the second half. So I think we'll get the data and make some decisions there. And then new programs. So we do have new programs in our pipeline. We haven't disclosed anything yet. Hopefully, in the second half, we'll be able to do something in that regard. And then also the DAC program with Seagen and Pfizer. This is a degrader antibody conjugate program where these payloads that we engineer teaming up with a great ADC team in Seattle to create the degrader antibody conjugates or DAC.

So that's another whole area. That's actually progressed quite well. I think we're the leaders there between Pfizer and Nurix teaming up together. I think some others are really going to try to move into that space. I do think it's the next generation of ADCs because you're bringing this incredibly powerful targeted payload into the tumor cell, and you don't have the toxicities of the toxin payloads. So this is a very exciting area. Some of the results there look quite good with our partner. And I hope to be able to share information with that -- with you in the future.

Excellent. Okay. Thank you, Arthur. Thank you, everyone.

Thank you.

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 bexobrutideg 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 bexobrutideg or Bexdeg for short, formerly NX-5948. 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 pirto, 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 pirto 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 bexobrutideg 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.

My name is Gil, and I'm a senior biotech analyst here at Needham & Company. It is my pleasure to have with me today Dr. Arthur Sands, who's President and CEO of Nurix. And as a reminder, viewers are watching and submit questions through the Ask-a-Question box. So Arthur, a little belated, but some introductory comments and maybe a quick word on the company's platform release.

Sure. So we're very excited to be entering Phase III this year for -- with our new -- our lead agent, bexobrutideg, which is a BTK degrader being developed for CLL. In addition, we do have ambitions for its use in I&I disease, and I'm sure we'll talk a little bit about that, so in autoimmune indications.

But all of the Bexdeg's success through the development so far really relates to our, I think, incredible drug discovery platform in which we have identified a whole host of novel degrader -- targeted protein degrader molecules against not only oncology targets, but also autoimmune targets, including STAT6 with our partnership with Gilead and IRAK4. I mean, STAT6, sorry, with Sanofi -- and then IRAK4 with Gilead, which are -- which is in the clinic now and STAT6 soon to be.

So we have a whole pipeline to discuss Gil. I know you're really familiar with our story overall. We're headquartered in the Bay Area, approximately 350 employees. And again, very exciting year to enter pivotal trials, registrational trials.

So maybe a good place to start is Bexdeg in CLL. Just a quick reminder for people kind of how the data looks like.

Yes. So we've reported at ASH most recently, an 83% overall response rate in fourth-line plus patients, so very advanced patients with CLL. So a very significant ORR. We also have some of the first PFS measures, progression-free survival measures that we've disclosed. Now at 22 months for our most advanced cohort of patients from the Phase Ia, which compares very favorably with competing agents, again, in very advanced patients.

So we're very excited to initiate, as I said, the registrational trials. We're already running a potential accelerated approval trial, which is a potential pivotal trial Phase II in these advanced patients, a very similar patient population to what we treated so far. So that's just highlights of the data. Of course, we get complete BTK degradation. We have great biomarkers that also all are moving in the right direction. And we can talk about other aspects of the data as you wish.

Have physicians shared any like initial thoughts? I mean, you already have a pretty decent data set. How has this been accepted by physicians?

Well, the best evidence for that is the rapid opening of our sites for these trials for these registrational trials, lots of interest. I think that's going to go quickly through the initiation phase for the Phase III. And then I would anticipate enrollment will go rapidly as well because the results are positive.

Of course, physicians prefer to put their patients on a drug that has a great probability of working. So I'd say, very, very well accepted. I think the degradation mechanism of action is being increasingly accepted and well recognized. That's been a very interesting process of education now for the past several years. And there, it's clear that degradation allows for addressing the resistance mutations to inhibitors. And so that's a very compelling molecular story that we've been able to show because, of course, we can catalog all the resistance mutations that our patients have that have been on these inhibitors and then show that these patients are responding.

So that's been -- that's really connected with investigators. And I think the other attributes of the drug, its long durability and now that we're getting the PFS data, durability of response is also connecting quite strongly with investigators and of course, with patients. We've had patients now on over 3 years on bexobrutideg.

Are you guys seeing any challenges or competition for the patients while you're enrolling these studies? I mean you kind of alluded to it sounds like you have a good selling point.

Yes. Well, it's a competitive area of CLL. There's lots of trials going on. There's lots of combination trials. We're 1 of 2 degrader mechanisms, so BeOne being the other company. There's some competition there, but that's not a lot of competition to be 1 of 2.

And we're in a good company. BeOne is certainly a leader in the field. And so I think that has lent a lot of credibility to the Nurix program, the BTK degradation concept in general. Of course, we think bexobrutideg is going to distinguish itself as a best-in-class degrader overall. But so far, the competition has not really been an issue because, again, we're very unique in our MOA.

Super helpful. So I do want to spend a second on the confirmatory study, which is also planned in the near term. You guys changed a little bit the way that you designed it. It was best available therapy. Now it's against pirto. Can you walk us a bit through the considerations there?

Well, so first off, pirto only recently gained full approval. So in terms of going against the comparator arm, it is generally best to go against something that is approved fully. So that gives you the broadest base worldwide.

And so with that and plus looking at our own data as it matured, that we became very convinced that we have a potential superior activity to pirtobrutinib as our data matured. We didn't really have our PFS data until late last year. So you really have to look at the data to be able to even predict the scale of your trial, power it appropriately, all of those things.

Suddenly, we could do that when we had all the data. It coincided with pirto's full approval. And so it was logical to then just upgrade the trial to really go against the latest approved agents, which we think we can beat.

I mean it also helps that it is aligned with your competitor as well, apples-to-apples, it's kind of thing.

Yes. So it's apples-to-apples, certainly. We're going to go toe to toe. I'm sure we can talk about differentiation later. But I think it's important. And also, things are competitive, as you mentioned earlier.

So you really have to design a competitive attractive trial where the control arm is the most recently approved agent. Your trial is relevant and will be relevant 3 years from now as well. So a lot of things go into the trial design, obviously.

Just as a clarification, are there any issues with this ex U.S. specifically?

I'm sorry, could you repeat that?

Ex U.S.?

Any issues ex U.S. No, we don't see any. It's been a very popular agent. So there's a lot of -- I think it's going to be attractive. We do have to make sure it's available in all of these different countries since it is recently approved. So there's a few logistical things. But I mean, this is going to be mainly a U.S. and European trial, right? These are -- and pirto is going to have wide distribution availability there, too.

All right. Let's spend some time on the competition. Maybe starting with how you guys view yourselves as differentiated from BeOne.

Well, we've shown some of the data of how we're differentiated at a preclinical level where we can actually compare compounds head-to-head in human cells, B cells, et cetera. And there, we are tenfold more potent on a cellular basis when looking head-to-head.

We're also -- we also see greater selectivity. We've measured off-targets very carefully through global proteomics. And the only thing we hit is BTK. And with the BeOne compound, we see many off-targets lighting up on the proteomic scan, indicating that they are hitting those in some way.

So I think that in addition to potency, which generally translates to efficacy, I think we're more selective. So we've got -- which translates generally to safety, I mean, just speaking in broad terms. So I think that, that will -- will ultimately be lend itself to a best-in-class profile.

It's a very important point, I think, worth emphasizing just considering how long patients stay on inhibitors of BTK as it relates to any safety differential would eventually show up if you wait long enough.

That's a major consideration. That is certainly true. And then also, of course, it increases the longevity of the drug in general, drug use in general, which, of course, translates to sales, et cetera.

But then there's another dimension, Gil, which is it also affects dose. So the safer you are, the higher you can dose. And we're dosing at our maximum dose tested at 600 milligrams, which we went through the randomization cohorts under Project Optimus of the FDA and submitted and they agreed with us that 600 was a safe dose to go forward to. Optimus is all about safety, really for targeted therapies. And so that gives us more coverage of mutations in our view, too.

So that -- all kinds of mutations, not just BTK mutations, but certainly all BTK mutations. So I think it can -- safety can also affect efficacy because you can not only dose for longer periods of time chronically, as you pointed out, but also you can dose at a higher level to cover bulky disease, genomic disease of all kinds in these patients. It's really important. It all translates to efficacy in the end, superior efficacy in the end.

And another important point, is this a winner takes all kind of market? Is this a market where you feel more than one competitor can live side by side?

It tends to be a side-by-side market unless there's a distinct advantage usually around safety, as you point out, because of the chronic use. And that's why you see zanubrutinib and acalabrutinib doing quite well. There's probably room for pirtobrutinib. This market is growing, forecast to grow to, I think, $12 billion a year or more in the next couple of years. So I think there's room. But again, if you do get an edge somehow, either safety being the most likely, then you can really become just the primary winner actually.

Okay. I do want to spend some time also on earlier lines. That's a larger portion. You guys are doing several forays here, combinations, et cetera. Just given length of therapy on earlier lines, is it feasible for you guys to like continue development in that setting?

It is. I mean you have to be very smart about how you design the trial so that you have endpoints that are reachable in our lifetime, right? I mean, which is our goal. We don't want to be waiting forever for results. So we're looking at these different approaches very carefully, trial design, et cetera. I'm not really prepared to talk about a second line or a frontline combo trial yet. Of course, the pirto head-to-head is a second line.

And -- but there, these patients advance more rapidly, unfortunately. So the time frames are reasonable. In frontline, whether it be combo or mono, you really -- we really have not outlined that design yet, but we're going to work very hard to make it a smart design so we get meaningful readouts in a meaningful period of time.

Any thoughts about another selective study, let's say, CNS involvement? You guys do penetrate the blood-brain barrier.

So we do have a cohort open for patients with CNS disease. And I do think eventually, one way or another, that should make it onto our label, although we'd have to see exactly how that happens. It is such a unique and relatively rare set of patients, but it's medically important for patients that don't have CNS disease also because what it means is you're providing coverage of the brain so that the brain does not become a sanctuary organ where -- which is what happens with chronic therapy, you can actually get them the cells eventually are selected for that are in the brain.

So you don't want -- obviously, nobody wants that to happen. So I think it becomes a medically important distinguishing feature, and we've had some dramatic results with patients -- for patients who had terrible CNS disease actually coming into the trial because we uniquely enrolled, allowed enrollment of those patients. So we'll have to figure out the regulatory approach there, but I do think medically, it's very, very important and will be another differentiator.

Let's shift gears a little bit to autoimmune with [indiscernible] A little bit on the change of formulation here. Kind of what is the logic? I mean, tablets versus the oncology formulation?

So the logic is several fold. So first off, when you have a new agent and you generally go in with one of the more straightforward formulations to manufacture to get into the clinic and look for results, which is what we did with our crystalline formulation. And it's had great results and been very rapid in terms of development and manufacturing.

And then with the new MOA, typically, one will look for better formulations to improve the pill burden, improve absorption, perhaps improve other -- certain other parameters. And these degrader molecules are actually rather large small molecules. So they do tend to have poor absorption, okay?

So let me illustrate for this. So we're dosing at 600 milligrams, but we're -- our blood levels that we achieve, but we're far more potent than the inhibitors. You measure the inhibitors. So why is our dose 600 milligrams if we're 10 to 100x or 1,000x more potent?

Well, not the absorption is fairly poor. So you have a good window to improve upon by working on other oral formulations, and you could get a lot more drug in, perhaps enhance efficacy as well and other attributes. The blood levels of our drug, just to compare it to pirtobrutinib, for example, to illustrate what I'm talking about, our therapeutic blood levels are approximately 2,000-fold lower than pirtobrutinib's therapeutic blood levels.

So that just shows you how dramatically different these MOAs are. So you don't need much drug to get in. And the more efficient you make that, probably the better results you're going to get overall. That's sort of on the PK/PD side.

Then on the commercial side, it does allow you to brand a different drug and very different doses are going to be needed and very different safety profiles will be generated. So with a different agent that is a branded different agent ultimately, you can distinguish all of those features. And in autoimmune disease, there are so many different ways we can go.

You guys did guide for some data later this year, especially from -- specifically from the study. Any expectations that we should have here?

So we've been talking about the healthy volunteer studies of the new formulation, which will help describe where we're going in autoimmune disease. So they'll be very relevant in many levels to the study design, to the indication choice and the data themselves, I think, will be important in these regards, even though it's healthy volunteers.

So there's so many biomarkers we can study with this approach that it becomes very graphic in terms of how you would align to the existing agents, so of inhibitors. So we have such biomarkers given degradation mechanism, we can really align our dose and align where we think we'll be efficacy-wise even based on healthy volunteer studies. So we'll do the best we can with that.

And last but not least, right, what kind of indications should we be thinking of? You have mentioned this in the past, just for reiteration.

Well, there's so many choices. I see them in certain buckets, and you want to consider the risk benefit, the pricing, the precedents, other drugs, competing drugs. But roughly, they can be grouped into dermatologic as one bucket, neurologic, like such as MS and then hematologic, there's the heme -- nonmalignant heme autoimmune ITP, WAIHA, those sorts of things.

In the dermatologic, there's a few categories. But in general, they're allergic based or severe allergy based, which could also include when you talk about allergy, then food allergy comes into potential play. So there's a number of areas we could go in. And each one, of course, is very different. We'll have different dosing and has different timetables for drug development.

So one of our goals would be do something where we can get results fairly quickly compared to other indications. But then the other, when you look at something like MS, which takes longer, that's so valuable and so unique, and we already know we have activity in the brain, that's also very attractive. I'm not answering yet because...

I'm not answering yet.

That's for the second half and show you the data that goes with it.

I do want to spend some time on STAT6, specifically because this is something you get asked a lot about. You have your partnership with Sanofi. Anything you can say about your progress there to date?

Well, it's been quite a great drug discovery road with Sanofi. We started the program in 2019 when it was just considered an undruggable target as part of our original Sanofi drug discovery alliance. And that target and then development candidate was selected just over a year ago.

So that triggered the IND-enabling studies by any calendar, typical calendar of drug development preclinical. And so we should be on the threshold of entering the clinic with Sanofi. Now it is up to them. They take control at development candidate stage. They control timing. They control news flow.

And of course, they're funding the whole thing at this point. And then after human proof of concept in the clinic, we then have our 50-50 opt-in option, 50-50 in the United States for a co-co. So that would be a time period that I think would be very exciting. But in the meantime, really, it's a Sanofi program. I can't think of anyone better to develop this. Of course, they have DUPIXENT and they have strategic interest in this area, other strategic interest. So I think this is going to be a very interesting program to watch this year.

So speaking of competition there, I mean, how do you feel this space has changed with the data disclosures from Kymera?

Well, it's gotten even more valuable. I think that their data is excellent. And I think that it shows that I do personally believe an oral will open up the market, as they have said quite a bit. So I think there's a lot of room for more than one agent.

So it's going to be bigger than the DUPIXENT market. So that I think it'd be quite substantial. And what else? I mean, it's not a lot to differentiate on so far. We get that question a lot ourselves, how are you different?

So I think that all I can say is that we optimize this with Sanofi kind of in lockstep with their standards. I believe that we've got a highly efficacious agent and exquisitely selective. So I think that we'll just have to see, ultimately, efficacy and safety, the whole name of the game.

But now with atopic dermatitis, I mean, safety is even more important, right, even way more important than even CLL, right? So I think what people are going to watch next in small molecule development in this area is going to be safety. I think you're going to see efficacy, but then how safe is it? Because DUPIXENT is very safe. I mean these biologics are very safe. So your small molecule has got to be absolutely clean as a whistle.

I do want to spend also a second on IRAK4. Let's not forget that's a program you guys are also running and actually may have nearer-term information. Any guidance there?

So it should -- on its schedule with Gilead, of course, it's similar structure to Sanofi. So they're running the Phase Is. And hopefully, we should see Phase I data this year. They've been in healthy volunteers I think, for over a year. So that should be important, and then we'll see where it's going to go from there.

So I think that's another great example of building a molecule that's exquisitely selective and safe and also shows efficacy. I mean it's not lost on anybody that the first IRAK4 degrader fell out of bed because of safety going into autoimmune disease. So this just illustrates that you really got to emphasize selectivity with these kinds of indications.

Not forgetting 2127, where -- what's the status here? How you guys view this program at this point? I know we're waiting on some non-Hodgkin's lymphoma updates.

Yes. So we've been -- that's been walking through Phase Ia dose escalation with the chirally controlled compound. So hopefully, we'll have data in the second half for 2127. Don't forget 1607 either, that's also...

That's next on my list.

Next on your list. Yes, we've had a couple of programs that have, shall we say, taken their time in Phase Ia because of dosing and figuring out just about every detail one possibly can and a few twists and turns. But now I think with 1607, we're at the stage of really getting to Phase Ib. I think 1607 is ahead of 2127 in that decision-making tree. And so I think I hope also in the second half to have updates on 1607.

Okay. I mean, yes, there were some challenges around formulating the correct dosing, but it seems you have worked through those.

I think we've overcome them. There was some simple actually GI tolerability challenges. It was -- in terms of once we learn how to dose and navigate that patients tolerate out that, that seems to disappear in a large fraction of patients, but you have to give their bodies a chance to adjust to the dosing regimen.

And it is definitely turning on the immune system. So I mean, we've shown -- we published that. We see the biomarkers moving in the right direction. We see some early signals of activity, which are really intriguing as a monotherapy. And so we're poised to be very excited about that program. We just have to get to the end of this Ia journey.

I mean maybe at the risk of sounding silly, but that one is -- that one always felt like the combination story is probably where it's at in the sense that it's immunological activation, you usually need more [indiscernible] than that.

Yes. So definitely, we set a high bar. We want to see some monotherapy activity. I think that, that -- then you have at least a much better chance of seeing the combo. I think some other agents went in with basically no monotherapy signal. And then there's going to be a miracle, a combo miracle and then it's going to work. And I don't think that, that's really the way it goes.

So I think that 1607 is a strong agent. I do think we're going to see -- you're not going to take it forward as a monotherapy is your point, ultimately. But you want to see some signal that is believable.

Yes. No, I agree. 100% agree. Right. Not giving short shift to the rest of the platform, you guys are going to have quite a lot of presentations at AACR. Any one of these you'd like to highlight?

I think there are 4 of them. So I'm not going to show any bias because I love them all, like my children. Then -- but in terms of where the next big wave of technology platform productivity is the DACs, the degrader-antibody conjugates. I think that's a really exciting area. We have not published a lot since signing up with Seagen, now Pfizer, of course. But that's an area that I would watch just as a technology itself, not only Nurix programs, but others.

Right. Little [indiscernible] cash position and kind of operational runway.

Yes. I think our last disclosure what, $650 million in cash. You probably -- I have to admit, I don't memorize every number, but that's approximately it, about 2 years of runway into 2027, so toward the second half.

So I think we're in good shape cash-wise. We're certainly well funded to get the Phase IIIs running. And I think it's going to be an exciting second half. I mean we've really had our nose to the grindstone for the first half, I have to say, we've been a little bit quiet, but we've been working on getting all these trials up and going.

Excellent. We're pretty much at time. So if you have any other item you'd like to highlight?

I think that we're going to have a great second half. That's all I can say. That's -- we'll have a lot more news flow and I think data flow. Like I said, this half has been really logistical and execution based.

That's fair. Thank you, Arthur.

All right. Thank you. Thanks, Gil.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Nurix Therapeutics, and presenting on behalf of the company, we have President and CEO, Arthur Sands.

Arthur, over to you.

Well, thank you, Tessa, and I'd like to thank the entire JPMorgan banking team for inviting us to this great conference. Another great year starting off here in 2026 jam-packed schedule. I will be making certain forward-looking statements. I refer you to our filings with the SEC.

So at Nurix, we're dedicated to our mission to establish degrader-based mechanisms at the forefront of patient care. And this is an important emerging class that we see in the context here as shown on this slide, as a major new class of agents. And as agents have evolved over time, we've seen many new categories of therapeutics.

Of course, if you go way back, small molecule inhibitors on the left, the original drugs, really very little innovation has taken place in the area of small molecules, I'd say, in terms of modality until targeted protein degraders all the way on the right. And these are unique small molecule drugs.

I'll describe some of the attributes that distinguish them and make them what we believe will be a category medicine at least as large as antibodies, share certain things in common with nucleic acid-based therapies in terms of knocking down targets or trying to knock out targets, which really have been reserved for the use of nucleic acid-based therapies where you could delete a gene with CRISPR or knock down a transcript.

But although these are very exciting and effective, but they do not have the breadth, or the expansive market opportunity that targeted protein degrader drugs have to knock down, or essentially knock out protein levels via small molecule agents that can be orally delivered. So, they hold this promise to fulfill this idea of being able to hit any target actually and do so in a very effective and pharmacologically relevant manner. So, we see the big picture is a new category of drugs emerging.

So, before I dive into describing that, just a great nod to our terrific 2025. We think we really had a terrific year achieving several key milestones, starting with entering pivotal trials with our DAYBreak-201 study. And this is in CLL. It's designed to be a study for accelerated approval for bexobrutideg, our lead BTK degrader. We recently -- very recently presented very robust results at ASH in Orlando, with an 83% objective Overall Response Rate in patients that had received a mean of 4 prior lines of therapy. So very heavily pretreated patients.

And for the first time, we revealed, we're able to calculate our initial calculation of progression-free survival or PFS at 22.1 months. And that's across all doses tested in the Phase 1a dose escalation arm of the study.

In addition, we secured the 600-milligram dose, which is our highest dose tested. We did not see any DLTs along the way under Project Optimus. And this really puts us in a very strong position to push on efficacy, with a safety profile equivalent to lower -- all the lower doses, basically, I'll show you some of the data there. But this 600-milligram dose, we've now taken into pivotal studies. And again, that initiated in October 2025.

With regard to our pipeline and our partnership momentum, tremendous progress made -- we're in collaboration with Gilead for our IRAK4 degrader, which is in an ongoing Phase 1 SAD/MAD study in autoimmune disease. And for STAT6, we are in IND-enabling studies, a STAT6 degrader NX-3911 with our partner, Sanofi. And we initiated our healthy volunteer study for bexobrutideg with our new formulation, which is specifically designed and intended for autoimmune disease.

So really, you see our emerging partnership pipeline and our wholly-owned pipeline really enabling autoimmune disease as the next major indication for Nurix. And we secured a very strong financial position. We strengthened our balance sheet with a very successful follow-on offering of $250 million that was led by JPMorgan. Thank you. And we earned significant milestones along the way, $47 million through our partnerships with Sanofi and Gilead and Pfizer. So, we're very well capitalized with cash and investments of approximately $650 million, greater than that. So that was all 2025.

Let's turn to 2026, where I'll spend most of the time giving you the most recent data from ASH reviewing that for our bexobrutideg, our lead program, our BTK degrader there at the top. I'll hit on some of the other programs and also at the end, be able to highlight our progression of bexobrutideg and our other programs into autoimmune disease.

So let me start off with, again, looking at the bigger picture here in terms of why degrading BTK and degraders in general are such an important new class of medicines. And this will be illustrated by bexobrutideg's latest results.

So first off, we are the first deg, which means we earned the Suffix deg, bexobrutideg deg, unlike IBS or MABS, because it defines a whole new category of drugs. And this was endorsed by USAN and international naming authorities, which really took quite a bit of work and really recognizes the fundamentally different pharmacology of these agents as compared to regular inhibitors or antibodies or anything else actually.

So, we are the first agent that has this new suffix. And why is that? Okay. So first, Degradation unlike inhibition removes all the functions of BTK or any target you degrade, unlike inhibitors. So, this includes the structural functions of proteins, which are known as the scaffolding functions of proteins as pictured here on the left of the protein falling apart or being -- it's actually being actively degraded by the ubiquitin proteasome system.

Number two, it acts -- these molecules act catalytically. So, a single drug molecule, as pictured on the very left here, cycles from capturing the E3 ligase, tagging the BTK protein with a ubiquitin ligase, a ubiquitin protein tag via creating this bridge between BTK, or the target protein and the ligase. And then once tagged, the target protein is degraded by the proteasome of the cell in a highly specific manner. The drug molecule is then released to remain in the cytoplasm and go do it again and again.

So, what does that mean? Well, we've calculated and actually measured that one drug molecule in a cell of bexobrutideg can degrade up to 10,000 BTK proteins per hour. So, one drug molecule can remove 10,000 target proteins. Compare that to the one-to-one stoichiometry of traditional inhibitors, extremely different, exquisitely potent is what that translates to.

In addition, what's pictured here is exquisite selectivity as measured by global proteomics. So, the upper left protein -- the upper left quadrant of this plot, all you see is one dot, which is the BTK protein as measured under proteomics. And all the other gray dots at the bottom are all the other proteins that don't move at all or are nonsignificant changes. So very significant degradation of BTK.

In addition, we are active against all known resistance mutations that have evolved in the presence of BTK inhibitors, the current class of drugs. And so it's pictured below bexobrutideg, you see bexobrutideg across the top. All green means nanomolar-based degradation potency in cell lines. And these cell lines across the bottom have been engineered specifically to contain BTK inhibitor resistance mutations that we are encountering in the clinic currently.

So, each of these confers resistance to different inhibitors. And then you see the list of inhibitors. And then the color is indicated in red means the inhibitor lost 5,000-fold potency and ability to kill these tumor cells. And blue is loss of 1,000-fold potency. Basically, they're inactive.

So, you can see the inhibitors have vulnerabilities across a wide spectrum of BTK inhibitor resistance mutations. But our degrader is mutation agnostic. It can degrade all of them. And so, this is very different again compared to having to design a new inhibitor for every mutation that occurs. That these degraders and our degrader has this terrific ability to address the resistance mutations.

This is really quite a phenomenal additional attribute and quite distinguishing for bexobrutideg. We cross the blood-brain barrier, and we can hit tumors. In this case, you're looking at a primary CNS lymphoma tumor in the pretreatment scans across the top, you can see in the red circles where the lesion was. By 8 weeks, complete response of lesion has disappeared. We've seen this not only in primary CNS lymphoma, but also CLL with CNS involvement, quite extensive CNS involvement.

So, these molecules have the ability to enter the brain and continue their catalytic activity to treat disease. very encouraging. And this all adds up to across the board, very robust objective clinical response rate of 83%. This is our Phase 1a data in its totality. And again, the progression-free survival, now measurable at 22 months, although not the final measure, we see this extending even beyond this, especially at our higher doses.

What does this look like for patients? This is their lymph node reduction. So, every bar on this graph is a patient, and we're measuring their -- the size of their lymph nodes as they've been reduced when on therapy. And right off the bat, you see the overwhelming number of patients, overwhelming proportion respond to this drug with significant lymph node reduction.

Across the bottom, you're looking at with these colored dots, the different mutations that each of these patients are harboring. So, in the top series of boxes are the -- what's called high molecular risk features. This is p53 and other tumor suppressor gene mutations, a whole spectrum of those. And then the bottom 2 rectangular areas are the BTK mutations, all the different types. So, when you add this all up, you see this is a heavily burdened -- heavily genetically burdened patient population. And regardless, the degrader shows this terrific activity across the board. So very, very impressive.

The gray boxes, by the way are wildtype -- wildtype mutation or they're not mutations, the wildtype status of each of these genes. And so, the degrader works in wildtype as well. So, it's not just mutation specific, although I've been dwelling on that, but it also covers wildtype proteins as well. So, a very broad patient population overall.

Here, we're looking at this 22.1-month progression-free survival curve as generated in our Phase 1a data set. These are patients that, again, are heavily pretreated, median of 4 prior lines of therapy, 83% response rate and this PFS curve, which is really showing great duration of response in this patient population. So, we're very encouraged by this.

And again, to emphasize, this is including all doses tested from our lowest dose of 50-milligram, those patients as well, 100 milligrams, 200 milligrams all the way up to 600 milligrams. So, we don't think this is even optimized yet.

So, turning to dose optimization. We were very pleased to have aligned on the 600-milligram dose under Project Optimus with the FDA as the go-forward pivotal dose. And what's so important under Project Optimus and in dose selection is drug safety. That's number one. And what we're looking at here on the right is the drug safety profile of the 600-milligram dose as compared to all other doses, so 70 patients compared to 126 patients, really good patient numbers.

And the bar graphs going each way show you rough equivalence between the 600-milligram dose size of the bars and the other doses. So really, there's no difference in safety profile between the high dose and all lower doses. This enables us to really push on efficacy with the 600-milligram dose while not sacrificing safety. And we see no dose-limiting toxicities, no systemic fungal infections, which we think is important. And I think that speaks to the selectivity of bexobrutideg and not hitting other targets associated with T-cell function.

So, infection is a known risk factor for patients with CLL, but it is also known to be an issue if there are off-target effects that can hit T-cells, and we think we're very clean against T-cells. In addition, from a cardiovascular standpoint, we're very clean. We only had one new event of atrial fibrillation in the trial. And this compares to the background rate of Afib in this elderly patient population. So, we're seeing only background rates there or essentially or below that, but at least at background.

And so, we're very encouraged by the safety profile. Again, this allowed us to move forward with the 600-milligram dose as the go-forward dose. So why is this important for efficacy? So, what we're showing you here is in that randomized Phase 1b cohort of 200-milligram versus 600-milligram under Project Optimus, the PFS, the early PFS curves in maroon there for the 600-milligram compared to blue for the 200-milligram dose.

And you can see right off the bat that we're trending towards even a higher PFS than that 22 months that I cited earlier with the 600-milligram dose. So, we think this is very encouraging from a safety and efficacy standpoint. It puts the drug really in a best-in-class profile for degraders and I think also for inhibitors.

And so with respect to that statement, here, we're just lining up a comparison between bexobrutideg data from the Phase 1a and pirtobrutinib, the latest data that they published in BRUIN-321, the non-covalent inhibitor from Eli Lilly, which has shown some excellent results.

Now granted, this is a cross-trial comparison, so take it with the appropriate grain of salt. But doing our best to look at some of these parameters, our overall response rate of 83% compares very favorably to the 65% with pirto. Median duration response, 20.1 versus 13.8. Median PFS, 22.1 versus 14. And overall, we think this compares extremely favorably to the most recently approved agent, new agent in the field, which was just approved December 3, just before ASH kicked off.

In addition, if you look at the bottom of the slide, we're achieving these results in a patient population that is quite arguably a more difficult-to-treat patient population than what pirto encountered in their 321 trial. So median lines of therapy, 4 versus 3 and greater than 4 lines of therapy, we've gone up to 11 lines of therapy in our trial. The prior non-covalent exposure, of course, now we're seeing pirto failures in our trial. About 1/3 of our patients have failed pirto, and yet we're seeing responses in those patients.

And then I think this is very important, the bottom bullet there prior BCL-2 inhibitor exposure, which is approved second-line therapy, venetoclax largely. In that population, we're seeing an 83% response rate versus 50% that pirto reported. So, we think along many lines of analysis, this puts bexobrutideg in an extremely competitive position to the non-covalent inhibitors and the leader in that space, pirto.

So that has led us to -- we've already launched this pivotal trial, I'm showing you here, but it's led us to also modify our Phase 3 design for our randomized controlled trial, which I'll tell you about in the next slide. But first, just a moment on DAYBREAK-201, CLL-201. This is up and running. It started enrollment in late October. We're targeting approximately 100 patients to enroll in this trial. We proactively altered the enrollment criteria to include patients that have failed pirtobrutinib as well as the prior BTK covalent inhibitor and a prior BCL-2 inhibitor, most likely venetoclax.

So the so-called triple-exposed population, an area of high unmet medical need. There are no approved agents. We were anticipating here pirto's approval, full approval. So that's why we altered this group to be in this triple-exposed population. And so, this is enrolling as we speak. And again, we're at the 600-milligram dose level. Our primary efficacy endpoint will be ORR, and this is designed for potential accelerated approval.

So, with the latest results that I described, this today, we announced we've modified our Phase 3 plan, our Phase 3 design, the confirmatory trial, randomized controlled trial will be between bexobrutideg at 600 milligrams once a day against pirtobrutinib head-to-head with standard dosing for pirtobrutinib of 200 milligrams once a day.

So, this is a modification from what we had formally announced, which was an investigator's choice arm in the control arm, which included traditional chemoimmunotherapy as an option. But given our results, as I just -- as I went over, highly competitive results and given that now pirto has full approval, this becomes a new standard of care, and this becomes a very clinically relevant and timely trial to implement with the latest approved agent in CLL going head-to-head.

We think this will really put us in a great position to harvest these results as they come and ultimately take up, we believe, an ability to prove that degraders are superior to inhibitors because of all the attributes, unique attributes to how we hit the target, how we remove the target so thoroughly and how we can address resistance. So, this is a major study, not just for CLL, but I think it will have implications for oncology more broadly with respect to degraders being the way to hit an oncology target as opposed to inhibition.

In addition to those main 2 trials, we are also launching a Phase 1b/2 to start to look at combination agents. Combination trials with bexobrutideg. Bexobrutideg plus venetoclax is going to be a key study ultimately, that's on our list here. Then a triplet, Bexobrutideg plus venetoclax and rituximab, and these are in the second line. And then obinutuzumab also, so anti-CD20s starting in the second line, but also enabling on the bottom there across the bottom, a frontline trial.

So moving bexobrutideg to the frontline in combination. And there are many other combinations possible given our excellent safety profile. And of course, given the efficacy we can deliver, we think we can drive very deep responses here in combination, and we're looking forward to initiating this trial in 2026 as well.

So just from a standpoint of what kind of patient populations we're looking at, in the second line and third line. Starting -- looking globally, there are about 60,000 patients that are treated initiating treatment per year. So, a very large patient population, just in the U.S., 19,000 in just the second line and third line. If we can penetrate the first line, that will grow. Current BTK inhibitor sales are annualizing at $12.5 billion per year, about $9.5 billion just in CLL. So, we're addressing very large markets. And I think the big picture here again is can the degrader displace the non-covalent inhibitors first? And then can we challenge the covalent inhibitors to show, again, degradation being the superior way to treat cancer.

So, we -- this is graphically showing you how we can unleash waves of clinical benefit and value creation. Starting in the dark blue, the accelerated approval trial, relapsed/refractory CLL, second line plus, that confirmatory trial now head-to-head with pirto and then moving into combinations of potential in the front line. But then also another wave of value creation in Non-Hodgkin's Lymphoma, where we've seen some great results in Waldenstrom's, 83% ORR, 83% to 85%, really corroborating our CLL results. And then we have designs to go into immunology and inflammation indications, including those based in neuro, derm and heme, where BTK inhibitors have made some inroads.

And I'll just wind up here, so we'll have some Q&A time. This is Nurix's industry-leading wholly-owned and partnered degrader portfolio in autoimmune disease. Bexobrutideg, we have a new formulation that we've made designed for autoimmune indications. It's a tablet formulation. It has certain PK/PD attributes that we think will be really appropriate for that. We're going to look at much lower doses for autoimmune disease than what we're seeing in cancer. This is a huge market opportunity.

And then our STAT6 degrader with Sanofi. So again, addressing a very large market opportunity and IRAK4 degrader with Gilead. So, I mentioned the SAD/MAD studies ongoing for bexobrutideg, we'll have data this year. For STAT6, we anticipate Sanofi filing an IND for the STAT6 degrader NX-3911. Those IND-enabling studies are ongoing under Sanofi's guidance.

And with this program, we maintain an opt-in right post human proof of concept for 50-50 cost profit share in the United States. It is a very important part of our portfolio with this very important option. Again, this is after we see data from Sanofi in patients with type 2 inflammatory disorders. We have a very similar option with our IRAK4 degrader with Gilead, picture on the right. This compound now called GS-6791 is in the SAD/MAD study currently, so about a year ahead of the Sanofi program. We expect to see data from this study this year.

So, a lot to look forward to in 2026, which is summarized on this slide. So -- in terms of our pivotal development pathway, enroll, enroll, enroll for our Phase 2 DAYBreak study, launch our Phase 3 confirmatory study with the new control arm, pirtobrutinib head-to-head and then initiate our combination protocols for bexobrutideg.

In terms of the I&I program, I think I already mentioned, we anticipate data from the Phase 1 with Gilead. We look forward to an IND filing for NX-3911, STAT6 degrader and then as well as many clinical updates anticipated for bexobrutideg with our additional CLL cohorts, including BTK-naive patients, BTK mutation patients with resistance mutations exclusively, CNS patients.

So, a number of CLL cohorts that are still ongoing as yet to report on. We look forward to reporting on them this year. And then also our NHL cohorts where we have not given any really substantive NHL data to date. And we have some exciting data. We've seen complete responses in basically in every category of NHL malignancies.

And then our NX-2127 zelebrudomide, we anticipate to report on the Phase 1a cohorts in dose escalation. So, I think I've taken up a fair amount of time, but left some for Q&A test, so we can go to that. Thank you.

Great. Thanks, Arthur. So, I thought I might start our conversation with a little bit of a bigger picture question here. How do you see your portfolio evolving over the next several years? And how do you think about relative risk and where you could see the highest reward?

So clearly, as I indicated, I think we'll have an I&I portfolio that will be substantial over the next couple of years. And the targets are already on the board that will be clinically reading out. So BTK, number one, IRAK4 and STAT6, probably data from IRAK4 before BTK and then STAT6 would come. So, I think those are 3 major target categories that basically cover many, many indications. So, we'll have that. We'll see that. And that will be -- with our options, that's part of our portfolio.

In terms of oncology, I think we've -- in terms of risk, I think, too, I think there's probably still risk in oncology, but we've significantly derisked. I think we've moved CLL from derisking to now best-in-class profile. So, it's not a matter of risk so much as how good can it be. So, I think that's a great position to be in. I think with some of our earlier compounds in oncology NX-1607, we're going to be able to derisk that in solid tumors. That's a novel IO agent where we've seen some encouraging results in 1a in prostate cancer and colorectal cancer. So, I think that could be derisked over this same time horizon.

And then I think with regard to new indications, we'll have to see. But I think that the risk profile has been really materially changed here for Nurix in terms of the degradation modality being effective, again, moving from risky to how effective is it.

And we're kind of -- well, not that fresh off, but relatively fresh off of ASH. Maybe you could talk a little bit about that conference for Nurix and -- but specifically, what the feedback you're really hearing from physicians and institutions around the asset and the BTK class overall?

So what we clearly heard at this most recent ASH was that bexobrutideg is really adopting this potential best-in-class profile. When you look at safety, dose at the 600-milligram dose level and you look at efficacy. I think it is dawning on people that this is really a best-in-class -- potential best-in-class agent, number one. Number two, that degradation mechanism itself is going to be a player and probably a big player in CLL and B-cell malignancies. And I hit on all the points of why.

And I think that we had tremendous uptake and enthusiasm from our investigators as we're launching these studies. So, I think that -- those were some of the main sort of take-homes for me in terms of what's next and majorly innovative in CLL, I believe the consensus that I sense was it's going to be the degraders.

Okay. And can you talk in a little bit more detail around how you think about the time lines for your pivotal Phase 2 DAYBreak trial? And how quickly do you believe you can enroll 100 patients? And what type of activity profile do you think could allow for registration in the U.S.?

So our goal is to fully enroll DAYBreak-201 by the end of this year and to have data in 2027. So, we're at the front end of enrollment going well, but we're still at the front end. So, we can't put a finer point on that yet. But as soon as we can, we will. And I think in terms of the data in terms of efficacy, we're in a patient population with no approved agents. So typically, the bar is rather low. And the accelerated approval opportunity should be significant.

So I can't quantify that either. But in this patient population already in the data we have so far, we've been seeing a response rate of about 65% or so. And this is, again, a heavily pretreated patient population. And what was the second part of your question?

I think you actually nailed it.

Okay. Great.

I think you nailed it. So -- and you talked a little bit today, Arthur too, just around the change to your Phase 3 trial. Anything else you would like to say on what drove that decision to not use a physician's choice arm? And like what were the key levers that you really thought about in making that decision and deciding that was the right decision for Nurix?

Well, driven by the data that I reviewed, so I won't repeat it here, but that was a key piece of decision-making information. But I think also that the goal here is to design a trial that can be practice changing that can really advance medicine. I mean, that's really what we're here for. And what we're really looking at here is taking bexobrutideg a degrader and looking at the best next class inhibitor made. And if we can beat that, that is practice changing.

And as I said, I think it has implications for all of oncology more broadly. So those -- that was a major strategic consideration for the change. There are logistical advantages and considerations, too. It's an easier trial to enroll. It's a simple head-to-head. Even the control arm is attractive to patients. This is the latest approved agent. So very attractive trial to be involved with. Either way, it's a win-win for patients to be involved. So that was another -- so those are the 3 main areas of consideration.

Okay. And at the current time, how do physicians tend to compare and contrast the evolving clinical profiles of bex deg and BeOne's competing BTK degrader. What are the lingering questions that physicians have as they are trying to understand these relative profiles?

So, there are classic questions that people grapple with in the early stages of trials. And so we have some physicians who say, well, these agents look more similar than different. That doesn't really say much. If you really read between the lines, we think they look very different. So, we think that we have exquisite selectivity, number one, as measured by global proteomics, and we've done some comparisons there that we think substantiate that. So, selectivity is key as it relates to ultimate clinical safety. So, we think we win there.

We have measured relative potency. We're 20x more potent on the cell-based assays for degradation than the BeOne compound, 20x is a large number. So that kind of potency, combined with safety usually translates to better efficacy. So, I think people are going to start to connect these dots and see us as a distinguished best-in-class profile, but that's sort of the forward-looking way. The current view is perhaps they're more like than they are different. And what this does, though, is it substantiates the field that it's not just one company showing these kinds of results and their response rate is very high, 80-plus percent. But now it's 2 companies, with different molecules corroborating similar results. So this is a real thing, a real opportunity.

This might be a hard question to answer in the time that we have allotted here, but where do you think the most compelling opportunities are for Bex deg beyond CLL?

So, we're very intrigued with our brain activity that we've seen in CLL. So, we're talking about seeing really dramatic responses in patients with advanced brain disease and tumor burden in the brain. And so that obviously opens up non-malignant CNS disease. The most large opportunity and significant would be multiple sclerosis, so MS is an area, I think, that we are highly interested in.

Now that would be a major next step for us. We're not declaring our indications yet, but we also are very intrigued by dermatologic applications, which could be faster, to proof of concept, may take much lower doses actually and really could offer another major more mass market opportunity.

So, I think those 2 areas are very intriguing. And then you have nonmalignant heme. So, things like ITP and wAIHA, where inhibitors have shown results as well that are positive. And a number of these areas, inhibitors have given us some proof of concept. But we have evidence that the degrader mechanism can be superior to inhibitors in autoimmune disease, just like it is in oncology. And again, because we're hitting that scaffolding function, which is a major signaling function that is completely unaddressed by inhibitors.

And maybe I'll just jump here and do like 1 or 2 more questions.

Sure.

So, what are the recent key learnings from the broader landscape targeting STAT6 degradation that you believe has -- may have read-throughs to NX-3911? And how does 3911 compare with other STAT6 degraders in development?

So clearly, the only other STAT6 degrader in development is Kymera. So that must be what you're asking about. I think they showed great data in Phase 1. I think they have established STAT6 mechanism proof of concept with their early data. So, it's highly encouraging for the field. We believe that they will go forward successfully. It is -- it will expand the market dramatically, as they've said in their presentations beyond the injectables. So, there's room for many, many compounds here. It doesn't -- it's not an all or nothing game here, a winner-take-all game. I think there's going to be several winners here. We've designed our compound to be a winner with Sanofi.

We've been working with Sanofi for 6 years on this compound from target inception to where we are now in IND-enabling. And we've met every milestone along the way in terms of optimizing these compounds to big pharma standards, if you will. So, I think this is another league in terms of 3911 is in another league in terms of preclinical development and polishing and rigor.

So, our goal -- our design goal is to be best-in-class. I mean, that's our design goal across the board. It's sort of -- that's a corporate policy. Now we have to see that play out with data, but that is -- that's our policy. We're down to a minute.

Yes, I might have to leave it there.

Okay. Well, that's good.

Arthur, thank you so much and to the entire Nurix team for being here. We really appreciate it. And thanks to all the investors for joining. Thank you.

Yes. Thanks.

Good evening, everyone. My name is Arthur Sands. I'm President and CEO of Nurix Therapeutics. And I'd like to welcome you to our 2025 Investor and Analyst event broadcasting here from Orlando, Florida after -- well, still in the midst of a terrific ASH, but getting near the end. But a lot of exciting new information at ASH this year, not only for our programs, but many others that are relevant to the incredible opportunities to improve therapies for patients with CLL and many other diseases covered here. So really absolutely terrific meeting.

So we're very excited to have you all tonight, and I'll be making a few opening remarks, and then we're going to dive -- do a deep dive into our data that was presented here today. We're very fortunate to have Dr. Alan Carr here from University of Miami, who will be presenting the data, a fantastic expert in the field, one of our key investigators. We're very excited to have you. Thank you, Dr. Alan Carr.

And then we'll have our Chief Medical Officer, Paula O'Connor, talk to us about our development program for bexobrutideg, our best-in-class BTK degrader. So let me dive in with our very exciting disclaimer slide, and then we'll move from that to the pipeline.

So I know, of course, we're going to focus on bexobrutideg or Bexdeg as we call it for short, NX5948 at the top of the slide. But just a reminder that we have many other terrific programs. And in addition, it was a really, I think, big day for our inflammation portfolio as well. So I would be remiss if I didn't mention the progress today made in the field with one of our colleague companies, Kymera for STAT6, our STAT6 degrader NX391 -- we have partnered with Sanofi that's in IND-enabling studies. I think it's a very exciting time to see degraders expand beyond oncology. So I definitely have to mention that program. And if there are questions tonight, we're happy to talk to those questions as well.

But in addition to STAT6, we have our IRAK4 degrader in I&I with Gilead. These are important parts of the Nurix pipeline. We maintain 50-50 options on these programs and then multiple oncology programs as well. And so let's go forward, but just again, a reminder that we have quite an emerging and significant pipeline.

As part of my introduction here, I'd like to tee up some of the key points about bexobrutideg that we find most compelling and we think defines its best-in-class status. So it was the first DEG. What do we mean by that? We're very proud of having the suffix -deg approved by international naming authorities for the nonproprietary version of our name. And this really relates to us the unique pharmacology and great potential of degradation as a truly differentiated class of medicine as compared to inhibitors. So a few of these points on the slides I'm going to run through, I think, underscore that.

But first and foremost, bexobrutideg is potently -- is highly potent and exquisitely selective degrader of BTK. And what I'm showing on the left here is a global proteomics plot that shows that the only protein we hit and that is degraded is BTK. And anything in the upper left quadrant is very significantly degraded. And you can see it's a long protein there.

Very clean drug. And this establishes, I think, the molecular underpinnings for bexobrutideg, having an excellent safety profile, which you'll hear about tonight as well as an excellent efficacy -- emerging efficacy profile. There are molecular reasons for having those profiles, and this graph captures it.

Let me back up here. Okay, yes. So the other major point here is we know that we can overcome the resistance mutations, mutations that evolve to the existing BTK inhibitors. And this is a very significant and emerging issue in the CLL space. And what's pictured on the left here is a heat map that shows in green is the most highly potent cell killing of these tumor cells. And across the bottom of this picture, you can see the variety of resistance mutations that we encounter in the clinic.

And what's immediately apparent, just looking at the colors is that all the inhibitors, we compared -- so we do an apples-to-apples comparison here with bexobrutideg. We're bright green across the way, which means nanomolar cell killing across all of these resistance mutations. And you can see red indicates a loss of potency of 5,000 fold. And there's a lot of red on the slide for the various inhibitors. and blue is 1,000 fold.

So all the inhibitors have their liabilities, and they miss these mutations, whereas the degradation mechanism can hit all of them. It's really quite remarkable, a major differentiator. I think there's a lot of great data today from pirtobrutinib, but you can see pirtobrutinib also has its liabilities. And so we think this is another big advantage for bexobrutideg going forward.

Another key aspect that we think is incredibly important is that by degrading BTK, we address the scaffolding function of BTK. And that's pictured here in terms of the protein literally being disassembled there at the bottom of the slide on the left. And so there are 2 major signaling pathways for BTK. There's the kinase function and there's this structural function or scaffolding protein. And we take out both of these. And we see this manifest in the clinic where we have patients who have kinase dead mutations that actually respond to degradation, but fail to respond to pirtobrutinib, for example, because BTK is no longer a kinase, but it's still a signaling protein. So this is a critical advantage of degrading the BTK protein. And I think actually many other oncology target proteins.

The next point here is that this process is catalytic. And so that's a word, but let me give you some numbers. So one, BTK -- 1 bexobrutideg drug molecule can degrade 10,000 BTK proteins per hour in the cell. So when we say it's catalytic, we mean it's very catalytic. So imagine 1 drug molecule taking out 10,000 oncology target proteins per hour. This is fundamentally different pharmacology from inhibitors where it's 1:1 and allows -- I think allows our incredible efficacy and potency to take place while maintaining safety because it takes less drug molecule to affect changes within the cell. This is, I think, a really important aspect of bexobrutideg's differentiated profile. We have activity in the CNS. And we not only, of course, have measured drug levels in the CSF for cerebral spinal fluid that are basically equivalent to free drug levels in the plasma, so 1:1. So we know we're in the brain. But what we're showing here across the top is a tumor that was in one of our patients with PCNSL. And then across the bottom, it may be a little hard to appreciate, but basically, it disappears.

We have had several complete responses in CNS lymphoma and some dramatic responses in CLL with CNS involvement. So this is a very important aspect of this drug. It creates a protection for the brain over the course of therapy so that it does not become a sanctuary for tumor cells. So I think -- and we're very fortunate, again, with Dr. Alan Carr, who's an expert in this area, I think he's going to be addressing some of the aspects of this tonight.

And then lastly, we have demonstrated a very robust clinical activity. I won't go into this 83% response rate, median PFS, which we have finally been able to measure in the Phase Ia, although it's still probably going to evolve and get longer, it's 22.1 months already. And with increased treatment time, et cetera, we expect this number to mature again. This is even including low doses in this calculation. So we're very excited about that, and we'll be looking in detail at the data associated with this tonight.

I'll just wind up here on what's -- what we look forward to the future. So what's pictured here is our clinical development plan in a graphic sense, we've launched what we call the DAYBreak series of trials. We love this name DAYBreak. It's really a hopeful name. It's a bright name. It brings hope, I think, to patients that are in the relapsed/refractory state, which is where we're starting at the lower level here, where we've designed a trial, we think, appropriate for accelerated approval. And then we really rapidly plan to move to the second-line setting with our randomized confirmatory trial, which we will call DAYBreak-306. We're still in the process of finalizing the design and launch of that. And then we see a combination trials in our near future. We're already working on designing those. And then really getting this kind of medicine to the front line that I think is going to be part of the future. And then on the lower arrow, we have great results in NHL. and Waldenstrom's. And Dr. Alan Carr will be addressing that tonight as well in the Waldenström. We look forward to future presentations on NHL. We have not even presented all of our NHL patients yet. We have over 100 patients in this categories.

And then finally, we also see a future in I&I and other areas and especially neuro-related I&I disease like MS, given what we know about our activity in the brain, so an incredibly bright future for the development of bexobrutideg in multiple clinical settings.

This is just acknowledging that even in the second line and the third line, if you look at the major markets, in the U.S. and Canada world and then in the U.S. on the right, these are really significant patient numbers that we can address, and we do believe this will have incredibly high economic value as a drug product as we get approval and market this exciting new agent. So that brings us to our review of the data from these 2 great presentations that were given today, the first one, an oral presentation in a really packed room here at ASH on CLL and some of the latest CLL and then the second on Waldenström's. And so let me just get fast forward here. If I can then we'll dive right into the program. And I'd like to invite Dr. Alan Carr up to review all of our data. And I'm sure there's going to be a lively Q&A session. I'll run that at the end after Paul gets search as to Dr. Alan Carr.

Thank you very much, Arthur. It's really a pleasure to be here to -- it's very exciting to share just review data on these 2 presentations. So the oral presentation on the CLL will be reeling first, and then we'll review the data on Waldenström. So we'll start with the CLL presentation.

So as you know, on the 5948 study, we divided it in Phase Ia and Ib. In Ia portion, we were trying to define the right dose of bexobrutideg. And so we'll be focusing initially on the CLL arm, but as you know, we escalated from 50 to 600 milligram. And then after we defined our safety dose, then we had a small randomized Phase Ib study that was related to the project optimal from the FDA, comparing the doses of 200 and 600 milligrams in patients with CLL with previous BTK inhibitor and BCL2 inhibitor exposure. In addition, the Phase Ib, we also have a lot of different cohorts with specific patient characteristics that are evaluating this dose that was defined in the Phase Ia of 600 milligrams. So we'll be viewing a little bit of both today. And then later on, we're going to have the volume to data that we're also going to review is kind of the same idea, the Phase Ia with the escalating Phase I doses from 50 to 600 milligrams and then the expiration cohorts in the Phase Ib.

So if you look at the -- let me show you. So if you look at the patient population on the CLL, we have a total of 126 patients. So on the Phase Ia, it's 48 patients. So the 48 patients that went through the dose escalation between 500 and 600 milligrams, all these patients were exposed to the dose, at least the dose. So all of them composed the safety population, and we have 26 patients that remain on treatment.

Out of the patients that are no longer on therapy, the 22 remaining patients, we see the majority of them are no longer on therapy because of progression. So we have approximately 14 patients that had either radiologic or clinical progression. So they're no longer on therapy, a very small proportion of patients that are not on therapy due to toxicity, so demonstrating the really the very well with very good tolerability of the drug.

And then on the Phase Ib portion, we have 78 patients initially, the 42 patients that were randomized, 21 patients, each arm between 200- and 600-milligram cohorts. Again, all these 42 patients were exposed to drugs and are and compose our safety population. 29 patients remain on therapy. And again, the patients that discontinued therapy mainly discontinued because of progression, very few patients discontinued from due to toxicity. We have the other 36 patients that are also on Phase Ib on those special cohorts or specific cohorts that we talked about.

For the Phase Ia, so patients that were treated between the dose of 500 and 600 milligrams, we have obviously a longer time of follow-up. So it's a total a median follow-up of 19 months. For the Phase Ib, all these patients treated or most of these patients treated with 600 milligrams. We have a small proportion with 200 milligrams, but it's a shorter follow-up of 9.8 months.

So what we're going to show you today is really the focus on the patients that received our full dose of 600 milligrams. So those are 16 patients that were part of the initial dose escalation and then another 20 patients that were from the randomized cohort and also 35 patients that receive 600 milligrams in the other specific cohorts. So first, we view the entire population, 126 patients between Phase I and Ib and then specifically the population that was treated with 600 milligrams. And we'll also take a peak on the comparison that was done on the randomized cohort between 200 and 600 milligrams.

Next slide. So this is the overall population of the study. So all 126 patients treated between doses of 50 and 60 milligrams.

So with median age 69, which is the expected median age for CLL. Typically, that's the median age that you see in a CLL study. Obviously, there is a disease of older patients. So you can see sometimes a median age of CLO is in the 70s, but for clinical trials, in general, we're going to be 69. But this is very representative. You see patients up to the age of 88. And one point that I'd like to make about whether this is a representative population, the fact that Arthur mentioned the CMS penetration. So most clinical trials will exclude patients with CNS involvement as part of including criteria. And because of the fact that these are harder patients to treat, these are patients that usually have much more aggressive disease and you don't want to confuse your data. And this is the beauty of bexobrutideg and it's actually one of the main reasons why that drove me to start having a relationship with Nurix and really having this drug available for our patients in our center is the fact that not only has the CNS penetration but really represents the real population that we treat patients relapse refractory B-cell lymphomas as the disease progresses very commonly, will have progression to CNS.

So when you have a study that allows CNS involvement, you're really representing the real population that you're treating every day. So these patients with a median age of 69 is a typical CLS the population that is involved in the clinical trial, but it's very important to remember that. And we see more commonly men and women in the study. So from 1/3 and 2/3 male and female, most patients are non-Hispanic. The 5 Hispanic patients are probably my patients from Miami. and most patients are white on this study.

Next slide. So when we look at the baseline disease characteristics, this demonstrates the very high-risk complex disease that we're dealing. So if we see and we focus on the column on the middle, the Phase Ia/Ib study. So all patients we see that we have a proportion of them with CNS involvement. And that is typically what you see in this group of patients, approximately 5% of patients will have CNS involvement in this setting. But when you look at previous treatments, most of these patients previously exposed to BTK inhibitors, including nearly or 1/4 of these patients 27% with non-covalent BTK inhibitors. Around 60% of these patients with BTK -- dual BTK and BCL2 inhibitor population. if you see only on the Phase Ia population, the 48 patients, you see that this population gets up to 80%. So 80% with previous exposure to BCL2 and BTK inhibitors. It's a smaller proportion, but you still see very high-risk patients, very complex patients previously treated with bispecifics, CAR T cell therapy. So no patients that have been treated with multiple lines of therapy. The median lines of therapy on all patients was 3, but in the Phase Ia was actually 4 previous lines of therapy.

And when you look at these patients, another factor demonstrates how difficult they are to treat is a lot of them would mutations, but also high-risk mutations like TP53, BLC gamma 2 or TP53 mutation.

All right. So let's review a little bit of the safety profile. So this is the safety of on the middle column, all the 126 patients that were exposed to the drug. So you see that treatment-related adverse events, any of them are around 75%. But when you start focusing on the high problematic risk mutations and mainly those that are treatment related, you see the numbers are remarkably small. So you see that approximately through the 50% grade 3 or plus on adverse events, but only around 1/4 of them were treatment-related.

When you see the series of adverse events you're starting to go to single digits for the adverse events that are treatment related. And there is no grade 5 toxicity. There's no mortality in the study. There's actually no DLTs in the study as well and also reflecting this good tolerability, very few patients having treatment discontinuation because of toxicity. So drug is remarkably well tolerated and therefore, meeting the ration of treatment of 7 months on the Phase Ia/b and 3.6 months with the 600 milligrams. But remember those patients are starting later on, on the study. So they've been exposed to the drug for a shorter period of time just because this dose later on as the study advanced.

Next slide. And when you focus on the treatment-related adverse events, what you see is that there are a few very important take-home points. One is that we do not see any new adverse events that are new compared to what we know, what we're used to with BTK targeting. So when you think about BTK inhibitors, which are -- is what we're very comfortable with and what we do generally in the clinic as standard of care. when you add a new agent that is targeting BTK, but in a different method, it is very confident to see that you don't have any new emerging new type of adverse events. So that makes it easier for physicians to just be comfortable with the drug to start where it's easy to drug right away. And when you see this graph, what you see is that on the right, you have all doses on -- I'm sorry, on the left, all doses on the right, only the 600-milligram dose. And what you see is what study is that doesn't seem to be at a dose-related toxicities. So we went up on the dose, and we didn't see worsening toxicity related to the dose. And the great -- most toxicities that are treatment related with Grade 1 and 2, very few grade 3 toxicities. The most common grade 3 toxicity was neutropenia, but it's very important to see that neutropenia, we don't see factors complications, where hematologists were used to dealing with neutropenia, so neutropenia doesn't hold from giving the therapy, especially when you have neutropenia that is easy to manage and neutropenia that doesn't lead to infectious complications and also some cytopenias with thrombocytopenia and anemia. Remember, these are patients with blood disorders, marrow involvement. So typically, these patients had low counts even at presentation at the start of therapy. So again, this is not really something that has held us from using the drug.

One thing that I noticed on the study and actually learned as we use the drug over a long period of time, some of cytopenias that we saw in the beginning were related to response. So some of the dose adjustments that I did in the beginning are no longer do. So it happens. But then as these patients are getting exposed for a longer period of time, start really responding these neutropenia is naturally resolved because the disease is better controlled. So we're learning how to deal with this without really impacting leading to treatment discontinuations or complications. But otherwise, most of them are Grade 1 and 2. And very important that not only there was no infectious complications, but another common problem that we see with BTK targeting is the issue with fungal infections. We do not see any fungal infections on this on the CLL population.

And this, I think, as a graph that really demonstrates the activity of the drug. So this is the reduction in lymph node size. So this is the lower the bar, the greater the proportion of decrease in size of the lymph nodes. So we see that a great majority of patients had a significant reduction in lymph node size. A lot of them more than 50% reduction lymph node size. The asterisk shows the patients that also had responses even though they had CNS involvement, so central nervous system involvement very aggressive disease.

And in addition to the aggression of the disease, the fact that most of these patients had mutations of high risk, so either BTK mutations or at least 1 or very quickly more than 1 high-risk mutations such as TP53, SFTP53, [indiscernible] notch one, some mutations that are associated with a very refractory disease. So despite the presence of 1 or more of these mutations at the same time, we see still see most patients having incredible response.

So this represents 83% complete overall response rate. Remember that when you're targeting B-cell malignancies with -- or treating with BTK targeting, the expectation is having partial responses. That is what you expect with these drugs. It's very uncommon to have complete responses. So when you see 83% overall response rate and you even see in this highly refractory resistant population, some complete responses, that is incredibly remarkable. This is something that you do not see every day.

But I want to bring attention to the disease control rate, which is 96%. So remember, these are patients that have gone through multiple lines of therapy, very difficult to treat. And a lot of times, just halting the disease progression, permitting some control of disease has an enormous clinical value. It allows you to control the disease to take it to something else, you take it to a car to take or just enough to control the disease and allows some improvement in quality of life. So even though we obviously look for the deeper response, the better, we want CRs, especially in this population, having partial responses, stable disease has an enormous clinical value. So this is the Phase Ia patients with a total of 47 patients, the median follow-up of 19 months, this is representing a duration of response of 20 months. And we see these responses in all subgroups. So this, when you're breaking them down on coding to risk factors. We have to take the caveat that some of these groups are very small numbers. So you have very large confidence intervals. But in all of them, there is no statistical significance on the response. So you see patients with TP53 mutation with BTK mutations that are dual exposed, exposed to previous non-covalent BTK inhibitor, which is obviously in the majority of cases pitubrutinib or patients that were continuing because they progress on a BTK inhibitor, patients with more than 4 lines of therapy. So in all of these subgroups, we see the same benefit from the drug without any statistical significance.

And this is the progression-free survival curve for the Phase Ia study across all dose levels. So again, those are patients that were treated between 50- up to 600-milligram dose. the median follow-up of 16 months and median progression-free survival of 22 months, which is again, it's never enough to emphasize how remarkable it is to have this type of curve in such refractory population.

And if we take a peak at the cohort that were randomized between 200 and 600 milligrams. So this is a population that was treated later during the study. we don't have as long as a follow-up. So the progression-free survival curve is not mature yet. But we start seeing a difference in objective response rates. So we see more responses with the 600-milligram dose. If you remember, we see this response, but we don't see an increase in toxicity with a higher dose. And we're starting to see a difference in progression-free survival, so really reinforcing that we probably picked the right dose. So the fact that we have a difference in response, very likely difference in progression free survival and as we've seen when we compare the toxicity profile, we don't really see any difference. So we're getting additional benefit of the response without additional toxicity there.

So for conclusions for our CLL portion, so this is bexobrutideg. It's a novel BTK degrader that is incredibly well tolerated and really has very remarkable activity, even heavily retreated population with the late refractory CLL. So we were able to define the 600-milligram dose as the recommended Phase II dose. And when we have evaluated the overall population with a follow-up for 19 months, we have a very high overall response rate of 83%, including even some CRs. It's only 4%, but it's something that we do not expect the median duration of response is 20 months and progression for over 22 months with all those levels.

Again, we may really see a difference when we start evaluating more carefully in the population that is receiving our recommended Phase II dose of 600 milligrams. And it's never too much to emphasize that we see this high response rates even in this very difficult to treat [indiscernible] subgroups, such as the patients with CNS involvement with multiple high-risk mutations.

And when we focus on the Phase Ib portion of the study, that randomized phase -- that randomized portion between 200 and 600 milligrams, which was really as a result of the project optimist from the FDA, we see higher response rate in PFS with a 6-mile or at least a suggestion so far on the curve of a better PFS with a 600-milligram dose, really reinforcing them. We really chose the right dose of fragment of Phase II dose. And as Arthur mentioned, we're certainly looking forward to the upcoming studies that are further exploring bexobrutideg.

So before we go to the Waldenström's macroglobulinemia data, I just wanted to give you an example. So I think this is very remarkable. It was very nice to bring it home. When you really have a case of a patient that you had in your hands and treated them in the clinic, and you can really put all these numbers in perspective and really see how the impact that you have every day when you're treating these patients and how much ever presents to their life.

So this is a patient with CLL with CNS involvement. And what you can see is that with over time what happens in the response and this graph very nicely shows the different compartments that you have disease involvement. Typically, with CLL, we're going to have different compartments, we have the lymph nodes, the disease circulating the blood, the spleen, the bone marrow in this case, a patient with also disease into CNS. And as you can see, typically, with these drugs is that you have progressive response over time. So as you continuously expose patients with these trials, we have a progressive improvement. So there comes the importance of the tolerability. These drugs need to be well tolerated, so that you'd be able to expose these patients with drugs for a progressive period of time. And what we see in this patient is that over a period of 48 weeks, we have slow clearance of all compartments. Some compartments tend to clear faster than the others. That's why you see some CRs and PRs happening different of these over different times in these boxes, but you see that by 48 weeks, all compartments of the disease have pretty much been cleared, and this patient remains on therapy, tolerating remarkably. So I think it's just a remarkable example, a very difficult to treat patient with very few treatment options having incredible benefit from the drug.

So now we will jump to the Waldenström data. So I'm having a [indiscernible]. There we go. So as we had the CLL, SLL cohort, we also had a Waldenström non-Hodgkin lymphoma cohort. And in the Phase Ia structure was very similar. So randomizing from 50 to 600 milligrams. It's very important to emphasize that also non-Hodgkin lymphoma, we also included CNS involvement. So these patients were not excluded from the study.

And then we had multiple cohorts on the Phase Ib with safety expansion. And we're going to focus on the Waldenström cohort on this presentation.

So those were 31 patients with Waldenström's. And again, showing that this is a population with very high-risk features. So median age is 71. 77% of them were male. And again, some patients with CNS involvement, there is a specific presentation of Waldenström [indiscernible], which is the Waldenström macroglobulinemia presenting with CNS involvement. So we had some patients that were treated on the study with Bing-Neel. Medium lines of therapy was 3. And again, we see that most patients were exposed to BTK inhibitors in reality, all of them were exposed, including 4 patients with previous pirtobrutinib exposure.

We have some patients with dual exposure to BCL2 and BTK inhibitors the data of venetoclax on -- which is the main BCL2 inhibitor is not as solid in Waldenström. So that's the reason why it's no surprise they have less patients exposed to BCL2 inhibitors in this group of patients.

On the other hand, you see most patients, 90% of these patients previously exposed to chemo immunotherapy because the typical treatment for these patients is a combination of [indiscernible] and rituximab or BTK inhibitors. as standard of care.

The mutation status is important. It has a different role in Waldenström but as part of a diagnosis helps us understand the expectations of response. And very frequently, you do not have the mutation status available in all patients. There are many reasons for that. Some next-generation sequencing don't actually capture this very well. So we have just typically request them, the hallmark mutation for Waldenström is 98. So you'll see that a good proportion of these patients has the mutation and it was tested, but not all patients were tested, especially for CXCR4. So this is the population that we have available. There are some patients that were not tested, which is very common in this setting.

So this is the safety profile on the Waldenström remarkable population. And what we see here is very similar profile as compared to what I showed you in the CLL. So you see most timing-related adverse events represent more than 10% of the population, most of them being grade 1 and 2. Again, you see cytopenias as the main complication what you see here that you didn't see with CLL as some grade 3 post-procedural hemorrhage. So we know what BTK targeting, you have some issue with platelet dysfunction, probably with some mucosal bleeding specifically in this population was a patient after surgery that had some anti-coagulation and had some bleeding postoperatively was a small sub-zero hemorrhage that was easily controlled. And these were completely resolved. This could be a little bit from the drug, has a lot to do with the disease itself because this is a disease where you have the production of a clonal protein. This clonal protein also impacts protein aggregation and very commonly, these patients with Waldenström will have issues with bleeding. So it's not uncommon to see some of this hemorrhage as we're seeing here. But again, it's a very small proportion of patients that were easily controlled.

For example, I had a patient that had with Waldenström's that now is in complete response only disease detectable when we did his bone marrow biopsy and previous exposure to multiple BTK inhibitors and he had a small surgical resection. We held the drug. He had no bleeding complication, the surgeon to me, yes. was a little us. He's probably just from his disease itself. He had held the drug. The drug was not present. We held the drug as we expect a few days before the procedure. And you still had a little bit of using during the surgery. That was easily controlled, which just demonstrates that this is really inherent to the disease.

And this is the response assessment. So we have our primary efficacy analysis with 28 patients and an exploratory efficacy analysis with 2 different response assessments that we can talk a little bit about. In 23 patients, we see that your objective response rate is 75% in the primary efficacy analysis and 83% with the exploratory efficacy analysis with a major response rate, which means very good response or partial response or better, about 60% and 70%.

One thing that is extremely important to tell in Waldenström's is that in Waldenström macroglobulinemia, you do not see a survival difference between patients that have a partial response or complete response. So having a partial response has the same impact on survival in these patients compared to complete responses. So it's very unusual to see complete responses in this population when you're using BTK targeting alone. So the fact that you have a very refractory population, you're still seeing objective response rate in the 70s, 80s is very remarkable.

There we go. And this is the graph demonstrating the responses over time. So we see that a lot of these patients had previous BTK inhibitors. Some of them would be 2 inhibitors, BTK inhibitors. Some of these patients but also previous pirtobrutinib as you can see, a lot of these patients didn't have information on the CXCR4 mutation status, but most of them as expected with [indiscernible] mutation. And you can see in these blots that most of these patients not only have responses but continue to response over time.

And we've seen responses even in those big new patients that had CNS involvement at present at baseline.

So again, this is our novel BTK integrator with a very important activity even in patients with resistant mutations, very hard to treat patients with Waldenström macroglobulinemia in a shorter median follow-up of 8 months, a lot of patients still on therapy showing progressive responses. So in the safety population, the drug was very well tolerated, no new adverse events. Most adverse events were low grade and easily controlled. There were no DLTs. The treatment-related adverse events led to drug discontinuation with no great fiber diverse events.

In this 28 response available patients, we saw durable and deepening responses in this heavily pretreated population. Major response rate of 60% overall response rate of 75%, including some very good PRs and 14 PRs. And some of these responses deeply over time as we expect this class of drugs. Out of the 3 patients with CNS involvement you have responded and so far have not progressed. And 1 data that we did not show, but it's another way that we evaluate Waldenström responses, how the paraprotein change over time and what we see is this progressive drop in IgM levels over time with continued exposure to bexobrutideg.

And it's very remarkable to say that 14 patients continue on therapy even after more than 6 months of treatment. And I think this is my last slide.

So now I'll hand over to Dr. O'Connor.

So everyone's worst nightmare was tripping in front of an audience.

All right. Well, first and foremost, I'm going to move back to the mic so that everyone can hear me. Thank you. I want to echo Arthur's welcome. We all know that you have choices with your time, and so I appreciate you taking the time to even to spend it with us and to review our programs.

Before I start, I just want to acknowledge that today has been a really good day for targeted protein degradation. The data that you're seeing presented by Dr. Alan Carr, the presentations earlier for Chimera really point to the fact that targeted protein degradation has a role in the treatment of patients, whether you're looking at oncologic disease or whether you're looking at immunologic disease.

So I want to shout out to our Chief Scientific Officer, who is responsible for our platform that has enabled us to develop this drug and other drugs. And we really look forward to bringing them all across the finish line and changing how patients are treated.

So this I've already said, has been a big year for us. And so as you can see, the most important thing is we've established the go-forward dose, the recommended Phase II dose for bexobrutideg or Bexdeg as we would like to call it. Equally and importantly, this has been approved by the FDA in accordance with Project Optimus but also approved by the EMA and the MHRA as they have reviewed our data sets.

We started our first Phase II trial, our first pivotal trial. This is huge. This is -- we have just moved from an early-stage small company to a real player. And so this is a seminal time for us at Nurix, and we anticipate starting a randomized controlled trial in the first half of next year.

We've already talked about the emerging data that we have that helps to differentiate our agent so once again, another shot out to Gwenn and her team for allowing us to develop such a specific degrader in bexobrutideg and then lastly, we've had great data this year, which you've already seen.

So Dr. Alan Carr has mentioned our high objective response rate. He's mentioned of 83%. He's talked about the duration of response. So remember, ORR is the ticket to the game. DOR and PFS are what allow you to win. And when you look at the data that we've generated thus far in our Phase Ia across patients treated from anywhere between 500 to 600 milligrams to have this level of activity and durability is remarkable, especially when you start thinking about the context in which we're developing this drug. So this is -- I hate to say, if you have to have CLL, this is a great time to have it because we have a lot of very, very active drugs.

And despite that, what we can see even as we compare ourselves to the most recent entrant, which is pirtobrutinib, the objective response rates that we are seeing are better than theirs, meaning in the BRUIN 321 study in the JCO paper, which is the most mature data from that data set, their ORR was 65%, their DOR 13.8 months. There median PFS 14 months in the all-comer population, but 11.2 months in those who were double exposed. And I'll remind you that in our study, in our Phase Ia, 83% of the patients are double exposed. So as you look at the bottom of the slide, what you will see is when you think about the patient population, our patient population is more heavily pretreated. Some of them have already seen a non-covalent BTKi, which was obviously not the case in the BRUIN 321 study, and they've been more heavily exposed to BCL2 inhibitors. And so to see improved relative responses, meaning higher ORR, higher durability of response, higher median PFS, that is a game changer and means that we have something to offer to patients.

Many of you know that before I actually went into industry, I used to take care of patients with lymphomas and leukemias. And every day that I look at this data, I think about some of my patients, the patients that I actually didn't have anything to offer. And yes, I wish that they were here now because we now have something to offer them.

Our first pivotal trial is a single-arm Phase II that you see here. We will be enrolling triple exposed patients. Those patients will have to have been exposed to either a covalent BTKi, a noncovalent BTKi and BCL-2 inhibitor.

This will be a global trial. We will enroll people and treat them at the 600-milligram dose level. We'll be looking at ORR as our primary endpoint, obviously, following for PFS and for safety. This program has already started with patients already being enrolled in Europe, and we hope to open several sites in the U.S. later will actually this month.

Okay. It's not just you. Okay. Our randomized controlled trial will begin in the first half of next year. In this case, we'll be focused on patients who've been previously exposed to a BTKi. They may be in as early as the second line setting. We anticipate that a lot of the patients who enrolled in this study just as was the case in the BRUIN 321 study will be double exposed.

We will have 400 patients approximately who will be randomized between Bexdeg or our control arm, which is an investigator's choice of pirtobrutinib or chemo immunotherapy.

We will follow patients for PFS. For those patients who are on the control arm who do, in fact, progress, they will have the opportunity for crossover that will increase the attractiveness of the study and help with the speed of enrollment. We will obviously follow for our primary endpoint of PFS and then also assess for safety. So this is our confirmatory trial.

And then our next trial that we will be initiating in 2026 will be the Phase Ib/II combination study, which will really set the stage for our combination study in the second line plus setting as well as the future frontline study. And so what you see is we will be looking at a series of venetoclax doublets or at least a bexobrutideg venetoclax doublet as well as 2 triplets, one with rituxi, one with obi. Once we've established the dose for these in the second-line plus setting, utilizing a fixed duration therapy, we will then assess the activity of these in the frontline setting, specifically looking at the doublet of Bexdeg and ven and then the Bexdeg ven obi triplet.

So we know based upon the data that we've generated in our 301 study that Bexdeg clearly has a role to play in the treatment of patients with CLL and other potential malignancies. And so we will begin first with our monotherapy approaches, utilizing our single-arm Phase II and our randomized controlled trial, the Phase III and then we will set ourselves up to ask the combination question with this Ib/II in anticipation of conducting pivotal trials in combination.

So it's a good day to be on the Bexdeg team. We look forward to building on the data that we've already demonstrated where we've seen a high degree of activity as evidenced by the objective response rate of 83% in our Phase Ia and a median PFS of 22.1 months. We've seen similar activity in Waldenström's. So this gives us confidence that there is a potential path forward here as well. And then although I've not presented it here, I will just dangle the plan to present other NHL data mid-year sometime next year, which gives you a view on our other NHL subsets. namely those that you see here, DLBCL mantle cell follicular. And given our conversation already, I want to highlight primary CNS lymphoma as well.

So thank you for your attention. I'll turn things back over to Arthur.

Okay. So I think let's open it up for Q&A. What's it? I have a few more slides, but I don't want to show them because I want to get to the Q&A because I think we've seen a lot of slides everybody today, there's some tire conference, nothing but slides. So -- and I know it's been a long day. So if we could, thank you, Gwenn Hansen, our Chief Scientific Officer, coming up for Q&A. And we have microphones in the room. And I think we also have the capacity to get some questions online. So why don't we go ahead and start? He's got a mic there. There you go. Roger. Yes, go ahead.

Great. congrats for a very successful ASH for Eric's team Roger Song, Jefferies. Maybe to the question, related to the doctor earlier comment related to the fungal infection seems so we start to see some differentiation among the degrader. Maybe also the team can give us some either molecular or mechanistic reason why Bexdeg may have lower risk or no risk for the fungal infection?

Yes. Thank you, Roger. I'd like to direct that question to Gwenn Hansen, our Chief Scientific Officer, who has conducted all of the selectivity studies, et cetera. So Gwenn.

Sure. Thank you for the question. I think this is a really important point in the field of degraders. The understanding of how you determine selectivity is something that we have had to really develop appreciation of in the field. And degraders really need to be assessed in global proteomic studies in very sensitive cell types that can really elucidate whether or not your drug is degrading off target. So we have shown some of this data recently in a couple of settings where we compare the selectivity of bexobrutideg to the B1 molecule as well as the AbbVie molecule. And it's very clear to us that there are off targets at clinically relevant doses for both B1 and AbbVie's molecules that we really do not see at those same exposure concentrations that we're using in the clinic.

So we really feel that some of the early signals that are being seen in the clinic are related to that, either ability to avoid off-target degradation or not?

Thank you next question right up here. Go ahead. yes.

Congrats on the [indiscernible]. Chris from Lucid Capital Markets. Maybe one for Dr. Alan Carr with this new data that we've gotten, do you have any new thoughts on how bexobrutideg compares to other BTK degraders in development?

That we have what was presented here at ASH with the B1, the greater. I think that's the best 1 that we have to compare we really don't have a lot of information on the AbbVie the greater what it has been, where it is. So we see between both, and that's what was just demonstrated on Saturday is that it seems that bexobrutideg has a little bit of a more not only better, more solid follow-up data, so more solid responses and follow-up, but better tolerability, we see less of these issues of concerns with cytopenias and infectors complications. So the numbers are relatively similar numbers a little bit better with Bexdeg. So that's really the best that we have today. It's really the fact that, yes, the class is extremely important. the plastic that we have is what was presented this weekend. And from the comparison that we have, it seems that there is really advantage that probably reflects what we're just seeing the fact that it's more selective and even more effective and with that, a little bit of a better response rate and less toxicity.

Okay. Let's go to Gil.

Gil Blum, Needham & Company. Another question for Dr. Carr. So in the water storms of cohort, I know these are really small numbers, but it looked like at least a couple of the patients that didn't do as well had more prior lines of agents. Any commentary there?

It's very difficult to say whether it's just a reflection of patients that were more lines of therapy. The more exposure they have, they become harder to treat. What we know is that mechanisms of resistance may change over time with a number of lines of therapy. Some of these may be less dependent on BTK pathway overall. So it's just probably a reflection of an even harder patient to treat, and it is such a small number. I don't think we can make much interpretation on that.

Great, Matt.

Matt Biegler, Opp Co. About a dozen patients post [indiscernible] here, 62% OR. Is that kind of the bar that you're seeing for the DAYBreak 201 trial. And then Dr. Carr, do you see this in the clinic as kind of an emerging unmet need for our patients that have been exposed to the non-covalent and the covalent than and/or maybe obinutuzumab.

I'd like to have Dr. Alan Carr comment, but also Paula, if you could comment on this question. Go ahead, Dr. Alan Carr.

So the truth is that covalent, non-covalent BTK inhibitors today kind of they are seeing very close to each other in the clinic in standard of care. Mainly when you go to community practice, I do a lot of these education sessions. And so they're kind of seen together. And even though there's a clear differentiation, it's still not that very well understood. But yes, you still see patients that very clearly who progressed with covalent BTK and non-covalent BTK inhibitor, and still will require more therapy. They still have venetoclax and you're going to see more and more of these combinations.

But I think that the point the two points here is not only that there is clear unmet need because these patients will indeed progress through a covalent non-covalent and venetoclax in used to need options, but also because we're combining these drugs, the mechanism of resistance changes, and this will increase even more than need for additional targeting additional options.

Paula?

And so I'll just put the number 62.5% into context, especially when you've seen an 83% response rate overall. The numbers are small. In that -- on that slide, that represented patients treated at all dose levels. So you have small numbers, but you have the majority of patients being treated at dose levels less than 600. So I don't think we have a full understanding of what we will see in our Phase II study.

That having been said, another really important point to note, as Dr. Alan Carr has already alluded to, is that stable disease is not included in your objective response rate. And for these patients, in particular, who have been very heavily pretreated, stable disease actually represents a win as well. So we look forward to providing potentially more data on these subsets at a future meeting midyear.

Great. All right. Let's go right there. Yes.

Yes. This is Sudan Loganathan from Stephens. For the team, for the Nurix team. I wanted to ask, when you stratify responses more by mutational subgroup, cytogenetics and depth of prior BTK inhibitor exposure are you seeing any early signals that particular biological subsets respond with different kinetics either in terms of time to response, depth of response or early PFS separation, particularly in the 600-milligram cohort?

Okay. That is a detailed question. I'm just going to open up to the panel, whoever would like to answer that first. And then we may have more than one answer because I think Gwenn may have an answer and Dr. Alan Carr has an answer to.

We all want to chime in. So I'm going to start with what we are seeing across the mutational profile. We're seeing responses across all types of mutations. That's number one. And there's no significant difference irrespective of the type of mutation that you have.

Number two, in terms of the time to response, that is a very difficult thing to tease out with the numbers that we have, recognizing that many of the patients who have non-C481 mutations may have also seen a non-covalent BTKi and/or have multiple mutations at one time. I think the most important thing is whether people respond yes or no, and we are seeing that. And then I'll turn things over to...

Dr. Alan Carr. I think I go ahead.

I'll tell you what I see in the clinic, which I think is one matters the most. And what we see is that responses are very fast so when we're starting patients on the drug to, you'll be feeling better next week. You can look at semi, you're going to see lymph node smaller next week, ongoing changes in our accounts in a week. So we see clinical responses that are very fast. So the clinical benefit happens very fast.

What I told you is that you see deepening of response over time. So you start seeing the clinical benefit and then you see this low, progressive response and the continued exposure. So the clinical benefit happens fast. And what we see from the response rate, the great majority of patients will demonstrate clinical benefit almost off back from the very first few weeks of their own therapy. And what we'll see over time is that then you start seeing progressive deeper results. That's why that graph was so nice because you can see that in different compartments, the depth of response happened at a different time point because it's just really how the disease behaves when you have just BTK targeting a single agent if you want to expedite responses, you use combinations and all that. But as a single agent, you see very fast clinical response.

And we're seeing this even in patients that are coming to us knowing they had multiple previous lines of therapy known to have mutations so I'm not concerned when I'm putting a patient on the study regardless of the imitation that may be coming to us and what I'm not going to put a patient on stenosis not going to respond because it has X, Y or Z mutation. So those the point that you bring asking about the time frame response is very important because you won't have clinical response. You want to have benefit fast and did you see very clearly.

Wow, I mean that is so meaningful that or a patient having being able to hear that, that reassurance thank you for that. Gwenn?

Yes. The only thing I think I will add to this, and this has already been said tonight, but we should reinforce it here. We haven't treated that many people at 600 milligrams to start, right? We were doing a dose escalation, then we did the randomization. So we are actually not going to really understand the responses across all the different carry types until we get more patients into our 600-milligram optimized dose.

We definitely understand that we have longer progression-free survival in 600 milligram. That is because it is covering the target the best compared to all the other doses. So I think it's just important for us to understand that we've seen incredible responses even at low doses, but the high dose is going to be very important.

Over here, Steve.

Yes, Steve Willey from Stifel. That was a good segue for my question, actually. So we know that patients were allowed to be dose escalated on an intra-patient basis and you showed the vignette of the CNS patient who was pushed to 600. So I guess in trying to contextualize the dose escalation PFS data in the context of knowing some of these doses that those patients were receiving were I guess suboptimal, do we know how many patients were eventually pushed to 600 through this intra-patient dose escalation that was allowed?

The protocol. Okay. So Paula, and I don't think the word pushed is correct, but go ahead.

Okay. So the way our protocol is written is that patients who were treated at initial dose levels of 300 milligrams or less had the opportunity to dose escalate. We did not require that these patients dose escalate. And so in addition to that, they only had the opportunity to have 2 dose escalations. So many actually have waited until we got to our recommended Phase II dose, which was in October. So I will be able to answer that question better because many patients have not actually had the opportunity to dose escalate because we had to get to the recommended Phase II dose.

And some patients that have had the opportunity have not done it. So I have patients that we had the option of escalating the dose, but we had absolutely no reason to do so, tolerated remarkably well, excellent response. So we discussed, would you like to increase the dose. And there was really no need to do so. So we're still trying to understand whether there was a need or so. So we just said, okay, let's see if we can just drag it a little bit longer and see if eventually something suggests that we might be losing response. And we need to have a reason to increase the dose and we'll do so. But I have patients at different dose levels and that we have had the option of increasing the dose we haven't had a reason to do. So some of the business are like, oh, I want the best as possible, less escalate. I really want it. And mainly that say, well, I don't expect changes in tolerability. So yes, where it can definitely increase but some patients like, why I need more? I'm happy where I am. So we've had both in the clinic.

Now that you've seen the 600 mg data randomized against the 2, would you?

Yes, we participated in the randomized portion I've been on the study really from the beginning, we're in the very first sites to open in the U.S. So I have really exposed patients from the 50 milligrams I participate in the randomized phase. So we have patients on 600 [indiscernible] very, very well.

And then just a quick curiosity question. So the waterfall plot that shows the mutational status of these patients. The VAT that's being reported is at 5%. And I would imagine the threshold for that is actually much lower in terms of sensitivity. So is that standardized across all trials? Like if I look at B1 protocol, would they be using a 5% threshold for mutational presence or absence?

From an investigator point, I will say there is really, really have no clear answer for that, right? So you can a 5% at is a very reasonable, probably clinically meaningful representative cut off. whether a smaller proportion really has significance is really difficult to tell. There is clonal pressure from different populations and you start really getting very complicated. So whether 1% or 5% is the right cut off, I think all I can tell you is that 5%, I think, is clinically significant. It's meaningful.

Paula or Gwenn, anything to add to that? If that's a scientific question. Okay. Let's go Okay. Back in the back there.

Greg Renza at Truist Securities. Congrats on a great weekend. Maybe another one for Dr. Alan Carr. Just with respect to chatter on the floors with amongst your colleagues around sequencing and how the various agents should be CLL-17, for example. If you want to say that continued therapy is the way to go, fine. It's just as equally effective. And if you want to use finite therapy combined and stuff, fine, just this as well, right? So then it gives you options and then it's just part of a very complex decision process when you're discussing with patients.

One thing that I see that tends to happen a lot is that when you go back to the first line today, when you're making a decision on which pathway you're going to follow, yes, you can combine a BCL2 inhibitor with a BTK inhibitor. But in essence, you're choosing between a backbone of BTK inhibition or BCL2 inhibition, right? And then as you go through the many different features that are going to decide, some are molecular features, some are social fishers, some of the patient that wishes that kind of guides you to s one way or the other.

And what we're seeing a lot are patients that just follow that path of BTK targeting because patients don't change much, right? So the decision that they made in the first line is the on the same decision they're going to make in second line, right? So the social situations are around the same and their life perspective around the same. So it's very common to see now patients are going to go from covalent, non-covalent to a degrader and then really going to BCL2 inhibition. I had a patient on the study that was exactly that. And actually, she was a very young patient that was treated initially by [indiscernible] with FCR and way back when she progressed. So with ofatumumab and lenalidomide also the study, then she moved to Florida. We start with nibrutinib and then came to me actually for the BRUIN study. Also I also was a main investigator in the BRUIN study, so she received pirto on BRUIN, did remarkably well. And then we could see that at every line of therapy, she was developing more resistance.

And then she progressed on BRUIN and shows quote on 5948 and had of incredible response. It was really exploding when she was started on BRUIN. They were really nice -- we even let me put on the study because he was being the verge of not being really a good candidate for the study because she was progressing so fast. She had a lot of electrolyte imbalances, her QTC her interval in the EKG was not that great. We start her on the drug. In a week, she was doing incredibly well. So and she had never seen a BCL2 inhibitor and she still hasn't, right?

So -- and you're going to see more and more of this is just you follow that path just because that's patients get used to it. You tell them it's kind of the same toxicity profile, so they're familiar with the class. They're familiar with the drug. So you're going to see more and more of this, especially now with the [indiscernible] indication after just a covalent BTK inhibitor. So going to become more and more of a norm.

Venetoclax is an excellent drug with combinations. I'm looking for, I'm going to participate on this because I really want to do this venetoclax requires additional layer of complex and a lot of patient wants to do.

Okay. Right here in front.

Tess Romero, JPMorgan. So specifically for you here, what are the lingering questions that you have at this point about the overall emerging product profile for Bexdeg and CLL? And what you would like to see specifically in next studies?

If you really want to know what I want to know there a chance to give us advice publicly.

So I'll tell you first what I so let me give you a little background. So I focus on the treatment of B-cell lymphomas, especially lymphomas that involve old people. So I treat a lot of CLL, do research of mental cell lymphoma and I have a special interest in CNS lymphoma. I really focus on CNS lymphoma.

And so let me give you the answer first for CLL. And I think what is happening with CLL and is something that we're not going to answer today, but it's something that is going to get more and more confusing, it's not only -- there's no question that bexobrutideg. It's incredibly active and is going to be approved and it's going to be used. I have no questions about that. I have been using the drug for more than 2 years now. I have trust in the drug, has worked in my hands, extremely well tolerated. The drug is phenomenal. I have no problem with that.

What is going to start getting more and more complicated is how are we going to really target BTK? You're starting to see the data of pirtobrutinib versus ibrutinib, for example, and you see that hint of overall survival benefit with pirtobrutinib compared to ibrutinib.

When we were approached for that study, I said, no, I don't want to be precept in the studies I want a dealer's choice. So maybe it wasn't ibrutinib, it's all this choice, maybe the number wouldn't be that incredible but still goes home, right? What is happening here? And I know that [indiscernible] is better tolerated than a [indiscernible] inhibitor. I was part of the study. I know how the drug works. But then what is going to happen, you're going to start seeing more and more pirto before covalent BTK inhibitors.

Are we killing a class? What is happening? Then you have Bexdeg which works even better, and it's been better tolerated. And I wouldn't be surprised, it is the same conundrum is going to happen. What is going to happen now and we're going to do this before pirto. Am I killing a class completely?

So this is something that this is what we've been discussing in the entire week. This is really what we in the entire weekend. It is what is going to happen is we have this more effective, better tolerated even better targeted drugs, what is going to happen in the class overall. But then comes the next point is that these drugs are remarkably well tolerated and are just primed to be combined. And then it opens an entire new discussion is how do you bear them? How can you really manage intermittent there or finite versus indefinite therapy? How do we integrate newer drugs, bispecific antibodies? We're combining with the venetoclax, but you have second-generation BCL2 inhibitors coming. We're combining with rituximab. Obinutuzumab is certainly better. what would happen if we combine with epcoritamab or vlufitumab. So it gets more and more fascinating and it's just wonderful because we have more and more options to treat patients.

And then what ends up happening is what we really need, which is really tailoring what each patient needs based on their social issues, based on their patient personal issues or their molecular features.

So then let me tell you a little bit just about CNS lymphoma because I just love CNS lymphoma. So I am incredibly excited about the drug for CNS involvement, not only primary secondary CNS lymphoma because not only the drug is incredibly active, but because so well tolerated and it's just again primed for combinations. CNS is not a typical inform what do you want to use a -- this drug as single agent, so you're expecting to combine. So I'm bugging Arthur every week to let me combine this drug with bispecific antibody, with other very effective agents because it's going to be a home run in CNS involvement.

I'm with you on that. Don't worry. Okay. Yes, Biren.

And maybe, I guess, a question for Dr. Alan Carr. On CNS involvement, what percentage of your CLL patients have CLL CNS involvement? And I think a second question also for you is on, I guess, with your experience, have you seen a dose response correlation to PFS even after program maxes out on BTK inhibition at lower doses? So I guess another way of asking is, is B1 leaving efficacy on the table by moving forward with the 200-milligram dose?

Okay. So the first question as far as CNS lymphoma and CLL. So I see a lot. Just because an expert I can just get a lot of referrals. So a larger proportion of my patients with CLL have CNS involvement.

Percentage, is it such a small percentage. The percentage that you see over time is really this 5%, 3% of the patient population overall. I see a lot. So I have patients with CLLs and CNS involvement, they were treated on the study and had responses. So I see more than the average physician in the community. Those physicians when maybe we'll see once the CLL patient was CNS involvement a year in their career because they're not common, but the factors that they are there, and it's certainly an issue, especially in these patients that get more and more treated, they become more and more resistant. It is extremely unusual, extremely to have CLL with CNS involvement at diagnosis.

These are typically patients especially fishes that have been treated not a typical CLL patient. The CLL patient that is just monitor and nothing ever happens and they die with the disease, not from the disease. This will happen more with the patients that develop mechanism resistance and have additional mutations and then they have more CNS involvement. All right. And the second question was...

The second question was around the dose response.

So two separate things. You asked me about inhibition. And as I told you, I was part of the drug development of pirtobrutinib as well. And on that study, we saw very similar things that we see here and which is really a fact of the class pretty much to some extent, right? We see differences still like with ibrutinib. We have more difference in dose response dose levels and toxicity. But in pirto for example, you had very good activity even at lower doses to the point that I am the global PI on a study that is evaluating 3 different dose levels of pirtobrutinib, 100 to 160 milligrams. So there's a possibility that in lower doses, you have very good activity and very much the same tolerability. So but what we have the data very clear with Bexdeg is that we're seeing that with the higher doses, we're overcoming these higher-risk mutations. So maybe you have better tissue penetration with a higher dose, maybe you really have better not a better credit because degradation even very, very low dose levels but there's something that allows a better response in the higher dose. So it's not necessarily more is more. But I think that a lot of these features you're not going to have available to you when you're evaluating these patients in the clinic.

So my recommendation then is go with the full dose because you're not expecting to have more toxicity and you're going to be overcoming any potential mutation that you might not really be identifying. But the truth is that if you have to adjust doses, there's a very good chance that you're going to if you have to hardly ever happen in the study. You have to adjust those because of toxicity, they were able to safely do so and now lose response. I don't know if I answered your question.

That was really helpful. And maybe a couple of questions for the company.

Sure. I guess I can answer questions. Go ahead.

Great. On the second line plus CLL pivotal study in the control arm, I believe the control arm is either pirtobrutinib or chemo immunotherapy. I think previously the company had defined chemo immunotherapy as IR or BR. Is that still the same definition? That's the first question.

And then second question would be I think there was an strict on that trial where the trial design for the control arm is subject to change based on changing standards and regulatory review. So if you could maybe provide additional color on what would justify a change in the control arm for the second-line pivotal?

Sure. I can address that. So yes, very astute to see that asterisk that was added. So the we operate in real time. This field is moving fast. I don't think there could be an ash that defines that more than this one with the approval of pirtobrutinib immediately before ASH kickoff and a lot of new pet data. And so the overarching principle in defining a control arm for a randomized controlled study, is that the control arm should be representative of the standard of care in the U.S., especially the primary area of market area for us and our population.

And so we are looking at what is that future standard of care as it evolves. And so I do think that's an active area for review for the company. And this is a very timely question and a time to look at that very closely. We are impressed with the pirto results. We think our drug is going to be superior. And we think that offers an advantage in terms of defining the control.

So stay tuned on that question, Biren, but it varies to good question. I'd say there's one more question. Yes, go ahead, Joe.

Joe Catanzaro from Mizuho. Two questions for me. One, maybe slightly boring. Why include rituximab combo in that combination study when obinutuzumab seems to be the preferred CD20?

And then second question, when do we start seeing MRD data? I recognize it's irrelevant in the context of relapsed disease, but I ask that because it seems like BTK inhibitor monotherapy is not very good at getting patients into MRD negativity. And so is there any reason to think that degraders might do a better job of getting patients there?

Go ahead, Paula.

So the -- I'm going to go with the last question because I can remember that. So we are, in fact, assessing MRD for our patients. We have not aligned on a time when we would present that data. We certainly want to have because we have sequential data. We're going to want to have a year or 2 years' worth of data before we actually present it. So that's one. Number -- what was your first question? Why retain because I worked on rituximab at Genentech when I joined industry that's not my so certainly, as Arthur has already mentioned, we are trying to set ourselves up to run future pivotal trials. And certainly, VR is a well-defined standard. That's one reason.

Another reason is in this world where people are trying to contain costs, some people will actually utilize rituximab or rituximab biosimilar because it is less expensive. And so we want to be able to provide with our clinical development plan, information that is going to inform how everyone treats their patients. So if that is their choice, then we will have data to support that.

So I told you that when I talked to belabor the Pert versus ibrutinib study. I told them, I wouldn't open a study because I don't think that ibrutinib is a fair comparator. And I told them, I would open it if it was a dealer's choice and they decided not to, we didn't open the study. So in this study, I would not have a problem in opening the study if I had that number one, because we have pirtobrutinib as an option and I think it is a more fair comparison for the U.S. for where we are today. But we know that in the global study, there are still many sites that is much more complicated to get obintuzumab. Rituximab at the proper doses, but those adjustment of 500 milligrams meter square. It's still a very reasonable anti-CD20 monoclonal antibody, mainly in the relapse setting. Yes, you have the run the data that is based on rituximab.

So when I'm asked what is your monoclonal antibody of choice, you're absolutely correct. the answer is on obinutuzumab, it is a superior antibody when you compare head to hatch rituximab. However, it kind of dilutes a little bit in combinations, and I think it's still a fair option, mainly as you think of a global study.

Yes. So thank you. I think that's all we have time for in terms of questions, I would like to make a few closing remarks. But with regard to this question, we do endeavor to address all the different segments of the patient population we want to help both in the United States and elsewhere with these trial designs.

So let me just make a few closing statements here in the last couple of minutes. It's at the end of the year, and I think it's appropriate to take a little look back at 2025. We really have achieved quite a bit at Nurix we're very proud of. Securing the 600-milligram dose, a lot of discussion about that tonight as per project Optimus, I think is a milestone. I think it's going to improve how we can address and treat advanced CLL and really get the best results overall.

We have initiated the DAYBreak study. It's a new day, I think, in CLL with DAYBreak. We're excited to see that move forward and enroll. And of course, our presentations here at ASH, I think, have been extremely well received, and we're very, very happy with what we've seen happen here.

With regard to our partnerships, we're very active. We believe in the partnership model. Gilead advancing GS-6791. They IRAK4 degrader through the SAD/MAD study. STAT6, going forward with Sanofi, we already mentioned that earlier. And I think that we've also seen a future for bexobrutideg in I&I, and we do have a new formulation, which we're pursuing through SAD/MAD studies as well.

We think in all of these I&I indications, we will have significant progress in 2026 and updates to look forward to.

We did present our first major updates on our Civil B inhibitor, MX-1607, which look quite intriguing, both at SITC and ESMO. And we've been very fortunate to have a terrific investor base, strengthening our balance sheet recently with a follow-on offering of $250 million, bringing our collective cash base to over $650 million and with the cash runway into 2028, which allows the company to do all of these great things with bexobrutideg and also move forward our pipeline.

As we look forward to 2026, just a little preview, we normally will give our bigger update on our 2026 goals at the JPMorgan conference in January, of course. But we do see multiple opportunities for new data in 2026 from cohorts in the Phase Ib. We've only been talking about Cohort 1 so far and then our Waldenström cohorts. But we as I said, we have approximately 100 patients in our NHL cohorts. We look forward to presenting that. bexobrutideg, we'll have the SAD/MAD study readouts in 2026.

And then turning to I&I, again, GS-6791 should have potentially Phase I results. We depend on Gilead for the timing of that, but that should be on the horizon. And we do anticipate an IND filing it with the STAT6 program with Sanofi and then also an IND filing for bexobrutideg and I&I so we are executing focused now fully on the pivotal development pathway with bexobrutideg. There may be some evolution of that pathway as we've seen and learned new data here at ASH this year. And we look forward to future updates in that regard.

So with that, I'd like to thank everyone for participating tonight. I know it's late here on the East Coast. I'd like to thank all of our investigators, thank Dr. Alan Carr so much. I felt there were so many very insightful answers tonight with learnings from you in the clinic, just incredible. Thank you. Of course, Paula and Gwenn, thank you, our entire executive team here.

And most importantly, to our patients. I'd like to thank all of our patients who have been dedicating themselves to our trial and trusting us and our physicians worldwide and trusting us with their patients. So thank you all very, very much, and good night. Thanks.

All right. Welcome, everyone, to Jefferies London Healthcare Conference 2025. My name is Roger Song, one of the senior analysts cover SMid-cap biotech in the U.S. It is my pleasure to have the fireside chat with our next company, Nurix Therapeutics, CEO, Arthur Sands.

Thanks for having us, Roger.

Absolutely. Great. Okay. So I think we have quite a few things to cover today. Why don't we start with the most near-term event that you will have at ASH, right? So you just announced you will have -- you announced before you will have data, the abstract presentation and then some event at ASH. Can you just give us an overview, preview what we expect to see at ASH? And then we can drill down a bit of details.

Sure. Yes. So we're looking forward to ASH. It's a big event for us every year. So we will be reporting on bexobrutideg NX-5948 follow-up data, longer-term data from the Phase Ia as well as data from the Phase Ib. I think the most relevant disclosures will involve the duration of therapy, duration of response, where now in the Phase Ia, these are the patients that have been on the drug the longest, so we can start to actually measure and look at PFS and duration of response, and so that's a critical factor. It will be the first time, I think, that we'll have enough time gone by on therapy to be able to measure this because we've had patients now over 2 years on therapy. So I think that will be one important component.

The other will be looking at the dose selection for the pivotal trial, which I'm talking about in CLL, which is our primary indication. That is we've selected the 600-milligram once-a-day dose for bexobrutideg. This is a result of running our Project Optimus randomized cohorts in Phase Ib, looking at 200 versus 600. And so this is, I think, an important development for the program. We're very enthusiastic about having the 600-milligram dose being selected and having FDA agreement with that selection. It enables us to maximize for efficacy, which is, of course, critical. And we can do that because the safety profile was very similar to the 200 and any of the other doses, too. We've tested from 50 to 600.

So having a safe profile allows you to test to proceed with your maximum dose to really push the efficacy envelope and maximize efficacy. This becomes important to address, we can degrade all of the BTK protein in the cell, even those proteins that have gained mutations as patients have become resistant to the current BTK inhibitors, including all the covalent, non-covalent. There's 5 or 6 mutations that come up, these resistance mutations. And we've seen this in about 40% of our patients. So bexobrutideg can degrade all of them, which is great. You don't have to design a specific -- a new drug for every mutation, right? This is -- has the ability to degrade them all. So dose and duration therapy.

Excellent. Okay. Great. That's the beauty of the degrader for the well-validated target. Another thing is that you recently -- we're going to talk about the pivotal design and then what's the recent alignment with the FDA. But one thing is that your -- the later line CLL pivotal study, specifically in the triple exposed patient population. Will we be able to see some of those data? I mean maybe specific kind of sub cohort we will get from the Phase I or Phase Ia or Phase Ib for the triple exposed patient?

So it's too early to really do a really meaningful subset analysis at this point. We simply don't have enough patients in each of the categories. And so I think that will be a future disclosure. We have focused our first pivotal study, which is a single-arm study in the triple exposed population because we do see excellent activity there, and that's an area of high unmet medical need. So there's really no therapy approved here. We're anticipating that pirtobrutinib, the non-covalent inhibitor from Eli Lilly will gain full approval and that, therefore, that accelerated approval potential shifts to this triple exposed population, at least that's our anticipation.

Okay. Yes. Maybe stay on this pivotal plan, assuming you will do the study in the triple exposed patient and then you get approval and the accelerated approval path. And how do you think about the -- when you launch the drug and then using the population versus you have a competitor and it seems they are not specific for the triple exposed. And you say you're assuming -- you're expecting this product will become a standard of care at least in the U.S. How about U.S. versus ex U.S.? How do you think about this launch will -- your label will actually set you apart from your competitor?

Well, ultimately, the most important label is, of course, gaining full approval as a result of the randomized controlled study. I think the accelerated approval really allows physicians to start to work with the drug early to use the drug in certain populations and to really start to get into the market. But it really is not going to be the largest market, and that's not the intention of accelerated approval.

So we're really looking forward to the full approval for -- which we designed a study in the second line. So just after covalent BTK inhibitors would be the first full approval goal. And that is a very large market. We're talking of over 10,000 patients per year likely.

Got it. So the accelerated approval path is really fast to the market and then the most high unmet need, that's the intention for the initial population?

Yes. Currently, yes. And this may change. So some of the accelerated approval is -- can be a moving target and is defined by the agency really at the time of filing. And I do think that we have not only the triple exposed population, but we have other cohorts of patients in the Phase Ia and b that will also support, especially the safety database, of course, the ultimate filings.

Got it. Okay. Got it. And then maybe circle back on the ASH. So CLL, BTK degrader space, you have a couple of players there. And obviously, you will give us a very big update there. And what are the other data points you are looking for? And then also you can give investors some contextualization and say, okay, these are the data may be meaningful for us to compare across different programs.

Well, in our -- we have a podium presentation in that session, BeOne will also be presenting, I believe. And it's always kind of interesting to see this competing degrader. These molecules are kind of neck and neck, tend to share the same session at every international meeting. So it is really interesting to see these evolve. I think there's a lot of attention from the investigator community on the degrader modality. So we'll be looking to see what they present. But also pirtobrutinib's progress is always very important to us as I think the latest -- what will be the latest entrant into the CLL market.

We also are very -- we'll be presenting a poster on Waldenström, where we also see an 85% response rate, so very high response rate like CLL. And I think we'll be very interested in the other presentations on Waldenström's and other NHL programs. We have yet to present any of our NHL data, but we have over 100 patients in each of those across the NHL indication. So we'll be monitoring progress in NHL, which is a very complicated field with a lot of combinations.

So I think we're also planning a combination trial with bexobrutideg in CLL. And so I think looking at all the latest combination data with the inhibitors will also be informative as we formulate that trial.

Yes, absolutely. Okay. So the pivotal study, you started in the third plus line triple exposed population in the -- it's a single arm and then also the confirmatory study, the second plus line for the comparator. Just remind us what's the statistical assumption you designed the study? Yes, we'll start on there.

So it's -- for the first accelerated approval, it's about 100 patients. And we haven't revealed our exact statistical plan for that, but it's a fairly straightforward single-arm study. And so I think that will be, again, fairly straightforward from a stat standpoint. The randomized controlled trial of bexobrutideg versus standards of care, plural, we currently have outlined an investigator choice control arm, which we believe will include bendamustine and rituximab as one option, also pirtobrutinib as another option. Another option could be idelalisib and RITUXAN. But we are studying that because in different geographies, we want to do one global trial, different geographies have different approval status for -- or end use status for these different drugs.

So we're studying that very carefully. We want something that will be the most appealing across the board, and we'll be in over 20 countries with that randomized controlled trial. But currently, that's what we've outlined in terms of control arm. But again, we have to have conversations with all the regulatory authorities and come out to some consensus view of what trial -- what single trial would play well across the globe.

Yes. So because it is dealers choice across different comparator arm, how are you going to manage the comparator arm performance in the way you designed the study?

So we have made certain assumptions about use in the comparative -- in the control arm, but also we need to integrate regulatory feedback as we implement the Phase III. So there may be some regulatory considerations there in terms of what proportions of patients are required or desirable in the control arm. So all that's ongoing work.

Okay. So certain -- maybe some range of the population or the percentage of the patient population need to use certain comparator arm within those trials?

Yes. I think we'll have to study that. We haven't settled on what the breakdown would be. We want it to be, again, an attractive trial. We want patients to be -- to feel that they will gain an important therapy by being in the trial regardless of where they're randomized. So there's still some items that we need to calculate.

Got it. Okay. And then you mentioned you will have a combination as option moving forward. And this is also very important to move into a real first and second-line CLL population. So I believe you are starting or you already started the combination Phase I study. So when are we going to start to see those combo data? And then how is the moving to the pivotal stage?

Yes. So to be clear, we have not started that study yet, but it's in planning stages. I think combination of bexobrutideg, a BTK degrader with venetoclax is something I think everyone would like to see rapidly, so the BCL2 inhibitor. So that will be an important combination to get going and to decide on the dose. Again, since we have a safe profile, we feel very confident about our ability to combine. We have to prove that again that the safety is there. And so I think venetoclax will be one.

We're looking at anti-CD20 as well, potential rituximab or obinutuzumab. Obinutuzumab will be more of a front-line combination. Rituximab will be in the second-line. And then we have other -- we could combine also with bispecific antibodies. I think there's a lot of interest in looking at some type of T cell engager, bringing the T cell into the equation with bexobrutideg. So that's another potential combination. So again, stay tuned for that. We have not actually implemented that trial. We're actively working on planning.

Okay. Great. Okay. So this is your CLL part of the story. But given you are a degrader platform company, so you are having other angle. And then maybe start with the -- just still the BTK degrader, you are also potentially can do the I&I indication. So remind us where you are for the I&I, I believe you start from the CLL cohort and then moving to nonmalignant I&I population.

Yes. So BTK inhibitors have made a lot of progress in I&I indications, many indications where they've been tried. There's people are seeing success across several companies. The advantage we would have with a degrader, however, is really, we think, significant because the inhibitors are really only addressing the kinase function.

And as in CLL, we're addressing both the kinase function of BTK and the scaffolding function. So -- and we've discovered through our CLL work, the scaffolding function or structural function of BTK by virtue of the protein simply being there located at a node in the cytoplasm, B-cell receptor signaling goes through that structural function. It's not just the kinase function. And it's actually quite a significant and powerful signaling function coming through that.

And so we think we can bring the same improved efficacy to autoimmune disease as we're seeing in CLL. And so we have a mechanistic rationale to have BTK degradation be an advantage in autoimmune disease. So we are and have developed a new formulation for bexobrutideg, which we think would distinguish its product profile. We have not revealed what those attributes are yet. We are currently in multiple ascending dose studies in healthy volunteers in preparation for potential I&I IND in 2026.

Got it. And I believe your bexo is also starting to get some data from the I&I population within the CLL patients. So where they are? And then do we expect to see any clinical data?

Yes, we were able to fairly rapidly -- we've opened a cohort in CLL for patients that have autoimmune disease also. So there's a layer of warm autoimmune hemolytic anemia in CLL in certain CLL patients. So we do have a separate cohort there. That cohort is not enrolled yet. And so we'll have to -- we have not forecast when we'll have data from that.

I should also mention we also have our CNS involvement cohort. That's another distinguishing feature of bexobrutideg is the activity in the CNS. So we enrolled patients with CNS lymphoma. And -- but again, on the I&I front, it's the wAIHA group of patients.

Okay. You have not yet enrolled patients?

Well, we have enrolled patients. We haven't completed enrollment, and we don't have enough patients to really report on yet. But we have enrolled patients, yes.

Got it. Got it. And then in terms of nonmalignant autoimmune disease, what are the -- BTK approved in multiple indications, including multiple sclerosis and then CSU. So what are the indications most that interest to you? And then also, how is the feedback you hear that may need to address on top of the -- beyond the inhibitor, the indication you can address?

So I think I mentioned the CNS activity because I think in MS, it is probably really one of the most interesting areas potentially given Roche's recent results with their BTK inhibitor in MS, I think were encouraging based on their press release. I think Sanofi's results have also been very encouraging, they had 2 major publications in the New England Journal of Medicine. And the central thesis there in terms of why it's advantageous as compared to the anti-CD20 antibodies in MS, which currently dominate really the MS market.

Is that you're blocking the actual microglia in the brain that are thought to be responsible for the neuronal -- the degradation of neurons and for the ultimate neuronal damage is driven by that brain resident inflammatory process rather than just depleting the B-cells, you actually need a molecule that can block the microglia activity. So that's the central thesis of -- and you'll really modify disease, the disease progression then. That is really the hope, and I think it is the most exciting thing in MS right now.

Data we have, we know we cross the blood-brain barrier, number one, from our CLL patients. We know we have responses with in patients that have CNS disease, quite dramatic responses. So we have clinical activity. Our drug levels in the cerebral spinal fluid, CSF are basically equivalent to the free drug plasma levels. So we get a 1:1, we're getting good exposure in the brain.

And then some of our recent data in animal models, especially the rat, we see basically 97% plus degradation of BTK, so removal of BTK from the microglia cells. So we have a direct measure of hitting this microglia hypothesis. Of course, the microglia are thought to be responsible at MS is the largest, but any neuroinflammatory type of disease. So I think that's a very exciting pathway. You're right, in skin, CSU and others, others have shown activity. So there's a lot of excitement in the field, and I think bringing a degrader into that realm could be quite interesting.

Excellent. Okay. We spent most of the time on the BTK as expected. But as we mentioned, you have a platform and you also have some partnership, right? So some of the high interest, high-value target, including STAT6 and IRAK. So maybe one is where is the status of those kind of the early partnership pipeline? And then also how you think about the read-through from the industry from other companies, you think -- compare your program with theirs and then once they get data and how you think about the read-through?

Yes. So the first one, IRAK4 degrader is with Gilead, GS-6791 is in a multiple ascending dose study currently. So they're conducting the Phase I program. That has been a discovery program with Gilead for the past 6 years. So we're very happy that it's in Phase I. We hope that we'll see data from that in 2026. That program has excellent profile. It obviously has sailed through all the safety studies. We have not seen any QT signal there, which is one of the signals that derailed another molecule in the space, not our molecule, but a competing molecule. So we're very happy with the profile of GS-6791.

And then the second one is in IND-enabling studies is our STAT6 degrader, NX-3911, it is with Sanofi, who's prosecuting the IND-enabling studies. We expect it to get a very long Sanofi number eventually, but NX-3911 is easy to remember. So it's a great profile drug. We were allowed to show certain data -- preclinical data for both of those recently. 3911, the STAT6 degrader is extremely potent. It's picomolar level degradation of STAT6, very clean safety profile. We showed the proteomic profile where the only protein degrader is STAT6. So it's very, very significant and clean. And that, I think, has gotten a lot of attention.

We know that Kymera will have data shortly. I think that's the program you're referring to, their STAT6 program. That looked quite good in Phase I. We look forward to their atopic dermatitis data. The big -- of course, the big goal is to have a Dupixent in a pill is the goal for this in terms of therapeutic profile, so a very large market opportunity.

Yes, sure. And then you do have the co-development and then co-commercialization rights. Right now, they control the early development, but you do have that. So remind us of where you are and how you're going to make that decision to opt-in to become the co?

Yes. Thanks for bringing that up. Yes, we have a very valuable opt-in right after human proof of concept for our STAT6 degrader with Sanofi. And that option would trigger a 50-50 co-development in the United States co-commercialization. So we get to see human data before we make that decision. Obviously, the data is what is the most important in terms of deciding factor. But if the data from the human studies of patients look anything like they do in the animals, which are fantastic atopic dermatitis results, asthma results we've seen in these animal models with Sanofi. And then obviously, that would be a great option to exercise.

IRAK4, similarly, we are able to see Phase I data. So we get to see the human data package from Phase I with Gilead and then make a decision about the option there. With the Gilead option, they do have 1 veto right. We have options on several programs across our partnerships. We actually have 6 options across 3 partnerships. So a number of these options will be hitting -- starting to hit in the '26, '27, '28 time frame. So we're going to have a lot of decisions to make, a lot of data to consider and a lot of very valuable options. Sanofi does not have that veto right. We were able to not have that in that agreement. So there's no veto right there, but...

That's interesting. Okay.

Yes. It's a little hope.

Yes. push pull. Okay. But lastly, you have a lead program in a very late stage and then potentially moving towards the pivotal. And then also you have earlier pipeline and also the partnership. How does your balance sheet look like? And then any other early pipeline you want to highlight to us for the last minute?

Yes. So we are very fortunate to have a great group of investors participate in the recent round. Raised $250 million, about a month ago. That counting that, it brings us to over $650 million in the bank. So we're in a very strong position runway through the beginning of 2028. So that's important. It allows us to get our CLL program fully underway. And also we expect during that time horizon, we'll have some of these options we talked about that will come to fruition. Fortunately, those don't cost us anything when we act on them. There's no option fee, but then we would be responsible for go-forward funding in the United States.

Yes. And obviously, if your data is positive, you make the decision opt-in, probably the investor community will appreciate the opportunity and then you can.

Oh, yes, that will be part of the equation.

Got it. All right. Thank you, Arthur, for this morning. And then thank you, everyone.

Thank you, Roger.

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.

Yes. So at Nurix, we're focused on targeted protein degradation as a new modality, first in CLL. So 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. And we target BTK, which is a validated -- clinically validated drug target, but 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 patients, CLL patients who have seen 4 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. So this degradation modality, we see as a fundamentally new way of targeting cancer targets, but 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. So a very broad therapeutic area potential. I've just mentioned our lead program a little bit, and we can talk in any direction like it to go.

Yes. 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, right? So you declared the nomination of a go-forward dose. You initiated the registrational Phase II program in triple-exposed patients. And then you kind of gave us an outline of what a confirmatory Phase III would look like.

So maybe starting with dose. I guess when I look at the clinical data that we've seen to date, right, there really hasn't been a ton of daylight between the 200 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 in the context of clinical data?

Yes. So we have not -- so we're going to be presenting at ASH #1 coming up here. So we will be talking more about this in terms of the actual data behind the 200 and 600-milligram doses. But those were the 2 doses that we took into our randomized Phase Ib under Project Optimus to really look for safety, which is the #1 -- having seen efficacy across the board, as you point out, but the question is, is there a safe dose that -- where you can actually push the boundaries of efficacy in terms of target coverage.

And so as you point out, the 600-milligram 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. So 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.

And so at the 600-milligram dose, we believe we can get better coverage across the board, across any of the mutations that we've seen in the clinic. And this should spell out in terms of better efficacy overall, longer durability, progression-free survival. So 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, and you really have to keep this enzyme suppressed almost completely in order to suppress growth of the cells. And that's why the 600-milligram dose is really an advantage. And it's also, as I said, reflects on the safety of the molecule.

Okay. On the accelerated approval trial, you've identified this triple exposed class of patients. Maybe you could talk a little bit about what that triple-exposed class is. And do we know currently what proportion of CLL patients kind of fall into that triple-exposed bucket? And then given pirto availability right now just from a geographic perspective, do you have to primarily enroll in the U.S. to capture all these patients?

Yes. So the 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. But they've also then been treated with a BCL-2 inhibitor, largely venetoclax. They may have received those at the same time in combination. And then the third item is a noncovalent so pirtobrutinib, most likely non-covalent inhibitor of BTK. So those 3 drugs are -- the shorthand is triple exposed.

So unfortunately, patients can sequence through those fairly rapidly. So -- and resistance then crops up. And so these are the patients that we see as an unmet medical need, and 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, these are -- we've treated already fourth-line patients. Triple exposed are essentially fourth line, but we've treated from 4th to 10th line patients that have seen all sorts of other therapies as well. So that's the category that we're going after here with the accelerated approval single-arm study.

Okay. And just in terms of where you'll have to center your enrollment efforts?

Largely U.S., but also Europe, and those will be the focal point of the 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 at the time of filing, yes.

And then 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?

Well, we know that they are included, I think, in everyone's trial at this stage. So I think B1, you're referring to B1. So yes, 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. But again, it's a review issue. And in general, the whole accelerated approval paradigm is really is questionable at this point in time, with this FDA, what does constitute accelerated approval, et cetera. And it's on a case-by-case basis. So we'll see. But again, it generally means a category of patients where there's no approved agent, and this would be the triple exposed population.

Because I was looking through the -- I think the B1 protocol. And I know that they're going to be including these patients, but I can't tell if they're prespecifying for these patients.

Yes, well you'd have to ask them. I don't...

Okay. Do you have any sense from that from your initial conversations with FDA, just with respect to what the duration of follow-up will need to look like at the time of filing from this triple-exposed DAYBreak trial that you're running?

In general, it's about a year. Yes. That's -- I think that would be about the number to target.

Okay. 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 prespecified menu of different control arm options.

Yes. So our goal with the confirmatory trial was to design a trial that could -- a single trial that could address the global -- sort of global formulary for CLL in the second-line plus setting. So we're targeting patients that have received a covalent BTK inhibitor but have progressed on that. And so that's the second-line trial.

And then -- so if you look for a global trial, then pirtobrutinib was not approved in many, many regions. And so one has to select a confirmatory or control arm that can be prescribed in those regions. And so 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. And then also Idelalisib, rituximab. So those 2 combinations as choices. So it is a challenge to develop a trial that can enroll globally, a single trial. And so that's our attempt at addressing the various geographies in one trial.

So 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. And I think it though is an active area for us to evaluate how best to really create, again, the most attractive control arm. So it is something that we're actively dealing with as we set up this trial.

Okay. 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?

So that's one option. It's not entirely attractive because if you give physicians choice, you really want them to have a choice, right, in terms of what to prescribe. So we're -- again, we're currently navigating that and determining the actual logistics.

And I would imagine how you navigate that would also dictate the way you think about powering assumptions as well, right? Because I would imagine that there's a different outcome assumption for each of these control arm therapies. And 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. So it's a moving target right now. So the beauty of Bexdeg is that we don't know our PFS, the progression-free survival number yet because patients are staying on this drug a long time. So it's -- but as our datasets evolve, especially with the Phase Ia, we hope to learn what will that number be? How -- what is the duration of therapy? So far, it just keeps getting extended out, which is excellent, but 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, right, because we want to design the trial that will win, and we want to know what our drug -- what it can do, how it can perform against the control. So 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. So 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-covalence as well.

Okay. Yes, I definitely want to talk about ASH. But maybe just one more Phase III study, right? So I think the initiation of this in terms of it starting in the first half of next year would align with this notion of, okay, you're going to have this DAYBreak trial data that you're going to submit to FDA for accelerated approval. And at that point, you need to have sufficient enrollment in the confirmatory Phase III.

So should we assume that the way that you're rolling enrollment of these 2 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?

Yes. That is definitely the goal is to make sure that the Phase III is sufficiently enrolled. The keyword there is sufficiently, and that's not well defined. But the sooner, the better in terms of getting the Phase III up and running. But 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 3 years from now.

And so those are things that we're taking into consideration here over the next few months. But yes, our goal is to initiate that trial in the first half of 2026.

Okay. So moving to ASH, we'll be getting an updated dose expansion escalation. I'm sorry, a question in the back, Renee?

You may have covered this, but this Phase III trial that is designed, it will be designed to look for a superiority standard of care or noninferiority?

So the question is whether or not the Phase III will be designed to look for superiority versus noninferiority.

It will be designed to look for superiority to the control arm, yes.

So 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? And is there anything that you would kind of suggest to investors that they should maybe pay -- be paying some attention to?

Certainly. The -- so the abstracts published, and it was sufficiently vague in order to allow us to present the data that we want to -- we think is going to be most impactful at the time of the presentation because, of course, you submit these abstracts in August and then the presentations in December.

So there's a big gap there, and there's a lot of -- there's data cuts that occur. But 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. So I think that will 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. So I think those 2 things because if you combine those 2 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. So 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. So I think it will be really interesting. We often end up on the podium together with our competitors, and it usually makes for pretty interesting sessions.

So this notion of being able to get better visibility into durability. I know at EHA, right, you presented the dose escalation data only, right? And that kind of is the segment of patients who have been on drug the longest, and that allows us to maybe better tease out what that durability might look like. The ASH abstract lumped the 2 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 and that would be the Phase Ia. Then the Ib section where we're able to look at a randomization and doses gives you this picture into the dose question, right?

So -- and then you can look at -- for safety, you can look at the groups together. So 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, right? So 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 to 600 milligrams, and they're all mixed together in terms of treatment duration. So 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 sufficiently long period of time, right?

So the snapshot that you'll see from -- at ASH and the Ia in terms of duration, I think, should be an underestimate basically of what the drug can actually do.

Okay. So one of the updates you also gave here in conjunction with this overview was this selectivity data, right? And I know that you and I have been kind of qualitatively speaking to this for a little while. But I think we finally saw a snapshot of it. And 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. And 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. So -- and we see the selectivity superiority based on proteomics, very in-depth proteomics. So when you're working with a degrader, you can actually do the proteomics on cell types of relevance, i.e., B cells, and we've done this head-to-head against B1 and against AbbVie's molecule. And you can see which proteins are degraded that disappear in the proteomic scan.

And for us, if you go at 10x the dose level that we treat, which is way you evaluate these drugs for selectivity, the only protein degraded is BTK. So it's really -- 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. AbbVie 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.

And 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. So this proteomic scanning is really the latest technology to show this ability. And I think before degraders and before the proteomics at this level, you couldn't tell how clean your drug was. So of course, we've been using proteomics for years. And so Bexdeg is an extremely clean selective drug, and we think that will translate to safety advantages.

People are familiar with the kinome scan to look for selectivity and kinase inhibitors. This takes it to a whole another level of selectivity. And so it's pretty impressive technology. So we think we're the most selective, and we think we're going to have -- that will translate to the both safety profile, and it also has translated to enabling us to dose at the 600-milligram dose level to get efficacy, maximize efficacy.

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?

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. And so in 2026, we expect to share those data, and that will really speak to the dose and also talk about which indication we intend to pursue. So this application of BTK in I&I, I think the inhibitors have gone there already, and 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 penetrants of Bexdeg is pretty exquisite. So 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, but where does MS sit on the hierarchy of things that you're interested in?

Well, given Roche's results, which I think are fantastic, on top of them Sanofi's result, I think it puts MS very high in terms of the target list for indications for a degrader. So the central thesis there is that they can inhibit the microglia, BTK in the microglia of the brain, and that will shut down the neuronal-based attack on neurons basically.

So what's impressive with Bexdeg is we've done all those experiments, okay, with -- in animal models. In rats, especially, we've seen near 100% degradation of BTK in microglia in the brains. And 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. So we have little doubt that we have activity that's profound in the brain. And we think that this can translate to a real advantage potentially in MS. So the microglia are really the target.

So it's really an exciting advancement of the field. But the advantage of a degrader versus inhibitor is that one Bexdeg molecule can degrade 10,000 to 20,000 BTK target proteins per hour. This is how the degradation is catalytic, how powerful it is. So it really will be able to deliver, we think, a much greater therapeutic effect than any inhibitor in the I&I setting.

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? And 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 antitumor effects, and we published that at ESMO and now again, at SITC, another dimension that we published. And the signal was the strongest in colorectal cancer and prostate cancer. So cancers are normally cold, cold tumors in terms of their response to anti-PD-1 antibodies.

So we're very encouraged by that. The biggest indicator for a potential successful IO agent is to see monotherapy activity. And we think we're seeing strong signals of monotherapy activity. The next step then would be to expand that and confirm those signals. So in a Ib study to expand cohorts as monotherapy and look for monotherapy activity against the tumors.

Okay. 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.

So it is a combination drug in one pill, in one molecule. It does deliver Revlimid-like activity along with BTK degradation. So 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. So that is currently in dose escalation. We want to finish that in 2026 and then determine the next steps for that molecule.

Okay. 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. But 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, right? So maybe the first-gen 1.0 version of an IRAK4 degrader from Kymera, now kind of the STAT6 degrader from Kymera. Where do you think there's opportunity to differentiate? And I guess in the case of STAT6, just given the magnitude of the opportunity, does that differentiation matter?

Well, 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.

So 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. And so really, you have very low tolerability for any safety issues. That's what happened to the first IRAK4 degrader ran into some types of safety issues, which was then canceled by -- with Sanofi and Kymera.

Ours is in MAD studies right now, healthy volunteers with Gilead. And we think that we have a very clean molecule, our IRAK4 degrader, we think will proceed nicely into the clinic. We work extremely hard to make that exquisitely selective and safe, and 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. And we really throw the book of these molecules, making sure that we find the cleanest molecule that degrades just one protein. STAT6, it's clearly the sole protein we degrade. So I think that we're in a good position there. Sanofi has taken that molecule, which is NX-3911 into IND-enabling studies. And in 2026, we should see it go into healthy volunteers.

Okay. And then what are you expecting from the IRAK4 degrader that Gilead currently has in clinical development? And I guess, do you have any freedom to communicate around progress that is made with that drug under the umbrella of that collaboration? Or 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.

So they've been very good to collaborate with in terms of publication. And they published, too. They presented this fall, September, they did a whole poster on GS-6791 is the Gilead number now. And then also, 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. And they're interested in atopic dermatitis, of course, and other -- there's, of course, a whole host. So yes, I think we'll be seeing data from -- I certainly hope so from the IRAK4 degrader.

Okay. 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.

Yes. So we have over $650 million in cash currently. This gives us runway through the end of 2027 into 2028. And this was strengthened recently. We're very fortunate to have a great investor base, with an offering we did of $250 million recently, and 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. So we're in strong financial shape, and we're going to have a lot of data readouts over the next several months here. Starting with ASH in the next...

Starting with ASH in the next week or next month.

Sunny Orlando. You can meet at Applebee's for beer.

Yes, that will be great to go to Disney World.

Thank you, Arthur. I always appreciate that.

Thanks, Steve.

Good morning, and welcome to the Nurix Therapeutics Conference Call. I'm Arthur Sands, President and CEO. And I'm joined today on this call by Gwenn Hansen, our Chief Scientific Officer; Paula O'Connor, our Chief Medical Officer; and Hans Van Houte, our Chief Financial Officer.

These are our disclaimers. At Nurix, we're advancing a pipeline of innovative targeted protein degrader drugs in oncology and inflammation and immunology or I&I, each with best-in-class potential. The majority of today's call will be focused on an important update on our lead program in CLL, bexobrutideg, or NX-5948 or Bexdeg for short. This will include our pivotal clinical development plans and some important new data supporting differentiation and Bexdeg dose selection for registrational trials.

Next, with respect to our partnered I&I pipeline, we are able to share with you today some new preclinical data from both STAT6 and the IRAK4 programs. Our STAT6 program is partnered with Sanofi, and this is the first public disclosure of preclinical data profiling some key characteristics of NX-3911. The exciting clinical candidate that is now in IND-enabling studies.

We will also describe for the first time, some key differentiation data from our IRAK4 program with Gilead, GS-6791, that is currently in Phase I healthy volunteer study. Importantly, Nurix maintains the potential to opt into these 2 partnered programs and a 50-50 co-development co-commercialization structure in the United States. This is an option that will be available after our partners have obtained human clinical data. Although we won't be discussing the exciting potential for Bexdeg in I&I indications today, I would like to mention that we continue to move a new tablet formulation through multiple ascending dose studies in healthy volunteers. This is a formulation that is ultimately intended for use in an autoimmune setting as a distinct product.

Overall, we believe the emerging best-in-class drug profiles of our BTK, STAT6 and IRAK4 degraders are no coincidence, but rather the consequence of Nurix's rigorous science focused on the discovery and development of targeted protein degradation drugs.

At the end of the call, we'll take questions on any topic including our recent ESMO poster presentation on NX-1607, our first-in-class CBL-B inhibitor, a novel immuno-oncology agent that has demonstrated some very encouraging single-agent activity in solid tumors. The poster is available in the resource library on our website.

Now before we go through our very thorough update, I do think it's important to take a moment to step back and place Nurix in the context of a much larger evolution of drug discovery that is taking place, literally before our eyes. We believe targeted protein degradation is poised to take the stage as the next major modality in medicine, probably on the scale of antibodies and potentially even larger since we can address a much larger target class. It is indeed inspiring to recognize the potential for such drugs with Nurix's pipeline truly on the cutting edge of this evolution.

So the headline for today's call is that we have announced the achievement of a significant milestone in the development of our lead program, the initiation of our pivotal trials in CLL. This advancement has been enabled by obtaining regulatory alignment on dose selection for registrational purposes with the FDA under project Optimus. Importantly, we also have alignment with global regulatory authorities, including the MHRA in the U.K. and the EMA in Europe to begin our global registrational program. As a reminder, Bexdeg also has fast-track status in the U.S. and prime designation in the EU.

The dose of Bexdeg we are taking forward into registrational trials is 600 milligrams once per day. This is the highest dose we tested in our Phase I studies to date in which we encountered no dose-limiting toxicities. This dose selection was based primarily on data from the Phase Ib portion of our study that included randomized cohorts of 200 milligram once daily and 600 milligrams once daily, according to the guidelines of project Optimus. We are very pleased that the 600-milligram dose group showed a favorable safety profile that was comparable to that of the [ 200-milligram ] dose group. By selecting 600 milligrams, therefore, we are able to maximize for efficacy while maintaining safety.

We believe this represents a strategic advantage of our competing molecules, both BTK degraders and inhibitors. The selection of the 600-milligram dose has enabled the initiation of our first pivotal trial, which has been named the DAYBreak study, a single-arm Phase II study in approximately 100 patients with relapsed/refractory CLL for potential accelerated approval, addressing a population of high unmet medical need.

Today, we are also announcing that this global clinical trial has initiated. In addition to [ DAYBreak ] CLL-201, we are actively planning the implementation of the Phase III randomized confirmatory trial in CLL in the second-line setting, moving Bexdeg up in the CLL treatment paradigm. Paula O'Connor will be describing our core CLL clinical development plan in this call.

Turning to the fifth and sixth checkmarked items on this slide. A key question we will endeavor to answer this morning is, what are some of the clinical and preclinical data that support differentiation of Bexdeg and the selection of the 600-milligram dose. Elements of this answer to this question can be found in some of our latest data that we will share today, which will be presented by Gwenn Hansen. Data that distinguishes Bexdeg from both BTK inhibitors and also the competing BTK degraders from B1 and AbbVie. We believe these data clearly support a best-in-class profile for Bexdeg.

As we turn to details on the Bexdeg update, I would first like to briefly highlight the overarching advantages of the degradation mechanism of action and of Bexdeg in particular. First, Bexdeg is active against not only wild-type BTK, but also the entire range of clinically relevant BTK mutations that render current BTK inhibitors ineffective.

Second, Bexdeg addresses the scaffolding function of BTK, a function that promotes tumor cell growth and B-cell receptor signaling and a function that is neglected by inhibitors.

Third, Bexdeg, like all bifunctional degrader acts catalytically, which means very low drug levels can deliver incredible potency. So what do we mean by that? Remarkably, we have measured in cells that 1 Bexdeg drug molecule can degrade between 10,000 to 20,000 BTK proteins per hour. This fundamental difference in PK/PD from inhibitors is what allowed us to justify recognition from the USAN drug naming authority that bexobrutideg deserved the new suffix, deg, which indicates an entirely new category of drugs, the degraders. And Bexdeg is indeed the first deg in this category. It's a real landmark.

Fourth, Bexdeg crosses the blood-brain barrier and has demonstrated significant clinical activity in the CNS of patients with advanced brain involvement.

And fifth, we have demonstrated robust clinical activity in multiple difficult-to-treat B-cell malignancies across the board in CLL and NHL. And last but certainly not least, we believe that Bexdeg, that are degraders for IRAK4 and STAT6 will bring their mechanistic advantages to autoimmune disease by addressing the scaffolding function of these targets, and by delivering the powerful catalytic activity of targeted protein degradation.

In some, we believe the best-in-class drug profiles of Bexdeg, NX-3911 and GS-6791 are no coincidence. So they are a consequence, once again, of Nurix's rigorous science focused on the discovery and development of targeted protein degradation drugs.

So now I would like to turn the call over to Paula O'Connor, our Chief Medical Officer, to provide a brief review of our previously presented Bexdeg data that was featured at EHA earlier this year and then an overview of our pivotal clinical development plan in CLL. So I will be changing the slides for you, Paula. And if you could prompt me by saying next slide, I would appreciate that.

I certainly will, thank you, Arthur. So next slide. Okay. So good morning. I'm Paula O'Connor, the Chief Medical Officer here at Nurix. I'm thrilled to be working here at Nurix as we advance the next wave of innovation on the BTK pathway with our best-in-class molecule bexobrutideg, as Arthur has already said.

We have confirmed our 600-milligram dose with the FDA, MHRA and the EMA and are moving forward at full speed on our pivotal programs. I'll review these in more detail in just a moment. But just to summarize, as you can see here, our Phase II trial, DAYBreak, the potential -- with the potential for accelerated approval is now underway with our first site activated earlier this month. Our key start-up initiatives are also underway for our confirmatory Phase III study. This study will begin in the first half of 2026. The entire company is laser-focused on the initiation and conduct of these 2 critical programs.

As Arthur has already noted, we have also had many positive interactions with the major health authorities regarding bexobrutideg. And as previously disclosed, we have received fast track designation with the FDA and prime designation with the EMA. These will be critical for us as we review our evolving data in our path toward registration. Our interactions have not only set -- have set the stage for our development of these agents, and it clearly informed our pivotal trial designs and our registration plans.

Next slide. In the next few slides, I will summarize the efficacy and safety data share for bexobrutideg most recently at EHA and Lugano. Every time we share this data, it reinforces the potential of this asset and the power of protein degradation. As you look at the slide, I'm going to direct your eye to the left, where you see the over -- the objective response rate in patients in the fourth line setting of CLL. As you can see here, the ORR of 80.9% has occurred in patients in whom 75% are double exposed and more than half has TP53 and/or BTK mutations, representing a group of patients with the highest unmet medical need.

On the right, you see the waterfall plot and the genetic profile of our enrolled patients, showing meaningful reduction in their lymph nodes over the course of therapy, irrespective of high-risk clinical and genetic features, including CNS involvement and the mutations I previously mentioned.

Next slide. The swim lane plot provided on this slide shows the speed, durability and depth of the responses we've seen with Bexdeg across dose levels. The median time to response is fast, less than 2 months. The treatment effect is durable with 17 of the 18 patients reaching a year on therapy continuing treatment. You can also see the pattern of deepening responses over time, evidenced by our first complete response being documented after 18 months of treatment and the first patient that is represented on this swim lane.

Next slide. The safety profile for Bexdeg depicted here remains consistent with our earlier reports, even in the setting of longer follow-up and increased numbers. There are no new signals, cardiac, infectious or otherwise.

In the next couple of minutes, I will turn to our clinical development programs that we have for Bexdeg. I'm pleased to share with you our 3 pillars for the development strategy for Bexdeg. They are, first, speed to market; second, addressing the needs of relapsed and refractory CLL patients as early as the second line; and third, utilizing combination therapy to further improve patient outcomes in the relapsed setting and potentially to move us to the front line.

Before delving into these pillars and how they address the needs of our patients, I will take a moment to give an overview of the CLL market. Across the major markets in the U.S., EU, China and Japan, there are approximately 120,000 patients initiating new treatment each year. 50% of these are in the second line plus setting. In the U.S. specifically, there are 38,000 new patient treatment starts each year, 19,000 of which are in the relapse setting. Our clinical development plan is competitive and is designed to address the needs of CLL patients across the global marketplace.

Next slide. This is a schema for our DAYBreak study. This, as we've already noted, has the potential for accelerated approval and started earlier this month. The study addresses the first pillar of our development strategy, namely speed to market. Utilizing this study, we hope to bring Bexdeg to physicians and their patients as quickly as possible. This single-arm Phase II study is designed with registration intent and has the potential for an accelerated approval. We plan to enroll approximately 100 patients with Bexdeg at our 600-milligram dose. The enrolled patient population will consist of triple exposed CLL patients, who have been previously treated with a covalent BTKI, a non-covalent BTKI and a BCL2 inhibitor. These patients have a clear and unmet medical need.

The primary endpoint for this study is objective response rate as assessed by an independent review committee and will be further supported by duration of response data. We are thrilled that this important study has started, and the team is working diligently to enroll it.

Next slide, please. The second pillar of our development strategy is to address the needs of patients with relapsed and refractory CLL as early as the second line, thereby helping a broader set of patients. This is the schema for our confirmatory Phase III study. We plan to enroll approximately 400 patients. They will be randomized to either 600 milligrams of Bexdeg given once daily by mouth or 1 of the 3 treatment options in the physician's choice control arm. These options include the globally relevant regimens of pirtobrutinib, idela and RITUXAN or bendamustine and RITUXAN. The primary endpoint of this study is progression-free survival, and we plan to initiate this study in the first half of 2026.

Next slide, please. The third pillar of our development strategy in CLL is utilizing Bexdeg in combination with other active agents in CLL to improve patient outcomes. The schema on this slide is for our combination basket study. The combination data generated in this study may support future registration studies in the second line or even the first line. The study is designed to establish the go-forward dose for Bexdeg in combination with venetoclax, venetoclax and Rituxan, venetoclax and obinutuzumab in both the second and first line patients. We will enroll approximately 20 patients in each cohort.

The dose that we identify in these cohorts may be used in our subsequent studies. This study, like the confirmatory Phase III we discussed earlier is slated to begin in the first half of 2026. The data sets generated in this study will inform future potential pivotal studies in CLL and may inform future development more broadly.

Next slide. So having reviewed our immediate plans in CLL with you, I will close this section out of our presentation by saying that we are mobilized as a company to enroll the studies I've just reviewed to support the rapid registration of Bexdeg in CLL in patients with relapsed disease, triple exposed disease, in particular as it relates to the Phase II and to address the medical needs of relapsed and refractory CLL patients as monotherapy or in combination. We look forward to sharing our emerging data with more patients and longer follow-up with you at the ASH meeting in December.

And so with this, I'm going to close this section and turn things over to Gwenn Hansen, who will give you more information on how we are differentiating Bexdeg from the other BTK directed therapies, as well as speak to our other pipeline agents. Gwenn?

Thank you, Paula, and good morning, everyone. So my name is Gwenn Hansen. I am the Chief Scientific Officer at Nurix. And today, I'm pleased to be able to share with you some new preclinical and translational data that we think underpin bexobrutideg's potential best-in-class profile.

Next slide. I will describe in the next few slides, several key points of differentiation for bexobrutideg including potency, mutational coverage and selectivity, particularly in comparison to key competitors in this space. This data, along with bexobrutideg's ability to cross the blood-brain barrier and show activity in patients with CNS disease, as well as today's disclosure of having reached alignment with regulatory authorities to use the highest dose tested of 600 milligrams as our go-forward dose for our pivotal and confirmatory studies, give us confidence that bexobrutideg represents a potentially best-in-class BTK degrader for the treatment of B-cell malignancies.

Next slide. First, in terms of potency, bexobrutideg demonstrates picomolar potency in primary human B cells, showing 20-fold more potency and fivefold more potency than B1 and AbbVie's degraders, respectively.

Next slide. Next, in terms of mutation coverage, bexobrutideg exhibits a pan-mutant profile, wholly distinct from known -- all known inhibitors of BTK, each of which showed 2 or more liabilities across this growing list of clinically impactful resistance mutations, that arise in the active side of the BTK protein and then in some cases, actually render the kinase inactive while still allowing it to drive cell growth and disease. This illustrates a scaffolding function that was otherwise unappreciated for BTK and ultimately, is not addressed by the numerous small molecule inhibitors that have been developed to date.

Next slide. Degraders in contrast are ideally suited to address scaffolding function, but also inhibitor driven resistance. Comparing Bexdeg's ability to kill the same DLBCL cells engineered to express again, the same set of BTK inhibitor resistance mutations, Bexdeg shows consistent levels of cell killing across wild type in all mutant forms of BTK, where both B1 and AbbVie's compound show liabilities against T474i and maybe slightly more severely V416L. So all these observed potency differentials between wild-type mutant forms of BTK, ranging from as little as fivefold to as much as 50-fold, might not prevent a degrader from obtaining clinical response in patients harboring these mutations the ability for a drug to provide a long duration of benefit to patients harboring cells with these mutations will require dosing that drug at exposure levels that far exceed that would be otherwise needed to fully degrade wild-type BTK and safely achieving such levels requires exquisite to greater selectivity.

Next slide. Looking closely at the dose and corresponding exposure levels observed in patients during Phase Ia or b of our trials, you see that our optimized dose of 600 milligrams shows steady-state clinical PK exposures that easily cover not only wild-type BTK that is shown here on the bottom of the PK plot with that dotted line, but also all of the previously mentioned oncogenic forms of BTK marked according to the free drug exposures necessary to completely degrade more than 95% of each protein form.

The ability to effectively degrade all or nearly all of the BTK protein found in circulating lymphocytes is something that we've been observing consistently in our translational data and is shown on the right-hand side of this slide, where we directly measure BTK protein levels following once a day oral dosing with bexobrutideg. This data shows that regardless of the dose that we have been using, we consistently eliminate BTK signal in the disease setting across baseline mutation profiles. However, with approval to proceed using a 600-milligram dose, we are assured that we can address the totality of relapsed or refractory disease that is otherwise amplified through the use of inhibitors that fail to fully control BTK function.

Next slide. Speaking directly to not only our motivation for exploring the 600-milligram dose during project Optimus, but maybe more importantly to why we obtained approval to move forward with our highest dose tested. This slide addresses our selectivity profile. Using a very high sensitivity mass spectrometry-based global proteomic approach, we have attempted to directly compare bexobrutideg to our competitor degraders and show here that we have an exquisitely selective profile that identifies BTK as the only target degraded at doses exceeding that required for near complete coverage of wild-type BTK. This superior selectivity profile allows us to safely dose bexobrutideg in our patients at exposures that meet or exceed what is necessary to completely eliminate malignant cells.

Next slide. Based on these data, we explored a more detailed dose response experiments to show selectivity over critical kinase targets, starting with targets that are well known to be off targets for BTK targeted agents. This slide shows those experiments using K562 cells, confirming that bexobrutideg displays a superior selectivity profile with respect to the tech protein kinase, which has been associated with bleeding and cardiac cyst safety effects across the spectrum of BTK targeted drugs.

Next slide. Further, profiling additional targets such as LCK, CSK and ADK in more detailed dose response studies in their respective cell types of relevance, we confirm the data that I just showed you from the global proteomic study, namely that Bexdeg has a superior selectivity profile. So in sum, we hope this data helps you appreciate our enthusiasm for what we think is a potentially best-in-class BTK degrader, bexobrutideg.

Next slide. Moving on from oncology to discuss our growing I&I pipeline. Next slide. I would like to highlight 2 programs that we have developed in partnership with Sanofi and Gilead and that are advancing through IND-enabling studies or through early Phase I clinical trials in I&I.

Next slide. First, through our long-standing collaboration with Sanofi that culminated in a licensing event earlier this year, we discovered and are now developing a highly potent and selective degrader of STAT6 that was derived from our [ delta ] degrader discovery platform. STAT6 is a transcription factor that plays a central role in mediating type 2 immune responses, which are implicated in a wide range of inflammatory and allergic diseases.

Eliminating STAT6 using targeted protein degradation offers the promise of controlling allergic and inflammatory diseases with high efficacy and fewer side effects than broader immunosuppressive therapies, while providing the convenience of a once-a-day oral dose afforded with small molecule therapies like degraders.

Next slide. Our compound, NX-3911 shows picomolar potency of degradation in human primary B cells in both the resting and stimulated states, suggesting that NX-3911 has a high catalytic activity and confidence to control the inflamed disease state in a cellular setting.

Next slide. Similar to the profile shown for Bexdeg, NX-3911 displays exquisite selectivity. Here assessed using global proteomics and measured across multiple human donors where we were able to quantitatively measure the protein levels of over 9,500 unique proteins. In this study, you see that STAT6 is the only protein that is modulated by this drug.

Next slide. This highly potent and selective compound also shows profound efficacy in preclinical models of both atopic dermatitis and asthma using either prophylactic or therapeutic dosing regimes, and assessed by measurements of serum IgE levels following 20 or 24 days of dosing, respectively. Importantly, in these studies, NX-3911 restored inflamed levels of IgE triggered by disease induction back down to levels found in naive animals, and that can be seen in the pink bar and the pink dotted line. In our experience, this level of disease prevention or control has only been possible in the context of genetic knockouts, emphasizing to us the promise of this new class of induced proximity drugs.

Next slide. Our second I&I program highlight comes from the first license development candidate emerging from our collaboration with Gilead. NX-0479 or now known GS-6791 is a highly potent degrader of the scaffolding protein IRAK4 that is an essential component of the mitosome that mediates [ toll-like ] receptor signaling pathway control.

Next slide. Several updates from this program have been communicated at recent conferences, including ACR and more recently at EADV in Paris. Here, we are showing just 1 vignette that speaks to the differentiation of our IRAK4 degrader in comparison to a competitor degrader from Chimera Therapeutics. In this slide, we are showing degradation in control of cytokine signaling in human basal keratinocytes, following treatment with either GS-6791 or KT-474. This data reveals our superior cellular potency, target coverage and control of inflammation in both basal keratinocytes in isolation as well as a model of reconstructed human epidermis. These data highlight the importance of the detailed cellular and in vivo disease cell profiling for this emerging class of induced proximity drugs.

GS-6791 has now entered the clinic, and we look forward to seeing how this agent performs in the clinical setting and ultimately having an opportunity to opt in, in the development of this potentially first-in-class I&I drug.

Thank you for your attention. And now I will pass the presentation back to Dr. Arthur Sands.

Thank you, Gwenn, and thanks, Paula, that was terrific. I'm going to just make a few summary -- statements here, and then we'll go to Q&A.

So I think you'll appreciate that Bexdeg has indeed the potential to produce incredible value for our pipeline over the course of its life cycle. We're looking at CLL. We're also interested in Waldenstrom's and NHL and of course, potentially I&I indications. You've seen and heard today that we have advanced bexobrutideg one step closer to registration and commercialization. The 600-milligram dose is selected as per project Optimus. We have regulatory alignment -- global regulatory alignment and our pivotal Phase II is initiated and the confirmatory Phase III planning is underway, and we anticipate launching that in the first half of 2026.

Indeed, there is definitely best-in-class potential emerging for bexobrutideg as well as our other pipeline programs, as Gwenn outlined. These partnered programs, STAT6 and IRAK4 have the potential for significant milestones in the future as well as data events anticipated in 2026 and 2027.

Regarding our cash balance and economic position, we're in a very strong position, having completed our registered direct offering. Our pro forma cash is anticipated to be $678 million, which can provide us expected runway into 2028. And during the Q&A, we will also be joined by Hans Van Houte, our Chief Financial Officer.

So 2025 here in Q4, we've really accomplished quite a bit as indicated by the check marks along the left-hand side of this slide, and we've discussed today. What we have remaining, we are presenting at ASH coming up in December. We have accepted abstracts at ASH, and we look forward to being there. And as usual, we'll plan an investor event as well.

In 2026, there's a number of very exciting milestones that we believe will be important. We have -- we'll have our Phase I a/b results in NHL, we've yet to disclose a significant NHL results. Those cohorts have proceeded quite well and had some impressive results as with our CLL cohorts. We have multiple cohorts in CLL in the Phase Ib portion of the study in very important patient populations, and we look forward to sharing those results with you as well.

As I mentioned, we do intend to initiate a confirmatory Phase III in the first half of 2026 as well as the combination study in CLL that Paula has outlined.

With regard to I&I, I think it will be a very exciting year in 2026. We will have our potential GS-6791 opt-in potential in 2026 based on Gilead's Phase I results, which is -- which are currently ongoing. And bexobrutideg, its own SAD/MAD study, which is currently ongoing. Also, we anticipate data for that in 2026. And again, this is intended to enable an I&I indication.

And then finally, the potential for the NX-3911-STAT6 degrader is really quite substantial, and we can anticipate an IND filed by Sanofi in 2026 as well.

So with that, we'll turn to the Q&A section, and I'm going to stop sharing, because I continue to run these slides. And we've got, I think, all members of our team on for the Q&A.

Let me see if I can see all the participants. [Operator Instructions] So I'd like to start, I think, with Roger Song, Roger?

Congrats for the start of the pivotal and then sharing with us a lot of the new data today. So my question is really related to the detail of the pivotal study design. Given your -- the Phase II is a single arm. So what is the stat assumption for the 100 patient for this post covalent non-covalent BCL2.

And a similar question for the second line -- second plus line randomized confirmatory study. You have a dealer's choice, multiple compared arms. So how should we think about the strategic assumption on the primary endpoint?

And then maybe more specific any caps for all of those comparator arm you will be enrolling in order to power the study?

Okay. Thanks, Roger. So Paula, I hope you got all that. Do you want to answer that question, please?

So Roger, thank you so much for your question. So addressing your first question, what are the statistical assumptions underpinning both of our studies? Certainly, you know that -- the -- each of our programs has been discussed with the agency. So while we're not going to go into all of the details that you would like, what I can certainly say is that we have alignment with the agency on the plans, specifically for the single-arm Phase II, and for the Phase III. We've touched upon the primary endpoint for the single-arm Phase II being the objective response rate with duration of response data as part of the supporting information.

So typically, as you know, the agency looks at the agents that are available and assesses to those patients and then looks at your results in comparison. So I think that's all I'm going to say there.

And then as it relates to our confirmatory Phase III once again, we have reviewed our program with the agency and are aligned on its design and the primary end point moving forward. So we feel really good about this. And as you will see with our emerging data at ASH, the data that we're generating really supports our ability to establish benchmarks in each of these studies that should support registration.

Next, we'll turn to Derek Archila.

Arthur, congrats on the update here. Just 2 questions from us. I mean, first, on the combo trial that you guys are talking about, I guess, maybe more discussion around the 450 mg dose. And I guess what you think could be the differences between 450 mg and 600 mg? And then also, just given the additional cash with the financing today, is there any plan to kind of expedite Bexdeg's opportunities in I&I?

Great. Paula take the first part, and I'll take the second.

Sure. As you know, Derek, it's very common to initiate a dose-finding study at 1 dose level minus or 1 dose level below your monotherapy dose. And so we're utilizing this approach as we start therapy. It is our hope and our plan that we will be able to advance that dose to 600 milligrams once we've demonstrated the safety and tolerability of the -- of the combination at 450. Arthur?

Yes. And Derek, regarding the second part of your question, the answer is yes. With the really successful -- extremely successful completion of this offering, we now are in a position to accelerate bexobrutideg's entry into I&I. And so I think that is really going to be a strategic value creation occurrence for us. So we're really interested in doing that. So thank you for your question, Derek.

Next, we'll turn to Brian Skorney.

Congrats on all the updates today. I guess maybe my question is on the confirmatory trial design. Just wanted to get sort of early thoughts on the control arm. You're not sure based on the proposed enrollment criteria. There's any studies you would specifically point to, to reference for what you might expect the control PFS to be -- just looking at like the benda RITUX, idela RITUX second-line studies, I think they're about 20-month PFS. Do you think is that a reasonable assumption to go on? Or are there -- since these studies were done kind of prior to BTK and BCL2 usage, are there reasons to think that the control arm would come in at less than 20 months or more than 20 months? Just any thoughts you had on those considerations?

Thanks, Brian. Paula, go ahead.

Thank you, Brian, for your question. So I think that your best analogs right now for BR and IR in the second-line plus setting are going to be based upon the BRUEN data, BRUEN-321. And while it is true that, that population is mixed with both BTKI and BCL2 inhibitor exposed patients, 50% of the patients did not have BCL2 inhibitor exposure and 50% did. And so your estimates there for the control arm in the 321 study with BR and IR is about 9 months, and the estimates for pirtobrutinib in that setting are 14 months. And so we anticipate truth being someplace between that in our ongoing study.

Well, let's turn to Gil Blum. Gil?

A couple of quick ones. I'm not sure I saw this, but how is the trial protocol and a pivotal study addressing the patients with potential CNS involvement? I have a follow-up.

Right, Paula?

So neither of our pivotal trials, the Phase II or the Phase III will enroll patients with CNS disease. However, we continue to re-roll those patients in our ongoing 301 trial. So we have a cohort designed specifically for patients with CNS involvement, and we'll have the opportunity to share that information in a future update.

And is there a difference as it relates to the intellectual property in regards to your competitors. Is there a -- we haven't seen any too much going on there, but are there similarities? Or is there anything you can comment on there?

Well, actually, no. I don't think we're going to comment on IP of our competitors at this point. We're in good shape with our intellectual property around bexobrutideg, so I think that's all we can say on that.

And as the last one as it relates to competition. It looked like your drug had a higher potency and molecular assays. But the overall doses that you guys are using, like the total dose is actually a little higher than what they're using. Maybe you can help us understand the differences in pharmacokinetics there?

Sure. Gwenn, would you like to take that question?

Sure, I will. So the dose ultimately really relates to bioavailability, so there are differences between degraders and bioavailability. But ultimately, our drug and our free drug levels in vivo are actually required to be lower in accordance with the potency to cover target protein. So I think in the end, it's better to compare the free drug levels when you're thinking about total drug needed. So that improvement in potency allows us to stay closer in line to the wild-type protein level target coverage than maybe other drugs that have differential potency of BTK.

We'll go to Matt Biegler.

Thanks so much for this update, guys, exciting news. So Arthur, can you tell me about the motivation for going after triplet exposed. I mean, ostensibly, you guys see pirto and the other non-covalent as kind of their own entity and the continuum of care. So I'm just -- I'm interested to know what went into that decision? And I guess more importantly, what do you think the bar is for success in pirto exposed population because I don't think we really have a lot of data on that. So I'm just kind of interested to hear your thoughts?

Yes. Thank you. So when we look at the emerging landscape in treatment of CLL, we believe that the non covalence will gain approval, full approval, pirtobrutinib in particular. And so looking at also the definition of unmet medical need, it is according to accelerated approval guidelines. We need to address a population that does not have any treatment alternatives. And so that would be this post triple exposed patient population. And so our goal there is to be eligible, ultimately for accelerated approval in the time frame of completion of the trial, and we think that's going to be the best positioning.

With regard to where is the bar and what kind of response rate we might see in this population? I think I'll hand that to Paula because we're talking about patient populations in the fourth or fifth line. Paula?

Yes. So Matthew, thanks again for your question. As you've accurately denoted, there is no -- or there are no great studies that speak to the activity of agents in this specific patient population. That having been said, if you look at monotherapy data for chemo or immunotherapy, so RITUXAN-based regimens or bendamustine or even chlorambucil, et cetera, in this fourth-line setting, you can see rates as in the 30% up to if we think about pirtobrutinib up to as much as 65%. Ultimately, those are not specifically in this patient population. So we know the truth is going to be someplace between this 30% and 60% range.

But that will occur or rather that assessment will occur at the time that the agency is reviewing the data. So that gives you a sense of what exists, but there are no perfect analogs.

Next, turn to Joe Catanzaro.

Maybe actually somewhat related to the last question. When you look at your data set, like and consider these triple refractory patients, what kind of efficacy are you -- can you say you're observing there relative to the broader relapsed/refractory CLL population that you've enrolled? Have you seen a notable difference or it's sort of similar behavior?

Paula, do you want to take that?

So thank you for the question. As you know, in our Phase Ia, we've enrolled patients from dose -- at dose levels from 50 milligrams to 600 milligrams in the 48 patients that we certainly discussed today, you might imagine that while we've treated patients who are triple exposed, they have not all been treated at the 600-milligram dose level. So what I can say definitively is that we've clearly seen responses, deep responses, including PRs, but it is hard for me to give you an exact number on what to expect at the 600-milligram dose level just because we don't have a lot of patients at that dose level.

That having been said, what we have seen is still consistent with our overarching data, which shows that our response rate is in the high 70s to 80s.

If I could squeeze a follow-up in maybe this 200 milligrams versus 600 milligrams, I think the Phase Ia was complicated a little bit for dose response because of intra-patient dose escalation at least from the outside looking in. In the dose optimization, 200 milligram versus 600 milligrams, was there an obvious dose response as it relates to efficacy? Did it come in response rate? Is it trending more towards durability is a little bit of both?

Thanks, Paula, any comments?

Well, you see me smiling or maybe you don't see me smiling, but know that I am smiling. So first and foremost, when the agency is looking at your data as it relates to this dose optimization, they are looking not only at safety, which is their primary objective and improved and a tolerable safety profile, but they're also looking at efficacy. And so suffice it to say that the balance of data, both safety as well as efficacy supported the use or the choice of 600 milligrams, not only by us but obviously by the agency. So we're really thrilled with that. And I look forward to seeing what we will show in our pivotal trials.

We'll turn next to Brian Abrahams.

Congrats on all the progress. Maybe just sort of how the overall landscape in CLL might play out. You spoke a lot about some of the preclinical advantages versus other degraders. I guess I'm curious how you see those playing out in the clinic if you're seeing any hints so far as you kind of look at others data?

And then I guess I'm also wondering how you would expect the initial commercial market and used to look here have -- potentially having 2 degraders available that might have different labels based on different accelerated approval trial designs, but having the potential for Bexdeg to have greater efficacy across more mutations, which may be relevant in a refractory population?

Thanks, a 2-part question. Gwenn, we'll give you the first part, which was about the differentiation, I think?

Yes, I think speaking to the differentiation, I think we see several key points that really speak to the ability of bexobrutideg to outperform the competitor agent. So first, really, it is the selectivity. We have observed such a safe profile across all of our doses. I think that really speaks to that distinction that I was showing you in all the preclinical data, particularly the proteomics that really just allows us to press on this target pathway.

So we're -- that high dose is really there because we have safety, which means we can control more of that signaling pathway than would otherwise be possible. And I think that really is -- the important point, I mean, the potency is supportive as well, of course, and the mutation coverage is obviously an advantage. So I'll pass it back to you, Arthur or Paula, for the clinical interpretation of that.