All right, everyone. I think we'll get started here with our next fireside discussion. My name's Derek Archila. I'm one of the senior biotech analysts here at Wells. Very excited to have Nurix Therapeutics with us from the company. We have Arthur Sands, President and CEO. Arthur, great to see you, as always.
Thank you, Derek. Great to be here.
Awesome. Well, you guys had some news this morning, talking about your Phase III trial design. So I'll let you run through some slides real quick, and then we can move over to the Q&A afterwards.
Great. Yes, I'd like to introduce some of the new information via some of our slides. These are our disclaimers. But before I dive into our Phase III program for Bexobrutideg, I do want to just take a step back and let everyone know how we see degraders in the larger context of the evolution of new therapies, as pictured on this slide. So all the way back to original small molecule inhibitors, antibodies, and, of course, DNA-based therapeutics, they've been designed to knock out or knock down targets. Now, with targeted protein degraders, pictured on the right side of this slide, we think this is a whole new class of drugs. Bexobrutideg, our lead program, is the first deg with that stem. Degrader for representing this new MOA. And we think it's going to be, of course, a major class of therapeutics.
At Nurix, we're able to take our degraders and address major target categories that have blockbuster potential. We'll be talking, of course, about BTK on the left, which is a target that's well known, clinically validated. However, BTK inhibitors in the space of CLL and B-cell malignancies have been developing resistance mutations, and our degrader can address those mutations, and we think this may be a property of degraders in general, being able to address current resistance mutations to known inhibitors to clinically validated targets, and then off to the right, we are very interested in our autoimmune portfolio, both with our IRAK4 degrader, which is being developed with Gilead, as well as the latest one to go into development with Sanofi, the STAT6 degrader. Off to the right, the STAT6 represents a whole category of undruggable targets that we can address with degraders.
And so this is how we distribute our target pipeline from clinically validated targets to targets that really would be better off with a degrader, such as IRAK4, to then the undruggable, the STAT6s of the world, which have real breakthrough potential. On this slide, it's just that our BTK degrader, Bexobrutideg, as I said, the first deg in this category of drugs, really checks all the boxes in terms of addressing the inhibitor resistance mutations, bringing to bear new efficacy function via the scaffolding function of BTK, which is the structural function of that kinase. And many kinases have the scaffolding function. We take that out with our degrader.
Degraders act in a catalytic fashion, that is, they pack the punch or the potency of biologics, although they are small molecules and are orally bioavailable and have the attributes of a small molecule PK and, of course, are eminently manufacturable. Bexobrutideg crosses the blood-brain barrier as well. We have activity in CNS disease, and I'll highlight a couple of patients with that. And then also, we see potential in autoimmune disease with Bexdeg, as we call it for short. This is, I think, some important foundational data before we get into the Phase III design. To the right on this heat map, what you're looking at is comparing NX-5948, which is Bexdeg, at the top across all the known resistance mutations that we're seeing in the clinic in our trials. And then, as you see, the potency drops off for the inhibitors.
We've listed both the covalent inhibitors as well as the non-covalent inhibitors. And as the boxes turn blue or red, that represents a loss in cell-killing potency of 1,000-fold, and blue in red is 5,000-fold loss in potency. And that's why those drugs don't work. And you can see that all the BTK inhibitors, although now representing upwards of $9 billion-$10 billion in sales, very successful drugs, but they all have their liabilities. And this is where we think Bexdeg and the degrader really will have a big advantage. And then off to the left, you're looking actually at degradation of BTK from our patients. That graph, the way that is conducted in the trial day zero, we take our first blood draw. We measure BTK protein levels in our patients.
And then you can see by day eight, all of the BTK is degraded, regardless of the resistance mutations that these patients harbor. And these, again, are from our patients in our current trial. So we get complete degradation, basically, at all doses tested. And then this is an important highlight. This is our waterfall plot showing the decrease in lymph node size. Each bar there is a patient in the trial. You can see the overwhelming majority of patients are showing decrease in their lymph node size, which is one of the key components measuring response. And across the bottom is the mutational burden of each patient. And regardless of what the mutational burden of these patients is going into the trial, they all have the opportunity to respond.
We have not seen any type of resistance mutation pattern that would prevent a patient from responding so far to our drug. Then I should have mentioned that the light blue are the patients with CNS disease where we're also seeing these responses. Translates to an overall objective response rate of 80% across the board. You can see the breakdown here. I don't have the safety tables here, but overall, very well-tolerated drug. We had no dose-limiting toxicities, no new atrial fibrillation or ventricular arrhythmias, which had been associated with some of the BTK inhibitors. So a very safe profile, well-tolerated overall. This is getting to our new disclosure today. We did Form 8-K these files. Really, the new disclosure is about item number two here, which is our Phase III plan.
I'll go into this in a little bit more detail on a subsequent slide and think, why don't I just dive forward to that. So here is the overall schematic for the Phase III trial. This is a randomized control trial, randomized one-to-one between Bexobrutideg and an investigator choice control arm. Here, for the first time, we're defining our plan for the control arm, which includes three options for investigators: Pirtobrutinib, which, of course, is a non-covalent BTK inhibitor that has accelerated approval already in the U.S. and Europe and is anticipated to gain full approval. And then also IR, or Idelalisib/Rituximab combination, as a choice as well. And then Bendamustine/Rituximab, or BR, as another choice. What this does is, in a single trial, it enables us to be clinically relevant across geographies. So we're offering standard of care of clinical relevance in multiple different countries.
We anticipate being in 20-30 countries in this Phase III trial, which will be between 400-500 patients. It maximizes our opportunity for enrollment across these geographies, and also we believe we'll address the current standards of care, so that's the major sort of update in terms of our trial design. In addition to this, we are planning our single-arm Phase II trial. We see that as an accelerated approval opportunity potential. That would be approximately 100 patients, and then the trial you're looking at here, this randomized control would be the confirmatory trial required for full approval. We have designs also to start a Phase Ib/II in combination with Venetoclax and other combination agents. That'll be a dose exploration trial in combination, so that's the third step in our overall development plan.
And then just to put this in context of which markets we're addressing with these trials, I think the most important one is, of course, in the middle there, that second-line position for Bexobrutideg, which is currently approximately a $2 billion a year market, forecast to grow to $5 billion a year. In the third line, which is where our results have been to date, the data showed an 80% response rate in the third line plus, actually, patients that have received over four lines, on average of four lines of therapy. Still a significant market of $1 billion-$2.5 billion in that third-line setting where we've generated all our data to date. But our Phase III program will be addressing the second line in the middle, that marketplace. That's the Phase III randomized control trial I just outlined.
And then we do have potential ambitions for the first line, which would likely be in combination. So that's my introductory remarks, and we can go on to questions.
Yeah, no, that's great. I mean, I guess in terms of what you just outlined for the confirmatory design, I guess how should we first think about the breakdown in terms of geography and the relevant investigator's choice for the standard of care? Is that going to differ between U.S. and some of the ex-U.S. geos in the trial?
Yes, it definitely will vary. That's why we wanted to offer sort of a real-world set of choices. We anticipate in the U.S. and Europe, it would primarily be Pirtobrutinib that would be selected. However, in Europe, IR is also frequently prescribed in the second-line setting, especially for high-risk patients, as well as BR. And outside of Europe and U.S., that can be up to 40%, between 40% and 60% of patients actually prescribe BR, even in the front line. Practice across geographies really does vary. We wanted to engineer a single trial that could really address all the options.
Gotcha. And I guess the other question is, how do you think about, I don't know if you discussed the powering at all in terms of how the trial is powered and what you would expect from that investigator choice arm in the trial?
Yeah. So we've analyzed different scenarios in terms of powering it. And I won't go into details of our stat plan at this time. But needless to say, we powered it, and we're sizing between 400 and 500 patients. There's quite a range there. We'll likely refine that as time goes on. But we do think this will be a very well-powered trial to show Bexdeg's superiority to the control arm.
Gotcha. And then as you think about this strategy relative to what we've seen with some of the competitors, maybe other larger trials, I mean, this seems more compact, maybe more financial-friendly in terms of cost. But I guess what drove you, again, for this type of design relative to maybe some of the other designs that we've seen for some of the BTK degraders?
Yeah, it is capital efficient. I think that's important in today's reality. I do think that you could engineer, I mean, some of the larger pharma have done six trials as they fully develop their drugs. And that's certainly potential. We may expand on this portfolio of trials as we go forward. This is a core set for approval, for first approval. And we likely will expand, especially in the combination areas. And so, yeah, there are different approaches here. We think this is a very efficient way to get the first approval and to get the full approval.
Yep. Gotcha. Okay. In terms of your expectations on how that trial, or actually both, obviously, the accelerated approval, but also the confirmatory trial, how they'll enroll, can you maybe give us some sense of kind of the timing and your expectations there, particularly with the confirmatory, which is more of a global trial?
Yeah. So starting with the Phase II, the 100-patient trial, what we've seen with some prior drugs is roughly about a year of enrollment. We have not forecast that yet. We need to start enrolling before we can make our own forecast. But that's what others have seen. I believe Pirtobrutinib, and its accelerated approval was approximately a year of enrollment time. There's a lot of enthusiasm for Bexobrutideg and for this trial. The results we've seen to date go a long way to spur enrollment and investigator enthusiasm for the drug. So we do think that we'll be able to enroll that trial quickly. With regard to the randomized control trial, the large Phase III, we really haven't forecast that yet. That obviously will take much longer. But stay tuned until we can get there.
Gotcha. I mean, I know this program is quite expansive. And also, particularly if you go into the first line, it becomes a much larger component and probably trial to run. So I guess, have you thought about in terms of bringing in a partner to help with DEL and ultimately defray development costs? Or where do you think Bexdeg ends up? Is it basically through a partnership, or is there some other sort of things that you were looking at from a strategy standpoint to get this moving through both kind of the second line and the front line trials?
What we've outlined, Nurix can do ourselves. We're pushing forward ourselves. That gives us control and speed, and we're intent on doing that. Ultimately, we could see partnership as being part of the future for Bexdeg. It is a very large opportunity. Multiple trials, especially to go to the front line, would be required. We do think it could end up being the way to maximize value. However, the second line opportunity is quite significant. I think if you look at return on investment in terms of the amount of money to go into these trials versus the potential return, the second line is really very attractive. The first line, we think, will continue to be dominated by the covalent inhibitors. These are very strong drugs. They're very successful drugs. However, all patients basically progress at a certain point.
The patient population is quite large in the second line. We think that's probably the best return on investment for us at this time.
Gotcha. Okay. And then as you think about the trial design between the competitors and your one that you unveiled today, I guess, is there going to be a good shot at really understanding the differentiation between these molecules based on the different trial designs? And obviously, there's nothing that you can ever do to say that it's apples to apples, but will we come away from these data sets being there's a clear winner here?
I think ultimately, yes. I think most drugs and their competitors ultimately are defined based on their safety profile. I think many of the drugs have a similar efficacy profile if they're well-designed for their on-target attributes. What's harder to anticipate is what's off-target and what shows up over time, and I think that's what has defined the front line with Zanubrutinib, taking market share from Ibrutinib because of safety, basically, selectivity, the safety based on superior selectivity or Acala, and I think we'll see the same thing with the degraders, ultimately. I think you'll see definition of off-target differentiation over time.
Gotcha. All right. And then in terms of just beyond CLL, can you just kind of walk us through the strategy for Bexobrutideg and Waldenström's and maybe non-Hodgkin's as well?
Yeah. So in Waldenström's, our ORR is 85% or 84.2%, to be precise so far, which is very high. Again, this is in a relapse refractory setting. So we do think there's an opportunity there that is the NHL category that is most like CLL. So the monotherapy opportunity there is significant. If you then look into the other NHL categories, and we have now actually over 100 patients in the other categories we have not reported on yet. We look forward to reporting on those. And we do think there'll be opportunity for Bexdeg in those categories, likely in combination, although I can tell you we've seen responses in every category of NHL. So we do think there's a broader opportunity there. Today, again, we're focused on the monotherapy and CLL right now.
Got it. Okay. And then maybe just in terms of how you think about BTK degraders and Bexobrutideg and autoimmune. So I mean, you have kind of this cohort in wAIHA that you're exploring. What should we expect from that? And what's the strategy given kind of the main focus on CLL?
Yeah. So we think the same advantage that we're seeing in oncology will exist in autoimmune disease. And we believe that's driven by taking out the total protein and addressing the scaffolding function of the signaling pathway of BTK, as well as the kinase function. So we think that's going to pay dividends in autoimmune disease, just like we're seeing in oncology. And so that means there is a broad opportunity. We started with wAIHA, specifically the autoimmune hemolytic anemia that overlays some CLL patients. That turns out to be a fairly small population. We pursue that as a proof of concept. We do believe that we can broaden that and get outside of oncology settings in I&I. And in the fall, we'll be describing a broader strategy there.
Gotcha. I mean, should we think about this as moving Bexobrutideg forward in I&I, or should it be another molecule just in terms of how IRAK4 falls and what you want to actually do kind of longer term?
I think the first one would be Bexdeg. And there's plenty of reason to believe that Bexdeg would have that opportunity. It's got the safety profile, we think, already. However, it is such a huge market opportunity. We do have other molecules coming. But they'd be several years behind. But we do think that there are attributes to BTK degradation that could even be further optimized, even beyond Bexdeg.
Okay. Gotcha. So I mean, do you think wAIHA in general or ITP? Or how do you think about the opportunity ahead of BTK? I mean, we also just saw what Rilzabrutinib just got approved in ITP. So they're starting to pave the way a little bit more in autoimmune. So there's a lot of different spaces, I guess, you could play. But is there any particular ones that you want to stay close to, maybe Heme, but maybe others?
So I think we're looking very closely at MS, multiple sclerosis. We have CNS activity already established in CLL and in NHL. Patients with severe brain disease, we're seeing clinical activity. So that's a very strong vote for pursuing an MS category. We really are also looking at dermatology and hidradenitis suppurativa. Suppurativa is an interesting opportunity, obviously more accessible, more rapid trials than MS. So there's some drug development potential advantages. In the non-malignant Heme indications, yes, ITP, that approval is encouraging. They tend to be smaller indications and more challenging to enroll. And I think with something like Bexdeg, we're thinking kind of go big is probably the smarter strategy.
Okay. Gotcha. Maybe shifting gears to some of the other I&I assets. So you guys have an IRAK4 as well as a STAT6 that you've got some collaborations with. So maybe start with kind of the IRAK4. This has kind of been some fits and starts with that target on the inhibitor front and then even on the degrader front with some of your peers out there. But I guess, why do you think that you might have kind of the best-in-class here? And how are you thinking about kind of the future? What are the next updates we should get from Gilead on that?
So yeah. We've been working on IRAK4 and STAT6 for the past five years, actually. One started with Gilead. It was part of our original Gilead collaboration. And STAT6, part of the original target set in Sanofi. So we've been working on this for quite some time and working with our partners, close collaboration. So these two programs have been subject to a terrific amount of scrutiny in their discovery and pre-development, if I can put it that way. And so I think both Sanofi and Gilead are very satisfied that we have met all the criteria required for what would be a big pharma type of discovery program is really what we launched with them. And we've been funded over $250 million so far for those two programs, essentially, as the lead programs. So these are big programs. And so we have been very careful.
Sometimes being second is better to look at things that you could learn from the front runner. In the case of IRAK4, we really did, with Gilead, the Rolls-Royce of preclinical studies on this molecule to de-risk any kind of QT potential issue there, which we never saw. We think it's a molecule-specific item, and it's not an IRAK4 issue. We feel very good about that. That molecule now is in healthy volunteer studies with Gilead running those studies. With STAT6, again, a very elaborate preclinical program, really de-risked completely. We've seen our degrader really basically imitate the STAT6 knockout mouse in terms of its efficacy. You're talking about profound removal of the target and a very clean and safe profile. We also do really exquisite proteomic profiling on these on all of our molecules to see any off-target proteins moving.
That's a technology that only now you can really take to the real extreme levels of seeing such high resolution in terms of other off-targets you can dial away from. That technology is very recent, actually, in terms of a power brought to drug discovery and building safer molecules. So I think this next generation of degraders that we've made with Gilead and Sanofi and Bexdeg, we've also, through the proteomics, looked at it, to really pick the cleanest molecules we could. And I think it's going to pay off in the clinic for safety. And of course, the efficacy is there because the target, STAT6, carries tremendous target efficacy, and so does IRAK4.
Sure. I mean, do you think inherently there's anything obviously challenging for targeting STAT6, but toxic? Are you worried about tox just on-target tox for STAT6? I guess that's always a question.
You can knock out STAT6, and the mice are perfectly happy. And they are normal, other than they make no IL-13, IL-4 response. And their type 2 inflammatory response is shut down. It's really a thing of beauty in terms of a target. So I mean, yeah. And the degrader is the perfect way to hit it.
Yeah. Yeah. I guess in terms of this clearly is very important to Sanofi given the Dupi franchise. So I mean, it sounds like it's been in the works for quite a while. And I think they also are partnered with a small molecule company as well. So I guess, are they just kind of hedging their bets with multiple programs? Or where do you think you fit in the hierarchy there with the two?
Our STAT6 program has survived several heads of research.
Oh, good. That's great. All right.
As a program itself, it is an incredible survivor. It has, at one point or another, been called the most important drug discovery program that they have. And I think it is one of the most important. And I think it has perhaps the greatest potential. And we're looking at an oral agent that has biologic-like efficacy, basically, or maybe even better. Because don't forget, Dupi is really not right on the signaling pathway, right? So I think it's going to be fascinating to see.
Gotcha. I mean, obviously, we have data from one of the competing agents by the end of the year. I mean, how are you guys looking to that to inform any sort of development strategies for you or just kind of understand the target better? What do you plan to take away from that data set?
We're cheering for them. I thought that Kymera's Phase I data looked great. I mean, everything that they showed looks like a green light. They should be able to see efficacy readouts. It would be logical. We're certainly hoping that they're very successful. We've got our running shoes on, and we're only a few steps behind, so.
I mean, do you think there'll be anything that emerges in terms of differentiation between the STAT6 molecules? Or do you think they'll be generally pretty similar? How do you think about?
It remains to be seen. The molecules, our molecule's not published. Their molecule's not published yet. So I'm sure as soon as these things are published, everybody will make them, by the way, around the world, as they have made Bexdeg and they've made our other molecules. So everyone will make them. Everyone will start profiling. And then we'll learn something preclinically first. Ultimately, again, the way molecules usually get distinguished is based on their off-targets, which are the hardest things to anticipate, right? So you don't really know how they'll be distinguished. Hopefully, both will be very safe. It's a huge market opportunity. There's obviously room for multiple agents in this space. So it's not an either/or.
Yeah, and then maybe just in terms of the overall platform, you guys have a penchant for developing really good degraders for hard-to-drug targets. But I guess, where are you kind of more even preclinical and discovery for other targets? I know we've talked about this balance between oncology and I&I and maybe more excitement for I&I in the future, but when should we learn more about that direction and ultimately the ability to finance other drug development candidates?
So hopefully in the fall, we will be able to describe more about our preclinical pipeline. So much attention has been focused on Bexdeg and STAT6 and IRAK4 in the last six to nine months, and appropriately so. But I think the potential is much broader than that, as you point out. Not only in I&I, there are, of course, always exciting oncology targets, new ones. But then I think even outside of I&I and oncology, there could be new targets that we could pursue and that we are pursuing. But we haven't had time, really, to highlight them. But we would like to do something like that in the fall.
Gotcha. Okay. Got it. And then maybe just lastly, in terms of just kind of the milestones for the rest of the year, and you tend to put out data at ASH also. So what should we kind of expect over the next six to nine months? And any kind of, I mean, this clarity on the Phase III, I think, is obviously what a lot of folks have been waiting for. But what should we kind of get for the rest of the year?
So ASH is a big event for us every year. Our cadence is really about every six months to have data updates on Bexdeg. We do anticipate other programs being presented in the fall. We'll be kind of awaiting announcing those. I think there's been a lot of questions we've had on our Cbl-b inhibitor and where that is. So I would expect we'd give an update on 1607 in the fall. I mentioned perhaps an update on our pipeline, our broader pipeline. And then 2127, our dual degrader, that would be a 2026 event. That's in dose escalation. It's the imid-like activity combined with BTK, primarily in NHL, where we've seen some dramatic complete responses in some very severe disease cases of DLBCL. So there'll be a number of pipeline updates. And of course, we're talking to Gilead and Sanofi.
We'd like to be able to provide updates on those molecules in collaboration with them.
Gotcha. I mean, they haven't given any timing in terms of for IRAK4, when we could get that data or when they could just present it?
No. I can't say what their timing is. But we encourage them to share more. Let's put it that way.
Gotcha. Yeah. I mean, actually, just hitting on Cbl-b and 2127, I guess, I think there's been discussion around really using maybe the upcoming data as kind of like, "Okay. Do we want to move these forward and continue to spend?" So is that still the case? And I guess, what would you want to see from those assets to really continue to drive continued investment there relative to maybe Bexadeg and IMiD or other preclinical assets?
For 1607, which is an immuno-oncology agent, a novel target, Cbl-b, seeing some signal of single-agent activity in a dose escalation trial that makes it believable that you'll have a meaningful anti-tumor effect in solid tumors, I think that would be a requisite for 1607. Some meaningful signals as single-agent activity. For 2127, we'd like to repeat the complete responses we've seen in MCL and in DLBCL in third-line plus patients as monotherapy. Those are really, if we can repeat what we've seen before when we had the first generation of that compound, now we have the second gen, then I think that would be a go signal there. In terms of relative investment, Bexobrutideg is really getting the lion's share, I mean, beyond the lion's share, lion's and tiger share of our investment.
Gotcha. Maybe just a degrader question. Obviously, Arvinas was out there ahead kind of with Bexdeg, a different area, but maybe not as differentiated as one would hope within the degrader space. BTK, seemingly way different, right? You're seeing a lot more differentiation. So as you kind of look at the landscape of targets, what gets you comfortable in terms of, again, are you going more against proven targets where you have to have that differentiation and kind of beat the incumbent inhibitor? Or are you going to focus on more kind of like the STAT6s of the world where these are undruggable until you make them druggable?
I think we're leaning in our future pipeline towards the undruggable or not successfully drugged people have tried. In the current pipeline, we have the BTKs, which proved the point, and fortunately, there is a differentiation ability with degrader and BTK, which I don't think existed necessarily as well in the AR/ER space, the ability to differentiate from existing therapies, so going after a clinically validated target obviously has some advantages because it's clinically validated, but it also is competitive and has disadvantages. BTK sort of had that sweet spot, and the big picture with the BTK degrader 5948 is that it has the ability to really displace the non-covalent inhibitors, so people have been looking for the second-line drug to the covalents, which have been very successful. The non-covalents seem to be a logical next step, except they're actually not differentiated enough, and they're just not strong enough.
The degrader is stronger and will basically displace, we believe, easily the non-covalents. And so then after that, will it move to the front line in CLL? It's an open question. It doesn't need to be a successful multi-billion-dollar drug.
Right. Gotcha. All right. Well, Arthur, we'll leave it there. Thank you so much for the discussion.
Great. Thank you, Derek.
All right. Congrats on the news as well.
Thank you.