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. 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.
Yeah. Maybe just to start off, a lot of things going on at Nurix. You guys announced a big deal on bexdeg and other things. Maybe give us the state of the business first, and then we can get into more specific questions.
Sure. Terrific. For those who don't know Nurix well, we are a multi-product, 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.
Yeah. To start off just on bexdeg and what underpinned the deal with Roche in terms of the strength of the data in CLL and the promise in some of these I&I indications.
Yeah. 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. On the efficacy side, we had 83% response rate in heavily refractory patients. We had 22.1 month 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.
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 de-risk 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. That includes not only the malignant heme, but also I&I and neuro, and Roche is the ideal partner for us in this respect.
In terms of just the CLL opportunity, you guys had already started the late line trial, and obviously, the Roche partnership opens up early in line. How do you think about the competitive dynamics with the next gen BTK inhibitors versus a BTK degrader? Within that class, how do you guys feel like you're differentiated versus the BeiGene or B1 molecule?
Yeah. A fantastic question. The BTK inhibitor space obviously started with ibrutinib and then acalabrutinib, zanubrutinib, and then the non-covalents like pirtobrutinib. With each of those, it has 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 is proven. In CLL, the BTK space right now is $13 billion annually. It is growing at close to 15%, and the indication space keeps growing. The BTK degraders are really the first to try to cross both oncology and I&I. The inhibitors have tended 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.
The data has been, I think, remarkable, and we are full steam ahead on all of that. In terms of differentiation versus our closest competitor, B1, it is hard to say right now. They are both showing fantastic efficacy in the 80s percent range, which is remarkable. I think ultimately, probably where we will 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 will just have to see that play out over time.
Got you. I guess when you think about the Roche deal in terms of the economics to you guys and ultimately the development plans too in terms of the costs, can you just walk us through stepwise how you go from where we are today and then building out the overall set of CLL opportunities?
Yeah, sure. 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. It was a $700 million upfront payment, $2.3 billion total milestone and upfront package. The cost sharing is 40/60 on the development costs, and it is a U.S. 50/50 profit share ex-U.S. royalty. People have asked, "Oh, is Roche taking over?" No, this is truly a collaboration. We have equal representation in all the joint governance, and we are 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.
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 ask 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 Waldenström and mantle cell. 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, additional CLL data, and anything else in the heme space?
Yeah. So in terms of bexdeg data, we are also, in addition to 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. We'll 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. 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.
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?
Yeah. 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%. 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. Then how does the durability overall look in those patients as well as the safety? Every time we've looked at the data, it continues to look very positive.
Yeah.
My expectation is it's going to continue to look that way.
Got you. Then maybe just to shift gears to the I&I side of the coin. We know BTK works in a variety of different indications, remibrutinib has proven CSU. There's been a variety of different MS trials. I guess when you think about the best differentiator there, is it more the efficacy play or more the safety play, given that there's been kind of a checkered past even in these MS trials about safety. To be fair, even remi's got some bleeding risk associated with it.
Yeah. These are great questions. 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. 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. It's never really been fully explained why many of these ran into liver tox signals. 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. In general, we think we are more selective than many of the BTK inhibitors. We are very encouraged by that. That's led us to feel good about moving into these indications.
Now, in terms of efficacy, do you think what we've seen in CLL in somewhat translates like full degradation of BTK will confer better efficacy in I&I? Again, is that part of that-
Yeah. No, that's , that was the other part of your question.
Yeah.
Yeah. I missed that. We have run a lot of preclinical studies looking at B cell activation, mast cell, basophil activation, and our BTK degrader is much more potent than all of the inhibitors. There is a potency. Now, potency could just relate to dose too, so you could get away with a smaller dose. But what we have 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. There is 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, 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 is more rapid, but it is 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 are not, and we think we can probably push the BTK mechanism a little harder than remi does.
Is there any insight? I know B1 had a trial of theirs in China, their degrader in CSU. Any insight to how that performed? It does sound like they want to move that forward. What do you think, what would your internal benchmark be to move something forward with an incumbent BTK inhibitor? How much better would you need to be and what differentiation would you want to see to move that forward into a global registration and phase III trial?
I think remi does set a bar. 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. We think we can probably do better than that. I think that bar is pretty well established now in terms of the composite endpoints on itching and hives and swelling that is associated with the disease.
Is there any specific part of the disease, whether it be, again, itching or hives or anything like that is more directly driven by the scaffolding function, or is that just too nuanced and we do not really know?
It's very nuanced, and we probably don't have all the right information, and I'm 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.
Okay.
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. BTK is impacting the disease in three different cell types. 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 we do with remi.
Got you. Then just on the other side, in terms of MS. 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 datasets that we've seen with prior BTKs, where do you want to establish the beachhead?
Yeah. 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 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. The microglia are immune cells that are resident in the brain. They're believed to be involved in some of the demyelination that's critical for the progression of the disease. 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 phase II MRI, or do you want to go into a longer trial? What is the design that you guys would like to do? Now with the backing of Roche, and the help there, you can fund any trial that you would actually like.
Yeah. One of the great advantages of working with Roche is having that collaborative team now that is working on finalizing the trial design for the phase II. There is no group out there that has more knowledge of, for example, biomarkers in the space. They have just run a full program for fenebrutinib.
Yep.
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. Ultimately, you need to show data on relapse rates or disability progression. Your ability to measure that in smaller studies, you really have to look at both surrogates as well as clinical endpoints.
We should think, again, more of a standard proof of concept, MRI, imaging-based endpoint study first before going all in on a phase III.
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 trials that will enable a registrational study. 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? I mean, you'll have to do some exploration, and I don't know if there's some differences in the tablet, but maybe you can kind of give us a view of should we be expecting multiple doses, and what sort of PD effect do you need to show to maybe drive efficacy?
Yeah. This is a great question, and it's part of the reason that we've run such a robust phase I program. 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. 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. 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 we just don't know yet?
Yeah. 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 mg once a day. 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? The good news is, again, we're working catalytically. We work at 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. Then that has to be resynthesized to come back. The target coverage is phenomenal, and it's very different than sort of one-to-one 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. 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 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 two and then kind of start to expand, or could that even happen sooner?
Yeah. 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's a long list of I&I indications, including some rarer 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 each therapeutic area team feels is best. 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've 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 de-risk this target and this class of drugs. Maybe just talk about your program, the partnership with Sanofi, and this just, I think, entered the clinic, 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.
Yeah. Great. So the program with Sanofi stems from a 2019 five-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 have initiated the phase I study for that program. We have shown some preclinical data. It is very potent, sub-nanomolar potent. It is probably the most selective degrader that we have made. It is incredibly selective. We think it is a fantastic drug, and Sanofi has disclosed they are in phase I. That study is a SAD/MAD healthy volunteer. They are also treating patients in that study.
Okay.
That study should inform our option decision. So 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. Yeah. So the Kymera data, we are eager to see how that pans out. So far, they have shown biologic-like activity with a relatively clean safety profile as far as we know. The more de-risked this target gets, I think the more value that will accrete to our program.
You talked about this phase I program will include a cohort of patients. Should we think about this as a similar type of program that Kymera ran with their phase Ib, kind of small cohort, uncontrolled, or is it more robust than that?
Yeah. 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 could've been described similarly. Yeah, that's really all I can say about it.
Got it. I guess when you think about STAT6 degradation versus STAT6 inhibitors, there's a few other 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?
Yeah. So I have two 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. All of the preclinical data supports that, and our experience with BTK and other targets suggests that this is a very safe and effective way of really maximally addressing a target. Now, when we talk about comparing, so this is the second point, when 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. The novelty around inhibitors is actually quite high as it relates to transcription factors. 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, and target coverage. It's not as easy to measure, I think, as an enzyme. Our view is you want to hit the target, degrade it.
Mm-hmm. Got you. Trial's ongoing, and as you said, you'll get a decision point at some point where you will see the data. Should we understand that, because it's a phase I trial, Sanofi's probably not going to report out results, but at some point, you'll just pop up and be like, "We've decided to move forward with the co-development plan," or how would that disclosure end up happening? I'm sure there's some sort of period where you will sit with the data, review it, and then come to that decision. I guess maybe high level, what are the mechanics of the decision-making process for you guys?
Yeah. Our option is triggered by results of a trial that were designed to assess safety, dose, and efficacy. Given that last piece, efficacy that would require at least a pilot phase Ib, in a disease setting. It is our assumption that the trial that they are 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 are paying $0 for the development, and then if we opt in, we would just pay our share going forward. There is no catch-up payment or nothing like that. In terms of their disclosure, we are eager to have them say more, I should say.
Yeah.
That is really going to be up to them.
Yeah. Seemingly an important program for them.
Yes.
I guess one of the things I would love to get your take on, so we cover Kymera, and I think there is differing views on where the efficacy needs to be for a STAT6 degrader relative to Dupi. Do you believe that it needs to mirror the efficacy, or it could still be 70%-80% of the efficacy of Dupi and still be successful because it is an oral? Where do you come down on that in terms of where you think it needs to be benchmarked?
I think you wrote a giant report on this.
I did. Go read it.
Yeah. I read it on the plane. That is fantastic. If you have not read it, you should read it. I heard the doctors that you interviewed had expressed that you could have a drug that is even a notch down versus the biologics and efficacy and would still be a huge opportunity. 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. The biggest opportunity is not to, for example, replace Dupi, but to expand the market. There are tons of patients who suffer for a long time, either before going on Dupi or never go on Dupi or something similar. I think a safe and effective oral truly expands the market. Yeah, I think there is a lot of room for this drug class to be a mega blockbuster.
Yeah. Great. With the last couple of minutes, we were just talking about it before we went live here, but the other components to your collaborations and what the overall Nurix platform is capable of. We were talking about the DACs and other things that you guys have done deals on. I guess, what is exciting to you guys? You have got a lot of collaborations, but internal pipeline that you guys want to start to develop because now you have got a big cash infusion, you can go any 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? Where do you want to take it?
Yeah, it is a great question. First of all, we think we have one of the greatest, degrader platforms out there. It has been very, very productive. Since our IPO in 2020, we have put six drugs in the clinic, including two in the last two years, STAT6 and IRAK4. We have more coming. In terms of where those programs are going to be, we are primarily focused in oncology and immunology, and I think that is where you are 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 is very much best-in-class potential and something that we could take forward on our own.
We also have I&I programs that we have not disclosed. Importantly, you mentioned the DACs. That was a deal we did with Seagen, now part of Pfizer. That is moving along very well. We have not disclosed much from it, but we do have options for 50/50 co-promote profit share on two programs. We have options for two programs out of the Sanofi, and we have options for two 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.
Do you think the direction is going to be more focused on looking at targets that maybe are just not appropriately a drug with inhibitors and kind of validated, but suboptimal? Or are you guys ready to take even more risk around targets yourself, like for an internal program?
It's a great question. Originally, we went with BTK as a very de-risked, 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 stay tuned. There's a lot under the hood.
Got you. Maybe just sketch out for us with the last question, 12- 18 months, what should we expect from you guys in terms of updates and internal and external partnerships as well?
Yeah, 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 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 NX-1607, which is our Cbl-b inhibitor, as well as zelebrudomide, which is our dual BTK IKZF degrader. Ultimately, if you think where we'll be next year, end of the year, we'll 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. Cool. Well, Jason, I think we'll leave it there. Thank you so much.
All right. Thank you.
Excellent.
Terrific.
Good to see you, man. Thanks.