Great, great. Good morning. Thanks for joining us, everybody. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. I'm very pleased to be kicking off the third day of our conference this morning, hosting Nurix Therapeutics, and we have Arthur T. Sands, the company's President and CEO. Thanks so much, Arthur. Before we get started, just 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. Thanks so much, Arthur. Really great to connect this morning. I thought maybe just I'll turn it over to you for some high-level comments on kind of where the company stands, what your strategic priorities are before we go into questions.
Thank you, Terence. Thank you for having us at the conference. Got a busy schedule today. Yes, we're about to enter pivotal studies in chronic lymphocytic leukemia as our primary program, lead program. It is our BTK degrader program, highly selective BTK degrader Bexobrutide, now with the name Bexobrutide, or BexDeg, as we call it. We're actively planning the phase 2 and 3 program. These will be pivotal studies, and I'm sure we'll talk more about the design. We did recently disclose our design considerations for the phase 3 study. That takes, you know, obviously a lot of our efforts now. We have a whole pipeline, as you know, that includes other degraders of BTK and IKZF1 and 3, that's NX-2127, in aggressive lymphomas. We have NX-1607, which is an inhibitor of protein degradation through SIKLB, which is an immuno-oncology target and stimulates T-cell development.
We're in phase 1 with both of those programs, testing NX-1607 in solid tumors. We then have a whole immunology inflammation pipeline as well. There, I think, most attention has been focused on STAT6 recently, degrader there. Again, very specific, very selective that we've discovered and developed with Sanofi, our partner for the STAT6 degrader. They've now brought that into IND-enabling studies. Also, IRAK4 degrader with Gilead, our other major partner. We have a growing interest in IND. Each of those deals that we have, and I should also mention our Pfizer deal, but they're all structured with cost-profit share options for Nurix so we can opt in after we see human data from these programs. That gives you a bit of a broad pipeline overview. I'm happy to talk about the platform and the technology, any direction you'd like to go.
Yeah, great. Maybe just before we go to the pipeline, just the platform, I know there have been a number of different iterations of the degrader approach. Maybe you could just give us kind of what your view is on kind of the key features of your platform, maybe relative to some of the others out there, and what's allowed you to develop it both in oncology and also on the inflammation side, because I think that is somewhat unique as well in terms of your approach, whereas it feels like some companies are either oncology or inflammation. You guys are obviously able to do both approaches.
Yeah. I think it has to do with the historical underpinnings of our science. We were founded based on science out of Berkeley and UCSF, all around E3 ligases, which are the enzyme system of the ubiquitin proteasome system that controls degradation. We're very ligase-centric, very basic science-centric on ligases in the early days of the company. This translated to being able to work across a broad set of ligases. There are over 600 in the human genome. We've been able to ligand a large number of those, so find binders to them, which has been rate-limiting. I think what distinguishes our platform is our really significant investment in DNA-encoded libraries of small molecules to find ligands. We've now recently augmented that with AI modeling of ligand finding. I think that's been, again, a distinguishing feature.
We call it our DEL-AI platform now, that has allowed us to ligand other targets and ligases that other people can't. We can very rapidly spread not only into true oncology targets but also into other areas like immunology and inflammation. We've even further leveraged this platform to develop what's called DACs, or degrader antibody conjugates, which is using the degrader molecule as a payload on an ADC sort of platform. They're distinguished, and we like to name DACs better, DACs, degrader antibody conjugates. That's our deal with Pfizer, originally CGEN. Our platform is very broad, and it's very enabling in many different therapeutic areas.
Excellent.
Yep.
On the Pfizer CGEN, is there anything getting close to a clinic there that you can provide an update on, or not yet?
We can't really describe those programs yet. They all were drug discovery programs, literally from protein-level scratch, a sort of beginning point. It does take some time, but they've progressed very rapidly. I think it's a great partnership given their prowess in ADC development, which is obvious. It's become, I think, a high priority for Pfizer to, again, find new payloads. It's been one of the rate-limiting steps for ADCs.
Okay, great. One other focal area right now for the whole industry, really, is just some of the changes at the FDA. We’d just welcome your perspective. Obviously, you're getting ready, as you said, for your pivotal program here for BexDeg. You interact with the agency, that business as usual. Are there any changes in terms of personnel, anything you'd flag, or you feel pretty comfortable with your ability to kind of interact with the FDA and advance all the priorities at the company?
We feel comfortable. I think our particular project team really hasn't changed much. I do think that they continue to be responsive. I think there's a high level of interest in degraders at the FDA as a new category of drugs. It's been not an issue for us. At the higher levels, I mean, if we were on the verge of getting our drug approved, I might be a little more concerned. In terms of launching into phase 3, I think it's more straightforward.
Okay. Maybe before we talk about the phase 3 design, you could just give us a highlight of kind of where you've come from, the profile of BexDeg that you've developed here and through the phase 1, 2 trials, and really what stood out most there and gave you the confidence to advance into this phase 3.
Turning to the fundamental engineering of BexDeg, we really designed the most selective and most potent molecule we could. We think that NX-5948 or BexDeg will have the superior profile of being exquisitely selective and the most potent. That translates—design goals like that generally translate into better efficacy and better safety of a molecule as compared to competing agents. I think we've been in targeted protein degradation and in ligase science for over a decade, and we've really learned all the tools of the trade in terms of achieving this optimization. We use the most sophisticated proteomics to see what we're targeting and see any off-targets. This has really been a great optimization tool. In terms of using proteomics and ligase science, I think it's easier said than done. I think we've perfected it. We've done this with our partners too.
I think we've benefited in terms of our partners' ability as well.
Yes. Maybe just on the safety profile, I know atrial fibrillation has been a focal point at the differentiation among the different BTK degraders. Maybe just talk through the safety profile that you guys have seen thus far in the early studies.
We've seen no atrial fibrillation above background levels, which, of course, do occur in the elderly population, but there does not appear to be any drug-related atrial fibrillation that you could attribute to the drug above background levels in this population. We have patients coming in with some atrial fibrillation. We have patients coming in with some hypertension. The cardiovascular profile looks quite good for BexDeg, and I think that's extremely important. Other BTK inhibitors do tend to have some off-target kinases that do affect the heart, and that's been well established. That's been an adverse event of special interest that we've been watching. We also see a very clean profile across liver enzymes and pancreatic enzymes, and that's also been associated with some off-target effects. I think this exquisitely engineered, clean, highly specific BTK molecule translates to better safety.
Okay. Maybe just on the pivotal program that you're starting later this year, give us the latest in terms of that design and how you're approaching it. Maybe we could dig into some of the subsequent trials that you might be planning after that.
We have an accelerated approval strategy for potential accelerated approval, which is a single-arm study in third-line plus population, which means in patients that have received a BTK inhibitor and progressed, their disease progressed on that, as well as having had a BCL2 inhibitor, most commonly venetoclax, of course. That category of patients has been identified by the FDA as an area of high unmet medical need. There are no approved therapies in that space currently. That is our one pivotal trial attempt for accelerated approval. Of course, you have to have the confirmatory trial, which is the randomized control trial, which we are also launching. That will be 400 to 500 patients. The single-arm trial I just mentioned would be about 100 patients. In the randomized control trial, our control arm, we've selected what we consider to be a globally relevant control arm. It is a global trial.
In the different geographies, we have different standards of care to address with the control. We are including pirtobrutinib, which is a non-covalent inhibitor, an emerging new agent we think has high relevance in the U.S. and Europe. We are including BR, or bendamustine rituximab, as an option, which is the standard of care in many countries across Europe and the globe. Then I deal with sublingual rituximab, or IR. It is a blended control arm, investigator's choice. It becomes a very kind of real-world type of trial.
Okay, great. Maybe just on the single-arm trial there, I'm assuming it's a response rate endpoint, and you need some durability of follow-up. What's the FDA agreed upon for what you need for approval for the accelerated basis here in this setting?
Of course, with accelerated approval, you never really have agreement with the FDA. It's a review issue at the time of submission, always. In general, ORR and progression-free survival are our key, key endpoints. I think most attention is on progression-free survival. Our ORR that we've already seen in this population, actually even a more advanced population than this, has been about 80%. We're in an ORR that's very high, especially since this is fourth-line plus patients in terms of our current phase 1. In the accelerated approval, we're going to be going up a line to third line. In our randomized control trial, we're going to second line. I should have been clear about that. We're advancing in lines of therapy, reaching larger patient populations and people that really should even have a better response rate, but we're already seeing 80%.
Our PFS is not calculable yet because patients stay on the drug, and they're seeing a long duration of therapy. Not having a PFS calculated yet is actually a good thing.
Yeah. What do patients right now in that third-line setting receive? Is it, is there a chemotherapy regimen? Is it palliative care? What's the typical therapy right now if we think about other, you know, trying to get at some benchmark on duration PFS as we look historically? I know you say FDA is never going to sign off on anything, but what do these patients get now?
It's a mixed bag, but a lot of bendamustine rituximab, a lot of BR still given third-line plus. Chemoimmunotherapy is, and we've had patients get CAR-T. We've had patients on bispecifics, experimental therapies that are still in drug development. A lot of patients have received a number of these therapies. Other toxic chemo regimens are tried. Yet, as we receive these patients, again, we're achieving this 80% response rate. I should mention also, we do take patients with CNS disease. We've seen some dramatic CNS responses, and that substantiates the fact that Bexobrutide crosses the blood-brain barrier and has brain activity.
Okay. What does that patient population represent in terms of numbers right now in the U.S., roughly? If you look at framing out the market opportunity in the third-line plus?
It depends on your source, but you could say between 8,000 to 10,000 patients, probably in this category. Unfortunately, growing numbers of patients. If you get to second line, then you're looking at about 16,000 patients. Even with third line and second line, you're looking at multi-billion dollar market opportunities. All of these patients, fortunately, there are effective first-line BTK inhibitor therapies. They are on therapies a long time, but then progression does occur. Those populations are significant in the second and third line.
Okay. Maybe just pivoting over to the phase 3 confirmatory trial that you mentioned. This does, I'm assuming, one-to-one randomization, so about half and half, half on BexDeg and half on physician's choice?
Yes, one-to-one.
Okay. It's a superiority endpoint. Is it PFS?
Yes.
Okay.
Yeah.
Can you give us any benchmark for the control arm? I know it's a lot of different therapies, but what's the, you know, where you expect that to shake out ultimately, given it's a mix of different regimens?
Yeah. With the BR/IR, you're probably looking at anywhere from 10 to 12 months of PFS. It can be higher, depending on the status of the patient. With Pertu, we've seen numbers like 14 months in their latest studies. That could also be higher depending on the line of patients that you're getting. There are some unknowns there. We do think the study has a high probability of technical success.
Okay. Is it fair to think like 20% is usually, I mean, that's usually the bar in oncology? Is that a good benchmark, roughly, that we should think about for?
20%.
20% improvement, sorry, for a comparison study in oncology?
I'm not ready to sort of be locked into a number that we have to hit, but you do want to have a substantial improvement.
Okay. Fair enough. I think this is a global study. Is there anything about geographic differences here versus maybe what was enrolled in your phase 1/2 trial that we need to consider just as we think about translating that phase 1/2 data to the randomized phase 3? I know line of therapy is obviously different, but is there anything about geography that would matter or not really?
I don't think so. I mean, I think we're primarily going to be enrolling in Europe and the U.S. We will include other countries, other geographies to make sure we do cover a broader section of the globe. That, I don't think, will make a substantial difference from what we've seen already.
Okay. Maybe as we look out further into the future, obviously this is the later line setting. Do you guys have aspirations to move even earlier? I know, you know, Lilly, for example, just read out some data in the frontline setting for pertubrutinib. As you think about the forward, is that in the game plan or is that dependent on a partnership? How do you think about addressing that first-line opportunity? You mentioned you've got great selectivity, great potency, clean safety profile. How do you think about potentially moving into the earlier, even earlier lines?
We think in terms of combination agent, with combination agents in the earlier lines. Although monotherapy, the first two trials I've been talking about are monotherapy to be clear. Yep. In the front line, there's a lot of interest in limited duration therapies that all are combination-based. We've actually also outlined a phase 1B/2 study to start looking in combination, BexDeg in combination with venetoclax and also anti-CD20 antibodies. Rituxan potentially, obinutuzumab is in the front line as an anti-CD20. That would give us some frontline optionality there as well. With regard to monotherapy in the front line, those are very long and expensive studies. I think one just has to ask if that investment really makes sense given where the direction of the field is going. I mean, upwards of half of prescriptions in the future may be in combination regimens rather than monotherapy in the front line.
Okay. What's the latest on, you know, going solo versus seeking a partner down the road? It feels like you guys can do that later line setting probably independently. If you do want to move to combos, is that something where you would seek a partner or you feel pretty good doing that alone as well?
The initial combination study, we can do alone. I mean, that's a dose exploration study. I do think that, and we have the financings to initiate all the studies I've been discussing, so we can go it alone, go fast, and, you know, really be directed on that core program of studies. One could do many more studies and build out the profile of the drug even further. Their partnership would probably be useful, even if it's only clinical trial partnerships where drugs are supplied by others; that may be interesting in combination. It's something that we always do consider, but we're really going forward on our own here in phase 3.
Okay. Have you given any timelines for when we could see initial data from these two pivotal studies, roughly?
We haven't given guidance yet on timing. I think the guidance we have given is to start the study on the initiation of the phase 2 study, the single-arm, in the second half here that we're in, in 2025.
Okay, great. I know you guys are planning to file an IND for autoimmune cytopenias for this batch as well later this year. Is that, maybe just talk to us about the rationale there and how to think about that opportunity.
What we have done, just to be clear, is we've initiated a cohort of CLL patients that have autoimmune cytopenia overlay in their disease, which is a subset of the CLL patients. We have several very interesting subsets, by the way, in the phase 1B trial, which include patients with high genetic risk factors, patients that have been in only second-line therapy and first-line therapy, and patients with certain BTK resistance mutations, and this cytopenia cohort. We actually have not specified an IND for this year in the non-oncology setting. It is definitely under consideration, and it's something we hope to shed more light on in the future.
Okay. Got it. You obviously have a couple other assets you mentioned, NX-2127, NX-1607 here. Maybe just take those in order. Kind of what should we expect here over the next 12 months for these assets as we look at important clinical catalysts?
Yeah. We did recently disclose that we will have a publication at ESMO for NX-1607, which is focused on our phase 1 results. It'll be our first disclosures on phase 1, the phase 1 trial, which has been quite a significant effort in NX-1607 with SIKLB inhibitor. I think that'll be interesting.
That's all comers, all types of tumors?
Yeah. It's 11 different solid basket trial, 11 different solid tumor indications, and really all about dose exploration. We take all comers there. I do believe we have a publication also at SITSI coming up. That'll be early November. We have a very busy schedule. I should mention on some of the other elements of the pipeline, Gilead Sciences will be presenting a poster, I believe it's a poster, on the IRAK4 degrader, GS6791, with their Gilead Sciences number now. Yep. I think that is coming up this month, I think, at a Paris meeting. Of course, ASH, we always.
That's a preclinical-like structure paper or something like that?
I don't know if the structure is in there, but it's all in the preclinical modeling, you know, in all of the animal models and why the IRAK4 degrader we think is it's such a superior entity. ASH will be at BexDeg. We'll be featured there as usual. We have a very busy medical meeting conference plus industry meetings. The targeted protein degrader conference in Boston at the end of October. We always are big participants there as well.
Yep. 2127, anything we should be focused on there, even if it's not this year into next year?
It'd probably be into next year in terms of medical conferences, but that's in a dose escalation phase of the phase 1 program.
Okay. Maybe just circling back on ESMO, 11 different tumor types, that sounds like it's going to be a decent number of patients. We should have a pretty good handle on safety. Maybe just talk to us about what some of the preclinical data showed here, like where were the strongest signals by tumor type or what do you think is a likely future next step here in terms of tumor type or pathway?
We saw very strong monotherapy activity in preclinical models across tumor types, including colorectal models, breast cancer models, and models we ran in combination with PD-1. What we saw was monotherapy activity from this very potent agent, very selective SIKLB inhibitor. I think in the phase 1 study, we'd like to see some signal of monotherapy activity. I think that's critical in order to be convinced that you have an immuno-oncology agent that can pack enough of a punch to actually have impact. I think some of the earlier IO agents really didn't have much in terms of monotherapy activity. We didn't see them progress successfully in combination. Ultimately, this drug will be given in combination. We do want to see some signal, even though, again, with 11 tumor types, it's hard. They're a heterogeneous patient population.
You're looking for some types of signals that give you confidence that you are having effects on the immune system.
Is there going to be any, I think it was supposed to have Taxol in combination. Is any of that data coming or that's a separate?
That's going to be a separate process. We really focused on monotherapy dose exploration. You really get the dose right, and the dosing regimen right. This is a very strong agent that stimulates the immune system, so you can imagine we went very gradually and very cautiously in terms of dose escalation.
Okay. Anything from the animal models on safety, tolerability, that was a kind of signal or something that as we think about the AE profile here in the clinic that we should keep our eyes out for?
With an auto, immuno-oncology agent that works, you should see at some point a fairly fulminant autoimmune response in an animal tox study, which we have seen. I think that obviously we don't want to dose that high in humans, but you try to establish your upper limits in tox studies. We've seen on target, if you will, tox associated with immune function.
In preclinical setting?
In preclinical, yeah. Okay, now in clinical as well with IO agents that work, one does see autoimmune AEs occur at a certain frequency. You just want that to be a tolerable frequency.
Yeah. Yeah. I know the checkpoint inhibitors, you see those with the checkpoint inhibitors, right?
It's associated with activity.
Yeah. Okay, all right, great. I'm guessing on the, maybe we pivot over to immunology. You mentioned, you know, Gilead Sciences has a poster coming up here, IRAK4. We'll stay tuned for that. On the STAT6 program with Sanofi S.A., anything you can share there in terms of, you know, just high-level thoughts about, you know, why is there a lot of excitement about this target? I've heard it compared to kind of like an oral Dupixent. Maybe just give us a little bit more flavor about the target itself. Anything more you can share on that front? I'm guessing there's not a lot because it's Sanofi S.A.'s program, but maybe just anything you can share.
Yeah, we can't, we don't have a lot of data yet that we can share. However, we are working on that for the fall. To describe it, we've been working on this program with Sanofi S.A. for six years now. It was part of the original Sanofi S.A. drug discovery collaboration, which I think we signed in 2019. This is a program that has been highly selected and well-developed, carefully curated with Sanofi S.A. every step of the way on the joint scientific steering committee around this program. STAT6, for those of you who may not be familiar with it, is a transcription factor in the JAK-STAT family of pathways, if you will. It's very specific. If you knock out STAT6, you have mice that are healthy otherwise, then lacking an IL-4, IL-13 response, type 2 inflammatory response. That's the only thing they lack. It's a clean target.
It's an exquisitely potent target biologically. We endeavored to make a degrader that was that clean and that potent. In fact, what we did have in the press release with them when we announced that they have brought this in now to Sanofi S.A. into IND-enabling studies, this is NX-3911, is that we achieved knockout-like levels, gene knockout-like levels with our degrader. That has been tested in several animal models. We always run the knockouts, STAT6 with our drug as a control. It's a beautiful drug discovery program, honestly. It's been put through a lot of paces with Sanofi S.A. to qualify as a drug development candidate.
Okay. Going into IND now, maybe next year there'd be some initial phase 1 healthy volunteer data?
Yeah, I mean, I would hope. Of course, that's up to Sanofi S.A.'s timetable. If they progress on a reasonable timetable, we should be in healthy volunteers by 2026. The IRAK4, we are in healthy volunteers now. That was a similar timeframe. That was licensed by Gilead Sciences about a year, year and a half before.
Yeah. STAT6, just remind me, can you measure that in healthy volunteers? Is there a way to measure that directly so you can see that knockdown levels in healthy?
Yes, you can. In fact, Chimera has done that with their program, which was quite convincing. You can see the degradation of STAT6. This is one of the advantages of targeted protein degradation, actually. You have built in the best biomarker that you can imagine in terms of on-target removal of the protein, especially with bloodstream-based targets. I'm sure we will look for that also in healthy volunteers. Of course, we've seen it in animal models, in every species we've been in. That is a good, a fair good marker, EV marker.
Those levels preclinically, like how does your data or Sanofi and yours stack up relative to Chimera on a preclinical basis? Is that something you can do cross-trial comparisons on, or is it difficult?
Not yet. You know, once everyone's molecule is published and we know what exactly is the development candidate, people will profile these molecules preclinically. That's already coming with the BTK degrader, for example, for us in Beijing, and people are making these molecules around the world and testing them. I imagine we will see it. I can speak to what our design goals were with Sanofi S.A., which would be, again, exquisitely selective and highly, highly potent and be very clean against all the off-targets that you could think of, and even those you can't think of, the proteomics. We think we've achieved that. We really are shooting for best-in-class STAT6 degrader.
Okay. Last question is on the cash position. You referred to this earlier in some of the BexDeg and ability to fund the current studies. Maybe just remind us what you said on cash runway.
Cash runway into the first half of 2027. I think we finished the last quarter with approximately $485 million in cash. We're in good cash position and able to launch this phase 3 program.
That excludes any future milestones from either Gilead Sciences or Sanofi S.A. or Pfizer Inc., the cash runway guidance, or do you guys include anything?
We have an operating history with them now where we do put in a discounted value to make sure that we are kind of keeping up with what we really have historically achieved. We do include some milestones.
Okay. Thank you so much, Arthur. Really appreciate you coming here today.
Thank you.
Absolutely.
All right.
Thank you.