Nurix Therapeutics, Inc. (NRIX) Earnings Call Transcript & Summary

Good evening. Good evening, everyone, and welcome to the Nurix 2024 ASH Investor and Analyst event. I'd like to thank everyone for attending here tonight at San Diego. We realize it's a little late here in the Pacific Coast and even later in the East Coast. I'd also like to welcome those attending via the webcast. In addition, most important thanks to our patients who have committed themselves to our clinical trials and to our physician investigators who have also committed themselves and are collaborating with us quite successfully on the development of our novel agents. And tonight, of course, we'll be focusing on discussing the data around our novel agents. These are our disclaimers. It has been a really terrific ASH 2024 all around. I feel, especially for Nurix, we had 3 presentations at ASH, 2 were oral presentations. We'll be focusing on the NX-5948 oral presentation today, of course. But we had 2 other, I think, important presentations, one on NX-2127, its mechanism of action; and also another focused on the crossing of the blood-brain barrier and some of the science behind how NX-5948 is able to achieve that and it has direct implications for our patients in the trial, and you'll hear about some of that tonight. So we've had a great ASH. We're very enthusiastic. It's our third ASH as a company, and we're looking forward to many more. Let me just take you through the agenda very rapidly, and we'll dive right into Dr. Shah's presentation. He will be recapping the presentation that he gave earlier today with some expansion in one of our NHL cohorts regarding Waldenstroms and then we'll go directly into Q&A session with Dr. Shah. He has a hard stop tonight at 9:00 and is heading to the airport. So we want to make sure we get full advantage of his presence here right upfront. And there's a lot of very exciting data to go through, and I'm sure a very interesting Q&A. We'll then turn to our Chief Medical Officer, Dr. Paula O'Connor, who will discuss some of our regulatory plans as we are soon to enter into 2025 and also present clinical updates -- very brief clinical updates on NX-2127 and NX-1607. We'll then turn, shift gears into discussing autoimmune disease and our new efforts in autoimmune disease as we see them in 2025. Gwenn Hansen, our Chief Scientific Officer, will lead off providing some of the backdrop data that has informed our decision-making and our planning for entering NX-5948 into autoimmune indications. And then I'll close out with a discussion of our I&I strategy. This will be a high-level discussion about how we plan to approach the I&I space with NX-5948. And then we'll have another Q&A session with our Nurix executives and we'll conclude. So with that, I would like to invite Dr. Shah to the podium to present NX-5948.

Great. Thank you for the introduction, and thank you to Nurix for allowing me to present this exciting data. We've been partners with them on this clinical trial and excited to sort of review the abstract we presented earlier today. So I think you guys are familiar with this. The title is efficacy and safety of the BTK degrader NX-5948 in patients with relapsed/refractory CLL, and these are updated results from an ongoing Phase Ia/Ib study. So why is this important? So we know that there are great treatment options for CLL. Targeting two enzymes, BTK and BCL2, is the mainstay of front-line treatment. However, as these treatments do become the mainstay in both front-line treatment and relapsed/refractory disease, that means, as more patients that then progress and now we have a new unmet clinical need for these patients who are dual exposed or dual refractory to these lines of therapy. We know that resistance mutations occur with BTK, and these have been well defined with both covalent nhibitors, and even now we're identifying mutations to noncovalent BTK inhibitors. So this BTK degrader NX-5948 has a different mechanism of action. It works through recruitment of E3 ligase binder that leads to ubiquination of the BTK enzyme and then proteosome degradation. And so this degradation of the entire molecule, preclinical studies have demonstrated that they can actually overcome treatment-emergent resistant mutations and disrupt BTKs scaffolding, and so potentially being a therapeutic option that's agnostic to the presence of mutations within the BTK. So this is a trial design that we're going to be discussing today. It's a Phase Ia/Ib trial, and it involved patients with both CLL, SLL and non-Hodgkin lymphoma and Waldenstroms. We're going to be focusing mostly on CLL, but you guys are going to see a few extra slides on Waldenstroms that we'll share after this abstract presentation. This was, again, a dose escalation study. So patients are treated at different dose levels to find the target dose. So adult patients, 2 or more lines of prior therapy. And then that led to a Phase Ib expansion cohort. We had 2 different dose levels for further exploration to really identify the best dose for this drug for future clinical trials. This is the patient disposition. So 60 patients were treated with CLL, SLL. And again, you can see that distribution of dosing, typical for a Phase I trial, 46 remain on treatment. There are patients that have discontinued treatment, most commonly due to disease progression, but you can see some of the other reasons for that in this slide. The patient demographics is a typical CLL patient, median age was 67 years, predominant of male, and you see here ethnicity and race distribution. This is looking into the disease characteristics of this patient. So I think a big question you ask when you look at a CLL dataset is, do these represent truly relapsed refractory patients? And I'll prove to you that they do. You see here a median of 4 prior lines of therapy, but it ranges from 1 to 12. And you also see here something that we don't see very commonly until CLL really enters the relapse/refractory state of having CNS involvement. So this is unique. Most clinical trials would exclude such patients. This trial allows it. I think you heard a little bit. They're learning why this drug molecule can get into the CNS and so we do have 5 such patients or 8% with CNS involvement. It's important to look at the lines of therapy they were exposed to. So 98%, nearly every patient, has seen a covalent BTK inhibitor, about 30% have seen a noncovalent BTK inhibitor. And then the other class of drugs, we think about are BCL2 inhibitors, 83% have seen those as well, and 82% are double exposed to both of these agents. There are other therapies like CAR-T bispecifics, et cetera, the small numbers that patients have seen. But the summary and takeaway is that this is truly hard-to-treat relapsed/refractory CLL. And consistent with that is as the disease evolves, clonally evolves over time and becomes this relapsed/refractory disease, you see more and more high-risk mutations. And so here, you can see that 40% of patients had a p53 mutation. We got BTK mutation similarly in almost 40%, and then we also have PLCG2 mutations, again, suggesting that this is clearly previously treated CLL. This is a safety profile. And when we did the safety profile, we looked at the entire population, so that includes the NHL cohort. That's the numbers on the right part of the graph. On the left is what we're going to focus on, which is the CLL, SLL population. Key takeaway is that the grade 3 or higher toxicities were generally low. Predominantly, they were cytopenia events, things like neutropenia. But I would like to make a note that this trial, again, unlike many other trials, they actually allow people to come in if they were neutropenic, if disease was felt to be the reason for that neutropenia. And so that can take time to resolve even with an appropriate treatment option. When we think about BTK-associated toxicity, certain things come to mind, words like atrial fibrillation, bleeding, bruising and diarrhea. And here, again, there was no new atrial fibrillation. There was one Grade 1 atrial fibrillation in a patient who had a history of atrial fibrillation. Again, there's low rates of grade 3 or higher bleeding events or diarrhea. And then in terms of treatment discontinuation. And I always tell people the best measure of a drug's tolerability is not really the toxicity profile we show, but how many people had to stop it because of a treatment-emergent adverse event, and only one CLL patient requires stoppage, again, focusing on that population. There were 2 grade 5 adverse events. One was a pulmonary embolism, the other one is under investigation, but both of these were not deemed to be related to NX-5948. This is an interesting slide that tries to show the biology of how this drug works. So this is looking within the blood and seeing the depth of BTK degradation that occurs after initiating this agent. And what is interesting is that whether they had wild-type BTK or BTK with different mutations, such as gatekeeper mutations, kinase proficient or even kinase dead mutations, you see rapid and quick degradation of BTK, consistent with the response that we're going to show. And you can see here some of the mutations that are present. These are common C481 mutations, L528 and then also mutations of T474. This is the overall response data for this clinical trial. So the primary overall response rate included patients with at least 1 response assessment at 8 weeks. It was 76%. This was largely partial responses. This is typical of many drugs in the CLL landscape. But what's interesting, which is also similar to other drugs in CLL, is that you see deepening over time. So the exploratory overall response rate now looks at patients who had more than 1 or at least 2 response assessments. And so what you see is that the overall response rate is evolving, deepening over time, and now you see an overall response rate of 84%. This waterfall plot is a diagram that really demonstrates, I think, the ability of this drug to have clinical efficacy. You can see here, nearly every single patient has some degree of response, and you see the dash line is where you sort of see the iwCLL criteria for a partial response. And then these orange boxes around some of these responders actually show that these patients, difficult-to-treat, CLL that's in the spinal fluid with CNS involvement, again, are also responding. At the bottom here, you see the mutational profile of the individual patients and how that impacted response. And the takeaway message is there is no pattern. So sort of with that preclinical hypothesis is that it seems that this drug is agnostic to the varying mutations that occur in patients with previously exposed CLL to other BTK inhibitors. Not only do we want to show that patients respond, but it's important to know that they continue to respond. And so this is a swimmer's plot looking at sort of the duration of response for patients. Now I want to note that follow-up is limited. The median duration of treatment is 4 months. So we need to continue to watch this data on an ongoing basis. But you can start to see that there's a subset of patients that are doing well. And some of these patients are actually doing well, some of the first treated patients were actually treated at the lowest doses, right, because that's how you do a Phase I dose escalation. But there's 5 patients who are now above 1 year. And again, you can see the ongoing responses in the majority of these patients. The median duration of response was not met. And again, if you look at this sort of diagram on the left here, the shaded areas show you the type of drugs they've been previously exposed to. So almost everyone has been exposed to chemo immunotherapy, covalent BTK inhibitors. The majority have seen BCL2 inhibitors. And then even the newest class noncovalent BTK inhibitors, there's a small subset that have seen these drugs as well. So in conclusion, this is an ongoing Phase I clinical trial. And we've demonstrated here that the BTK degrader NK -- NX-5948 demonstrated an encouraging clinical profile in a difficult-to-treat relapsed/refractory CLL population. This was well tolerated with low rates of grade 3 and higher toxicity. And again, consistent with that low rates of discontinuation due to treatment-emergent adverse events. There's been no new safety signals with longer duration of follow-up, but I'll say, right, drugs that you're on for many years, you do need to continue to follow for the presence of new toxicities. We showed here robust and deepening evolving clinical responses even in heavily pretreated patients, some with CNS involvement, and those with many high-risk mutations, including BTK, PLCG2, P53. The overall response rate was 75%, and it deepens to 84%. And again, we are optimistic that we will continue to evolve as we get longer duration on treatment, right? And the median duration of treatment is still short. However, we've seen durable responses in the subset that started this trial earliest on with several patients now beyond 1 year. So I think, the Nurix team is going to talk more about their developmental plans. But I wanted to conclude this abstract presentation, but I am going to add something additional that we did not present at the ASH meeting today, which is some early data that was presented at the IW-Waldenstroms macroglobulinemia meeting, looking at some of the preliminary findings for NX-5948 in this disease histology. So this is a little tease out of the NHL cohort. The NHL cohort has multiple arms because BTK-targeting agents can have actually activity across B-cell malignancies, and we're hoping to learn through this clinical trial what those signals look like in these varying histologies. But here, we've gathered enough data to share a little bit of the Waldenstroms experience. So those of you not familiar with Waldenstroms, it's sort of a chronic blood cancer with a very specific profile, leads to high levels of IgM, and patients can have complications from cytopenia nodal involvement. And in difficult cases, they can have sort of a high viscosity and thickening of their blood that can lead to complications. So here, we have 13 patients with relapsed/refractory Waldenstroms. Median age is 74. Again, a male predominance. In this population, CNS involvement was 0, but that's just consistent with the disease that would be a very rare finding. Looking at the median lines of treatment, again, sort of heavily pretreated 3 prior lines. And when you look again at the exposure, 100% have seen prior BTK inhibitors, small subset have also seen pirtobrutinib, which is a noncovalent BTK inhibitor. And again, everybody has seen chemo immunotherapies. This disease has different mutations. So MYD88 and CXCR4 are known mutations within this disease, and you can see their distribution here. So this is just a quick look here at the efficacy of this patient population. Again, really encouraging data here. Overall response rate of 78%. Again, largely driven by partial responses, which is typical, again, based on the criteria that we use to measure response in this entity. And you can see here, again, we have limited duration of follow-up, but some of the longest patients are now beyond 1 year. And again, when you look at what they've been previously exposed to, they've all had prior BTK exposure, which is one of the mainstays for this disease entity. This here is looking at IgM levels. I mentioned that, that is a biomarker that we follow for disease activity. And so you can see here, again, evolution over time. And so you see a deepening of the IgM response occurring in patients the longer they're on this therapy. And you can see here how that looks like from different dose levels. Again, we see disease activity independent of the dose level that's been administered to these patients. So again, just a quick peek here. This is existing data in my mind. And definitely, again, hopefully something the company will continue to pursue because there are treatment options needed for relapsed/refractory Waldenstroms. And so here, we have that data on 13 patients with 3 prior lines of treatment. I have seen both chemotherapy and BTK inhibitors. We have an overall response rate of 78%, and again, sort of evolving responses over time. You saw that with that IgM response. And so again, I think these data clearly support continued development, specifically in the Waldenstrom's histology in addition to CLL, which we discussed. Phase Ib is ongoing. With that, as we mentioned, I do have a flight that I need to make. And so I think we're going to do.

I'll be the moderator.

You're the moderator. Perfect.

Thank you , Dr. Shah. Thank you. Thank you very much. So this will be our Q&A section 1. I would ask the questioners to please focus on the clinical data for NX-5948 and related questions around CLL or Waldenstroms. The regulatory section, Paula O’'Connor will address next, and then we can talk more about regulatory. So we can start with questions. And we have some mics in the room, too.

Brian Skorney from Baird. So in the areas of improvement about the number, you just keep on saying that if someone didn't have a lymph node response, they probably didn't have CLL. So I guess the question is what kind of patients with progressive disease here, can you give any sort of characteristics of withdrawal, their mitigating factors or their Richter's transformations that were diagnosed as CLL they came into the study. Help us understand what -- is there any driving factors understanding what is a progressive disease.

Sure. So number one, there are patients that didn't have nodal disease, but had marrow involvement. And so then they're not going to sort of fall under iwCLL response criteria. Number two, there were patients, and I'll tell you a patient of mine, that a relapse refectory CLL was felt to be the initial diagnosis. Started NX-5948, progressed, but on biopsy was found to have Hodgkin's form of Richter's transformation. So those patients are out there. There are, again, some patients that didn't -- obviously, that went on and then did progress with disease. I don't have all of that data on what they look like and what their mutational status looks like. And that's stuff that the Nurix team as been actively evolving to get that data to understand like is there a phenotype out there that is maybe resistant to this specific BTK degrader. That's just -- we have -- as I mentioned during the ASH meeting, at this time, it's hard to discern that when you have an 85% overall response rate and no pattern. So 1 or 2 patients in a small clinical trial like the Hodgkin, you take that patient out, and your overall response rate is now up to like 90%, right? So what I would simply say is no drug is working 100% of the time. And I know Nurix is committed to understand the biology of those patients that failed to respond. Some of them, again, some of those -- why not every patient is evaluable for response also has to do is if your disease burden is circulatory and marrow, again, you can't do nodal assessment. And so they are not on that waterfall plot.

Thank you. Gil?

Gil Blum from Needham & Company. How do you feel about the results in the CNS lymphoma patients because that's rather unusual. And we're kind of missing 1 patient here. So we have like 4 out of 5.

Yes. So that might have been a patient, again, that didn't have evaluable. So the stuff on the waterfall plot were patients that had nodal disease that could fit iwCLL criteria. And so very likely, and Paula can clarify, that would have possibly been a subject that didn't meet that, or they haven't hit the time point for assessment. So remember, early data. And so these graphs continue to evolve rapidly. To get back to your CNS question. Bad CLL, when you get like fifth, sixth line or lots of mutations, it can go into the CNS, and it is very difficult to treat. And this is one of the few clinical trials that I have participated in that didn't exclude those patients. Almost uniformly, trials don't want to treat patients like that because, well, they are difficult to treat. But obviously, they had the data that this gets into the CNS, and we're seeing responses in those patients. And so I think it's exciting to know that there is a signal to get into the CNS. And a part of the NHL arms are actually looking at those patients with primary CNS and secondary CNS lymphoma because anything -- any sort of lymphoma that gets into CNS are some of the most difficult for clinicians to treat.

And as a related question, do you think that this is potentially a way to get the drug approved specifically in patients with CNS?

So I don't think I would aim -- I mean, so I don't want to get into too much about approvals because that's sort of a topic I'll leave for the company. But I don't -- it's a niche. And I don't think like that specific information is going to drive the approval or lack of approval of the drug. I think it adds to the totality of data and sort of makes it a better molecule for patients to get. But I think that what's going to get it approved is the data you saw today. I mean we saw a group of patients that have seen multiple lines of therapy enriched for bad mutations, and at least, again, I'll say the follow-up is limited, right? So I am very honest about the data. But so far, you're seeing high levels of responses with the low toxicity profile. That's the sort of drugs that people want to take. And when you run out of clinical options, which there's a growing group of these double exposed, double refractory patients, it's CAR-T or which has, what, a high toxicity signal and the risk of potentially dying from some of those toxicities are novel agents like this. And these are the conversations we have in our clinic and why some patients opt to even do a clinical trial.

Go ahead.

Derek Archila from Wells Fargo. I just was wondering if you could comment on the duration of exposure and kind of the response kinetics that we're seeing for 5948, how does that compare to what we saw with BeiGene? And I guess the expectation that some of these PRs might convert to CRs.

Yes. I mean, so BeiGene had longer median duration of follow-up. If you saw that presentation, I think they're about 10 months. And here, our duration of treatment is shorter. And we're clearly seeing the deepening of response. We saw it in the CLL group. We saw it in the Waldenstroms Group. And that's actually consistent with other BTK targeting drugs. So there are patients that have achieved normal counts, but not all investigators have done a marrow to look and see if they've actually cleared the marrow. So it is very possible that some of these PRs convert to CRs. I'd also like to take a step back, and if you heard me during the presentation, the focus on CR is misguided, right? Like that's not necessarily the endpoint that matters for all of these patients, right? Getting into a CR and CLL doesn't mean you're cured, right? It just means the depth of remission. But controlled disease, taking a pill and feeling well is also okay, especially in the setting that this has been used as like a fifth line treatment, right, median of 4 prior lines. So it's just each lymphoma is very different. And there are other lymphomas where CR is what the whole story is about. But PRs and good quality of life on an oral agent that's tolerable with good duration of response, which, again, we need more follow-up, I'll keep saying that, I think is actually an important endpoint more than aiming for this CR.

Yes. Go ahead in the row.

This is Kripa from Truist. I know Dr. Shah, you said that there was really no pattern in terms of who responded. But just wondering if you could see anything between the patients who were on prior noncovalent versus covalent inhibitors, and if that would make any difference to how you take the drug forward.

Yes. I mean, I showed you the data. So again, I always tell people like you need events to be able to do separation and come up with sort of these variables to predict outcomes. So here, the problem we have is -- it's not a problem, it's a good thing, right? You have a really high overall response rate. And then you look at what they were exposed to and you look at all the mutations, there's nothing you can tease out yet. So is it possible with more time, more patients, more follow-up, maybe we'll learn when we have enough non-covalent BTK exposure that their DOR is less. But I really just can't make any comments to that right now because we just don't have that data, mainly because it sort of worked in the majority of patients. And so it's hard to tease out who were those few patients that didn't respond, one of which I know is mine, who had Hodgkin's, right? Like so I don't know. I sort of -- I think I'm repeating myself here, and I apologize, but I'm not sure if I can get you that answer that you're looking for.

And since you mentioned the Hodgkin's patients, I was just wondering if you have any thoughts, they didn't present any data, but do you have any thoughts into how the drug might work in NHL patients versus the CLL patients?

Am I allowed to speak of my clinical experience with the drug.

We're not going to go.

Yes. Sorry.

So he's not allowed. So let's start with that.

I tried.

And then I would say that we did just give you some information for the Waldenstroms patients, and that is a subset, if you will, of non-Hodgkin's lymphoma. We certainly are looking forward to presenting a bigger part of the story in 2025 times now. That's the best...

Tried to pull a fast one on me.

Okay. Next question. Is it Roger? Go ahead.

Great. Roger from Jefferies. I'm going to ask some questions, Dr. Shah is allowed to answer.

About this data.

Yes, about this data, yes, particularly for your trial experience related to the dosing, because we saw BeiGene compare -- another BTK. They -- specifically already select those move forward. So -- but I think Nurix is doing the right thing to pick choose to those randomized. So maybe my question is your trial experience, how you think about the efficacy and the safety in terms of the different dose, given they are moving forward the mid dose and high dose. So just give us a...

I mean, look, I think the dose optimization is really important. I think this drug at every dose level, right, I sort of showed that data, we saw clinical efficacy. Dose optimization is better to be done now than post marketing or finding out later. In drugs like ibrutinib, there was actually a history of perhaps the dose was too high, right, and that led to some of the adverse signals. So I think the company is making a good clinical decision, and they're investigating these 2 doses to really determine what that best dose is for their pivotal clinical trials. Obviously, we're gathering that data. And when they analyze both the clinical activity and do all the ancillary assays and look at the depth of degradation, look at the DOR, that's going to guide that decision-making along with getting more safety data, which is why they're selecting these 2 doses. So I mean, I don't think that's a concern of mine. I think it's a good decision and being judicious because once you make that dose decision, right, there's really no going back.

Great. Next question?

Yes, Steve Willey from Stifel. So I know that there's pretty discrepant outcomes in patients who are either double exposed or double refractory. I think there was a poster presentation from Dana Farber on that tonight. So just wondering if you can speak to the proportion of patients who kind of fit into that double refractory bucket within this population specifically. I think BeiGene had broken out that like 90% of their patients had discontinued prior BTKI due to progressive disease.

We didn't have that data. And so I don't believe we have that data at this time. Looking specifically at double exposed versus double refractory, I think that's a great question. And as this data sort of evolves, you have to often tease that data out from sites. It's sometimes not clear. It's obviously data that hopefully Nurix is listening and can get that as part of a future presentation. But if you just take a step back, like 1 to 12 prior lines, like double exposed, double refractory, like whatever it is, these are not like easy-to-treat CLL patients, right, like TP53 mutations in 40%, right? That's not the starting population. You don't see that percentage in newly diagnosed CLL. So something has happened for them to have these mutations and things of that nature. But I believe this data they can get to you in a future presentation.

Go ahead. Yes.

Greg Renza from RBC Capital Markets. Dr. Shah, just to follow up from the discussion today in the Q&A. As you've spoken about, these are the hardest-to-treat patients, you mentioned just that philosophy of putting the best drug first, and I won't hold you to discussing the comparator and the best comparator for future trials, but maybe just build on that philosophically about putting a drug...

I mean, I think that's a philosophy that you see throughout oncology, right? If you have your best drugs go first, then you get longer duration of response, less toxicity, better quality of life. I mean, that story has played out in CLL. Why did we stop getting ibrutinib to the majority of patients? Because something better came along, potentially more efficacious, definitely safer, right, in the second-generation BTKIs. We're seeing the story continue to play out with noncovalent. And now we have a new class. And the only way we'll know if it's better is if we continue to see high efficacy, you go from relapsed/refractory to second line to first line. But theoretically, the question I would want to see answered as a clinician is does degradation of BTK prevent mutations, right? And we can't answer that because we're not treating that population, you would need treatment naive. But if you could prevent mutations through a different mechanism of action, then could you get even better, more durable responses. And so time will tell if they can continue to develop this drug and move to those earlier phase trials and maybe one day get to less refractory patients. But I mean that's the goal of oncology is continue to do better. I always tell people like ibrutinib was an incredibly great drug until something better came along, right? And so I don't negate how wonderful that drug was because in 2012 through 2015, it saved lives. And now I don't prescribe it, right? But that's only because better options came up. And that's okay because that's what we want for ourselves and for anyone, right, as we move treatments forward.

Next question. So we have -- there's a couple of hands up front here.

It's Matt from OpCo. It seems like kind of a relatively high proportion of CIT-pretreated patients. Do you think that's indicative of the broader population here because usually, CIT is reserved for kind of more healthier patients?

So I think that reflects like who these patients are. So like patients with CLL have a long history. So like if you got CIT in 2012, right, and then you've got 5 years of remission, and then you went on a BTK, and then you've got another 5 years of remission, right? Then you get a BCL2, and then you got -- now you've got like 2 to 3 years of remission. And now you're on fourth line therapy, right? So it's just reflective of when this trial is being developed. Now in 2030, right, the story will be that everyone in 2017 and '18 will have only had a BTK inhibitor. And then -- you know what I mean? So it's just CLL often has a long history behind it because people do -- even chemo immunotherapy got many people durable remissions, and then they got sequential lines of treatment.

Yes. Is it still a frontline treatment for you? I know MD Anderson has been pushing for its use for a while, but others have kind of shied away and...

Pushing what's used for what.

For like frontline CIT.

I don't know anybody who's pushing frontline CIT, chemo immunotherapy. We should not be pushing frontline CIT in patients with CLL. Yes. That day has passed.

Okay. Upfront here.

Yes. Roger Song from Jefferies. So kind of following up on the dosing. So great to see the deepening responses. I was kind of wondering where -- what doses -- at what doses you see that? And what's the expectation for the deepening responses between the 200 and the 600?

Yes. So we haven't seen like a dose response differentiation. I mean, even the lowest dose levels, those were the patients on the swimmers plot that had the longest DOR because they've started at the lowest dose. And so you're sort of seeing responses at all these different doses. Obviously, the team at Nurix did a lot of science and investigation and said, we want to further investigate the 200 and 600. To me, it's about optimization, but I feel comfortable offering, based on the data we have, my patients either dose. But it's about optimization, and teasing out really, again, you want to make sure that you're choosing the best dose when you go to your pivotal studies.

Great. Are there any further...

I must be doing a really great job.

We gave you most of the time for questions, which is great. I might have a question for you about...

Sure.

From what you've seen of our drug and, of course, BeiGene, the only other degrader, what combinations would you be most excited to see with the degrader?

Yes. I mean, so we know that BTK-targeting drugs combine very nicely with CD20 antibodies. They combined nicely with BCL2 inhibitors. So I think those are the natural combinations you want to go to first. But I mean, there's lots of investigation. We saw some data about BTK and CAR-T, right? There's also BTK and bispecific antibodies, right? So why would I say those combinations? Because these drugs can often lower disease burden and then allow a bispecific or CAR-T to come in and clean things up. And by doing so, limit some of the toxicities with some of these immunotherapeutic agents, which have a higher degree of risk when you have higher tumor burden. So I think there's lots of natural partners to investigate and definitely worthwhile doing because we saw, again, lots of data in CLL about doing combinations to get people deep responses for shorter periods of time that lead to prolonged sort of remissions.

Excellent. And then Paula, I just want to give you an opportunity to make any comments you'd like while Dr. Shah is still here. Any questions?

So I must always have something to say. I don't have much to add, though, this evening because you've been so complete. I think this is an incredibly exciting time for us in the CLL space, and I'm really just happy to be a huge part of it. I think degraders are going to change the way medicine is practiced. And I'm really happy to have an opportunity to show how.

Great. Thank you. Well, I know that your airplane chariot awaits you.

It's my daughter's third birthday. And since I'm a terrible father, I had an ASH baby. So the only birthday I made was her birth. And so I promised to fly home as quickly as I can. So I do apologize. I hope this gave you the information you needed. And thank you. It's been exciting for me to be part of this drug and mostly to be able to offer patients something, which is why at least we do this. So I'm going to step out and enjoy the rest of the meeting.

Well, thank you, Dr. Shah, so much. And tell your daughter happy birthday for us all in the room here. Okay. We're going to move now into a regulatory update and some high-level development plans for NX-5948 with Paula O’'Connor, our Chief Medical Officer. Paula?

So this is the part that you've all been waiting for. All of the answers right here, right now. So my first time presenting to you guys was a year ago. And I was pretty nervous at that point in time. I'm less nervous now, but I'm nervous for a different set of reasons. And the reasons why I'm nervous now is because 2025 is going to be our year to put up or shut up, right? And that's what we are prepared to do. One of the things that we did this year, in particular, was to get ourselves ready for the point of getting to pivotal trial initiation. And so what you see on the slide in front of you now sort of highlights some of the key milestones that we have achieved in this year. So first and foremost, in January, we achieved Fast Track designation, as you know, for patients who are treated in the third-line setting post-BTKi, post-BCL2 inhibitor. This gives us the opportunity to engage more frequently with the agency about our program, which also speaks to, once again, how they see the potential for this program. We then had our end-of-Phase-I meeting. And as you know, an end-of-Phase-I meeting is one where you have a discussion with the FDA about your plans moving forward, right? You review your Phase I program, and you start laying out what you intend to do in your registrational path. Then we started expanding our program, as you can see to include sites globally. Certainly, speed is an issue, and we know that in order to have a successful CLL registration program, we are going to have to enroll patients all over the world. We certainly also know that the sites in Europe, in particular, when you're thinking about France, Poland, Italy and Spain are some of the major drivers for enrollment in registrational trials in CLL, and we're opening our sites there this year. And then I think most important -- or maybe not most importantly, but equally importantly, it's literally in the weeks leading up to this meeting, we actually achieved an EU prime designation. Prime designation, as you know, is basically the European equivalent of breakthrough designation. So this is the EMA also saying, okay, we see that this is a drug with great promise for patients, and we want to play a part in making sure that you do what's necessary to actually get this product registered. I should also note that when you think about EU prime, just like breakthrough designation, just because everyone applies, it doesn't mean you get it. So about 25% of applicants will actually get this EU prime designation, and we were one of them in 2024. And that is setting us up for what we need to do in 2025. So in the last couple of minutes, Dr. Shah gave you an overview of our current status in CLL. I'm not going to belabor that. You heard him, you asked your questions. The real question is where the heck are we going to go in 2025. We've already acknowledged that we are planning to start a pivotal program. And the approach that you should have seen or certainly you have heard us talk about is an accelerated approval approach where you're doing a single-arm Phase II, which has to be accompanied by a confirmatory trial. We know even from the presentation today at ASH by the FDA that this is a viable strategy. And obviously, we've had an end-of-Phase-I meeting, so we've talked about some of our Phase II plans. When you think about the patient population that we are going to be doing our work in, especially as it relates to the single-arm Phase II, we're going to build upon the data that we've already generated. That patient population that we have this Fast Track designation. So third-line patients who have been exposed to a BTKI, who have been exposed to a BCL2 inhibitor. We already know what to expect in this patient population, and we know we can deliver. At the same time, these are not the majority of the patients. And so we want to expand our knowledge in a randomized controlled trial, which would be our confirmatory trial, and that will also be started in 2025. The goal here is to move up in line. So you'll see that we're looking at patients who are in the second line plus. For those of you who want to know the comparator arm, I'm not going to tell you tonight, okay? But suffice it to say that it is a comparator arm that will enable us to move into the second line plus. You all heard from Dr. Shah that it may, in fact, be best to treat your patients with the most active agents in the earliest lines of therapy. We also know that in CLL, there are 2 approaches generally speaking. One is monotherapy approach, and then the other is a combination approach. For the vast majority of patients who are elderly and who want some sort of palliation of their care or palliation of their disease, control of their disease -- palliation is a terrible word, because palliation, people think, oh, you're basically just helping me stay alive. Well, that's not a bad thing. But we want to do more than just help people stay alive. We want them to thrive, right? And so certainly, as we are looking at our approaches to earlier lines, we are looking at a monotherapy approach, which is that palliation approach, that approach where we're going to give people a single agent and see how they do. And then we are also going to be looking at a combination approach, which is really designed for patients who want the biggest bang for their buck right away because they want a fixed dose of therapy, for example, and then they want to be off of treatment. So we have 2 paths to the expansion into the front line. That will be a monotherapy trial where we will be looking head-to-head versus our investigator's choice of BTKIs. And then you also see a combination with another agent, and you heard some of the key agents that Dr. Shah already mentioned, meaning CD20 agents and venetoclex being prime choices for a combination to be used in the frontline setting. And so that gives you a sense of what we're doing. We are looking at a monotherapy strategy. We're looking at a combination strategy. We're starting in the third line plus in post-BTKI, post-BCL2 inhibitor-exposed patients and moving to the front line.

We'll do Q&A.

We'll do the Q&A. I'm sure there are lots of questions, but we'll hold them for now.

Yes, keep going, and we'll get through these.

Great. So Dr. Shah gave you an overview of our NX-5948 program. And in the next couple of minutes, I'm going to give you an overview of our NX-1607 program and our NX-2127 programs. I'll remind you that NX-1607 is a CBL-B inhibitor. For those of you who are wondering that CBL-B does, it's basically a regulator of immune activation. When you inhibit the CBL-B pathway, you basically allow for T cell activation against your tumor of choice. What you see in front of you now is the trial schema for ongoing Phase Ia/Ib trial. As you can see on the far left-hand side of the slide, you can see our eligibility criteria. And then in the center, you see the dosing strategies that we have utilized in this experiment. And in this trial, we have looked at both QD dosing and BID dosing as ways to address some of the GI toxicity that we saw very early on in the program. We're now getting ready or approaching Phase Ib. And when we do get to Phase Ib, as you can see here, we will be looking at a multitude of different indications, very much like we've done in our 5948 study where we're looking at more than just CLL, right? We will be looking at more than just one indication when we get to Phase Ib. So in this last year, we've been really quite successful in that we have made a significant progress in terms of addressing the GI toxicity that we've -- that I noted on the previous slide, but also in basically being able to see that we are getting a biomarker impact. So what you see in front of you now on the left-hand side is basically the response in terms of Phospho-HS1, so that is a marker for -- a biomarker for immune activation, T cell activation. And what you can see is that with increasing doses, we are getting greater levels of that phospho-HS1 biomarker. This leads us to believe that we are approaching a dose that will be clinically meaningful for patients. And in fact, we have seen some high-level activity in the patients that we've treated to date. So long story short. We continue our Phase Ia program for our NX-1607 trial or drug. And we are looking forward to presenting, at some point in 2025, the outcomes that we have seen for patients. Right now, we have successfully addressed the GI toxicities by looking at different dosing strategies, and we have actually started to see, as we've increased our PHS1 levels, activities such as stable disease, tumor shrinkage as well as the biomarker responses that I've already noted. So stay tuned. We look forward to speaking to you next year as we get the full results of this Phase Ia trial. NX-2127, as you may remember, is another BTK degrader. It is differentiated from NX-5948 in that it is both a BTK degrader as well as an immunomodulatory agent. So there is -- it also degrades IKZF1 and 3, very much like lenalidomide. This program, as you know, started prior to our NX-5948 program and was presented at ASH in 2022 and in 2023. At that point in time, we were in Phase Ia and getting ready to go into Phase Ib. We did have a manufacturing issue where you know that we had a chiral product. The agency requires that you have a uniform product. And so now we've addressed that manufacturing issue, and we have reentered dose escalation with the chirally pure product. What you see in front of you right now is the trial schema. So on the left, you see the eligibility criteria. In the center, you see the dose escalation on the top for the original drug product. And then you see on the bottom, the dose escalation that's being associated with our new or chiral pure product. We have entered dose escalation at this point in time and look forward to presenting more data to you sometime in 2025. After we continue this dose escalation, which, by the way, enrolls patients with CLL, SLL, MCL and other histologies, although we're focused specifically on NHL with this product, we look forward to presenting that to you in the second half or at some point next year. Many of you have actually seen this case before. This is a case that we presented, I believe, actually last year. And you may be saying, well, why the hell are you presenting it? Oh, pardon me, excuse me, why the heck are you presenting it to us again this year? A year can make a huge difference. It makes a huge difference in the lifetime of a product, but it also makes a huge difference in the lifetime of a patient. And so what I want you to recognize here is that this patient that we presented to you last year is an 84-year-old woman. And notice I said is, right? She is an 84-year-old woman with DLBCL following a transformation of her Waldenstrom's macroglobulinemia. She was treated very aggressively, as you can see, with 4 lines of therapy, including R-ICE chemotherapy; R-CHOP, which are the standards for DLBCL and relapsed DLBCL; and ultimately started to participate in clinical trials after progressing on those agents. She joined our trial after progressing on the rituximab, ibrutinib and lenalidomide regimen. Actually, she had a lot of cytopenias and wasn't responding. So she hadn't relapsed per se, but she hadn't fully responded. Within 8 weeks of starting NX-2127, our dual degrader, she had a complete response. What's important now is that it has been almost 3 years, and this patient remains on our trial and remains in a complete remission. That is remarkable. So for this patient, this year has represented yet another birthday. And so we heard Dr. Shah talking about the importance of a 3-year-old birthday. While the same actually exists for an 84-year-old because you have your family, you want to spend time with them. So this is something that's really remarkable and gives us reason to believe in NX-2127 and its development in aggressive lymphomas. And so we look forward to generating even more data. The second case that I'm going to present to you is yet another patient that was treated on the NX-2127 program. This is a patient with mantle cell lymphoma, and you all know that mantle cell is a highly aggressive disease. In this case, we're dealing with a 64-year-old woman who was treated with R-CHOP or R-hyper-CVAD and Ara-C, a stem cell transplant and then went on to subsequent aggressive therapy. Unfortunately, she progressed. When she entered our trial literally coming directly off of her previous chemotherapy, she had multiple sites of disease, which you can see here circled in red. By 8 weeks, this woman had another complete response. It is not typical for patients with advanced stage, multiple-site lymphomas, aggressive lymphomas, whether they be DLBCLs or mantle cells, to have complete responses within 8 weeks. That, in and of itself, is remarkable. What's even more remarkable, however, is that this patient stayed on our study for 17 cycles of therapy, and then decided, well, I haven't had any disease. So why can I stop my treatment? And so she did, and that was over a year ago or approaching a year ago. So the idea that this patient has not only had a complete response despite having had multiple of very aggressive therapies in prior, that, in and of itself, is remarkable. But then to stop therapy and to remain in remission for a year, despite their very aggressive disease history, now that should be making like the hairs on your neck stand up or on your arms. So it certainly is doing that for me. And for me, this is my reason for believing that 2127 has a future in the treatment of patients with aggressive lymphoma. So this is what we're looking forward to seeing more of in 2025. So long story, short. For 2127, we will continue dose escalation as per the new or the updated design with our current product, and we look forward to sharing those results with you when they are available, but it's certainly a product, which clearly has something that is special about it, and we look forward to seeing more in 2025.

Okay. I think we're going to shift gears now to discuss inflammation and our applications of the NX-5948. I'd like to invite Gwenn Hansen, our Chief Scientific Officer, up to give us a brief background around some of the recent scientific findings that point us in this direction.

Yes. Thank you, Arthur, for that introduction, and thank you, everybody, for being here today after very long ASH. So we have been talking about hematopoietic malignancies throughout the course of the meeting and tonight, but I want to point you to where we think our 5948 drug can go, and that is beyond malignancies. So if you really go back to the fundamentals of why we're even interested in BTK, I think we're driven by the genetics. So the genetics of BTK in both human and mouse tell you that if you remove this protein, you have a fundamental shift of biology in that you are unable to make antibodies. And the inability to make antibodies within a system has consequences on the immune system, but can also have very useful applications in the setting of disease. And so we think degrading BTK in the context of immune disease has real potential, and that is not only really represented very well by the genetics, but also reinforced by the positive clinical experience of BTK inhibitors in the space. But we know from our experience in malignancies that inhibitors have limitations. They definitely effectively control B cells signaling, but there are some aspects of signaling that aren't fully controlled. And we think part of that is because there is a scaffolding function of BTK that really wasn't appreciated previously. We've illustrated that very well in the context of malignancy. But there's another aspect that's important to point out. BTK sits downstream of several different receptors on different immune cell types. So we've talked extensively about the B cell itself, but there are also myeloid cells in which there are receptors that BTK propagate signaling. And those myeloid cells are very important for a number of different types of immune-related disease. So by blocking BTK, we may have impacts in a variety of different settings that could go beyond some of the newest agents that are coming out and having impacts in these settings, these are B-cell depleters. In the context of blocking BTK, you can block BTK and signaling in cells beyond B cells. And therefore, there can be some thinking that the effects of BTK degrader could go beyond the agents that really are targeting solely B cells. So what is our evidence for this? We have a couple of slides here. Some of this data was shown at the recent ACR meeting, where we presented some of our preclinical rationale for where we want to go in immunology and inflammation, so here, I'm showing you the potency of BTK and blocking B-cell activation in comparison to many of the BTK inhibitor agents that have shown good promise in this setting. So rilzabrutinib, remibrutinib, acalabrutinib and fenebrutinib, you can see that BTK degradation is more potent, 10 to 100x more potent than the potencies observed for those inhibitors. And the other thing in this graph that's important to pay attention to is that we're driving the suppression of the BTK pathway signaling to a lower point than you can achieve with the inhibitors. And so that, we think, is an indication of fully suppressing the pathway, but removing that scaffolding function that sits at a low level and can propagate signal underneath the enzymatic activity that the kinase really controls. So in addition to being more potent than these other inhibitors, if you look in the other cell types. So here, I'm showing you some myeloid cell types. These are monocyte activation assays, and I'm comparing the activity of NX-5948 compared to the same set of inhibitors that were on the previous slide. And what you see here is that we are again seeing that more potent suppression of pathway activation. And this is with 2 different stimulations, plate bound IgG2 stimulation or IL-1B stimulation. So basically, whether you receive a signal from circulating a stimulant or whether you receive a signal that is representing maybe a broader connection with the surface of B cell, very, very potent control of this pathway and more potent than inhibitors when you use a degrader. And so what is the consequence of that? The consequence of that is a very, very potent control of disease modalities as we can read out in preclinical models. So we've shown many of these models before. Systemic lupus, lupus nephritis, multiple sclerosis and rheumatoid arthritis. So if we go across the spectrum of different preclinical models that can illustrate how degradation of BTK is impacting the immune system, we basically can control -- or we can show efficacy that is equivalent to standard of care or to the best model agent in every single case that we've gone into. And basically, that just illustrates how prolific the activity of BTK is in the immune system. So just to wrap up and then hand off to Arthur. Every single dose of 5948 that we have used in the clinic from 50 milligrams all the way up to 600 chose very consistent removal of the BTK protein from the cell types of interest, and this is in the clinic. This is a preclinical assessment. This is in patients. Why is that important? Because we're not only controlling the BTK enzymatic activity, we're removing that scaffolding function, and we're eliminating the ability for receptors on the surface of these cells to signal to the nucleus. And the one factor that we are extremely proud of is the fact that we are actually seeing activity in the CNS. So the activity here illustrated on this graph is in PCNSL. We've seen it in CLL with CNS involvement, rapid exposure into the CNS is controlling B cell activity in the brain, and that is giving us the idea that in the context of I&I, we could have impacts in diseases like multiple sclerosis. And this is all coupled with a very favorable safety profile that we've observed to date. So this is just a prelude of our preclinical data. And now I'll hand it off to Arthur to give you our strategy and how we're going to apply 5948 in that setting.

Thank you, Gwenn. I am going to just take one click back because that upper left-hand graph is one of my favorite graphs from our oncology trial when you look at how every dose really flatlines BTK levels. And -- but it also tells you in the context of I&I, we have a very wide dose range that we can work with, depending on the inflammatory disease we go after. And that really gives us a lot of flexibility because some autoimmune diseases are tougher than others, and likely will take a high dose. And others may take a very low dose, and we have the rationale to be able to supply that. But I want to talk about our strategy and our vision. I'll start with vision, and that is to introduce the first BTK degrader into autoimmune disease that has practice-changing potential in medicine. So this would be the first example of a BTK degrader going into these diseases. And we think, it does have a potential to change the practice of medicine in these fields. One of the challenges with this mechanism of action, as Gwenn outlined, is that it pretty much works in every model we put it in. So then the question is where do you go clinically? You can't go into every autoimmune disease all at once. So I want to share with you some of our considerations that were built into our thinking and how we came to our plan for 2025. So first off, this BTK degradation is a novel mechanism of action. We all know that. And that means it should be focused on areas of very high unmet medical need where there's a very obvious risk benefit ratio because we are testing something very new here in autoimmune disease. So we're talking about serious autoimmune diseases should be prioritized. Speed to proof of concept. There are a lot of very serious autoimmune diseases. Some take longer than others to see if your drug is working. So we do believe it's very important to give preference to indications with the potential for a very rapid proof-of-concept readout. And we're looking at 12-week trials as really being the first step. And that will give us confidence and a lot of information to build going forward into the longer duration indications, which then we could tackle. The third is dosing and formulation. So again, wide ranges of doses need to be enabled, and this is something they're tackling by looking very carefully at dose. We're actually exploring novel formulation as well for I&I, and I'll talk a little bit about that at the end as part of our plan. That additional formulation is already being tested in healthy volunteers. And then fourth, the medical marketplace. So an oral BTK degrader can address very large, multiple, very large markets, but they need to be able to mesh with the oncology market in terms of pricing and then that also should take into account dose, et cetera. So again, we're talking about severe indications that would warrant really a good price point for an oral BTK degrader in autoimmune disease. So this is the way we approach this to develop what we call our systematic approach across multiple organ systems for I&I. So first, we're going to be focused on hematology indications. This does several things for us. It allows us to leverage our existing hem-onc expertise, and we have a great hem-onc team with the company already. And we can achieve, we believe, very rapid proof of concept in CLL patients who also have warm autoimmune hemolytic anemia, or WAHA. There's a significant segment of these patients. They're often excluded from clinical trials as our CNS patients. And we can go forward in this area very rapidly with a protocol amendment, not requiring necessarily a new IND to explore this patient population in WAHA. It could also enable then other future hematologic purely non-oncology heme applications as well, and that would be a logical next step for us as well. Second, we are very interested in dermatology indications. And we do think hidradenitis suppurativa HS is a significant area of unmet medical need. And there's a strong rationale to consider a BTK degrader here. There's been proof of concept provided early by some BTK inhibitors. But they seem to leave room for improvement. And we think that the BTK degrader could really take advantage of that and provide that to patients. And then we could go forward into subsequent expanding indications in CSU in dermatology. So we're actively evaluating this as a part of our plan as one of the expansion opportunities. And then third, we are also very interested in going into MS. And clearly, we have brain activity. And this is a very logical third step for us. These are longer trials, and they take, obviously, longer periods of time to establish proof of concept. Patients need to stay on the drug longer. And so this is the ordering of our sort of systemic approach into autoimmune disease. So I'll just finish up here with our next steps for this implementation in 2025. I mentioned we're going to open a new cohort in patients with CLL who have WAHA, and that is underway. The protocol amendment is already underway, and we think we can achieve that in the first half and begin dosing very rapidly. That will be followed, again, by a effort in nonmalignant heme, and that would require new IND, and that work is underway for the nonhematology -- nononcology indications in again, emphasizing WAHA first. You could imagine expanding into ITP after that. Third, we are in the process of conducting our healthy-volunteer study to study a new formulation. And this may help us address this broader range of doses needed. This is something that I think would further distinguish these drug products from the oncology form of NX-5948 and give us a lot more flexibility in terms of pricing and marketing. On the fourth point there, we are exploring these additional indications into other organ systems, as I've mentioned, derm and neurology. And then we do plan to provide additional information on a broader autoimmune pipeline in 2025 as well. So NX-5948, the BTK degrader, will then join with our STAT6 degrader under the Sanofi collaboration and our IRAK4 degrader in the Gilead program as well. And so we're targeting a first half of 2025, probably second quarter R&D Day where we can loop all these together and present a future update. So I'll just close on a slide that I think pulls a lot of things together in terms of what we have here at Nurix with regard to our entire pipeline. So we are, first and foremost, going to successfully execute NX-5948 full development plan in CLL, and Paula has walked through that at a high level, and we think that can be rapidly implemented. Secondly, as I mentioned, we'll go into I&I indications in a systematic way, in a stepwise way. And we will -- and Waldenstroms is on the list, I should mention that, because we are encouraged by those results, and we will be looking at regulatory paths forward in Waldenstroms as well. And then I already mentioned our collaborations. NX-1607 and NX-2127, we're going to drive to proof-of-concept data in 2025. And I think that they will both provide exciting clinical updates then. And then finally, we're going to be advanced -- continuing to advance our innovative degrader pipeline. We have a whole pipeline of oral degraders. We focus on those in the clinic right now, but there are many others coming. And we're very interested in progressing our DAC technology, our degrader antibody conjugate technology as well, and that's well underway with our collaborator of Pfizer. So we'll give you updates on our platform at R&D Day in the future. And I think at that point, we can take sort of an open-ended approach to Q&A. We have about, I think, 15 minutes remaining on our schedule. So I will open it up to Q&A. I'll moderate, and we can start. Do you need a microphone? There you go. Steve?

Yes. Can you maybe just speak to the nature of the GI toxicity that you're seeing with 1607? I mean is this nausea, vomiting, is this autoimmune colitis? Just curious if you can provide a little bit more color on it.

Yes, it's nausea and vomiting. It's really GI tolerability more than toxicity, but it's nausea and vomiting. It occurred in about 30% of the patients. And so we have developed different strategies, including antiemetics. And Paula, do you want to comment on that?

I think you summarized it perfectly. It's predominantly Grade 1/2. But nevertheless, for patients who are going to be on a daily oral therapy, you need to manage that sort of tolerability issue.

And then I know this was being dose escalated both as mono and in combination with paclitaxel, I believe?

Yes.

So can you just kind of speak to what you need to do in terms of resetting dose escalation? Should you move to the BID formulation, which it looks like you will.

Yes. So the -- what has taken a long time is that we've done a lot of different dosing regimens, not just BID, but also step-up dosing in dosing this agent, which is perhaps not surprisingly required for what is potentially a very strong IO agent as we know. So the direction where we'll probably land is a step-up dosing regimen. I think we're already there potentially at the 30-milligram BID being the final dose in that step of regimen. But there might be one more to test, which would should be going to 40 mg. And we can -- I'll triangulate on that based on that biomarker data that Paula showed because we really are at the range we need to be in animals where we see the antitumor effects. Now with regard to paclitaxel, and then we'll layer in paclitaxel combination again. And we would also likely layer in an anti-PD-1 combination at that point, once we establish that monotherapy dosing step-up regimen.

And just one quick one, sorry. The "clinical responses" that you're seeing, are those RECIST responses? Are there anything that you can say about the nature of the clinical responses you're seeing?

Not at this time, but they're very encouraging. That's what I can say.

He's not allowed either.

Joe Catanzaro, Piper. Maybe first one for you Gwenn on BTK scaffolding in autoimmune. Appreciate the one chart you showed showing deeper inhibition of B-cell activation suggestive of a scaffolding role. Wondering if you have any thoughts on how you go about sort of more definitively proving that there is a scaffolding role for BTK in autoimmune?

Yes. So it took us a while to walk into this idea that definitively, we could show it in malignant setting. And that, I think, now is very clear. So I think what we're going to be showing is more transition and proteonomics analysis in the model systems where you're looking at disease cells being stimulated by their native receptor engagers. And I think that is where you're going to ultimately be able to tell the difference between the inhibitors and degraders.

And then my second question. So if I look back at EHA versus today, it looks like the rate of L528W ticked up a little bit, be it small numbers. Wondering if you have any view on where that mutational spectrum is going and whether that influences how you think about what a second-line comparator arm could be?

So are you directing that to me? Or are you directing that to Gwenn? Or both of us?

I think that's more so you, Paula.

Okay. So I think as you -- I know all of you know this -- the incidence, the prevalence of the different BTK mutations is an evolving story. And that number is going to change as we see more patients being treated globally with acala and zanu and then also with pirto as well. So I don't think I can give you a ceiling number or what I anticipate will be the number because I honestly do not know the number. What we can certainly say is that 50% of our patients have non-C-481 mutations, and that's a big proportion of patients with BTK mutations. In terms of the comparators that we will be using in our suite of studies that we conduct, what I would say is that we are setting ourselves up to ask a series of questions that will address the global standards. And so that will include all of the common -- most common treatments for CLL in the relapsed/refractory setting, but also in the second-line and front-line settings recognizing that we'll be looking at a monotherapy strategy as well as combination strategies.

A question here?

I think the nomination of MS doesn't come as much of a surprise to anyone, I guess, given some of the recent data that we've seen from others. Is there a treatment setting that you're thinking of? Or is it kind of too early? Like would it be relapsing remitting or primary refractory?

I think it's too early to say. I think that -- I think all of them are open. There's been some disappointments in some of the different MS settings. However, that may be an opportunity for the degrader where we are hitting this target harder. So I think there's every reason to -- you could justify trying in all of them actually. Now the question is where do you start and fund. What do you fund first? And what can you get an earlier readout first? So we'd have to study that a little bit more thoroughly, but there's definitely a mechanistic rationale to do them all. Another question here?

Yes, Brian Skorney for Baird. Maybe for Paula, just -- could you just comment on sort of what the threshold of data for the 200, 600 randomized cohort is to initiate a pivotal in the post-BTK, post-BCL2i? Is there like a number of patients that need to be seen? Or is it just more qualitative information from?

So the guidance from the FDA in regard to dose optimization is typically that you have cohorts of around 20 patients each and that you basically look for not only safety being the predominant, but also the activity difference. And so we will look.

Roger?

In terms of the I&I, I understand you want to use the WAHA's proof of concept. But how much read-through from the WAHA to the other different organ system based on your model? And then a follow-up question is, the WAHA, how likely are you going to push towards the registration or maybe as the first indication, the real indication for approval?

Well, there were some great WAHA posters here today from some of the inhibitors and also an interesting press release from J&J on WAHA and what an important indication it is in I&I. So I think that, first off, we do believe that the CLL experience with WAHA will read to the non-oncology WAHA setting. And one of the beauties of that disease indication is it comes with highly quantitative biomarker readouts, i.e., elevation of hemoglobin to give us a very strong proof of concept. In terms of the read-through from WAHA to derm or other indications, I think we don't necessarily need to look at WAHA. We can look at the inhibitors in the derm indications that have shown proof of concept that BTK inhibition does show promise, but again also room for improvement. So I think there gives -- there's a better direct proof-of-concept validation to provide the rationale for the derm indications. And also on the dosing front, I don't think there will be a lot of read through. I think we're going to h4ave to test a few doses in each of these indications because they're very different. So I hope that answers your question, Roger. One point I'd like to go back to on the mutation discussion that was earlier. We do all focus when we look at the mutational spectrum on the mutants, of course, but over half of the patients had wild-type BTK, which I do find remarkable, and we look beyond that sometimes, but they have wild-type BTK and yet they've stopped responding to BTK inhibitors. And I think that's another interesting finding that is perhaps the scaffolding function of BTK sort of showing itself or announcing itself in a subtle way. But there is definitely something more going on there in those patients that is beyond the kinase function. So are there any other questions? Yes, one here in the row.

Thank you. Is there a dose-dependent increase in AEs that you've seen with 5948? And how might that impact -- I know Arthur said that you would have to test multiple doses in I&I, different indications might need different doses. But is there a dosing range that you think could be safer for I&I indications?

So we have actually reported on our safety profile by dose. And certainly, as we look at the profile at all of the dose levels, we do not see any dose dependency. The dose optimization is really going to help us -- in the CLL study is certainly going to help us just understand, yes, 200 is tolerable, 600 is tolerable, and then we will make a decision. That is a presumption that, that is what the data is going to show you actually have to do the assessment, and we will do that. Given what we've seen in the CLL NHL space, my supposition is, in fact, that we will see similar degrees of tolerability, certainly if we are looking at dose levels that are less than the 50, we have not assessed dose levels that are higher than 600, so I can't speak to that. But certainly, everything that we've seen, thus far, suggests that the safety profile will be quite tolerable.

Anything to add, Gwenn? Maybe not.

Not really related to safety, but I will say that each of these diseases will have a different amount of pathway control that is needed to get efficacy. And so the ability to explore multiple doses to get at the dose that is relevant for that particular disease is important. And so if we have this wide dose range that allows us to eliminate BTK in a wide dose range that is also safe, we have the best ability to find an actionable dose in each of the indications that we're going to pursue.

And for 5948, I know you're continuing to do the studies in lymphoma. And with 2127, it looks like you're focused mainly on the lymphoma's no CLL. Is there a point at which you would decide we're going to go with 5948 only in CLL and 2127 in lymphomas?

So I think we have said...

Go ahead.

So I think that we have said that our focus for 5948, is, in fact, CLL, although we continue to explore to understand the activity. You've certainly heard Dr. Shah speak to the fact that when you're looking at certainly the aggressive lymphomas, monotherapies are not the approach. You want to be looking at combination therapies. And so one of the beauties, if you will, of NX-5948, given its safety profile and its broad degree of activity is, in fact, that it would be perfect to combine with a variety of agents, whether they be bispecifics, CAR-Ts, chemotherapy, et cetera. That, all having been said, when we look at NX-2127, you are effectively already looking at a combination therapy with a single pill. And so the responses, These durable responses that I showed you in the DLBCL in the mantle cell patients are really, really exciting because to have a -- to have a single pill that has 2 modalities to control your disease, B cell and T cell engagement, is huge, especially when you consider the tolerability of that single pill compared to your typical combination regimens, which are not, generally speaking, well tolerated.

So I think with that, I think we're out of time. I do just want to reflect one moment on just how exciting today was, I think, for NX-5948, for our patients, for the benefit that we see it bringing. The session today was really tremendous. The energy in the room was fantastic. The Q&A is great, not only here, but there. And when we look at the overall profile of NX-5948, it really does look like a potential drug in the making here, and we intend to follow through. So thank you all for joining again tonight and on the web. And very importantly, thanks again to our investigators and our patients committed to our trials.