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

Welcome back everyone to the 2024 RBC Global Healthcare Conference. My name is Greg Renza, the Senior Biotechnology Equity Research Analyst here at RBC, and we're pleased to have Nurix Therapeutics today. Joining us from the company is Arthur Sands, the President and CEO. And of course, if you have any questions for Arthur in the audience, do please feel free to ask those during our Q&A at the end. With that, Arthur, it's great to see you.

Thanks for having us, Greg. Great to be here.

I think we'll just have you kick it off just with an intro for those who aren't as familiar with Nurix and a brief introduction to the company.

Sure. So before I lead into that, just I will be making certain forward-looking statements and refer you to our risk factors filed with the SEC. We're advancing a very broad pipeline, which I'm showing on this slide for those of you who can see the slides. We've been focused with our wholly-owned pipeline on BTK degraders. These are molecules NX-5948 and NX-2127 that degrade BTK, which is, of course, a highly validated target in B-cell malignancies. And 5948 is advancing primarily in CLL, while 2127 is more focused as a dual degrader mechanism, not only BTK, but IMiD-like activity, so Revlimid-like activity combined with the BTK degrader. So we're focused there on aggressive lymphomas, such as diffuse large B-cell lymphoma and mantle cell lymphoma. We also have NX-1607, which is a CBL-B inhibitor. This is an inhibitor of an E3 ligase, which raises protein levels, the degraders will suppress protein levels, and this is an immuno-oncology being developed in Phase I across approximately 11 different solid tumor indications currently. We have multiple programs with partners Sanofi, Gilead and Pfizer, formerly Seagen, focused on using our target approaching degraders in -- hitched to antibodies as a new form of ADCs, which we call Degrader-Antibody Conjugates. So a very broad pipeline in oncology as well as now moving into inflammation and immunology with several programs, most notably the IRAK4 degrader, which was licensed by Gilead. And also, we recently announced the STAT6 program, degrader STAT6 with Sanofi. And for all of our partnerships, we maintained cost, profit, share options after initial human development. So that's just a quick pipeline overview.

That's great. And certainly, I think the maturity and the updates on the I&I aspect of the Nurix story have been rather interesting and robust over the last several time periods. But maybe we'll stick with -- certainly with the B-cell side with 2127 and 5948, just build a little bit, Arthur, on what's being explored here? You mentioned the BTK with 5948, but also the duality of 2127. How do we think about these 2 programs in a comparative way?

Yes. Let me skip over to what's labeled to Slide 64. So the slide numbers don't actually make sense. But this is a slide that shows how we see 5948 sitting with 2127 across the B-cell malignancy landscape. So the landscape of B-cell malignancy is pictured here. The circles represent the relative size of each indication in terms of patient numbers. CLL, or chronic lymphocytic leukemia is one of the most common -- is the most common adult leukemia. 5948, we see really with the potential to be addressing this whole area of CLL as well as Waldenstrom's and other indolent leukemia and lymphomas, which are pictured to the left side here, and that's because as a pure BTK degrader, 5948 can address these, the BTK mechanism works. We know this through the success of BTK inhibitors. We have superior aspects of degrader, which I'm sure we'll talk about a little bit later, Greg. And then if you look at 2127 across the bottom there, we see that really predominantly in the DLBCL, which is diffuse large B-cell, and MCL categories in terms of these aggressive lymphomas. And here a dual-acting agent or a combination agent, which is essentially what 2127 is, combined BTK plus IMiD-like activity is really required to get dramatic responses. And we've actually seen some dramatic complete responses in each of these categories. So that's how we see really providing the first best -- first-in-class and best-in-class degraders to address multiple aspects of B-cell malignancies.

Great. So certainly a complex market, many slices to the pie and 2 assets that can speak to that. We know that 5948, you'll be sharing an efficacy update mid-'24, just provide us, Arthur, with a preview of what we should be looking for in terms of focus, patient numbers, maybe the extent of those efficacy readouts as you build on this program.

Yes. So we are focused on 5948 for a midyear update. We will be at EHA. This is the trial design I'm showing now on the slide, labeled 65, NX-5948 trial design. This is the trial status at our last presentation at ASH. So at EHA, it will be another full 6 months more of enrollment and data compared to the ASH. You can see at this time, the arrows indicating where we were in dose escalation for CLL and NHL. They have their separate dose of [ NX-5948 ]. So we should pretty well cover all of the doses essentially for the EHA update. As I mentioned, 6 months more of data, a significant number, a greater number of patients as well as length of follow-up for each patient, duration of therapy for each patient. And then we are enrolling patients in every category, as we've mentioned earlier, off to the right. But at the EHA update for this, we're really going to be focusing on CLL rather than the NHL categories. And the goal here will be to look at the doses across the board in CLL and see if we can identify doses that we think would be the doses to select for expansion. So greater number of patients, longer duration of follow-up at EHA. And then also, very importantly, further description of the resistance mutation story and how our degrader can address these resistance mutations, which is a big part of the scientific advantage of degraders.

Okay. All right. And then what would be a reasonable benchmark to evaluate this data that folks, to us, bring up at BeiGene's 16673, the 70% ORR at ASH last year. And I know comparisons are difficult, but there are some reference points that folks are looking at as you're thinking about more of these patients and the dose levels.

Yes. So what we've guided to is between 50% to 70% ORR across all of our dose levels. So we're ranging from 50 milligrams to 600 milligrams [ here at CLL ]. So that's quite a dose range, and therefore, we bracket what our target ORR is between 50% to 70%. Clearly, at an optimized dose or at higher doses, 70% would be interesting success target, but that's what we've guided. It is hard to compare between trials. We are also enrolling. If you look at the slide, at the bottom, the CNS -- patients with CNS involvement, both primary CNS lymphoma and secondary CNS lymphoma as well as CLL with CNS involvement. So I mentioned that because that's a very challenging category of patients. I don't believe others are enrolling in that category. So we do have a very advanced patient population and also one with a large number of resistance mutations. So -- but we will be providing that update.

And maybe just building on what you mentioned, Arthur, just on the blood-brain barrier, certainly indicated from the AACR data with those patients who have CNS involvement, how significant is that just to build on what you're pointing to?

Well, so in general, across all of the CNS lymphoma, leukemia if you're looking at 5% or so of patients and very severe disease category. In general, there's no real therapy for these patients. We have reported on our first complete responsing with the primary CNS lymphoma patient. And then also a partial response, quite significant partial response in a CLL patient, and that was the AACR presentation with CNS involvement, who actually had complete clearance of the tumor cells from the cerebral spinal fluid, which was quite a result and long duration of therapy. So we think this is going to be a potential distinguishing feature for NX-5948. We showed that it does cross the blood-brain barrier. We see the drug in the CSF. We see this clear clinical activity. And sometimes we get the question, well, it's only 5% of patients. Well, 5% of patients and high unmet medical need. But I also think it's important if we look at the CLL case, for example, that patient had been on acalabrutinib when they developed CNS disease. So the way I look at it to is if you can take a degrader like 5948 and keep the disease out of the CNS, when you're looking at 95% of patients who would really prefer not to get CNS disease in the first place. So I think that's going to be a potential distinguishing feature when we're just talking about CNS activity.

That makes sense. And then as we see here, the 1b dose expansion, maybe just thinking more forward looking, just help us outline a potential path towards registration for 5948, possible accelerated approval options, what those time lines could look like?

So we do have fast track status for 5948 already, which has been focused on the post-BTK inhibitor, post BCL2 inhibitor line of therapy, so third line, a plus line of therapy. So that is clearly an area of high unmet medical need and one that could be eligible for accelerated approval. But we think there's more opportunity than that, actually, because we think 5948 could move up in lines of therapy. So based on the profile we're seeing against these resistance mutations, et cetera, we think that a second-line confirmatory trial would also make sense. We haven't outlined these plans yet specifically. That will be, I think, a second half sort of idea based on the data, the totality of the data. But then we're also very interested in some small potential rapid indications, such as Waldenstrom's, which is an NHL that is high unmet medical need, could also be accelerated approval type of pathway. And then, of course, we talked about the CNS lymphoma. So there's -- if we look at multiple approaches, we haven't outlined exactly what the pivotal approach. It will likely be more than one pivotal trial so that we can cover some of the smaller, faster indications as well as this larger will be a slower approval pathway in CLL, for example. So a combination of these kinds of pivotal trials.

All right. That's great. And you nicely laid out 5948, positioning with 2127, and sure we'll come back to 5948, but just going with 2127, just the BTK degradation, the IMiD activity, are there synergistic effects that we can anticipate from this dual approach for 2127?

Well, definitely. So part of the theory of the combination for 2127, I think we're going to be talking about again DLBCL, for example. There have been some trials done with combining ibrutinib with lenalidomide and rituximab. And those 3 in combination have produced some pretty dramatic results with DLBCL and similar to what we're seeing with 2127, which combines BTK degradation with IMiD-like activity. And I'm referring to trials done at MD Anderson with that triple [ combination first ]. So now with 2127, it's a single agent, oral once a day. So very convenient. We're enrolling patients that have been post CAR-T, post bispecific failures as an oral agent. And we've seen, as I mentioned, some impressive complete responses as case studies so far. And the one patient I recall an 84-year-old woman, who have been on -- had R-CHOP or ICE, was actually CAR-T ineligible, had been on rituximab, ibrutinib and lenalidomide, and then came on to our trial and she had a complete response within the 8 weeks and has now gone over 18 months' of duration of response. So we see the duality, the combination effect really being important and 2127 puts it in one molecule.

And then maybe just the plans to start the 1b expansion portion of 2127 in DLBCL, MCL as well as CLL. This is following the recent lift of the clinical hold...