Hi, welcome to our fireside chat with Nurix. I am Rob Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined by Arthur Sands, the CEO of Nurix. Arthur, thank you for joining us today.
Rob, thank you for having us.
So I understand you have some slides for us, so why don't you start off there?
I do. I'll start out with a few slides just to frame things. We have our disclaimers, of course. So as we will be talking extensively about targeted protein degradation, I wanted to take a step back with this first slide and look at how we see it fitting in the landscape of evolving therapeutics, which, of course, have been very successful if you look at antibodies and nucleic acid-based therapeutics. And of course, small molecule inhibitors off to the left here, going back 100 years. But all of these modalities seek to knock down or knock out their target or inhibit it, but somehow knock it down. And they have varying degrees of success for that. But with degraders, this is a small molecule approach that can actually remove whole proteins and remove multiple classes of proteins in a way that's oral, is once-a-day dosing with our drugs.
So lots of advantages over nucleic acid-based therapies, which can be, of course, quite awkward, but effective. And even over antibodies. And in fact, having antibody-like efficacy or biologic-like efficacy in a small molecule. So this is a large evolving opportunity that can touch many areas of disease. Just to take a glance at our pipeline, on the top is our oncology pipeline, and on the bottom is our II pipeline. We'll be focusing, I think, largely on Bexabrutadeg or Bexabrutadeg NX-5948 at the top, which is entering pivotal trials. But we have other several wholly owned degraders, Zelbrutamide, which is a dual degrader of BTK and IKZF1 and 3. So it has IMiD-like activity combined with BTK for aggressive lymphomas. NX-1607, I think a real sleeper compound, which is an inhibitor of targeted protein degradation, inhibitor of Cbl-b in immuno-oncology.
We expect to have updates on that in the fall. Our I&I pipeline is really gaining a lot of momentum most recently with the STAT6 option exercise by Sanofi. This has been a five-year discovery program with Sanofi. So far, they have invested over $125 million in our STAT6 degrader program, and now they are taking it into IND-enabling studies and will go into healthy volunteer studies. Before that, Gilead exercised their option to our IRAK4 degrader. They are in healthy volunteer studies right away, already currently as we speak. Our own Bexabrutadeg, again, we see opportunities in autoimmune disease. So we have an emerging portfolio here as well. Bexabrutadeg is the first degrader.
It has the extension of degrader or DEG, which we had to support and actually lobby for, if you will, and the international naming authorities, because it is fundamentally different than inhibition. We demonstrated that by showing the first checkmark there. We can degrade not only wild-type BTK, but also BTK inhibitor-resistant mutants. Where BTK has gained a mutation that renders BTK inhibitors useless, we can degrade them when we've seen clinical activity there. Number two, we can take out the whole protein, which eliminates what's called the scaffolding function, which is a structural function, a signaling node. We think maybe perhaps half of the BTK signaling is actually coming through the protein structure itself and not the kinase. Again, why degradation is superior. We see, of course, it has this catalytic activity. In the middle of the slide there, NX-5948 bexabrutadeg crosses the blood-brain barrier.
We've seen some dramatic results in patients with extensive CNS disease, some very dramatic medical stories, and we're very encouraged by that. I'll go accelerate here so we can get to Q&A. But just on the right panel, this is looking at cell killing of NX-5948, all in green across all the different mutant BTKs we're seeing. You can see we're highly potent across all of them. And then we've compared ourselves to all the inhibitors, both the covalents and the non-covalents. And blue represents drop-off of a thousand-fold in potency. This is why ibrutinib doesn't work against C481S. And then red is a 5,000-fold drop-off. So when we talk about BTK resistance mutations, we're talking about the current drugs that are selling about $10 billion a year, losing all activity against the target. It's a dramatic medical issue.
If you look on the left side of the slide, this is looking at BTK degradation in our patients. So we take blood draws at day two through day 29 when they start dosing. And you can see, just regardless of the mutation they're harboring, we get complete degradation of BTK by day eight. And this is what the lymph node reduction plot looks like. It's dramatic. So the vast majority of patients showing reduction in their lymph node sizes. The light blue patients are those bars, those patients with CNS involvement. This is basically a very terminal diagnosis once you get it, but we're seeing dramatic responses there. And then across the bottom, you can see the mutation status, BTK being the top line, but also all these other resistance mutations that these patients have in their cell line, in their cells, and yet we're still seeing responses.
Again, I think why degradation looks so superior. It translates to about an 81% overall objective response rate there at the top line. We have our first complete response seen in a patient who's been on the drug for now over two years. So really impressive. And we keep seeing these responses improve over time. So the longer they're on the drug, we get great durability. We don't yet even know the durability of response because it keeps getting extended over time as we go. And the safety profile is very well tolerated. This is the clinical development plan that we outlined just last week, defining our accelerated approval opportunity with 100 patients in item number one there. This is a single-arm trial. We think it has the potential for accelerated approval.
Then that's backed up by the randomized confirmatory trial, item number two, which will go against a globally relevant control arm, pertubrutinib, BR, bendamustine, rituximab, and IR that we anticipate 400-500 patients for that trial. Then finally, we're initiating exploration of combination therapies, first with venetoclax and then also including antibodies potentially to enable a phase three program in combination. So with these three steps, we'll cover pretty much the waterfront of the CLL market, and we think addresses all of the regulatory questions too, we'll face. A little bit of a zoom in on the phase three design. I think I already hit on this, but we can talk more about it, Rob, as we go. Again, a clinically relevant control arm across geographies globally, addressing all the current and emerging standards of care, pertubrutinib being included in that, which is an emerging non-covalent.
This trial design across the bottom addressed. Is that you?
Yeah.
Okay. It addresses the major lines of therapy. Starting from the left is third line plus. That is where we've seen our 80% response rate. This alone is a significant market, currently at about $1 billion, forecast to go up to $2.5 billion, but our phase 3 program is in the second line, in the middle line. So addressing approximately 16,000 patients, this is a very significant market opportunity. We have two trials where we'll be looking at potential positive outcomes there, and then we have plans that could potentially take us into the third line, largely—I mean, the front line, the 30,000 number, largely in combination, so this is overall trial of the phase 1 trial. We have many subgroups to report on.
This will contribute to our news flow going forward here, not only in the blue, which is CLL across the top, but also Waldenstrom's and the non-Hodgkin's lymphoma. Just one headline here in Waldenstrom's, we're seeing an 84.2% response rate, so very high. These patients have received multiple lines of therapy. All of the numbers I've shown you are all in patients who have progressed on BTK inhibitors. So to see this kind of response rate at these levels is quite impressive. We're very, very happy with the Waldenstrom's response. Just close on this, we have lots of upcoming events and news flow. Next week, we'll be presenting to our European investigators on Bexabrutadeg and Zelbrutamide at the International Workshop on CLL in Krakow. We are with Gilead is presenting at the European Academy of Dermatology and Venereology in Paris on the IRAK4 degrader.
So that should be very interesting. We'll be at ESMO with 1607 in Berlin, which is our Cbl-b inhibitor, followed up by some very interesting more preclinical data at SITC here. And then, of course, ASH is a big event for us always. So I hope I didn't take all the Q&A time.
No, no, you're good.
But I gave lots of substance for your questions, Rob.
Yeah, no, no, thank you for that. So I think one of the interesting aspects about Bexabrutadeg, and you sort of pointed out within the preclinical data, it's really the protein, not just the kinase domain that is really important to inhibit in CLL, because you have these kinase-dead mutations and you're still showing efficacy in that population. So I think that that is a major differentiation versus the covalent and non-covalent inhibitors such as Pirto, right? So when we think about this treatment paradigm in CLL, obviously we've got the covalent inhibitors and we've got the non-covalent inhibitors. So how do you see the evolution of this treatment paradigm evolving, especially after the press release from Eli Lilly today that showed that Pirto met its primary endpoint in front-line CLL patients?
Well, in many ways, if you're going to get CLL, it's kind of the best time in history to get it. There are lots of options. But let me show you, go back to one of my data slides to say why I think the degraders will outperform the non-covalents ultimately. So first on this slide, I highlighted the BTK mutations of that top row, but in a number of those that are colored, these are patients with BTK mutations. However, the gray, the light gray, these are wild-type BTK patients. And yet they have progressed on an inhibitor. And 30% of our patients in this trial have progressed on Pertubrutinib already. Okay, so this is a drug that's not even fully approved and we're already getting progressors in our trial. So there's something left in BTK, which we think is the scaffolding function. It's not just the kinase function.
Yes, we proved that when we published it in Science a year and a half ago with Memorial Sloan Kettering collaborators. We proved that kinase-dead mutations still signal, yeah, and we take them out, but even BTK that has its kinase active, look at that, 60% of our patients still have wild-type BTK, and yet the drugs don't work. The inhibitors don't work, so that tells you we're doing something fundamentally different. The other one is this slide, so look at the non-covalents. They all have their liabilities. They're not looking that different than the covalents. In fact, the covalents look better, if you ask me, so when people were thinking about where do we go after the covalents and PIRTO was designed in that era, they wanted to hit C481S, and if you see there, that C481S column, PIRTO is green. It is very effective there.
But they didn't anticipate all these other mutations. And it's ineffective there, and nor was it ever designed to be effective. Whereas the degrader, 5948, we can take it all out. So I think the non-covalents are going to be there as an option, but I don't think they're going to have the kind of durability. And that's from everything we hear so far from investigators in the field.
Yeah. You know, one of the other things that a lot of investors are also thinking about when they think about BTK degraders is the competitive landscape, because obviously there are two other players here. We've got B1, and they presented data for their BGB-16673 at EHA. And obviously the ABBV compound, ABBV-101, we've only seen preclinical data for that one. But how are you thinking about the potential advantages of Bexabrutadeg over, let's say, B1's data set, which we do know about? Give me some context there.
So it's going to have to be proven out over time. It's still very early. We do think that our efficacy looks similar to their efficacy. We think we may have certain safety advantages. The structure of these three molecules is now known, and we are profiling them preclinically to look at the molecular selectivity. And are we more selective? We think the answer is yes. Are we more potent? We think the answer is yes, than the competitors. We'll share some of that data in the future. That should translate to better efficacy and better safety as we look at hundreds and thousands of patients. So we have to wait for the patient data, but that's the underpinning of differentiation, the selectivity and safety. That's the first thing. That's also true with kinase inhibitors.
In fact, BeiGene did a great job by having a more selective zanubrutinib, ibrutinib, and displaced that market. But then if you look at this marketplace also, it's not an either/or. There's plenty of room in this market. All of these drugs are multi-billion dollar drugs, and they all get their segment of the market. And there may be advantages or disadvantages to one or the other. But in the end, not only is it a $10 billion market now, but it's forecast to go to 15 or 18. So there's more and more room because BTK as a target is such a superior target and can address so many disease states.
Yeah. You mentioned your confirmatory phase three trial design here. And I wanted to get your thoughts because obviously we saw the FDA release some guidance documents in the middle of August around overall survival being the endpoint that they would like to see more often being the primary. So considering what your primary endpoint is in that phase three, do you think you might have to refine that trial design to have OS as the primary endpoint?
I don't think so in the B-cell malignancy space. I think its PFS will continue to remain the primary endpoint. OS tends to be a secondary endpoint, sometimes I guess a key secondary endpoint depending on how it's. But in the B-cell malignancy space, patients fortunately do survive a long time. And it's different than the solid tumor space where OS becomes apparent more quickly. So there's some practicalities to it, but I think PFS will probably remain as the key primary endpoint.
Okay. You know, for the comparator arm, obviously it's not just PIRTO. There are a few other regimens that you've allowed in there. Maybe talk to us a little bit about what that treatment pattern looks like here in the U.S., but also in the E.U., because obviously there are different protocols in place.
Different protocols, different reimbursements, different standards of care, different medical views on what works and what doesn't. PIRTO, we think, will be an important choice in the U.S. and Europe primarily. It was not a cheap choice, so it's not going to be everywhere, but rituximab plus bendamustine, that when you're looking at standard of care, it's like still 50%-60% given rest of world, even in the front line and second line, so significant use of BR. IR, idelalisib, rituximab, very more common in Europe and very well received there, so we've included a blend that we think can maximize enrollment, addresses standards of care and even emerging standards of care in different parts of the world, and therefore should give us the best sort of regulatory approach.
You know, we're obviously expecting to see a data update for Bexabrutadeg later this year. Could you help frame any expectations around that data release?
We anticipate being at ASH. It's a big venue for us. We always share the latest data that'll position Bexabrutadeg really, I think, for its pivotal push. I think it'll be one of the key looks at data that says, okay, this is going to have a great effect in our pivotal design studies. I think that's what number one people will be looking at. In addition, we always have more preclinical data supporting this. Again, the differentiation I alluded to, I think that'll be highlighted in the fall. I think those will be the main parameters. We are presenting at a couple of European venues, mainly for our investigators to get prepared for the phase two and the phase three. The data releases, we tend to center on major U.S. settings and major European settings.
Yeah. Now, one of your other clinical stage assets, which I'm particularly intrigued in, is 1607, the Cbl-b inhibitor. So I'm curious, for people who aren't familiar with the Cbl-b biology, maybe provide a little context around it and what opportunities this compound actually has in pretty much a vast amount of solid tumors potentially.
Yeah. So NX-1607 is an inhibitor of Cbl-b, which is an E3 ligase that basically turns off T cells. So it degrades the signaling proteins downstream of the T cell receptor. If you can block Cbl-b, you turn T cells back on across the board in a very powerful manner. In addition, NK cells and dendritic cells. So we address the entirety of the tumor microenvironment beyond the checkpoint inhibitors. The preclinical data, I'm not showing this here, but the preclinical data showed in combination with anti-PD1s, we get terrific anti-tumor effects. We also see strong monotherapy results, which is important. But I'd urge you, if you like Cbl-b, go to Berlin on October 17th. We do have a poster there, which will be the first clinical disclosure of our phase 1 trials. Yeah, and we're talking about probably over 60 or 70 patients.
I think it'll be very interesting. I think this has a great potential, this target. People have been trying to drug this for a long time. Of course, being E3 ligases, I think we have the best molecule.
Yeah. You know, obviously there's been a lot of enthusiasm around the PD1, PDL1, VEGF inhibitors. Rather than potentially combining with just a checkpoint inhibitor, you think that that's the route you might want to go with the bispecific combination?
I definitely think we can combine with this oral agent, once-a-day oral agent, with multiple different cancer therapies. I do think the VEGF anti-PD1s are a very interesting combination, but other PD1 combinations, I've seen some really, I think, impressive data with radiation, with some chemotherapies, so I think we could have a broad combination potential here. What we're looking for in the monotherapy is some signal of monotherapy activity, because you do need to see something in monotherapy to convince you that it's worth investing in the combo.
Yeah, no, I completely agree with you there. Why don't we shift gears a little bit to your autoimmune programs? Obviously, you've got the agreements with Gilead and Sanofi for the IRAK4 and STAT6. Maybe remind us around the economics of that and why you're so excited about those programs.
So the important economic part is 50/50 in the US. That's sort of for both of those programs. Because we have product rights, we can then exercise after we see human data, which is a very powerful position to be in. They prosecute the initial early development program. They share data with us. We then have our option to opt in. STAT6 is one of the most exciting, I think, autoimmune targets in type 2 inflammation there is. The STAT6 degrader is designed to be a Dupixent-like molecule, Dupixent in a pill, if you will. So I think that's really a big area. IRAK4, that is also a very powerful autoimmune target with Gilead. They've broadcast that they are interested in rheumatoid arthritis, but also potentially other autoimmune diseases.
So I think we're going to have some really great optionality at the company as these programs come through in the clinical development plan.
Yeah, no, I completely agree with you there. You know, when we think about STAT6, obviously a lot of people will think about the Kymera program, which is also. They have a STAT6 program there too. Wanted to get your thoughts on the preclinical data there, and I know that we're expected to see some data from them. I think by year end for STAT6, so give us your thoughts around how you view that program.
So we think their phase one data in healthy volunteers is excellent. And I think it really bodes well. They've shown potent degradation, rapid degradation, excellent safety profile. I mean, hats off to them. I think that's really fantastic. They are going to be talking about atopic dermatitis data, so you can ask them about the future and their expectations. Clearly, there's high expectations. Our goal with Sanofi, and again, we've been developing this for five years with them, is to create the absolute best molecule we could manufacture and invent with them looking over our shoulder every step of the way. So that was an intense program. And they've invested over $125 million in that program to date. And it's one of their high-priority programs, one of ours. So if everything we've done on the design plan is correct, it should be a best-in-class molecule.
Okay. I guess the last thing I sort of wanted to talk about, because I find this approach very novel and extremely intriguing, is the degrader-antibody conjugates. I know you and I have talked about this in the past. Give us a sense as to what sort of targets that you would want to degrade using this approach versus just an oral degrader approach.
Yeah, so these are ADCs that have a degrader as their payload instead of a standard toxin. So these are called degrader antibody conjugates. We started this deal with Seagen. With Pfizer taking over Seagen, it's grown. And it has a great potential to target proteins within the cell that are required for viability. So we do see targeting viability-based targets that could not be targeted with a plain small molecule, but use the antibody to improve that specificity to the cell. So even though we will be targeting, call it toxic targets within the cell, it's specific to those targets and those cancers. And it gets away from the non-specificity of the toxins, which if they break off are toxic generally. So we've got two layers of specificity, but we've got very powerful cell-killing targets that the degrader will take out. That's the concept.
Now, we haven't revealed any of those targets, but when the time comes with Pfizer, we will. And I think it's a whole new class of ADCs, DACs, that are going to be very exciting and really will expand what ADCs can do.
Yeah, and there really aren't that many other companies that are working on this. I know C4 has a collaboration. I know Prelude's also working on something similar to this. So you're really at the forefront of innovation here from a modality perspective.
We did the first deal in the space, and we did the best deal. Afterwards, there was a flurry of other deals. So I mean, you know, great minds think alike. People realize this can work. The question is, who's going to make the right molecule and get it there first? And I think Pfizer is a fantastic partner. They've upped their interest in this deal after taking over Seagen. It's obviously of strategic priority for them. And the big thing, you know, holding ADCs back is, can you improve the payloads? Yeah, we have the antibodies, but can you get the payloads that'll really deliver the efficacy?
Yeah. Well, that's really all the questions I had. I want to open up to the floor to see if anyone has a question that they would like to ask.
So I'm at the clinic with my nephew, and I wonder, do you see any signals that are relevant for MS specifically in labs? But do you have any thoughts on why or why not?
Right. The question is, some of the BTK inhibitors that have been used in MS have shown liver tox, and do we see any signals that might be worrisome with the degrader? The answer is no, we don't, and we've now been in several hundred patients, cancer patients whose livers have seen everything. We feel very good about the safety with regard to liver and the degrader modality, so we don't think it's MS-related. We don't think it's like something to expect. It's probably typically off-target of the small molecule inhibitors. The other thing to keep in mind is these small molecule inhibitors have to be taken at very high drug levels, so the chemical burden in the blood system is actually very high compared to a degrader. Our degrader blood levels are 1,000- to 2,000-fold lower than inhibitors, than the BTK inhibitors. That's a lot.
Yet we're seeing these results. That's because, and we've measured this one. One BTK degrader molecule, NX-5948, can take out 10,000 BTK proteins per hour. One drug molecule, 10,000 targets per hour. Fundamentally different PK, PD, which should translate to better safety, is the point, and give you the efficacy.