Welcome to our next fireside chat. I'm Robert Burns, a Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined today by the CEO of Nurix, Arthur Sands. Arthur, thank you for joining us today.
Well, thanks for having us. Very happy to be here.
Awesome. Maybe let's just start from a high level. For investors who may be newer to the Nurix story, could you provide a brief overview of the company, the platform, and your pipeline today?
Yeah. We're focused on targeted protein degradation, which is a new small molecule approach to actually removing protein targets, disease targets from the cell, via the ubiquitin proteasome system. So removal, targeted removal of the protein, which gets a more thorough hit on the target compared to inhibition. Our lead program is BTK, a BTK degrader called bexobrutideg. Recently just signed that great deal with Roche, which I'm sure we'll talk about, for CLL, chronic lymphocytic leukemia, and non-Hodgkin's lymphomas, where again, we're removing the BTK protein and we get a more thorough, a deeper efficacy response, can address resistance mutations to inhibitors. The inhibitor class was a $10 billion a year class, but a lot of resistance mutations coming up, so degradation removes that with bexdeg, as we call it for short.
Then we have a whole inflammation program, partially with bexobrutideg, again with Roche, but also our STAT6 program with Sanofi, which is in phase I, and our IRAK4 degradation program with Gilead, which is completing phase I. Then we have a host of other undisclosed targeted protein degrader projects. So we're about 12 years old. We're based in the San Francisco Bay Area, and had a very successful entry into the clinic with bexobrutideg, and now starting phase III.
Yeah. No, that's perfect. So I guess the major news, as you just alluded to, was that massive Roche collaboration for bexobrutideg. So can you talk a little bit about what made Roche the right partner for this asset relative to all the other major pharmas out there, the economics of the deal, and more broadly, how the partnership changes the opportunity for Nurix and its shareholders?
Sure. Well, so Roche was the right strategic choice to fully develop this drug across multiple indications in oncology, but also in autoimmune disease, where we've specified CSU, or chronic spontaneous urticaria, and MS with Roche. Again, global experts. So they're the right strategic partner, and I might add, it was a competitive process to get this deal, because bexobrutideg really has such a best-in-class potential for any BTK drug, I'd say, inhibitors or degraders. But of course, the degrader aspect brings the superiority of efficacy, because we remove not only the kinase function, but also what's called the scaffolding function of the protein, which is another signaling function. At any rate, so Roche, they've been great to work with from the beginning, and they've followed this program for actually several years.
We signed this deal in June. It was a landmark deal, as you point out. We're talking about $700 million upfront, and then another up to $2.3 billion in milestones, development milestones and sales milestones. That's significant if you look at the economics of that. Then of course, probably even more significant is that it's 50/50 in the United States.
Yeah.
So we retain product rights in the United States. We get milestones and royalties ex-U.S., which are substantial. And of course, they've got the whole ex-U.S. infrastructure, which we don't have, so we get the strategic expansion, j ust from an operational standpoint. And then they have the best portfolio of B-cell malignancy drugs.
Yeah.
CLL and NHL, they have the best antibody portfolio, the best combination portfolio for our drug to go with. So when you add it all up, I mean, it's really —and then scientifically, we're so aligned, and it was an intense deal process, but it really worked well.
Yeah.
It worked the way a deal process should work. Through all the diligence, and boy, are they diligent, I might add.
I believe it.
I wouldn't do it again. I'm glad that deal got done, and it's a great deal. Strategically, they're the best fit.
Yeah. One of the things that I noted when I was looking over that press release and the deck that you guys put out was the massive expansion in the development opportunities for bexobrutideg, not just within hematological malignancies, but also within I&I, right? You mentioned Roche's complementary portfolio. Obviously, they got fenebrutinib in MS. They have a bunch of other bispecifics in B-cell malignancies. Talk to me a little bit about how this expansion, or go into detail a little bit more about the expansion opportunities from a clinical dev perspective for bexobrutideg.
Yeah. That was really the second part of your first question, too, i s like, what does this mean for bexobrutideg as a drug and for shareholders? Really, it is an unprecedented sort of breadth of development that now we can do with Roche that we could not do. This BTK mechanism really is analogous to the CD20 target. A RITUXAN-like molecule. CD20 has so many uses with the right molecule. Bexobrutideg, I think, is that versatile. With Roche, it can be put to work in all these different settings.
Now, in the oncology setting, the combinations are critical. Although our monotherapy activity is 80%-plus overall response rate, 85%, et cetera, in relapsed/refractory patients who have become resistant to inhibitors.
Yeah.
BTK inhibitors. Our monotherapy trial, which is the phase III against pirtobrutinib, I believe we are going to see that degradation is superior to inhibition. This is a big expansion opportunity for targeted protein degradation in oncology in general. Then you have all the antibodies with Roche.
Yeah.
The anti-CD20s, RITUXAN, obinutuzumab, some of the bispecifics are going to be very interesting.
I completely agree with you there.
Roche, they were very frank with us. They are like, "We do not have an anchor BTK mechanism in oncology. We have fenebrutinib.
Yeah, but that is just MS.
That is just MS. That has been missing in our portfolio, and we were not just going to bring another inhibitor into the clinic, but the degradation mechanism is so unique, and the profile is so best in class-like so far. At any rate, then if you go to non-oncology, you look at what is going on with BTK, remibrutinib with Novartis has done very well in CSU, and now they have talked about their MS data. There again, degradation can be superior. In fact, we have shown all of our curves comparing to remibrutinib and fenebrutinib and others. We are 10 to 100-fold more potent than any of the inhibitors—
Yeah.
—against in terms of B cell inactivation. What is more for MS, and I think very important is the microglial hypothesis for MS. Microglia are basically the immune cells of the brain that are driven by BTK, and they are resident, and they are responsible, it is thought, for the chronic neuronal damage that occurs. Even if you block with an anti-CD20, the peripheral B cell activity you are not going to get at those microglia.
Yeah.
That is what causes the debilitating progression. That is what is so exciting about the whole BTK hypothesis. Now, the thing is that, again, degradation hits it better than inhibition. We have shown we degrade BTK in the microglial cells of animals in the brain, and we have brain activity established in our CLL patients who have brain disease.
So we have unequivocal brain activity with this drug. Plus, of course, we see the drug levels in the CSF and the plasma. But the fact that we can remove BTK from the microglia, I think it directly addresses a central hypothesis of MS debilitation. That is really what the potential is here for the MS. Then, there are many other diseases you go after, too.
Yeah. When you add up the potential commercial opportunity across all these different indications and lines of therapy, what does that look like with Roche now as the partner here?
Well, I think it tells you something, first off, that a company like Roche, or again, it was a competitive process, is a large market opportunity.
Yeah.
That is the only thing that is going to be a driver for—
Absolutely.
—any of the pharma, right? It is multibillion dollar.
Yeah.
I mean, no matter how you model it. You can go anywhere from $2 billion a year to $10 billion a year, depending on what you want to model. Excuse me. But I think the very fact that it has that potential is what we need to know right now.
Yeah. I completely agree with you. Before we get into the updated bexobrutideg data that you presented at EHA not too long ago, can you help level set us on the current CLL treatment paradigm and how that treatment typically evolves across the various lines of therapy here?
Typically, CLL is a chronic disease, a disease of the elderly. It's the most common adult leukemia in the world. In the old school days, it was watch and wait. You'd wait and see if the disease progressed. If it got worse, then you would get chemotherapy, which was harsh treatment. That would be bendamustine, and it would be any number of other chlorambucil in the early days. A lot of side effects, very toxic. People used to hold that back. Then you had ibrutinib, the BTK inhibitor.
It was relatively non-toxic. People started getting treated earlier and better with the BTK inhibitor. It was one of the first targeted therapy stories after Gleevec, I would say, a major story. It really is standard of care. Start with an inhibitor. Ibrutinib's sort of fallen away. It was up to over $5 billion, $6 billion a year, but it has off targets. Acalabrutinib from AstraZeneca, zanubrutinib have come up more selective, now they're taking over the markets. In total, it's a $10 billion a year BTK inhibitor or CLL market. It's very substantial already. After that, after the inhibitors, you have BCL-2 inhibitors, venetoclax.
They can be given upfront. Targeted therapy, a little more toxic, a little bit less tolerable, but really very effective. The combinations seem to be quite good in second line. Most patients will start with one drug in first line, an inhibitor. If they progress, you add BCL-2. Some people believe you just do the doublet up front, start with both drugs up front.
After that, you pretty much have nothing. These inhibitors are what is called covalent inhibitors, and that is where Lilly came along with Loxo originally with the non-covalent pirtobrutinib. Pirtobrutinib is trying to take up that second-line position. Also in first line, it looks quite good, but it is an inhibitor, and it is non-covalent, and the question is: What is the real lasting power of that drug compared to a degradation mechanism, which again, is stronger, deeper. We think that is why we are going head to head against pirtobrutinib—
Yeah.
—in the second line as our first phase III.
Yeah.
That is 620 patients. That trial is up and running. It is an international trial. Roche is going to be driving the ex-U.S. and Asian. We are driving U.S. I hope that helps give you the i dea of the treatment progression. After the BCL-2s and such, there is not really much. CAR T, mixed bag so far in CLL.
Yeah. With that as the backdrop, walk us through the data that you presented at EHA for Bex, and help frame the expectations around the data updates that are going to be coming later this year for Bex.
I think at the EHA, the two exciting cohorts that we presented for the first time were basically frontline patients.
Yeah.
Naive patients that never been treated, this is a phase I trial with 20 patients in each cohort. I didn't think we'd get many treatment-naive patients because there's a lot of treatment options with the inhibitors.
We enrolled that very fast. We also had patients that had just seen one BTK inhibitor, so we had our first pure second-line patients, if you will. We had treatment- naive. We had BTK second line. Early patients basically, there we're looking at 85%-90% response rates. Very high.
Yeah.
I think that was very encouraging. Plus, it gives us the rationale for moving to the front line. Because we had basically a frontline cohort.
Yeah.
Which the FDA will allow you to do in a small number of patients in a phase I. As I said, it enrolled really quickly.
Yeah. I note that you've got two pivotal trials ongoing now, DAYBreak CLL-201 and the DAYBreak CLL-306 trial. Maybe walk us through the trial design of each of those trials. With regard to DAYBreak CLL-201, when do you think that we can anticipate trial results from it? What is the timeline for potential NDA submission here to the FDA for an accelerated approval?
Yeah. It's a DAYBreak family of trials—
Yeah.
—that we're starting, and we've started. DAYBreak CLL-201 is in the third-line plus. It's very advanced, a high unmet medical need patient population, where there are no agents, no approved agents. That's the definition of enabling an accelerated approval, if you will. We're enrolling. We're going as fast as we can. Our goal would be to complete enrollment by the end of this year or in the first half. It's only 100 patients. However, there are not many of these patients yet because they're post-pirtobrutinib patients. You had a covalent, you had the BCL-2, and you have to have had pirtobrutinib. It's a slower trial to enroll, but it's a very important patient population for potential accelerated approval. I'm not going to give a timeframe now because—
Okay.
—we have to work on that.
Yeah, no problem.
Plus, I have to collaborate with Roche on—
Yeah.
—whatever I say.
Disclosures.
It's going well. DAYBreak CLL-306 is the head to head against pirtobrutinib.
Yeah.
That is the 600-patient second-line patient population. These are patients that failed a covalent inhibitor, then they need a new treatment. It is the Lilly drug versus our drug.
I note that BeOne also presented some data at EHA, and they had a 94% objective response rate with that 200-milligram dose and PFS of 24.4 months across all dose levels. With BeOne planning to file for accelerated approval later this year, how should investors be thinking about the efficacy profile of bexobrutideg 600 mg versus tacabrutideg, which is BeOne's drug at 200 mg? More broadly, where do you see potential differentiation of bexobrutideg relative to tacabrutideg?
If I am not mistaken, the numbers you are citing are from early parts of their phase I trial.
Yeah.
That was 16 patients at 200 mg. They dosed up to 500 mg, and they went with the 200 mg.
Yeah.
When the investigator was asked at the podium why, they said safety issues.
Yeah.
I think that's telling because we had no dose-limiting toxicities to 600 mg. Then you apply classic oncology development strategies, which is, okay, look, if it's safe, max the dose—
Yeah.
—and you are going to get better efficacy because you got to cover all sorts of tumor burden for these patients. All these patients are different. They have different mutational burdens, different sizes of tumors, bulk of tumors. More is generally better if it is safe.
Yeah.
Our drug is safe, and we can dose up, and so that is what we did. I do think safety will be a differentiating factor between the two drugs is kind of what I am saying indirectly, or maybe directly. People are going to be the judge of the data as they come out in these larger cohorts.
Yeah.
These are still small cohorts for both companies. That is on the different. But on the very positive efficacy side is that both companies are seeing good efficacy.
Yeah.
Which is very reassuring. In completely separate hands, you are seeing this degradation mechanism showing such superiority.
I think it is validating for—
Absolutely
—for degradation or inhibition.
Yeah. It's great, yeah. Independent validation.
Why don't we shift gears now to two other partnered programs, namely IRAK4 and STAT6. Maybe walk us through the economics behind those programs. What sort of market opportunity do those two assets hold?
They're huge market opportunity to start there. STAT6 is basically considered the small molecule target equivalent for DUPIXENT.
Right? So safe target blocking the IL-4/IL-13 pathway. It's a transcription factor, so no one's really hit it well. Hard to target with an inhibitor. Kymera, of course, has got the lead there, and is doing extremely well with their STAT6 degrader. And then we're, I think, next in line—
Yeah.
—with our partner, Sanofi. We have 50/50 economic option in the U.S. We started that program with them in 2019. They have invested into the program over $100 million in cash through that time, and been with us through the discovery and development of NX-3911 SAR something something 272. They have a lot of numbers. It is going well. IRAK4 is with Gilead.
That is completing phase I. STAT6 is in phase I, and we look forward to data, hopefully from those over the next 6-12 months, 18 months.
Okay, perfect. Obviously you mentioned the Kymera program. We will not touch base on that a little bit. How do you view that asset from a competitive positioning perspective, given the data we have seen released to date, and some of it just came out probably this past week or last week, I should say.
It looks quite good. I think it bodes well for the STAT6 franchise w hich is extremely large. Kymera has their projections, which dwarf DUPIXENT, really, according to Kymera. Which I could see, because if you had a safe small molecule, it is going to be a huge opportunity. Which means there is room for more than one drug.
Yeah.
And more than one player, more than one company. There will be multiple drugs here. There may be some inhibitors that actually make it too, which would be great. It is not a zero sum game here.
Okay, good. Beyond your clinical stage programs, one of the modalities that you guys are developing, which I am fascinated with and so is major pharma as well, is the DAC class. And those are the degrader-antibody conjugates. Given the novelty of this structure, talk about the mechanistic rationale behind it, and what sort of targets do you believe are best suited for DACs?
Degrader antibody conjugates, mechanistically why they are exciting is that you can attach a degrader to an antibody, and the degraders are hyperpotent targeted therapies. Before, your ADCs, you would attach a toxin which was hyperpotent toxic therapy. You need to have a hyperpotent molecule. A plain old inhibitor won't work.
Yeah.
Because it's one-to-one stoichiometry. People have tried those, they don't work. The degrader is one drug molecule degrades 10,000 protein targets per hour. 10,000 per hour. One molecule, versus one to one of an inhibitor.
Yeah.
You're enabling now, you have a payload that's strong enough, but is also targeted. It's not just generically toxic. Because what happens with ADCs is you don't actually drag many payload molecules into the cell.
Yeah.
The numbers are low, and that's why only the toxins really worked.
Yeah.
They have all sorts of fallout effects. These degraders are potent enough, so now you can add targeted therapy to the cell with targeted therapy within the cell. I think it is going to be a whole new generation of ADCs. We have renamed it with originally Seagen DACs, then now Pfizer.
Yeah.
Those programs are going great. It is a new technology. It does take two companies. They bring the antibody technology. We bring the degrader tech. It is a great collaboration.
Yeah. It is interesting that you mentioned the inhibitors as a payload, because obviously we saw, I believe last week, I forget which major pharma, but they entered into agreement for KRAS inhibitors used as a warhead on, let us say, an ADC. Right? It does not make much sense to me, given what you just said with the one-to-one stoichiometry. So you think a KRAS degrader would be better than just a straight up KRAS inhibitor being attached to the antibody conjugate?
Well, it depends what they mean by inhibitor, too.
Yeah.
With the RAS target, because some of the inhibitors are actually induced proximity agents—
Yeah.
—like degraders. Some of them work like a reference drug. It is an induced proximity drug. So, it depends what they mean—
Yeah.
—by inhibition there. It's a little tricky with RAS, which doesn't have a classic binding site.
Yeah.
It's not an enzyme really. I don't know. I'm not familiar with that program, but I would surmise that a DAC approach to RAS would actually be kind of interesting.
When do you think we might get some disclosures with regard to your DAC programs?
Well, not today. Maybe later.
I had to go fishing for it.
I know. We work with Pfizer now, so we have to talk to them. [inaudible]
Sounds good. Well, Arthur, thank you for joining us today. I really appreciate it.
Okay. Thank you very much, Robert. Thank you.