ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

Welcome, everyone. I'm Yigal Nochomovitz. I'm one of the biotech analysts at Citi. As long as I can remember, we always do a targeted oncology panel at our conference, so this is the 2023 version of that panel. So we have 3 terrific companies. From IDEAYA, Paul Stone, CFO; from ORIC, Matt Panuwat. Am I saying that correctly?

That's correct. Yes.

Okay. Good. The Chief Business Officer. And from Syndax, Mike Metzger, the CEO. So thank you all so much for taking time out of the one-on-one schedule to chat a little bit. Maybe we can just go down the line and just do a quick 2- to 3-minute high-level overview of what the company does, what are the key assets, maybe the key studies, and then we can get into a discussion about design considerations for targeted oncology drugs. So you want to kick it off, Matt?

Sure. Yes, Yigal, thanks for having us, first of all. So I'm Matt Panuwat, the Chief Business Officer of ORIC. ORIC is a clinical stage oncology company, and our name encapsulates our mission. So ORIC stands for overcoming resistance in cancer, and so we are 100% dedicated to oncology. We've built a pipeline of potential first-in-class and best-in-class therapies. We have 3 programs right now in Phase I studies. We will be reporting out all 3 of those clinical data sets over the next 6 months or so. We're a company of about 90 employees. And so we have full research and clinical development capabilities in-house at ORIC. We've hired a stellar research team. It's led by our Chief Scientific Officer, Lori Friedman, who used to run translational medicine at Genentech. She has brought in her team that she's been working for, for a long time. That makes up a large portion of our research group. Our clinical, regulatory and development capabilities are led by our Chief Medical Officer, Pratik Multani, who had the same team at Ignyta, and so our clinical development team has a lot of experience developing therapies, especially in lung cancer. And so we have a number of other individuals, including myself, that have business development experience at companies such as Medivation and Ignyta. So we've assembled a really nice team. Our pipeline today consists of both internally generated programs as well as BD and in-licensing. And so that was our strategy from the early days is really to be source agnostic. And so essentially half of our pipeline today has been in-licensed, half of it has been internally generated, and that's something that we will likely continue going forward. In terms of our data sets, we have 3 programs. Again, we'll be reporting data over the next 6 months on all 3 of these programs. Our first one, we will be presenting at ESMO. It's ORIC-114. It's an EGFR and HER2 exon 20 inhibitor that we'll be presenting initial data there. Our second program is ORIC-533. We'll be presenting that data in the fourth quarter of this year. That is an orally available potent small molecule inhibitor of CD73 for multiple myeloma. And then finally, we have ORIC-944 for prostate cancer. That's an allosteric PRC2 inhibitor that we'd be presenting data in the first quarter of 2024. So it's an exciting time to be at ORIC, and we'll be busy over the coming months. Thanks.

All right. Cool. Paul?

Great. Hi, everybody. I'm Paul Stone. I'm the Chief Financial Officer at IDEAYA Biosciences. We're a precision medicine oncology company with really a strategic focus to build a pipeline of potential first-in-class therapeutics for solid tumors. Our strategy since day 1 has had the idea that we would build a fully integrated company. We're currently a little over 100 people, similar size to ORIC but with full capabilities from target identification, discovery, validation, up to biomarker identification validation and drug discovery including structural biology. And we think this full integration, supplemented with CROs and external resources, really enables us to execute broadly. We've also had a partnering strategy that's made us capital efficient. Our early focus we founded in 2015 was and still is on synthetic lethality where we look to be able to indirectly target drivers of tumors. We think this area is really ripe to explore new targets that can be really impactful for patients. So fast forward now, a little over 7 years into the company, we've got a pipeline of 4 clinical programs, most advanced of which is darovasertib, where we're starting a registrational trial in metastatic uveal melanoma. We also have an earlier stage Phase II trial in primary uveal melanoma with darovasertib. Second program is IDE397. This is a MAT2A inhibitor where we're focused on tumors that have MTAP-deletion. So this is 15% of all solid tumors. It's a pretty massive patient population. We have a monotherapy arm in which we are in our dose expansion, and then we've just initiated first patient in a combination study with Amgen in their MTA-cooperative PRMT5 inhibitor. Third program is a PAR inhibitor. It's a first-in-class target in the same pathway as PARP inhibitors, but mechanistically differentiated, and there, we plan to explore -- or we're in dose escalation right now. We plan to explore expansion cohorts in ER-positive, HER2-negative breast cancer, which is about 14% of all breast cancer as well as in HRD ovarian, about 50% of ovarian cancer. Our fourth clinical program we just initiated with GSK is a Pol Theta helicase inhibitor. Again, a first-in-class program on the helicase, Pol Theta, and GSK is going to be sponsoring this clinical trial, and we'll evaluate it in combination with niraparib in patients having homologous recombination efficiency. First 3 programs are wholly owned. Obviously, that fourth one is partnered with GSK. We have a late, I would say, late preclinical program focused on Werner helicase, which we believe should be the next one going into the clinic. So really excited to be here and present today.

Great. Well, thank you. Thanks for having us, you all. Good to be here and see a full room of people. I'm Michael Metzger, I'm the CEO of Syndax. I've actually been at Syndax for about 8 years, so it's been a really fun run for us as we built this company. We're also a precision or a targeted oncology company. We're developing 2 molecules, both in heme. One is revumenib, which is a first-in-class, potentially best-in-class menin inhibitor, and looking at it both in KMT2A and NPM1 acute leukemia, both adults and pediatric patients. We'll have the first pivotal data set to emerge out of that late-stage trial this quarter. So we're in September. This is -- it's coming soon. And that's -- again, this is a subset of patients who have KMT2A leukemia, and we expect to hopefully have a positive data set and then file an NDA before the end of this year. So that's -- again, that drug is addressing about 40% of AML and ALL, 2 adult -- 2 different lesions, one NPM1, one [ KMT2A ]. The second indication for that drug is NPM1. We're enrolling that trial, and we'll have pivotal data, we believe, next year. The second drug that I'll mention is [ axatilimab ] [Audio Gap] drug, it's a global collaboration. We have 50% of the U.S., and we collaborate closely with Incyte on that program and it has many expansion opportunities. The most recent update there was on the AGAVE trial, which was a pivotal trial in chronic graft versus host disease, which was positive on all doses that were tested in the pivotal trial, And we're moving quickly to work with the agency and get that drug on file with working with our partner, and that should be by the end of this year. So that was a positive data readout. We have another one coming hopefully soon here, and that will lead to, hopefully, expansions for our programs into other indications, [ top ] line indications, combinations that we're doing as well with standard of care. So it's an exciting time for Syndax. And we're -- as I think some of the others have mentioned there, we are an in-license and develop model, and so what we do is we bring in molecules from outside companies and develop them. We have all the capabilities internally to do that. And we're looking to also build a commercial organization to launch our drugs in the U.S. And so we're at a point now where we may have 2 drugs, which is an uncommon thing for a small company, have 2 drugs that get approved in a very short period of time. At the same time, in fact, and that we could launch into a very focused call point. So it's a really exciting story for us.

So you all have nonoverlapping sets of targets that you're pursuing as you just nicely articulated, but nonetheless, there are certainly themes in terms of developing targeted therapies for oncology and other indications. So if you could talk a bit about some of the challenges and opportunities, what are the design considerations? How do you think about target selection when designing a targeted therapy? How do you think about a biomarker strategy as well as potential combinations? Just at a high level, what's the thought process given, of course, you're playing in different sandboxes.

Yes, I think a couple of parts to your question. I think the one -- the biggest challenge, I think, we see is, one, as we evaluate programs for in-licensing or come up with our own targets internally, is really just the sheer volume of other programs out there and competitive landscape. And so I think there's just been so many companies that are focused in oncology, doing so many great things. It's always one thing to have a program that has your typical challenges, with the biology, making a good drug, but really trying to figure out what is out there today, what is coming -- and so what are the treatment landscapes. So we seem to -- as we evaluate these new targets and new programs, we really just seem to be spending most of our time on really understanding the competitive landscape and what other people are doing for that target or for that indication. And so I think we've been very meticulous about all of our programs having some sort of level of differentiation. And whether that's with our ORIC-533 program that has a very unique clinical development strategy, we're going into an indication that nobody has went after before, or ORIC-114 program that's designed to have brain penetrants, which is a unique feature that other people haven't focused on, which is important for indications like lung cancer, and our ORIC-944 program, it's binding the target in a unique way. And so again, really trying to be differentiated. And then as you had mentioned, the biomarker strategy, we really want to make sure we can see single-agent activity and use biomarkers to really inform early clinical development to make sure the programs and the molecules that we put into the clinic are actually doing what they think they're doing. And so I think all of that together is very critical on sort of how we think about new targets and new programs.

Yes. I think to state the obvious, biomarkers for patient selection is sort of the hallmark of precision medicine oncology, right? There's biomarkers for pharmacodynamic regions, for showing target engagement, for showing biological effect, but ultimately, it comes down to patient selection. And so I think you do need to integrate a strategy very early on. Starting as a synthetic lethality company, you naturally identify a biomarker. That's really the start of the journey. One of the things we've learned is that you have to iteratively qualify that biomarker, not just genetically, but as you develop chemical equity, as you develop compounds where you're having activity, you need to really pharmacologically validate your biomarker hypothesis, and it's an iterative cycle. So we start that cycle very early on as one of our approaches I think from a strategy selection, it falls into a couple of buckets for us. One is we try and find biomarkers that are on the major panels already and that can impact a meaningful patient population. So as I mentioned, in MTAP, for example, it's 15% of all solid tumors, which is a massive patient population. I mentioned PAR program, where we're in breast cancer with biomarker strategy. That's 14%. But these are biomarkers that are well known. That's one strategy. The other strategy is to go after indications where the indication itself becomes the biomarker. And so our lead program in darovasertib, a PKC inhibitor, this is a pathway in uveal melanoma where there's no approved therapies in the primary setting, there's one approved therapy in the metastatic setting for patients that have a specific serotype, HLA-A2-positive serotype. But there, in the metastatic setting, the initial selection, 90% plus of these patients have a specific mutation. And so there, the indication itself becomes the biomarker. Another example of that is actually the intersection of the 2 is in MTAP, where the MTAP deletion is on the major panels. But even within that framework of patients that have MTAP deletion, we believe that not all tumor types will respond the same, but we have identified specific indications where we see them as most responsive. So we're trying to keep a simple of approach as possible, ultimately, to find those patients, but still be driven by the underlying biology and the mechanistic understanding that really underlies that. But it's definitely a program-by-program effort, as was noted.

And I obviously agree with what others are saying. I think a couple of other themes I'd like to touch on, one is the dose. I think we can all agree that precision medicine has advantages, right? We all -- if you know what the target is, you can hit the target, you can inhibit it over a dosing interval, you can have a -- if the biology is right, you're having a strong biological effect. The question often is with what dose and what's your therapeutic index? And so how do you work through that in early-stage trials? And it's kind of related to the second point, which is the speed at which we work, right? In precision oncology, it's unlike a Phase I trial in other diseases where you're trying to figure out the dose and the safety, and you're not really sure what efficacy looks like. You pretty much know what efficacy looks like early on in precision oncology. So you got to be sure that you don't run ahead and discount the importance of finding the right dose, and sometimes that means doing more work and expanding it at various doses before you nail that down. And I think that is appreciated by the agency, by the way. Doing more exhaustive work does actually pay dividends in the end. And then it's -- the counterintuitive part is you're moving so quickly. I mean, we've been from first patient to a potential NDA in 4 years. That's fast. And so there's a lot that goes into actually getting a drug to market, and it's not just about proving out the biology. It's often the CMC, the other aspects of this that take time and you have to be quite precise about how you go about it. So I think the speed at which we work kind of sometimes can get in the way of what we're trying to accomplish here. And so I think you have to just make sure you're very disciplined about that and have the right expertise in-house to figure it out.

So it sounds like you're referencing, I assume, Project Optimus to some extent. You're arguing for it as a way to help advance the dose selection. Other thoughts as far as Project Optimus? Do you see it as a positive or a hindrance? How much is it slowing down or improving the dose selection?

I mean I can only speak for ourselves. I mean, the way we've always approached it is very much in line with Project Optimus. I mean it's the name of something, right, an initiative. But from our standpoint, it's always been how we've conducted ourselves. And I think that probably goes for a lot of people in this industry. It's not about cutting corners. It's about actually exhaustively exploring the dose. All of our trials have done that. If you look at our Phase I trials, we've started at a certain dose. We knew it was likely to be biologically active, and we've moved through the dose continuum. We've actually looked at intermediate doses on revumenib. We've split out how we've dosed on a strong CYP versus a non-strong CYP. So we've done a lot of that work to understand how the drug works, and done it early. And we'd also done -- in our pivotal trials for AGAVE, for instance, where we have 3 doses, right, of what we would think is a minimally -- potentially a minimally effective dose, which, of course, is agreed to with the agency, turns out to be potentially the best dose, right? So I think we're very -- you got to remain open to it. And I think as drug developers, we are. We're trying to make sure that we do the right thing for the drug.

Yes. I think our Chief Medical Officer, Darrin Beaupre, who was at Pfizer before joining us, and early in his career at Amgen, Pharmacyclics, and then way earlier in academia. He's got a similar perspective. From his perspective is it's really just creating an initiative around what is really best practices for early-stage clinical trials. Now I think there's probably anecdotal examples of where people feel the agency has pushed them too far, et cetera, but I think that was probably happening even before there was a defined name to it, but I agree, I think that what he would share if he were sitting here was that it feels this has been best practice for a while. You have to understand your molecule and the doses that you're -- range of doses you could potentially explore, and that balance between tolerability and efficacy.

Yes, I think I would definitely agree with the other panelists for sure. I think the other thing -- we definitely don't feel like it's cumbersome. I think in some ways, you do want to get that dose, right? I think in a lot of ways, targeted therapies have made so many advances. I think a couple of things that we keep in mind is patients might be on your therapy for a very long time, and so making sure you get the dose right, you're showing it's safe, not only that it works, is one. And then a lot of -- depending on the indication and the target you're working on, a lot of the molecules we're developing, we are thinking about combination approaches as well. So making sure you get that dose right early, we find, is important. So I think it's better for the long-term viability of any program. It does accelerate things, moving it forward, testing more doses, doing food effect studies, earlier than you might otherwise have. But we view it -- I think it's a positive thing for patients and programs in the long term.

What about the other design consideration? This is a relatively specific question, but the covalent versus the non-covalent inhibitors, do you -- how do you -- do you try to bucket into one of those? Or you just look for the best drug and try to steer away from one class to the other class?

Yes. We actually have a pipe -- we have both. So we have a pipeline of covalent inhibitors and non-covalent. So I would say what you said is right. We look for the best approach for the actual target we're going after. There are a lot of limitations on making a covalent inhibitor. You have to have a free sustain. And so not all targets are -- you can make a covalent inhibitor for most targets. But when that is available, I think we definitely evaluate the pros and cons of both. And at the end of the day, you want kind of the best molecule that has potency, selectivity and all the drug properties you want, whether it's covalent -- I think there's many examples of great covalent inhibitors out there. There's obviously many examples of non-covalent inhibitors. So we do evaluate both of them in our programs.

Yes. I mean as a recovering chemist, I can validate that approach. I think it's highly dependent on target and the profile we're looking for, how long do you need to have your drug sitting on the target to get the biological effect you want. And then, as you mentioned, balancing among the other properties. This is a multifactorial problem when you're doing drug discovery and you've got to optimize everything at once. There's usually trade-offs. And sometimes the covalent interaction can help on some of those trade-offs, and sometimes it can cut against you.

I'm not going to add anything else to that. I think it is very target specific, God bless you. And yes, I think it obviously depends on what you're trying to drug and the technology that you're utilizing.

I know you mentioned some of you do in-licensing, but you also have in-house discovery. So there's AI now, there's machine learning. There's a whole -- there's a lot of advanced algorithms to help design protein-protein interactions, to design molecules. Are you leveraging that in your work, in your discovery work, to find better inhibitors or to understand binding interactions better? How much does that play a role in the early discovery for you guys?

Well, it's not that much. Because we're working on more mature drugs. But obviously, it is a topic of great interest, certainly around chemistry, right? I mean there's other areas too, but I think the ability to kind of churn through new chemistry. Once you know the crystal structure, you know a lot about the target biology. I think you can get to new scaffolds more quickly. And that's a great advantage, right, for new drug discovery. But again, it's not something that we're as focused on.

Yes. Okay.

I'm happy to jump in. For us, I think we think about functional genomics and bioinformatics as integral to our entire research and development area, from early target identification discovery, biomarker identification discovery, validation, and as noted, even chemistry on the SAR. But there's a couple of aspects of it. I mean it's a great word. Instead of thinking about AI, artificial intelligence, we like to think about RI, real intelligence. And for us, what does that mean? It means like having multifactorial data analytics in areas where there's real-world data sets that inform the training of those data analytic approaches but also content specific. So doing it in the context of your specific programs where you bring a lot of specific knowledge on a target or the biology or something else. Like it's integrated with that machine learning capability. And to us, that confluence of our content with databases and data analytics that are well trained based on real-world data, like that's kind of the sweet spot. So, yes, I think we apply it across the board, but we're applying it to selective components of it. And what the ultimate goal, like, for example, the chemistry side, just accelerating your SAR cycle to become faster, get to your -- hopefully hone in on your lead compound sooner.

Paul, if I could ask you a little, let's move into some more pipeline specific questions so we can give you a chance to talk about the where things stand in development. So you have the Phase II data for daro and crizotinib in the front line [ in ] MUM, but you're going to have some new data soon, I believe, at ESMO, the ctDNA data. Can you just talk a bit about what we should expect to see there and how that will further inform our understanding of the response rates relative to what we've seen already?

Yes, absolutely. Yes. So just for context, as you noted, this is our program where we're evaluating darovasertib in combination with crizotinib in which we are initiating a registrational trial. We presented Phase II data in this patient population, which really had spectacular results. We showed an overall response rate of 45% in first-line patients. This is in a setting where previous clinical trials including the one approved therapy, for a subset of these patients, is showing a 5% response rate. And so just really differentiating, and we're showing PFS about 7 months, where historically, people have seen about 3 months. And so again, the program is really now well set up for this registrational trial. The ESMO presentation is really, I think, an opportunity for investigators to present -- we have to be careful. We have to stay within the 4 corners of what's in the title, right, of the ESMO data. But really to present ctDNA data, and as you can appreciate, it will correlate that ctDNA data with responses and efficacy we've already shared in our most recent update in April. Why does this matter? I think it matters in a couple of ways. Metastatic uveal melanoma is, right now, before our drug, before the Immunocore drug, there were no approved therapies, and these patients would get metastases and they would die in 10 months. So it's really a horrific disease. And why does it matter? There's a clear trend. You can look at Immunocore data across different trials. You can look at our data across different trials. And the earlier you can catch these diseases, the metastasis, usually the better outcome. So I think ctDNA, for this program and then just more broadly, even cell-free DNA, circulating tumor cells, these could be liquid biopsy approaches to really identifying metastasis much earlier than when it will show up on a scan, for example. And so ultimately, this correlation is starting to build a real-world data set that could support some of this earlier detection capabilities and maybe even earlier treatment intervention. So it's the start of that. The other aspects of program updates that we've not tied to [ ESMO ] but that we have guided for the second half are just what is the prevalence of HLA 02:01-negative patients versus HLA 02:01-positive data, patients in [ a ] serotype is a question that we're getting from investors a lot. And so that's one of the other aspects of data that come out the second half of this year.

Okay. Michael, so you mentioned it already, we're very close to the data, the pivotal data for revumenib KMT2A AML and ALL. So tell us about just the process there. Are you close to getting the trial data cleaned and data locked? What can you share in terms of what would be considered the successful outcome of that study? And then if you could talk about the NPM1 enrollment and where that stands, too.

Yes. So before I forget, because I'll probably forget your last question, so I'll answer it first. The NPM1 enrollment is going well and we're excited. [indiscernible] another way. The -- look, the data set is coming. We've given our guidance this third quarter. So that's our guidance. So by the end of the month, we'll have it out. And we're extremely excited about it. And the reason we're extremely excited about it is because what we've shown previous to this last year at ASH, we updated our Phase I data set, which was roughly 60 patients of data in KMT2A and NPM1 patients, and we showed at the RP2D a 27% response rate, median duration of response of about 9 months. Very high MRD rate, highest that anybody has seen for targeted therapies, in roughly 80% of patients, and I think not only getting patients to MRD but getting them to transplant in about 40% of responders. So it's a big percentage of patients doing very well, staying on drug for a long time in a disease where they have no other options. They literally have a handful of weeks until they're not able to respond anymore and go on to hospice. So it's a very dire circumstance for many patients. And these this drug, revumenib, seems to get them to very deep durable responses. And so that was shown robustly at ASH last year, and I think it generated a lot of excitement. I think for this trial, same enrollment criteria, same setup. We're enrolling KMT2A patients, both AML and ALL, and we expect to have similar results. I mean that's our expectation. Similar results to what we showed last year, and I think that would be fantastic for these patients to be able to have a drug that gives them hope and gets them to a deep durable response. I think the way to think about it is -- in terms of the data, is having more than half the patients get an overall response, right, that's a pretty big deal, and getting them to transplant. In this particular trial, we're able to put patients back on drug after transplant, which is an extension, if you will, call it, maintenance in the relapsed/refractory setting, which could set up much longer time on treatment potentially. So it's something that really hasn't been seen in this patient population. Not only is there a drug for the first time, but also being able to give them a longer-term option.

And just explain to everyone, for those less familiar, to put them back on drug after the transplant, will that accrue to the duration, in the way you do the math?

It will. So the way the agency reads the endpoint for duration, median duration, is calculated all the way through to relapse. So you're not censoring the patients for transplant, it's best response when they go to transplant. So they read the endpoint, CR/CRh at the time of transplant, and then beyond that point, patients will continue on drug as long as they do, and then they count duration when they come off therapy and they relapse. And so if they're able to go back on therapy, that is actually a -- that accrues to the benefit of the duration calculation, yes.

Okay. Matt, you mentioned the EGFR HER2 exon 20, 114. So there's -- the data is coming up soon at ESMO, if I'm not mistaken. So just remind us what the pitch is there in terms of the differentiation and the better brain penetration, and what would a good readout look like for you for this initial Phase I?

Sure. So yes, ORIC-114 was designed for selectivity for exon 20. So specifically designed that. It was also designed to have brain penetrants. And so we think those features are what makes the program unique. We will be presenting at ESMO coming up next month. And so what we're looking at, the data, we expect to present about 30 to 35 patients worth of data. About half of those will probably be in an active clinically effective dose. And then we are enrolling patients with brain mets that is somewhat unique from some of the other studies ongoing out there. And so potentially mid-single digits, patients should have some form of brain mets. And so what we really want to show there is preliminary signs of clinical activity, especially intracranial activity. I think that's what we're really looking forward to that would be highly differentiating other molecules. We just haven't seen that type of activity in lung cancer in the population we're going after. Usually 1/3, at least 1/3 of patients have some form of brain mets when they enroll in studies, and obviously, many of them progress with brain mets on these studies. So we think it's a very important feature, not only being able to treat those patients, but also preventing brain mets and keeping patients on therapy for a longer period of time. It is -- this will be our first update for Phase I. It is a dose escalation data set, so we want to make sure it's clear. The focus will not be on ORR since we will have patients across a number of different doses, and we will not have a good read on durability yet. Those will be obviously focuses of future updates. But really understanding the safety, the PK/PD and early signs of clinical activity, especially intracranial activity, we think that will be very important.

And will you have enough information to get to an RP2D by that point? Or that will take additional exploration?

Actually, we haven't said that yet.

Okay. Okay. No worries.

But I think it will be clear on where we are with that update.

Okay. All right. Back to you, Paul. Maybe if you could talk a little bit about the MAT2A inhibitor for solid tumors, the 397. So I mean, obviously, there's been a lot of movement in that space recently with Mirati and Amgen. So I just -- could you talk about the overall strategy for 397 and the combo approach with the Amgen PRMT5?

Yes. It's really, really exciting to see the recent regained enthusiasm for this patient populations, this -- patients with MTAP deletion. We've got a program that's targeting MAT2A, and we think that based on the underlying mechanistic studies we've done, that there are some priority tumor types as a monotherapy where we can see and really exploit the synthetic lethality relationship. So when you have an MTAP deletion, you have an endogenous elevation of methylthioadenosine, and that's an endogenous tumor-specific inhibitor of PRMT5, which is a methylation enzyme. Our drug hits MAT2A, which limits the methyl donor. It's called SAM or S-Adenosyl methionine, and it's really that combination that gives you selectivity in tumor cells relative to normal cells. But as I mentioned upfront, we believe that there are certain indications in which this endogenous MTA is really effective at providing this synthetically full relationship with our drug. And so our monotherapy strategy is focused naturally on those tumor indications. And this is non-small cell lung cancer, bladder, gastric and esophageal. But even there, it's pretty meaningful. Like 30% of bladder patients have MTAP deletion, roughly 16% of non-small cell lung cancer patients have MTAP deletion. So we think there's a meaningful opportunity there as monotherapy in those priority indications. Interestingly, the preclinical data also led us to a combination with MTA-cooperative PRMT5 inhibitors, which directly inhibit the methylation enzyme PRMT5, and we've got a clinical program now started. We just dosed our first patient with Amgen. It's an Amgen-sponsored study. We're still retaining all rights to our compound. Obviously, they have the rights to their compound, and then we're collaborating in the clinic. It's 50-50 cost share when we jointly own the data, jointly own any intellectual property that comes out of it. But preclinically, it's really exciting. We're seeing efficacy where we're getting complete responses that are durable. We stopped dosing in these PDX and CDX models at 40 days, and even up to 100 days, there's no tumor regrowth. And we're doing that at a fraction of the dose. So for our compound, literally 1/10 of the dose we used in monotherapy preclinically, for the Amgen compound, 1/3 to 1/4. So I think the idea with the combination strategy is to really -- with the lower dose opportunity and a phenotypically different efficacy response, you've really got a broader therapeutic window. So that means we should be able to take this into other indications where the endogenous MTAs, maybe effect is not as not as pronounced. So we should be able to expand before -- beyond those 4 priority tumor types that I mentioned on monotherapy. And the combination, we should see deeper responses and we should see more durable responses. So that's the strategy. And I think we've set up the clinical trials to -- we're on what we think is going to be the definitive experiment. The relationship with Amgen is not exclusive, so we're not -- ultimately, we can work with anyone that has a PRMT5 inhibitor, and obviously, that will be a business decision that's in front of us, but it should be good to see that data start to...

Have you said when that data are coming?

No, we've not given specific guidance here. We just dosed the first patient. But I guess I would say, if you look at this objectively, I was encouraged -- and we've had the discussion internally with Amgen, but as an objective measure that investors can look at, because we've gotten this question, Amgen really highlighted this program as part of their most recent earnings release, including a whole slide in their corporate deck. It was one of only a handful of slides that were early clinical programs, so I think this is an important program for them. I think there's been some recent summaries from analysts and other banks that have noted it's an $11 billion opportunity just in the U.S. for total addressable market. I mean -- so this is definitely on Amgen's radar. They've guided towards a pretty expansive global trial. Once we get through the dose escalation, the focus is going to be, for the first trial that they've publicly announced through NCI, will be in non-small cell lung cancer, 180 patients, global. So I think it really is on their radar. And I don't think they're going to be shy about putting out the data as soon as we've got a meaningful data set.

Okay. Okay. And then Michael, beyond AML, talk about some of the solid tumor approaches with revumenib. You've got a study in front line CRC, obviously, front line -- not front line, but there's a CRC stress study. Yes. But can you just talk a little bit more about that and the strategy there for the solid tumors?

So I think what we feel good about is the -- we understand the mechanism of action of revumenib. I think the opportunity to see that in other -- how it operates in other disease states is something that we're interested in pursuing, solid tumors, obviously, being of interest, too. And so when you think about the mechanism, the upregulation of beta-catenin, it's this idea that a lot of solid tumors are upregulated in that pathway. And this mechanism, the interaction between MLL1 and menin and blocking that interaction seems to have a profound effect on that pathway. And so our ability to kind of dose patients and perhaps interfere with that in colorectal cancer, which is one of the ones that's upregulated the most in the beta-catenin pathway. And so -- we've been looking at solid tumors. That's the first one that we're looking to investigate. We have a small Phase I signal seeking trial looking at -- first is dose escalation, but essentially to get to a signal in that population. It's, unfortunately, in colorectal cancer, third line plus. These are metastatic patients who don't have a lot of options. There are a few drugs that are approved there that have a disease control rate of roughly 15% and a response rate of less than 5%. So we're talking about a relatively low bar and a very difficult to treat disease. And so our thought is, let's try to establish some monotherapy activity. Even seeing prolonged stable disease in this patient population could be pretty impactful. And so we're looking at this first in dose escalation and try to get to a potential dose for further studies then we'll evaluate the safety and efficacy of that and hopefully have some data before the end of the year.

And then obviously, there are a few other players in the menin inhibitor space. So just give you a chance to sort of comment in terms of how you see revumenib's competitive positioning relative to the field.

Well, look, I think we're in a great spot. I think this is a large market opportunity. We're addressing roughly 40% of AML and ALL with this mechanism. We are going to be the first to market. We'll have the broadest label [ of indications ], [ a little bit of ] pediatric and adult are the first indications, and [indiscernible] will be adults and pediatrics AML and ALL. That's the breakthrough therapy designation, and that's ultimately, what we'll show data on in this coming data set. But that will be the first indication. And then we believe we'll get NPM1 as well, which will cover the full up to 40%. So being first to market is extremely important. And we think we'll be best-in-class as well, and the data that we've shown so far supports that. So I think the competition -- it's good to see competition. I think if you're alone in the space for too long, you wonder whether it's worthwhile, right? And I think from our vantage point, we've always believed it's worthwhile, but now pharma does as well. So we have others that are behind us, some more than others, but I think we're in a very good competitive position to leverage what comes in the data set over the next -- for a while here. But I like our position.

And then last question back to you, Matt. So let's talk about the CD73 and the multiple myeloma angle. As far as I know, you're the only CD73 that's in myeloma. Talk about the scientific clinical rationale for that and how that came about and what you want to see in the first data set coming up this year.

Yes, great question. So we have taken a different approach with our CD73 inhibitor. Again, we're different. We have a more potent molecule and it's orally bioavailable. And so that's different from everyone else in the field. The CD73 inhibitors in front of us, almost all of them are in solid tumors in combination with PD-1. So it felt relatively crowded and a challenging path. And so what we've done is move forward in multiple myeloma. The rationale for that is really based on a lot of the work that we had with the collaboration with Ken Anderson at the Dana-Farber. And so he has been publishing more recently on this is that adenosine could be a driver in multiple myeloma. There is increased adenosine in patients that are later line multiple myeloma. He does have an assay that he takes bone marrow from patients treated at the Dana-Farber and has shown that if you treat it with a CD73 inhibitor, you can actually get lysis of tumor cells. And so that gives us a lot of confidence to go into multiple myeloma, and so that's a program, obviously, that we'll be reporting data on the fourth quarter of this year. Secondly, we also recently signed a clinical trial collaboration with Pfizer to potentially combine ORIC-533 with Pfizer's BCMA CD3 bispecific antibody that recently just got approved, elranatamab. And so that could be a potential path forward for the program in multiple myeloma.

And these would be patients that have failed the [indiscernible], the proteasome inhibitors and so forth?

Yes. So this first update will be -- again, it will be a dose escalation data. It's monotherapy. It will be in very late-line patients. And so patients will be triple-class refractory and plus other therapies out there. That's right.

Great. All right. Well, thank you very much, gentlemen. It was fun. And we'll see you here next year.