Okay, great. Welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts here at Citi. Welcome back to the Citi Oncology Summit in the first quarter of the year. It's my pleasure to have with me senior management from Arcus, Terry Rosen, the CEO, and Juan Jaen, President. Gentlemen, welcome. Thank you so much for taking a few minutes to chat. Really appreciate it.
Thanks, Yigal.
Sure. I think everyone is obviously super familiar with you guys, given the debate in the TIGIT space. Nonetheless, it would be helpful if you could, Terry, if you could just kinda level set, kinda give us the quick overview of the pipeline and what are the key upcoming catalysts that people need to be aware of, and just at a high level, how Arcus approaches drug development differently from some of your peers.
Thanks, Yigal. That's awesome. Thank you, everybody who's joined. We're always excited to chat with the external folks. Maybe I'll start off with ARC-7. I think everybody at this point who pays any attention to us knows what ARC-7 is, so I'll just jump right in. We're clearly very excited about the data that were just presented in December at the ASCO Plenary. What we showed there was more than a doubling of the median PFS for the Dom/Zim anti-TIGIT, anti-PD-1 versus Zim, the anti-PD-1 in that frontline high PD-L1 non-small cell lung cancer. To get a bit more quantitative, you know, that was a median PFS of 12 months for Dom/Zim versus 5.4 months for Zim and, you know, really awesome hazard ratio of 0.55.
I think importantly, while everyone hates cross-trial comparisons, we hate cross-trial comparisons, but nonetheless, people love cross-trial comparisons, when it comes to Q&A. I think it's important to note that that PFS for Dom/Zim exceeds the publicly available phase III data for not only anti-PD-1, but anti-PD-1 plus chemo, you know, KEYNOTE-189, in this setting. As a reminder on that, anti-PD-1 or KEYTRUDA plus chemo, resulted in about nine-month PFS in that high PD-L1 group in KEYNOTE-189. you know, below our median PFS of 12 months at the last interim analysis of ARC-7.
Since these data were presented, and this was one of the principal reasons we really pushed to get them out there in an investigator forum, so rapidly, we've been sharing them with sites, we've been sharing them with investigators, you know, as we're, you know, enrolling these phase III studies. We've been really thrilled with the response that we've received from the investigators. Been very well received. We'll have additional data to present at ASCO. That'll be on all 150 patients from the study. As you know, we also have a very broad development plan for Dom. That includes 4 phase III trials across lung and upper GI cancers. In fact, we're doing more planning together with Gilead.
I think not only internally, but, you know, we're really encouraged by the investments we see being made across the industry in TIGIT. Clearly, the field is, you know, expanding. AstraZeneca in the last earnings, you know, talks mentioned that they've initiated a new trial with their anti-TIGIT PD-1 bispecific antibody. I'll remind people that actually has an Fc-silent TIGIT arm. I think it's, you know, interesting. As you know, we have the collaboration with AstraZeneca on PACIFIC-8 in phase III lung. Clearly, you know, they've seen all our data. I think that probably has had some influence on them.
You know, beyond Roche, Merck made it very clear in their last earning calls that, you know, TIGIT's a big part of their plans going forward, and obviously have a number of phase III trials. The large pharma, you know, beyond us is clearly speaking with their feet and their $. While Dom has been such a, you know, intense focus for a lot of folks, I think we have a lot more going on and a lot more that we're advancing. Let me spend a little bit of time on the rest of the portfolio. Let me start with a molecule AB521, our HIF-2alpha inhibitor. We really think that's, you know, a drug waiting to happen given the validation from the Merck Peloton molecule.
We're looking at that now in ARC-20. That's a phase I, 1B study in second line RCC. I think, you know, Yigal, you asked about our approach and our differentiation. Really, you know, from day one of Arcus, the place from a technical standpoint where we differentiate is in the small molecule class, and that's holistically not just the medicinal chemistry. I think HIF-2 is probably a prototype there. It's a very exciting class, but it's also a transcription factor. That's why you've seen despite, you know, the success with the Peloton Merck molecule. There's very few molecules, at least in the clinic, and that's because as a transcription factor, it's very difficult target to hit. That's certainly a source of the little competition.
I think it demonstrates the strength of our small molecule discovery group, and particularly, that's why we, you know, put so much energy into what we think is a best of class molecule and a best of class profile. It's a very clear and tangible aspect, so this isn't just a narrative. The thing that we've already demonstrated in the early clinical trials, and, you know, we're continuing to expand on that, is that we can achieve higher drug levels than with Belzutifan, and, you know, that'll give us the opportunity to hit the target harder. Where that study stands, the second dose escalation cohort, which is 50 milligrams, is now enrolling. That's a very pharmacologically meaningful dose.
You'll recall, we did a healthy volunteer study that lets us start at a very meaningful dose. While ARC-20 dose escalation was designed as an all-comer study, we do think that given the mechanism, we may get a few, you know, clear cell RCC patients in. As a matter of fact, the first patient in was. We hope to and expect to achieve our dose for expansion by the middle of the year and then start the 1B portion in the second half of the year. I think as the year goes along, you'll hear more details on a more expansive plan around that in the second half of this year.
We have two important randomized readouts for Etrumadenant in prostate cancer ARC- 6 and colorectal cancer ARC- 9. We expect to have those data in-house this year. We also have ongoing phase II studies for both Etrumadenant and Quemliclustat in non-small cell lung cancer and GI cancers, which will generate data in the future. I think with the collective set of trials we're doing for those molecules, we feel with the multiple hypotheses, whether it's combinations or settings, we're giving those molecules their best opportunity to succeed. We'll read out on both of those this year and probably early into next year.
We also have, a big thanks to the Gilead Sciences collaboration, another unique aspect of Arcus Biosciences, not only are we growing such a substantial development capability, but we maintain and continue to grow the discovery organization. In fact, we have 3 potential first in humans or INDs this year. The first I'll call out is what we think will be a best in class small molecule AXL inhibitor, and that will primarily derive from its selectivity. That is expected to enter clinical development in the middle of the year. We expect to target STK11 mutant tumors with this molecule. We have a CD39 antibody, which will also enter clinical trials by the middle of this year.
Finally, and third, our first molecule for inflammatory disease. You'll see us doing more in immunology. We'll talk a little bit about more about this target a little later this year, but this is a target people will be familiar with. We think, again, it has best in class potential. We expect to enter the clinic either by the very end of this year or otherwise early into 2024. We're just entering preclinical development there. We continue to have, you know, multiple discovery programs in oncology. As I said, we're adding immunology. A couple of these oncology programs are part of the early oncology research collaboration with Gilead. The last point I'll make, you know, we're well capitalized.
We had $1.2 billion at the end of September last year. I think very importantly is that 50% cost share, I think that's hugely enabling on all of our clinical programs except AB521, that net comes from our collaboration with Gilead. I'll stop there. That was a mouthful and, you know, Juan and I are happy to, you know, take your questions.
Yeah, no, that was a very comprehensive. Let's see. Let's start with TIGIT. You mentioned 150 patients, more data at ASCO. I think everyone is curious to know more specifically what can you say about what we'll learn incrementally at ASCO from ARC-seven. I know you've gotten this question, literally 1 million times, but nonetheless, I think it would be helpful if you could just run through again, you know, why we shouldn't be necessarily comparing what you showed with Zim monotherapy to what's been shown with Pembrolizumab and why that comparison may have, you know, may be troublesome or not necessarily be valid.
Sure. Let me start with the Zim piece. You know, I think the first thing is, you know, the data that we have generated already. Any investigator that's worked with Zim has continuously commented it looks just the same as any anti-PD-1 looks like. Pembro. The data sets that Gloria generated, including their approval in China in classic Hodgkin's lymphoma, if anything, if you were to compare across trial, it looks a little better than Pembro. If you were to look at the data they presented in cervical, also similar.
I think it's been discussed sort of ad nauseam, how real world data, for all the reasons of the, you know, the timing of those initial studies with Pembro in the clinical trial world at the time, what the other options for patients. Both the time and the evolution, how that has changed things. I think the best, you know, if you want to put the cherry on top of the whipped cream, that describes a lot of the analysis that's gone into that, you know, I think is reflected in the PERLA study that Glaxo just read out, where they looked at essentially the KEYNOTE-189 type of study. You know, the Tesaro Glaxo antibody plus chemo versus KEYTRUDA chemo.
That KEYTRUDA PFS, you know, was several months lower than what you see in KEYNOTE-189. We feel the best data, and I think everybody agrees on this, really comes from the cross-internal trial comparison. The last point I'd make is just, even differences in scanning intervals, which, you know, Andrew shared, you know, analysis. I think it has been done by an academic group that, you know, showed even that can affect pretty substantially PFS. We have all the confidence in the world in Zim. To the initial part of your question about what we'll be sharing. We will share the full 150 patients. By that point, all patients will have, you know, had at least two scans.
You'll have both more mature data, by roughly five months or so, from the last interim analysis, as well as the totality of that patient population from our study.
Obviously, the other huge question is with respect to the Roche program and the SKYSCRAPER-01. You know, how does that impact your thinking? We're all waiting for the overall survival data, obviously. You know, if that works, that's, I think, easy. If it doesn't, how does that impact your TIGIT strategy and your willingness to invest in the program?
I wanna emphasize our decision making at this point is really driven by our own data. You know, we have a very compelling data set. It's a substantial data set. Unless we learn something unexpected, you know, somehow Tiragolumab had showed absolutely nothing. You know, we're focused on our data set. We're focused on the evolving data set and very committed, both us and Gilead. I'll just remind you know, our study is different than their study. They're different compounds, different trial designs, study sizes and assumptions. We don't really, you know much more about, you know, SKYSCRAPER-01 than what's been in the press releases. What I think is also important, this is really, I think, important for the field. SKYSCRAPER-01 is just one study of many.
You know, we have the ARC-7 data set. We have 4 phase III studies ongoing. Merck clearly was emphasizing that last earnings call, how important anti-TIGIT is to their, you know, their future. They've got a number of phase II and now more and more, I think 5 phase III studies. Clearly they have data that at some point they'll share. BeiGene has several studies. AstraZeneca's seen our data. They're moving aggressively with their bispecific. I think what you're gonna start to see, there's been sort of a hyper fixation on SKYSCRAPER-01 because for a while it was the only game in town. At this point, I think everybody, you know, is looking at their own data and making their decisions in the smartest way, driven by their own data. You know, Genentech Roche will make their decisions based on their data.
You know, we and Gilead feel quite confident, as well as Taiho, as well, based upon the data that we have ourselves.
It's interesting at the ASCO plenary session in December, I think it was Solange Peters. She was talking about defining some of the pathways, specifically CD226, for developing biomarkers for the TIGIT antibodies. You know, could you comment or expand on that thought? What are you guys doing to hone in on how to find the best biomarkers for the TIGIT antibodies? Would we see some of that maybe at ASCO?
Juan, why don't you share what we're looking at, how we're thinking about that?
Sure. Just a couple of points. First of all, we don't think that, you necessarily need to enrich for a patient population beyond what we are de facto already doing in studies like ARC-10 to select for PD-L1 high, patients in that particular setting. Having said that, we agree that the biomarker analysis can be really informative in terms of understanding, shedding more light on the potential mechanism of action. Underline the activity of Domvanalimab. Along those lines, we've collected a very large, number of markers related to the TIGIT CD226 pathway, including, quantifying levels of the ligand, as well as, both TIGIT and 226. Still very early.
We're literally in the process of processing a lot of that data. It may very well be that there are some of that data that finds its way into the June ASCO update.
Okay. The other, the other feature of ARC-7 that maybe doesn't get talked about as much, although I've mentioned it in my research, on the triplet. You didn't see an additional benefit on adding the Atumma. Although my argument, as I think you know, is that it was in a sense some potentially a sort of a hidden positive in the sense that since it was open label, you didn't see an inherent bias with the three drugs. Nonetheless, I'm just curious, given what you saw there with ARC-7 and seeing essentially the same TSS or maybe slightly lower with the triplet, what is your level of comfort in continuing to invest in the Atumma?
I know you mentioned you are doing some additional studies there.
Yeah. We're actually still very excited about Atumma, and let me hash that out in a, on a couple of fronts. Obviously, on the ARC-7 front, we did not see anything, and, you know, and we noted this even at the third interim analysis, we were not seeing any substantial differentiation even at the third interim analysis. We are pointing it out, and we wanna see on OS whether there might be some differentiation. Obviously, we'll learn that in the latter part of this year.
The piece that we remind people and ourselves, while it was very exploratory, we did see, you know, a couple of intriguing responses in those patients that had progressed on the monotherapy and then went into another arm that would look at those in the t-triplet. I'll remind people that those have to be confirmed progressors. We're continuing, you know, to monitor that. We'll have additional patients. Clearly that part lags the rest of the study because those patients have to have progressed on the PD-1. We thought that was an intriguing part of the study. I think a number of investigators also find that as well.
I think the other part though, gets at, you know, the fundamental hypothesis that we're looking to test, and ARC-6 and ARC-9 are a little bit closer to home on that. That gets to the chemo-containing combinations. If you go back to when we first started to work on the ADP adenosine pathway, one of the biggest drivers for us, and that's why, you know, we were into the chemo combinations perhaps earlier than some of the others, which have more gravitated that way, including AstraZeneca. It is a reminder, those particular types of chemos that kill cells through an immunogenic cell death type of mechanism, cause the generation of a, you know, a very substantial levels of adenosine as part of their killing process.
We think that those types of settings are obviously, you know, at the top of the list for exploration, and that's amongst the reasons why we see ARC-6 and ARC-9 is such important readouts. I'll also remind everybody, and we continue to have an interest in this as well, the data that AstraZeneca generated with their CD73 antibody in COAST, in stage 3 lung, which also includes, you know, chemo and radiation, both known to that you have the situation where you're inducing CD73 as well as in inducing PD-L1.
You know, we think that's another quiver, if you will, or arrow in the quiver of suggesting the mechanism does have a role that could be important in cancer.
Yeah, we did a. As you may remember, about, I think it was a year ago, we did a very big deep dive on the CD73 space. While we're on the topic, I think, some people don't have to read that report. If you could just tell us, so Oleclumab is the one you're referencing, I believe, the AZ, the AZ compound. Tell us about the pitch for Quemli versus that one? I mean, yours is a small molecule, obviously. Apart from that, what is potentially more interesting or differentiated with the Quemli?
Juan, why don't you talk a little bit about what we know about Quemliclustat and how it differentiates from the antibody, you know, biologically and, you know, physical chemically.
Oleclumab is what I would describe as a first generation CD73 antibody, and it's well established, public information that it doesn't work particularly well against soluble CD73. It's a molecule that exists both as a cell-bound as well as a soluble portion. We designed Quemliclustat to inhibit equally potently both the cell-bound as well as the soluble form of the enzyme. That's one main difference we believe potentially consequential. The second one, of course, as you pointed out, is a small molecule we anticipate that's gonna have easier reach for the deeper corners of the tumors than your average antibody will.
Okay. Makes sense. Then, Terry, just going back to ARC-6 and ARC-9. I think people are less familiar with those trials. If you could just kind of quickly go through the design. I mean, I think it's pretty straightforward. Just, if you could go through, when are we getting those results?
Sure. We'll have those results. We haven't, you know, we'll have them in-house, and then we haven't decided yet, which conference that we'll share them. They're both randomized studies, and I'll let Juan talk a little bit, you know, about what we're looking at, in both of those.
Sure. In ARC-6, we're looking at metastatic CRPC. We started the study with three different cohort settings. We discontinued one of them fairly quickly based on a futility analysis. The data or the cohorts that will yield some data today, one is a very late-line chemo-free combination looking at Etrumadenant plus Quemliclustat plus Zim or PD-1 antibody. Then we have a second line cohort in which we're combining, these are patients that have progressed on NHT therapy. We're comparing Docetaxel plus or minus Etrumadenant plus Zim versus Docetaxel alone. That's what we are looking forward to within ARC-6. In ARC-9, we're looking at two separate cohorts.
One is in the third line plus the chemo, in which we are combining, Etrumadenant plus, FOLFOX. Comparing that to a standard of care Regorafenib, and a second line cohort in which we are combining FOLFOX plus or minus, Etrumadenant and Zim as the additive on top of the standard of care chemotherapy. Both of those cohorts, again randomized cohorts in ARC-9, will also be yielding data in 2023.
Okay.
You may recall a couple years ago, we presented data from ARC-3, which was a couple of single-arm cohorts, in which we showed what appeared to be, that still appears to us, as a very interesting activity data set for Etrumadenant plus FOLFOX in across different lines of therapy. The data that we showed a couple years ago was particularly interesting was Etrumadenant plus FOLFOX in a late line cohort in which both PFS and OS were significantly higher than what's now accepted as the standard of care, Regorafenib or other late line standards in CRC.
Do you have a thesis as to which of these, the prostate or the CRC is sort of more likely to show something, based on the biology or not?
you know, I think they're complementary hypotheses. I think colorectal is a particularly interesting one. GI adenocarcinomas, of course, of which CRC is one of the tumors that fall into that category, are particularly high in CD73. As you know, MSS CRC is not particularly sensitive to IO approaches. A hypothesis is, that we're exploring in this trial, is that adenosine may be one of the factors that prevents T-cell response to that tumor, particularly following immunogenic chemotherapy like FOLFOX. it in prostate is a little different. I think what we're exploring there is a little bit more of the this alternative source of adenosine generated by PAP, which is a prostate cancer-specific source of adenosine. I think they're both equally interesting but somewhat different hypotheses that we're testing.
You know, Yigal, one other sort of... I mean, if you just always look at like experiments that would be confidence enhancing, the fact that we already had the data from ARC-3, clearly, you know, made us feel good about sort of colorectal. That was the genesis of ARC-9. While it was early, and we'll see what happens in ARC-9, you know, Juan's team had generated some interesting biomarker data, albeit small number, single-arm study, you know, that showed an interesting correlation. Going in the direction of the, you know, high CD73 population, you know, having better outcome, which is interesting that since even though it's single arm, that is a negative prognostic. We, you know, that certainly gave us impetus to invest in the randomized study.
Sorry to jump around a little bit, but I do wanna go back.
No, that's okay.
I do wanna go back to it. You were kind of going.
Yeah.
Not in a linear way, but it's okay. You mentioned some of the other phase IIIs. Let's can we just go through those? There's quite a few. You have this, you have the ARC-10, the STAR-121, the STAR-221. I might be missing one. Let's just go through each of those. You made some recent changes to ARC-10. Why did you do that? What are the goals for that study? Timelines for the data for that one.
Yeah, that's great. Let me start with that ARC-10 question. We're actually thrilled that we could make the protocol amendment to ARC-10 and that the FDA agreed we could do that as an amendment. The real genesis of that change was simply how the field has evolved since we initially designed that, which to give you a sense how long ago that was, it was before we had even, you know, signed the Gilead collaboration. As the world changed, the thing we accomplished there was very clear. We went from a 3-arm study involving chemo to a much simpler and what we feel is better design, where we're running, where the control arm is now KEYTRUDA. That results in a number of things.
It simplifies it. It's two arms. Probably most importantly, though, if you look at all four of the registrational trials we're running, we are running versus the global standard of care. Not only from a registrational standpoint is that important, but we feel from an ultimate adoption, in labeling, et c, the fact that we're running now against Pembro is a big advantage. Of course, what that does is it makes it better for physicians and patients as well. That enables expansion of a global footprint into both the U.S. now as well as Western Europe. Simpler, better design that makes it attractive to patients.
On none of these studies, just because they're all basically getting up and going, they're relatively early, we really haven't commented it yet on the timelines. The other trial that I mentioned that you didn't mention, just to call it out, and then we can get into STAR-121 and STAR-221 is PACIFIC-8. PACIFIC-8 is the trial that we're running in collaboration with AstraZeneca. That involves Durva plus Dom versus Durva. As you know, Durva is the standard of care there. They have like something like 90 plus % of the market.
Everyone will recall, we worked out that agreement under the umbrella of the Gilead collaboration and very shortly after we commenced the Gilead collaboration because we felt AstraZeneca was the right company. You know, they have the platform, they know the investigators, they know the field. To have them execute that, you know, we feel is an awesome opportunity. The way that's structured, you know, we get all of the anti-TIGIT economics, they get the Durva economics. That was the one trial I just covered that you didn't mention.
Okay. I know you sort of answered this already with respect to the ARC-7 and thinking about Zim versus Pembrolizumab. Nonetheless, I think some people would still appreciate just a little bit more perspective maybe on, you know, as you mentioned, you're going up against Pembrolizumab in ARC-10, but the active is Dom plus Zim. You know, just help us understand, you know, why that is not necessarily gonna be a limiting factor.
Sure. We discussed contribution of components very extensively with the FDA. We have our seven data set. The other thing is, that in STAR 121, which you may get to, but I'll point out one element of it. We actually have STAR 121 for those of you who aren't familiar, is our study that involves chemo and PD-L1 all comers. It's Dom Zim plus chemo versus KEYTRUDA plus chemo. We're also running an arm. KEYTRUDA chemo is the control, but we're also running an additional arm that is Zim chemo to get yet another direct comparison. That's all been discussed with the FDA.
In any of these situations, you know, we've had a lot of discussions, not only from a regulatory standpoint, but with KOLs and physicians and investigators. The key thing will be is, you know, do we beat the standard of care in each of these? That'll be what's adopted and what's looked at. We feel very good, as we talked about before, that Zim looks just like KEYTRUDA. One thing that I'd just like to describe is that since this question comes up, for those companies really looking to be, you know, players in the field, it's not so much looking to come in with a like a biosimilar or go out as a monotherapy, but the ability to execute price, deal with the secondary pairs.
It's very, very important that you have an anti-PD-1 that you can control. I can't even describe, a lot of times people don't even recognize just even the execution of a trial, not only the cost of having to use, you know, in this case, we're using the KEYTRUDA as standard of care. The logistics, if you don't have your own anti-PD-1, you're at a very substantial, you know, disadvantage just from an execution standpoint. Our general feeling, and again, we've done a lot of market research on this, Gilead's in complete agreement, is what you're gonna see play out over the next several years is the anti-PD-1 is really gonna become the commodity. In this case, you know, the Dom is going to become the, you know, the more innovative component.
In fact, you know, not only us, but Gilead also, when we talk about we start to think of Dom Zim as even becoming the backbone. You know, this field is gonna go on and on and on beyond where we are today. The, the way I think that things are starting to shape out, and they play out, is basically what you can think of as anti-TIGIT turning anti-PD-1 or anti-PDX into super anti-PDX. At some point, that's gonna just look like a single entity, and then others will put things on top of that, you know, super checkpoint combination in the future.
Okay. On the yeah, no, thanks for that. On the point around contribution of components, just so everyone's clear, I mean, for ARC-10, you're going up against KEYTRUDA, but you do have, as you mentioned, you do have the Zimberelimab monotherapy as well, if I'm not mistaken. How is this gonna work in terms of the way it's analyzed? It's gonna be Dom plus Zimberelimab versus Pembrolizumab as the primary comparison, and then Dom Zimberelimab versus Zimberelimab as a secondary? Or how?
No. Yeah. The comparison will simply be Dom Zimberelimab versus KEYTRUDA. That's in ARC-10, there's only the two arms, but we have supportive data from ARC-7 that we'll be able to share with the FDA. The key thing is gonna be that you beat the standard of care, which is KEYTRUDA, which would be, you know, that's very, you know, you're gonna look to see that that's, you know, in a clinically and statistically meaningful way, and that'll drive its adoption, as part of the whole process. This is something we do with the FDA since we have such a broad and holistic program.
You know, a lot of our discussions, will talk about, well, if we have this from this study, this arm from that study, as part of your ultimate regulatory package, will that satisfy the requirements? Those are the type of, you know, regulatory discussions we've had, you know, relating to those contributions to components.
Yeah. Sorry, Terry.
Go ahead, Juan.
If I may add something, because I think, earlier you mentioned the three-arm design. Terry was referring to STAR-121. That's the PD-L1 all-comer study in non-small cell lung cancer in which we have three arms.
In there. That's it. In there. Oh, I'm sorry. Go ahead.
I was gonna say the main comparison there will be Dom Zimberelimab plus chemo versus Pembrolizumab plus chemo. There's a third arm that will enroll fewer patients that will look at Zimberelimab plus chemo, and that will give us within that study also the opportunity to address contribution of components on a chemo backbone. The main comparison will be Dom Zimberelimab chemo versus Pembrolizumab chemo.
Okay. Just to clarify then for ARC-10, it's what is the main comparison?
ARC-10 is.
KEYTRUDA.
KEYTRUDA.
Okay.
KEYTRUDA versus Dom Zimberelimab.
Is that, I guess on clinical trials, it still shows there was a Zimberelimab monotherapy.
Yeah, that's just, that goes back to the, that hasn't shown up on clinical trials. Now I understand your question because we've gotten that a couple of times. That was the old design.
Okay. All right.
We thought that was a real advantage on multiple fronts to make the switch to KEYTRUDA as the control arm. In fact, that's what we went and proposed to the FDA when we did that. They liked that as well.
Okay. The other one, the STAR-221, the GI trial, we'll just go through that one quickly.
Sure. Juan might have to talk about the rationale and everything about that study.
Yeah. The STAR-221 is being operationalized by Arcus. The one that we were just talking about, STAR-121, is being operationalized by Gilead. Scientifically, the rationale in both cases is similar and stems from the fact that, as Terry pointed out, we believe that a PD-1 TIGIT double is gonna work well in settings where PD-1 works, whether it is a single agent or in combination with immunogenic chemotherapy. Using the rationale and the fact that we saw some interesting responders in our phase I study looking at dom plus Zim, we've shared some of that data previously, gives us a lot of excitement about looking at a combination of TIGIT plus PD-1 plus chemo. In a setting that is quite unique.
Our competition is looking to the extent that they're looking as at esophageal cancer. They've chosen to focus on squamous histology. Our study is particularly focused on adeno adenocarcinoma of the upper GI. We'll be looking at gastric, gastroesophageal junction and esophageal adenocarcinoma. It's a real opportunity to be first, take advantage of the fact that that particular space is not as crowded as some of the other settings are.
You don't care about HER2 status, right, for this, you're just looking broadly?
At this point, HER2 positive, or we're focusing on HER2 negative.
HER2 negative. Okay.
The study design there is two arms. Sorry, yeah, two arms looking at, Dom, Zim, chemo versus Nivolumab plus chemo. That being the standard of care in that setting.
Okay. Let's talk a little bit about some of the other, the earlier programs. I think you mentioned you're starting the AXL inhibitor trial soon. What's the pitch on that asset? There have been a number of other AXL inhibitors, if I recall, but I don't know how far they've gotten in the clinic.
Yeah, I mean, essentially every TKI that you can name, probably has AXL to some extent. Depending on the year, people have over time chosen to highlight the AXL component of what's otherwise a fairly nonspecific TKI profile.
Yeah.
We decided to go and make the world's best, most potent and selective AXL inhibitor, which I think we accomplished, the molecules AB801. We think we can take advantage of some of the data that's been generated by earlier compounds. Lately, two of our competitors have shared early, but intriguing data in advanced non-small cell lung cancer and second-line plus ovarian. We've chosen to steer our AXL inhibitor program towards a second line non-small cell lung cancer population. As Terry pointed out, the STK11 mutant subset of that is particularly interesting from a biological perspective.
I think at this point, we're aiming towards an unselected population, and we'll take a look in a randomized fashion, comparing standard of care chemo against chemo, plus our AXL inhibitor in that second line non-small cell lung cancer population. Again, the plan is to initiate that study towards the middle of this year.
Would you ever think about combining with one of the KRAS drugs? Because I think that's an area of interest for this STK11 mutants, right?
It definitely is in of interest. It's also some of the stuff that we haven't talked about publicly is also targeting STK11 mutant tumors. Down the road, I could see both the opportunity to combine with KRAS inhibitors, but also with some of the other things in our portfolio way down the road.
Okay. Then the CD39 antibody is new, or you're starting a study there? Remind everyone what CD39 does, and what the relevance of that mechanism is blocking that target?
CD39 is an enzyme that's involved in the degradation of extracellular ATP. When, when cells die in a particular fashion, we refer to it as immunogenic cell death. One of the things they do is they spill over massive amounts of their guts into the surrounding environment. ATP is recognized by the immune system as a, as a sign of danger. CD39 removes that sign of danger. What we're trying to do by blocking CD39 is enhance the ability of dendritic cells to recognize a dying cancer cell and mount orchestrate an effective T-cell response against that tumor. It's not the first CD39 antibody to make it to the clinic. We just don't think that some of the earlier entries have properly tested the therapeutic hypothesis that I just formulated.
we're gonna go in a very focused fashion into a combination and tumor type that we think best aligns with the hypothesis that I just outlined.
it's similar conceptually to the adenosine blockade, but with an antibody, right? Is that fair?
You know, I actually, I don't like the classification of CD39 as a, as an adenosine type of approach. Even though one of the consequences of preventing that hydrolysis of ATP may in fact be affecting the amount of adenosine, it's fairly upstream. We're primarily focused on the effects, the benefit of having more ATP in the tumor, and the resulting enhanced activation of dendritic cells.
Yigal, You know, Yigal, I think one thing with it's, it's really, it's almost like the push-pull. In one case, blocking adenosine is removing something that's putting a brake on the immune system, if you will. Blocking CD39 keeps the thing that actually has the activating effect present. They're literally two different hypotheses that happen to involve the same biological pathway, but in one case you're doing something that activates, in the other case, you're removing a repressor.
Got it. Okay. That's helpful. Then earlier, Terry, let's just talk about HIF-2 alpha again.
Sure.
I think you mentioned that you're getting better drug levels than Merck. Is that the differentiator for AB521, or is it also more potent? Is it this is a PK type argument?
I'll let Juan describe that. His team like they this is really an amazing molecule that they, you know, an optimization effort. Why don't you describe what we're doing and the advantages, et c?
Yeah. I mean, I think the company is nominally more potent than Belzutifan, but I wouldn't, that's not the first thing I would highlight to anybody. It's primarily the ability to reach significantly higher circulating levels of the drug than what's inherently possible with Belzutifan. Belzutifan's half-life and whatnot is fine as a small molecule drug. They just reach a point of saturation where going higher in doses does not translate into more amount of drug being absorbed. The question on the table that we intend to evaluate clinically is whether pushing the amount of drug higher than what Belzutifan can reach translates into a better clinical activity profile.
Okay.
The data we've generated so far in the first cohort in the dose escalation study in cancer patients, but in an earlier study in healthy volunteers, is very supportive of at least the fundamental premise of a compound that has phenomenal human PK that hits the pathway extremely well. In fact, I've been surprised on the positive side. If anything, our prediction was a little bit conservative. It's doing more biologically and this is just measuring peripheral PD. It probably works a little bit better than I even I expected. So the next step is to confirm that that higher exposure, you know, we think we may very well be able to go to 3, 4 times the amount of drug that Belzutifan achieves.
The next step will be to confirm whether that, in fact, translates into greater clinical benefit.
Okay. Terry, tell me if I got this wrong, I thought you said that one of the carve-outs in the cost share with Gilead is AB521 is not part of the cost share. Is that right? If so, why is that?
Yeah. Gilead hasn't opted into that program yet. They're clearly very interested in it. We'll see how that plays out. They keep in mind the 50% cost share starts occurring when they opt in, and that trigger hasn't been reached yet for the HIF-2 program. It's still They have the option to opt into it.
Got it. Okay. Okay. This was great. I think we hit most of the highlights, maybe not every single trial, but hopefully most of them. Thank you very much. It was great. I'm sure we will be chatting any day now around here.
Soon. Yep. Thanks for including us. This is a pleasure. Thank you everybody else who joined in. We appreciate it.
Yeah. Thanks, Yigal.
Take care, Yigal. Take care.
Thank you. Bye.
Bye.