Terry Rosen: Thanks for the two questions. This is – and I’m going to walk and chew gum at the same time, since those are two different programs. So what I’ll comment is, you can think about RCC from a standpoint of both development, the need, ultimately commercialization. It’s – there’s multiple lines where you can think of going. And so, we would probably move up a bit from where that third-line population was. And you could think about patients that have received anti-PD-1 and or TKI. So you’d be – you wouldn’t have Belz’s standard of care. We feel like that’s a great place to go. Insofar as your question about ARC-10 and the strategy there, so clear – let me give a couple of points on that. So clearly, like with many therapies, and particularly in cancer, it’s one of those places where obviously there’s a Goldilocks spot.
But physicians do, and patients tend to be more focused on efficacy than safety, within reasonable bounds. And I think as time goes along and physicians become both more comfortable with the liabilities of a therapy, how to administer it, as well as a conviction about the real efficacy. That’s what’s happened in a very continuous way in this high PD-L1 population, going from anti-PD-1 alone and increasingly to anti-PD-1 plus chemo, particularly in a more healthy patient population or with a patient with a bulkier, more rapidly progressing tumor. We think that’s only going to be more enhanced, particularly with a molecule like dom, which we’re already seeing from a study, for example, like EDGE-Gastric, that essentially doesn’t bring any additional side effect liability on top of anti-PD-1 plus chemo.
So we think that that’s going to further cannibalize that particular approach to treating that population. So we do feel that STAR-121 best addresses that population with the best opportunity to become the standard of care for all comers. What I’ll also say, from a biological standpoint, I think one of the important things is you move like down the spectrum from toxic agents, beta-tubulin inhibitors, to things that are – you very much understand the biology. What you really want to start thinking about is less the organ that you’re treating than the biology that you’re treating. And we do feel and the biology that supports anti-TIGIT is a couple of things. At the highest level, CD155 is a bad thing. If you’ve got CD155, what’s CD155 is doing is, And what CD155 is doing is it’s keeping you from getting all of the mileage that you might otherwise out of anti-PD-1, because anti-PD-1 relies on CD226 to get its full efficacy.
And so when you have CD155 engaging that CD226, you’re losing part of what you might otherwise gain. And that’s the whole rationale. And now what’s being borne out clinically behind anti-TIGIT and why we feel like the best place to go for anti-TIGIT is where you already know that anti-PD-1 works, and that PD-L1 all comer population with chemo is absolutely right down the middle of the fairway for where you want to go with a molecule like dom.
Unidentified Participant: Helpful. Thank you.
Operator: We now turn to Robyn Karnauskas with Truist. Your line is open. Please go ahead.
Robyn Karnauskas: Hi, team. All right, several questions. Thinking about the 200 milligrams of Cas, do you think there’ll be a diminishing limit of returns if you actually – but do you think you could push the efficacy up higher? What are your thoughts on 200 milligrams? Second question is about the other one. How is different from Zanza? And third might be, do you think you could leapfrog? You know, how you cut ARC-10 and you did a different trial? Leapfrog into frontline with 521? Is there a strategy there, and how do you incorporate your own 801 into that process? There’s a lot going on there, but maybe you can take those at once.
Terry Rosen: So – the second question, what was that Zanza question? What was 801?
Bob Goeltz: Yeah, the other compound.
Robyn Karnauskas: The 801 – so for 801 how is it differentiated from Zanza? I know it’s just AXL only. And could you incorporate that with your clinical trials going forward, right. So you’re doing all these Zanza clinical trials. The second question would be 200 milligrams of Cas. Like what do you think is going to happen there? Are you pushing a limit already? Do you think you get greater efficacy? And third would be, could you leapfrog ahead giving your Phase 1, 2b trial and go into first-line RCC, because you’ve done brilliant things in the past by cutting things off and like skipping ahead of other people, giving the knowledge you have to get first-line indication versus refractor indication. Thanks.
Terry Rosen: Great. So I’ll start with the 200 milligram and I’ll be brief on that. We do think that’s probably overdosing, but we want to see it, because we’ll also – it’ll give us some additional safety data if we do go higher, does it do anything else on the other physiological roles of HIF-2alpha, but we do think that the 100 milligram dose is really hitting the target hard enough. But we’ll see what we learn from 150 or 200 milligrams. Juan, you want to take the 801 questions?
Juan Jaen: Yeah, sure. Zanza, as well as Cabo, is primarily a VEGF-TKI. It inhibits AXL with both molecules with decreased potency. But the clinical activity and it’s really generally accepted to be the result of VEGF inhibition. So the 801, we believe, is going to be a more surgically effective inhibitor of AXL, but probably not the first thing you would reach for in the context of RCC, where the rush on we primarily to go after a VEGF-TKI.
Terry Rosen: So the place where we see AXL going are things like STK11-mutant non-small cell lung cancer. And by the way, on 801, since you ask about it, I might as well call out a bit. We have completed the healthy volunteer dosing. PK profile and safety profile look really good. So this is, in our minds, the first molecule that has the selectivity to really test the AXL hypothesis. So we’re very excited about that molecule. Jen, you want to comment or Dimitry on the 521 leapfrogging into a frontline setting?
Jennifer Jarrett: Yeah, sure. Definitely –
Dimitry Nuyten: Yeah, sure. I can comment –
Jennifer Jarrett: Go ahead, Dimitry.
Dimitry Nuyten: So we are considering all options and we could leapfrog into the first-line. We could leapfrog into the adjuvant setting, but we really want to make sure we select a setting for the first registrational trial that is a mix of different factors. It has to have the data, let’s say, safety and early efficacy data to support it. It has to be a sweet spot when it comes to competitive timelines to Merck, there’s other considerations about timelines to readout. A first-line trial is an interesting market opportunity. But, for example, the bar in first-line is higher than in second-line. The time to readout is longer, of course, in first-line than in second-line. So we are considering all these different options and we’ll make a decision and communicate that in the near term future what our first opportunity would be that we pursue, but it’s a factor of multiple factors.
Robyn Karnauskas: Great and –
Terry Rosen: See Robyn, though, I [technical difficulty] since you asked about that, I would like to emphasize the point of your question. Conceptually, though, is really good one. HIF-2alpha is going to end up being really important. I think that’s why Merck has started to call it out as blockbuster. AB521 barring some weird, unforeseen thing, it’s a drug. And so the real question is, how do you fully exploit that? And if you ask me about our portfolio, it’s definitely something that, as we aggressively move towards this first study, we want to look at very hard, how do you expand the footprint of the HIF-2alpha program? That’s a really huge opportunity. And we actually think because it’s so hard to get a good molecule, you’re not going to have anyone come in with a better molecule than us. So, we feel we’re going to end up better than Belz, and it’s – there’s not going to be commodity here.
Robyn Karnauskas: And I’d like to thank Dimitry for making me feel not so bad pronouncing all these names. So Zanza worked for me, Cas worked for me. Thank you very much, Dimitry. Appreciate it.
Dimitry Nuyten: My pleasure. Absolutely.
Terry Rosen: I’m told that Cas is Cas, not Cas too. That’s what I’ve been told. So –
Robyn Karnauskas: I’ll work on that, Terry. I’ll work on that.
Terry Rosen: And I can’t tell the difference.
Operator: We now turn to Daina Graybosch with Leerink Partners. Your line is open. Please go ahead.
Daina Graybosch: Hi guys. Thanks for the questions. I have three on Cas getting into the PK/PD data. First, on Page 31, where you show the area under the curve. I recall initially talking about the value proposition for Cas that you expected a much higher absolute area under the curve. But what I see here with the 100 milligrams is pretty similar in range to the 120 and 240 milligrams for Belzutifan. So I wonder if you can talk to that that you’re ending up in the same range. And then on pharmacodynamics, you have two different pharmacodynamic readouts here. First is the percent EPO change on Page 30, and then the percent hemoglobin or the absolute change in the hemoglobin on Page 32. Which of these PD readouts do you believe is more correlated to what you expect in efficacy?
And if I look at the hemoglobin, you’re sort of in range of belzutifan, and you’re modestly higher or looks to be modestly higher in percent EPO? So my final question is, how much better efficacy do you expect to drive with these similar to modest increases in pharmacodynamic markers versus belzitufan? Thanks.
Terry Rosen: Thanks, Daina. So I’m going to tie it together. So I think the key point, I’m going to define what’s better PK and what’s better PD. So PD, as you know, encompasses everything, tissue penetration, potency differences, pharmacokinetic differences. So the PD readout what we’re saying, and we think this is the value proposition, no question, is that at 20 milligrams of AB521, you’re getting the same horsepower. And let’s use EPO as the marker that you get out of the approved and used dose of belzutifan. Now the PK advantage has nothing to do with an AUC relative to belzutifan. The PK advantage is that when we go to fivefold higher doses than the dose that gives you that equivalent activity on the PD marker, we get fivefold higher exposures.
So if there’s more water to be squeezed out of the activity stone, we’re hitting that with fivefold the equivalent PD dose of belzutifan. So that – that’s the value proposition. The PK advantage is that you can go higher from that maximal effect with respect to hemoglobin or EPO, we don’t look at either of those, per se, as something that’s predictive of, more or less predictive of the activity in the tumor setting.
Daina Graybosch: Can I state it back? So you’re hitting it fivefold more dose than what gets you to the pharmacodynamic marker. And you believe that will give you a much better efficacy, even though neither of these pharmacodynamic markers with fivefold greater dose really had that much more effect than Belzutifan?
Terry Rosen: That is correct. But not only is it correct, that’s what’s predicted, and that’s what – that’s the difference between the physiological maximal HIF-2a – as you know, as you know, HIF-2 is a transcription factor, so it regulates a hundred things. Its effect on EPO has nothing to do with what’s going on in the tumor. So we know going in that basically you’re going to max out HIF-2 in the – or EPO inhibition. And so that just becomes a marker for how hard are you hitting this thing? And then the fact that we can go 5x, what you can get out of the Merck molecule is what makes us feel good about hitting the tumor harder.
Daina Graybosch: That’s very helpful. Thank you.
Terry Rosen: Thanks, Daina.
Operator: We now turn to Li Watsek with Cantor Fitzgerald. Your line is open. Please go ahead.
Unidentified Participant: Hi there. This is [Rosemary] [ph] on for Li. Thank you so much for taking our questions. So, to start with, casdatifan, do you happen to see any dose response when it comes to toxicity, the safety profile? And do you have concerns for greater side effects when you go above 100 milligrams? And then one question on your TIGIT programs. Sorry, go ahead.
Terry Rosen: No, go ahead. You finish your questions.
Unidentified Participant: [Technical difficulty] so the question for TIGIT. So you said you plan to show some data from the ARC-10 trial, which was discontinued. So you have any color on when this could be and what kind of data we would expect, and would it potentially impact any thinking around the trials that you still have going on? Thank you.
Terry Rosen: Thanks. So the dose response, to be clear, the 20 milligram dose that we used is our lowest dose, is already pharmacologically relevant. As we noted, you’re seeing essentially a maximal effect on EPO suppression at that point. So I would just say, with three patients on each of the doses, with 6 on the 50, we wouldn’t say that we see any meaningful differences, nor do we expect that. And similarly, because of what we know, and this just gets back to how I was answering Daina’s question, there’s either feedback mechanisms or other non-HIF-2 mediated ways that EPO is produced. And so you hit this maximal effect on that endpoint, which to-date has been the primary side effect and is very manageable. So that is the anemia.
That’s a correlate of that EPO suppression. And basically, that’s been very manageable. So at this point, we don’t have any expectations that going higher will induce any more of a liability, and we certainly haven’t seen it hit the 100 milligram dose. The other place where we’re keeping a close eye is, in fact, on hypoxia. That has to do with HIF-2 inhibition in the lung. Again, that may also be something that’s maxed out. It’s normal physiology. It’s something that we’re paying attention to. Some of these things may also be dependent on individual patients, particularly when you think about EPO, if there are patients that have compromised kidney function. But to-date, we haven’t seen anything of concern, and we’ll just see what happens when we go to a higher dose.
And certainly on those initial 30 patients, nothing that we’ve seen to-date has caused us concern. And to make the point, we have not yet seen a DLT. On the anti-TIGIT ARC-10 data, that’s just something we’re considering. We haven’t made a decision on that. But if we did do that, the idea would be that we would do a cut of the data and a cleaning of the data when we would extrapolate that, we would have mature PFS minimally. And at this point, with the data that we have in hand from our other studies, it wouldn’t affect any of the studies that were – it would not be decision-making data. Thanks for the questions.
Unidentified Participant: Thanks, Terry.
Operator: Ladies and gentlemen, this concludes our Q&A and today’s conference call. We’d like to thank you for your participation. You may now disconnect your lines.
