And, in fact, when we first saw the very earliest data, even when only 15 patients or so had been scanned, the data were looking interesting. And to your point, it’s actually, even though it’s 50 milligram, that’s 2.5 the PD equivalent of the Merck belzutifan clinical dose. The 150 milligram cohort is just starting, as you noted. So, 50 came after 100.
Jonathan Miller: Okay, makes sense. Last quarter and this were both, you highlighted that ORR at the 100 milligram dose, I assume, is already similar to belzutifan, and the implication there being that given belzutifan’s time to response, that ORR could in fact deepen as you get more scans under your belt. So, in the intervening three months, have you seen ORR increase? I mean, I noticed that in both this quarter and last quarter using similar language, saying that you’re hitting similar ORR levels to belzutifan. But now we’ve gotten presumably more scans on these patients. Do you see those late responses or I suppose I should say later responses more akin to belzutifan’s time to response?
Terry Rosen: Yeah. So if we were using the same language, it was because we were reiterating what we said at the end of the – when we gave the last update as opposed to like, it’s a fresh description. So all we would comment is the data continue to look good along the trajectory of what we were seeing then. And we have no plans to give updates until the medical conference. And then you’ll see the full picture.
Jonathan Miller: All right, fair enough –
Jennifer Jarrett: And I think that you’re correct that – I’m sorry, here you’re right this is a mechanism where the response kinetics are on the slower side and the average time to response was about four months in the LITESPARK study. So, similarly some of our responses may take more time.
Jonathan Miller: Okay, makes sense. And then lastly, just as we think about the two different TKIs that you’re exploring combinations here, can you give us a little bit of color about what you’re looking for to pick between them? You’ve highlighted the importance of safety versus Lenvima as a driver here. So are there clear no-go signals that would push you one way versus the other? Or is it something else that you’re really looking at?
Terry Rosen: Yeah, so I would say it’s more strategic in timing. And we’re thinking about different settings. And I think what you’re going to see, and this is primarily for competitive reasons, not playing any games. As this year goes along, we’ll be very transparent about our development strategy. Some of this, it’s not even that we’re in the decision-making process, we know, but we want to let time play out a little as we get closer to those studies coming online. And you’ll see there’s different lines of therapies, there’s other combinations we’re thinking about. In addition, you can imagine even that we might go in both directions in different settings. So we’ll describe that as the year goes along.
Jonathan Miller: Right. Thanks very much, guys.
Terry Rosen: Thanks, Jonathan.
Operator: Our next question comes from Jason Zemansky with Bank of America. Please go ahead.
Jason Zemansky: Thank you. Good afternoon. Congratulations on the progress. Really appreciate you taking our question. Maybe just to take a step back on the adenosine pathway, just starting development efforts, it looked like the pathway was upregulated across a number of tumor types. And while there are certainly very encouraging signals in colorectal and pancreatic cancer, there have been some admitted setbacks as well, both in cold tumors like prostate and seemingly at this point NSCLC as well. I’m curious, have you cracked the code at this point in terms of which tumors are likely to respond, especially as your datasets emerge and mature. Are there additional signals that give you confidence in the mechanism at this point, especially as you start to look longer-term that maybe some additional indications?
Terry Rosen: Yeah. Thanks, Jason. So, I think what we’re probably looking at right now, when we think about sweet spot, from what we’ve learned, and this was a big part of what we thought going in, is less the organ and more the biology and therefore, the treatment. And what I mean by that is, if you look at the three studies that we’re pointing to right now, MORPHEUS-PDAC, our own pancreatic study, and the colorectal study, they’re both situations that were going right on top of immunogenic chemotherapy. And that going into this, that was sort of down the middle of the fairway for us, where you have a setting where the killing cells, it’s in this immunogenic way with chemotherapy. And what’s extraordinarily well understood about those settings is that, if that ATP spills out from those initial cells dying, you produce a ton of adenosine.
And so, if you’re able to mount any sort of immune response, those T-cells are hit by adenosine. And that’s physics, that adenosine, there’s a million papers that are going to tell you if a T-cell sees adenosine, it’s going to sleep. And so the phenotype of the response that we’re seeing in each of these studies is very similar. So the places that we are thinking about beyond the current settings would be just those something where the standard-of-care is an immunogenic chemotherapy, but there’s headway above that to actually get the benefit of when you think about that immune response that might be induced by chemo, that you can enhance that by mitigating the effects of the adenosine that forms. So that’s the way we’re thinking what’s the most we’ve learned to-date and there may be more you learn with time, but that’s the primary learning to-date.
Go ahead, Juan.
Juan Jaen: Sorry. I think a fair element would be tumors that tend to be very high in CD73 expression. So that pretty much takes you to GI tract and long adenocarcinomas as places where you have the convergence between a high level CD73 immunogenic chemotherapy.
Jason Zemansky: Got it. Perfect. Thanks for the color.
Terry Rosen: Thanks for the question.
Operator: Our next question comes from Daina Graybosch of Leerink Partners. Your line is open.
Jeff La Rosa: Hi, this is Jeff on for Daina. Thanks for taking our questions. So we have one on cas and one on the etruma. So I guess starting with cas, we noticed Novartis has an oral ASCO for their HIF-2 inhibitor. How is cas differentiate from that molecule? And in that context, what are your expectations for that ASCO presentation? And do you think Novartis’ decision to discontinue its further development? Has any read through to cas and your program?
Terry Rosen: I want to comment what we know about the Novartis molecule, and I’ll start off zero read through, but I’ll let Juan comment on the Novartis molecule or whatever –
Juan Jaen: Yeah, in vitro evaluation of the compound suggests that it’s a reasonably potent HIF-2alpha inhibitor in our hands, maybe an order of magnitude weaker than cas is. As you know, there’s much more that goes into making a high quality drug what it does in terms of pharmacokinetics, drug-drug interaction, PK/PD, we’ll have to see. But definitely going in, it was sort of not a great contender, purely from a potency standpoint.
Jeff La Rosa: Okay, great. And then on etruma, how is the recent Roche PDAC data and the upcoming ARC-9 data change your view at all on etruma’s potential therapeutic opportunity relative to quemli? And put in other ways, do you see any clinical settings or you’d expect a treatment to outperform quemli? And do you anticipate initiating any additional randomized Phase 2 or Phase 3 trials for treatment this year? Thank you.
Terry Rosen: So on the first question, while some people have speculated otherwise, we look at both molecules as we sit here today, as great molecules and great potential. And to be honest, if things continue along the way, we said this from the beginning, once we start to get good data, and the more good data they come, the more this is something one will contemplate. You might even think about combining the two at some point, because there are certain situations where you may be able to generate adenosine through a mechanism that’s not CD73-mediated, in which case blocking its action could be advantageous. So what we’re going to say is, as of today, we’ve just seen, and you’ll see the data for yourself so you can decide.
We think we got very compelling data with both molecules. And going to your question about Novartis. I’m just going to use it as an opportunity, we’ve lived under an umbrella of some early studies done that, frankly, with very bad molecules. And we always talk about it’s a molecule quality, it’s the combination and it’s the setting that makes the difference. And so we think, going forward, there’s still a whole lot more to be learned with these, despite the fact that each of them could be on a trajectory. In fact you know we’re starting the pancreatic trial as late as early next year and as early as late this year. And we do expect to do more with etruma. The only reason we are sharing specific details of what the plan will be.
And obviously, after you see the details of our data, there will probably be more questions about exactly what we’re going to do in the future. But we’re still working through those details together with Gilead, we’re preparing for discussions that we’ll be having with the FDA. We want to think about exactly what would be the ideal control. That control and standard-of-care has evolved. When we started, it was regorafenib. Now it’s moved much more to in the direction of lonsurf + bev. So there’s a number of things that we want to work through, but you can definitely expect, and when you see the data, you will expect that we’d be crazy to not be doing something more with the molecule. So we’re working through that.
