... Welcome back, everyone. This is the final session of the second day of the Biopharma Back to School Summit. So hopefully everyone has sharpened pencils and is taking good notes. So I'm Yigal Nochomovitz, a biotech analyst here at Citi. The next company is ORIC Pharmaceuticals. I've been covering them for many years, following the progress. And pleased to introduce Jacob Chacko, the CEO of the company, and of course, Dominic Piscitelli, the CFO. So welcome, Jacob and Dom. Thank you both for participating.
Thanks for having us, Yigal.
Appreciate it. So I guess maybe to start out, if you wouldn't mind, just you know, giving just an overview of the you know, the pipeline and what are some of the key objectives of the company, and you know, you recently bolstered the balance sheet, as I understand, so you got a little more runway, so tell us about just what are the key readouts, which we'll of course get into in a lot more detail.
Sure. I'm happy to jump in here, Yigal, and I'll keep it short 'cause I know you have a lot of detailed questions on the pipeline.
Okay.
So ORIC is a clinical stage oncology company. ORIC stands for Overcoming Resistance in Cancer. In a nutshell, that's the mission of the company. We obviously, cancer is a very, very large area, so within oncology, we tend to specialize primarily in small molecule drug development in solid tumors, specifically prostate cancer and lung cancer. So we have two clinical stage programs that are in dose optimization right now, getting prepped for the start of phase 3 studies that would initiate potentially next year. And one of those is ORIC-944, which is a PRC2 inhibitor that's being studied in combination with two different AR inhibitors, apalutamide from Janssen and darolutamide from Bayer. And we can talk about the mechanism of action there and why we're so excited about that.
But essentially, that's a target that has been de-risked by competitor data that shows that when you combine a PRC2 inhibitor in combo with an AR inhibitor, you get dramatically longer durability, longer PFS outcomes than with an AR inhibitor alone. So as I mentioned, that's in dose optimization right now with two different combo agents on the AR inhibitor side, and we plan to initiate the first phase 3 study first half of next year. That is joined in the pipeline by ORIC-114, which is a brain-penetrant small molecule for lung cancer, specifically for three different targeted therapy populations of interest: EGFR exon 20, EGFR atypical mutations, and HER2 exon 20. As folks will know, all three of those are patient populations that have had a dearth of options, in fact, no options, of drugs that are brain penetrant.
The reason why that brain penetrance is so critical, of course, is because so many patients with non-small cell lung cancer, particularly with these mutations, end up developing brain metastases. And so that is also in dose optimization in cohorts across all three of those populations, again, with the goal to initiate the first phase 3 study next year. Company is super well-funded. We've done quite a bit of capital raising this year to shore up the balance sheet. We'll talk about the specifics of that, but long story short, we're in the second half of 2028, which gives us cash runway, importantly, past the phase 3 primary data readouts for both programs. And in fact, it's over a year past the phase 3 primary data readout from ORIC-944, the prostate cancer program.
Quite a good position, in terms of where we are, from a stage of development perspective and appropriate funding for that.
All right. So maybe... That's great. So maybe just a brief, a word about, you know, what's the current standard of care in the setting that you plan to pursue, the phase 3 programs in prostate cancer, and a bit about, you know, the market opportunity there, where you could improve.
Yeah. So within prostate cancer, I mentioned that the target of interest here for ORIC-944 is called PRC2. That's an epigenetic modifier. As people have been following the development of therapeutics within the prostate space, you'll be aware that the AR inhibitors, the androgen receptor inhibitors, of which there are three: enzalutamide from Pfizer, apalutamide from Janssen, and darolutamide from Bayer. Those three drugs have transformed the treatment of prostate cancer, and that even that statement is an understatement, if you look at just what they've done for patients. So those are all small molecules. They're pills that patients take, and they've treated tens of thousands of patients around the world, giving them phenomenal outcomes across the whole gamut of the prostate cancer landscape.
But those drugs, like most drugs, if not all drugs within oncology drug development, eventually patients end up progressing, even as good as those drugs are. And so what has really eluded the field within prostate cancer is what comes next. So as good as those androgen receptor inhibitors are, as good as abiraterone is, and collectively, those four drugs, those three AR inhibitors and abiraterone, are what are called ARPIs, androgen receptor pathway inhibitors. Those four drugs collectively do great for patients, but eventually, the patients progress, and at that point, when you talk to clinicians, when you talk to patients, the only real viable option today is chemotherapy. Of course, where we and where several companies are trying to develop therapeutics is really to come after those AR inhibitors and resensitize patients.
The promise of a PRC2 inhibitor is that what it seems to be doing as an epigenetic modifier is that when a PRC2 inhibitor is dosed in these patients, mechanistically, it looks like the tumors, rather than mutating, evolving, and essentially becoming androgen receptor independent, the PRC2 inhibitor on board is able to rewire the machinery such that the tumor continues to stay AR dependent, and therefore an AR inhibitor can continue to work. And so I referenced competitor data, clinical data that's already de-risked this mechanism.
Of course, as folks who have been following the story know, Pfizer has presented a lot of data, both phase I as well as randomized phase II data, that shows that the combination of their PRC2 inhibitor along with their AR inhibitor, enzalutamide, gets dramatically longer durability PFS outcomes than you'd otherwise expect, so in two different settings where the drug was tested within metastatic CRPC, essentially with their PRC2 inhibitor along with their AR inhibitor, they're able to get roughly three times the PFS that you would otherwise expect with an AR inhibitor alone, they then ran a randomized phase II study that replicated that magnitude of results.
So essentially, in a post abiraterone-treated population within metastatic CRPC, the control arm was given enzalutamide, and that control arm of roughly 40 patients achieved a median PFS of exactly as you'd expect, of approximately 6 months. Whereas the treatment arm, which was given enzalutamide plus Pfizer's PRC2 inhibitor, was able to achieve a median PFS of 14.3 months. So more than doubling of the PFS in that setting, and then all the other ancillary measures that you would look at as well. So things like PSA fifties, PSA nineties, RECIST responses, everything was more than double in the treatment arm as compared to the control arm. So clearly, de-risking of the mechanism, it's been the real first proof of concept, at least in the clinic, of that mechanism of action.
Of course, for people that have followed the story for a while, you know that there are several PRC2 inhibitors that have been developed in the past and studied in that same population, and not been able to show that same type of profound therapeutic benefit. The main reason being that all of those drugs suffered from various degrees of really horrendous drug properties. And so if you look back at the field of failed PRC2 inhibitors within prostate cancer, what you will see is some common threads, which is short half-life. And when I say short, I mean very short. We're talking about a one or two-hour half-life for a lot of those drugs. And as if that wasn't bad enough, several of those drugs were plagued by things like CYP autoinduction.
And so they would, those drugs would rev up the CYP enzymes, and they, those drugs were also metabolized by the CYP enzyme. So essentially, they would rev up the very same enzymes that are metabolizing the drug, and in several of those cases, you would get things like dose-dependent decreases in exposure, which, again, is the opposite of what you wanna do. You know, so the more drug you give, the less exposure you are getting, and some of the drugs were so bad, they were given, you know, three times a day and in combo with a CYP modifier, just to try to get to the right exposures.
Now, it seems like Pfizer has solved quite a few of those issues because their drug appears to have about a four- or five-hour half-life, which obviously isn't amazing, but it's certainly far better than one- to two-hour half-life. They haven't said, but it doesn't look like the drug has CYP autoinduction if you look at the PK data that's been shared. And so it looks like they have been able to achieve exposures, and clearly from the clinical data it seems to be implied that they're getting good exposures and an ability to actually test this mechanism in the clinic the proper way, and why it's why you're seeing those results. Now, in the case of ORIC-944, this is a drug that we acquired from Mirati back in 2020. The Mirati chemists did a phenomenal job.
They looked at this field of PRC2 inhibitors and the poor drug properties, and essentially sought to optimize on the drug properties and come up with a drug that had no CYP autoinduction and had a better half-life, good bioavailability, all the things you look for in with good drug properties, and they seem to have been able to do that. So with ORIC-944, we have a 20-hour clinical half-life. The drug is therefore dosed daily in contrast to, you know, several of these other drugs, Pfizer included, that are dosed, you know, BID. And like I mentioned, some of them were even dosed TID. The importance of that is not just, by the way, convenience of daily dosing versus two times or three times a day dosing.
The real issue is from a pharmaceutical property perspective, a PK/PD perspective, what you're essentially trying to achieve here with an epigenetic modifier is you wanna cover Cmin for 24 hours of the day, so that you know you've got target coverage, but the toxicity is gonna come from hitting Cmax. And so when you have a drug that's got a very short half-life, where you're trying to brute force exposure by giving big boluses of the drug two times a day, you essentially run into issues by hitting Cmax and therefore seeing toxicity. And that's obviously that risk is mitigated with the profile we have with ORIC-944, because you've got a 20-hour clinical half-life, the drug being dosed one time per day.
It just enables you to cover Cmin, you know, in a more effective way, without sort of tempting that Cmax in the same way that a shorter half-life drug would do, and so that's sort of the theory of the case, and that's what we're testing right now, and I'm sure we'll get into some of the early clinical data that we've shared earlier this year.
So, no, that was great. So you mentioned a lot of important points. So if you have better tolerability, as you're pointing out, that could potentially lead to, you know, better ability to stay on the therapy and therefore better PFS. I mean, are you making the argument that that's part of the value proposition, or that would be above and beyond what's necessary to be competitive in the marketplace?
Yeah, that's absolutely part of the value proposition. You started your questions by asking just around the state of play within prostate cancer drug development, and what I would suggest is that if you look at the course of those AR inhibitors and the drug development of those three big AR inhibitors that I mentioned to you, enzalutamide, apalutamide, and darolutamide are almost indistinguishable on efficacy. If you look at any setting in which those three drugs have been studied, the efficacy looks the exact same. From a toxicity point of view, all three are well-tolerated drugs. Apalutamide is perhaps slightly better tolerated than enzalutamide, and darolutamide is perhaps better tolerated than all the other two drugs. But it's really minor differences in the profiles of those three drugs.
And the reason I sort of set the stage with that, Yigal, is this is such a large patient population, that even with those three drugs having fairly indistinguishable profiles on the toxicity front and completely indistinguishable profiles on the efficacy front, all three of those drugs are blockbusters many times over, even though apalutamide was second to market by six years, and darolutamide was third to market, you know, in an additional year after that. The point being that with as large as the population as this is, with as large of an unmet need as this is, a second player or a third player with a totally undifferentiated profile can have, it can be quite meaningful to patients clinically, and obviously, you know, the commercial success that comes with that.
The reason I lay that groundwork is, if the base case here is that we are just the second player to market with a PRC2 inhibitor that can be combined with an AR inhibitor, and if we do it with a profile that ultimately is completely undifferentiated from the first mover, Pfizer, this would obviously still be hugely valuable to patients and a commercial success. That's not, that's not the base case for what we think the TPP is gonna end up being, for the reasons I mentioned to you earlier, that with the better drug properties of the compound, who knows whether that'll translate into longer, efficacy outcomes like, PFS, and ultimately OS?
But at a base case, if all we can do is have a better-tolerated profile, which for all the reasons I just outlined earlier, we ought to end up with a better-tolerated profile, that would be a huge home run for this drug in terms of the overall profile within the broader competitive landscape. Now, there's two big forms of tox, just from a class perspective, that you'd expect with the PRC2 inhibitor, so you should expect to see GI tox in the form of diarrhea, nausea, vomiting, and then heme tox, various penias. And you can just look at the tazemetostat label. Tazemetostat's a PRC2 inhibitor, and you can get a good sense of seeing those two major types of toxicities. Certainly, Pfizer sees those toxicities. Certainly, we see those toxicities.
I would argue that we, even in our early clinical data, show a lower incidence of those toxicities, both in terms of number and overall incidence rate and severity of those toxicities as compared to what Pfizer has shown, and I do think that that is the drug properties in effect.
Okay, and then there's another aspect too, which I wanted to ask about. Again, sort of delving into the biochem a little bit, you know, in the past, you've referenced not only PRC2, but the domains, the EED and the EZH2. Aren't there some differences there as well with respect to mevro and your compound that are worth highlighting?
Sure. I figured we only had forty minutes for today's fireside-
Oh, forget the question.
... so I was gonna, I can certainly-
Thank you
... highlight those and give a quick biology lesson. So PRC2, I mentioned, is an epigenetic modifier. It has three different subunits to it. For companies that have attempted to develop drug candidates targeting the PRC2 complex, they have focused on two of those subunits, either EED, which is how you achieve allosteric inhibition of the PRC2 complex. That's what we're doing. That's what Novartis had done in the past with a compound called MAK683. And then there's the catalytic subunit, which is called EZH2, and that's where Pfizer has been focused and some of the other competitors have been focused. There's no real... Short answer, Yigal, is there's no real difference in targeting one of those subunits or the other, at least in terms of initial ability to inhibit the PRC2 complex.
So in other words, if you have two drugs, both have exactly the same drug properties, exactly the same potency, one is an EZH2 inhibitor, one's an EED inhibitor, they should be equally good at that initial inhibition of the PRC2 complex. Where you would expect to see a difference biologically is potentially that things like long-term resistance from things like bypass resistance from EZH1 or acquired mutations to EZH2, those are mechanisms of resistance that would be relevant to an EZH2 inhibitor. In other words, diminish the long-term efficacy of an EZH2 inhibitor and would not be relevant to an EED inhibitor. So if anything, there ought to be an advantage to drugging EED rather than EZH2 from that perspective.
Okay, well, let's get into some of the important clinical data then. So you had a pretty significant update. I believe it was the end of May of this, just a few months ago.
Yep.
So maybe just kind of recap what the key learnings were out of that in terms of both what you saw on the key metrics, PSA fifty, PSA ninety, which obviously have important implications for translation to PFS, and then into the future into OS, as well as you know, where you see dose, and of course, as you pointed out at the beginning, the combos with APA and Dara and how and how that you know, those doses will intersect with your chosen dose or your planned dose for ORIC-944.
... Yeah. So at the end of May, we shared that update that you mentioned. It was an early dose exploration update, which, you know, what I glossed over at the beginning is we already had a substantial experience with ORIC-944 being dosed as a single agent, which is where we started to just establish the single agent properties of nine four four to understand what the half-life looked like, what the safety profile looked like, understand where, from a PK and PD perspective, we ought to see efficacy once the drug was dosed in combination. And so we basically got to start out of the gates in the combination dosing at therapeutic levels of the drug.
We tested, as part of that May update, we presented data that we had tested in patients at various dosing cohorts, which included 400 milligrams, 600 milligrams, and 800 milligrams of ORIC-944, tested in combination with the labeled doses of darolutamide and separately with apalutamide. We essentially looked for, you know, early on, we wanted to understand what the combination profiles were of ORIC-944 with darolutamide and separately of ORIC-944 with apalutamide. The short answer is that those profiles were nearly indistinguishable as you looked at things like PSA50s and PSA90s. As you highlighted earlier, in prostate cancer drug development, you look at a hierarchy of clinical endpoints. Obviously, the long-term endpoint you need to see is OS and radiographic PFS.
You know, Pfizer's obviously more advanced than us with their program, so they've already been able to get those glimpses of radiographic PFS that I quoted earlier. But before that, it's kind of tried and true in prostate cancer drug development. You look at things like PSA activity, so PSA 50s, the ability to reduce a patient's PSA levels by 50%, and then also PSA 90s, the ability to reduce those levels by 90%, as early surrogate markers of what ought to translate into long-term durability measures. The other thing that people have started to look at, we, of course, we're looking at as well, although it was not part of the May update, is looking at things like ctDNA as another measure of an endpoint that ought to translate to long-term durability.
You know, those are things that we looked at, and we commented specifically around PSA fifties and PSA nineties as part of that May update on the efficacy side. Of course, you also want to look at safety. The name of the game here is gonna be, as you alluded to earlier, drugs that are well-tolerated in combination with the AR inhibitors, because that's how you ultimately are gonna get long-term PFS in these patients. It's not just the efficacy, but also a drug regimen that can be well-tolerated by these patients. Ultimately, beyond CRPC, which itself is a massive commercial market with high unmet need, you're also...
Anyone developing a drug in this space in combination with an AR inhibitor is obviously gonna want to look at CSPC as well, castration-sensitive prostate cancer, and that's a population in which this tolerability profile is gonna be even more important, just because the tolerance for a drug that's poorly tolerated there is low. And so you're gonna really want to optimize around the toxicity profile of a regimen. And so we reported on all those measures as part of the May update. And the short answer is, even though it was a small N, in the sense it was seventeen patients, it still was able to replicate a very preliminary update with just six patients that we had presented earlier this year in January.
Namely, what you saw there was, in contrast to Pfizer's rate of confirmed PSA fifties of 34% in their randomized data set that they presented, our rate of confirmed PSA fifties was 47%. In contrast to their confirmed PSA nineties of 12%, our rate of confirmed PSA nineties was 24%. So already out of the gate, you're seeing an improvement in both the PSA fifties and PSA nineties, albeit small N, but I would argue a substantial enough N that you can start to gain some level of confidence on what the emerging profile of the drug is, at least with respect to things like PSA fifty and PSA ninety. It's comforting to see that there's some daylight where we're north of Pfizer's numbers on both of those metrics.
I think even more important than that, as I alluded to earlier, is if the ultimate end profile of this drug, when all is said and done, is a PFS and an OS that are indistinguishable from the competitor, but the toxicity profile is better, that will be a home-run scenario unto itself. And, and so that's where I took real comfort in looking at the toxicity profile that we were able to present, which, as I alluded to earlier, we did see the expected on-target tox of heme tox and GI tox, just like Pfizer did. But again, we saw, lower incidence and lower severity of all those kinds of toxicities. And then, in addition, Pfizer had a 40% rate of alopecia in their data set.
To our knowledge, that's not an expected on-target toxicity of a PRC2 inhibitor, and we do not see any alopecia, and so, from an overall toxicity profile, the drug looked about as good as you could hope for at that early stage, even though it was dose exploration, where we were clearly testing, you know, not only therapeutic doses, but we were doing dose finding. So we pushed the dose to try to find where we would see the level of toxicities.
I would argue that as we move forward in dose optimization and are honing in on the ultimate phase 3 dose and regimen that'll be used, if anything, that toxicity profile ought to even get incrementally cleaner than what you saw as part of the May update. Now, one thing that's worth noting, which is relevant here, because I mentioned that the three drugs are nearly indistinguishable on all these different metrics, the three AR inhibitors are nearly indistinguishable on all these different metrics. One area in which they are distinguishable is the fact that apalutamide and enzalutamide are both well known to be CYP inducers.
What that means is that because so many drugs are metabolized by the CYP enzymes, and this would be true of Pfizer's PRC2 inhibitor, as well as our ORIC-944, both are metabolized by the CYP enzymes. So therefore, when you combine with either enzalutamide or apalutamide, you do expect to see a DDI, where apalutamide and enzalutamide push down the exposure of the combination drug that's being dosed with them. In other words, clearly Pfizer has to, and we would also have to, push to, for a higher dose of the PRC2 inhibitor than would otherwise be the case, to kind of back solve for the right exposures, just given the impact of apalutamide and enzalutamide as CYP inducers.
Darolutamide is well characterized as not being a CYP inducer, so you would not expect to see the same DDI with darolutamide. So the implication of what I just mentioned, just from a PK perspective is simple, which is that the final dose that we end up selecting of ORIC-944 that would go along with apalutamide, would almost certainly be higher than the final dose of ORIC-944 that we would dose with darolutamide, and that's just because of this DDI.
You said four hundred, six hundred, eight hundred, and there was also some discussion of an even higher dose, if I'm not mistaken. Twelve hundred? Is that still on the cards or that's-
Still on the... Yeah, the-
Okay.
Yeah, so that's still on the cards, and so, you know, what people will remember back from that May update was essentially, I think the way to think about it, just conceptually, is, we got experience in dosing ORIC-944 at either 600 mg or 800 mg with each of apalutamide and darolutamide. And then, again, because of this expected DDI with apalutamide, for that matter, the same thing would be true of enza, is, that we always intended to then go higher in the dose exploration in the combo with apalutamide and to go lower in the dose exploration with darolutamide.
Okay.
Conceptually, the way is, the way to think about it is that the 600 mg dose and the 800 mg dose of ORIC-944 will have experience with both apalutamide and with darolutamide. From there, the 400 mg dose of ORIC-944 will have experience with only darolutamide, and the 1200 mg dose of ORIC-944 will only have experience with apalutamide.
Okay. And when, what, how much more work needs to happen, and how many more patients before you settle on a regimen then for the Phase 3 to sort out this, to sort this out?
Yeah, not a whole lot more, is the short answer.
Okay.
We do have an update that's coming in the second half of this year, and that'll address your question very clearly in that update.
Yeah.
So, as part of that, our next ORIC-944 update, you know, essentially, the point of that update is to lay out the rationale as to why we chose the provisional recommended phase 2 doses that we chose for each of the combos, for apalutamide combo and for the darolutamide combo, to satisfy the Project Optimus requirements. And so I would think of that update as, you know, probably fairly incremental in nature to the May update, just because I think we have so clearly telegraphed, you know, where we're heading in terms of dose selection for the two combos. But as part of that update, we'll give you the specificity as to exactly what doses did we select for ORIC-944 in combo with apalutamide, and separately, what doses did we select for ORIC-944 in combo with darolutamide.
As part of making that case, we'll obviously add any new patients that we enrolled since the May update as part of that dose exploration, which, as we've said before, would be less than a handful of patients, just given how far we already got in dose exploration as part of the prior update. More importantly, as we lay out those rationale that include efficacy measures like PSA fifties and PSA nineties, again, you've seen most of those already, but it will also include, very likely, ctDNA, which is, as I mentioned, another metric that people look at in terms of trying to triangulate to what might ultimately lead to long-term durability outcomes. We'll also potentially share, you know, PK or PD data and, of course, safety data.
And that'll lay out the rationale for the Project Optimus doses that we ended up optimizing against, and really, more than anything, set the stage for the update, the data update in Q1 of next year, which is really where you'll see new data. And that's really all about laying out the you know provisional recommended phase 2 doses and which one are we gonna select as the phase 3 dose, because the plan for this is for the first phase 3 study to start first half next year.
Okay, and then you're as you pointed out at the beginning, you're gonna do both of these combos essentially in parallel in two phase 3 trials, the apalutamide and the darolutamide, or are they staggered, or how's it gonna work?
Yeah, so that's one thing that's worth clarifying, which is we're certainly doing, we certainly did dose exploration, and we certainly are and will be doing dose optimization of both AR inhibitor partners in parallel with one another. We will not be taking both of them forward into the first phase 3 study, only because we are a small biotech company, can't afford to do two mirrored phase 3 studies with, like I said, indistinguishable AR inhibitors. So, so the long story short, Yigal, is when we start that phase 3 study first half of next year, we will have selected one of those AR inhibitor combo partners to be our combo partner of choice for that first phase 3 study. And we'll only be running one of them in that first phase 3 study.
Doesn't mean we can't run a different one in a different phase 3 study, but we'll pick one of them, and rather, there's just no point in doing two parallel phase 3 studies with each of those drugs.
What are the considerations in terms of which one you would go with first?
Yeah, so that, that's probably the most common question we get, is which, which drug would we pick, for the phase 3 study? I think I, I'm not being coy when I say, it, it really is sort of, indistinguishable on the profiles of the two compounds, and there's not a reason why we would preference one over the other. So as you look at the data we've already generated, again, aside from the DDI that is expected with apalutamide and is not expected with darolutamide, related to the CYP induction of the AR inhibitor, that the AR inhibitor causes, at least apalutamide and enza cause. Aside from that one characteristic, there's no other difference in the efficacy or the toxicity profiles of those drugs, at least no meaningful differences.
And so it comes down to, you know, other considerations ultimately, which will be, you know, as we think about long-term development partners and who can help us not only with this first phase III study, but other phase III studies. You know, there's a lot of other considerations that would come into play that I would characterize more as strategic in nature than having to do with the drugs themselves. Now, look, you can make an argument as to why apalutamide might be the better combo drug. You can make just the same number of arguments as to why darolutamide might be the better combo drug.
Now, apalutamide does have the DDI that I mentioned, so all things equal, you'd rather not have a DDI when you dose your drug with another drug, 'cause it means you don't have to do as much dose finding and dosing up to kind of back into the right exposures. But on the other hand, darolutamide is dosed two times per day and with food, and apalutamide is only dosed one time per day, and it doesn't matter if it's with or without food. And with 944, it's dosed one time per day, and it doesn't matter if it's with or without food. So there's reasons why you could say it ought to you know, the combo partner ought to be apal. There's other reasons why it ought to be daro.
What I love about that setup is it's actually not clear to anyone, ourselves included, that one of those drugs is clearly the better partner for us than the other, which means we have two excellent, you know, amazing AR inhibitor combo agents we could think about, and two excellent partners in Bayer and Janssen that we could think about moving forward with.
At the current moment, the arrangement with Janssen and Bayer is, what is the nature of that? That it's just, it's a supply agreement or?
It's a supply agreement. So we get free drug from provided by both companies, so that we can do our dose exploration, our dose optimization, and that's it. So there's no strings attached, there's no economics exchange, no rights exchanged. It's nothing more than a free drug agreement.
Right. And I'm assuming the fact that you would use less less drug with daro is not a major consideration just from the perspective of COGS, given that's sort of the tenth decimal point.
Yeah. I mean, it's always better to have lower COGS-
Right
... but when COGS are as low as they are, yeah, that's not a, that's not a major consideration. Yeah.
Okay. All right. Well, let's. We've spent a lot of time on prostate cancer. Okay, let's shift over then to one-one-one-four, which has a name now, enosartanib, if I'm saying that right.
You said that exactly right.
Okay.
At least the way that half our team says it.
How the other half says it?
I, I don't wanna say it, 'cause I don't agree with the way the other half says it.
Okay. So you mentioned a few things there in terms of the EGFR exon twenty, the atypical cluster, and then the HER2 exon twenty. So maybe you can just walk us through what you've shown in each of those settings so far. It is quite a competitive space, as you know, so what is your strategy there to, you know, to differentiate?
Yeah, I'll take that one, Yigal.
Sure.
So yeah, we don't disagree with you. It is somewhat of a crowded space, but at the same time, we think there's significant room for potential differentiation here. You look at some of the molecules, some of the data that we've seen to date, we still see, you know, some good response numbers on an ORR basis. But at the same time, you see a lot of both on- and off-target toxicities. The two things that we really like about ORIC-114 is two: one is our safety profile. So based on the data that we've shown previously at ESMO, we saw very little on-target toxicity and actually minimal off-target toxicity, and I think that's attributed to the clean kinome profile that we have when we kind of profile it versus the competitors.
And then, probably more importantly, as Jacob kind of alluded to in the preamble, was the CNS activity. You know, a third of these patients do present with baseline brain mets, and it is often the point of first progression. So having a CNS active agent here is potentially differentiation here that should translate into better efficacy and longer duration as well. So those are the two things that we've seen, both preclinically and in our early data set, that keeps us excited about this. And we've got a number of data readouts, both in the second half of this year, going into mid-2026 as well. So in the second half of this year, we'll be reading out three patient populations in the second line or later setting.
This is second line, EGFR exon 20, second line or later, HER2 exon 20, and then second line or later, atypical EGFR as well. So we're expecting to show here is about 25 patients in each of these cohorts across the two provisional RP2Ds. As you remember, to satisfy Project Optimus, we brought forward 80 and 120 once a day for all three of those cohorts. In addition to that, we'll give you guys an early look on first-line EGFR exon 20. In the first-line setting here, we'll have about 15 patients worth of data that we'll share. Then jumping to the data that we expect in 2026, we have two data readouts. One is again in the first-line EGFR exon 20. This is actually an interesting approach.
We're the only one that are really combining with amivantamab. If you look at the competitive space, most people are taking one of two approaches here, either monotherapy against chemo or combining with chemo against chemo. So, given our profile, both on the CNS activity that we've shown, and then on the safety profile, it does make an opportunity for us to kind of differentiate here and combine with amivantamab. So that's. We're excited about that. And then we'll also share the first-line atypical EGFR data in mid 2026 as well. So we've got a number of data readouts in call it the next nine to 12 months.
Correct me if I'm wrong, but you've made some strategic decisions recently about where to prioritize among the pretty large set of opportunities you highlighted in first and second line, so.
Yeah, that's correct. That's correct. I think it was back in February of this year, we have made a strategic decision to not pursue the second-line setting, and that's really driven by two things, right? Obviously, the second-line setting is smaller than the first line, so we wanted to focus our you know, operational and capital on the first-line setting. And given the cost of capital, it just didn't make sense to kind of pursue that second-line setting. So, we're really focused on the for the second half readout, I think the major focus will be on the first-line setting, and then obviously the readouts in mid 2026 will also be focused on that first-line data set.
And then for the front line, you know, how are you thinking about this atypical setting? You know, it's a very fast-moving space. It's been recently identified. There's a long list of mutations, as you know, a lot of players. You know, what's your strategy there in order to carve out differentiation?
Yeah, I think that the data will drive our strategy in the first-line setting. You're absolutely right that people seem to be cutting that data a little differently. Some people are more a strict definition of PACC mutation while others are allowing more classical-like mutations as well. We are enrolling a broader group for the current study, but for the phase 3, I think that's a little TBD, which will be driven by our data set, obviously.
The differentiation there, Yigal, is gonna be the same as the differentiation of the populations, which is it'll come down to the CNS activity of the drug and the clean kinome profile of the drug. Those two means of differentiation, so in other words, the CNS activity and then the safety profile, ought to translate across all three of these populations. All three of these are populations that, like I said, are just woefully underserved in terms of the ability to have clean, well-tolerated drugs that importantly have CNS activity.
Yeah.
So that applies to atypicals as well.
All right. You know, one of the other companies in the space received FDA feedback, as you know, for their phase 3 for atypical.
Yep.
It was interesting because, I mean, some people thought this was a bit of a surprise from the FDA, that they had the kind of dealer's choice of afatinib and osi, which obviously makes things more challenging because, you know, you kind of serve a lot of different needs there from the point of view of the different atypical mutations. Because as you know, some of them are approved, and some of them... So how are you thinking about that from a longer term perspective, given that FDA?
Yeah
... feedback?
Yeah, we certainly took note of that regulatory design for the, for their phase 3 study. We're not as advanced as they are, certainly, to have had those level of conversations with FDA. But all I can say at this point is we took note of that and had the same observation that you did. It was also interesting to note that chemotherapy was not one of the physician's choice regimens as part of the control arm. Chemo is generally in control arms in most oncology studies, just 'cause it is thought of as a standard of care, even if it's not the standard of care. So yeah, we noted those same things that you did.
Very good. Thank you both, gentlemen. Appreciate it.
Thank you for having us.
We'll look for the updates-
We appreciate it.
Look forward to seeing them.
Thank you.