I will be making some forward-looking statements during the course of this presentation. So starting on slide 3, it's my privilege today to tell you about ORIC Pharmaceuticals. So ORIC stands for Overcoming Resistance in Cancer. In a nutshell, that encompasses the mission of the company and the pipeline that we've assembled. We're really excited because we think we've put together one of the most exciting pipelines in small cap oncology today. I will spend most of my time today talking to you about two programs that last year advanced through clinical proof of concept and are marching towards potential registrational studies, initiating as soon as 2025.
We've brought together a lot of deep expertise in the oncology space, specifically in the precision oncology and translational areas, which has enabled us to accelerate our trial timelines and gives us richer data that comes out of our trials, helps us with patient selection strategies, and in a lot of ways, has increased the PTS for the various programs in the pipeline. One of the unique things about the way we have built the pipeline is that we have dual engines for building that pipeline. And what I mean by that is we, for years, have had phenomenal internal discovery, drug discovery capabilities, but we pair that up with opportunistic business development when we find a great target that somebody else has got a better approach on.
And so that's put together a pipeline that's really through both of those sources of pipeline building, which I think gives us an opportunity to be agnostic as to the source of the target, but rather best molecule wins. So when we find a good target and a good molecule, whether that's internal, homegrown or external, it's all fair game, and that's really what's led to the pipeline that we have today. We have an experienced management team that has worked together for many years, in most cases for years, even prior to our time at ORIC, and that's enabled a really successful camaraderie in building of the pipeline and the company together. And finally, a strong cash position, which I think these days is even more important. So we ended last year with $235 million of cash.
That provides us runway into 2026, and that is even in light of the very advancement of the two programs that I talked about that we'll get into more detail today. There's lots of upcoming anticipated milestones. We'll, we'll cover these in the, in the course of the presentation. So taking a step back before we talk about the pipeline itself, I made some comments about the team that we've assembled at ORIC, and, and on slide four, we try to conceptually show you the sources or the origins of that team and really the areas of expertise. So we have distinguished founders who have a long history of drug development, primarily in the prostate cancer space. We've got a discovery research team with the leadership that has come primarily out of Genentech, with a history primarily in breast cancer.
A development, clinical, and regulatory team that's come out of both Aragon and Ignyta, which has expertise in both lung cancer as well as prostate cancer. And then finally, a finance, business development, and strategic team that hails largely from Ignyta and Medivation. As I mentioned to you, this, the team has worked together for many, many years in these prior settings, and it's enabled us to be a really high-functioning team at Oric as well. The other thing that comes out of the source and the origins of that team is really primarily the focus of the company tends to be prostate, lung, and breast, just given the team members that we've put together. Slide five shows you the clinical pipeline that we're so excited about.
As I mentioned or alluded to in my opening comments, ORIC-114 and ORIC-944 are the two clinical programs that last year achieved initial proof of concept and are advancing pretty rapidly towards what we think are registrational studies in potentially 2025. I'll spend most of my time today talking about those two programs. With ORIC-114, it's an EGFR exon 20 inhibitor, and with ORIC-944, it's a PRC2 inhibitor for prostate cancer. What I'd call your attention to is really the far right column of this slide, which is the key differentiation. I'm sure you're all very used to hearing companies talk about the differentiation of their programs. In the oncology space, it is more critical than ever to have programs that are truly differentiated, just given the competitive intensity in that space.
In the case of ORIC-114, our EGFR exon 20 inhibitor, from the time we in-licensed this program, which was back in 2020 when it was preclinical, we had been touting that this program is, has got a safety advantage and most importantly, a CNS advantage. What I mean by that is the other programs, both approved and in late-stage development in EGFR exon 20, have never shown the ability to treat CNS metastases. That is critical just given the prevalence of CNS metastases in that patient population. You have seen this time and time again with various targets in the lung cancer space, whether that's ALK, ROS, RET, EGFR, you name the target. What was so striking to us around the EGFR exon 20 space is the lack of other drugs having that CNS activity.
Those are the two areas, the CNS activity and the safety tolerability profile, that we viewed as the potential angle towards best-in-class differentiation for this program. I'll show you data in the course of this presentation that are really the highlights of what we presented at ESMO 2023 last year that start to make that case, I think, quite compelling for ORIC-114. ORIC-944, the PRC2 inhibitor, you can see around the key differentiation, it's really about having best-in-class drug properties. This is a class of drugs which has been plagued by poor drug properties, and I'll get into what I mean by that later in the presentation. In the case of ORIC-944, we presented data actually just earlier this week.
We presented the data that shows that it is well on its way to establishing a best-in-class profile in terms of having those better drug properties and being a better combination agent to combine with an AR modulator in prostate cancer. We won't have time today during the course of the presentation to touch on our other clinical program, ORIC-533, in a great amount of detail. That's a CD73 inhibitor, which is small molecule, orally available, being developed in multiple myeloma. And then obviously, we do have some other earlier-stage discovery research programs as well, including ORIC-613, which is a PLK4 inhibitor for breast cancer, which has gone through IND-enabling studies. Slide 6 shows you what was an incredibly busy year for us in 2023. So there was a lot of accomplishments in the pipeline.
In the case of ORIC-114, we presented data, initial phase 1b dose escalation data at ESMO of 2023. That, like I said, started to establish its best-in-class profile in terms of both the safety profile as well as CNS activity. The plans for ORIC-114 are big. This year, we plan in the first half of this year to initiate multiple expansion cohorts in the three populations of interest. That's EGFR exon 20, HER2 exon 20, as well as atypical EGFR mutations. And then, the plan for that, assuming that the signal continues to look strong, would be for that program to enter registrational studies in second half of 2025. For ORIC-944, our PRC2 inhibitor, as I mentioned, we just earlier this week released phase 1b dose escalation data that showed its best-in-class drug properties.
We also announced that we plan to initiate combination studies with one or more AR inhibitors in the first half of this year in anticipation of potential initiation of pivotal studies for that program in the second half of 2025. For 533, we just presented results for this program at ASH of 2023, so just about a month ago. Those results were profound in the sense that that was the first time that a CD73 inhibitor has ever shown single-agent activity in any indication. So again, we're quite proud of that program. The next step for that program is combinations with various classes of agents in the myeloma space.
One thing that we did announce is, at the end of last year, is just given the amount of focus for the company on both ORIC-114 and ORIC-944, and trying to advance both of those programs into registrational studies next year, we've made the decision that ORIC-533, advancement into combination studies will be with the help of a potential future partner. In other words, ORIC will not be doing that ourselves. On the discovery research side, I did mention we have a selective and potent PLK4 inhibitor, which is orally available. That taps into a synthetic lethality pathway that essentially makes it a good candidate for TRIM37 amplified breast cancers. That's one that is a potential first-in-class target and with very novel biology.
ORIC-613, we last year, during the course of the year, advanced it through IND-enabling studies. And then finally, on the corporate side, we completed in the middle of last year an $85 million PIPE financing at a premium from five healthcare-dedicated funds. That extended our cash runway into 2026. That cash runway is a very conservative estimate from the point of view that it is funding everything that I've just talked about. It's funding, including the starts of those pivotal studies, the CMC that goes into that. It does not make any assumptions about other funding coming from potential BD or any other potential discontinuations of earlier programs. So in other words, it is a well-funded balance sheet. So let's dive into the programs themselves. ORIC-114, our brain-penetrant EGFR HER2 exon 20 inhibitor.
You can see here on the target product profile on slide 8 for ORIC-114, but I'll, I'll boil it down to something much more simple for you, which is really the problem statement. As I mentioned before, the EGFR exon 20 space has been plagued by two main issues. One is safety and tolerability with drugs that either are showing incredible amounts of wild-type toxicity, which takes the form of either rash or diarrhea, or in the case of most of the drugs, significant off-target toxicities because of what is really dirty kinome profiles. Secondly, the drugs in this space have lacked CNS activity.
As I've mentioned before, you have seen this play out time and time again in the course of ALK, ROS, RET, EGFR, even KRAS, the importance of having brain penetrance for these TKIs that are targeting lung cancer, and that's because of the prevalence of brain mets in these patients, both at initial presentation, as well as the brain being the initial place of progression for those patients. So in the case of ORIC-114, we thought that its target product profile, trying to address both of these two issues, was the key differentiating factor, and it was the main thing that we wanted to see out of the phase 1b results.
As you can see on the far right of the page, we did start to demonstrate that in the phase 1b results that we presented at ESMO of 2023, in the, in the sense that we saw a well-tolerated safety profile. We saw systemic activity, importantly, post-amivantamab, which is the only approved EGFR exon 20 inhibitor in the, in the space, and importantly, we saw CNS activity, the first CNS activity that has been shown by any drug in that space. So slide 9 shows you why the CNS activity is so important, and this is a case study that reflects the experience of mobocertinib, which originally had an accelerated approval in this space. Unfortunately, that drug, because of its poor profile, did not confirm in its confirmatory study, so it's now been withdrawn from Takeda by Takeda from the market.
In the case of mobocertinib, they showed in their experience that 35% of patients at initial presentation had brain metastases. They showed that the brain was the main site of progression for those patients, certainly for the ones who had brain mets at initial presentation, but even across all patients, 40% of them, the first site of progression was in the brain. Most importantly is what I mentioned to you, is, the activity differential that you see in patients with versus without brain mets, and mobocertinib is not an outlier in this sense. If you look at all the other targets in lung cancer that I mentioned to you, you will always see this differential in the performance of those drugs in patients with versus without brain mets. In this case, you can see a profound difference in the PFS of these patients.
You can also see a profound difference in the ORR of these patients, in those with versus without brain mets. I alluded to amivantamab earlier in my commentary. Amivantamab from Janssen is the only approved EGFR exon 20 drug in this space. At ESMO, they presented the results of their Papillon study that was the confirmatory trial that will likely mean that amivantamab moves to the frontline study. I think what has maybe been underappreciated is, at the same time that Janssen presented those data, there was a paper that they published in the New England Journal of Medicine with a subset analysis that showed the difference in performance of patients with versus without brain mets on that drug, and again, it's a profound difference in those with versus without brain mets. It again shows you why it is so important to have CNS activity.
Alectinib in the ALK space is a drug that often gets talked about as a phenomenal shining example of great clinical benefit for patients, and obviously a very commercially successful drug. Alectinib does $1.7 billion of annual revenues. Where the differential for alectinib comes in, though, it was the fourth ALK inhibitor to market. What you will see is that its response rate is not dramatically different than the other ALK inhibitors that have come before it. Its PFS, though, is dramatically different, and that's because in the patients with brain mets, they perform just as well as the ones without brain mets in the case of alectinib, because it is a CNS-penetrant drug. So that is why it is so important. So turning to slide 10, this is the design of our part one, part two, and potential accelerated approval cohort strategy for ORIC-114.
Again, last year and the year before it, we got through the dose escalation, part one, which was intended to look at the primary and secondary endpoints you see on the slide. But like I said, to boil it down, it was really intended to look at, does the drug have a safe, well-tolerated profile, and is there evidence of CNS activity? And it was able to show both. Slide 11 is our attempt to show you a comprehensive overview of the options in this space, the drug options in this space. And there's—I wanna spend some time on this slide because there's quite a few important characteristics to draw your attention to. First of all, I'll point you to the enrollment, which is that almost every drug in this space that has come before us has excluded patients who've had a prior exon 20 inhibitor.
Almost every drug in this space that has come before us has also said that if a patient has brain mets, if those patients are not treated for those brain mets with surgery or radiation prior to coming onto the study, they're not allowed on the study. So those are two important exclusion criteria that are really, in some ways, cherry-picking the patient population that have been rolled into those studies. You can see on the far right, in the case of ORIC-114, and in the column second to the right, in the case of Blueprint's program, which they just announced discontinuation, that both compounds allowed patients with prior exon 20 inhibitor, both drugs allowed patients with baseline with brain mets that had not been treated. And so you can see just a profound difference in the patient population that we enrolled.
Now, despite enrolling that significantly more difficult patient population, we also now, along with amivantamab, are the only two drugs that are shown to systemic complete response in the lungs. Amivantamab, as I mentioned, is the approved EGFR exon 20 program, and we are the only one that has shown a complete response in the brain in a patient who had not previously been treated with surgery or radiation. That's in our short treatment experience, while these other drugs have treated upwards of 500 patients at this point. So you can see here on slide 12, the waterfall plot that shows you the tumor regressions that we're getting, and most importantly, you can see the heavily pre-treated nature of these patients, including how many of them had had prior amivantamab.
I'll draw your attention in particular to the lower row on slide 12, which shows you the evidence of CNS activity that we were able to see in this population. This slide 13 really highlights to you a really critical case study, and I couldn't have really come up with a better case study for the differentiation of this program. And what I mean by that is, this is a patient, a 55-year-old female patient, who was treated previously with chemotherapy and progressed, then went on to amivantamab and actually did quite well on amivantamab. Was on study for about a year on amivantamab in response, eventually progressed in the brain, and she progressed in the brain with four small lesions.
The importance of those lesions being small is that the blood-brain barrier was likely not compromised because of the size of those lesions being quite small. She had not had surgery or radiation, which means she could not have gone on to almost any other study other than ours, came onto our study and had a complete response in the lungs and a complete response in the brains. And at the time of ESMO, was in cycle 9 and ongoing in response. We also showed activity in HER2 exon 20, which is a second population of interest that you can see on slide 14. And then finally, slide 15 is an area that we are also interested in looking at, which is atypical EGFR mutations.
This is a really important population from the perspective of the fact that it is actually larger than the EGFR exon 20 population. It is also quite underserved. Afatinib gets used in this population today. I think any clinician you talk to will tell you that afatinib is a very poorly tolerated drug with a lot of toxicity. Clinicians and patients are hungry, those with atypical EGFR mutations, to have a better drug in that space. And you can see, at least based on the preclinical work, how potent we are within that area. We actually are more potent, slightly, against atypical EGFR mutations than we are against EGFR exon 20. So this is a patient population we just started to enroll in Q4 of last year, and it's one that we're quite excited about.
So, in wrapping up on ORIC-114, you can see a lot of activity that's slated for the next two years. 2024 really is about dose expansion cohorts in the three populations of interest, which is EGFR exon 20, HER2 exon 20, and atypical mutations of EGFR. And then ultimately, assuming that we continue to see good signal, good activity, and the differentiation on the best-in-class profile that I mentioned, we would plan in second half of 2025 to start registrational, potentially multiple registrational cohorts in these populations of interest, in anticipation of potential NDA filings as early as 2027. So given the time we've got, let's jump straight into our PRC2 inhibitor, which is ORIC-944.
So again, you can see on slide 19 the target product profile that we're shooting for, but I'll boil this down for you quite simply, which is that the PRC2 class, both the approved drug tazemetostat, as well as the drugs that are in development, have just been a poster child in many ways of poor drug properties. And what I mean by that is things like short half-life, things like dose-dependent decreases in exposure, CYP autoinduction that leads to dose-dependent decreases in exposure, and insufficient drug properties in a number of different ways. In the case of ORIC-944, with the data that we shared earlier this week, we show that we've got better drug properties than those drugs, and we believe best-in-class drug properties. Slide 20 is just a quick refresher on the biology.
Many folks, when we first tell them about our PRC2 inhibitor, say they haven't heard of PRC2 as a target, and we tell them: "We guarantee you have. It's just you probably know it as EZH2," which is really the first-gen programs targeting the PRC2 complex, focused on one of the two druggable subunits, which was EZH2, the catalytic subunit. We have focused on, with this program that we in-licensed from Mirati several years ago, the EED subunit. We believe that what Mirati came up with in this program is a drug that has better drug properties than what's come before it. I mentioned to you that the promise here is to combine with AR modulators. You can see on slide 21, a highly conceptual diagram of some very complex biology.
What I'll simplify it to say is that the second-gen AR modulators, which would be enzalutamide, apalutamide, and darolutamide, have had phenomenal success for patients in the prostate cancer space. Eventually, though, those patients progress. There's resistance that comes up. What is thought to be the case is that the prostate tumor is in an AR-dependent state initially, but upon AR modulators being acted upon those tumors, you eventually get the tumors modifying themselves in terms of lineage into an AR-independent state, and that's when enzalutamide, apalutamide, and darolutamide start to lose their efficacy. And so the thought here is that a PRC2 inhibitor, which is an epigenetic modifier, can actually keep those tumors in an AR-dependent state, and thereby accentuate the activity of those next-gen AR modulators.
Slide 22 shows you in vitro work that actually proves out this synergy. Now, this work mirrors work that was presented by Pfizer initially, showing where Pfizer showed that with their EZH2 inhibitor in combination with enzalutamide, they see a synergy of the two together in vitro. We're seeing the exact same thing. So, to simplify this experiment that is depicted here on slide 22, these are cell growth assays, where you're looking at varying dosing concentrations of either the PRC2 inhibitor or enzalutamide, and then also looking at varying concentrations together. You then feed that into a synergy analysis model. In this case, we show three different models, and essentially, what you're looking for is the score output that's coming out of those models. So anything that's -10 or lower tells you that the two drugs would actually are actually antagonistic.
Anything that's positive 10 or greater tells you that the two drugs work in synergy with one another. So in other words, the growth inhibition you can see from either of them alone gets accentuated when you put them together. And as you can see here in all three models, we show synergy with values that are 10 or greater. We also replicated what Pfizer was able to show, which is that they see synergy in combination with enzalutamide as well. Now, the phase I here was all about showing the drug properties, and that's what I mentioned. So you can see on the far right of slide 23, the objectives here was to show strong drug properties, to validate the...
What we predicted to be a long clinical half-life, show that we could get dose proportional increases in exposure, so show that we would not have CYP autoinduction, show strong target engagement, and finally, show that the drug was safe and well-tolerated, and we were able to do all of those things. Slide 24 is a quick snapshot of the PK profile of the compound. The two main issues for the drugs in this space have been short half-lives, as I mentioned, and/or CYP autoinduction. You can see tazemetostat has both issues. In the case of Pfizer, they've only got one of those issues, which is a short, relatively short half-life at less than 4 hours.
In the case of ORIC-944, we were able to validate in the clinic that our preclinical prediction of a half-life greater than 10 hours is, in fact, correct. It is greater than 10 hours, and, and we do not have a CYP autoinduction issue. On the target engagement side, on slide 25, you can see maximal inhibition of an H3K27 trimethylation assay. Again, this is very comparable, in fact, slightly better than what Pfizer has shown in the same assay system, looking at the same target. And importantly, we see very low interpatient variability, which is something they do not see. They see higher interpatient variability, so that should be important as well.
Then finally, as we think about the phase 1b results and the totality of those on the left-hand side of slide 26, you can see on the safety front that at any dose that we would consider taking forward, which are really 600 mg QD, is but the most likely dose we would take forward into combination studies initially, we see only Grade 1 and Grade 2 treatment-related AEs. In fact, it was only at 900 milligrams QD that we saw our first Grade 3 AE. So the plan for this is to start combos with one or more AR inhibitors in the first half of this year.
That's really about dose finding, less so than signal seeking, because we really are looking to fast-follow what Pfizer is doing in this space, with their PRC2 inhibitor, in their case, in combination with enzalutamide. Obviously, in our case, we can consider combining with enzalutamide, but we also have two other fantastic options in apalutamide from Janssen and darolutamide from Bayer. And so the plan here, would be to start the registrational studies in the second half of 2025. Given the time that we've got, I wanna make sure we have some time for Q&A, so I'm gonna, for 533, our CD73 inhibitor in myeloma, I will just say, as I mentioned, that we presented results at ASH that showed, a good half-life. It showed only Grade 1 and Grade 2 AEs.
It was the first single-agent activity seen with any CD73 inhibitor. We had multiple patients with double-digit decreases in urine paraprotein, serum paraprotein, or both, and we showed decreases in soluble BCMA levels, which are often indicative of activity, anti-myeloma activity. All of that said, just given the focus of the company, the enormous focus of the company on the first two programs, we plan to partner this program in terms of taking it forward into future combination studies. So with that, why don't we open it up to questions, Anupam?
Cool. Thanks, Jacob, and so just as a reminder, you can old school, you know, raise your hand, and I'll call on you. You can submit a question through the question portal, and I will get it here, or you can email me. So those are the three ways to ask a question, so but I'll start here. So, last December, actually, the team and I wrote a note that said, "Hey, like, for this initial update, a win scenario would be, you know, good PK exposure, H3K profile, and good safety." I feel like based on your presentation, you hit all of those metrics, but if you wanted to comment on, maybe PK exposure, I don't remember if I saw that in there.
That was in there, and your note, I think, summarized nicely what we were trying to see out of the phase 1 study. And so part of our disclosure earlier this week was intended to check all of those boxes that you just rattled off. So we do see good PK, we see good dose proportional increases in exposure. Importantly, we don't see CYP auto induction. We see a long half-life that's greater than 10 hours, which is much greater than the other programs in the space, and then very good target engagement and safety. So I, I believe we've checked all the boxes on the scenario that you and the team outlined.
How do you think about this update relative to, say, what competitors have shown, in particular, Pfizer? I think there were other compounds from Constellation and others that tried to go into prostate.
Yeah. There's been a lot of programs that PRC2 inhibitors that have tried to go into prostate, and as I said, I think what has sunk most of those programs has been the poor drug properties, it's been the short half-lives, it's the thing, the CYP auto induction, which leads to that, that phenomenon of a dose-dependent decrease in exposure, and you've seen that with tazemetostat. You saw in the case of Constellation's first-gen compound, they dosed that drug TID in combo with a CYP modifier. So just a whole host of problems. Now, it looks like Pfizer is showing better data than what's come before, and I think it's no surprise that they've showed a better drug profile so far than what's come before, at least better than the other programs. We believe that we've got a drug profile that is even better than theirs.
The results that Pfizer showed last year, and from a single-arm study, I think most folks are familiar with, but I should probably just highlight for people's attention, were profound. When Pfizer combined their EZH2 inhibitor with enzalutamide in patients who had progressed on abiraterone but never had enzalutamide, they saw a PFS that was over 17 months, a radiographic PFS that was over 17 months, when they should have seen 4-5 months. So that is really profound that they've been able to do it, and it seems like they've been able to do it with a drug that has better drug properties than what's come before. So I think that that's really what I think will lead to a better outcome in this space.
So in the presentation, you mentioned... Well, first, questions from the audience? All right. So, you mentioned initiation of combo study in the first half of this year, maybe a pivotal study in the second half. Maybe you can talk about what are the gating factors and operational aspects that you need to do to hit the initiation of the combo study in the first half?
Yeah. I mean, at this point, the team's done the heavy lifting. We were doing a lot of heavy lifting in 2023, so that's why we're comfortable announcing that we plan to initiate the combo studies with one or more AR inhibitors in the first half of this year. The reason to do more than one AR inhibitor is obviously to just get dose-finding experience with the multiple of the options here. I think if you talk to clinicians, they would tell you that enzalutamide, apalutamide, and darolutamide are all fantastic drugs for prostate cancer patients. They have profiles that are very, very similar in terms of efficacy and in terms of safety, and so we would be quite happy with any of those options.
And really, we can, you know, potentially work on getting free drug supply from one of those companies that would be interested in the study that we're running. In the case of apalutamide and darolutamide, they don't have a label in this particular line within castration-resistant prostate cancer, so there's a lot of reasons why they ought to care about this strategically. And then, second half of the year will be about, you know, refining that dose-finding work in combo with those AR inhibitors, and then getting ready, like I said, for potential pivotal studies in the second half of 2025.
From a market perspective, is there a reason why you would use one AR, ultimately, versus, you know, right now, you're studying a couple?
Ultimately, for the pivotal study, I think we would choose one to take forward. I think that's just the simplest path forward, is to have a combo with one AR inhibitor that, that we end up developing. All three of them, like I said, are phenomenally good drugs in terms of the efficacy and the safety profiles. They are all three commercially quite attractive drugs because they've got such strong profiles. All three are blockbuster drugs. Even though apalutamide and darolutamide were second and third to market, years after enzalutamide, they've already achieved blockbuster sales, annually. So, any of those would be a good option on the phone.
I guess you've already committed to first half combo initiation, but you've also committed to a mid-year update for ORIC-944. What would that mid-year update encompass?
Yeah. We've said we'll have another update mid-year, and that is intentionally generic language that could encompass any of a number of things. It could be as simple as good news. We've initiated the combination studies that we talked about. It could be one or more drug supply agreements that we're getting free drug into those studies. It could be additional clinical data if we choose to do so from the single-agent experience, but we're not committing to that at this point. And importantly, it actually could be preclinical data, which I know people yawn when they hear preclinical data, but in this case, I think, you know, there's quite a bit of preclinical profiling that can be done of us head-to-head versus the other major PRC2 inhibitors in prostate models.
There's profiling of us, us meaning ORIC-944, plus an AR modulator versus one of those other PRC2 inhibitors plus an AR modulator, and those will all be quite telling as people try to benchmark which is gonna be the best PRC2 inhibitor for combos with AR modulators.
Question from the audience?
I'll ask you just, like, a philosophical question on overcoming resistance in cancer. From a high level, you know, it seems to me... I'd love to know your take on the importance of NK cells and the programmability and the, you know, how that is in the-- how you look at that for overcoming resistance in cancer and recurrence?
Yeah, it's really hard for me to give a one overall sweeping answer on, with regard to NK cells. What I'll say is that the team's just got an incredibly deep expertise looking at multiple pathways of resistance, whether that's acquired resistance or bypass resistance, and trying to figure out ways to address that. I think PRC2 is actually a phenomenal example of different ways of resistance and that understanding, in the sense we often get asked the question: Should EZH2 inhibitors or EED inhibitors react differently versus one another? Meaning the two different subunits that you could drug for the PRC2 complex. And our answer is actually, from a resistance point of view, it ought to be better to drug the EED subunit than the EZH2 subunit, because EZH2 inhibitors would be susceptible to bypass resistance from EZH1. They also could be susceptible to EZH2 mutations.
That's not the case with EED. So again, another reason why we focused on the EED subunit in the case of the PRC2 complex.
Maybe we'll switch gears to ORIC-114. How close do you think you are to identifying an RP2D, and how much more data and follow-up do you think you'll need?
Yeah, I'd say we're pretty close to identifying potential RP2Ds. I think, as folks remember, at ESMO of 2023, which is not that long ago, we announced that we were continuing to dose escalate 'cause we had a wide therapeutic window. We had not yet hit MTD at that time. So I'd anticipate first half this year, we'll have the potential RP2Ds in hand. I think, as people know, with Project Optimus guidance from FDA, you don't have an RP2D as early these days in studies as you used to. You've got to have a couple provisional RP2Ds that you then take forward into expansion cohorts and then have your conversations with FDA about what is your actual formal RP2D to take into accelerated approval studies or registrational studies.
So I'd say Anupam will have by, you know, midyear, a good sense of the provisional RP2Ds, certainly. But the final formal RP2D that goes into the accelerated approval cohorts for next year, I don't know exactly when that'll be.
Got it. And then you mentioned CNS activity. When you talk to doctors, how important is the CNS activity for ORIC-114 as a potential differentiation point for the product?
Yeah, it's, it's hugely important. And, you know, I reflect back on my experience at Ignyta previous to this. Back then, in 2014, 2015, almost 10 years ago, there was a debate amongst the lung KOLs as to whether a drug ought to be CNS-penetrant or not, because there was a contingent that thought if a drug gets into the brain, there's a benefit for it to treat CNS metastases. There was a different contingent that said, "Well, maybe then you'll see toxicities from getting into the brain." I think now it is dogma amongst lung KOLs that you want a brain-penetrant drug because the prevalence of brain mets is so high at initial presentation. Importantly, patients who originally appear without brain mets, in many cases, actually do have brain mets.
They're called micromets, and they don't show up on imaging. In the patients who truly don't have brain mets, even on imaging or not, they will eventually develop the brain mets. So that is the main source of resistance that a lot of these drugs, a lot of these patients are experiencing. So clinicians will tell you it is super important to be a brain-penetrant drug.
You talked about your cash runway into 2026. What does that assume in terms of the key milestones for 114 and 944?
Yeah. So we're very conservative when we provide our, our cash runway guidance, and what I mean by that is there's no risk adjusting in here. We're saying that the entire pipeline is continuing without attrition. We're funding all of that. We're funding the starts of these registrational studies. We're funding the CMC that goes into that. We're not assuming anything from a business development perspective. So, for example, with ORIC-533, we're looking for a partner to take that forward into combination studies that would presumably come with some economics that come with it, but we're not assuming anything on that economic front. So it's a conservative number when I say into 2026.
Any final questions? Okay, thanks, Jacob.
Great. Thank you.