Great. Good morning, everyone. Thanks for joining us here at the Goldman Sachs Global Healthcare Conference. And, you know, good morning on our second day of the event to everyone who's joining us online as well. And we're thrilled to have the team from OREC here this morning, and we'll just get right into it. Maybe to start, there was some news last week, not from you guys, but from Fulcrum, which was an update that has obviously been top of mind given the mechanisms of action overlap. Maybe you could speak to the Fulcrum update on COSER-ODR and any potential implications for your program and prostate cancer and metastat.
Firstly, thanks for having us here at the conference. It's always a great conference. We were just talking about the long flight across the country. So at a high level, last week, Fulcrum announced the discontinuation of their PRC2 inhibitor, which they were studying in sickle cell disease. If you read the press release, the press release kind of states that the FDA's position is really based on three things. One is the risk benefit profile for sickle cell disease, which is obviously very different than it is for oncology. Two was the previously disclosed malignancies they saw in their preclinical tox work. And third was the ongoing secondary malignancies that Tasmetastat is seeing in various indications as well. So obviously that was, people think that's a read through to us. When we take a look at this, we think the implications are limited when we look at Renzi-Medostat. And again, that's really for three reasons. One is that we've dosed over 100 patients both as a monotherapy and in combination with AR inhibitors. We have not seen any instances of secondary malignancies. Based on the pre-work we've done, which is a four-week tox and a 13-week tox in two species, which is a requirement for oncology, which is different from non-oncology, we have not seen any signs of malignancies as well. And third, I think most importantly is, as I said before, the risk profile for prostate cancer is very different than sickle cell disease. So that's, I think, first and foremost. When you think about any drug, it does come down to the risk-benefit profile, taking into consideration therapeutic area, taking into consideration the overall patient population as well. We also went on to say that over the last six months, obviously we've had a number of interactions with the FDA as we imminently look to start a phase three study, and there's been no change to our base case plan. Now, as you can imagine, with the news on Tasmettis now, which I think happened in the first quarter, secondary malignancies was a topic that came up as well, but there was no delay or anything in our timing. And lastly, last week, we did announce that we have completed the end of phase one meeting. The three objectives of that meeting were, first was to finalize the protocol. The second was to confirm the dose selection that we picked for the Phase III study, which is 400 mgs once a day of rinsimetastatin in combination with darolutamide. And third was to determine any other prerequisites that were required for the initiation of the Phase III study. So we did enough last week that, you know, the protocol is finalized, the dose is confirmed, and there's nothing else kind of precluding us from starting that Phase III study. So we expect to start that study imminently. At the end of the day, I think our view is this all comes down to the risk-benefit profile of the drug. Even if you look at some of the prostate cancer drugs today, like docetaxel, some of the PARP inhibitors, some of the radioligands, you know, there is some small percentage of patients that see these secondary malignancies. So, again, it all just comes down to the risk-benefit profile, which, again, oncology is very, very different than sickle cell disease.
So maybe we could talk about a more relevant comp within the prostate cancer context, which is Mevro-Metastat. And could you just speak to, like, the mechanism of action, differences and distinctions between RENZE and Mevro?
Yeah. So going way back, I think, you know, PRC2 inhibitors in general have been studied in prostate cancer for a number of years. I think the number one issue has been the first generation PRC2 inhibitors have been plagued with poor drug properties, poor in vivo potency, very, very short half-lives, called one to two hours. And some of these also had SIP auto-induction, where you actually saw a decrease in exposure with repeat dosing. We think Mervometastylans call it a second-gen PRC2 inhibitor. We think they've improved on a number of those. They've got good in vivo potency. They've increased the clinical half-life from about one and a half, let's call it five hours. And they don't appear to have this SIP auto-induction issue. issue. And as you can see, that has translated into a pretty profound benefit based on their randomized data they presented at ASCO GU in 2025. You know, what we bring to the table, I think, is we continue to have good in vivo efficacy. We have a clinical half-life of 20 hours. And we think that could be a key differentiator for us because with these epigenetic modifiers, what you want to do is cover semen for, you know, 20, 24 hours. And we're able to do that with that. Now, Pfizer's half-life being, you know, five, six hours does require BID dosing, so you do have this kind of peak to trough, and our view, and I think Pfizer's view as well, is that a lot of the on-target toxicities is CMAX driven, so we're able to prevent that
with the once-a-day dosing. Great. You started to allude to this, but as you think about that differentiation, how would you expect to show up in, like, clinical benefit, and what maybe tie that into what you've actually seen in the clinical data you've produced today.
Yeah, that's a great segue. And I think what we expect that to see is in the safety side of things, and I think we have seen that. And as you know, we had a pretty comprehensive Q1 update. The Q1 update was really, the objective of the Q1 update was really threefold, is one to select the patient population that we were going to study the first phase three and select the dose of RENZ metastat that we're going to move forward with, and thirdly to determine which AR inhibitor we're going to pick for the first phase three study. As you know, we're studying both with apalutamide and with darolutamide. We did that. We selected a dose of 400 mg of rinsimetastat, and we decided to go with darolutamide for the first phase three study. So if you look at that data update, I think first and foremost, the efficacy that we've shown, primarily on the PFS, because that's ultimately the regulatory endpoint, it's highly competitive to what rinsimetastat is shown compared to merrometastat. If you look at the landmark analysis at five months, and we're looking at five months because the average follow-up we had, the median follow-up, I should say, was five months. We had a landmark analysis of about 84%, which is right on top of what Pfizer showed at five months, both as their ASCO GU data in 2025, I think it was about 80%, and then ASCO GU 2026, it showed about 84%. So the differentiation really comes on the safety side. So we were able to show that highly competitive efficacy with a differentiated safety profile. So if you look at the adverse events, the safety events, us versus Pfizer, you can see both the frequency and the severity of events were significantly less. If you look at grade three treatment-related adverse events, we had mid-single digits. I think depending on which data set you look at, the 875 BID in the Fed or the 1250 in the fastest state, they had somewhere in the mid-30s to high 40s. So we think safety, at the end of the day, will win out here. obviously dealing with older men that are on therapy for an extended period of time. So I think that's the key differentiator so far, what we've shown now. Could that translate into longer PFS, longer term? We'll have to run that out to see what that looks like.
One of the things that's come up in our conversations kind of subsequent to the data was just like nonspecific discontinuations in the phase one trial. Maybe you could just contextualize that for us and help us think about what you guys saw in your early phase one update relative to apples to apples comparisons versus MEVRO or other prostate cancer trials.
Yeah, I think that's a good question. That's something that we've gotten a lot of questions about since our last data update. I think a couple of things. We addressed that in a few ways. I think one, what we saw in our study is no different than what you typically see in other phase one studies for prostate cancer. Just to remind people, it is a phase one study. The primary endpoint is safety and PK. It's not an efficacy endpoint. I think that's kind of one. When you look at other phase one studies in prostate cancer, there's been many that's been reported recently, including my vermetastat and some of the other T-cell engagers and other things like that, it's very common that you have early kind of non-related discontinuations. So I think that's kind of one. In these early phase one studies, you don't always have perfect clarity on exactly why there are discontinuations, short of something definitive like a safety or an adverse event. And so patients can discontinue for a variety of reasons. Often it's attributed to something like withdrawing consent or physician's decision. What's a little bit unique in prostate cancer studies, you also have the phenomenon of increasing PSA. And so often patients can come off the study, especially in a phase one study where the endpoint safety can come off early, not for radiographic progression, but just to move on to other studies or other therapies. And so that's something that you typically see in phase one studies with prostate cancer, even though the prostate cancer guidelines discourage that. They encourage you to stay on treatment until radiographic progression, which is a key kind of regulatory endpoint. You know, as we move forward, you know, thinking about a phase three study, a lot of times that resolves itself, usually because the primary endpoint is something efficacy. In the case of member metastatic, radiographic progression-free survival or overall survival, patients, physicians are often blinded to PSA response to not have any bias in the study. And so you see that is kind of typical in the way the progression of clinical studies for prostate cancer trials are conducted.
You've guided just writing another update from the program later this year, and maybe you could just talk about the scope of update that you're going to provide. What kind of things should we be expecting there?
Yeah, so we provided updated guidance in January of each year, which we do on a regular basis, and at that time, we specifically intentionally called it a program update to give us full optionality or flexibility on what we provide there. So that could be a number of things. That could be an update on where we are at the first phase three study, which we refer to as MLA-S1. It could be our thoughts on a second phase three study in prostate cancer. It could be potentially a third, another study outside of prostate cancer, or it could be some additional data update as well. Now, obviously, we're expecting the MEVPRO-1 data update as well, so it could also be some color on the results of that study and anything we learned from that study as well. So that's kind of broad. Obviously, we'll provide additional details at a later point.
Within that range of things you just said, one of them is data in the post-ARPI population. And so what do you think you need to have to be able to write a robust update such that it would be worth sharing in the second half of the year in terms of patient numbers, et cetera?
Yeah, specifically on the post-AR inhibitor population, I think, one, we're obviously excited by the data we've shown so far. I think when you look at radiographic progression-free survival, it looks fairly consistent to what we've seen in the post-abiraterone setting. I think you asked a good question, what do we need to see to kind of move that one forward? I think, one, we want to see a little bit more patients responding the same way that we have in our initial bolus of data, and then, two, I think a little bit longer duration is what we want to see. And so, again, as Dominic said, similar to the post-abiraterone patients, we had a median follow-up of about five months, and so the five-month PFS actually stands out pretty well compared to other therapies in the space at that landmark. So I think we want to see a few more months of duration to see if that holds. And I think that we would get pretty excited by that moving forward, since there is a significant unmet need there.
And remind us what the benchmarks are for RPFS at five months?
Yeah, it's relatively similar to the post-abiraterone setting in that you see a lot of patients, either one in clinical studies or two in the real world, getting AR switch. And so this would be the opposite. So instead of patients having received abiraterone and getting an AR inhibitor. This is kind of the vice versa. They're getting an ARPI, so the AR switch would be abiraterone. And in that setting, there's been some recent phase three studies that reported data. You typically see an RPFS of about three months. And so the AR switching is typically shorter, as patients do worse, having seen an AR inhibitor switching to abiraterone. So I think that's one. Chemotherapy is about the same, so about seven to eight months. That is a five-month landmark PFS and a 60%, whereas we're tracking about 85%. And I think the other interesting benchmark there, it is a relatively small data set. It's a population that Pfizer has not been focused on with Medvermetastat, but they did report phase one data in one of their earlier updates a couple years ago in that setting. And there they showed a five-month landmark PFS in the high 60s. And so, again, there's some separation there. Again, it's small data sets to compare, but I think what we're seeing so far is very encouraging.
Sorry, did I? You covered it. You got it. Okay, let's talk about the Registrational Study Himalayas 1. Maybe first speak to the dose selection at 400 MIGs, and are you confident kind of with that selection, and it sounds like you've had these regulatory conversations that you've satisfied any sort of project optimist or other requirements?
Yeah, I think we disclosed this on the Q1 update. We did complete an extensive exposure response analysis across a number of different measures, looking at the correlation to exposure to both the efficacy and safety, and the key takeaway there is that from an efficacy standpoint, there was no statistical difference in the dose on the safety there was, so that was a key driver. So this is actually the ideal scenario of Project Optimist, right? You want to maintain the efficacy without pushing the dose too much from a safety standpoint, and as you pointed out, we did complete the end of phase one study, and the FDA was satisfied with the completion and the way we approached Project Optimist. So 400 is our dose going forward. We feel good about it, and we'll have data probably in early 2028 from the phase 3 study.
One of the key strategic questions you answered with the update earlier this year was the decision on combination agent of darolutamide. Maybe you could talk about the advantages you saw partnering in that direction, both with Prisecta as a drug and Bayer as a partner.
Yeah, I think at the end of the day, we think both apalutamide and darolutamide are both great drugs. I think what we've said to date, there's really been no drastic difference between the two agents combining with apalutamide or with darolutamide. I think at the end of the day, and we know this, right, we know enzalutamide and apalutamide are CYP-inducers. And when you're combining it with R-drug as well as membrometastat, you have this kind of CYP interaction, the CYP-DDI, which decreases the dose or the exposure, I should say, of R-drug and membrometastat as well, which requires you to increase the dose. And I think that's why Pfizer is required to push their dose as well. So that's a big difference, I think, when you look at the difference between going with darolutamide and apalutamide. Again, we think they're both great drugs. We just think from a differentiation standpoint, this further differentiates us from Pfizer in the first phase three study. Now, to be clear, you know, the decision to proceed with the first phase three study, darolutamide, does not preclude us from using a different AR inhibitor in the second phase three study in prostate cancer that we choose to go. So I think that was the key driver. They're both great drugs. And if you ask, you know, a number of KOLs, I think they'd stack rank the 3R inhibitors. They'd say, you know, the cleanest. From an efficacy standpoint, I think most people would say they're generally the same. I think from a safety standpoint, first they'd say darolutamide is the safest drug of the And if you look at some of the, you know, darolutamide, I just kind of rehash history here, but enzalutamide was launched back in 2012. apalutamide came six, seven years later in 2018 and darolutamide came a year after that. And darolutamide's a run rate, call it three, three and a half billion and they're growing at 50 to 60%. So they're kind of one of the leaders in the space and they're growing exponentially there. So I think that's another factor we think about. Obviously we want to hitch our wagon to the key driver there. And the further differentiation on safety here, we think the better it is for us for this indication.
So you mentioned that you've reached FDA alignment. What can you share about the parameters in the registrational program that you're going to start here in the near term?
Yeah, so I think, you know, obviously we don't go into intimate detail on our FDA interactions, but at a high level, the study design is a 600-patient study, 300 in the treatment arm, 300 in the control arm. The dose we select, as we said, is 400 of RENZ-metastat plus the approved dose of darolutamide. The control arm will be a physician's choice of AR inhibitor or docetaxel, and, again, the primary endpoint will be radiographic PFS. Now, we're expecting to start that study imminently. We think it will take about 15-16 months to enroll that study, and we could have top-line data as early as early 2028.
Okay. What would you expect the mix of docetaxel versus AR inhibitor to be based on real-world utilization trends?
Yeah, I think generally speaking, we'd say the range is close to 50-50, maybe it's 40-60 on the extremes. But depending on which KOL you speak to, there's definitely a preference that each KOL has on what they like to do and some of that may be regional or their experience with the drug as well. So I think, yeah, I think that's generally real. Now, if you look at Pfizer, I think they're generally assuming, it appears they're kind of assuming that similar split between AR inhibitor and docetaxel as well.
Right. All right. That's a great transition to MEF Pro 1 data, which is away from you all, technically, but is a big catalyst for the cost this year. Maybe just remind us briefly of the trial design relative to the Phase 3 that you guys are taking forward.
Yeah. To be honest with you, we've obviously done our own independent work around our stats and our trial design, and it is very similar to MEF Pro 1. And just to remind everybody that, again, it's 600 patients. They're using 875 BID in the fed state of member metastat plus the approved dose of enzalutamide versus the control arm, which, again, is physician's choice between docetaxel and enzalutamide. That study is powered to show a hazard ratio of, I think, about 0.66 or 0.65. They're assuming the control arm does 6.75. And if you do rough math, it appears they're assuming, you know, around six months for enzalutamide and about seven-ish months for docetaxel. So if you assume 50-50 split between the two agents, you get to this blend of 6.75 in the control arm. For the treatment arm, they're assuming 10.2. Now, as you know, they showed about 14 months at ASCO-GU in 2025 in their randomized data set and the more recent update at ASCO-GU 2026, they showed about 14 months. So they're assuming some level of degradation. So we think that study's well-powered. We think that study has a good chance of being positive as well.
It's pretty common to assume some level of degradation from early studies into later studies in oncology. But I guess, how would you guys think about that level of 14 months to 10 months in transition from a smaller study to a later stage trial?
Yeah, I think generally speaking, I'd say that maybe a little bit on the conservative side, based on we've seen multiple data sets that they've presented where they've confirmed the 14 months. But again, we think it's an appropriately powered study. And, you know, even if they're able to show 10 months, I think 10 months in that setting is a big win for the class, for Pfizer, and then direct read-through to us. I mean, if you look at other agents in the space, you know, Plavica, for example, in a pre-chemo patient population is probably close to 10 months. So this, as you guys know, in this study design, you're looking at metastatic CRPC patients. These are patients that had failed abiraterone, and they could have seen up to one round of chemo as well. So in theory, these are more heavily pre-treated patients than the plebictal pre-chemo patient population.
I think the other maybe small point to mention as well is Pfizer is using an improved dosing regimen and formulation in their phase three. So they are switching from the 1250 BID in a fasted state into their 875 FED. And I think the data they've shown on that, obviously, one, way more tolerable than their original regimen that they used in their phase two randomized. And then two, the data they presented earlier this year at ASCO GU, the efficacy seems like it's tracking a little bit better as well. The PSA response is a little bit better. The PFS hasn't been reached yet. And so there's actually potential for that it could exceed. In their earlier phase one study, they also showed 17.1 months. And I think as Dominic said, I think we believe if it is a positive study, that should be very commercially relevant when you look at the benchmarks. There are not many therapies in prostate cancer that have beaten the chemotherapy control So I think that's one really interesting thing, that that is the standard to actually beat. And so if they are able to do that, that would be fairly significant. The only other benchmark out there is Plavicto that is doing very successful, competing well against docetaxel. That has an RPFS of about nine months. And so we think if Pfizer can post results in the 10 months is kind of what they're assuming. With an oral therapy that's relatively, you know, generally well-tolerated, we think that would be very successful for the program and the class.
Is there anything that you might take into consideration on seeing their data that could inform Phase 3 kind of at the margin in your own design?
That may be difficult. Obviously, we don't know when the MEPRO-1 data will be released. I think the guidance is mid-26 or second-half 26, which basically means the rest of the year. I mean, we're early June, so we don't know when that's coming. As I said before, we're imminently starting the Phase 3 study, So, you know, it may be highly unlikely that we'd be able to kind of read into that. The other thing I'd say is that, you know, Pfizer typically will present top-line data, just telling you the study's positive and maybe a very little color around that. So we won't know the details about that as well. So, I mean, realistically, it may be very difficult to kind of see why, you know, get any color on what they've disclosed other than whether the study hits or not.
Maybe you could just talk about, like, a world in which, obviously, your base case is that it succeeds on efficacy and it looks reasonable from a profile perspective. Is there a world in which the trial disappoints but you guys still feel confident in Rinsome at a set, and what would that look like?
Yeah, we kind of think about it in four buckets. One is there's a big win where they just kind of knock it out of the park. Two is where they barely win. Three is where they barely miss, and four is where they really totally dismiss, Which, you know, I'd say four based on the data that we've seen, based on the powering of their phase three study, we think is kind of off the table. In the middle two, I think it's interesting because we really would need to understand why they barely made it or why they barely missed. Again, we think the key differentiator for us to date based on the data that we presented really comes in the form of safety, right? Better safety, you're going to get better compliance, you're going to maybe get longer duration as well. So I think that's the key part. Now, again, when Pfizer presents that detailed information, we'll be telling. They obviously have three studies ongoing with Memphra 1, 2, and 3. So we'll have to just see, obviously, what they present when they give this top-line data update.
Maybe you could talk about the market opportunity and this first indication that you've selected, and could you provide, like, a high-level view of what you think the opportunity is there?
Yeah. So, I mean, I think, one, just to start off, we think it's a very significant commercial opportunity. Again, we're kind of going into patients that have previously failed in ARPI, specifically abiraterone. You know, one thing to point out, if you look at, you know, the kind of prescriptions in the U.S., abiraterone right now is tracking about 50% of prescriptions in the ARPI market. So there's very significant abiraterone use in the U.S. global as well. And so we think there are a lot of patients that have failed abiraterone, roughly half the market. And I think there's pretty good statistics out there that kind of cite 35,000 to 40,000 metastatic prostate cancer patients. A majority of them have had, had seen a prior ARPI, potentially up to half of those would have seen abiraterone as their ARPI of choice. And again, one of the benefits with the PRC2 inhibitor, what we're starting to see with our data and the mevrometastat data is you have the potential for really long duration of therapy with never metastatin, the randomized phase two, a 14.3 month PFS. If you kind of add those numbers together using kind of typical pricing for an ARPI, you can easily get to a 3.5 plus year opportunity just in the U.S., just in the post-abirateron setting. Again, if we were to move forward in a post-AR inhibitor setting, that would be essentially about the same market size, again, just in the U.S. alone. So it's a very substantial market opportunity with a very
significant on that need. Yeah. And again, it sounds like your expectation is you'd share this
market. So how do you think about kind of share? Yeah. And again, as Matt said, we think that TAM is $3.5 billion in the U.S. If you just do some rough math, it's the number of patients and duration and using some average price. When you look at the ex-U.S. market, if you look at prostate cancer, it's probably 90% or 100% of the U.S. market. So overall, we think worldwide that could be close to a $7 billion opportunity. I think when we think of market share, we kind of look at it two ways. One is you have the perfect analogy with darlutamide, right? You have a drug that came out seven years after enzalutamide. The only difference is really on the safety front, and that's doing $3.5 billion, and that's growing 50% per year. I think the other thing is we've done, actually Matt and our head of commercial have kind of done an independent market research with the party. And based on that market research, if you just kind of put the profiles of our drug versus Mevro and the only differentiation is safety, we should, safety does matter here is the point, and we think that could be a huge differentiator, especially as you kind of move up into early lines of therapy like castrate-sensitive prostate cancer, where patients are, you know, not on drug for months, but they're on drugs for four years, you know, or so.
Great. Maybe we can pivot for the last couple of minutes here to the EGFR program. It's specifically designed for potency against Exxon 20 and atypical mutations, and that drug is OREC-114, and I know there's a new name, but this one's easier for me to say. So let's start with how the agent is theoretically differentiated versus the range of other EGFR programs.
Sure. Yeah, we call it enozertinib is kind of the new name. And so, yeah, preclinically, you know, the molecule, I think a couple things, was designed specifically for Exxon 20. So prospectively screened and designed for that. I think that's one differentiator. That is not true for most of the EHFR exon 20 inhibitors today. And then two, also prospectively designed to be brain penetrant. And so we thought that that is a key feature preclinically that was missing in the marketplace. I think there's been a number of companies, a number of therapies that have been going after EHFR exon 20 for a while. We always felt the landscape was missing, like a truly good brain penetrant drug, which is extremely relevant in lung cancer. As you see from studies and other prevalence reports, that at least a third of patients will actually present with baseline brain mets at diagnosis or the time they enter clinical studies, and a majority of them will actually progress with brain lesions over the course of their therapy. And so what we've seen with other targeted therapies for the other oncogenic drivers is that you really need a brain-penetrant drug to be very successful, to have very long duration of therapy. And so we think that that is kind of the key differentiator. That was early preclinical data and how it was designed. We have presented clinical data now where we're actually seeing that. And so those were the things that we really wanted to see in the clinic. And so I think, one, that we look at the potency and selectivity, which is what it was designed for, and we're actually seeing that in the clinic. Safety perspective is some EGFR kind of toxicities where we see none of the off-targets that other therapies have, such as cardiotoxicity and QTC prolongation, CPK elevations, liver enzyme elevations, things like that. We haven't seen any of that. So I think that's one very good. Two, we're enrolling extremely heavily pretreated patient population. We're allowing extremely broad enrollment criteria for CNS criteria. And so one of the distinguishing features is that we allow patients to come into our study with so-called active brain metastases. And so they do not have to have been treated. They can come with full active CNS metastases. That's very different from other studies that will restrict patients from having brain metastases at all. Some studies allow it, but they have to be treated with things like radiation. And so that's kind of key. And what we have seen from our early data, we're actually seeing really dramatic responses in those patients. And so we think, again, that is the differentiating feature that we have presented so far. We think that that will translate into kind of long duration of therapy that has the potential to do that, and so we're excited to kind of continue to update folks with the
progress of that program. Great. You did share an update in December, and you, I think, anticipate sharing another update kind of mid-year this year. Maybe you could talk about the data today and the
scope of the update we could expect. Sure. I can cover the data, and then I think Dom can kind of point you to what to expect going forward. So I think a couple of the things that we've shared is is we are really prioritizing first-line patients, and so we initially started enrolling patients that were previously treated. Now we're really focused on the first-line patients, both in the EGFR-XN20 side and the atypical side. What we've seen just from a high level so far, I think the efficacy in terms of initial ORR seems to be as good, if not better, than what other therapies have reported, both in terms of EGFR-XN20 and atypicals. The safety profile as well looks as good better than anything else. And so I think we feel extremely excited by that. And then I think the one thing that is extremely differentiated is what we've seen on the CNS side. So again, in both of those patient populations, that's the first line, EGFRXN20 and the atypicals, we enrolled patients with active CNS mets. Patients had measurable CNS mets. And in both of those populations, we had a 100% CNS ORR in those patients with measurable disease. That has been something that has not been reported yet. And so we think, again, that one speaks to the differentiation and I think leaves us hopeful that we'll see a long-term duration of benefit there. Other companies that have reported data, especially in the Exxon 20 side, most of them actually do not see a benefit in patients with CNS metastases, which is why a lot of times those are excluded from clinical studies. And so we're seeing activity in patients that aren't even allowed to be enrolled in other faced in other studies. We saw a couple updates at ASCO. There's a company, Dizal, reported data with sunvenertinib. They had extremely restrictive CNS criteria, but when you look at the data, they actually had no benefit in patients that actually had CNS metastases, even though they were required to be treated. And so that was kind of the third study. We've seen that with others as well, is that there's just no benefit with some of the other therapies out there if patients have any sort of history with CNS disease. And I'll take the second part. So we have a pretty
comprehensive update in the second half of the year. This will be at the 80-mig dose, which is kind of the recommended dose we're going forward with. So in first-line EGFR, exon 20 is a monotherapy. We'll have 20 to 25 patients worth of data. In first-line EGFR, atypical, we'll have another 20 to 25 patients of data, and then we'll have about 20 patients or so in exon 20 first-line with combination with ambivantumab as well. So it's a pretty comprehensive of update we'd expect to see there is obviously systemic response rate, CNS response rate, safety tolerability, and a look on durability as well. You know, when we think about the benchmarks in each of those respective areas, we think, you know, more or less it's that 60% plus from a
systemic response rate. Maybe briefly you could touch on what you see as the market opportunity or the size of the market in this population, particularly given the competitive landscape?
Sure. Yeah, I think when we think about this space, it's a smaller opportunity in terms of patients-wise than prostate cancer, but there is the potential for really long duration of treatment. What's been pretty well characterized is both of the EGFR populations we're targeting. Exxon 20, people typically cite about 2%, maybe a little bit higher of lung cancer, and that will get you several thousand patients in the U.S., about 4,000 patients. The atypical side seems to be a little bit bigger. I think it's commonly cited about 3% of lung cancer. And so that, again, that will get you kind of another 6,000 patients. So with about 10,000 patients, the potential for long duration of therapy, you know, typical drug pricing, you can easily get to multi-billion dollars just in the U.S. for both of those is a TAM. The one thing that's a little bit different with targeted therapies, in our view, is you really want to have a best-in-class therapy. It is rare that you see markets kind of split evenly in targeted therapies. So again, we want to have a best-in-class profile if that is true. That's a very substantial commercial opportunity for both of those populations we're targeting. Again, if you add both of them together, it's about 5% of lung cancer. That is kind of in the ballpark of an ALK market, and we've seen that market in the U.S. globally is about $4 to $5 billion split between kind of the two leading therapies there.
Okay. Maybe in our final minute here you could talk about cash runway and the clinical activities that are embedded in that guidance.
Yeah. So we ended the first quarter with $420 million in cash investments. That gives us cash runway into the second half of 2028. That does assume, obviously, the phase three study for RINZ-Metastat. MLA is one that we're starting imminently. That also assumes us starting a phase three study for enuzertinib in early 2027. So that's fully burdened in there. I think the other key takeaway is, as I said before, we're expecting top-line data from the first phase three study with RINSE in early 2028. So we've got Cash Runway well past that going into the second half of 2028. So we're well capitalized at this point in time.
Beautiful. Well, it was great having you. Thanks for the conversation today, and thanks to everyone who joined us. With that, we can turn it off.
Great job.