ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

All right. Thank you guys so much for joining us here for the Goldman Sachs Global Healthcare Conference. We've got the team from ORIC today. And maybe we'll just start. You guys can provide a brief introduction of yourselves.

Sure. Thanks for having us, [ Karen. ] So ORIC stands for overcoming resistance in cancer. And in a nutshell is the mission of the company. As you hone in on the areas of our focus, we are small molecule focused within solid tumors. Given the team that we've recruited, our expertise tends to be within lung, prostate and breast, and that's where all the programs right now clinically and preclinically that we're focused on are in one of those areas. Our 2 most advanced programs are ORIC-114 and ORIC-944. ORIC-114 is a brain-penetrant TKI for EGFR Exon 20, HER2 Exon 20 and atypical EGFR mutations, and then ORIC-944 is a PRC2 inhibitor for prostate cancer that we're developing right now.

Perfect. And then maybe do you guys want to introduce yourself personally as well?

Happy to do that, sure. My name is Jacob Chacko. I'm the CEO of ORIC.

Dominic Piscitelli, CFO.

Perfect. All right. And then you mentioned ORIC-114 mutant EGFR inhibitor in non-small cell lung cancer. I guess, can you just first describe the agent and the development strategy you have in place there?

Yes. So ORIC-114 and actually ORIC-944, both were in-licensed into the company back in 2020. So we have a two-pronged approach to the way that we've built up the internal pipeline. One is through internal discovery. So we've got full capabilities in-house at ORIC to do soup to nuts on the internal discovery front, and we've done that with multiple programs in the pipeline. But then we also will in-license programs from time to time, opportunistically if we see an interesting target. In general, we like to say the unvalidated targets with very difficult biology for the in-house discovery team to work on and to plays new ground and hopefully have first-in-class opportunity. So a good example of that is our PLK4 inhibitor, OCIC-613, which is essentially IND ready at this point. But in terms of the 2 programs I just mentioned, ORIC-114 and 944, those were both brought in through in-licensing. And in-licensing is perfect for us for validated targets. So a good example is in the case of OR 114, EGFR Exon 20, HER2 Exon 20 and atypical mutations are validated oncogenic drivers within non-small cell lung cancer. Really, the issue has been -- as you look at that space, the issue has been drugs that are not Brain penetrant and such a high proportion of these patients at initial presentation have brain metastases. Patients also progress with brain metastases. And so it's for that reason that we got excited about this program back in 2020 to bring it in.

Okay. You mentioned, I guess, some of the target product profile of the drug. But as you think about like the key features that give you some confidence this can be a differentiated program in the EGFR space. Just talk to us what some of the key future were and why you were attracted to in licensing this asset?

Sure thing. It's threefold really. So as you rewind back and think about the history of drugs that have been developed within this space. So right now there's only one approved compound. It's amivantamab from Janssen. Amivantamab, and I'll put a couple of others in that same bucket, like mobocertinib from Takeda, which has now been pulled from the market, bosutinib for those that remember that from Spectrum. All of these first-gen inhibitors that were going for this indication, they all essentially suffered from a couple of different liabilities. So one was lack of CNS activity, and we'll get to that in a second. But on top of that, they have off-target toxicities or in the case of the drugs that just rattled off, they've got EGFR wild-type toxicities. And so in the attempt to drug the EGFR Exon 20 mutations, they're also getting quite a bit of wild-type toxicities, which leads to 2 major classes AEs. One is GI AEs in the form of diarrhea, for example. The other is skin AEs in the form of rash. And so amivantamab obviously has quite a bit of rash as part of its target product profile. Mobocertinib from Takeda, which I mentioned is now withdrawn had quite a bit of GI talk. So that's kind of epitomizes the EGFR wild-type toxicities that you do not want to have in this space. In next-gen compounds, there's a series of 2 or 3 compounds that are in later stage clinical development have done a nice job of, for the most part, dialing down the wild-type toxicities like the diarrhea and the rash but they still have quite a bit of off-target toxicities because their kinome trees are very dirty. So you'll see things like QTC prolongation, you'll see elevated liver enzymes, elevated bilirubin, elevated CPK, a whole host of things that you don't want to see as part of your target part profile because of the dirty kinome trees. They've all got that issue and then they've got a third issue, which is lack of CNS activity. So anywhere from 35% to 50% of these patients at initial presentation have brain metastases. The majority of patients will progress in the brain on these drugs that are not brain-penetrant. Takeda -- mobocertinib and Takeda had a fantastic data set that showed this at ASCO of 2021 in a very large population that was the first site of progression. And so it's -- those are the 2 issues that we see with the drugs that are in later stage development. So they have done a nice job of dialing down the wild-type toxicities but they have quite a few off-target toxicities, and they have a lack of CNS activity and that's what drew us to ORIC-114 when we had licensed this back in 2020, is the fact that it actually has optimized across all 3 of these criteria. So in the data set that we presented at ESMO last year, we showed good early evidence that showed that we are not seeing much in the way of EGFR wild-type toxicity. So again, a minimal amount of diarrhea and rash, no off-target toxicities and then importantly, CNS activity.

Great. So you mentioned this but we'll go there now. You've reported initial Phase Ib data for the agent at ESMO of last year. Maybe more specifically, what did that data show? And what were some of the key takeaways from those results?

Yes. So first and foremost, we made this point at ESMO, and we've continued to make the point since then, which is that there has been no other data set in the space that any company, any drug has put forward, which has been in the same population that we presented at ESMO. And what I mean by that is in that ESMO data set within EGFR Exon 20, 81% of the patients that we treated had already had an EGFR Exon 20 inhibitor before they came on to the study. Those patients were excluded from the other studies. So if you had a prior Exon 20 inhibitor, you literally could not go on to the studies of those other compounds. The second thing is we allowed patients with active brain metastases to come on to the study. And this is a really, really important criteria. So every other drug in the space that's in development now in their studies were excluding those patients with active brain mets, meaning if a patient had brain metastases, in order to get on to the study, they had to have been treated with surgery or radiation before coming on to the study. We did not make those 2 precondition of our trials. So in other words, a patient could have had a prior Exon 20 inhibitor. In fact, 81% of patients had a prior Exon 20 inhibitor and then they also could have had active brain mets when came onto the study. So 86% of the patients who came on to the study had brain mets at baseline. Within that population, we had multiple examples of confirmed RECIST PRs. And in fact, even a confirmed CR in the brain and in the lungs within our EGFR Exon 20 population, we also had of multiple examples of RECIST confirmed PRs in our HER2 Exon 20 population. And in both populations, importantly, we had multiple examples of patients who had active brain metastases where the lesions either shrunk or disappeared. And probably the very best shining example that we highlighted at the time was a 55-year old lady who had non-small cell lung cancer. She -- her prior treatment history was that she had been on chemotherapy and progressed. And one on to amivantamab. That's the only approved drug in the space. She had done quite well in amivantamab actually. So she's been in response for a year on amivantamab, but progressed exactly where you would expect she would, which is in the brain with 4 small lesions in her brain. Because she had amivantamab before she would not have qualified for the other trials because she had brain mets that had not been treated with surgery or radiation, she would not have qualified for the other trials. Qualified for our ORIC-114 trial within 2 cycles of being on therapy had a complete response in her lungs and a complete response in her brain, and the worst toxicity she had was grade 2 toxicity. And at the time of ESMO was on study for 9 cycles and ongoing. So again, a shining example of what we think that this drug can do in a broader patient population and why we're so excited about the development path going forward.

So with that data in hand, talk to us about kind of like what the next steps were and then kind of probably are ongoing for the development there?

Yes. So at the time of the ESMO update, we were still dose escalating. So earlier this year, we were still dose escalating. So earlier this year, we did select the 2 provisional RP2D and this is really a response to Project Optimus. So we selected 80 mgs and 120 mg once a day as the provisional RP2Ds. We also announced the initiation of the dosing of the dose expansion studies in 3 cohorts of patients. This includes the EGFR Exon 20 patients, HER2 Exon 20 and the atypical EGFR. What we've said with regards to this program is that we provide a data update in the first half of next year with regards to those 3 expansion cohorts.

Okay. And in terms of number of patients and the duration that you'll have at that time?

Yes, we haven't given -- yes, sorry, go ahead...

What's the goal I said?

Yes. Yes. The goal is basically to determine the go/no-go at the end of the day. We haven't given specific numbers of patients, but this is several dozen patients across the 3 cohorts. When you look at the prior therapies here, if you think about the EGFR Exon 20, these will be second-line patients. They will be EGFR exon 20 naive, which is more comparable to the data set that the amivantamab, the Cullinan and others have shown so far. The HER2 again, Exon 20. These are patients that we've seen prior therapies. The only thing we're really excluding there is prior HER2 exon 20 TKIs. And with the atypicals, they could have seen chemo, they could have seen afatinib or they could have seen osimertinib as well. So the goal will be the first half of next year really to select the RP2D. Obviously, look at the data set determined whether it's a go/no-go and then we're looking to jump into registrational studies in the second half of next year. Now given the unmet medical need here with CNS activity, there is an accelerated approval path here. So we do think there is a single-arm accelerated approval path that we could file going forward in the second half.

And just to add some context to the 2 provisional recommended Phase II doses that Dominic just talked about. So you mentioned that we recently selected 80 milligrams daily and 120 milligrams daily as the 2 provisional RP2Ds and to help you understand the wide therapeutic index of the drug. Back at the time at ESMO, the very first dose level at which we saw a confirmed RECIST response was at 40 mg daily. And so the 2 go-forward doses are 2x that level and 3x that level, which just speaks to the very wide therapeutic aim mix that we're seeing with the company.

Helpful. Then as you think like where this market is moving on the forward, obviously, there's a couple of updates from amivantamab over the past year. We've seen other programs moving through the clinic. How do you think the EGFR Exon 20 market is going to shape up? And then where do you see the best fit for all of that, kind of the competitive land?

Yes. Given the way the market has taken out over the last couple of years with several different drugs sort of falling by the wayside, if you will. And now with mobile certainly being withdrawn, amivantamab is the only drug that's now approved in the space. And obviously, with PAPILLON that read out last year, that drug will move to the front line. Obviously, amivantamab has some issues with it that I mentioned to you earlier, which is the EGFR wild-type toxicity in the form of rash. Also the fact that it's infused. It's given by IV. Obviously, Janssen is moving that to a subcu formulation but that's still not as good as an oral small molecule in terms of ease of administration and then has the lack of CNS activity. All of that said, they will be moving that drug into the front line. And so there's really 2 different flavors of confirmatory studies that companies in the space have taken. So there's either you go head-to-head with chemo. That's one flavor of confirmatory study in the frontline setting in the chemo-naive population or -- and that's what Takeda attempted with mobocertinib and, of course, they didn't beat chemo. The other flavor is you combine with chemo and then compare to chemo. So that's what amivantamab and Janssen did, where it was ami plus chemo versus chemo and ami plus chemo, trumped chemo alone. And so both of those are under consideration for us internally as we think about what the frontline confirmatory study might look like. There's a third path, though, which is available really only to us a brain-penetrant TKI, which is potentially a combined with amivantamab. So that would be potentially to have a treatment arm, which would be ami plus 114. It's a lot -- it's akin to the HER2 tucatinib combo that people are familiar with on the HER2 side of things. And that might be a way that we would think about developing this going forward.

So beyond the Exon 20 population, I guess, how are you thinking about some of these other EGFR typical and HER2, what data have you seen? And where are you moving forward with those programs?

Yes. So one of the things that we liked a lot about this program, when we in-licensed this originally from [indiscernible] back in 2020 was that it's quite potent for not just EGFR Exon 20 but also HER2 Exon 20. And in fact, at the time of the ESMO update, we had even more responses on the HER2 exon 20 side of things. And so it's looking quite good in terms of the clinical activity we've seen in both of those populations. Now a third population that you mentioned, EGFR atypicals, it's a relatively new population in the space. Right now, afatinib is the only drug that's approved for EGFR atypic. I think as people who are familiar with afatinib now they've got 3 different atypical mutations in their label. Talk to 1 clinician or 100 clinicians, you're going to get the same answer on afatinib, which is that they hate using afatinib, and that's because it is a very, very toxic drug. And so clinicians are really clamoring to find a drug that does not have the toxicities of afatinib that could be used in this atypical EGFR population. The interesting thing about the atypical EGFR population is that it's actually 50% larger than EGFR Exon 20. You start to add up some of these population sizes. EGFR Exon 20 is about 2% of lung. Atypical is about 3% of lung and then HER2 Exon 20 is about 1.5% of lungs. And so all of a sudden you're sitting on a population that's about 6%, 6.5% of non-small cell lung cancer, which is 50% larger than ALK, just to put it in context. And so that's why we think that these 3 populations are well worth studying. And with atypicals, this is somewhat serendipity because our drug was originally designed for EGFR Exon 20 and HER2 Exon 20, but because of the homologies you see a lot of these EGFR Exon 20 inhibitors that are also potent against atypical mutations. And so as soon as people start looking to atypical mutations, we did our own profiling of ORIC-114 against the typical mutations and found out that it's actually slightly more potent for atypical mutations than it is even for EGFR Exon 20. And so that's what got us excited about now developing atypical mutations as well as a third population of interest. At the time of ESMO last year, we hadn't yet started enrolling that any patients with atypical mutations but we are now focused on that as a third population as well.

And will we get the first update that will be [indiscernible] expansion study to come next year?

That's right. Yes. So the 3 cohorts that Dominic mentioned for the first half '25 next year are the 3 that I just mentioned, EGFR Exon 20, HER2 Exon 20 and atypical.

And then, I guess, how do you get confidence based on the clinical data that you guys have seen, the preclinical data you've seen and the clinical data from other competitors around that atypical population?

Yes. So we've profiled our drug against afatinib. We've profiled our drug preclinically. We've profiled our drug against furmonertinib preclinically. It's got a much wider selectivity window for the atypical mutations versus wild type than those 2 drugs. Also, it achieves regressions in vivo atypical models at a 2.5 mg per kg dose. I mean it's very, very potent. And so we see the same kind of activity in vivo with that molecule as we do actually even better activity in vivo than we do with that same -- with our drug in EGFS Exon 20 in vivo models. And so in all the profiling we've seen thus far, everything would suggest that translate to the atypical population as well.

I'll let go decision. How should we think about the registrational path for each of those [indiscernible] atypical Exon 20?

Yes. No, that's a great question. So because of the CNS activity there, we do think that we can get an accelerated approval. So we would anticipate doing a single-arm study, starting those studies in the second half of next year. And realistically, we could be filing NDAs in the second half of 2027. So obviously, you have to think about the confirmatory study, which we could talk about as well in the first-line setting as well. But we could be kicking off those registrational studies in the second half. And the beauty of it is, again, the single-arm studies are much smaller, much quicker to get your answer from an approval standpoint.

That's true across all 3 of those groups? Always brain mets always...

That's right. Yes. I think the brain mets, as Jacob said, there's really 3 areas of differentiation. The on-target tox, the off-target tox, and I think, obviously, the CNS is probably, in my view, the biggest thing. Even we talked about amivantamab in first line with the PAPILLON study in combination with chemo, great results in first line, and they're probably going to take a big part of the market share there. But if you look at -- there was a subset analysis in the New England Journal of Medicine, and if you look at the patients with a history of brain mets and without brain mets, there's a huge difference in the patient's response. I think the hazard ratio was for those with a history of brain mets versus 0.33 for those without. So it's a severe unmet medical need. If you go back and you look at the targeted therapy space in lung cancer and you go back to ALK, EGFR, KRAS, typically, the CNS agent seems to win. At the end of the day, you should see better responses, you should see a longer duration as well. So that's what we think this is a highly differentiated asset and this is what really gets us excited. And as Jacob said, the data at ESMO that we presented last year really kind of checks that box. So I think to date, we're the only ones that have shown CNS activity in a patient with an active brain mets. So I think a lot of people have shown activity but it's more with patients with treated brain mets. We're the only ones that are really recruiting patients with active brain mets.

Then as you referenced it to all asked on the registrational trial confirmatory piece of the puzzle. I guess how are you thinking about it today? And also like what will you look to gain insight into as that market evolves post PAPILLON to better inform your treatment or your decisions there?

As mentioned earlier, the confirmatory would be in any of these would be a randomized study. And that's gold standard for FDA. At this point, FDA obviously wants you to get your confirmatory study started as soon as possible. And that would be in our best interest as well given the commercial opportunity there. And there's nothing really at this point that we'd see in the way the space would evolve that would change any of that from our perspective in terms of how we think about the next steps.

Okay. And then in terms of patent on 114?

Yes. So the -- the composition of matter patent on 114 is 2040. Obviously, that does not include any potential patent term extension.

Okay. Great. Maybe we'll spend some time on ORIC-944 then. Maybe just so we could do an overview of the asset where you bought it from and why you're into in the target?

Yes. So this is another example of a validated target that we -- it was perfect for us to look for from an in-licensing perspective. So we brought this in from Mirati back in 2020. Mirati was essentially -- the leadership in running, we knew quite well, and they were essentially frustrated that the public markets only ever want to talk to them about KRAS while they had a very novel and exciting earlier-stage pipeline. So we got to look at it, saw the PRC2 inhibitor. Mirati had done profiling versus tazemetostat in heme models and a variety of different heme models where it knock the pants of tazemetostat in those models. They had not done any prostate models. And PRC2, which is the overall complex and target here has been implicated in prostate biology for years and years and lots and lots of literature. Everyone with a PRC2 inhibitor in the clinic has studied it in prostate. Unfortunately, everybody was coming for the PRC2 inhibitor, those PRC2 inhibitors have had terrible drug properties. And I say terrible, I mean, terrible. Half lives on the order of 2 hours, 3 hour half-life, SIP auto induction to the point that drugs get dose-dependent decreases in exposure. So you'll see things with prior PRC2 inhibitors, like TID dosing with a SIP modifier. I mean it's just the worst of the worst in terms of drug profile. Now there's a drug that I'm certainly -- certainly we'll talk about, which is Pfizer, which it seems to be the best of the PRC2 inhibitors, thus far, and they have achieved phenomenal data in terms of PFS in combo with an AR modulator, which was always the promise of how this drug would end up being developed. What we like about this is Mirati synthesized a lot of different EED inhibitors, a lot of different EZH2 inhibitors, which are basically the 2 subunits of the PRC2 complex that you [indiscernible]. They didn't take a view on EED versus EZH2. They just picked which drug had the best drug properties, which drug had the best in vivo activity. It was essentially what is now ORIC-944.

Okay. I see. So maybe you could talk a little bit. You referenced it's been a known target in prostate cancer but like how does it work? And then have you taken a view sense on the EED versus EZH?

Sure. So I guess I spend 2 hours talking about the biology of how it works in prostate I will boil it down in 12 seconds, which is really what's thought is for folks that have followed a prostate space, you know that enzalutamide, apalutamide and darolutamide, in other words, the next-gen AR modulators have done a phenomenal job for patients in terms of efficacy, toxicity, the overall clinical profile. You get very long durations on those drugs. But eventually, the tumors become AR-independent at which point the AR modulators stop working. And so the holy grail within the prostate space has been how do you get those AR modulators to work for longer. And the biology is PRC2 is an epigenetic modifier and essentially through its impact on a variety of different genes you're able to keep the tumor in an AR dependent thing. And so you see this preclinically, you see this in vitro models, you can see that preclinically, you seem to be able to keep the tumor in an AR dependent state, and therefore, get better activity out of those AR modulators by combining with the PRC2 inhibitor. Now -- and now Pfizer has shown that at least with Phase I results thus far, that they're also seeing that clinically. Now we didn't take a view on EZH2 versus EED. As I mentioned, Mirati just made both kinds of inhibitors and the one that empirically one was ORIC-944, which is what I like about the experiments that they ran. Now just to kind of walk you through the theory at all, if you've got 2 different compounds that have exactly the same drug properties, exactly the same potency, one is an EED inhibitor, ones in EZH2 inhibitor. They should be equally good at inhibiting the PRC2 complex initially. Where you should see a benefit is in the long term from a point of view of resistance, an EED inhibitor ought to be better than an EZH2 inhibitor because it would not be susceptible to bypass resistance from EZH1 or acquired mutations to EZH2, both of which will be a problem for EZH2 inhibitors. So in theory, we would have an advantage in the long run. Now let's go back to the original supposition I said, which is 2 different drugs with exactly the same drug properties, exactly the same potency, we feel very strongly that our drug has best-in-class drug property.

Okay. You did present some data earlier this year and preclinical data at AACR, I guess, summarize what we've seen from a key takeaways from this data? And how does that reinforce what you've seen in the Phase Ib?

Sure. So as I mentioned, the half lives in the space have been on the order of 2 hours or 3 hours. You things like SIP auto induction issues with some of the other drugs that have been in the space and have come before us. What we've revealed thus far in the data at the conferences that you mentioned is a half-life, a clinical half-life of 20 hours for 944. So consistent -- totally consistent with QD dosing, very good drug properties, no SIP auto induction. You see very tight interpatient variability. So in other words, very little interpatient variability as you look at the PK and the PD data, and you see really good target modulation. You look at something called H3K27 methylation to look at that. And then the other thing that's really important is just as Pfizer has talked about in terms of preclinical work they've done to verify that there's synergy and combined with an AR modulator, we show the same synergy in combination with AR modulator. And then back to my other point about EZH2 versus EED inhibition upfront, we've done really elegant RNA analysis, looking at gene transcription factors activated by either EED inhibitors like ours or an EZH2 inhibitor like Pfizer's, and we see an R-squared value of 0.88, meaning that the 2 act the same. It's an exquisitely nice line of best fit as you look at that analysis.

Great. And so you've referenced the Pfizer data a couple of times. It's obviously you've got more clinical data then. But what should we note about those results and what makes you really excited about this?

Yes. What makes us excited. So Pfizer just a level set, for folks that aren't familiar with their data set, is in 2 different -- in a Phase I setting, they study 2 different populations within metastatic CRPC. One was a population that had abiraterone and then was getting enzalutamide for the first time but in combination with Pfizer's EZH2 inhibitor. second population was a population that progressed on enzalutamide. It was getting enzalutamide again. So essentially enzalutamide rechallenge but in combo with their EZH2 inhibitor. And what you saw in both populations was essentially 3.5x to 4x the radiographic PFS that you would otherwise expect with enzalutamide alone. So really profound increases in the radiographic PFS. So in the enzyme-naive population, abiraterone experienced, they got a 17-month median radiographic PFS versus what you'd expect is about 4 to 5 months, and in the enza experience population, they got close to a year of radiographic PFS versus what you'd expect, which is about 2 to 3 months of radiographic PFS. The other thing is Pfizer's got a Phase II randomized study in that enza naive population, which we get asked a lot of questions about as to when Pfizer is going to present their randomized Phase II data. But I think the important thing for people to understand is that's an open label randomized study. So in other words, Pfizer absolutely knows a result of that study. Earlier This year on their innovation day, they announced that they're going to greenlight not just 1 but 2 Phase III studies for global pivotal studies for their program based on the results of their Phase II and their Phase essentially should bode well.

Yes. And maybe just to add to that, they actually had powered that study with a hazard ratio of 0.5, which obviously shows a high level of confidence in that study as well. So we're anxiously looking for that data. We obviously don't know when they're going to put it out. It's a question better for Pfizer.

All right. I was going to say, there's obviously a number of antigen receptor inhibitors on the market. So as you think about your own combination programs, like talk to us about how you're selecting partners or...

Yes. I think, as you know, there's 3, I think, next-generation AR inhibitor. So there's enzalutamide, which is co-owned by Astellas and Pfizer, apalutamide, which is owned by J&J, and then darolutamide, which is owned by Bayer. Honestly, all 3 are great drugs, both clinically and commercially. Combined, they're doing around $10 billion in sales. So we don't have -- we don't think there's 1 agent that is necessarily a favorite. They all have kind of their pros and cons to it. Darolutamide in theory would have less DDI, so maybe there's a benefit to that. There is some SIP DDI when you combine with apalutamide or enzalutamide but that could easily be overcome with increase in dosing, just to keep the exposure to the same. Another consideration would be that both apalutamide and darolutamide are not approved in the metastatic CRPC setting. So obviously, it should be interesting for both J&J and Bayer. And lastly, if you look at the 3 agents, enzalutamide is a first to come off patent. The LOE on that is 2027. So that's the consideration as well. But at the end of the day, we've designed the Phase II dose -- our current Phase Ib dose escalation study to be -- to allow for all 3 agents. So we don't have necessarily a favorite. That decision kind of be deferred until we kick off that potential registrational studies next year.

I think the important thing is all 3 are fantastic drugs. And so we are agnostic to which of the 3 that we end up moving forward in the pivotal studies in combination with ORIC-944, which is you just think about from a BD or strategic perspective, is a very good thing for us that we don't have a preference among the 3.

Yes, great. You do expect to provide a program update I think, this year. So what should we look for from that update?

Yes. So again, we presented the initial dose escalation monotherapy data in January. The guidance at that time is we started dosing with one of more AR inhibitors in the first half of this year, and we provide a general program update. So that isn't necessarily going to be any new clinical data. That will just be more of an update on where we are with the program. If we've started dosing, which agents we started dosing and kind of how we're thinking about next steps.

As you think forward of like where this combination could go, how are you thinking about it being in a naive patient population versus the rechallenged population? What do you think -- where do you think this will end up?

Yes. So right now, what we know in terms of Pfizer's Phase III studies, I mentioned that they've green lit 2 different Phase III studies in the metastatic CRPC population. One population is that abiraterone experienced population but enza naive. Second population they have green lit is actually not that enza rechallenged population but actually going earlier. So they're going to the treatment-naive metastatic CRPC setting. Those 2 populations make a ton of sense to us as well from a biology perspective, also, obviously, from a commercial perspective. I think as you look at the landscape of prostate cancer drug development, though, obviously, it would make sense for us to go even earlier than that potentially into the hormone-sensitive setting as well. So all of those would be of interest to us. What I will say is, as small biotech company, we feel very good about having the financial resources and then the operational bandwidth to be able to handle the 2 Phase III studies we just talked about. So the abiraterone experienced metastatic CRPC setting and the treatment naive CRPC setting. I think we can go even earlier than that, that's when it would make sense to have a bigger -- exactly a bigger partner on board. But internally at ORIC, we have strong balance sheet, strong runway, and we have the head of clinical development for apalutamide is our head of clinical development at ORIC. And so we feel very good about being able to execute on the 2 studies in the CRPC setting.

Okay. I had another question but maybe I'll come back I'll remember it. But first, you just talked about cash runway. So cash runway, what's the status? How do you guys think about capital sources?

Yes, very long but I'll let Dominic put this specific to it.

So we actually did complete a pipe in January, $125 million pipe with 6 top-notch health care specialist funds. So with that, we ended the first quarter with $331 million in cash on investments. Based on our current operating plan, that gives us cash runway into late 2026. And that is a fully burdened number. That does assume that we're moving forward with both 114 and 944, and we're kicking off these registrational studies that we just talked about for both programs in the second half of 2025. And so obviously, we're very thoughtful about how we raise money. We love to have good long-term investors in our cap table. So are we thinking about that. Obviously, we're not going to go into any specifics today, though.

Okay. I remember my question, which was, it sounds like the differentiation as you think about having a potential best-in-class efficacy profile is partly on duration, given what you said about EED versus EZH. So like how do you think about when you can start to bear like to prove out the differentiation between your program and the Pfizer program?

Yes, I'll put it this, [ Karen. ] And so as we looked at every -- our team is on our homework. So as we look at every preclinical experiment we can run, whether that's head-to-head with Pfizer's drug, whether it's in combo with an AR modulator, versus Pfizer's drug in combo with an AR modulator, with the in vitro synergy experiment when we've looked at the translational data, the single agent clinical data, every single possible metric where we can compare to Pfizer's drug, we look as good or better in every one of those metrics. At the end of the day, we don't have to be better in terms of if you look at a $10 billion population and you look at the prior -- exactly, when you look at the prior analogs of enzalutamide, apalutamide and darolutamide, apalutamide was the second drug to market by years in that space and does $2.5 billion of sales growing at 25% a year. Darolutamide is the third kid on the block, years after the other 2 and is already a blockbuster growing 40% to 50% a year. So -- well, bottom line is here, our goal is just continue to execute and just be as good as Pfizer. We don't have to be any better and this will be a huge opportunity.

That's a pretty good place to end. Thank you so much for joining us. Thanks to everyone who is joining us here. I appreciate all the time.

Thanks for having us.

Thank you.