Great. Welcome everyone. Thanks for sticking with us, through the afternoon hours of our first day of the Virtual Oncology Leadership Summit. As you know, I'm Yigal Nochomovitz. It's one of the biotech analysts here at Citigroup. If you have questions for ORIC management during the session, just email me, and I will scan them and, and be able to relay them to the company. So with that, it's my great pleasure to have with me, senior leadership from ORIC, Jacob Chacko, the CEO, Dominic Piscitelli, the CFO, and Pratik Multani, the, the CMO. So thank you all so much for taking the time. I think it's a story that a lot of the people listening are familiar with, but nonetheless, Jacob, I think, helpful to set the stage for us, give us just a quick sense of the pipeline, what are the key priorities for the company, over the course of 2024. Sure. Thank you for having us, Yigal. I think most folks are well familiar with the pipeline, so I'll keep my introductory comments quite quick. We are a company that, from a big picture perspective, focuses on cancer resistance. ORIC stands for Overcoming Resistance in Cancer. That, in a nutshell, sort of tells you a lot about the pipeline that we put together. The specifics of the pipeline, though, are that we've got to focus on small molecules primarily and in solid tumors primarily. And so with rare exception, you'll see that that's what the pipeline entails. We have three different programs that are in phase I-B studies currently that folks are familiar with. There's ORIC-944, which is a PRC2 inhibitor that's being developed in prostate cancer. There's ORIC-114, which is an EGFR and a HER2 exon 20 inhibitor being developed in non-small cell lung cancer. And then there's ORIC-533, which is a small molecule oral inhibitor of CD73, which we're developing in multiple myeloma. As most people are probably familiar, within just the last 4-5 months, we've had readouts on all three programs. The company has also publicly stated that for two of those programs, ORIC-114, the EGFR and HER2 exon 20 inhibitor, as well as ORIC-944, the PRC2 inhibitor, we've seen enough data from both ourselves as well as, in some cases, competitors to give us preliminary proof of concept such that we want to take those programs forward to the next stage of development. We anticipate that by second half of 2025, we could potentially have both of those programs in pivotal studies. So quite a bit of activity going on at the company. All right. Good. That was a very good, efficient overview. There's obviously been a lot of a lot of eyeballs on ORIC-944, your PRC2 inhibitor. So let's start there. First of all, if you could just walk us through the biology of targeting PRC2 and specifically the EED domain, and why that's important for prostate cancer. And then we can move into some of your early data and the competitive landscape. Sure. We could probably spend the entirety of the session, Yigal, talking about the underlying biology of a PRC2 inhibitor and epigenetic dysregulation. But so I'll leave my comments at a very high level, which is that essentially what happens, in prostate cancer, folks are very familiar with enzalutamide, apalutamide, and darolutamide, which are second-gen AR modulators that have done a phenomenal job for patients with prostate cancer. Eventually, those prostate tumors, though, end up evolving to get escape around those drugs. And essentially what ends up happening is that the prostate tumors, become less and less AR dependent over time, eventually end up, getting more AR independent. And so the thought is that a PRC2 inhibitor, through its, impact on epigenetic, regulation and dysregulation can actually push the, prostate tumors to stay in an AR dependent state. So in other words, a state in which those other second-gen AR modulators have their best activity. And so the thought is, and we've shown this through preclinical data, another competitor, Pfizer, has shown this through their own preclinical data, that there is synergy in combining an AR modulator with a PRC2 inhibitor. Now, there are nuances that we can get into as to what we mean by PRC2 inhibitor. In our case, it's an EED. It's through targeting the EED subunit of the PRC2 complex. In the case of Pfizer or other competitors, it's through targeting the EZH2 subunit of the PRC2 complex. In either case, you expect to have strong inhibition of the PRC2 complex. And like I said, we can get into some of the other nuances later in the discussion. Well, it is a pretty sophisticated crowd, I think. So is there a comment you want to make in terms of why EED versus EZH2, or is it just another way to attack the target? Yeah, it's at the highest level, Yigal, it's another way to attack the target. What I'd say is, though, there has been the PRC2 inhibitors have been around for a long, long time. The whole first-gen approach was really focused on, the EZH2 subunit that we mentioned. I think for folks that have followed the space for a long time, people will be well aware that that the number one property, the number one issue or problem in the space has been drug properties. And what I mean by that is if you look at the various PRC2 inhibitors that have come through over the course of time, whether that's EZH2 or even in the case of an EED inhibitor that came before us in MAK683, what you've seen is one of one or both of two problems. One is a short half-life. So oftentimes, the drugs in this space have a half-life on the order of anywhere from 1- 4 hours, which is obviously quite short. The second issue has been CYP autoinduction. And so that's a property whereby, you know, the only approved PRC2 inhibitor is tazemetostat, which happens to be an EZH2 inhibitor. Tazemetostat actually has both of these issues of a short half-life as well as CYP autoinduction. And it's well documented that you get dose-dependent decreases in exposure for those drugs that have CYP autoinduction issues. And so in the case of ORIC-944, it happens to target the EED subunit of PRC2. But really, we were agnostic as to which of the subunits you would target, the whole point being we just wanted a drug that had good drug properties. This is a program that, we acquired from Mirati back in 2020. And what we like about the approach that the Mirati scientists took when they were developing this drug is Mirati was also agnostic as to EED versus EZH2 inhibition. They saw the same issues we did, which is that the drug properties for these PRC2 inhibitors, whether they were EED-focused or EZH2-focused, have been quite poor. So Mirati laid out a high-bar target candidate profile. They then synthesized several EED inhibitors as well as EZH2 inhibitors. And they just let the preclinical experiments dictate which program won. So they put them all through the paces in terms of what met the high-bar target candidate profile in terms of drug properties. They looked at the in vivo activity of the various compounds. The one that empirically won was the drug that is now ORIC-944, which is an EED inhibitor. So that's what I love about it is it was literally just an empirical preclinical experiment that brought this drug to the forefront in terms of what Mirati was developing. Now, separate from that empirical experiment, there is absolutely theoretical rationale why it is better to target the EED subunit than it is to target the EZH2 subunit, the main, main factor being long-term resistance. So on a like-for-like basis, an EED inhibitor and an EZH2 inhibitor that both have exactly the same drug properties, exactly the same potency, you would expect to see equal ability to inhibit PRC2 activity, upfront. Where you would still see a difference, though, potentially is in the long run around resistance. And that's because EZH2 inhibitors would be susceptible to acquired resistance mutations, in EZH2. They'd also be susceptible to bypass resistance from EZH1 or bypass activation from EZH1. That neither of those pathways of resistance would be applicable to an EED inhibitor. So that's why, on a like-for-like basis with equal drug properties, equal potency, the tie, if you will, would go to you would be broken by the EED inhibitor's ability to prevent long-term resistance. But there is a big supposition to what I just said, which is that there's like-for-like drug properties. And again, we don't think there's like-for-like drug properties. We actually think 944 has fantastic drug properties compared to the competitive landscape out there. Okay. That was very comprehensive, very helpful. So let's shift then to the clinical. So you showed us the phase I-B data, a sneak peek at the phase I data in January. Summarize that for us. And then, of course, the next big update is in the middle of the year. What should we expect in terms of the obvious questions, the number of patients, the key metrics we need to be looking for? What would you see as the threshold for success to move the program forward? Thanks. Yeah. Let me have Pratik, our Chief Medical Officer, cover what we just presented, and then I'll talk about expectations beyond that for future data updates. Sure. Thanks, Jacob. So, the data that we presented came from our ongoing phase I-B study of ORIC-944, single agent in advanced prostate cancer. And as with any phase I dose-finding study, you know, we had the standard objectives for the trial, such as single agent safety, pharmacokinetics, and demonstrating target engagement. But on top of that, with the issues that Jacob just really went into that have compromised the first- and second-generation PRC2 inhibitors, one of the overarching objectives of this, excuse me, initial readout was focused on demonstrating that ORIC-944 did have best-in-class potential, based upon its superior drug properties. So we showed in this update a number of points. First, preclinically, we disclosed data demonstrating true biological synergy with AR inhibitors in prostate cancer models. And so this really sort of further supports our development path of combining ORIC-944 with AR inhibitors. Second, getting to Jacob's points, we demonstrated strong drug properties with ORIC-944. And that was, as I said, a key objective of this data disclosure. No CYP autoinduction, a long half-life, greater than 10 hours compared to historically the less than four hours with the other PRC2 inhibitors. Robust target engagement. And this was measured by H3K27 methylation in peripheral blood cells. And we saw maximal decrease across multiple dose levels starting as low as 200 mg once daily. And then finally, a well-tolerated safety profile with only Grade 1 or 2 treatment-related adverse events, less than 900 mg dosings. So safety, target engagement, and importantly, the drug properties that Jacob referenced. Okay. And then, Jacob, do you want to touch on how we should think about the next set of updates in the middle of the year? Yeah. So what we announced at the start of the year, Yigal, was that, sorry, it looks like my computer's having some lag issues. Are you all able to hear me? I can hear you. It's a tad choppy. I don't know if the Open Exchange can clean that up, but I can hear you. Yeah. It might be that our CFO, Dominic, is pretty cheap and hasn't given me a computer upgrade in a while, Yigal. So it might be the error on our side. But I'll try my best on the audio. So we gave an update at the beginning of this year, that, for, you know, the data update that Pratik provided. But beyond that, we said operationally, we had seen enough from a competitor program, namely Pfizer, to greenlight the ongoing advancement of the program. And I'm sure we can get into what it is we saw out of the Pfizer data that we found interesting. And so what we said was that from an operational perspective, our plans in the first half of this year were to start the combination work of ORIC-944 with one or more AR inhibitors. There's obviously three different options out there for second-gen AR inhibitors. There's apalutamide from Janssen. There's darolutamide from Bayer. And then there's, of course, enzalutamide from Pfizer Astellas. And so we said that we would combine 944 with one or more other AR inhibitors, as part of dose-finding work, all of that in anticipation of, like I said, in the second half of 2025, starting potential registrational studies, with one of those AR inhibitors. The other thing that we said in the beginning of this year was that we anticipated providing another program update in the middle of this year. We were intentionally generic in the language we used of same program update, the reason being that could be anything from an incremental clinical data update, out of the single agent dose experience. It could be simply just a program update talking about the fact that we, you know, had in fact gotten the combo studies, you know, up and running. It could be the provision of free drug agreements in place with one or more parties. It could be additional preclinical data because actually, this is one of the few areas where additional preclinical data could be quite de-risking, certainly if it was preclinical data that compared us head-to-head with Pfizer or compared ORIC-944 with an AR modulator head-to-head with Pfizer's compound with an AR modulator. So it could be any of the above, Yigal. We just wanted to sort of give ourselves maximum flexibility in terms of what that update would look like in the middle of the year. Okay. So that we'll obviously get narrowed down at some point when we start to see conference abstracts and the like, disclosed. Is that fair? That's fair. Correct. Okay. And then you cited the three ways you could combine with the AR modulators. Sounds like you're testing all of them. Is there one that's preferred, or it's just a question of seeing how they play together, you know, in a human being? Yeah. Why don't I ask Pratik to talk about whether there's one that's preferred? And maybe even before he does that, Yigal, I'll just kind of talk about what it is we saw from the Pfizer data that got us excited about greenlighting the moving forward of this program in combination with one or more of those AR modulators. I think, again, at this point, many folks are well aware of the Pfizer data that was presented last year. This is a program that they've been developing over the course of a number of years. They had their first major update on this program at ESMO of 2022 that showed a headline PFS number that was very interesting. But it didn't really give you the breakdown of the different patient populations. And I think what was new to people last year was that on a Pfizer earnings call in May of last year, they provided a more detailed breakdown on two different populations of patients in the CRPC setting who they had given their drug in combination with enzalutamide. In the case of one of those populations of patients, those were patients who had already had enzalutamide and progressed. So they were Enza experienced. They were then getting Enza for a second time, but this time in combo with Pfizer's EZH2 inhibitor. There was a second population of patients who had never had Enza, had only had abiraterone and progressed, were getting enzalutamide for the first time, but again, in combination with Pfizer's EZH2 inhibitor. What they were able to show in both of those populations was a profound improvement in what you would have expected in terms of radiographic PFS. In the case of the Enza experienced population, where you would have expected 2-3 months radiographic PFS, they were able to see something on the order of 3x that in terms of radiographic PFS. In the case of the Enza naive population, where you would have expected 4-5 months of radiographic PFS, again, they saw three times that in terms of the radiographic PFS that they saw in the combo with their EZH2 inhibitor. Those data, I think, are what got us, you know, excited about pursuing this, in combo with one or more of the AR inhibitors that you referenced. Then I'll ask Pratik to comment specifically on whether we view those AR inhibitors to be different. Well, the short answer to that question is actually, we don't have a preferred AR inhibitor at this point. They're all biologically sort of, acceptable in terms of the synergy and the clinical effect we're trying to achieve. So they're all, right now under consideration, enzalutamide, apalutamide, darolutamide. They're all clinically and commercially successful. So there's no, you know, winner from that perspective necessarily. So we are, as Jacob said, planning to look, at identifying the recommended phase II dose of ORIC-944 with one or more of these AR inhibitors just to give us flexibility for further development downstream. That said, each of the AR inhibitors are not identical in terms of some of the drug, properties. Enzalutamide and apalutamide both induce CYP3A, which increases the metabolism of ORIC-944. To compensate for this drug-drug interaction, we would expect to need a higher dose of ORIC-944 in combination. And this is true for other PRC2 inhibitors as well, including the Pfizer 1497 molecule. So, you know, they themselves had to updose the 1497 in order to compensate for the DDI with enzalutamide. And so we would expect the same. The only molecule that doesn't have that property is darolutamide with no CYP induction. And so we wouldn't necessarily expect to adjust the 944 dose in that combination. Okay. But you're saying that doesn't necessarily make Dara a better choice. It just means it's just the choice to achieve the same exposure. Exactly. Yeah. Yigal, I think if you talk to KOLs in the space, whether that's oncologists or urologists who all have lots and lots of experience with the three different AR inhibitors, I think they would tell you that they are all fantastic AR modulators. They've all done fantastic for patients. The efficacy is right on top of one another. The safety profiles are right on top of one another. So it actually gives us maximum strategic flexibility as we think about what's the right partner to take forward into a global phase III study. The other really interesting aspect here is that enzalutamide goes generic in 2027. And so, it's really not only Janssen with apalutamide and Bayer with darolutamide that ought to care about a new novel mechanism of action in the form of a PRC2 inhibitor. It's really any large pharma with the prostate franchise ought to care about a new PRC2 mechanism here that could be combined with a soon-to-be generic enzalutamide, you know, as early as 2027. Okay. Now, my understanding, and I don't know, you know, how accurate this is, but I believe that there is going to be an update from Pfizer. You mentioned you referenced the update last year in May. What more can we say about the next update from their program, and how might that impact your view of the development for your ORIC-944? Yeah. It's a great question, Yigal. I think probably Dominic can tell you that the most common question we get these days is about the data from another company, not ourselves. It's really people asking about when is Pfizer planning to provide an update here. And, so I think folks will just probably have to ask Pfizer to figure that out, I in terms of when they're providing an update and what form that update will take. I think people are aware that they're having an oncology R&D day at the end of this month. And then I think there's been some talk of an update from them in mid-2024, which I think, you know, some people are assuming will be ASCO. But, you know, I don't know, beyond that, any of the details of what they're providing or what they're planning to share or not. From our perspective, I think what we saw from their update last May was more than enough, in terms of, providing de-risking to the path, taking this forward. There's obviously two different populations in the CRPC setting where, like I said, they achieved 3x the radiographic PFS that you would expect to see. So while it would be, you know, helpful and informative to see a little bit more info from them or a little bit more of a data update from them, I think we've seen what we need to see in terms of, greenlighting the next stages of development for our own program. Okay. But just to remind me, the work you're doing in the combo with the three AR drugs, those are in patients that are naive to those mechanisms, or they've seen them before? I wasn't clear. Can you just clarify to compare it to what Pfizer did? Sure. Pratik can talk you through that as well as the overall big picture study design. Yeah. Yeah. So the dose-finding that we're doing for combination would be in patients analogous to the Pfizer population in terms of patients who have come off of abiraterone but haven't had any of the AR signaling inhibitors. Because as Jacob was saying, there was the Pfizer cohort that had prior XTANDI that then was rechallenged with the combo and showed some nice activity. But you're in your combo work, you're not going to be rechallenging with Enza, right? Plus they then did not have Enza prior when you do Enza plus 944. Is that correct? Correct. Okay. And then as far as the pivotal, I know it's a bit of a ways off. I think you referenced 2025, Jacob, and you have a lot to figure out in terms of combinability. But, is there a base case as far as what you would do there? I mean, would you follow the retreat with XTANDI plus 944? I mean, not necessarily XTANDI, but AR mechanism plus 944. Is that the base case, or you just need to do more work to sort this out? Yep. Well, Pratik and his team tell me that second half of 2025 is not that far off, Yigal. So let me ask him to comment on that one. I think there's a lot of options on the table still. I I think I think the biggest signal, that Pfizer has disclosed to date is in the AbbVie experienced patient population. And then, you know, giving them an AR pathway inhibitor in combination with PRC2, in our case, ORIC-944. I think that would be sort of an obvious population, to go after. But there are other populations as well. You know, as you said, sort of the post-AR pathway inhibitor retreatment with combination. So right now, it's all on the table, frankly. Okay. But it would be a population that's seen one of the primary like it's seen AbbVie. You wouldn't go to frontline. Is that true? It's all up for discussion and debate, Yigal. I think the population that we know for sure ought to be part of it just based on well, actually, there's two populations that, you know, Pfizer has at this point de-risked in terms of the data that they showed. But I think the one that is probably most exciting just in terms of ability to have the most and longest impact on patients that we've seen thus far is that post-abiraterone, pre-enzalutamide, or pre-second-gen AR modulator population. That said, the biology and the biological rationale would suggest that you probably ought to test it even earlier. So pre-abiraterone in a CRPC setting, for example, or maybe you want to go into an even earlier setting, so a CSPC setting, or hormone-sensitive setting. I mean, all of the above could be, you know, studies that ought to be run at some point. I think if you look at the history of prostate cancer drug development, you know, not just within PRC2 inhibitors, but more broadly for drugs that have been approved in the space, you've seen multiple lines of therapy where drugs have gotten their approvals. You know, for example, enzalutamide's approved in three different, lines of within prostate cancer, in three different settings. And so, that is probably the long-term plan for the program is to eventually be developed in multiple different phase III studies that are really covering the prostate landscape. So, you know, I think as we alluded to in our initial comments, we as a small biotech are absolutely capable, both financially and operationally, of running one or two of these pivotal studies, you know, for in prostate cancer. But if you're going to really develop this correctly, you ought to get the help of a big, large pharma partner to do this in multiple different settings. And that's, sort of the advantage we have here of having many parties that ought to have an interest in this just strategically. So that at some point, we would foresee ourselves striking a global partnership to be able to develop this the right way, which is in multiple different settings, including the earlier line settings that you alluded to. Okay. I think we've covered 944 in a substantial amount of detail, which is good, unless there's anything else you wanted to touch on. Okay. Let's move to 144. Obviously, this is the exon 20 EGFR HER2 inhibitor. Also, you presented some recent data at ESMO last year, dose escalation. Maybe we could start with a quick recap of that. Sure. Pratik, you want to go for that? Sure. So happy to recap the data we presented at ESMO. But before I get into the specifics, I think it's important to provide some context of how we ran our study and the patients that we enrolled versus previous phase I studies with other EGFR exon 20 inhibitors. So almost every other drug that has come before us in this space excluded patients who had previously been treated with an EGFR exon 20 inhibitor and excluded patients with untreated brain mets. Now, these are two very important exclusion criteria. And really, apart from us, the only other company that included these patients in their phase I was Blueprint. Now, we all know that Blueprint recently discontinued the development of their program. So, at this point, it's really just us. And so we have allowed patients who had previously been treated with EGFR exon 20 inhibitors and patients with untreated brain mets, which then, if you compare across studies, our broader inclusion criteria led to 81% of the patients that we enrolled previously were treated with an EGFR exon 20 inhibitor, and 86% had baseline brain mets, including active and untreated brain mets. And so that, is really the context in which to put our data. So in these heavily pretreated and, I would say, advanced, patients, ORIC-114 was well tolerated. We had minimal EGFR wild-type related toxicity and little to no evidence of off-target toxicity. Most of our adverse events were Grade 1 or 2, a low rate of Grade 3 diarrhea at only 6%, and no events of Grade 3 or higher rash. And then only a 4% dose discontinuation rate due to safety. So the safety profile, we think, is a winner for the molecule. And then on the efficacy side, our sort of premise going into development with this molecule was demonstration of CNS activity. And we were able to demonstrate that across multiple dose levels and in both patient populations that we enrolled in the trial, EGFR exon 20 and HER2 exon 20. In particular, just to highlight, we presented a case of a patient who had previously been treated with chemotherapy and then got amivantamab. And she actually did very well on amivantamab for almost a year, but then progressed. And the site of her progression is not surprising given that amivantamab doesn't have CNS activity, which is she progressed in the brain as well as systemically. So after that, she came on to our trial, and these are active brain mets. They had not been previously treated with surgery or radiation. And this patient, nicely went on to a confirmed complete response, not just in the lungs, but also in the brain. And this patient, as of the data cutoff, was still ongoing at 9 cycles on treatment. So a very good outcome for this patient, despite having now come off of chemo and amivantamab. And really, just to highlight, this is the only demonstration of an EGFR exon 20 inhibitor giving you a complete response in the brain, in a patient who had active brain mets. So in addition to this one, we also presented another case of a patient treated at a low dose, 45 milligrams, who had two of their three CNS lesions resolve on study. In the patients with HER2 exon 20 mutated lung cancer, we saw also multiple responses across a range of doses, including one partial confirmed response that had actually 100% decrease in all the target lesions but had some persistent non-target lesions that prevented it from being called a complete response. So based upon all of these data, you know, at that we disclosed as at ESMO, as Jacob said, we've made the decision to go into multiple dose expansion cohorts in the first half of this year with a look towards registrational activities next year. Okay. And then how are you thinking about those registrational activities? Because obviously, as you pointed out, there's, you know, some competitors in the space, AMI plus chemo in the frontline, and there's some other oral TKIs also in pivotal studies in the frontline, as well as second line. You know, what are your thoughts and how you might differentiate from those? I mean, of course, you mentioned AMI not having the brain penetration, but some of the oral TKIs are also, you know, claiming brain penetration. They're claiming it, but not demonstrating it. I think that's an important distinction to make. And so we have really persisted with our view that we have an accelerated approval opportunity with ORIC-114 based upon our demonstration and, you know, we have to continue to demonstrate it, CNS activity. And so despite some of this changing landscape, we feel that this opportunity exists. CNS activity really has been kind of a driver for best-in-class profiles, not just in EGFR, but across a lot of targeted therapies in lung cancer. And that's, you know, for obvious reasons. A third or more patients present at baseline with CNS mets, and those who don't, many of them, if not all of them, given enough time, will go on to develop CNS disease. If treated with non-CNS active agents, they will more likely relapse in the brain, which is what you saw in what was, you know, sensibly a successful PAPILLON study, the frontline amivantamab chemo study that you referenced. You know, they had a positive study, but if you dig into the data and look at how the patients who had brain mets fared versus those who didn't, the hazard ratio for the patients with a history of brain mets was considerably inferior to those who didn't. And so again, you're still missing out that CNS activity and compromising the outcomes of the patients who have CNS mets at baseline. And so, you know, time and time again, ALK, ROS, RET, and then, you know, sort of conventional EGFR mutations, the drugs that come in with demonstrable CNS activity have come to the top. That's where we think the opportunity for ORIC-114 persists. Our, you know, our base case then is an accelerated approval opportunity with ORIC-114 based upon this CNS property. And are you still in the dose you've highlighted or you've determined the dose at this point, or is there still more work to do there? And can you flesh out in a little more detail what some of these dose expansion cohorts would look like? Sure. So we are going to be starting dose expansion this first half of this year, and those will be in three patient populations. First, EGFR exon 20. Now, not the patients that we enrolled in phase I. These will be patients who are naïve to a prior EGFR exon 20 inhibitor. Then patients with HER2 exon 20 mutations. And then something we haven't gotten into yet are patients with atypical EGFR mutations. Oh, yeah, that's an interesting comment. Are you referring to the class of what are called the PACC mutations or something else? Exactly. Yeah. Tell us about that. Yeah, Yigal, it depends on who you ask. Some call them PACC mutations. Some call them uncommon mutations. Others call them atypicals. We tend to call them atypicals, but they're all referring to the same thing. But yeah, Pratik can talk about why we're excited about that opportunity as well. Okay, sure. So, actually, you know, maybe we didn't get as much press at ESMO. We actually had a separate poster that outlined the work that we've done preclinically in these atypical EGFR mutations. So first of all, the patient population is actually larger than EGFR exon 20. And with all the competition that we've referenced in EGFR exon 20, there's very little in the atypicals. In fact, the only approved agent, afatinib, for three specific mutations is highly toxic and really not well accepted by physicians or patients. And so there's, I think, a wide open opportunity for development for this specific set of mutations. And as I said, potentially a larger patient population overall. So at ESMO, we showed that we have high potency against a range of these PACC mutants. In fact, our potency against many of them is higher than our potency against EGFR exon 20, which is why we've started enrolling them not just our plans for dose expansion, but even in our phase I so far. I'm curious, I mean, with this is a fairly new class, this is atypical or PACC. I mean, when you designed 114, was this sort of rationally designed to potentially address these, or was this sort of more of a serendipitous finding that it happened to have activity against this broader set of mutations? Yeah, it's more the latter, Yigal. So we actually in-licensed this program from Voronoi. So we didn't design this ourselves. What we liked about the program when we in-licensed it was that it was exquisitely potent, exquisitely selective for EGFR exon 20 and HER2 exon 20. It was brain penetrant. And so it really had the key characteristics that we thought would differentiate it in those two populations, which is the CNS activity. And then also on the safety side, we didn't expect to see a lot of wild-type toxicity related to EGFR. And importantly, we did not expect to see a lot of off-target toxicity, which a lot of these other programs have a lot of issues with off-target toxicities because of their kinome trees that are not very clean. What was completely serendipitous was that there does appear to be some homology between EGFR exon 20 and these atypical mutations, such that, you know, a handful of compounds are quite active against both. As Pratik mentioned, this drug actually happens to be even more potent against the atypical EGFR mutations, slightly more potent against the atypical EGFR mutations than it is against EGFR exon 20 mutations. And so that gives us an even wider therapeutic index for the atypical mutations relative to EGFR wild-type than we have in the case of EGFR exon 20. So the fact that in the ESMO update, we already showed clinically very strong activity with 114 in EGFR exon 20 mutations as well as HER2 exon 20 mutations. And the fact that the drug is even more potent against atypical EGFR mutations should bode very well for what we will eventually show clinically in atypical EGFR mutations. Again, one thing I want to be very clear on is at the time of ESMO, we had not enrolled any patients. We hadn't tried to enroll any patients with atypical EGFR mutations because we were really just focused on those first two populations, EGFR exon 20 and HER2 exon 20. So when we provide an update in the first half of next year, it will be an update on the first two populations, EGFR exon 20 and HER2 exon 20, but importantly, it will also include atypical EGFR mutations, the first patients that we enrolled with those mutations. And the reason I think that's so important, Yigal, is for a second, if we just let's just focus on the EGFR-related mutations. Let's put HER2 exon 20 to the side just for argument's sake. If we are only developing this drug for EGFR exon 20, it is—that's a larger patient population than either ROS1 lung or RET lung. And on top of it, if you add in atypical EGFR mutations, it's now a larger patient population than ALK lung. And so I know that one of the main critiques of the targeted therapies, especially in recent years as they've fallen out of favor with investors, has been somewhat disappointing commercial launches. But really, we think here that the opportunity for 114 in, you know, a couple of these different populations, so let's say EGFR exon 20 and atypical EGFR mutations, is actually quite substantial and something that investors, I think, are missing these days. Okay. That's very helpful. An area I think people maybe have explored less is the HER2 exon 20. What is the scale in that population, the market size there? And what about some of these? Do these HER2 selective TKIs not work in the exon 20 setting? Or even like in HER2, would that work? Tell us a little more about that. Yeah, I'll talk just at a high level about the size of the population, then ask Pratik to comment on your other question. HER2 exon 20 as a population in non-small cell lung cancer is just slightly smaller than EGFR exon 20. So it's on its own a quite attractively sized population from a commercial opportunity and patient impact perspective. And it happens to be one of the three populations that we're looking at at the time of the ESMO data update. We in fact had one more confirmed PR in the HER2 exon 20 population than we did even in the EGFR exon 20 population. So it is very much on our radar. But let me ask Pratik to comment on your question around the competitive landscape and in particular the role of in HER2 in that space. Yeah, happy to. So, for HER2 exon 20, actually the only approved agent, the only benchmark right now is ENHERTU. Overall response rate of just under 50% with a duration of response of they had multiple dose levels, so 16.8 months at the lower dose level. But even at this lower dose level, they had 40% of patients developing Grade 3 or higher treatment-related adverse events and a 13% rate of interstitial lung disease. So with that efficacy, it comes quite a bit of toxicity. And although ENHERTU has demonstrated CNS activity, in that study, they excluded patients with brain mets that required steroids. So that excludes patients who have sort of larger brain lesions. And as I said, we don't do that in our studies. There are two molecules in development, a Bayer molecule and a BI molecule. They're still very early stage. They have response rates of about 40%. We don't know what degree of CNS activity they have. So those are the benchmarks. We feel good about our potential, though. So this is in fact, Yigal, a less crowded space than EGFR exon 20 in terms of the competition that we face here in the clinic. And the exact same aspects of differentiation apply here, which is the safety profile of 114 and then also the CNS activity of 114 ought to bode well for our ability to differentiate in this HER2 exon 20 space. By the way, just one. I mean, that's not really trivia, but it's just interesting details that, you know, the ORIC-114 that you licensed has activity against both EGFR and HER2 in the same exon. I mean, is that I don't think that's a coincidence. Is there something? Was there some sort of like gene duplication, or is there very significant homology between EGFR and HER2 that results in activity against the same exon with this molecule? I'm just curious. Yeah, I don't think it's coincidence either, Yigal. I think there is some homology, which is why it's potent against both. Okay. Yeah, makes sense. Now moving. And then just one other point, Yigal. Sorry, I just wanted to follow up on one point that Pratik was making just around the role of HER2 in this space, because I know HER2 has earned some well-deserved praise for its activity in breast cancer. But I think that you can see in the HER2 exon 20 lung space, it is not very widely used, not certainly not the kind of use that it gets on the HER2 amplified breast side of the indications. And the best indicator of that, if you look at we were very explicit and transparent about the prior therapies that our patients had received at the time of the ESMO update. And you can see in the case of EGFR exon 20, the vast majority of patients had received amivantamab prior to enrolling onto the study. In the case of HER2 exon 20, it was only a small number that had actually previously received ENHERTU. There was really a smattering of lots of different other drugs, including investigational drugs that those patients had received. But ENHERTU really doesn't get widespread use in that HER2 exon 20 space, namely because of the toxicities that Pratik mentioned to you. The ENHERTU literally has a higher incidence of Grade 3 interstitial lung disease than we have total Grade 3 incidents for ORIC-114. So there's a real toxicity issue for ENHERTU and the HER2 exon 20 side. You mean if you add up all the Grade AEs across everything, it's less than the whatever you say. It's less than the 13% interstitial lung disease that are Grade 3 or higher for HER2. That's at their lower dose level, right? So they're. Right. Okay. All right. So then okay, so let's move on to 533 quickly. I know that's one you've sort of deemphasized and you gave an update last year around ASH. So what is the plan there? I mean, it's kind of, is it fair to say it's like on the shelf or how do we characterize the status? Yeah, let me ask Pratik to just summarize what we presented at ASH a couple of months ago, and then I'll talk about how to put that into the context of what we're prioritizing and deprioritizing. Sure. So we conducted a phase I study in patients with refractory myeloma with single agent ORIC-533. We were able to show a number of things PK-wise, a clinical half-life of 24 hours, so once-a-day dosing, incredibly well tolerated with no Grade 3 treatment-related adverse events, Grade 3 or higher. And we were able to demonstrate multiple points of immune modulation, CD8 positive T cells and NK cells. So we were modulating the immune system as we had intended with a very clean safety profile. And then something finally that is unique to this pathway, we were able to demonstrate clinical activity, clinical evidence of antimyeloma activity, including reductions in paraprotein levels in multiple patients. Yeah. And so, you know, when you put it into context, Yigal, we were actually really excited about what we presented with ORIC-533 at ASH in the sense that it is, as Pratik mentioned, the only time a CD73 inhibitor has been able to show single agent clinical activity. In this case, it's in eighth line, ninth line myeloma patients. And people have to keep in mind, it's through a, you know, pretty indirect mechanism of action in the sense it's not directly cytotoxic as a CD73 inhibitor. Essentially, what you're expecting is that the CD73 inhibition that's provided by 533 is turning down the adenosine levels in these patients and thereby turning up T cell activity and T cell engagement. That's what's leading to ultimately the multiple myeloma cell lysis and, you know, the multiple examples of patients that had paraprotein decreases, as Pratik mentioned, including one patient with a minor response by the working group criteria. All of that would suggest that we want to take it forward into combination, most likely with the BCMA-directed therapy, because that's where there's the strongest scientific rationale for combining this mechanism of action with an approved class of myeloma therapies. That said and that's probably what we would be doing in a vacuum, but we're not in a vacuum. We're in a situation right now, which is, you know, quite a good situation of having both ORIC-114 and ORIC-944 having a substantial amount of de-risking in terms of taking those forward into the next stage of clinical development. And like I said, we want both of those programs to be in pivotal studies by the second half of next year, second half of 2025. And that is really right around the corner. And so the company operationally needs to focus all our resources on getting those two programs ready for pivotal studies, you know, six quarters from now. And that being the case, we just don't have the bandwidth to also ourselves move 533 forward into a combo, you know, with a BCMA-directed therapy. And so that's what we announced at the time of ASH, that we do intend to finish out the single agent dose escalation here over the coming months with ORIC-533. But after that, we intend to pursue hopefully a partnership where someone with an existing myeloma franchise and ideally a BCMA-directed therapy could take that forward for the combo studies. And we can then focus our attentions on 114 and 944. Okay. And then there's one more program to discuss, which is still working its way towards the clinic, which is the PLK4. Tell us a little bit about that target. Where would you want to develop that asset? Yeah. So with PLK4, this is a program that is relevant to a synthetically valid pathway in patients that have TRIM37 amplifications. You tend to see those in about half of neuroblastoma and about 20% of breast cancers. This is a first-in-class potential first-in-class opportunity for us with a differentiated and selective program. And so we've had mentioned last year that we had a development candidate that we were putting through the paces on IND-enabling work. Nearly all of that has been completed at this point, but we have not yet said what the explicit plans for this program are, namely because, again, we're very, very focused on ORIC-114 and ORIC-944 at this point. And so with the entire clinical team's bandwidth focused almost exclusively on pushing those two programs forward, we've said that it's TBD on what we plan to do with ORIC-613, the PLK4 inhibitor at this point. So stay tuned for more updates later in the year. Sorry. So you mean that you're pausing the pre-IND work or you're doing that, but just at a very low capital commitment? The latter, continuing to do the pre-IND work at a low capital commitment and really just not wanting to take the eye off the ball on either 114 or 944. And so at some point, you know, later this year, we'll have an update on exactly where we stand with 613 and what we plan to do with it. Okay. And we got to bring Dominic into the conversation. He's been waiting patiently. So, can you report on the financial health of the company, the, you know, the cash runway, what, how you might, how you're allocating capital across the various programs, et cetera? Yeah, sure. So, Yigal, we ended 2023 with $235 million in cash and investments. As you know, we did complete a PIPE financing in January. We raised $125 million in gross proceeds from six specialist funds. There were three existing funds and three new investors in that PIPE as well. With those proceeds, including the PIPE finance, we did extend our cash runway into late 2026. And that's a fully burdened number that assumes success on both 114 and 944 as well as our earlier stage programs. And as Pratik and Jacob outlined today, that does assume initiating registrational studies in the second half of 2025. So that's, again, a pretty hefty number that doesn't assume any partnerships or anything on any of the programs as well. So from a cash perspective, we feel pretty good about where we stand today. With regards to business development, as you know, our strategy is to kind of use a two-pronged approach to building out the pipeline, using both obviously our internal discovery engine as well as business development. If you look at our pipeline today, as you can see, we've got both internally developed internally developed programs as well as in-license programs. So that's still part of our strategy. Obviously, given the focus on 114 and 944, we have a very high bar for what we bring in. And the last thing I'll say is given the team's area of expertise, we really focus on prostate, lung, and lastly, on breast cancer as well, so. Okay. It's not for lack of trying. I mean, we have just to be clear, we've been looking for the last 3.5 years since we last in-licensed a program. We've been looking at literally dozens and dozens of different programs because, as you can imagine, in the current market environment, there's a lot of opportunities with companies that either don't have sufficient management team bandwidth or cash or both. So we're looking at an abundance of those opportunities. And, you know, we hope to pull the trigger on something, but it's got to clear all our high bars in terms of the scientific differentiation, the potential for clinical differentiation, and, of course, economics that makes sense for us. So nothing yet, but we're going to continue looking. By the way, that just makes me, you know, wonder, with the PLK4, is it that you couldn't find something externally so you felt just you'll make your own? Or how did that or another. That's a great question. And actually, it comes into something that's a bit more philosophical in terms of how we think about which of the programs lend themselves towards internal discovery, as Dominic mentioned, versus which ones lend themselves to being in-licensed. And so in general, Yigal, if it's a novel, unvalidated target, novel mechanism of action, unvalidated target, those are the kinds of things we like to work on from our own internal discovery capabilities because we can then build the in-house expertise around what is oftentimes very complex biology. And PLK4, I would absolutely put into that bucket of types of targets. So that's why we worked on it internally. Our team got a jump start on that target, you know, a couple of years, actually, before there were two seminal publications in Nature on PLK4. So that's the kind of thing that really lends itself nicely to working on it internally before others even know about a target or have the wherewithal to focus on it. And then EGFR exon 20 is a perfect example of the kind of target where it's a validated target, very clear mechanism of action, well understood by folks. It's really more about the differentiation of a specific molecule versus what's otherwise, you know, already out there. And that lends itself to in-licensing in many cases where it's not really about novel biological understanding for those validated targets. It's more about just, you know, some angle on the chemistry. And if someone else has a better approach or a more advanced approach than what we have, we're perfectly happy to in-license it. So in the case of the PRC2 inhibitor for prostate and the EGFR exon 20 inhibitor for lung, that both were in-licensed. But I'd argue those were both more along the validated end of the spectrum on targets. Makes sense. Then just final question. I mean, most of the focus for this year will obviously be on 944. Did you want to just run through the catalysts for the year? I know 114 will be later next year. Yeah. Dominic, do you want to talk about that? Yeah. I think we covered most of it during the call today, but just to quickly run through it. For 114, what we've said is we're going to initiate the expansion cohorts in the first half of the year, and then we provide an update in the first half of next year. So stay tuned for that. And then 944, again, kind of the milestones are starting the combination studies in the first half of this year, then a program update midyear from ourselves. And Jacob kind of outlined what the options are around that. And then lastly, kind of the registrational studies in the first half of next year. I mean, it's not our catalyst, but obviously, any read-through from competitors are something that's kind of on people's radar as well. Yeah. And so I just want to clarify one thing. The start of registrational studies in the second half of next year. Oh, yeah. Thank you, Jacob. Dominic's really applying the time. Put some pressure on Pratik. Put more pressure on Pratik, yeah. If you say it, if you say it, you know, it's like it's real now. So he has to do that. All right. Well, this was a lot of fun. Thank you again. A lot a lot to look forward to. Very exciting few quarters coming up for you guys. So I'm sure we'll have plenty to chat on soon. Thank you. Yeah. Thanks for having us, Yigal. We appreciate it. All right. Take care. Thank you, Yigal. Thank you.