Welcome to this fireside chat with ORIC. My name is Michael Schmidt. I'm a biotech analyst with Guggenheim, and I'm pleased to welcome Dominic Piscitelli, CFO, and Matt Panuwat, CBO. Welcome, guys. Thanks for joining us. So Dominic, just a high-level question to start out with. You guys have three clinical-stage oncology programs now in the pipeline, and each of them pursuing you know different targets and pathways. Can you just remind us of your general pipeline strategy and how you select your programs? Yeah, sure. So, first of all, thank you for having us here at the conference and the opportunity to present today. So ORIC is a clinical-stage oncology company. Our name really encapsulates our overall mission, which is to overcome resistance in cancer. With regards to our strategy around building a pipeline, a couple of things. I mean, it's really a function of the team that we've assembled, going back to our founders, who've got extensive experience in drug development and primarily in prostate cancer. Looking at our research team that primarily comes from Genentech with a focus on breast cancer, and then looking at our clinical team, who comes from the likes of Aragon and Ignyta, with extensive experience in prostate and in lung cancer. So the three key areas of focus are prostate, lung, and breast cancer. Now, our approach is a little bit different. We kinda have a two-prong approach to building out our pipeline. We do have all the necessary internal research discovery engine in-house, so that feeds our pipeline. And the second approach is business development, which is led by Matt Panuwat, our CBO, and we really look at opportunistic, opportunities to bring in exciting programs that are highly differentiated or first in class. If you look at our pipeline today, it's both comprised of internally developed programs as well as in-license programs as well. So, just real quickly, we've got three programs, as Michael said, in the clinic. ORIC-114 is a brain-penetrant EGFR HER2 exon 20 program. ORIC-944 is an allosteric PRC2 inhibitor that we're exploring in prostate cancer, and the third program is, ORIC-533. This is an orally bioavailable CD73 inhibitor that we were exploring in multiple myeloma. So I'll stop there, and then we'll get into each program a little bit later in the presentation. Sounds good. Thanks, Dominic. So yeah, let's maybe start out with talking about ORIC-114, as you mentioned, your EGFR HER2 exon 20 inhibitor, and we saw some initial phase I data at ESMO recently last year. Just remind us of the key takeaways and how is the, the molecule positioned in, EGFR exon 20 landscape based on that? Sure. Thanks, Michael. So ORIC-114 is our EGFR exon 20 inhibitor. We announced our initial data from this program at ESMO just in October. I think there's a couple of key takeaways that we'd like to highlight on the program. I think one, what's very notable is the types of patients we enrolled in the study. It's very different than most of the studies going on in EGFR exon 20. First of all, we actually allowed patients to come into our study if they had been previously treated with an exon 20 inhibitor. Any number of exon 20 inhibitors, that's unusual in the space. The second types of patients we allowed in the study is patients that had untreated or active brain mets. And so those are two very important distinctions. There's a number of other EGFR exon 20 inhibitors in development. All of the studies before us basically excluded these types of patients. It's just ORIC, ourselves, and another company, Blueprint Medicines, that were allowing these types of patients. Since our data update, Blueprint has discontinued their program, and so, you know, we think that's an important distinction in the types of patients we enrolled. Because of this criteria, over 80% of patients enrolled in the study had already received a prior exon 20 inhibitor. 86% of patients had some form of brain metastases at baseline. That includes untreated and active brain mets, so it's a very heavily pretreated population. Despite these types of patients, we demonstrated that ORIC-114 is very safe and well-tolerated so far. It's still in dose escalation. We also demonstrated systemic responses. We demonstrated intracranial responses across a number of doses and a number of patients. So we're obviously very excited by that profile. The one thing that's very notable is we had a patient enroll in our study that had progressed on amivantamab, which is the only approved agent for exon 20, had progressed on chemotherapy, came into our study with active brain metastases that had been previously untreated. Came into our study, had a complete response in the lung, had a complete response in the brain, and at the time of data cutoff, was on ORIC-114 for 9 cycles, and ongoing at the time of data cutoff. And so that's something that hasn't been seen before, a complete intracranial response in a patient with untreated brain mets. We're obviously very excited by the program. We are advancing this into dose expansion cohorts in the first half of this year. Great. And, you mentioned the Blueprint program. So the exon 20 category is a little bit shifting right now. We saw the J&J PAPILLON trial read out positively, which will probably move amivantamab into first-line patients, first treatment of first-line exon 20 patients. You mentioned Blueprint, so maybe talk a bit more about sort of where you see sort of the greatest unmet medical need right now and sort of the opportunity for the drug in the landscape. Yeah, I think great, great question. I think, you know, our philosophy, we in-licensed this program several years ago, and when we looked at the landscape, I think the biggest significant unmet need here, which was then and still remains to be the case, is that there is not a brain-penetrant, you know, inhibitor that's very advanced in development. You're right, I think the Janssen study was positive. We would expect that to become a frontline therapy, amivantamab plus chemotherapy. There's two things to note about it. I think one, in the patient enrollment for their confirmatory phase III, they excluded patients with untreated brain mets. And that represents at least a third of the population. About 35%-45% of patients have some form of brain metastases, and then to ultimately develop brain metastases as they progress with the disease. So I think that's significantly missing in this landscape. And so not only amivantamab, but all of the other programs in development as well, don't appear to be brain-penetrant. We think that's a very important distinction to be able to treat these patients. And this is a recurring theme that we have seen in targeted therapies for non-small cell lung cancer. When we look at the ALK, the ALK space, the ROS space, the RET space, EGFR activating mutations, it has always been a brain-penetrant molecule, is necessary for a best-in-class therapy. So again, we're still early in development, but we think we have the potential to be best in class in this space. Yeah, and just to add to that, you know, the PAPILLON study, again, great results, but if you do look at the subset analysis that was presented in the New England Journal of Medicine, they, they broke out patients with a history of brain mets and patients without a history of brain mets, and the hazard ratio for patients with a history of brain mets was 0.63, and for patients without brain mets is 0.33. So it's pretty clear- Mm-hmm that they're not addressing these patient population, the mets addressing, and again, 35% of these patients. And it is, you know, Takeda actually put out some data a couple of years ago that the brain is a point of first progression in, like, 40% of these patients as well. So it's, it's a clear unmet need. We did think Blueprint was, you know, our, our most, our competitor in the sense, so the fact that they backed out is obviously a good thing for us. Obviously, we need to show the activity in the broader patient population, which we hope to do in the expansion cohorts. Yeah. Yeah, good, good, good segue to the next question. So, how close are you to identifying a recommended phase 2 dose? And talk about your expansion cohort plans and, you know, what are you looking at there? Yeah, that's great. Two great questions. So, with regards to the next steps, what we've said on this program is, as Matt said, we're going to start the dose expansion portion of the study. We're enrolling three groups of patients here. We're gonna do EGFR exon 20, HER2 exon 20, and EGFR atypicals. So that's what we expect to do in 2024. We said we'd initiate those in the first half of the year. We said we would present data in the first half of 2025. Now, that data readout will be comprised of two components. It'll be kind of the updated data from ESMO on the dose escalation data, as well as the data from the dose expansion portion. Now, with regards to the selection of the recommended Phase 2 dose, as you know, Mike, with Project Optimus, it's not as straightforward as it used to be. So the current plan is to move forward with two potential candidate RP2D doses for the dose expansion. It's really at the completion of the dose expansion, we'd select the RP2D, and that would be the dose you'd want to move forward in the potential registrational studies that we could start as early as second half of 2025. These expansion cohorts, are they...? Talk a bit more about the patient makeup. Are they pretreated? Are they less pretreated? And what is the bar in each of these three cohorts, in your opinion, in terms of efficacy? Yeah, I think the easiest one to focus on is probably EGFR exon 20. You're right, you know, the patients, as Matt said, the patient population that we enrolled, 81% of the patients had seen a prior EGFR exon 20 inhibitor. So this patient population, we're looking for patients that had not seen that. So this would be more equivalent on the same patient population as amivantamab enrolled and the Cullinan enrolled, except for the fact that we are enrolling patients with active brain mets. So the bar there, I think, you know, if you look at Cullinan, and it's 35%-40% response rate, so we'd want to be somewhere in that ballpark with. Obviously, we want to show some CNS activity as well. Is it the same for the atypicals and the HER2 space, or is it different there? Do you want to take that, Matt, or? Yeah. What was it? Sorry, I missed- Oh, just as sort of the efficacy bar in the atypical mutation subset and the HER2. Yeah, it's, it's generally about the same bar. Right. The landscape is a little bit different. There's different therapies in each one, but we're basically shooting for the same thing with the same profile in, across the indications. Okay, great. Perfect. All right, so then let's, excuse me, let's switch gears to ORIC-944, which is your PRC2 inhibitor, as you mentioned. So this is PRC2, first of all, it has two subunits, I understand, EZH2 and EED. You know, first of all, perhaps remind us of the mechanism of action and what is the mechanistic rationale of pursuing prostate cancer, specifically with ORIC-944? Sure. So ORIC-944, we call it an allosteric PRC2 inhibitor. People have been studying PRC2 inhibitors for a long time. Most people have chose to drug the subunit from the EZH2 angle, so there's a number of EZH2 inhibitors that have been developed for a long time. ORIC-944 is targeting the same target differently through the EED subunit. The main flaws that people have seen with the first generation PRC2 inhibitors is they're plagued by very poor drug properties. They all have short half-lives, they have CYP autoinduction, you get decreases of exposure over time. And so our philosophy with this program is just there hasn't really been a great PRC2 inhibitor that has been studied in the clinic. We in-licensed this program several years ago from a company, Mirati. We in-licensed the whole portfolio of PRC2 inhibitors. They had done a very extensive job of looking at EZH2 inhibitors, plus EED inhibitors, and had selected ORIC-944 as the best candidate out of their portfolio. Regarding the biological rationale for prostate cancer, which is a little bit different than some of the other indications where EZH2 inhibitors are approved, like follicular lymphoma, is that in prostate cancer, patients are on AR-directed therapies for a long period of time. They work extremely well, but over time, those patients progress, and prostate cancer becomes less AR dependent. Mechanistically, these epigenetic modifiers, like ORIC-944, are able to keep prostate cancer cells in an AR-dependent state, and actually reverse that progression into an AR-independent state. and so there has been a lot of excitement combining a PRC2 inhibitor with an AR inhibitor, and that's something that we look forward to do with ORIC-944. Great. And then you did, I believe, earlier this year, disclose some very early clinical data from the program. Just remind us of the learnings from that and how the study's been progressing. Absolutely. Yeah, so we just presented, you know, very early initial data last month to give folks a sense of sort of where we are with the program. I think, one, we presented some new preclinical data that basically showed there's strong synergy preclinically with ORIC-944 plus the combination of an AR inhibitor. We did compare that to kind of our leading competitor, Pfizer, and so we look comparatively similar from a synergistic perspective. So it was promising for us to show that. Secondly, which was our rationale for the program, to demonstrate that it has very strong drug properties. Again, that was kind of our main thesis of the limitations with other therapies out there. We did say that our drug has a half-life of at least 10 hours. And where other therapies, tazemetostat is the approved agent, it has a half-life of three hours. And again, in prostate cancer, our main competitor is Pfizer. They have a half-life of about four hours or less, so we thought it was promising to show that. Thirdly, we wanted to demonstrate that we have very robust target engagement, and so we did show that in peripheral blood cells. We're seeing maximal target engagement at doses as low as 200 milligrams once daily dosing, and then, of course, it was well tolerated. So that was important for us to see, primarily grade one and grade two adverse events. We did see a grade three event at 900, and so we're exploring doses lower than 900 milligrams QD. Great. And, you know, there's... As you mentioned, there's a few other programs that are going into prostate cancer. I think the Pfizer programs were the most, they're the best known, peer in a way. You know, first of all, remind us, what we know about the Pfizer program and how it reads through to you guys, if you can? Yeah. So I'll go first, and, Matt, feel free to chime in as well. So, Pfizer, for those of you that don't know, they did present some data on their Q1 earnings call, which basically showed the combination in two patient populations. One's where, XTANDI-experienced, where they showed a radiographic PFS of 8.7 months, which if you look at the historical benchmark there, it's about three months, so it's about a 3x improvement in that patient population. They also showed in an XTANDI-naive patient population. These are patients that may or may not have seen chemo, went on to abiraterone, and then went on to the combination of XTANDI plus their PRC2 inhibitor, and they showed a radiographic PFS of 17 months. You know, they quoted on their call as well, the benchmark there is five months or so. So again, this is a 3x benefit. The two caveats to that data set is that it was a small N. It was 12 patients for the, for the XTANDI-naive patients. In addition to that, it was a single-arm study. So we thought that data was super compelling. As Matt has said before, people have been exploring data, combination data in prostate cancer with PRC2 inhibitors forever. The issue's always been poor drug properties. Pfizer's drug seems to have good, better properties than, let's say, the first generation. So that I think it's a direct read-through for us, right? As you said before, it's part of the same complex as the two druggable subunits. If you look at the published data, both the clinical data, that's out there for EED inhibitors and EZH2 inhibitors, there is really no difference. Again, this is not prostate, but it's other indications. Their only other PRC2 inhibitor or EED inhibitor that was being explored in oncology was MAK683 from Novartis. They did discontinue that program. They did have less than desirable product profile as well. So we think it's a direct read-through to us, and we're anxiously awaiting that data set. I think that most recently they said mid-2024 is what we've heard. Okay, sounds good. So that's for their randomized phase II- That's a good point, Michael. So they do have an open-label, ongoing, randomized study. They've basically, it's 40 patients that are on the XTANDI arm and another 40 patients that are on the combination of XTANDI plus the PRC2 inhibitor, and these are patients that had failed abiraterone. Okay, so that should provide some clear proof of concept or additional proof of concept. And then, yeah, perhaps talk about your plans for the sort of phase I combo study. I think you talked about it briefly just now. You know, is there any one of the two or three approved AR inhibitors that is preferred for the combination with nine four four? Yeah. So the three approved AR inhibitors are enzalutamide, apalutamide, and darolutamide. Pfizer's obviously combining with enzalutamide since they don't have that drug with Astellas. We think that all three drugs are great. Preclinically, we don't see any difference in combining the three agents with our PRC2 inhibitor. And again, clinically and commercially, both, they're all great drugs. Obviously, apalutamide is owned by J&J, and darolutamide is owned by Bayer, who've obviously got great franchises in the space. I think combined, the three agents are doing close to $10 billion a year, so it's a huge opportunity. ... Right. And then, remind us what additional clinical data you're planning to share this year and how we should interpret the outcome from that? Yeah. So the guidance that we've given on this program, just to run through that real quickly, is we expect to start the combination dosing in the first half of this year, and that could be with one or more AR modulators. We do want to have some flexibility there if we wanted to, for strategic reasons. What we've said is we will provide a program update mid-2024, and this is me- not me-- You know, we're just keeping this very vague, to be honest with you. This could be just an update on where we are with the program. It could be some additional, clinical data from the single-agent part of the study, or it could be just a general update on where we are with the program and some preclinical data that we've done comparing ourselves to other drugs or in combination with, an AR modulator. Right. And maybe if we—going back to the Pfizer, the possible Pfizer update on the randomized phase II. So you did mention they had shown 17 months PFS in phase I, single-arm study, you know, much higher than the bar. You know, We'll see what they produce in phase II. But is there a, you know, a particular hazard ratio or a PFS differential that you think might be more or less compelling as we look at that Pfizer data, how—and how it translates to your program? Yeah, that's, that's a great question. So when you look at this patient population with a novel hormone therapy, you'd expect to see 4-5 months, let's say 5 months. With chemo, you expect to see 7 months. So I think if they show something, let's call it 10 months or so, I think that's a huge win for a chemo-sparing regimen, and that's obviously a great read-through to us. And, you know, again, we're saying we have potentially best-in-class drug properties. Whether that translates into the clinic, we'll see. Mm. But everything we've done internally is our drug is as good as Pfizer's 1497, so. Great. All right, then maybe in the last few minutes, touching on ORIC-533 and the rest of the pipeline. So, just real quick on ORIC-533, you had some data at ASH. Just remind us on, you know, sort of that program and how you think about it, in terms of next steps. Sure. So, ORIC-533, we presented data for the first time at ASH just a couple of months ago. This is a single-agent kind of dose escalation study in very heavily refractory multiple myeloma patients. The results we presented kind of checks all of our boxes of what we wanted to see from the initial data. One, it was orally bioavailable. Nobody has shown that before with a CD73 inhibitor, so it's nice to show that we could make an oral drug. Most of the drugs in development are antibodies. It had a very nice clinical half-life of about 24 hours, so we believe this will make a nice once-daily oral therapy for patients with multiple myeloma. It was extremely well-tolerated, so that's important as we think about long-term development in multiple myeloma. It's primarily in combination with other therapies. Most of the other therapies in multiple myeloma have a lot of toxicities, so having something with a very clean safety profile was important to us. We didn't have any Grade 3 or higher adverse events across, you know, these heavily pretreated patients. It is it's an immune therapy, and so we wanted to see activation of T-cells. We wanted to see activation of NK cells and really make sure we're affecting the immune system, so we were able to do that. And then we also saw very early signs of preliminary clinical activity. We saw reductions in paraprotein. We saw reductions in soluble BCMA. So it really kind of checked the box for us in terms of this first initial update. Okay. And then, lastly, you also have a preclinical program targeting PLK4. Just remind us, you know, what the potential is for that program and how close to an IND you are. Yeah. So, ORIC-613 is our selective PLK4 inhibitor. This, we went through IND-enabling studies last year. So the biology here is basically that TRIM37 amplification is seen in about 20% of cancers, and they're associated with poor prognosis and relapse. TRIM37 amplification requires PLK4 for growth and survival, so we'll be inhibiting PLK4. So this is kind of a synthetic lethality approach. We haven't given much guidance on next steps on this program, but we are excited about this program. There has been some competitors that have come out recently in this space, so this is, you know, a very competitive space. Right. All right, so it sounds like in the near term, we'll stay focused on 944, the Pfizer data, and then your own update around mid-year? I think that's well said. I think we think there's a lot of potential on both programs, 114 and 944. As Matt mentioned, we are gonna look to partner 533. We think the best path forward there is combination. So it's really laser-focused both on a capital standpoint and a resource standpoint, focusing on 944 and 114. Great. Well, with that, I think we can wrap up. Thank you so much, Dominic- Great. Thank you. Thank you. Matt. Yeah. Thanks.