All right, great. Well, good morning. My name is Michael Schmidt. I am a senior biotech analyst with Guggenheim. It's my great pleasure to welcome ORIC to this fireside chat with us today. We have Dominic Piscitelli, CFO and Chief Business Officer as well. So welcome. Thanks for joining us. And Dominic, before we jump into Q and A, could you please help us with a quick overview of the company? Yeah. First, I want to thank the Guggenheim team and Michael for having us here at the conference and the opportunity to present here. So ORIC is a clinical-stage oncology company. Our name really encapsulates our mission. ORIC stands for Overcoming Resistance in Cancer. Given the team that we've assembled and the expertise of the team, our key areas of focus are prostate cancer, lung cancer, and breast cancer. And again, because of the team and the capabilities that we've put together, we do have a two-pronged approach to building out our pipeline. So we have our internal research discovery engine, as well as development and regulatory capabilities. And we complement that with opportunistic business development, which is led by Matt here to my left. Right now, we have two programs in the clinic. The first is ORIC- 114. This is a brain penetrating EGFR HER2 exon 20 program that we're studying in lung cancer. And then we have ORIC-944, which is our allosteric PRC2 inhibitor that we're studying in combination with AR inhibitors in prostate cancer. So I'll stop there, and we can jump into the Q and A. Great. Thanks, Dominic. So why don't we start out talking about ORIC-114, the EGFR HER2 exon 20 inhibitor? We saw phase 1 data at ESMO last year, 2023. And so just remind us of the key takeaways from that initial data disclosure on ORIC-114's efficacy and safety profile. Yeah. So we did present our initial POC data. This is dose escalation data at ESMO last October. A couple of things I just want to call out here. If we look at the patient population that we recruited here, this was a heavily pretreated patient population. Most of the other competitors in the space excluded patients that were pretreated with exon 20 inhibitors, and they also excluded patients that had active brain mets. So we allowed both of those. So as a result of that, about 81% of the patients in that study, in the dose escalation study, had seen a prior EGFR exon 20 inhibitor, and about 86% of the patients had baseline brain mets, including active and treated brain mets as well. In this heavily pretreated patient population, we did see responses at multiple doses, both systemic responses and CNS responses in both cohorts, the EGFR exon 20 and the HER2 exon 20 patients. In addition to that, the drug was well tolerated. We had no grade 3 rash at the time of the ESMO disclosure, and we only had a small percentage of patients that had grade 3 diarrhea. We did highlight kind of the ideal patient vignette. There was a woman who was 55 years old. She had failed chemo. She had failed amivantamab. She went on to our drug, and she had a complete response in both the lung and a complete response in the CNS. Now, this was a patient with an active, untreated brain met. This is what you want to show if your drug is really active. And again, we showed a complete response in that patient as well. So that's kind of what checked the box for us from a differentiation standpoint and allowed us to move forward on that program. Great. And then just remind us on what you've done in terms of RP2D selection. And I know you're enrolling now dose expansion cohorts. Just remind us which patients are being assessed here and in what cohorts? Yeah. So at the time of the ESMO presentation, I think we dosed up to 75 milligrams. We were still dose escalating. We had not reached the MTD. Since that time, we have selected the two provisional RP2Ds. And again, this is in response to Project Optimus with the FDA. And we're moving forward. We have moved forward with two doses, the 80 mg once a day and the 120 mg once a day. So we've basically started dosing three expansion cohorts in Q2 of this year. One is the EGFR exon 20. These are second-line patients. Then we have HER2 exon 20. And again, these are second-line patients as well. And the third bucket is the EGFR atypicals. Now, we had not presented any data at the time of the ESMO presentation. This is a new cohort of patients that we had added on based on some preclinical work that we had done with the research team. Great. And so maybe then diving in a little bit more into the exon 20 lung cancer opportunity. So we've obviously seen the J&J Papillon trial results late last year, and there's been data on other TKIs that are sort of forthcoming as well. And so maybe just talk about where you see the greatest unmet medical need right now in the exon 20 EGFR space and how we should think about ORIC-114's positioning relative to other EGFR exon 20 inhibitors. Yeah. I'm going to take that one, Matt. Yeah. I think just to follow up on what Dominic has said about the data we've shown and both how the molecule is developed preclinically. But we really think the key source of differentiation for ORIC-114 is the CNS penetration. I think you referenced Janssen's Papillon study. That was kind of the phase 3 study in first-line patients that was actually positive. What's interesting is a couple of things from that data set. I think, one, if you drill into the patient population and the subset analyses, in patients that had any form of history of brain mets, which was about a quarter of those patients, actually did much worse. They had a much higher hazard ratio than patients that did not have any form of CNS activity. So that would tell you it suggests there is an unmet need in those patients. The other thing in the enrollment criteria for that study, they exclude patients that actually have any form of active brain metastases. So they're kind of excluding a key portion of the patient population. We estimate at least one third of patients will actually present at diagnosis with some form of brain mets. Of course, we're enrolling those in our studies. We're enrolling active brain mets. It is not required for patients to have previously treated brain mets. So that is a very unusual feature of our study. Again, it speaks to kind of the differentiation that we see and that we want to see in the clinic. So we feel that that is a main source of differentiation for 114, not only to be able to treat those patients that actually have brain mets, but also in the longer term preventing patients from actually developing brain mets in the first place. And we hope that that would lead to much better clinical benefit, a lot longer progression-free survival than what we've seen so far with other competitor molecules. I think you said this cohort is enrolling second-line patients. Have those patients received amivantamab before? Are they amivantamab or EGFR exon 20 naive? Sort of what sort of type of outcomes are you looking for in the cohort next year? Yeah. So we are enrolling both types of patients. So we will be enrolling patients that had prior chemotherapy and prior amivantamab. And we also more recently have initiated treatment-naive patients as well. And so we're looking forward to kind of generating data on both types of those patients. What we've seen more in the previously treated patient population, which is what we've seen from most of the competitors, kind of the ORR that others are reporting are kind of in the 35%-40% range. That's kind of what we have is in that range. And that's kind of what has given other companies confidence to launch pivotal studies in that patient population. All of the pivotal studies ongoing right now exclude patients with active brain mets. So we are enrolling those. And so technically, we would be enrolling a more heavily pretreated patient population. But we would expect with our drug, we want to be consistent in that range that other people are reporting. Gotcha. All right. Great. And then switching over to your HER2 exon 20 lung cancer cohort, where there's obviously an HER2 approved now and other TKIs that are being evaluated. So again, talk about sort of the opportunity for 114 in that context. Yeah. So this is in the HER2 exon 20 lung cancer space. The competitive landscape's a little bit different. So there's some companies going after the EGFR exon 20 or the HER2 exon 20. We are actually pursuing both in parallel. The landscape is different, but there are active molecules. I think we've seen data more recently from Bayer and Boehringer Ingelheim. So they have both moved their molecules forward into phase three studies in front-line lung cancer. And so we're actively monitoring them as well. Our potential areas of differentiation are exactly the same. And so we do hope to have a much more safer molecule. Again, our molecule's designed to be very specific for exon 20 mutations. So we've seen that preclinically. We've seen that in the data that we've presented at ESMO clinically. We hope that that continues. But what we've seen from the other programs in the space, not only do they have the on-target EGFR toxicities such as diarrhea and rash, but they also have off-target toxicities, Grade 3 liver enzyme elevations, QTc prolongations, things like that that can really limit long-term durability with those molecules. So that is a source of differentiation. The other thing, same as we have with the EGFR Exon 20 space, but the CNS penetration we think will be highly differentiating in the HER2 space as well. The two molecules that have moved forward haven't reported preclinical data that their molecules were actually designed for CNS penetrance. We have seen from the Boehringer data, they have reported an ORR in kind of the 60% range. So it's a very active molecule. What they've also reported in the patients that actually have CNS metastases, their CNS response is less than half of what they see in the lung, so I think that speaks to they don't have a sufficiently brain penetrant molecule. So hopefully, we can improve on that, and then what we've seen from Bayer, there have been no reports that their molecule is brain penetrant. They exclude patients with active brain mets, kind of the similar theme that we see in EGFR exon 20, so our areas of differentiation are relatively consistent. Great. And so it sounds like you'll be updating the EGFR exon 20 and the HER2 exon 20 cohorts at the same time. Is that correct in the first half of next year? Yeah. So we haven't given specifics on how we're going to do it, Michael. The goal ultimately would be to report on all three expansion cohorts in 2025. What we end up doing, first half, middle, and second half, maybe we'll provide a little more guidance, which we typically do at the beginning of each year. We kind of reset our guidance and give the street a little more guidance on the timing and expectations. What we've said for the three readouts is, again, we want to see all three readouts next year. The goal would be to really select the RP2D, assuming a go scenario. So we want to make a go, no-go decision based on the competitive profile, select the RP2D. And the goal would be to start a registration study as soon as the second half of next year. Now, because of the profile here, because of the CNS unmet medical need, we do believe there's an accelerated approval path forward here. So this is a single-arm study. Obviously, we can talk about the confirmatory study we'd have to do as well. So that's the kind of current plan. Again, we'll provide a little more specificity early next year. With regards to number of patients, what we'd like to see here is about two to three dozen worth of patients in each of the cohorts in order to make that decision on the go, no-go next year. Understood. And before we move on, just on the atypical EGFR mutations, obviously interesting opportunity given the relative frequency relative to exon 20 being higher. And just real quick, what do we know about 114 in that context? Yeah, a couple of things. I think one, yeah, we are excited by that opportunity. I think one, it does seem to be a much more prevalent family of mutations. So it's expected to be larger than the EGFR exon 20 space, which we estimate a little over 2% of lung cancer. I think others are estimating that the atypical patient population could be 3%, potentially higher than that, which is much bigger than some of the other targeted therapies like ROS and RET and TRK and some of the other targeted therapy markets. So it's a relatively sizable population. It's a very significant unmet need. There aren't any therapies that are approved broadly for atypical population. So it is a wide open area. What gets us really excited by the space is kind of the preclinical data we've generated to date, which we have presented. As Dominic mentioned earlier, our molecule was designed to be very potent for EGFR exon 20 and HER2 exon 20. Since then, we have profiled our molecule on atypical mutations. And it just so happens to be much more potent on the atypical mutations than we see in the exon 20 space. We are excited by that. We have presented data at many conferences, most recently a few months ago, where we've profiled our molecule against all kind of the known competitors. And what we've seen there is it seems like our molecule is much more broadly active and much more potent than the other molecules in the space. We are excited both by the data we've generated in exon 20 space. We know we have a safe and well-tolerated molecule. We know we have CNS activity. Now combined with the preclinical data, we think we have a very strong candidate for atypical mutations as well. Okay. Super. So we'll look forward to seeing some of that data next year, 2025, as Dominic mentioned. So perhaps switching gears to ORIC-944, the PRC2 inhibitor. So maybe just stepping back, what makes PRC2 an interesting target in prostate cancer? Yeah. So if we look at the PRC2 complex, obviously, there's two druggable subunits. There's the EED subunit, which is what 944 is, and then there's the EZH2 subunit. Broadly speaking, companies have been exploring PRC2 inhibitors in prostate cancer for many, many years, going back to GSK, Constellation, Epizyme, both as a monotherapy and in combination. And there's been some interesting data. I think the issue that we've kind of come to realize is the first-generation PRC2 inhibitors have been plagued by poor drug properties. And what I mean by this is either short half-lives or the CYP autoinduction issues. And there's been a couple of companies that have shown this where they actually have a decrease in exposure with repeat dosing. So no one has shown profound single-agent activity in prostate cancer. It's all been about combinations. The biology is somewhat complex here. The theory is that as you treat patients with AR inhibitors such as enzalutamide, apalutamide, darolutamide, over time, the cells, the prostate cancer cells, become more AR-independent. With epigenetic modifiers like ORIC-944, what you're basically doing is synergizing it, pushing the cells to be more luminal, pushing the cells to be more AR-dependent, and allowing the AR inhibitors to work better, and I think Pfizer's done a good job of kind of profiling this preclinically, and then obviously, they've got some pretty interesting data that I'm sure we'll talk about today. Right. And then you have already reported some phase 1 data on 944 as a monotherapy earlier this year. And so just remind us of the key takeaways. Yeah. Its clinical profile, perhaps relative to the other inhibitors out there. Yeah. So we did present our initial dose escalation monotherapy data at a conference earlier this year. The objective of that readout was really focused on demonstrating potential best-in-class drug properties. Again, if we look at the first generation, again, we have the short half-life and the CYP autoinduction issue. So tazemetostat, for example, had a three-hour half-life, and they had the CYP autoinduction issue. Pfizer, they have a half-life slightly shy of four hours, but they've solved the CYP autoinduction issue. What we showed is a couple of things at the conference. One, we showed good synergies preclinically with AR inhibitors. Basically, you can compare ours towards Pfizer, and we were on par, if not slightly better. We showed good target coverage. We showed good tolerability as well. And we showed a clinical half-life of about 20 hours. So overall, everything we've profiled our drug versus Pfizer's compound, Mevrometastat, I'd say we're as good, if not slightly better from a comparison standpoint. So it's because of that that we feel comfortable kind of kicking off the combination studies with both AR inhibitors mid this year. So we started dosing with two drugs, with apalutamide, which is obviously J&J's AR inhibitor, and then in combination with darolutamide, which is Bayer's drug. Matt here was able to secure clinical supply agreements for both of the drugs, which as a CFO, that's obviously music to my ears because that's huge savings from a cost perspective. And the benefit also is you have strategics like J&J and Bayer at the table kind of providing input on the study designs and considerations as well, so. Right. And so what are learnings from the Pfizer phase one data so far? I know they updated some of that earlier this year. And they obviously did move forward with advancing two phase three studies in prostate cancer now. Yeah. I'll take that, Matt. Yeah. It's actually pretty interesting what they've shown so far is they've kind of over the last maybe two years or so, they've kind of given us incremental data on what's going on with their program. Earlier this year, they had an innovation day in February where they highlighted a lot of their more promising programs. And they did give an update to their phase one study with Mevrometastat. Initially, they were developing this molecule in combination with enzalutamide. So they're kind of leading AR inhibitor. And they took patients that had previously failed an androgen receptor pathway inhibitor, so primarily abiraterone or enzalutamide. And what they saw in that patient population was pretty dramatic radiographic PFS, which is the known regulatory endpoint in prostate cancer. The data that they highlight was in patients that had previously been treated with abiraterone and then were put onto the combination regimen of their PRC2 inhibitor plus enzalutamide. They saw a radiographic PFS of 17.1 months in that patient population, which is very dramatic. What Pfizer has said is that you should expect a radiographic PFS of about 4.8 in that patient population. So dramatically better than anything else out there in prostate cancer in that patient population. That is the study that one of the studies that they have moved forward in their phase 3. They presented some updated data with that at ASCO. They had a poster at ASCO this year reiterating the same efficacy, but they gave a little bit more details on that study looking at the patient demographics. A little over half the patients had also received chemotherapy. It is a very heavily pretreated patient population in prostate cancer, so a fairly dramatic effect. They have also showed in patients that previously were treated with Enzalutamide in that patient population, again, they got Enzalutamide again plus Pfizer's PRC2 inhibitor. They saw almost a 12-month radiographic PFS in that patient population. Pretty interesting data from that early data set. The key caveat is obviously it's a phase one study. It is a combination study. It was not a randomized study. There's a lot of caveats to that. I think the other thing that they have pointed out too was that they find the data that they've shown to be interesting, but also that they have randomized phase two data that they have moved forward with. They actually have an ongoing open-label randomized study that has been going on for several years. They said that data that we haven't seen yet has given them a lot of confidence to move forward into phase 3 studies with that program. They recently said on their last earnings call two weeks ago that this randomized data set from their program, they expect to present it in a couple of months. I believe they've confirmed that we should expect that data at ASCO GU. And so we are obviously excited to see that. And since then, this year, they kicked off two phase 3 studies to move forward. So they are aggressively pursuing the program and are actively speaking about it. And the data that we've seen so far, while small, is pretty interesting. Right. And so that, yeah, ASCO GU data should be really interesting for the category as well. And there was some data recently also from Ipsen at ESMO from a similar approach in prostate cancer, which looked a little bit more mixed. So I think the randomized study was less conclusive. Just what do you make of that result? Yeah. Yeah. So data came out with Tazemetostat. This was a molecule that was being developed currently by Ipsen. This was a program that's kind of been abandoned in prostate cancer. This is one of the first-generation EZH2 inhibitors that had a lot of liabilities with it. I think one, it's not a very potent molecule. And then two, as Dominic mentioned, it's plagued with kind of all of the poor drug properties, a really short half-life. It has CYP autoinduction. You get lower exposures over time. So it was never really a good model, a good molecule to really test the hypothesis for a PRC2 inhibitor in prostate cancer. But they did come out with randomized data at ESMO this year that came out. And the data, it's hard to interpret, but basically with their combination, they saw 16.6-month radiographic PFS. And that's with Tazemetostat plus enzalutamide. And the control arm that they had enzalutamide also did quite well. It was a little over 13 months. And so that was kind of the data set they recently presented. A couple of the big differences from the Pfizer study is that one, this was a much earlier patient population. So they did not allow chemotherapy in this study. Two, they enrolled a very less pretreated population. And if you look at kind of the baseline demographics, there weren't very high PSA levels. So they really enrolled much more indolent diseases. But it's really a study that is kind of inconclusive with a molecule that isn't being actively developed in prostate cancer. So we look forward to kind of the Pfizer randomized data coming out soon. Right. Cool. Sounds good. And then obviously, as you mentioned, you have your own phase one combo study now up and running with either of the two AR inhibitors. So do you have any line of sight? Which one might be the more preferred combination for 944? And also talk about your expectations for potential disclosing data from your combo study next year. Yeah. I think the short answer is we think all three AR inhibitors are potentially good options. I guess enzalutamide, darolutamide, and apalutamide combined, they're doing $10 billion in sales. I think each one has their slight pro or con to it. The short answer is we are moving forward right now with both apalutamide and darolutamide. The protocol does allow the addition of enzalutamide if we wanted to add that as well. So we don't think there's necessarily a preferred AR inhibitor at this point. We think, again, they're all great drugs clinically and combineable based on everything we've seen to date preclinically. With regards to our data readout, what we've said, again, we just started dosing the combinations in the second quarter of this year. This is dose escalation data. The objective here is obviously to find the RP2D or provisional RP2D for 944 in combination with those two agents. So we're kind of not committing to when we'll provide a little more color on that. Again, maybe we'll wait till early next year. We'll provide a little more color on kind of what to expect and when to expect that initial combination data. Right. And then maybe in conjunction with competitor data next year as well, sort of what do you need to see sort of to make a phase 3 go decision for your own combinations? What type of data would give you enough confidence to move ahead? Yeah. So we're kind of moving our base case is to move forward and to start a phase 3 registrational study in the second half of next year. So our objective here again is through the dose escalation to select the RP2D, do some dose expansion, and then kind of move forward into that phase 3 study. I think right now we find ourselves only five-to-six quarters behind Pfizer. And we don't want to lose that kind of fast follower advantage that we have there. If we wanted to wait for that mature phase 3 data, phase 2 randomized data, again, we'd be waiting 17 months. It just doesn't make sense. So assuming we don't see any surprises in the data set and the combination, we're ready to move forward into that phase 3 study in the second half of next year. Great. So it sounds like a very busy 2025 ahead of you with one month for data in each of our space and then 944 in prostate cancer. So really looking forward to that. Yeah. Sorry. Thanks, Dominic and Matt. Really appreciate the time. Thank you, Michael. Sounds good.