All right. Thank you, everybody, for joining us for ORIC Pharmaceuticals. We've got the management team here joining us this morning. I appreciate everybody's time this morning, and great to have you guys down to Miami. Let's start with a brief introduction to ORIC and where you stand heading into 2024. What are you excited about, and what are the key topics that you want to make sure investors are focused on? Yep, sounds great. Thanks for having us. So ORIC stands for Overcoming Resistance in Cancer, which, in a nutshell, is the mission of the company. We've got three different programs that are all small molecules in various phase I-B dose-escalation studies. We're excited about all three of them. We just had a readout for ORIC-114, our EGFR exon 20 program at ESMO, which I'm sure we'll talk about. And then we've got a readout for ORIC-533, our program for multiple myeloma, coming up at ASH here in December. And then finally, ORIC-944, PRC2 inhibitor for prostate cancer, where we'll expect data next year.// Excellent. Well, let's start with that, ESMO update you mentioned, for 114. That's EGFR HER2 exon 20. Exon 20, obviously a very challenging indication. We recently saw an approved agent pulled from the market for failing a confirmatory study. There are also multiple agents in development. What's the current bar in the exon 20 space, and what is your differentiation from other attempts, or other approaches, I guess, in development? Yeah. So I'd say the first-order analysis of the EGFR exon 20 space, and for that matter, the HER2 exon 20 space, is that they're, it's crowded, that there's a lot of different programs that are either... Like you mentioned, amivantamab is approved from Janssen, or multiple agents in clinical development. I think the main issue is those drugs are not brain-penetrant. It has become dogma now in non-small cell lung cancer that you want a TKI to be brain-penetrant. The whole point is 35%-50% of these patients at initial presentation have brain mets. And so these drugs that are ahead of us in clinical development in this space do not have that brain activity, can't address patients with brain mets. Amivantamab, which is the only drug that's approved now in that indication- Okay ... just got approved, got its front-line approval based on the PAPILLON study, but excluded patients with active brain mets because it's not a brain-penetrant. It's a more antibody. Exactly. Yeah, so that's where ORIC-114 has real differentiation, is on the brain penetration, also on the safety. So that's the other thing that has held back EGFR exon 20 drugs historically, has been safety issues that are either EGFR wild type-related, like GI tox or skin tox, or off-target toxicities. And there's been a variety of problematic off-target toxicities from the other competitors as well. So in the ESMO update that we just presented, we saw a very safe profile for the drug, and importantly, we saw CNS activity, which is the whole main thesis about the differentiation. Mm-hmm. Well, let's dive into that. Yep. Let's dive into that data a little bit more. Obviously, let's start with the EGFR population. Four responses in 16 patients, it's a good encouraging early sign, obviously, for a relatively small cohort. But people are gonna be comparing it to Takeda's molecule or to other molecules in development. So how do you position those 16 patients, and then, as you say, the subset that have CNS activity? What are the bars there, and what are the real comps that we should be looking for? Yeah. I would tell you that there is no bar for the population that we enrolled, that we presented at ESMO. And what I mean by that is, all the other agents in their phase I, phase II studies excluded patients who had had a prior exon 20 inhibitor- Mm-hmm ... and excluded patients who had active brain mets. In other words, brain mets that had not already been treated with surgery or radiation. We did not exclude either of those populations. So the population we just presented at ESMO, 81% of the patients already had a prior exon 20 inhibitor. 86% of patients had CNS mets at baseline. There's not a single drug in the exon 20 space that has presented as difficult a population as the one we just presented, and we still saw the activity that you mentioned. To be clear, how many of those responses were in patients that didn't have brain mets at baseline? Patients that didn't have- Yeah, you had 86% with brain mets at baseline. Oh, the, Yes ... the activity- How many- Yeah, several of the responses were in patients with active brain mets- Right ... at baseline. And importantly, we highlighted in, we highlighted one patient in particular who was the perfect case study for this drug, which is a patient who, she had had chemotherapy and progressed. She had had amivantamab and progressed. After 11 months on amivantamab, she progressed in the brain with four different lesions in her brain. Wouldn't have been eligible for any of these other drugs because she would have been excluded from those studies. She was eligible for ORIC-114, came onto the study, had a complete response in her lungs, had a complete response in her brain. That is the first complete response in the brain for any EGFR exon 20 drug in a patient who had not already been treated for their brain mets. So that's the promise of this drug and the differentiation of this drug. The thing that I think people are kind of missing on the EGFR exon 20 space is, like I mentioned, the first-order analysis that says it's crowded. The second criticism we hear is that the launches of other targeted therapies in, for example, ROS lung or RET lung, have been disappointing. And they have been. They've been smaller. But I'll tell you, EGFR exon 20 is a different population. It's larger than ROS, it's larger than RET. We haven't even talked yet about HER2 exon 20, where we actually had more responses- Mm-hmm ... in that ESMO update, was in HER2 exon 20, which doubles your population now. And then there's a third population called atypical mutations in EGFR that are not exon 20-related, which is 1.5x the size of EGFR exon 20. We are more potent against atypicals than we are against EGFR exon 20. At the time of the ESMO update, we mentioned that we had just started enrolling patients with atypical mutations. But my point is, if you add up any combo of those three populations or all three populations, you're now talking about a market that is bigger than ALK plus ROS combined.... alectinib in the ALK space is a $1.7 billion drug. So I have no concerns about the ability of this drug to have a successful commercial launch once it eventually, hopefully, gets to that place. And maybe one of the reasons that some of the recent targeted therapies have struggled on launch is diagnosis and testing for- Correct mutations that aren't already standard part of the panel. But obviously, EGFR is commonly tested for. That's exactly the dynamic that's different here. So I came before ORIC, I was at Ignyta, which we sold to Roche, that we developed a ROS, a ROS drug that was, CNS active. I was on the board of Turning Point Therapeutics. I've seen this before. I've seen the clinical trials unfold before. I'm telling you, EGFR exon 20 is different than ROS, it's different than RET, because, like you said, clinicians are used to, for many years, testing for EGFR mutations. Mm-hmm. Before we move off of EGFR, there's one thing I wanted to ask about that ESMO data. The data contained a number of different doses, but your responses in EGFR didn't seem to me to show a lot of dose response. You saw two of those responses in cohort 2 and two in 75, none in the 45, so like or none in the 60, I'm sorry. So, and likewise, the safety signal also doesn't seem to be terribly dose-dependent, at least in the initial data set you showed at ESMO. How should we think about where the dose is going as we get to larger studies or expansion cohort? Yeah. I mean, what we mentioned at ESMO is that we had not hit MTD at that time, and we were gonna continue to dose escalate. There's a massive therapeutic window that we were able to see in the clinic. So we saw robust response as low as 20 mg BID in the study, and at the time of the ESMO update, we were already at the 50 mg BID and 120 mg QD doses. So in other words, there's a massive therapeutic window. We said at ESMO we'll continue to dose escalate until we hit MTD. On your question about specific doses and the dose response, I just tell you, dose escalation studies, you're looking at small n's in an individual cohort, so I don't make too much of that. The PK curves are beautiful. I mean, it, like, you just continue to see very nice dose proportional increase in exposure. I mean, I ask primarily because, we know the FDA has become very focused on dose optimization- That's right. and, so I wondered about the opportunity if you're already saturating target or if you felt like you were getting to where you needed to go, to move forward at a lower dose than hit, than going all the way out to MTD. No, I mean, the PK curves continue to look good. So as of the time of ESMO, the guidance was that we'll continue to escalate until we hit MTD. So I wanted to ask, especially in the HER2 patients, we're maybe less familiar with the, you know, exon 20 as a targetable subset. Can you give us a sense of where you expect to sit in this particular landscape? Especially, you have a good response in the HER2 exon 20 population as well. I think you had, like, four partial response. Yeah. Yeah, let me dive into that. I'll do it quickly because I wanna make sure we leave time for our other two programs as well. So with with HER2 exon 20, there's not a lot that's out there. That, you know, there's ENHERTU, obviously, which is phenomenal in HER2 amp. But HER2 exon 20 lung, ENHERTU it doesn't get used a whole heck of a lot. I think part of the issue is that ENHERTU is really, really toxic. And so if you look at the ENHERTU profile, there's a ton of Grade 3 tox for ENHERTU exon 20. In fact, ENHERTU has more Grade 3 interstitial lung disease than we have total Grade 3s in our experience thus far with ORIC-114. I think the safety angle, and then also the brain penetrance angle, is equally applicable to HER2 exon 20 for us. Does HER2 exon 20 have the same importance placed on brain penetrance as the EGFR- It does - broader population? Yeah. Yes. Great. Next steps for this program before we move on to others. Next steps- Next steps. Yeah, continue to dose escalate, do dose optimization work, and then, as early as 2025, launching multiple registrational studies, which would be single-arm, accelerated agent, accelerated approval, trial designs. But we should expect to be seeing expansion cohorts next year, presumably at- Oh, first half 2025 is the guidance right now. Okay. Makes sense. Let's move on to 533. This is your CD73 program that you're talking about in myeloma. Let's back up to a high level here. This is the adenosine axis. This is a place that recently and not so recently has been getting really intense skepticism from investors after multiple disappointing results from other companies. What are folks missing about this axis, and what are you hoping to achieve that others have failed at? Sure. I think there's a couple points to make. I think, one, there are different pathways in the or there's different ways to hit the adenosine pathway. I think we're hitting it from CD73, which we believe is the most efficient way to shut down adenosine. What we've seen clinically, there are a number of other programs. AstraZeneca is currently in a phase III study with oleclumab. That is the only molecule in the adenosine pathway that actually has shown positive phase II randomized data. So that's somewhat promising for the target. What we've seen preclinically with our molecule, we've benchmarked it against all of kind of the known competitors, both in the CD73 field, in addition to the adenosine receptors. We see much more potent activity, more potent adenosine shutdown, more T-cell activation. We've published pretty extensively on that. Better than other targets in the adenosine pathway, better than other molecules in the adenosine pathway. So we believe we potentially have a best-in-class molecule in the CD73 space. When we looked at how to develop it, we took a totally different approach. There are a number of other molecules out there. Again, the oleclumab data is in combination with the PD-L1 inhibitor. It's kind of a long and hard road to actually show that you're differentiated in that, in that type of field. So we took a different approach. We started working with a KOL, Kenneth Anderson from the Dana-Farber, who has been publishing recently that he believes adenosine is a driver in multiple myeloma. He has shown that patients, when they progress with multiple myeloma, have higher levels of adenosine. So we started working with him for several years. We didn't announce anything, but a lot of work was going on behind the scenes when we were developing our molecule preclinically. And what he's shown is really interesting activity. He takes multiple bone marrow samples from patients that he treats, and he's shown with the CD73 inhibitor, you can actually show multiple myeloma cell lysis. ... consistent with other standard of care therapies in multiple myeloma. So, we're the first CD73 inhibitor to go after multiple myeloma. Mm-hmm. At first, anyway, it's really a lot of, not a lot of adenosine axis approaches in myeloma in general. There's a couple of A2As back in the day, I think, but- That's right. That's right. Yep. Yeah. Exactly. Okay. So great. ASH data coming in a few weeks here, what should we be expecting, and what's the population in phase I here, you know, for our cross-trial comparison purpose? Sure. Relatively consistent with our other programs, it is a dose-escalation study. This will be the first time we're presenting initial phase I data. Dose escalation, it's monotherapy. It'll be in very heavily pretreated multiple myeloma patients, so we are focused on that setting. The patients, you know, are expected to be triple-class refractory, penta-refractory. Mm-hmm. So kind of the most heavily pretreated patient population. CAR-exposed, at post-transplant, all of that. Correct. Some, yep. Some. Okay. And is that where we should be expecting the program to go? And obviously, for phase I, that makes sense. Myeloma, a very competitive field in the earlier lines of therapy these days. You know, how do you see the CD73 landing in the broader landscape as you go into expansion cohorts? Yeah, I think any way you kind of look at multiple myeloma, it's really, you know, a combination game at the end of the day. You know, first-line therapy is triple or quadruple combo, so I think that's kind of the long-term potential, is to combine a CD73 inhibitor with other agents. And so that would be our expectation here. We did establish a collaboration with Pfizer about a year ago, where that study, Pfizer would actually run the next study. It would be in combination with their BCMA bispecific. Mm-hmm. And so I think there's a lot of rationale on why that combination would make sense. That collaboration is at our discretion, so if we decide to move that program forward, in their combination, they would actually run the study, which is kind of one potential path forward for this molecule. So obviously, safety, very important as we think forward to combinations from this initial data set. But what are your bars, and what are you hoping investors pay most attention to when we see this data at ASH? Yeah, great question. So I think a couple things. I think, one, I should have, you know, clarified, we have an oral CD73 inhibitor, so that's the first one. So I think obviously demonstrating it as oral has good PK/PD properties like you would expect with everything else. I think safety is critical. I think what we've seen with other programs, there doesn't seem to be any on-target tox that, you know, others have shown in the CD73 pathway. But I think, again, as we look to combine this with other agents, you want to make sure, it's very tolerable, as you know, with- Tox hasn't been the issue so much as lack of efficacy. That's right. Yeah. Yeah. So we want to see some modest single-agent activity, and that would green-light us to move forward into combos. Makes sense. In the last few minutes, maybe we can touch on the 944. Sure. PRC2 isn't as familiar as, you know, EZH2, subunit of the complex. Can you remind us what we should expect, you know, from the PRC2 as opposed to the EZH2? Yeah. So people always tell us they are not familiar with the PRC2 complex, and I always tell them they are. Yeah. They just don't know it, which is... PRC2 has three different subunits, two of which are druggable. EZH2 is the one that everybody is aware of because of tazemetostat being approved as an EZH2 inhibitor. But we're drugging a second subunit of the PRC2 complex, which is EED. You don't expect any differences between EZH2 and EED in terms of initial efficacy or toxicity. Where you would potentially see a difference is that EED is not susceptible to the same resistance mechanisms that EZH2 inhibition would be susceptible to. So EZH2 is, in theory, susceptible to acquired mutations to EZH2. It's also, in theory, susceptible to bypass resistance from EZH1. EED doesn't have those same liabilities. So if there's any advantage between the two subunits, it's that EED is the better one to target. Possibly better duration of response there. Possibly. Yeah, possibly. Uh- Is it also that comes to, you know, your mission of resistance, if the other two subunits have more chances of, like, cancer resistance to the drugs or? Yeah, like I said, in theory, the EZH2 subunit has a greater chance of resistance. But the reason I say in theory is 'cause we haven't seen a data set from one of, you know, from tazemetostat, for example, that has followed patients for a long time and said, "Hey, this is exactly where the resistance is coming from. You know, what the dominant mechanisms of resistance are. That's right. Yeah. So what are the... Obviously, prostate, also a very active space these days. Looking forward, here, should we expect to see combination development? What are the relevant combinations here, especially from the perspective of that, resistance, forestalling? Yeah, I think so here, we have a roadmap that's been laid out for us by Pfizer, because Pfizer's got a PRC2 inhibitor, and they showed data earlier this year that where they combined their PRC2 inhibitor with enzalutamide, a next-gen AR modulator, and they had phenomenal data. They got three times the radiographic PFS that they should have been seeing. So in a population where they should have seen four to five months of radiographic PFS, they got 17 months of radiographic PFS. And so they'll have some randomized data next year that'll obviously be really interesting to take a look at. But in what they've already presented, they've really shown the promise of a PRC2 inhibitor in combo with an AR modulator. Your molecule versus theirs, how should we be combining the two of them together? I guess we'll see when we present our data, but from everything that we've seen so far, both clinically and preclinically, we think that we ought to be every bit as good as Pfizer's PRC2 inhibitor, if not better. Yeah, that initial readout's coming first quarter next year, I believe. What should we be expecting to see in that first readout, and again, here, what are your bars for taking it forward? Yeah, very similar to what we mentioned with myeloma, which is that there's never been a CD73 inhibitor with single-agent activity. There's never been a PRC2 inhibitor with single-agent activity. The promise is ultimately for combos. So here, we really have to think about combining, combinability. So you want to see a good, safe profile. You want to see good PK. You want to see good dose proportional increase in exposures, good target engagement, and good half-life. I mean, I know that sounds disappointing to people, but literally, the PRC2 inhibitors have had such bad half-life, such bad drug properties, that alone would put us a leg up on any of the other drugs, Pfizer's included. Makes sense. And, when we move beyond that escalation data, expansion data, expected when? Sorry, say that again. Expansion data for presumed expansion cohorts- Oh ... either monotherapy or combo. Don't know. I mean, the next update for this is the public guidance is Q1 of next year, and then updates beyond that we'll get to them when we get to them. Fair enough. So then maybe just in closing, what's your current cash position and, and runway, and, and how much flexibility do you have to get through some of these near-term updates and fully explore the path forward? Yeah, great question. So we ended the last quarter, $256 million. That gets us through late 2025, and so that'll get us through a number of milestones. That assumes a fully successful scenario, every program- All three ... moves forward, including preclinical programs as well. Mm-hmm. We think we have a lot of, lot of financial flexibility. Makes sense. Any other updates we should be paying attention to or things we didn't get to? This is probably enough for people to dig into, three, three clinical stage programs. I think we did a reasonable job for 20 minutes. Great job. All right. Well, thanks very much for joining us, and I really appreciate your time this morning. Thanks for having us. Thanks a lot.