Hi everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Jacob Chacko, the CEO, and Dominic Piscitelli, the CFO of ORIC. Thanks so much for joining us today in London. Thanks for having us, Maury. We're going to do a fireside chat format. For those who are new to the story, if you can provide a one-minute intro of ORIC and your key programs. Sure. I'll make this brief. ORIC stands for Overcoming Resistance in Cancer, that in a nutshell is the mission of the company. From a focus area, we're almost exclusively focused on solid tumors, specifically lung, prostate, and breast. We have two different programs, actually three different programs that have completed phase one dose escalation recently. Two of those programs, ORIC-114 and ORIC-944, are focused on lung in the case of 114 and prostate in the case of 944. And the big headline is, if all goes according to plan, we'll have both of those programs and the pivotal studies by the end of next year. So obviously, quite a bit of operational heavy lift between now and then, but we're quite excited about both. So we can dive into the specifics of either one of those. Great. Yeah, I think that's a great overview and good start. And so let's talk about 944 first. And so one of the questions we have is that Pfizer, at their last quarterly update, they noted plans to disclose phase 2 randomized control data for their EZH2 inhibitor, mevrometostat, in the coming months. And we think this could be at the ASCO GU meeting in February of next year. It's an open-label study, and they've looked at the data. They made a decision to advance this into two ongoing phase 3 studies. This is a challenging patient population. Maybe talk about the data that they've shown and what your views are on the control data that they could show in this update. Yeah. So what Pfizer has shown thus far for mevrometostat, which is their EZH2 inhibitor, is that in combination with enzalutamide, they are seen in two different metastatic CRPC populations, radiographic PFS numbers that are anywhere from three and a half to four times what you would expect from enzalutamide alone in those populations. So those two populations in the phase 1 setting being one, a population that's had abiraterone and then is receiving enzalutamide for the first time, but in combination with their PRC2 inhibitor. And then the second population, which has had enzalutamide already, is getting enzalutamide for a second time, but again, in combination with their PRC2 inhibitor. And so those are the two populations that I mentioned where they're seen in the case of the first one, the post-abiraterone population, a radiographic PFS of 17 months. In the case of the second population, the enza-experienced population, they're seeing a radiographic PFS of close to a year. That's the phase one results that they've shown thus far, with the most recent update from them, I believe, being at ASCO this year. So simultaneous with all of that, they've, as you mentioned, also have, we understand, an open label randomized phase two study that is focused on that post-abiraterone population. Sounds like within the last few weeks, they've confirmed that the results of that study will be shared in the coming months. I think people believe that's ASCO GU. Got it. And is there potential for the Pfizer combo arm to show longer radiographic PFS as more patients get dosed in this study? I guess, what are your views on what the control data could potentially show relative to their phase 1 data? Yeah, so I guess there's a couple pieces of your question, Maury. So in terms of control arm expectations, it's a population. These prostate populations have been super well studied across many, many data sets. So I think for that control arm population, people are expecting to see roughly five months of radiographic PFS. I think Pfizer themselves quotes a study called the CARD study as a benchmark. And when they were talking about their phase 1 results, and the CARD study showed a radiographic PFS in that population of 4.8 months, I think you'd be hard pressed to find many outliers aside from that five to six month range for the control arm. In terms of the treatment arm, I don't know what to expect. I mean, it's their study. You'd have to ask them. But I assume that the results will be positive, just given that I think the other key factors other than the ones we've already mentioned is that within the last few months, Pfizer has started not one, but two global phase 3 studies for that drug in similar prostate populations. And so we are assuming that the study, the randomized phase 2 study, is positive. But beyond that, I don't have any expectations around the treatment arm. Got it. Okay. And yeah, you mentioned the CARD study, which I think shows a relatively low bar for radiographic PFS. What does the real-world data look like based on KOL feedback? And I guess, is there potential for enzalutamide to overperform potentially in light of patients being diagnosed earlier, potentially being less severe? Yeah. A key point here is it all comes down to the specifics of the patient characteristics. And that's why I'm hesitant to comment on my own projections or estimates of what Pfizer might show in their own data set, because it comes down to the specifics. But when you look at a typical metastatic CRPC population and one that's had abiraterone already and then is going to get enzalutamide for the first time, which is what our understanding of their control arm in this study is, and then assuming that it's what I'll call typical incoming patient characteristics, which in many cases, including in Pfizer's phase 1 experience, you expect to see PSAs that are somewhere around the, call it 40 or 50 range, as opposed to some of the other data sets that have been different than that, you would expect to see five months of radiographic PFS. And there are many, many, many data sets that all show that roughly five to maybe six months of radiographic PFS is what you ought to expect to see in that population. There's, to my knowledge, one dramatically different outlier data set out there that was actually just published recently, which was from Ipsen. And they had an enzalutamide control arm that more than doubled the numbers that I just quoted to you. But I think the reality there is if you again dig into the details of the patient population, that was an incredibly indolent patient population. So for example, as you look at the PSAs for those patients, both in their treatment arm as well as their control arm, the incoming PSAs were mid-single digits as opposed to that 50 nanogram per deciliter PSA that I just talked about that is more typical of this population. Got it. Makes sense. Yeah. So the latest metastatic data, I think those patients were probably earlier stage, potentially easier patients to treat. Yeah, or earlier stage, or just a more indolent disease. Right. Yeah. Okay. And so coming back to your 944 program, how should investors think about read-throughs from the Pfizer program data update? Is there any reason to think that any EED inhibitor like 944 would behave any differently than an EZH2 inhibitor like mevrometostat? Yeah. Short answer is the read-through should be high, so there's no difference. There should be no difference between if you kind of paint a hypothetical, which is you've got two drugs, exactly the same drug properties, exactly the same potency for PRC2. One of them targets the EZH2 subunit of PRC2. The other targets the EED subunit of EZH2, sorry, of PRC2. They should both be equally good at shutdown of the target and initial inhibition of the target. The biology, there's a lot of biological literature that would suggest that from a long-term perspective, long-term resistance perspective, it's actually preferred to target EED rather than EZH2. The main reason being that EZH2 could be susceptible to either acquired mutations in EZH2 or bypass resistance of EZH2 by EZH1. Neither of those resistance mechanisms would be relevant to an EED inhibitor that's targeting the PRC2 complex. So if anything, it should be preferred to target EED over EZH2. But upon that, the initial inhibition, look, we've examined that matter every which way as to is there any difference on initial inhibition of the PRC2 complex, and it doesn't look like it. In fact, there's a pretty elegant RNA-seq analysis that our team has done, and that's publicly available, that shows an R-squared value of something like 0.88 when you look at the genes that are the gene signatures that are activated by an EZH2 inhibitor versus an EED inhibitor. So they should be the same. A lot of overlap there with that data. Correct. A lot of read-through. Got it. Okay. And you've talked about 944 performing at least as good or better than mevrometostat. Talk about the measures where 944 is looking better than mevrometostat to give investors greater confidence in your program. And could targeting EED lead to better efficacy versus EZH2 in patients? I mean, it sounds like you don't think that's going to happen, but maybe talk a little bit more about just what you're seeing with 944. Yeah. So based on the single agent data that we put out earlier this year, you can see that 944 in the clinic, in the patient experience, had a clinical half-life of 20 hours. That compares to some of the earlier programs in the space that had a half-life of more along the lines of two hours. Pfizer hasn't said what their half-life is for their program, but based on the PK curves that they've put out, we estimate it's approximately four-hour half-life that they've got. So our 20-hour half-life is clearly better than a four-hour half-life if that's indeed where theirs comes out. Their drug is being dosed BID. Our drug is being dosed QD. So that would be consistent with what I just told you on the half-life. Neither drug appears to have CYP autoinduction, which was a key failing of several of the earlier stage compounds, CYP autoinduction leading to dose-dependent decreases in exposure. So as you dosed some of those other drugs higher, you actually got lower exposure of the drugs. That doesn't seem to be the case with Pfizer's drug. It's certainly not the case with our drug. So those are all to the benefit of ORIC-944 in terms of the drug profile. And then we have very little, at least based on the single agent experience, very little interpatient variability as you look at PK, as you look at various PD markers. And so that should also be to the benefit of ORIC-944. One thing to be clear on, though, while we think that there's certain aspects of 944 that are clearly differentiated versus the Pfizer drug to our benefit, we don't think we have to be better. So this is, I think, the clearest, most relevant analog if you look here is actually just look at the AR inhibitors themselves. So enzalutamide, apalutamide, daralutamide, which are the three main next-gen AR inhibitors. The efficacy data from all three of those compounds looks exactly the same. So they are undifferentiated in a sense from an efficacy point of view. And those three drugs collectively do $10 billion of sales per year, even though apalutamide was second to the party, that drug is closing in on $3 billion of sales a year, growing 20+% a year. And daralutamide was third by a long shot, third by many, many years to the finish line. And that drug is closing in on $2 billion a year of sales, growing at over 50% a year. So bottom line being that very good drugs, even if equivalent in this large indication, there's room for more than one. Got it. And for 944 combo studies, which AR inhibitor, apalutamide or daralutamide, would make the most sense and perhaps lead to the biggest beneficial efficacy impact without safety liabilities? And neither of these drugs are approved for use in the metastatic CRPC setting. How does that shape your thinking as well as Bayer and J&J's thinking about the regulatory path? Yeah. So back to my earlier comments, all of these AR inhibitors look nearly indistinguishable from an efficacy point of view. So from that perspective, we're agnostic as to which of the AR inhibitors we combine with. Obviously, as you alluded to earlier this year, around the middle of the year, we started dose-finding, dose combination work in combo with both apalutamide from Janssen and daralutamide from Bayer. Both companies have drug supply collaborations in place with us where they're providing free drug into our dosing work. We don't see any reason why we ought to see differential efficacy between the two in combination with ORIC-944. So we're remaining open-minded as to which of those compounds we would choose to take into a future phase 3 study. Got it. And in terms of your other question about how neither drug is approved, of course, in the CRPC setting, we think that probably makes it all the more important for both Janssen and Bayer to sort of help support this work in combination with ORIC-944 because it could be a path to a label in the CRPC setting for those two drugs. But from a mechanistic point of view, we don't have a preferred party. Got it. Okay. And have you considered potentially running a small enzalutamide combo arm to directly compare 944 versus Pfizer's drug? We've considered it. We have the ability to do that the way that our protocol is written at our option. We can start an enzalutamide combo arm as well. It probably wouldn't be for the reason you suggest. So we don't see there's not a need to try to generate a data set that's directly comparable to Pfizer's. I think if anything, it would be more relevant from the perspective that enzalutamide goes generic in 2027. And so obviously, any company with a large prostate franchise, so aside from Janssen and Bayer, you've got AZ, Merck, Novartis, any company with a large prostate franchise ought to care about a new novel MOA in the prostate space. With enzalutamide going generic in 2027, it might be in our best interest to go ahead and get some dosing experience in combo with enzalutamide solely from the perspective of a party that doesn't have their own AR inhibitor wanting to make a play for a new MOA. Got it. And you've kind of provided some hints here, but have you thought about just phase 3 trial design and which prostate populations you may focus on going forward? Yeah. We've thought a lot about it. Probably not going to say a lot today about it. Our plan is to start one or two phase 3 studies as early as the end of next year, as early as the end of 2025, otherwise early 2026. That metastatic CRPC population is probably where we would focus. I think the key area to drill down beyond that would be basically prior treatment history. Obviously, Pfizer has two phase 3 studies underway right now in that metastatic CRPC population. We'd have to decide for ourselves whether those are the two populations that would be of high interest to us or whether we would choose a different set of prior treatment histories. But we would initially, like Pfizer, focus on the metastatic CRPC setting. Got it and is there a potential to see some early data from your program sometime in 2025? Do you think you'll have enough visibility to, based on that, would you be able to start one of those studies too? What do you think? Yeah. We just started, as Jacob alluded to, we just started dosing the combination into two cohorts. And again, one is with daralutamide, one is with apalutamide. The objective of that study is to select the RP2D. The short answer is it's a little too early to commit to when we'll share some data. As you know, we typically do present kind of updated guidance in the new calendar year. Stay tuned for that. With regards to your question on starting the phase three studies, yes, we do. We think we should have sufficient data to start that study in the second half of next year. Got it. And for that study, I guess, any thoughts on what the endpoints and control arms for Pivotal could be and if you think there's scope for accelerated approval there? Yeah. I think the short answer, if you look at the recent approvals in prostate cancer, and even if you look at the two studies that Jacob alluded to that Pfizer's doing mevrometostat one and two, the primary endpoint there is radiographic PFS. So that's kind of our base case assumption. Obviously, you could have OS as a secondary endpoint. So our base case is we'd have to do a randomized study here, and accelerated approval is probably not the base case scenario for us. Got it. Okay. Okay. And so let's shift gears then from 944 to 114, which is your Exon 20 oral TKI. You're going to have multiple data sets and catalysts from this program in the first half of next year. So to start off, what should we expect for the cadence of catalysts for the three different cohorts you're assessing in the dose expansion? And will you do all updates at the same time or stagger the updates? Yeah. Great question, so as you know, we selected the provisional RP2Ds early this year. That's 80 and 120 once a day. We started the dose expansion cohorts, and those are three buckets of patients. The first is EGFR Exon 20. The second is HER2 Exon 20, and the third is EGFR atypicals. We have said basically we'll provide an update in 2025 on all three programs. The objective of the updates in 2025 is really a go, no-go decision on each of those cohorts. Assuming there's a go decision on one or more of those cohorts, we would obviously select the RP2D, and the goal would be to start that registration study in the second half of next year as well. Because of the unmet medical need primarily around CNS, we do think there's an accelerated approval path here as well. So with regards to sequencing and timing, it's TBD. We haven't provided any specifics on that. Maybe we'll provide a little more color early next year. Got it. Okay. And for the EGFR Exon 20 landscape, there's perception that it's a highly competitive and crowded space with amivantamab and several TKIs out there as well. Will 114's clean kinase profile and the CNS activity that you get, will that be the key differentiators in the clinic, or are you also looking for other ways to win strategically too? Yeah, I think you're right. I think based on the preclinical profile and the early data that we shared, we think the two areas for potential differentiation here are twofold. The first is safety and tolerability. And safety and tolerability kind of comes in two forms, right? There's the on-target toxicity with some of these EGFR inhibitors in the form of rash and diarrhea. And then there's a lot of off-target tox as well. You see QTc prolongation, elevated liver enzymes, you see anemia, hypertension. And then so that's kind of the off-target tox. So that's one area of potential improvement. And the second thing, which is probably a bigger one, is the CNS activity. We don't believe any of the current approved or late-stage agents have seen really good CNS activity. The reason this is so important in this patient population is, at baseline, if you look at data sets, it ranges from 35%-45% of these patients present with baseline brain mets. In addition to that, it's the point of first progression on a number of patients. If we're able to demonstrate that, I think that would be a key differentiation for our program. Got it. And how do you expect the potential better safety and CNS activity to translate to durability for 114? And is there a good drug that exists that could be an optimal comp or benchmark for this? Yeah, there's a lot of good comp or benchmarks for it, which is in the targeted therapy space. I think there's numerous examples. If you look at ALK, if you look at classical EGFR mutations, you look at ROS, where a not first-to-market program came along but with a CNS active profile and was able to become the best-in-class program in the space. So if you drill down on ALK specifically, alectinib is a drug that does $2 billion of revenue a year. It was not the first. It was not the second. It was the third ALK inhibitor that was approved, the first two being drugs that did not have CNS activity. If you go back and kind of unpack the data, alectinib had an ORR that was not dramatically different than the drugs that came before it. What was dramatically different was the PFS, the durability that alectinib was able to achieve. And the way it was able to achieve that is because of its CNS activity. And if you really dig down on these data sets, what you're going to notice is that the PFS for patients with versus without brain mets is dramatically different in drugs that don't have CNS activity. And so the overall aggregate PFS number that gets quoted for the non-brain penetrant drugs is artificially short because they basically can't handle the patients that have brain mets. They also see first site of progression being in the brain. In the case of alectinib, you didn't have that dramatic difference of PFS in the patients with versus without brain mets, which led to a much larger overall, much longer overall aggregate PFS number. And so that's exactly the pattern that, like I said, that you've seen in other spaces. And in this space, specifically EGFR Exon 20, you've seen the same pattern. So mobocertinib from Takeda, which has now been pulled from the market because it didn't confirm, and it's a confirmatory study, had a great data set. I think at ASCO 2021, where they showed the PFS for that drug in patients with versus without brain mets, you saw this, again, big delta between the two. And then amivantamab, which now is the only drug approved for EGFR Exon 20, when they presented their results at ESMO last year, there was a corresponding New England Journal of Medicine paper that showed the hazard ratios in the patients with versus without brain mets were dramatically different. So that's where it ought to translate into ultimately in the PFS, that the PFS of a brain-penetrant drug ought to be better than the PFS of a non-brain-penetrant drug. Got it. And one of the other questions is just on whether you would expect to see similar responses in CNS as well as systemic. Do you think 114 can do that, or do you think there could potentially be some confounding factors that may have led to competitor programs that show different response rates too? Yeah. A general rule of thumb, which is quite helpful because there's a lot of companies or drugs out there that'll sort of try to point to anecdotal data as evidence of CNS activity. But I think at the end of the day, you shouldn't see a large delta between the systemic ORR and then the CNS ORR for a drug that is truly brain penetrant. You'll always have some delta, but it's generally on the order of, call it 10 points of ORR difference. But in some of these other data sets where you see a company quoting a CNS ORR that's much wider than that in terms of the delta between the much lower, in other words, than their systemic ORR, it's typically because the drug really isn't that brain penetrant. And maybe they might have a compromised blood-brain barrier. So that might be the confounding factors. Got it. So in other words, you'd anticipate to see similar response rates then between. Fairly similar. Yeah. And just when thinking about the competition enrolling studies currently, how has investigator enthusiasm been for 114 relative to the competitors? I mean, look, I can't speak to what the competitors are seeing in terms of enrollment trends, but I'll tell you, we're, I don't know, the fifth or sixth or seventh EGFR Exon 20 inhibitor that's ever been developed, and we have no issues enrolling our studies. So there's clearly a lot of demand for a drug that's got a profile that is differentiated on both the safety side as well as the CNS activity side. Got it. And looking to next year with potentially starting multiple accelerated registrational cohorts in the second half of next year, wanted to get a sense of how we should think about the bar for success and each of these data updates that you have next year, and also about the patients that you enrolled for context. Yeah. Great question, Maury. So just to level-setting, the first thing is these are second-line patients. What we want to show is about two to three dozen's worth of patients in each of the cohorts. If we think of the bar for EGFR Exon 20, obviously, it's well established there. We think the bar is about a 40% ORR. When you jump to atypical, it's probably the same. It's about 40%. And then lastly, HER2 Exon 20 is probably closer to 50%. The one key differentiator, I'd say, that from a patient population, again, these are second-line patients, but we are allowing patients with active brain mets, and some of our competitors had not done that previously. Got it. And maybe just in closing, if you want to talk about the market opportunity for these indications and anything else you can say about the data updates next year or two would be helpful. And then maybe Dominic, talk about cash and cash runway as well. Sure. I know we're running out on the close of time, so I'll be quick. On the market opportunity, it's fairly large, as you hear from that noise. It's roughly 6.5% of non-small cell lung cancer in the aggregate. So EGFR Exon 20 is roughly 2%. HER2 Exon 20 is roughly 1.5%. And EGFR atypicals is roughly 3% of non-small cell lung cancer. So collectively, that's 6.5%. You put any two of those populations together, and it's larger than the size of ALK, non-small cell lung cancer, just to kind of frame the market size as a comparator. And then, Dom, you want to talk about cash? Yeah. So we ended the year with $282 million in cash. End of the quarter, excuse me, third quarter with $282 million in cash and investments based on our current operating plan that gives us cash runway into late 2026. And that is a fully burdened number. That does assume we're starting registrational studies for 114 and 944 in the second half of next year. Got it. Awesome. Thanks, Jacob. Dominic, thanks for joining us today. Thank you, Maury. Thank you, Maury.