Thanks, everyone, for continuing to join us on the Stifel Targeted Oncology Forum. Happy to do the next fireside with ORIC. I've got Jacob Chacko, the CEO. Dominic Piscitelli, the CFO. Thanks so much for joining us. Really appreciate it. Thanks for having us, Brad. Can we just start off with a brief introduction to the company, and if you could discuss the company's priorities for 2024 as well? Yeah. I'll keep it very, very brief because I know we're limited on time and I want to dive into the programs. The company went public about four years ago. We're advancing a pipeline of small molecule drugs targeted at various mechanisms of resistance in oncology. The internal expertise of the company is primarily in prostate, lung, and breast. Almost without exception, those are the tumor types you will hear us speak about. We've put the pipeline together through both internal discovery as well as opportunistic business development in licensings. In terms of priorities, Brad, it's really the two programs that are now marching towards pivotal studies that we hope to initiate in the second half of 2025. That's ORIC-114, which is a brain-penetrant inhibitor of EGFR Exon 20, HER2 exon 20, and atypical mutations of EGFR. And then ORIC-944, which is our PRC2 inhibitor that accomplishes its task via allosteric inhibition of the EED sub-unit, and that'll be developed in prostate cancer. So really, it's all hands on deck advancing those two programs now in advance of, like I said, starting pivotal studies, hopefully in the second half of 2025. Yep. Well, let's start with the second one, the prostate program. I'd love for you to cover just the underlying hypothesis of how PRC2 inhibition/EZH2 inhibition will resensitize patients to AR inhibitors after they've progressed on them. Yeah, sure. I could probably speak for the entire 25 minutes about just that, so I'll try to keep it at a very high level, which is to say that the second-gen AR modulators, namely enzalutamide, apalutamide, and darolutamide, have done a fantastic job for patients with prostate cancer. But eventually, those patients end up developing resistance. And what ends up happening is that the tumors, over the course of time, become less and less AR-dependent. And so the AR modifiers, at that point, lose their efficacy. And so essentially, the PRC2 inhibitors, via their impact on various transcriptional activities, essentially push the tumor to stay in a luminal state, to stay in an AR-dependent state where the AR modulators can continue to have their efficacy. So at this point, we and Pfizer have shown preclinical data that validates that synergy of combining a PRC2 inhibitor with an AR modulator. We have shown really interesting RNA-seq data as of AACR a week ago that shows that EZH2 and EED behave the same in terms of transcriptional activity. Pfizer, of course, as people know, has shown really compelling clinical data that shows that synergy in action, where they're getting on the order of 3-4x the expected radiographic PFS in two different populations by combining their PRC2 inhibitor with enzalutamide. Yeah. And I think you hinted at my next question is, how should we think about any difference between the allosteric PRC2 inhibition mechanism that you have versus what we would call EZH2 inhibition, which Pfizer talks about? Yeah. Dominic, you want to cover that? Yeah. I think at a high level, again, if you look at the PRC2 complex, there are really two druggable subunits. There's EZH2 and EED. Theoretically, there's really no difference between the two. There is a theoretical biological benefit to hitting EED over EZH2 because you do see some potential, some potential both acquired or bypassed resistance with hitting the EZH2 subunit versus EED. But again, that hasn't been proven in the clinic. But out of the work we've done profiling our program with other EZH2 inhibitors, there's been no difference in the two subunits, so. Can we walk through the history of external clinical data to support PRC2 inhibition in this specific context of prostate cancer? I mean, you mentioned the Pfizer data. Any other details you want to talk about there? And then we do know there were inhibitors out there from Constellation, Epizyme. I think the former was in when we were testing it at one point. What have we learned? Yeah. I think that Dominic will cover the details of it, Brad. But essentially, the road is littered with PRC2 inhibitors that have fallen by the wayside, namely because of drug properties. But Dom, you want to talk about the specifics? Yeah, of course. So there's always been a strong biological rationale for pursuing PRC2 inhibitors in prostate cancer. And companies have been exploring this for many, many years. If you go back to GSK, Constellation, and Epizyme, as you mentioned, I think the main theme there, as Jacob alluded to, is that their first-generation PRC2 inhibitors, if you look at Constellation's first generation, CPI-1205, and Tazemetostat, they were just plagued with poor drug properties. And what I mean by that is just short half-lives as well as a CYP autoinduction. And with this CYP autoinduction, you actually saw a decrease in exposure with repeat dosing. So there's been some studies. I think Constellation did have a randomized combination study ongoing with 1205 and enzalutamide. They never reported on that. That program was deprioritized, and they kind of moved to their second-gen program. Tazemetostat, on the other hand, did have a randomized study, which is now Ipsen, combining it with enzalutamide, and they did not present that data. Now, they did present some initial phase I-B data back in, I think it was late 2022, at the SUO meeting, the Society of Urologic Oncology. They showed a radiographic PFS of 11.1 months, which we thought was really interesting. The only problem with that dataset is they didn't tell you how many of those patients had seen a prior AR inhibitor. So the data has been mixed, but I think a lot of that had to do with underlying drug properties and the issues we've just talked about. Okay. Well, then what have you learned from your clinical monotherapy data with 944, both in how it acts and how it behaves relative to the Pfizer compound? Yeah. So ever since we saw the Pfizer data that was presented in May of last year, Brad, on their earnings call that highlighted the really phenomenal PFS outcomes in the two different patient populations that they were seeing, we started benchmarking every way we possibly could on the preclinical side, on the translational side, with any single-agent clinical data that was available between the two compounds to basically say, is there any place in which we would be inferior to Pfizer on any of the characteristics? And we've yet to find an area where we're inferior to them on the characteristics. We're at least as good, if not better. Now, on probably the most important characteristics around drug profile in the clinic, Pfizer's half-life looked like it's about four hours or less. Our half-life that we just unveiled at AACR, again, about a week ago, was 20 hours in the clinic. So that obviously is quite a bit longer than Pfizer's half-life and the half-lives of the drugs that Dominic had quoted earlier. Like Pfizer, we do not have CYP autoinduction. Again, that's been an issue for prior PRC2 inhibitors. We have very tight variability in terms of interpatient variability. There's very, very little interpatient variability. And I think that that's due to the good drug properties of ORIC-944, the long half-life, which, like I said, is compatible with QD dosing. In the case of Pfizer, they're giving 1250 BID, so 2.5 grams of drug per day, split between two different hefty doses. For us with ORIC-944, with that 20-hour half-life and the good PK and exposures, what we're taking forward into combo dosing is 600 milligrams daily as a QD dose. And so I think there's a number of different factors on which we compare quite favorably. Of course, as you go earlier and earlier and look at things like in vitro synergy in a Bliss analysis, both compounds show good synergy in combination with AR modulators. And then, of course, at AACR, again, about a week ago, we showed head-to-head single agent versus Pfizer and combo with darolutamide, one of the next-gen AR modulators, that we get incrementally greater TGI in those assays than what Pfizer is able to achieve either as a single agent or in combo with darolutamide. Along all those factors, I think we feel quite confident in the way that the drug is profiling versus Pfizer's drug today. Okay. Now, I have a series of questions to grapple with this aspect of this being a combination drug where the efficacy really becomes atop a monotherapy. And what that means for a biotech is they collect data and think about prioritizing. And the first is there's been some debate about why Pfizer didn't show an additional set of data that was from a randomized study that they had at their recent oncology day where they announced they're moving the drug forward into phase IIIs. I'd love some comments on how you interpret that. But more importantly for you, how do you maintain confidence to continue to put resources behind this program given that unknown? Yeah. Yeah. And I think ultimately, Pfizer probably has to answer that question, Brad. I can maybe hypothesize as to why they didn't show the randomized phase II data yet. But maybe before I do that, just as we, how do we get confidence in the dataset and the fact that ultimately we think that this is going to be the next new novel mechanism in prostate cancer, at least based on what Pfizer has generated thus far? So I mentioned earlier the phase I data results that Pfizer generated. Obviously, that was in an uncontrolled setting. But what I would tell folks is that these populations have been so well studied for so many years that you just know exactly how that ENZA experienced population is going to perform if you give them enzalutamide for a second time, which is two to three months of radiographic PFS. Pfizer, in their dataset, in their phase I dataset, generated 11.7 months of radiographic PFS. In an ENZA naive population in that CRPC setting, a population that's had abiraterone but not yet had ENZA, they should get four, five months of radiographic PFS in that setting. Pfizer was showing 17 months of radiographic PFS. Two different populations in that phase I setting where they're seeing this profoundly increased radiographic PFS versus what you would otherwise expect in those populations. Secondly, the phase II study that everyone is hoping to see the results of, keep in mind, that's an open-label randomized study. In other words, there's not a black box that Pfizer is going to unveil to themselves and to the rest of the world all at the same time. They are seeing exactly how that study is going along the way. That study is powered for a 0.5 hazard ratio on PFS. So first of all, that is bold to study that, to power that study for a 0.5 hazard ratio. Secondly, on their innovation day that they just covered at the end of February, they highlighted that the reason they're greenlighting not just one, but two phase III studies for this program by the end of this year is based on the totality of their phase I and their phase II experience. So I think the likelihood that that phase II randomized has not achieved that 0.5 hazard ratio is quite low at this point. So I think just all signs give us quite a bit of confidence that when they eventually reveal those data, it'll be positive. I would say from our perspective, from a decision-making perspective, we're not waiting on seeing that randomized data from Pfizer to get confidence in advancing our own program into the clinic into later-stage studies. Like I said earlier, the plan for us is to start pivotal studies in the second half of 2025. Okay. And I guess what internal clinical catalysts will you have in hand at the time you're commencing those in the second half of 2025, both additional monotherapy data and how much combination data? Yeah. Given the key mechanism here is around the synergy, I think additional monotherapy data is not going to be particularly de-risking at this point, given that I think we've proved in spades that our drug has the characteristics of best in class in terms of the drug properties as a single agent. So I think more than that, Brad, what we've mentioned in terms of public milestones is that first half this year, we intend to start combinations with one or more AR inhibitors. So by sometime next year, we'll obviously have a dataset in combo with one or more AR inhibitors that we can be looking at. Now, I think that'll be too early to look at any kind of PFS numbers, obviously. The timelines and math wouldn't let us be able to see anything approaching the 17-month PFS that Pfizer has quoted in their ENZA naive population. But obviously, we'll have quite a bit of experience to see, a, is it easily combinable with those AR modulators? And And we're not seeing anything in terms of tox that might be concerning. I don't anticipate there would be anything like that to worry about, just given the mechanisms we're talking about. And I think more importantly, are we seeing quite a few patients who are staying on study for a long time? So even absent a PFS number, we'll be able to see something like that. In terms of public disclosures, I'd say there's probably nothing even next year on the combo side that would be mature enough to present. I don't want to commit to that just yet at this point. I think that's probably for sometime after next year for us to start looking at PFS numbers from the phase II combo work. Like I said, in the meantime, we're not going to wait in terms of starting that phase III study. To be clear, Brad, if we saw anything dramatically surprising, like I said, on either the tox side or quite a few patients coming off study early for whatever reason that caused us to have doubts about our own program or the mechanism, obviously, we're not going to dive headlong into a phase III study. I think, like I said, right now, it's all hands on deck because all signals seem quite positive. Yeah. Makes sense. Does PSA 50 matter here at all in the context of this approach? Sometimes KOLs and investors really latch onto it for certain modalities. Sometimes they don't. How do you think about this? Yeah. I mean, I kind of chuckle a little bit when people ask us, "Well, do you get concerned that you haven't seen comprehensive PSA 50s from Pfizer yet on their combo study?" And the reason I chuckle is I think about the hierarchy of endpoints across oncology, but especially in the prostate space. It really is all about OS and then a durability measure like PFS. And then it's something like radiographic responses and kind of lowest rung on the ladder, PSA 50s. People use PSA 50s as a proxy of what you ought to see in future later studies. So the fact that Pfizer has already shown profound radiographic PFS, I'm not overly concerned about what they're going to show or not show on the PSA 50 side. Okay. And now, how do you pick an AR inhibitor combo partner between the four of them? I think ENZA might not be ideal because Pfizer owns it at least in the U.S. apalutamide, darolutamide, really interesting new drugs, but not technically approved in mCRPC. What's your thought process here? Yeah. I think this is where things get really interesting to our benefit, Brad. So as we sit around and look at this, Pfizer with their PRC2 inhibitor obviously is going to combine it with the drug that they own half of, which is enzalutamide. Of course, Astellas has the other half of that drug. We have the benefit of getting to select across all the AR modulators. So enzalutamide, apalutamide, and darolutamide have all done phenomenal for patients. All three drugs have fantastic efficacy. I think on the margins, people would say it's hard to differentiate between those three compounds. Certainly, Bayer, which owns darolutamide, and Janssen that own apalutamide are hungry to get into the metastatic CRPC setting, as you mentioned. And so there's a lot of reasons why combining with one of those drugs might make strategic sense for one of those other parties as you think about the ability for them to not only have greater durability in the lines in which they're currently approved, but even more important than that, for them to even have an avenue to get into a line of therapy that they're not currently approved in. There's a lot of strategic reasons why it might make sense from their angle to combine with ORIC-944. And then certainly from our perspective, we're agnostic amongst those three compounds. Enzalutamide, by the way, goes generic in 2027. One of the things that's equally on our mind is even beyond Bayer and Janssen, you've got AstraZeneca, Merck, Novartis, Astellas, big companies with big resources that know how to develop drugs that have prostate franchises that ought to care about a novel PRC2 mechanism that they could combine with a soon-to-be generic enzalutamide in 2027. All three of those AR modulators are on the table as potential partners for us in the future. This is why we mentioned that in the first half of this year, we would start combos with one or more AR inhibitors. It probably behooves us to get experience with multiple of those different AR inhibitors in terms of the combo work so that as we think about the pivotal studies and we choose just one to take forward into pivotal studies, we've got a full slate of experience. That'll also obviously be important to a future partner as we think about longer-term global collaborations. Yeah. Makes sense. Switch over to your EGFR inhibitor then, 114. And we'll start with Exon 20. Right now, you've got the antibody available for patients, Amivantamab. Likely in the next couple of years, two, three potential approvals for new Exon 20 TKIs like you have. What did you like about your initial phase I dataset you showed last year that gives you the confidence to continue to push this program forward with all that competition in not a super small, but a smaller patient population? Yeah. I think what I love about this setup, Brad, and keep in mind, I mean, I've been a student of the targeted therapies for a while now. I was at Ignyta before. I was on the board at Turning Point. And as I think about the different targets within the targeted therapy space, I can't think of another setup as attractive as this one where you've got in ORIC-114 what we think is clearly a best-in-class profile in terms of both CNS activity and the safety tox profile. And I'll talk about both of those in a second versus both the approved drug Amivantamab, the once-approved but now withdrawn drug, mobocertinib, and then the drugs in later-stage development. And then you look at the profile of those drugs that are out there today. There's just nothing that compares in terms of having the CNS activity and then also, like I said, the safety and the tox profile. EGFR Exon 20, on top of it, is a larger population than ROS. It's a larger population than RET. It's a population that has been tested for far longer than ROS or RET. That's another important dynamic. Investors often point to the poor launches of some of the ROS inhibitors. What I would say is ROS still doesn't get tested for as widely in community settings, which is where 80% of the oncology patients are treated as probably it should be tested for. That's not the case with EGFR Exon 20. EGFR mutations have been tested for as long as there's been a first-gen EGFR inhibitor. That dates back many, many years ago. EGFR Exon 20 gets picked up on that. So I'll just say, even from a clinical trial perspective, it's palpable the difference in the ability to find EGFR Exon 20 patients, even with us being the, whatever it is, fifth or sixth competitor out there in terms of timelines, it's easy for us to find these patients in a way that was just not as easy on the side of, on the ROS side of things. So I think the setup is actually really quite nice here. And then, as you mentioned, the smaller patient population, EGFR Exon 20, like I said, is bigger than ROS, bigger than RET, and gets tested for more than those. On top of that, you've got EGFR atypicals, which because of the homologies in the target, we're actually more potent for EGFR atypicals than we are against EGFR Exon 20. And EGFR atypicals, again, is a space that does not have a CNS active compound being developed there. And so this is where ORIC-114 has such an advantage. You add up those two populations alone, and it's bigger than the size of ALK. So I really do think people are sleeping on the commercial opportunity of this program. And you harken back to the ESMO dataset that we presented. So even though that was an early dataset, we've already shown more CNS activity in that dataset than every other drug in the field combined over the last five, six years. And that's because we've got a brain-penetrating compound. The only real competition that we had on the brain-penetrant side for a drug that was designed to be brain-penetrant, that had high potency for Exon 20, was Blueprint. And as folks know, Blueprint has discontinued their drug. And so now that leaves us as kind of last program standing that's got that CNS activity. Last year at ESMO, we showed multiple examples of CNS activity in patients with active brain METs. This is the thing that I'd sort of caution you and others on is you'll always see compounds in this space sort of wave anecdotes of one or two patients where they might have seen some activity in a brain MET. You have to ask those companies, are those patients previously treated with surgery or radiation? Because every one of the other programs in the space, other than us and Blueprint in the early studies, excluded patients from their studies with brain METs unless they had been treated with surgery or radiation. So that obviously confounds the analysis of whether a drug is CNS active or not. We don't do that exclusion. We had multiple examples, like I said, of patients with activity in active brain METs.. Then on the safety tox profile, people talk a lot about the EGFR wild-type tox and wanting to minimize EGFR wild-type tox, which comes in the flavor of diarrhea or rash. We certainly have done that with ORIC-114. But the other thing we've done on the safety tox side is minimize off-target tox. So these other compounds in the space, you'll see things like ALT elevation, AST elevation, bilirubin, anemia, QTc prolongation, CPK increase. These are all flaws of those drugs because of their dirty kinome trees. Those are treatment-related toxicities that it's important to kind of dig into. We don't see those with ORIC-114 because it's got an exquisitely clean kinome tree. Yeah. Very important points, especially relative to the cross-trial comparisons of these programs. I guess, how do you envision pivotal development for this? We've seen, obviously, a lot of companies going the classic monotherapy frontline route. Do you have interest in second line as well? And then also, what about a frontline chemo combination, which AstraZeneca eventually got around to with the classic mutations? Yeah. In the spirit of sort of, yeah, in the spirit of walk before you run, I think our first interest right now is the second-line populations of post-chemo. That, of course, would be the angle for a single agent accelerated approval. So when I talk about starting pivotal studies for this program in the second half of next year, that would be in these various targets of interest, EGFR Exon 20, HER2 Exon 20, and the atypical EGFR mutations. It would be in a second-line population post-chemo, but Exon 20 inhibitor naive in those populations. But absolutely, we're interested in the frontline as well. We've already thought through the frontline strategy. It's interesting. Every drug in the space has taken one of two tacks. Either you combine with chemo and then compare yourself to chemo, or you just go head-to-head with chemo. Obviously, mobocertinib failed their head-to-head with chemo, but mobocertinib, I think, for reasons people know, was not such a great drug. We have an interesting path in front of us, which is we might do something totally different than those two strategies, which is what if we combined with Amivantamab? Amivantamab is the only drug that's approved in the space. It's an antibody. It's not brain-penetrant. It's a bispecific. It hits EGFR Exon 20 as well as MET. There's a lot of reasons why a combo of a brain-penetrant TKI like ORIC-114 with Amivantamab might be quite interesting. So that's a potential strategy we might think about in a regimen that does not have chemo in the treatment arm. And that's a path that would only be available to us. Again, like I said, as the only CNS active compound in the space. So that's a novel strategy we might pursue. But I'm not ruling out one of the more traditional strategies either. We're kind of thinking through all of that right now. Got it. Now, you mentioned the uncommon, non-classical, atypical mutations. You have a plethora of terminology for that group. How extensively have you profiled 114 against all of these mutations? And how has the relative selectivity shaken out relative to EGFR wild-type? Yeah. So we've actually put out some of that data preclinically at some prior medical conferences. I think it was ESMO of last year. We had some preclinical characterization there. And that's where we showed that we're actually slightly more potent for the atypical mutations than we are for Exon 20. On the EGFR Exon 20 side, we have a window anywhere from 2x to 10x of selectivity for the Exon 20 mutations versus wild-type. That's done the way you should, which is in like-for-like assays, not trying to mix assays like some people do to sort of quote these exorbitantly high therapeutic indices. And as you can see, we have an incredibly wide therapeutic index on EGFR Exon 20, Brad. The first activity we saw was at 40 mg daily, meaning first RECIST response was at 40 mg daily. We just announced that the go-forward provisional RP2Ds for that program are 80 mg and 120 mg daily. That should tell you about the therapeutic index in EGFR Exon 20. We are more potent against the atypical mutation, so even a larger therapeutic index than that on the atypical mutation. I feel very confident given the activity we've already seen in EGFR Exon 20 that now that we've started to enroll those atypical mutations into the study, that we ought to see just as high, if not higher, of a good therapeutic index there. And then can we just close out with comments on the cash balance and runway, particularly the timeline for which you're starting up potentially multiple pivotal trials at the end of next year? What are the milestones in between that? Yeah. So we ended January with $352 million in cash. And as you know, we did complete a $125 million PIPE in January as well. So with that, we expect the current cash to take us through late 2026. And that does assume, as you said, registration studies for both 944 and 114. So that's a fully burdened number there. For milestones, obviously, we had 114. The first milestone there was to initiate the dose expansion, which we announced early this week. So the next update on that program will be the first half of 2025. And for 944, the kind of the milestones there were to initiate the combinations with the AR modulators in the first half of this year, a high-level program update mid-year as well. So those are kind of the cadence of milestones for us for this year. Okay. Perfect. Well, we will leave it there. Jacob, Dominic, thank you so much for joining us today. Thanks for having us, Brad. We appreciate it. Thanks, everyone.