All right. Hello, everyone. Welcome to Day Three of Cantor's Global Healthcare Conference. My name is Prakhar Agrawal. I'm a Biotech Analyst at Cantor. For our next session today, we have the team of ORIC Pharma. Representing ORIC, we have Jacob Chacko, CEO, and Dominic Piscitelli, Chief Financial Officer. Gentlemen, thank you for joining us early morning. Thanks for having us, Prakhar. Maybe we can start off with some of the key priorities for the company. Right now, obviously, you had a lot of updates this year. Maybe just walk us through that before we go into the specifics. Sure. Happy to jump in there. We've got two lead programs: ORIC-944. Maybe stepping back for one second. ORIC focuses on resistance within oncology. Obviously, oncology is a big space. Within that space, we tend to focus specifically on small molecule drug development for solid tumors. Within solid tumors, lung and prostate are areas that we know quite well. Our two lead programs are ORIC-944, which is a small molecule PRC2 inhibitor that's being dosed in combination with two different androgen receptor inhibitors in castration-resistant prostate cancer. ORIC-114 is a small molecule TKI that's being developed, brain penetrant, in three different non-small cell lung cancer targeted therapy populations where brain metastases progression in the brain is quite an issue. Both of those programs are in dose optimization right now. Both of those programs are potentially headed into the start of Phase III studies next year. There's quite a bit of data, as you alluded to, that will be coming out over the course of the next year on both programs. OK. We can start with ORIC-944. Maybe before going to some of the clinical trial data out there, just walk us through the similarities and differences of 944 with Pfizer's drug Mevrometostat which obviously had really good Phase II data as well earlier this year. Yeah. People have been hearing about and listening to the PRC2 inhibitors in prostate cancer for a long time now. There's a big preclinical rationale on Biology of why you would combine a PRC2 inhibitor in combo with an androgen receptor inhibitor in prostate cancer. We could spend the next 30 minutes talking about that biology. I'll just summarize it by saying that essentially what the thesis is, is that there are three big androgen receptor inhibitors: enzalutamide from Pfizer, apalutamide from Janssen, and then darolutamide from Bayer. Those three drugs have transformed the state of care in prostate cancer today. They're prescribed across the continuum in prostate cancer, across all different lines of prostate cancer. Patients do very well on them. They're well-tolerated drugs. Collectively, they do over $10 billion of revenue per year. That is a marker of just how well they have done for patients. The issue is, as is the case in most oncology indications, that patients eventually become resistant to those drugs. Essentially, what ends up happening is that the tumors evolve to become AR independent, Androgen Receptor independent. It no longer matters that you're giving an AR inhibitor. The biology suggests that if you give a PRC2 inhibitor, you can actually—PRC2 is an epigenetic modifier. Through those epigenetic modifications that it makes through inhibition of PRC2, you can essentially push the tumor to stay in an AR-dependent state. The issue has been that all the first-gen compounds that came after this target, and there's been numerous of them, have essentially had very, very poor drug properties with one to two-hour half-life. Some of them have had CYP autoinduction, where they rev up the CYP enzymes, and they are also metabolized by the CYP enzymes. They'll get really funky phenomenon like dose-dependent decreases in exposure. Pfizer seems to have fixed a lot of that with Mevrometostat. They've never said what their half-life is, but it looks like it's about four or five-hour half-life. It does not seem to have CYP autoinduction. Now in two different CRPC populations in the Phase 1 setting, and also in a randomized Phase 2 population that they revealed earlier this year, they've seen really phenomenally long PFS in combination with their androgen receptor inhibitor. As I mentioned, their properties are better than the first-generation compounds that have come before. Their potency is better than the first-gen compounds that have come before. ORIC-944 is a drug that we acquired from Marathi five years ago. The Marathi chemists had observed the same things that we had, that the PRC2 inhibitor field was littered with these poor drug properties. They came up with a drug in ORIC-944 that has a 20-hour clinical half-life, is very potent, as potent as Pfizer's drug, has no CYP autoinduction. In other words, really clean, good drug properties. We dose that drug Q.D. The benefit of dosing Q.D. is not just that we're dosing Q.D. and Pfizer's dosing B.I.D. Even more than that is you think about just the pharmacokinetics here and what you're trying to achieve. This comes back to your question of just how it compares to Pfizer's drug, is that with a four or five-hour half-life and being dosed B.I.D., it's a challenge to try to cover C min, which is what you need to do for efficacy, without also tempting C max-driven toxicities. With a 20-hour half-life where we're able to cover C min and get that better target coverage, but without these big spikes for C max, which is where the toxicity comes from, it ought to lead to a better overall profile. Got it. That leads to the next question. In May, you presented some Phase 1 data from the dose escalation study. Just remind us of what you saw on the efficacy and safety side, and how did it compare with Mevrometostat? Yeah. I couldn't be more pleased with the data that we presented in May because even though it was a small n, it was 17. It was large enough to start to see some of the clinical proof of concept that I mentioned, of the theories I mentioned, that with that, this 20-hour half-life, we ought to get that better target coverage without the C max-driven toxicity. As you try to do the comparisons, I always hesitate to do comparisons side- by- side of drugs at cross-trial comparisons, especially with the fact that Pfizer is so much further ahead of us. Obviously, we're trying to de-risk this program right out of the gates. What Pfizer showed in their randomized data set earlier this year was, first of all, I mentioned they're further ahead of us. What they ultimately showed that matters is PFS. They had a PFS that was over 2x as long as what the control arm of enzalutamide alone was able to achieve. What was important is they also gave you clues as to other auxiliary measures like PSA-50s and PSA-90s. The accompanying PSA-50s and PSA-90s that went along with that phenomenally long PFS in the case of Pfizer was a 34% confirmed PSA-50 rate and a 12% confirmed PSA-90 rate. In our data update in May, as opposed to Pfizer's 34% confirmed PSA-50 rate, we had a 47% confirmed PSA-50 rate. As opposed to their 12% confirmed PSA-90 rate, we had a 24% confirmed PSA-90 rate. Even right out of the gates, we're seeing better PSA activity that ought to translate to longer-term durability, just like it did for them. Importantly, on the toxicity side, you should see two big classes of toxicity with a PRC2 inhibitor. Folks can just look at the Tazemetostat label, which is the approved PRC2 inhibitor, which is developed in heme indications. You can see there's two big classes, which is GI tox in the form of things like diarrhea, nausea, and vomiting, kind of just that constellation of GI tox. You'll also see heme tox, various penias. You certainly see that in our drug. You certainly see that in Pfizer's drug. You definitely see a lower incidence and lower severity of those toxicities in our profile that we presented in May than what Pfizer has presented thus far with their drug. There's also potentially, I can't really tell. I'm not sure what the source of it is. In the case of Pfizer, 40% of their patients have alopecia. We don't see any alopecia in ours. That's actually quite important in this prostate cancer population, is not having alopecia. Overall, we were very, very pleased with the activity we saw. Right. I realize it's a small sample, but the population that you tested versus Pfizer's population, was there any differences? Yes. There was one difference, which is ours was more heavily pretreated. That was the other thing as well. Both populations were focused on the CRPC population for patients who were post- abiraterone. Every single patient had already had abiraterone before they came onto our study, before they came on the Pfizer study. Prior chemotherapy was allowed in both studies. The one big difference, though, was we're an earlier stage study. In addition to all those things, we also allowed anything else. We had a whole lot of other therapies that our patients had experienced, including IO and KLK2 and all these experimental therapies before coming onto the study. Our median lines of therapy for patients before they came onto the study was three. Pfizer's was effectively one or 1.5. OK. One question we had gotten was, how do the responses vary by chemo? If you can comment on that. Yeah. The short answer is they don't. We did a subgroup analysis to when we looked at what was the PSA response rate for our patients who had had prior chemo versus not had prior chemo, and there was no difference in response rates. You normally would expect, by the way, to see a difference in response rates for people that are pre versus post- chemo. I think the difference probably here what explains the fact that there was no difference is that our patients had so many other therapies as well. It's not just as simple as an analysis of who had chemo and who didn't have chemo. Right. On safety, you had presented pooled data across the different combinations, darolutamide and apalutamide. Please speak to the implications of that when people, investors, are comparing these data versus Pfizer's. Yeah. I mean, it's always tough to do these comparisons because especially in dose exploration, you've got a variety of different doses. In our case, we're testing two different AR combo partners in combination with ORIC-944, and it's hard to kind of tease that apart. What I would say is that my view or our view is that the safety profile we presented in May is about as bad as it's going to get. If I can describe it that way, what I mean by that is that in dose exploration, one of your goals is to push dose to find the safety threshold and, in fact, go beyond a dose that you would take forward into Phase 3 studies because you want to know where that line is. That certainly, we got to that point with at least one of our drugs that we were testing back in that May update. I would tell you that as we then hone in on what is the selected dose that we'll take Phase 3 studies, it ought to be cleaner, if anything, than the profile we presented in May. One thing that's important for people to keep in mind is there were no subtherapeutic doses that were used in that May data set, the reason being that we had a long experience of dosing ORIC-944 as a single agent before ever going into the combo studies. We started out of the gate at therapeutic doses. OK. For the next update, the combination data in the second half, just lay out the expectation in terms of the patients and what are you hoping to see on efficacy. Sure. For the second half update for ORIC-944, the way we're describing this for people is it's more incremental in nature. Obviously, the May update was pretty substantial. The second half update is going to be a little bit more incremental in nature, a little bit more of an operational update. What I mean by that is essentially the focus of that update will be laying out the rationale for what are the doses that we chose for Project Optimus purposes. As you all know, for Project Optimus, you need to choose at least two potential go-forward doses and then enroll a certain number of patients across those to basically establish the efficacy-toxicity relationship. We will lay out the rationale for why we chose the doses we chose to go along with apalutamide and separately the doses we chose to go along with darolutamide. That could include any of the following rationale, which would be efficacy measures like PSA-50s, PSA-90s, although you will have seen substantially all of those already. One of the other things we've said is we will only add up to another handful of patients as part of the second- half update, the reason being that we went faster than we expected in the first- half of the year. When we gave that May update, we actually had already honed in on what the selected go-forward doses were going to be with darolutamide. We were very close to honing in on selected go-forward doses with apalutamide. There was not a whole lot more dose exploration to go, which is why you're not going to see a lot more patients as part of that second-- half update. Back to what you may see to kind of give the rationale for the doses we selected, PSA-50s, PSA-90s. ctDNA is a question that we're getting a lot about. People would love to see ctDNA. I think it's being incorporated more as an exploratory endpoint Phase 3 prostate studies these days. It's certainly something we've been looking at from the outset of the study. We could potentially share ctDNA, including on those original 17 patients for anyone that we had it on, and then potentially PKPD and certainly safety as we kind of lay out the rationale. Really, that update is a little bit more about then laying the groundwork for the Q1 update of next year. Q1 of 2026, we plan to give the dose optimization update. That's a really substantive one because that update will be a bolus of new data. It'll be focused on just potential go-forward RP2Ds. At this point, what we're saying is there's so much work that's going on on the dose optimization side because there's two different combo agents that we're testing with apalutamide, which is Janssen's drug, and darolutamide, which is Bayer's drug. There's two different populations within CRPC that we're evaluating. One is a post- abiraterone population, and another one is a post-AR inhibitor population. Obviously, within each of those parts of the schematic, there's at least two doses that we'd be testing, Dose 1 and D ose 2. At this point, what we're comfortable committing to is that in the Q1 update, folks will get to see at least one combo agent drug, so either our combo work with apalutamide or darolutamide, at least one of those populations, so either the post- abiraterone or the post-AR inhibitor population, and any doses that we had selected within that. Sorry, any doses we had tested within that. For any one of those doses, it'd be 10- 12 patients. Assuming two doses, that's 20- 25 patients' worth of data that you'll get to see in one population with one combo drug. Right. What about the duration of response? Especially in the second- half update, is that something you'll have enough of a longer follow-up to show that? That'll be for the Q1 update. The Q1 update, you certainly would get to see some measure of durability because everybody, ourselves included, wants to see that durability. That'll be in that Q1 update because you'll have a cleaner data set at that point. You'll have two doses and 10- 12 patients per dose, and that'll be the time to look for durability. One thing I want to be clear on is that will not be a mature PFS number. It just, by definition, can't be, just given where we are kind of timeline-wise. We ought to be able to do some kind of three-month landmark analysis, four-month landmark analysis, just whatever makes sense with the data set that we've got at the time. One question we've gotten is, do we want to see the Pfizer Phase 3 data before we start our own Phase 3? We've said we want to start our Phase 3 study first half next year. Another question we've gotten is, do we want to see our own mature PFS data before we start our own Phase 3 study? The answer to both of those is no. We think it just would be irresponsible at this point to wait that long. There has been so much data at this point that's been generated by Pfizer, generated by us, that has de-risked this mechanism in at least one of these prostate populations that if we were to try to wait for those things, all we would do is put ourselves further and further behind Pfizer. There's a race to the finish line at this point because we do think that this mechanism is going to really dramatically change how these prostate cancer patients are treated. The timelines are quite fast. For one of these studies, let's take the post-abiraterone study just as one example. That is Pfizer's first Phase 3 study, MEVPRO-1. They started October of last year. They say their primary completion date is end of this year. That's 15 months, and they're going to have data presented next year. It's very quick. It's a 600-patient study, and as we've powered that study for our own purposes, if we were to do that as our first Phase 3 study, we also think it's a 600-patient study and 15 months in duration. The point being that starting first- half next year, that study, we would by mid-2027 have our Phase 3 data readout. That's why it's so important to go fast here and not just delay things waiting and waiting. Right. You mentioned briefly about Phase 3 plan in the post-abi setting. Do you foresee any sort of changes in terms of the designs or sample size versus some of the ongoing Pfizer trials? No material changes. We still haven't committed to which of those two populations would be our first Phase 3 population, but the study sizes aren't dramatically different. Whether we go into the post-abiraterone or the post-androgen receptor inhibitor population, neither one. The study sizes are actually relatively manageable. They're small. The timelines are fast. There haven't been any material changes for us as we compare those two populations. Pfizer's not looking at the post-androgen receptor inhibitor population. They're, in fact, starting two other Phase 3 studies. One is already underway for them. It's a treatment-naive population in CRPC, and then there's a third that supposedly is going to get underway in CSPC any time this year. They're clearly putting big dollars behind the program, and we intend to do the same thing. One big thing just to kind of level set for folks is as we think about the data updates that are coming up, the rationale we lay out, I did mention different doses of ORIC-944 with apalutamide versus with darolutamide. That's something I think people are quite familiar with at this point, but it's probably worth a minute explaining, which is that apalutamide and enzalutamide, Pfizer's drug, those are both well-known, well-characterized as CYP inducers. What they do is they rev up the CYP enzymes. Lots of drugs are metabolized by CYP, and they kind of push down the exposure of drugs you're trying to combine with them. Certainly, that's the case that Pfizer's experiencing with Mevrometostat and enzalutamide, and we experience that when we combine ORIC-944 with apalutamide. We do not experience it when we combine with darolutamide because darolutamide is not a CYP inducer. That's why, harkening back to my earlier comments, we kind of already had a line of sight to what the darolutamide combo doses were back when we did the May update, but we said we need a little more time on apalutamide because we just had to keep doing some dose exploration. It's pretty straightforward. It's not rocket science. It's just dosing higher to basically get back to the same exposures. That's why the doses certainly will be different that we end up testing with the two drugs. Right. Maybe just speak about the commercial aspects here. What's the opportunity for ORIC-944 in the broader scheme of prostate cancer? Yeah, that's a great question, Prakhar. First of all, I'd say this is prostate cancer. This is a large tumor, a large number of patients, unfortunately for the patients. If you look at the AR inhibitors that Jacob outlined, both enzalutamide, apalutamide, and darolutamide combined, they did $11 billion in sales last year alone. As Jacob said, they're used across the treatment paradigm, both in CSPC as well as CRPC. If you look at the CRPC setting, the metastatic CRPC setting, it's about 50,000- 55,000 patients. It's generally split across three patient populations. The two patient populations that we're currently studying are the post-ABI and the post-ARPI settings. Each of those are about 15,000- 20,000 patients each. If you did the rough math on that, each one of those is about $3.5 billion of addressable markets in the U.S. alone. That's U.S. alone. Combined, that's a $7 billion market in the U.S. This is combining with the standard of care. Obviously, there's a simple adoption aspect to this as well. AR inhibitors are used obviously across the treatment paradigm by urologists, by oncologists as well. That is kind of the current market we're pursuing right now. We do think, as Jacob alluded to, Pfizer is studying the CSPC setting. We absolutely think that there is room for us to move up there. We should be moving up there. Those studies are much larger. They take much longer. They require a lot more capital. That may be better suited for a partnership at some point down the road. Right. Given that Pfizer is a little bit in the lead here, are there any sort of nuanced differentiating attributes that you could show with your combination approach? Yeah, I'd start by saying that given the size of this market, you don't necessarily have to be different. The perfect analogy is AR inhibitors. I worked in innovation, so I'm very familiar with enzalutamide. We launched that in 2012, and that did $6 billion in sales last year and has grown about 15%-1 6% year- over- year. Apalutamide actually was launched six years later, so it was launched in 2018, and last year, that did $3 billion in sales. It's grown about 25%. A year after that, darolutamide was launched, and that did about $2 billion last year. The point being, those drugs are basically indistinguishable, and they came six years apart. Assuming we were the same, that would be in a very strong position from a commercial perspective. Now, as Jacob outlined up front, the early data that we presented here, we have seen higher PSA responses. We have seen a better side effect profile as well. Obviously, if you participated and you had any of those in Phase 3 study, that would obviously increase our market share. If you look at market share, second to market within two years with the same profile, the second drug probably captures 30%- 35% of the market with the same profile. Obviously, you have some differentiation. Even if it was just safety, that would obviously increase that market share significantly. OK. Maybe we should talk about 114, which does not get that much time these days, but maybe it should. Ezetimibe, I think that's what it's called now. Yeah. Could you talk about the reasons why you remain excited about 114? Yeah. As we profile the competitive landscape and we profile our preclinical data as well as our clinical data, I think the two areas that we think we're differentiated and we're excited about is, one, is safety and tolerability. The second is CNS. Starting with safety and tolerability, when you look at these drugs, there's really two forms of toxicity. There's on-target toxicities. You think GI. You think rash. You want to maintain that. You're going to have some level of rash. You're going to have some level of GI. You don't want that obviously to be too high. A lot of these other drugs that are out there have off-target tox. You see drugs with elevated liver enzymes, elevated ALTs. You see QTC prolongation. If you look at our kind of screens compared to the other competitors, ours is really exquisitely clean. That should translate into less off-target toxicities, which could be an area of differentiation. Probably more important is the CNS activity. If you look at these patients, about a third of these patients present with baseline brain mets. A majority of these patients, actually, the point of first progression is in the brain. Having a CNS-active agent here could really be game-changing. Obviously, it helps the patients longer and obviously increases duration as well. If you go back and look at targeted therapies in general and you look at patient drugs that are CNS-active versus drugs that are not CNS-active, you don't necessarily see a difference in the response rate. It really translates into longer progression-free survival. That's where the differentiation could play out for us. Maybe double-clicking on the brain-penetrant differentiation, as we compare some of those response rates, the CNS response rates across trials, a lot of companies say that they have CNS responses, let's say, for ArriVent's, firmonertinib. Please clarify the CNS activity and the right way to sort of compare the CNS responses across trials. I think the right way is we are literally the only company in the space that has shown the ability to treat CNS mets in a patient with active CNS mets in EGFR exon 20. Full stop. There's no other company. As people have kind of alluded to, maybe they have CNS activity and maybe they don't. I know that ArriVent that you mentioned has shown that kind of activity with atypicals. I'm not aware of seeing any data that shows a patient scan, show the data that you've got a reduction of a met in a patient with active brain mets in EGFR exon 20, other than what we showed at ESMO 2023 with ORIC-114. OK. Ezetimibe has data in the second- half across multiple cohorts, EGFR exon 20, HER2, and atypical. Just frame expectations on efficacy, safety, and how many patients should we expect? Yeah. This is a more substantial update, unlike ORIC-944 second- half update. Here we are studying this in four different cohorts of patients. The dose expansion is comprised of three groups of patients. These are second-line or later patients, and it's EGFR exon 20, HER2 exon 20, and EGFR atypicals. We have made the strategic decision for both commercial reasons and cost of capital reasons not to pursue the second line. This is kind of a read-through to the first-line setting as well. Here, we'll show you about 25 patients in each of those three cohorts, so a total of about 75 patients across the two doses we're studying. The two provisional RP2Ds that we selected here were 80 and 120, also 120 once a day. If you think about the benchmarks that we've kind of set for ourselves here in EGFR exon 20 and the atypicals, the OR is about 35%. That rate excludes patients with active brain mets. That's the benchmark we kind of set for ourselves. For HER2 exon 20, the benchmark we've kind of set is about 50%. That's a little bit higher. There has been some good data from competitors there. That space is definitely getting more competitive as well. I'd say the bar is getting higher for the HER2 exon 20. We're also going to give you an early look on first-line EGFR exon 20 as a monotherapy. Here, we'll show you about 10- 15 patients' worth of data, and the bar here is about 55% top line OR. What percentage of the population that you will present could have CNS mets? We will see what patients come. We'll look at the data. It could be in all those subsets of patients that we could see some patients with CNS mets. OK. Across these three, EGFR exon 20, HER2, and atypical, where do you see the biggest value right now for ezetimibe? Yeah. If we look at the three patient populations, EGFR exon 20 is slightly over 2% of non-small cell lung cancer. HER2 exon 20 is about 2.3%, 2.4%. The EGFR atypical is probably 3%. Combined, it's about 7% of non-small cell lung cancer. It's a pretty significant patient population. If you combine any two of those patient populations, it's over 4%, which is basically the size of the out market. The out markets are a significant treatable opportunity there. I'd say they're generally equal, but obviously, the atypicals are slightly bigger from a patient population standpoint. OK. Remind us about the status of the amivantamab combo trial. Yeah. We started the, maybe taking a step back. This is combining ORIC-114 in combination with amivantamab in the first-line non-small cell lung cancer for exon 20. If you look at other competitors, they've basically taken one of two different approaches. They've done it monotherapy or they did it in combination with chemo. Given our profile, both from a safety standpoint and on the CNS activity, we worked with J&J. During the combination with the amivantamab, we did get a clinical supply agreement from J&J. That data will be in mid-2026 here. We started enrolling this study earlier this year, and we'll have data in mid-2026. OK. You guys have your hands full with a lot of updates over the next 12, 13 months. What are your thoughts on the strategic options for 944 and enozetinib? When would be the right time to partner either or both assets? Yeah. What I would say is we're not dogmatic about that, Prakhar. I think our view is that we ought to continue to be dynamic as we think about what's the right time to partner one or both programs, continue to be dynamic as we think about what's the right definition of partnership. Meaning partnership means a lot of different things in biotech. It could be as simple as a drug supply agreement that enables Phase 3 studies that ORIC is running. As folks know, we topped up the balance sheet in a big way earlier this year in two different slugs, and we have a long cash runway that's in the second half of 2028 that is past Phase 3 data readouts for both programs. In fact, over a year past Phase 3 data readout for ORIC-944, which is the readout that's going to make us a commercial company. That's one style of partnership. It's just a drug supply agreement. You could also out-license something entirely if it made sense. Certainly, for something like ORIC-944, and we have aspirations to develop that in CSPC, potentially even outside of prostate cancer, that's something that might lend itself to a much bigger BD, co-co type collaboration. I will say we continue to stay very close to our various partners, not just Bayer and Janssen, but everybody that cares about prostate, everybody that cares about lung on the pharma side, know them all on a first-name basis. At the right time, we'll do what's right for the programs and for the company and for our shareholders. Yeah, you did take several steps to strengthen the balance sheet. Just remind us about the cash runway. Yeah. I think Jacob hit it real quickly. The pro forma cash, given the PIPE financing we completed in May and the subsequent ATM activity, we ended Q2 with $436 million in cash and investments on a pro forma basis. That gives us cash runway into the second- half of 2028. That assumes full success for both our programs. What that does is, Jacob, I'll just reiterate it because it is important. It gives us cash runway past the top line Phase 3 readout for both programs, 114 and 944. It actually gives us runway a year after the 944 Phase 3 readout, which would be mid-2027. OK. That's all the time we have today. Thank you, ORIC team, for joining us. Thank you to the audience for listening in. Thanks for having us.