It's Michael Schmidt again from the Guggenheim Biotech team, and it's my great pleasure to welcome the next presenting company, which is ORIC Pharmaceuticals. With us today we have Jacob Chacko, CEO, and Dominic Piscitelli, CFO. Welcome, guys, and thanks for joining us. Thanks for having us, Michael. Jacob, you guys have built a very diverse pipeline. There's 3 drugs in clinical stage development now that are addressing very different targets. Maybe first, could you talk about your general principles of target selection? Sure thing. I'll talk about general principles of target selection, but some of it harkens back to the team that we've recruited. We've got full slate of internal capabilities on the internal discovery side, on the Business Development and strategic side, and then obviously on the clinical development side. What it's enabled us to do is we've got a philosophy internally that we call Best Molecule Wins. Essentially, the point there is if there's a target that we like that we can work on, from an internal discovery point of view, obviously we will do it. If someone else has a better approach or more advanced approach, then we're perfectly open to and happy to in-license the program. There's a lot of companies, I think, with great internal discovery that get stuck in a mindset that they have the best internal discovery and no one else does, and it prevents you from doing good in-licensing. We've, I think, shown an ability over time to fill the pipeline with targets, both internally discovered as well as licensed from external parties. What it's enabled us to do then from a target selection point of view, Michael, is we like to have a mix of, you know, validated targets as well as novel targets in the pipeline. I think, you know, the novel targets are the ones that tend to gravitate more towards things that we should do from internal discovery. The validated targets tend to be the ones that we will look to in-license. Across the spectrum, we've got three different programs. ORIC-533 is a CD73 inhibitor, oral, small molecule, homegrown. We've got ORIC-114, which is an EGFR exon 20 inhibitor that's brain penetrant that was in-licensed. We have ORIC-944, which is a PRC2 inhibitor for prostate cancer that was in-licensed. Obviously there's a, an earlier stage PLK4 program that was homegrown, that we'll talk about today if we have time. Great. Maybe let's start out by talking about ORIC-533, your CD73 inhibitor. You know, that's a target where we've seen, you know, a number of antibodies in other compounds, you know, pursue with, I would say perhaps mixed clinical data so far. There's still a Phase 3 study ongoing by AstraZeneca in stage III non-small cell lung cancer. You guys are focusing on multiple myeloma, which is different from what others have been doing. Perhaps first, can you talk about how well understood is this target in multiple myeloma? You characterized the CD73 results so far as mixed, and I'd say that's probably generous given what the field has shown thus far from what we think are suboptimal molecules and suboptimal approaches. We obviously think we have something quite differentiated with our small molecule oral inhibitor. We've pre-clinically profiled this every which way and are convinced that it's got a best-in-class profile versus small molecule and antibodies against CD73, and also as it compares to the broader adenosine pathway, any program you can use to target it, whether it's CD73, CD39, or the adenosine receptor antagonist. Despite that confidence in the preclinical profile of this program, years ago, when we were still private, the question that we posed at our board and to our investors was, how do we carve out a clinical development path that has some white space here? Every single company with a CD73 inhibitor is doing the exact same clinical development plan, which is you take your CD73 inhibitor, you pick your favorite IO agent, and you pick your favorite solid tumor type, and you sort of go hope for the best. The oleclumab data in the COAST study, we actually think was a positive data set and a really good step forward for the field. We can come back to the I-O combos in a second, but back to the multiple myeloma rationale, as one of our investors had known Ken Anderson at Dana-Farber for two decades, at that prompt that I mentioned, spoke up and said he was aware that Ken Anderson has been separately doing work that implicated CD73 as a potential therapeutic potential in multiple myeloma. Through that connection, we got connected to the Anderson lab, established an MTA, did work with ORIC CD73 inhibitors in Dr. Anderson's proprietary ex vivo patient assays, where they're literally these are derived from patients being treated, relapse/ refractory patients treated at Dana-Farber. He saw very good activity with our CD73 inhibitors in those ex vivo assays. That's what gave us confidence to pursue the path. The biological rationale that he had elucidated was essentially that in these patients with myeloma, you see five to six times the levels of adenosine that you see otherwise in someone without myeloma. If you could put a CD73 inhibitor into that environment, you could perhaps tamp down the adenosine levels, thereby you get increased T cell activity, and it's the increased T cells that'll do the killing, the actual multiple myeloma lysis. That was the rationale behind pursuing this. We believe we are the first company to pursue this, but it's through that collaboration externally. Gotcha. You know, would that also work with an A2A inhibitor or CD39, or is that something that's unique to CD73? I mean, I suppose that the rationale hinges on turning down the levels of adenosine and therefore turning up the T cell activity. Anyone that can really aggressively turn down the levels of adenosine like we can with our CD73 inhibitor, you know, could in theory pursue it. That comes back to the first point, which is as we have pre-clinically profiled our compound, it looks to be best in class. Gotcha. You initiated a Phase I study, and you guided to data in the first half this year. Talk about, I guess, what do you need to see to advance this to next steps? Correct me on one thing. This data's guided to the second half this year. We likely use a major medical conference to put out those data. You know, we're enrolling a patient population. This is the tried and true development path in myeloma these days, which is a relapse refractory population, triple-class refractory, in many cases, quad or penta-line refractory. Short answer is you're not expecting or hoping to see much. You don't need to see much to know you've got an active agent. If we can see modest single- agent activity in that population, and by that I mean 10% responses, and even if it's not, say, bona fide responses by the working group criteria, if you've got a handful of patients where we're seeing double digit decreases in M-pr otein, any of that would signal that we've got an active agent as a single agent, and then the next immediate development path, as is true in the myeloma space, would then be various combinations. You've got four major classes of approved agents in the myeloma space now, the CD38s, the IMiDs, the proteasome inhibitors, and now BCMAs. Any of those would be potential combination partners for us, as a next step of development. Gotcha. You did announce a collaboration with Pfizer recently as well to look at potential combinations with their, I believe with their BCMA bispecific, right? Mm-hmm. Can you talk about sort of what drove that and what's the thought process behind that collaboration? Sure thing. You know, our work with Dr. Anderson, we made public to the world at ASH of 2021, just over a year ago. Right after that, every strategic with a myeloma franchise wanted to learn more about CD73 and myeloma, Pfizer among them. As a result of those conversations, and because Pfizer is trying to build out their myeloma franchise and they were excited about the potential mechanism here that we were elucidating, as we got to conversations with them and as they learned more about that on the preclinical side, and then saw some early clinical data from our dose escalation study, they got excited, and we got excited about doing a potential collaboration together. In terms of that, really, there's two big components. One is a $25 million equity investment that Pfizer made into ORIC. That was announced at the end of last year. The really important operational piece, aside from obviously the cash and the extra runway of that equity investment, is the potential for Pfizer to run a Phase II combo study for us with their BCMA agent. The reason that's so beneficial is one thing we were really sensitive to was tying our hands operationally. ORIC has discretion as to whether we wanna run a combo study. If we wanna run a combo study, which class do we wanna run it with? If it's a BCMA, which BCMA agent do we wanna run it with? If the answer to all those is, "Yes, we wanna run a combo, and we wanna do it with a BCMA agent, and we want it to be Pfizer's," then Pfizer will run that study for us. From our perspective, it's operationally fantastic, gives us lots of degrees of freedom. Obviously, if that's the path we end up down, Pfizer is a fantastic partner to run that combo for us. Gotcha. Okay, looking forward to that kicking off. All right, maybe let's switch gears and talk about ORIC-114, your EGFR exon 20 inhibitor. There's obviously a lot of those molecules out there, and some of them are approved, 2 of them are approved, an antibody and a small molecule. Maybe first talk about those unique features of ORIC-114 that could potentially differentiate it from the other available agents. You know, I'd say the first order analysis of the EGFR exon 20 space is always that it's a super crowded space with lots and lots of programs. I always chuckle a bit when I hear it because the reality is you've got to be brain penetrant. I mean, this is a play that has played out over and over again in the targeted therapy space. Prior to ORIC, I was at Ignyta, and we were developing a drug that was brain penetrant. Back then, there was a debate about whether you wanted a TKI to be brain penetrant to handle brain metastases. Now I can tell you there's zero debate. Amongst the KOLs, it is dogma. You must have a brain penetrant compound. As you look at all the major targets in targeted therapy land, the winning compound is a brain-penetrant compound. We think EGFR exon 20 is gonna be no different than any of the other targets have been. When you then focus on which of the compounds that are brain-penetrant, it is, it is really just us and one other competitor that's in the clinic now, Blueprint, that claims to have a brain-penetrant compound. Everybody else doesn't have a brain-penetrant compound. The two approved agents are leading agents. That's why we think that's the critical flaw in the profile of all of those programs, and it's a much, much smaller competitive set than people see at first order. Gotcha. Okay. This drug's in Phase I as well. Perhaps talk about, the study, you know, how it's been enrolling, and again, what investors should expect to see this year. Sure thing. This is a program that we in-licensed from a, at the time, private South Korean company, called Voronoi. Having done that in-licensing, it made a lot of sense to actually, and part of our pitch to them was to start the study in South Korea. That's where we started the study initially, in Q1 of last year. Enrollment, South Korea is fantastic. Those sites are fantastic for enrolling targeted therapy studies, as several companies have experienced. We opened the U.S. IND at the end of last year, and initiated our first site as well. We anticipate in the second half of this year, again, at a major medical conference, we would look to present the first look at data from this program as well. Just like in the case of our CD73 inhibitor, we expect in this case we'd have roughly 30 to 35 patients worth of data that we'd be able to share at that time. At least half of those patients ought to be at a clinically active dose. If you just look at general prevalence of brain mets in these populations, it's about a third. We ought to have half a dozen patients at a clinically active dose that have brain mets, and we should be able to then see whether we have activity in brain mets or not. That's the whole hypothesis here, or the thesis here of the differentiation is that we should show that we have that brain penetration, that activity in intracranial mets, and then, you know, it's off to the races from there. Right. We may obviously get registration data this year, from amivantamab and then also, the Takeda drug in first line exon 20 non-small cell lung cancer patients. You know, with that in mind, I guess how do you think about next development steps? You know, is there an opportunity to focus just on brain mets patients? Is there an opportunity to go straight into first line? You know, how do you think about next steps after this initial Phase 1 study? Yeah. As the two approved agents that have accelerated approvals now generate more data and then eventually get full approvals, you know, I'm gonna start to sound like a broken record, because they don't have activity against brain mets, they have not closed the door on us or other agents that do have activity on brain mets. Again, that's a regulatory path that you've seen play out in multiple other TKI spaces as well. It's very clear that would be the case. In terms of, you know, next steps, if things go well with our early data, we would look to pursue, you know, a single agent accelerated approval pathway. You know, it'd be a standard registrational path at that point. Okay. Super. Lastly, let's talk about 944, your PRC2 inhibitor. you know, again, you know, can you maybe just remind us of, you know, differentiation perhaps from the EZH2 inhibitors and, what are some of the unique features of this drug? Sure. I'll take that one. ORIC-944 is our allosteric PRC2 inhibitor. We in-licensed this from Mirati in August of 2020. The thing we really like about this, Mirati really took kind of an independent view and profiled a number of EZH2 inhibitors and EED inhibitors, and this was their lead molecule that they took forward. If you look at the PRC2 complex, there's two druggable subunits. One is EZH2 that most people are familiar with. There's obviously approved agents on the market, and there's a number of other companies that are pursuing it. Then there's EED's, the other druggable subunit. The two key differentiation is one is biological one. One is the there's a potential resistance you see with EZH2 inhibitors, both in an acquired resistance to EZH2 as well as a bypass resistance to EZH1 that hopefully we can overcome it with the EED, hitting the EED subunit. The second one is a little more concrete in the sense of drug properties. You know, the first generation EZH2 inhibitors really had poor drug properties in the sense of, you know, short half-life, three to four half-lives. Some of these had, actually dose-dependent decrease with multiple dosing as well. We think we could have better drug properties, and this is just a better drug profile for pursuing in prostate cancer. Okay. Maybe talk about the mechanism in prostate cancer. I think, you know, how validated is it, is it in that setting? I think it's very validated. I think that's why there's a number of companies that have been and continue to pursue the PRC2 complex in prostate cancer. At a high level, you know, the PRC2 complex has multiple mechanisms when it comes to castrate-resistant prostate cancer. Two key things is it basically turns down the genes that regulate tumor suppression and actually turns up genes that regulate EMT and neuroendocrine differentiation. That's the underlying rationale, and that's kinda what we're pursuing, as well as a number of other companies, including Pfizer, Ipsen, Constellation have one as well. Every company with an EED inhibitor or an EZH2 inhibitor is looking at multiple tumor types, and prostate is on the list of every one of them. Gotcha. Then maybe can you talk about what we've learned from those other programs, perhaps the Pfizer or Ipsen programs, and how it may read through to your study? Yeah, that's a great question, Michael. late last year. Maybe I'll start off with Pfizer. Pfizer presented some data late last year combining their EZH2 inhibitor with enzalutamide, and this was in patients that had failed a prior AR modulator, so this could have been Abi or abiraterone or enzalutamide. They showed a PFS benefit of about 8.7 months in this patient population, which is pretty compelling. If you look at the historical benchmarks, it's typically 3 to 4 months in that patient population. Ipsen as well presented some data late last year combining tazemetostat with enzalutamide in patients that have failed. Most of the patients in that study had failed a prior AR modulator, and they showed a PFS benefit about 11 months. We thought that data was pretty compelling as well. They're both running randomized studies, so we're obviously keeping a close eye on that data to see if it makes sense for us to combine it either with an AR modulator or a PARP inhibitor. Gotcha. I know there's some activity in sickle cell disease as well. Just remind us of, you know, what we've seen there and if there's an opportunity outside oncology. Maybe I'll start off by saying our primary focus is oncology. That's what ORIC stands for, Overcoming Resistance in Cancer. At the same time, we're opportunistic when possible. We've been keeping a close eye. There's a company called Fulcrum that has shown some interesting data in sickle cell. They initially showed some data in healthy volunteers, and they continue to dribble out data in patients with sickle cell disease, and it's somewhat interesting. The key thing there, at the time of the healthy volunteer data, we got a number of inquiries on what rights do we have for this molecule. ORIC-944 was licensed from Mirati. We have therapeutic rights for all indications globally. you know, pending positive data from Fulcrum later this year, I think they're gonna provide an update in Q4 of this year. We do have the optionality to pursue it ourselves or look for a partner in sickle cell disease. All right. Very interesting. Jacob or Dom, I guess can you talk about the Phase I study? You know, what types of patients are enrolling in that, and what should we expect to see in the second half? se 1b study in late-line advanced prostate cancer. These are patients that have seen one or two more AR modulators and up to two rounds of chemotherapy. There's really late-line patients. There's really nothing available for these patients. This is an all-comer patient population as well. What we've said is we'll provide an update the second half of this year, most likely at a major medical conference. Just framing expectations here as well, we're expecting about 30-35 patients' worth of data, and about half of those patients would be at or around the clinically relevant dose. Great. Lastly, you did mention your PLK4 inhibitor. You know, again, what makes this an interesting target and- This comes back to your first question, Michael, around just how we do target selection. PLK4 is a novel target. It's totally unvalidated. As far as we know, we've got a first-in-class approach targeting PLK4. PLK4 was the subject of a couple of high-profile Nature papers that came out in, I believe, 2021. Our team had a head start of, you know, over 1 year before that because our biologists had come upon this target separately as something that was pretty interesting. I won't say how. Started working on the program. You know, PLK4 is relevant to a synthetic lethality pathway that's implicated with TRIM37 amplifications. You see that relevant to about 20% of breast cancer and about 1/2 of neuroblastoma. Like I said, we think we've got a first-in-class program there in terms of a selective PLK4 inhibitor. We picked a DC last year. That's one of the things we announced. It's going through standard IND-enabling work right now, including tox work. Assuming it gets through all of those hurdles and filters, then it could enter the clinic first half of next year. What's more exciting or interesting about it, though, is just, you know, back to your first question, which is just as we continue to replenish the pipeline, our internal discovery team is fantastic at finding these novel opportunities. We've got other undisclosed programs in the pipeline, again, largely targeting novel biology, novel opportunities where we think we've stumbled up on something, you know, sooner than others. Stay tuned for more updates on that one. Great. Well, looking forward to a number of data readouts in the second half then. With that, I'll thank you. Dom wouldn't let us end. Yeah, I gotta give you a financial pitch here. Talk about cash and runway. We end With the $25 million from Pfizer, we ended the year with $228 million in cash and investments. Our current runway is into the first half of 2025. Just to provide a little more color on that, when we provide cash runway, that assumes full success for all of our ongoing clinical studies as well as our preclinical studies. It's a fully burdened number. The point being, obviously, if there's any attrition, that would further extend our cash runway into later 2025. Great. Well, with that, I'll thank you, Dom and Jake. I really appreciate it. Thank you. Thanks, Michael. Thank you, Michael.