ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

All right. Great. Welcome back, everyone. I think everyone knows me. I'm Yigal Nochomovitz, one of the biotech analysts at Citi. This is the second day of Citi's Virtual Oncology Leadership Summit. It's great to have the senior management of ORIC here, Jacob Chacko and Pratik Multani. Thank you both so much for joining. We really appreciate the time.

Maybe, Jacob, if you want to just kick it off with the high-level introduction to ORIC. What's the business strategy? What are you focused on? A little bit on the 3 clinical stage programs that you're running right now? And some of the -- just your thoughts conceptually on how you select targets and your approach to drug development?

Sure thing, Yigal. There's a lot wrapped up in that. Thank you for having us today. We appreciate the time with you. So ORIC stands for Overcoming Resistance In Cancer and that in a nutshell encompasses the mission of the company and the pipeline that we've tried to put together over the years. I think there's a couple of really special aspects of how we put ORIC together. One is that the team that we recruited has largely known each other for years and worked together in prior environments. And that has helped a lot in terms of just turbocharging the efficiency with which we work. It also helps dictate to your question, some of the targets that we are most interested in. So at a high level, our research leadership team largely has come out of Genentech. Our clinical leadership team largely worked together previously at Ignyta. And then, of course, our founders, Rich Heyman, Charles Sawyers and Scott Lowe. Rich and Charles, in particular, have long expertise of developing drugs in the prostate cancer space. So with Charles' & Rich's expertise in prostate cancer with Pratik and his clinical team's expertise in lung cancer and then Lori Friedman, our Chief Scientific Officer and her Genentech's team expertise in breast cancer, those tend to be the areas that we are most interested in. So prostate, lung and breast. Apart from that small molecules is certainly the area of focus more so than biologics. But I think the really unique aspect to all of how we put the pipeline together is that internally, we have a mantra of best molecule wins, and what I mean by that is we start with the target of interest. So essentially, is there a target with a high unmet need within the oncology population for either resistance, acquired resistance has been an issue or even innate resistance right out of the gate. And there is some fatal flaw with the drugs that are attempting to drug that target, or in some cases, no drugs are attempting to drug the target because so far, it's an undruggable target. It's a first-in-class opportunity. So with that mantra of best molecule wins, we then figure out sort of work backwards from there. If it's a novel target with novel biology, obviously, that entails a lot of biological risk. Those are the ones that we tend to work on with our internal discovery team because we have been really conscious over the years of putting together all capabilities within the internal discovery side. And so we're able to do that with our internal discovery team. But on the other hand, if it's a target that is highly validated where the biology is well understood and in this case, EGFR Exon 20 is a great example of that, biology is super well understood, it's a validated target. If there's someone else outside of work that's got a more advanced approach or a better approach than what we're doing, then we're very happy to think about in-licensing as well. And so if you look at the pipeline, there's 3 clinical stage programs today. ORIC-533 is a small molecule oral inhibitor of CD73, that kind of falls in that first category of targets that I mentioned where perhaps it's less validated, certainly in the area that we're studying it, which is multiple myeloma, it's less validated. And that's one that came out of the novel biological insights from the internal discovery team at ORIC. On the other end of the spectrum, we've got EGFR Exon 20, ORIC-114, that's a small molecule. It's brain penetrant. It's being developed right now in Phase I for EGFR Exon 20, HER2 Exon 20 and Pratik will talk a little bit more about that later in the conversation with you. That's one that we in-licensed. So we found a company, Voronoi, that was at the time, private in South Korea that was developing this brain penetrant inhibitor. The fatal flaw of everything that had come before in the EGFR Exon 20 space was not having CNS penetrance so that's where we saw a particular opportunity for this program and we in-licensed that. And then PRC2, ORIC-944 program, which we're developing in prostate cancer, again, a small molecule. This is one where Mirati had developed a fantastic molecule with better drug properties than the EZH2 inhibitors and the EED inhibitors that have come before it. And so we got excited about that and in-licensed it. And then if we have time today, I'd love to talk about some of the internal discovery work that's going on, that's preclinical. Again, an example of a novel target based on novel biology that ORIC [indiscernible] PLK4, which is relevant to synthetic modality pathway in breast cancer and neuroblastoma. So a lot going on in the pipeline in short, but I think what really enables that capability is the team that is totally agnostic to whether we in-license great compounds or develop them internally at ORIC. It all just depends on the level of validation of the target and frankly, ideally that it lines up with our strategic areas of focus.

All right. Awesome. A lot to cover. So I guess the order doesn't matter too much, but let's start with CD73 since that's first on the list. So ORIC-533, a bunch of questions. So first of all, tell us how is it differentiated from some of the other CD73s out there? Obviously, it is a fairly crowded space. And I think it was about a year ago that we actually did a deep dive here at Citi on the CD73 space but then also talk about some of these novel biological insights because you're going into myeloma, which is different. And as far as I understand, not an area where others have explored the CD73s. You did some interesting work, I believe, with Harvard, with Dana-Farber to help advance the thesis that the CD73 could be relevant in myeloma. So yes, walk us through that thought process.

Sure thing, Yigal. So ORIC-533, which is our CD73 inhibitor as well as the other 2 clinical programs that I mentioned, all entered the clinic in first half of last year. And this is one where this is homegrown, as I mentioned. So ORIC had developed this through our internal discovery capabilities. The challenge with CD73 -- you did a great job in your overview that you published last year. The challenge with CD73 is there's a chemistry challenge to come up with a small molecule that is poorly available as an inhibitor of CD73. That's why as you look at the field, almost all the earlier molecules, certainly from pharma, where antibody approaches, not small molecule approaches, and many of the companies that have attempted to come up with small molecule approaches haven't been able to make them orally available. So some have defaulted to a small molecule delivered by IV. So we are one of the only programs out there that's orally available small molecule inhibitor. Years ago, so when we were still a private company, 3-plus years ago, we had profiled this compound in every way you could. So we had looked at multiple potency assays, we compared it to the leading, what I'll call the sort of, the leading brand name inhibitor across the adenosine spectrum for the various nodes you could target. So for example, in the adenosine pathway, which is thought of as an immunosuppressive pathway, CD73, CD39 and the A2A receptor antagonists are the 3 major classes of compounds. We've compared to each of those and just shown far greater potency with ORIC-533. And so that was an important first step in establishing its differentiation. But beyond that, and I think this is where a lot of the field has fallen down actually is in these tumor microenvironments, you get very high levels of adenosine. And so an important experimental condition in the preclinical profiling of these inhibitors is looking at inhibition in the face of very high levels of AMP. So essentially to replicate that high adenosine environment that you see in the actual tumor microenvironment. And this is where even inhibitors that on their surface seem to be potent, they fall down. And you see orders of magnitude differentiation there in the potency of ORIC-533 versus those because ORIC-533 not only has picomolar potency, but also has a slow off-rate. And so that differentiation, we thought would bode well for ORIC-533 if we were to ever take it down the traditional path, which I think you alluded to in your opening questions, if you look at the CD73 inhibitor space, pretty much every inhibitor, almost without exception, is doing the exact same clinical development program. And what that is, is you take your CD73 inhibitor, pair it up with your favorite IO agent, pick your favorite solid tumor indication and we hope the best in a combo IO study. And that's been a field that has been sort of littered with mediocre results within the CD73 space, really a clinical development plan. It's been littered with mediocre results. I think it was oleclumab really at ESMO, I believe, it was 2021 that had the first large randomized data set that finally started to validate CD73 as a target within the IO space. You alluded to our work with Ken Anderson at the Dana-Farber lab. One thing back again, this is 3-plus years ago when we were still private, the conversation we had at the Board level was, look, this compound is quite differentiated from other CD73 inhibitors that are out there. But if we are just going to go be the whatever is 6, 7, 8 inhibitor that is going to pair with an IO combo in some solid tumor type, it's going to take many years, hundreds of patients to see if there's any signal. And even if there is a signal at that point, it's going to be comparing apples and oranges to try to compare how does that signal compare to that generated by our many competitors. So one of our investors at the time back when we were private, continues to be a top 10 investor [indiscernible] today, essentially had known Ken Anderson for 20 years and was aware that Ken Anderson, and his lab independently had come upon CD73 as having potential therapeutic relevance to multiple myeloma. And the rationale that they had elicited was or laid out was essentially that in myeloma, like in other tumor types that I mentioned earlier, you see very high levels of adenosine in these patients and myeloma patients are 5 to 6x the levels of adenosine that you see in people without multiple myeloma. And so Ken Anderson and his lab hypothesized, if you could put in a CD73 inhibitor into that environment, could you turn down the levels of adenosine. And by doing that, turn up T cell activity and then T cells can do what they're supposed to do, which is kill the myeloma cells and lead to myeloma cell lysis. So that was the thesis that he had laid out and our investor was aware of this because of the close ties that they had to one other. So he put us in touch -- we established an MTA with Dr. Anderson and his lab and then Dr. Anderson tested ORIC's CD73 inhibitors in these proprietary ex vivo patient assays that his lab had developed. So these assays are fantastic because they're as close to a clinical experiment as you can get in a preclinical setting, which is for patients treated at the Dana-Farber, which are relapsed/refractory patients, triple-class refractory, some had seen BCMAs as well. These are exactly the kinds of patients we'd be enrolling in the trial. They take bone marrow aspirate from those patients, and that's what they're using to derive these ex vivo patient assays and to run these models. And he's run these models on every major myeloma drug that's been developed in the last 20, 30 years. And so in doing that, saw good activity with ORIC's CD73 inhibitors as a single agent in that setting and that's what got us and what got Dr. Anderson excited about starting ORIC-533 as a single agent in multiple myeloma initially. And then eventually, as Pratik will get to, we can talk about what the long-term clinical development plan may look like. So not only is the program differentiated on the preclinical rationale and the preclinical profiling, but importantly, also on the clinical development plan. And as you alluded to in your comments, there is no other CD73 inhibitor that we're aware of that is pursuing myeloma. First of all, no one knew about this outside of ORIC and Dr. Anderson until about a year ago when we published our first results pre-clinically and now we're hearing talk of others starting to look into it, but we've certainly got a lead as a first-in-class opportunity.

That's super interesting, especially since there's been so much activity in myeloma with so many different mechanisms. As you know, that this hasn't been struck upon until very recently. So is the thinking that you would -- is the goal to achieve a monotherapy activity, as you alluded to? Or obviously, since you're hoping to reengage the immune system that you'd want to enhance that with an IO or that's not really the primary strategy?

Yes. Pratik, you want to take that?

Yes. Let me jump in on that one. First of all, just to say, it's nice to be able to speak with you here, although it seems like I should schedule a ski vacation sometime in the near future. So let me just walk you through sort of our development plans and our thinking. As you take a program from preclinical into the clinic, you do sort of have to start at the beginning with every program. And so we are currently in a Phase I study with ORIC-533 as a single-agent, dose-escalation study. And these are patients who are triple-class refractory, but in almost all cases, more than that nowadays with these other available agents. So they're not only triple-class refractory, but often [indiscernible] refractory as well as having seen either one or the other of the newer biologics, such as the bispecific antibodies or even CAR-T. And so it's a very refractory patient population in our Phase I. That said, we are guided by our preclinical work, which suggested to us that we were going to not encounter much in the way of toxicity or nonclinical GLP toxicology study is really -- were very clean and exquisitely clean. And so our expectations going into the clinic were that we were going to be able to dose-escalate without significant safety signals and really needed to be guided by biological activity. And so in this dose-escalation study, we are heavily guided by not just PK, but also a host of [indiscernible] dynamic biomarkers that we're measuring at baseline and longitudinally while patients are on study. And this includes what you'd expect for immunomodulatory agents. So immune cell, flow panels to look at different subpopulations of T cells and NK cells and dendritic cells and then also cytokine panels. And then importantly for us, CD73 is our target. And so we want to be able to measure that we're hitting that target and [indiscernible] and so we also have in the study baseline and on study, not just blood measurements of functional CD73 activity but bone marrow measurements as well since, as you know, myeloma is largely a bone marrow-based disease. And so with that, we expect to be able to identify a maximally biologically active dose coming out of Phase I. But because we're in a patient population, as Jacob said that is in many ways, mimicked by the patient samples that went into the ex vivo work that Ken Anderson did, we do expect that we should be able to see some degree of clinical activity. Now given the fact that we are in such a highly refractory patient population, we would certainly be gratified by seeing responses, the clinical responses in this study. But really, the bar for us is not even bad. And it's something that we've discussed with Dr. Anderson and our other investigators, which is if we can demonstrate that we're moving clinically measurable markers of myeloma burden [indiscernible] protein, which is essentially a marker of myeloma burden if we're able to demonstrate decreases in [indiscernible] protein in the blood or the urine using this totally novel mechanism for myeloma, that for us would be a green light to move to the next stage of development. If we see convincing responses, then there is potential for single-agent development and a single-agent therapeutic but the name of the game in myeloma really is combination therapy. All of the active agents are rarely now given as single agents but are in multiple, see double or even triple drugs, if you count betamethasone combinations. And I think, ORIC-533 with the potential for having a very clean safety profile of big clinically, it's also had a very minimal potential for drug-drug interaction, metabolism, et cetera, making it potentially very combinable with these other active agents. And so there's a lot of interest amongst our investigators and the KOLs that we've spoken with about bringing this into combination with the other agents that are available.

And can you just quickly walk through just some of the basics of how many patients are we expecting to see when you do the update, second half of the year? And I don't know if you're able to say, but obviously, people will be interested in when you talk about decreases in some of the myeloma biomarkers, what would be considered a meaningful reduction?

So as Jacob said, we started enrolling the state last year. I think by second half of this year, we would expect to present the data at a major medical conference. We'd expect to have about 30 to 35 patients. We're on track for that, of which probably about half are at what I would call a biologically relevant dose and so that would be sort of the data set that we'd be looking at. What we would expect, what is clinical activity, double-digit percent decrease in [indiscernible] 10%, 20%, 30% decrease in these markers, not enough to qualify for [indiscernible] response but still something that wouldn't happen spontaneously in these patients and is measurable clinically and beyond just the biomarkers that we're measuring against CD73 functional activity.

Yes. Let -- I'll just jump in with one other thing, which is, as we think about just decision-making for future, how we'd like to develop the program. There's really kind of 3 avenues being overly simplistic about it, which is in this first Phase I data set that Pratik described, I think we think a cut point of 20%, 10% and 0%. And basically, what I mean by that is if we see 20% activity in that population, which is a very high bar given just the late stage of these patient populations, that's kind of what I think it was a home-run scenario, at that point we'd be pursuing both single-agent accelerated approval pathway as well as various combinations, all in parallel with one another. A more base case outcome is, I think, if we can see like Pratik mentioned 10% activity or in lieu of 10% activity or 10% response rates can we see, like he said, in a handful of patients, double-digit decreases in [indiscernible] protein, in which case we'd be excited about combination pathways as the next go-forward set, but not single-agent accelerated approval. And then if we see de minimis activity, obviously, that is a situation where we would probably look to deprioritize the program, absent some outside funding that helped us push it forward.

Okay. Makes sense. And in terms of the design of the molecule, you referenced the very clean GLP nonclinical tox, we'll just talk a little bit more about that in terms of how you were able to achieve so far. I mean we'll see the data, obviously, what appears to be good safety profile?

Yes. I mean CD73 as a target is not particularly on-target tox ensuing targets. So I think just from the biology, it was one that was a little more straightforward. But apart from that, it's also, like I said, it's a picomolar potency, and it's highly selective as well. So in terms of off-target tox, we don't expect much either. So that's where we come to the conclusion that Pratik articulated, which is that this is not likely to be an MTD-driven decision in terms of what we choose as the final recommended Phase II dose.

And the other piece of the CD73 mechanism that people talk about is that hitting the soluble versus the membrane ground, I believe, do you -- how does it work with 533? Do you hit both? Or does it -- do you believe it makes a difference?

We hit both and not sure if it makes a difference or not is the short answer. We've heard the same theorizing about it, but I'm not sure that there's actually a clear answer to that, at least not one that I've seen yet.

All right. Got it. All right. Well, let's move on and talk about 114. So tell us about that.

Maybe before we go to 114, I think it's probably also relevant to folks just because it is highly timely that we, at the end of last year, signed an agreement with Pfizer around a clinical collaboration for ORIC-533, the CD73 inhibitor. So that's probably worth just touching on for a minute or 2 as well and how that impacts our thinking about the go-forward pathway. So combos with BCMA, just given that BCMAs are the sort of newest game in town in multiple myeloma drug development had some pretty stellar results with patients even in that relapsed/refractory setting. It was high on our list that a combo with a BCMA agent might be one of the paths that we want to take this forward into if we see the kinds of activity levels that Pratik and I articulated earlier. So after we reveal the indication of interest for CD73 at ASH for 2021, we had conversations with Pfizer and multiple others that have myeloma franchises who wanted to understand more about CD73 inhibition in myeloma. And out of those conversations with Pfizer, we did end up having lots and lots of dialogue with them on the preclinical rationale, showed them under CDA, some of the early data generated in the clinical study. And then that's what led to 2 things. One was the $25 million equity investment that they made into ORIC at the end of last year. But the other thing, which is almost more important from a go-forward operational decision-making point of view was the potential for a clinical collaboration. So a clinical collaboration [indiscernible] potential Phase II combo study with in-combo with their anti-BCMA agent, [indiscernible]. And so the beauty of that for us is that if we -- after seeing the Phase I experience decide that we do want to pursue combinations and one of those combos that we want to pursue is in-combo anti-BCMA agent and we want it to be Pfizer, we can then pursue that. We would pay Pfizer as an outside CRO, essentially, and they run the study for us, which is hugely valuable, obviously, because they can do it cheaper and faster than an outside CRO, can, but as Pratik said at the time, what was invaluable from that perspective is Pfizer just finished running a global Phase III study with their BCMA agent. And so just being able to plug right into that clinical trial apparatus with those KOLs would really turbocharge the development time lines here as well and really tap into all the knowledge that they've developed over the last years developing that compound. So that's a really attractive option for us as well as we think about decision-making towards the end of this year, having seen a full Phase I experience about what the next steps are and whether that entails a combo with BCMA. One thing I like about it is Pfizer is a great partner in all of this, and they understood, obviously, us as a small biotech company, we couldn't commit at the outset absolutely, we are running that trial. So really the discretion is on our side, if we want to run that combo, if we wanted to be with the BCMA agent, if we wanted to be Pfizer's BCMA agent, then those are all in our discretion to say yes to those and then potentially green light that trial.

And anything on timing -- so assuming you're in your [indiscernible] case or your base case as you articulated with the data before, for the monotherapy, how quickly would you be able to start that combo with them if you chose to?

Yes. I think all of that's under discussion right now. I mean, because obviously, these are open-label studies. So it's not like that there's some final reveal at the end of the year where we figure out whether it's attractive or not. So along the way, we'll be trying to read tea leaves even before we get to the second half readout to figure out whether it makes sense to green light one or more combos. And if so, get the planning work underway, which would involve obviously all the basics of writing the clinical protocol itself and getting the trial infrastructure up and running, but also CMC making sure that we've got drug to run those combos and just a whole slew of internal work streams that we're thinking through right now. So in other words, we'd be ready to start those combos shortly after seeing those -- the data in the second half of the year as opposed to needing to at that point, get everything up and running from a standing start. So we can be pretty timely in that way. The other question that we've gotten along those lines is just whether there's any appetite to pursue what we call the more traditional avenues of CD73 inhibitor development, which is in combo with IO agents in solid tumors. That's certainly something that we're open to but I think as I alluded to in my earlier comments, we don't think that that's necessarily the right development path, sheerly using ORIC's development dollars off our balance sheet. So if there's a partner, Pfizer or otherwise, who would like to develop or help us develop the drug in combo with an IO agent in solid tumors, we'd be open to something like that. But I think that alone, our own balance sheet is not the highest priority right now. But we'll obviously keep watching AZ and oleclumab in what they generate with that molecule and combo with PD-1 and then figure out whether there's something to do there.

Yes. And just one more question. Obviously, since you have this differentiated angle with myeloma, what can you say about on the freedom to operate or IP front in terms of patents or pending patents that you're working on to protect your ability to develop CD73 in myeloma specifically?

Yes. What I can say is we have a very savvy IP council that is all over it and has been, not only here, but for the other molecules as well. And various interesting angles that we see. So all the basics in terms of composition of matter patents are in place already for all 3 clinical programs that take us out to 2039 or 2040, depending on which molecule we're talking about. And then beyond that, we continue to actively put a patent estate in place around each of the molecules to further protect them in case that they one day do become commercial.

Okay. Got it. All right. So 114, the Exon 20 EGFR HER2. So obviously, not an uncrowded space, I would say, but you have some potentially interesting differentiation. So can you talk about that, specifically the ability to penetrate the CNS and then, of course, you also are going to have initial Phase I data for this program in the second half of the year. So just the basics, the design and again, the same sort of question, expectations for the data readout in terms of the number of patients and the types of metrics that you're looking for to achieve proof of concept?

Yes. So I'll take the first part. I'll ask Pratik to talk about the design and data expectations. So I like the way you phrased it, Yigal that it's not an uncrowded space. I think we can call [indiscernible]. It's a very crowded space in terms of EGFR Exon 20. But I do think that the first order analysis here is that -- is wrong in the sense that when people paint the entire EGFR Exon 20 space with the same brush and say that they're all the same and it's a crowded space, and I think if you just look at shared number of programs, yes, it is absolutely a very crowded space. But if you focus on what matters, which is which are the programs that are brain penetrant, it all of a sudden becomes not at all crowded. And this is one of the things that we liked about this target. So years ago, when we first started hunting for EGFR Exon 20 programs out there, Takeda with mobocertinib, J&J with amivantamab, neither one was approved yet, but everyone assumed that they would be approved. The profile of those compounds was so-so on the efficacy front, pretty bad on the tox front, I'd say probably mobocertinib even more toxic than amivantamab and no CNS activity, no appreciable CNS activity. And so that is a profile that, as you look at the TKI space generally, and this is why I mentioned the Ignyta clinical team that we've got that is now the ORIC clinical team had experience developing entrectinib, which was a small molecule, brain-penetrant TKI. In that case [indiscernible]. But we know that space -- we know those are the targets and target therapy land inside and out. And if you look at the history of every single target in targeted therapy land, the winning agent may not be the first one that was developed, but whatever becomes a winning agent is one that is brain-penetrant. And this used to be back in the United days 5, 6, 7 years ago, there was some debate about whether you wanted the drug to be brain-penetrant or not. And maybe you'd see CNS toxicities if you were brain-penetrate. And what's become dogma now amongst KOLs and amongst the actual real-world physicians treating these patients is you want a brain-penetrant inhibitor that is clean. It's got to be clean. It can't be sort of a dirty inhibitor that gets into the brain and then hit a [indiscernible]. But if you've got a clean inhibitor that is selected for the target of interest and is brain-penetrant, it enables you to treat patients with brain mets, including those with active brain metastases and also, the thought is that it allows you to prevent the development of brain mets in patients who are presenting initially with brain metastasis. So that should translate into longer duration of responses as well and maybe ultimately better response rates. But that's the -- that was the huge unmet need that we saw within the EGFR Exon 20 space. So after the agents I mentioned, mobocertinib and amivantamab, there's a whole host of other agents that are in later stage development. Again, none of which have CNS activity or brain penetrants. And so seeing that flaw in the space, this was back to my -- the mantra of best molecule wins, the target that we liked a lot, it's one that had restarted from a standing start at that point, we would have been years behind. And so instead, we went hunting for it. And we found this private -- at the time private company in South Korea, Voronoi that had developed what they reported to be a brain-penetrant EGFR inhibitor, EGFR Exon 20 inhibitor that was clean. And so we did a lot of diligence. The whole process took a year from the first conversation we had with them till the time that we actually signed that deal and in-licensed the compound. And the reason it took a year is because we obviously, went through all the diligence with them and what they had generated, but we also brought the compound into ORIC under MTA and then did our own diligence, ran our own experiments and validated not only the selectivity, but also the brain penetrants. And so that's where the solution set starts to shrink quite quickly. And the proof in the pudding of which compounds or which companies think their compounds are brain-penetrant versus not is look at the inclusion/exclusion criteria for the drugs in development and see, do they include or exclude patients with active brain metastases. What you'll find is that every single compound that's ahead of us in clinical development has excluded patients with active brain metastases. The only other company that we're aware of that is including patients with brain metastases at a similar stage of development is Blueprint. Blueprint acquired a private company called Lengo Therapeutics. They paid $250 million plus upfront and another $200 million plus [indiscernible] milestones to get that compound, which is at a similar stage of development to ORIC-114 and they -- and we are enrolling patients with active brain metastases. So we're convinced that if you have a drug that actually is brain-penetrant, that's the development strategy you ought to take, which is to enroll those patients with active brain metastases to try to show that you actually have that brain-penetrant. And that's the profile that we'll ultimately win in this space. So as long as we can ultimately be roughly as good as the others in terms of efficacy, hopefully better in terms of toxicity and certainly way better in terms of CNS activity, that's a winning profile from our perspective. But let me stop there and ask Pratik to comment on your other questions around development plan and data expectations.

Sure. So as Jacob said, we are actively in Phase I, and we are enrolling patients with the targets of interest for ORIC-114. So EGFR Exon 20 insertion mutations, HER2 Exon 20 activating mutations and HER2 amplification. That's another potential area of development for ORIC-114. With respect to EGFR Exon 14 -- EGFR Exon 20 and HER2 Exon 20, it's largely non-small cell lung cancer that we're seeing and with HER2 amplification, we're seeing mostly breast cancer and a bit of GI tumors. It's important to point out, though, that we are developing this drug. We are running this Phase I study and the landscape of some of these currently, although they have accelerated approval available agents. So some of the patients, especially who have EGFR Exon 20 may have seen amivantamab or mobocertinib, more generally, it's been amivantamab, but we are enrolling and we expect, again, by the second half of this year to have 30 to 35 patients worth of data in totality, about half of them at what we estimate to be the clinically active dose but as Jacob said, our thesis in this program is that ORIC-114 brings to the table a best-in-class level of CNS activity. And so that's what we'd be looking for within this population of patients. So if you look at just the general prevalence of brain mets in patients and here I'm talking about non-small cell lung cancer, it's about 1/3 of patients. We have a low filter for enrolling these patients, as Jacob said, we are committing patients with active brain mets to be enrolled in the Phase I. So we expect within the clinically active dose population to have maybe half a dozen patients who have brain mets enrolled in the study. And so we would be looking in particular at those patients and whether we see evidence of clinical activity because that, for us, will be sort of a decision point of whether we have clinically demonstrated our preclinical -- our profile of having CNS penetration and clinically demonstrable CNS activity and that we hope to be able to demonstrate in the second half of this year with our disclosure.

Okay. Perfect. So Jacob, you mentioned the other asset, the Blueprint one, just curious, can you comment any further there in terms of any benchmarking you've done with respect to the degree of CNS penetrants? Just curious how you're defining CNS penetrants? For example, with the company you mentioned, you licensed -- one can claim you have CNS penetrants, but until you actually get the compound in-house as you did and really check, you may not have a good grip on that. So when you talk about CNS penetrants for 114, how much are you actually getting in terms of concentrations?

Yes. So back -- I'll take your multiple questions in order. So the comparison to Blueprint compound that they got from Lengo has not been possible to do in a direct head-to-head setting because we don't know the structure. It's as simple as that. So we have done a lot of profiling versus other competitor compounds in this space. But once we know the structure [indiscernible] case of Blueprint compound that they got from Lengo, we haven't been able to. What we have been able to do is at ACR last year, they presented the first -- at least publicly available preclinical data from their compounds and doing the sort of cross-trial preclinical comparisons across the posters because obviously everyone does kind of a similar profiling. We think that our agent is potentially best-in-class, even better than that one that they in-licensed. And that's in comparing the brain-penetrants and looking at the luciferase assays, the degree of progressions you get in those intracranial luciferase assays, which looks more profound in the case of ORIC-114 than what we saw with their competitor. But the obvious caveat to that is these are cross-poster comparisons and not in a head-to-head environment. And from my recollection, they didn't have a control in that experiment either. So it's hard to even use that as a gauge to try to standardize across. In terms of what we looked at, so what [indiscernible] did and what we did, we looked at essentially everything you can preclinically to validate the brain-penetrants of the molecule. In terms of [indiscernible] we looked at multiple species of 3 different species and saw anywhere from 0.25 to 1.5 on the unbound KPU use and then most importantly, on the luciferase assays and the intracranial model saw deep, deep progressions in those models. And we did have controls in those models. So we -- as control -- as we looked at that versus mobocertinib. We looked at that versus osimertinib. And this is on par or better than osimertinib in those models. And obviously, osimertinib is thought of as a clinically active brain-penetrant molecule. So that's the profiling that we had done. I haven't, to be honest, seen anything nearly as expensive from any of the competitor compounds. So we have a high degree of confidence that this ought to translate into the clinic. But like Pratik said, we'll need to see in the second half of this year when we present those data, if we can actually demonstrate that clinically. And that will be the first step in derisking the profile of this compound. Obviously, brain-penetrant and brain-penetrant alone is not going to be enough to have a competitive profile here, but we think that's the key area of differentiation as we think about what is ultimately competitive years down the line as this hopefully continues in development. As you look around the space, the good response rates in the Exon 20 space are basically systemic response rates that are in the, call it, 30% to 40% response range and then tox profiles that are fairly toxic. I think in the case of some of the molecules, maybe more so than mobocertinib, they are somewhat manageable toxicities. But with amivantamab, you have infusion site reaction, which is also a problem as well. And so hopefully, with this, we're able to demonstrate a tox profile that's a little cleaner than what the others have been able to demonstrate and then ultimately, the CNS activity on top of it. With a bigger evidence, bigger, longer time line, I think durability as well, obviously, will be a key aspect of it. But in the spirit of walk before you run, I think first things first, we want to just improve the brain-penetrants and goal of 114 later this year. And again, back to my point about ORIC-533 and the go-no-go decisions, I mean, we push ourselves really hard internally to only put resources after the highest potential projects. And so in this case, the go-no-go is if we cannot demonstrate brain-penetrants with this molecule, I would then scratch my head to think, well, what's the competitive differentiation coming years after these other agents that I just mentioned in which case we would stop development of the molecule. We can't show that brain-penetrants at the end of this year. So we're really crystal clear prospectively internally, and we voiced that externally about what the go-no-gos are for each of the programs, so we can continue to funnel money to the highest potential projects internally.

Okay. So there are some other -- I believe there's some Phase III readouts in first-line Exon 20 EGFR this year, if I'm not mistaken. I mean, obviously, based on your comments, it sounds like that's interesting, but maybe not necessarily super relevant to your decision process? Is that fair?

Yes. I'd say bluntly, it's irrelevant to the decision process in the sense -- again, this is a conversation that I'm quite used to from years ago back in the United days developing entrectinib, which was being developed as a brain-penetrant inhibitor years after crizotinib had a full approval. The question of the [indiscernible] was that with a full approval for the same target ahead of us, did that mean that we could no longer do a single-agent accelerated approval pathway? Was FDA going to close the door on that and require a randomized trial. And I think you've now seen time and time and time again, if there's a brain-penetrant compound coming after compounds that are already approved in full approvals ahead of them that don't have brain-penetrants, that door is still wide open in terms of single-agent accelerated approval pathway. So obviously, we'll watch what the final data sets for those accelerated approval agents look like just to keep track of where the competitors are, but it has no bearing on how we think about our regulatory strategy or path.

Okay. Well, that's a perfect segue to Mirati for other reasons related to KRAS. But let's talk about PRC2 and 944.

But maybe if I could just [indiscernible]? Can we talk about HER2 Exon 20 for a second? Maybe Pratik can just talk about HER2 Exon 20 and why we're also quite excited about that as an opportunity for 114.

Yes. I don't want that to get lost in the noise because the opportunity with HER2 Exon 20 activating mutations in non-small cell lung cancer, frankly, is about as large as EGFR Exon 20, about 3,000 to 4,000 patients each in those 2 indications annually in the U.S. And so as I said at the top, when I was describing the study, we are actively enrolling those patients in our study. And so it's a parallel active area of development because either one is bigger than what Jacob described for ROS1 in terms of patient population [indiscernible]. And HER2 is the approved agent in EFGR Exon 20 but as with these other agents in HER2, we feel it does carry a safety burden. And so -- and ORIC-114 has a number of advantages, we think potentially, again, CNS activity would be an advantage. This is an oral small molecule, so in terms of just convenience and dose titration and then potential differentiation on safety. And so we're excited about the HER2 Exon 20 opportunity. And then not to put it in third position, but the HER2 amplification opportunity. So here, again, there's HER2, there's tucatinib, what our head-to-head preclinical work against tucatinib shows that we have the potential for even better CNS activity. And here, you're talking about breast cancer, where CNS mets are equally problematic as in lung cancer. And so we think 114 has the potential for a best-in-class here as well. And then tucatinib in terms of the opportunity, it has projected sales of over $1 billion. And that's in the context of HER2, we wouldn't expect our mechanism and tucatinib either to have cross resistance to HER2. So we would look to either sequence in front of after or potentially in combination with HER2 or HER2 amplification. So there are other equally exciting development pathways for 114 that we're pursuing in the context of our Phase I.

Okay. Got it. Perfect. Okay. So I just want to make sure we cover all the assets before we run out of time. So PRC2, Jacob, just talk about the mechanism, how is it different from the EZH2, the other EZH2s out there? What are you doing differently? And why are you going into prostate?

Yes. Sure. As you mentioned, Yigal this was developed by Mirati, it's one that we in-licensed. It's a target that we like a lot. We licensed this in August of 2020 for Mirati. What I like about it is -- so PRC2 is a complex that many people think they're not aware of, but I guarantee you they're aware of it because there's 3 different subunits, one of which is EZH2. And so that's the subunit that people are most familiar with and where most of the compounds, the first generation compound started in terms of China drug PRC2. It's maybe -- it's really just us and -- with EED inhibitors in the clinic for oncology. The theory of the case in EED is that there's 2 advantages, 2 major advantages, the EED over EZH2 inhibition, which is, number one, the biological advantage that with the EED inhibition, you can get around problems like bypass resistance of EZH1 to the EZH2 inhibitors, you can get around the acquired resistance around the EZH2 inhibitors and that's the biological theory. The more tangible, I think, theory is around drug properties. We just simply stated that the EZH2 inhibitors, including tazemetostat, the approved EZH2 inhibitor have terrible drug properties. And so that's been a real issue for those. Tazemetostat for example, has a dose-dependent decrease in exposure and so problems like that, I think, have really hindered many of the EZH2 inhibitors with the exception of maybe Pfizer's EZH2 inhibitor that's now in later-stage development. And on the EED side, you can at least in the case of ours and have been able to get better drug properties. What I like about it, though, Yigal is that Mirati didn't take a view. Their internal chemist didn't take a view on EZH2 versus EED. They made a bunch of them, EZH2 inhibitors and EED inhibitors and compared them all to a high bar target candidate profile and it was this EED inhibitor that won on the target candidate profile. Now they, like others, with PRC2 inhibitors, had focused their first set of models on heme models like DLBCL, and it looked superior to tazemetostat in those models. So we looked at that under diligence and we said that's pretty interesting. But we, at our core, are not a heme company, really like the expertise I talked about earlier, our expertise is prostate, lung and breast and prostate is an area where there is a lot of evidence and everybody with an EZH2 inhibitor or EED inhibitor is looking at prostate amongst other tumor types as one of the areas of development. And the reason for that simply is there's been a lot of preclinical and biological evidence that PRC2 dysregulation is implicated in prostate cancer. There's a whole lot of complicated biology that I'll summarize by saying you essentially with PRC2, you end up turning down things like tumor suppressors and turning up processes like [indiscernible]. And there's a lot of biology that underlies that, which is why everyone that has developed these inhibitors, like I said, is looking at many tumor types, but prostate is always on the list. So Mirati had not done any of the prostate in vivo models. They don't have the same prostate expertise we do. So we brought this just like the other molecule, ORIC-114 mentioned, we brought this under MTA into ORIC, ran it through our own preclinical experiments, including a couple of different [indiscernible] models in prostate cancer and saw very good activity there. 80% to 85% TGI in models where others have kind of topped out at 40% to 45% TGI. So that's what got us excited initially to develop this as a single agent in prostate cancer. And of course, Pratik can kind of get into what we're hoping to see there in terms of clinical study design and eventual clinical data and with the later stage steps might be for development.

So yes, here, so we are in Phase I, as Jacob said, and we are dose-escalating in patients as a single agent in patients with advanced prostate cancer. So these are patients who are post AR modulators, AR pathway inhibitors, either one or more, and they may have had up to 2 chemotherapy regimens. So essentially refractory all-comer patient population and importantly, at least right now, we're not doing any preselection, although it's some of our hypotheses, do potentially put preselection as a further development opportunity. And so by later this year, in the second half, we would expect to disclose at a major medical conference about 30 to 35 patients worth of data, about half of them at a clinically active dose. And so we're on target for that. So within this dose-escalation study within this patient population at the active doses, we are looking to ultimately demonstrate responses as a single agent in these patients. The threshold is low given how refractory these patients are. So for our bar for essentially single-agent development would be an ORR somewhere in the range of 15% to 20% coming out of our experience so far. We'd have a lower threshold to pursue combinations, as you probably know, the EZH2 inhibitors. They are largely being pursued as combinations with AR pathway inhibitors. And so that's certainly another development opportunity. We see clinical activity, but something that's shy of what would be necessary for single agent development.

Okay. Great. So we just literally have 3 or 4 minutes. So Jacob, maybe just spend 60 seconds, if you wouldn't mind, just very quickly on the discovery programs. PLK, for example. And then the other obvious, an important question that I'm getting frequently is in terms of the cadence of readouts for the 3 Phase Is we've talked about, is that -- do we know the order in which those are going to happen? Is that something you're still figuring out? Or do you know you just can't disclose the order at this point? And to the extent you can be more granular about when in the second half, that would be great.

Sure thing, Yigal. So we continue to have an active internal discovery effort. I mentioned PLK4 in my opening remarks. PLK4 is a target that we selected the development candidate last year, we're doing standard IND-enabling work this year, including tox work and assuming if it gets through the tox work clean this year, that would be ready for an IND next year, probably first half of next year. And PLK4 is target that we think we've got a first-in-class approach to a first-in-class opportunity here. It's relevant to a synthetic lethality pathway that occurs in the presence of [indiscernible] amplifications, and you find that in about 20% of breast cancer and about half in neuroblastoma. So that at a high level is kind of how we think about the initial clinical development plan there. And like I said, it's a first-in-class opportunity. So we'll continue to work on that and hopefully put that in the clinic first half of next year. Meanwhile, we continue to work on other undisclosed targets in the internal discovery pipeline and continue to hunt actively for other opportunities through our business development channels, which, as you can imagine, in a distressed environment like the one we're in, there's lots of opportunities out there. So we continue to look at those as well. In terms of the cadence of readouts, all 3, like Pratik had mentioned, we envision happening in the second half of this year at major medical conferences. We have not yet decided the order of those, and it's because I don't know the order of them. I mean it just kind of depends on what we think will be the right venue and when the data are ready. I think the major conferences are all generally clustered in the same time of the year. It's kind of ESMO [indiscernible] Conference and ASH are probably the 3 most highest profile conferences in the second half of the year. So I would guess it's one -- some combination of those 3 that we would use and the other question we get a lot is, most likely, we're not going to present all 3 at the exact same conference, so we'll try to maybe spread things out a little bit.

Right. Yes. Of course, given one is the myeloma. So -- and then just last question. So just real fast. Just the financial health, the cash runway, I mean, you got the $25 million, which is great from Pfizer. Anything else, any other non-dilutive capital that you're expecting that could push out the runway further, just robust.

We'll always take non-dilutive capital if it's available [indiscernible]. There's none in the near term that we're expecting here, but the Pfizer money was important, the extra $25 million helped us extend our runway into the first half of 2025 and I want to be really clear, when we say first half 2025, we take a very conservative stance into how we give that cash run rate guidance. So we are assuming every single program, clinical and preclinical continues to work with no attrition where ultimately, every go-no-go is a go decision, so we're funding the next stage of development. We're funding the CMC that goes into those next stages of development. So in other words, that is a very fully burdened number and in fact, quite conservative when we give that guidance. And we are hunting actively on the [indiscernible] front as well. Like I said, there's a lot of distressed situations out there where companies just can't afford to keep pushing things forward. And so we're trying to be opportunistic there. And I do hope that sometime in, call it, the next 12 months or so, we're able to land another interesting program from our in-licensing capabilities and efforts as well. So stay tuned on that. Last thing I'll mention, Yigal is just because it's relevant as we think about ORIC-944, the question we often get there because I mentioned all my comments around 944 EED in oncology, but there's obviously a company out there, Fulcrum Therapeutics that is looking at EED inhibition in sickle cell disease. We can get the fusion about whether we have any plans to go into sickle cell disease. We're not changing our company name anytime soon. It continues to be Overcoming Resistance In Cancer. But I can tell you, we're watching really, really closely what Fulcrum is doing over there with an EED inhibitor because obviously, we have full worldwide rights for Mirati for all indications with our EED inhibitor. And if that proves to be a fruitful mechanism in sickle cell disease, that's obviously of high interest to us as well.

All right. Very good to know. So we'll have to leave it there. Thank you both very, very much, great discussion, and we're looking forward to the data, obviously, so it will be fascinating. Thank you so much.

Great. Thanks for having us, Yigal. We appreciate it.

Take care. Bye.