Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great, great pleasure that I'd like to welcome Jacob Chacko, the CEO, and Dominic Piscitelli, the CFO of ORIC Pharmaceuticals. Thanks so much for joining us today, Jacob and Dominic. We're going to do fireside chat format. So maybe to start off, if you want to give a one-minute intro to the story, your platform, and programs.
Sure. Thanks for having us, Maury. So, ORIC stands for Overcoming Resistance in Cancer, which, in a nutshell, encompasses the mission of the company. The pipeline is focused on small molecule drug development for, various solid tumors, but most specifically, our areas of expertise are in lung, prostate, and breast. We have 3 different programs that just completed, phase 1 studies, 2 of which we've announced we're taking into later stage development ourselves at ORIC. I'm sure you're going to want to focus most of your time on those. One is ORIC-944, which is a PRC2 inhibitor for prostate cancer. The other is ORIC-114, which is a, brain-penetrant TKI for EGFR exon 20, atypical EGFR mutations, and HER2 exon 20 mutations. Maybe I'll just leave my commentary there, Maury, 'cause I know you've got a lot of questions.
Yeah. Yeah, I think that's a great intro, and, let's start off with 944, which is your oral PRC2 EED inhibitor. So just digging into that more, how is this differentiated from Pfizer's 1497, which is an EZH2 inhibitor of the PRC2 complex? And maybe to start off, is there any reason to think that targeting EED could lead to better efficacy versus targeting EZH2 mechanistically in the clinic?
Yeah, so if I take a step back from just Pfizer, obviously, Pfizer is the PRC2 inhibitor that has shown really profound activity in combo with enzalutamide, which has gotten everybody very excited about the target in prostate cancer. But in general, as you look at the history of PRC2 inhibitors, whether they're EZH2 or EED, they have had very, very bad drug properties, and that comes in the form of short half-lives on the order of 2 hours or 3-hour half-lives. Also CYP autoinduction, where you literally get things like dose-dependent decreases in exposure. That was the issue with tazemetostat. Now, Pfizer seems to have corrected part of that equation in that they've got. Their compound looks like it does not have CYP autoinduction, still seems to have a relatively short half-life.
All that being said, Pfizer has shown really phenomenal data, as I said, in combo with enzalutamide in two different populations. One is a CRPC population that is post-abiraterone, and then also they've shown phenomenal activity with enzalutamide after enzalutamide. Now, as we compare ourselves to Pfizer, our drug properties look even better. So we also do not have CYP autoinduction. We have a half-life of 20 hours compared to what looks like more like 4 hours for Pfizer. Far less interpatient variability for us, just really good PK properties, PD properties, very well behaved on the drug properties.
We brought this program in from Mirati back in 2020, and what I love about the work that Mirati did is essentially Mirati looked at the space and said, "Drug properties is the main issue." They made a bunch of EED inhibitors, a bunch of EZH2 inhibitors, put them all up against their high bar target candidate profile, and what won was the drug that is now ORIC-944, as having the best properties. In theory, if you have two drugs that have exactly the same drug properties, exactly the same potency, one targets EED and one targets EZH2, which are two parts of the PRC2 complex, they should be equally good at inhibiting the complex initially.
But over the long term, you should actually have the benefit, get a benefit by targeting EED because EED inhibition is not susceptible to acquired mutations of EZH2 or bypass resistance from EZH1. So, those should both benefit us with our compound. But remember my initial supposition, which is two drugs with equal potency, equal drug properties. Again, we think our drug has better drug properties than the Pfizer compound.
Got it. And you mentioned half-life close to 20 hours? I think last time we spoke, you said it was greater than 10, but it seems like it's a half-life... Are there any other properties that you want to highlight based on the drug?
Yeah. Last time we spoke in Q1, at that point, all we were saying is we were affirmatively confirming that our preclinical estimate of the clinical half-life, which was greater than 10 hours, was in fact correct in the clinic. We have since then affirmed that the half-life, this came out at AACR a couple months ago, is actually 20 hours for us.
Got it. And yeah, maybe talk more about the preclinical data showing 944 performed at least as good or better than 1497. And talk about the translatability of the data and specific measures where 944 is looking better than 1497.
Yeah, given how stellar the Pfizer clinical data have been in the two different populations, we have done everything we possibly can to benchmark our compound versus Pfizer's preclinically, translationally, based on the single-agent data they've put out thus far and our own single-agent data. In every single metric, we look as good or better than Pfizer. We've done synergy analyses. These are cell growth assays where you take varying concentrations of the drug and varying concentrations of the AR modulator. We have verified the experiments that Pfizer has put out on their own drug that shows that their drug is synergistic with enzalutamide. We've done the exact same experiments with 944 and seen the same or better synergy levels in those experiments.
We've done in vivo experiments, again, head-to-head with Pfizer and also in combination with an AR modulator versus Pfizer's drug in combination with AR, AR modulator, and again, numerically, we have higher TGI. So there's not a single metric that we've compared, side by side with them, where we see, 944 looking worse than their drug. In every metric, it looks the same or better. And to be clear, this is such a large unmet need, such a large addressable population in the metastatic CRPC setting, that we don't need to be better. Obviously, we think that all these, everything I just rattled off ought to help us be better, but we think we just need to be as good to have a really phenomenal drug here for patients.
Got it. And, earlier this year, you showed initial clinical safety, PK profile, and evidence of target engagement for 944, and you've guided to having an additional program update mid-year. What can we expect from this update?
Yeah, so, earlier, as you said, Maury, earlier this year, we did provide the initial monotherapy data for ORIC-944. And again, this is really, given what's been plagued with the, PRC2 inhibitors in the space, is really trying to demonstrate best-in-class drug properties, which I think we've checked that box. So the next two guidance that we provided with this program is, one, is to kick off the combination studies with one or more AR inhibitors in the first half of this year, and then provide a program update. Now, given we just presented the clinical data, we just presented a bunch of preclinical data at AACR, this will be more of a general program update on where we are, with the program. So no clinical data is expected really at this update.
Got it. Okay, that's helpful. And for Pfizer's phase 1 combo data with enzalutamide in earlier second-line metastatic CRPC, patients showed some signs of durable anti-tumor activity in both enza-naive and experienced patients. But they've yet to show controlled phase 2 data, which they must have seen since it's an open-label study. What's your interpretation of the efficacy signal they're potentially seeing in the phase 2 control data versus the phase 1, and why do you think they decided to not show their controlled phase 2 data?
Yeah, so I think we Dominic and I joke that I think the most common question we at ORIC get is, when is Pfizer going to share their randomized phase 2 data? The short answer is, I think, go ask Pfizer. We don't know. But the, you know, just to kind of level set in terms of what we've seen so thus far and why we interpret their phase 2 to have been positive is. So in the phase 1 setting, I mentioned two different populations within prostate. One is in the CRPC setting with patients who are post abiraterone, who've never had enzalutamide. They're giving their drug plus enzalutamide, and what they've reported thus far from the phase 1 experience is a 17-month median radiographic PFS.
The comparator there, if you gave enza alone, and this is well documented in all the different data sets, is you'd expect about 4-5 months of radiographic PFS. In a different population, an enza-experienced population, Pfizer is reporting that when they give them enza again, so in other words, enza rechallenge plus their EZH2 inhibitor, they're getting close to a 12-month median radiographic PFS. That's a population where they should expect to see 2-3 months of radiographic PFS. So clearly, in two different populations, they're blowing the benchmarks out of the water. They do have a phase 2 randomized study ongoing, which is what everybody is so eager to see the results of. The only thing I would say is, for one thing, is that phase 2, we understand to be powered at a 0.5 hazard ratio for PFS.
That's a pretty bold powering for Pfizer to do on that study. Second thing is, it is open label. This is the piece that I think a lot of people have maybe overlooked, is it is a randomized study, but it is an open-label randomized study. In other words, they're not waiting to unveil the results of a black box to themselves. They're seeing exactly how that study, you know, is doing and has done. So they announced earlier this year on their Innovation Day that they're gonna green light not just 1, but 2 phase 3 global studies for this program. So all signs point to that phase 2 study being positive.
Obviously, we haven't seen the results. I don't know why they wouldn't have shared those results. Obviously, you know, top of mind could be competitive reasons, and then the second could be that, you know, they've talked about starting these 2 phase 3 studies. Maybe they want to try to line up the phase 2 results with the start of their phase 3 studies. These are just hypotheses on our end.
Got it. Yeah, it makes sense. What are your latest thoughts on assessing AR inhibitors such as enza, apalutamide, or darolutamide to combine with ORIC-944? There's good rationale for daro based on the clean CYP activity with no DDI, but what's your current thinking of which AR inhibitor would make the most sense and lead to the best clinical results?
Yeah, the short answer is we're agnostic. We think they're all great drugs, both clinically and commercially. They've been huge successes and a great option for patients. Each one has their own advantages. As you said, darolutamide, you would not expect to see some of the CYP DDIs you would see with apalutamide or enzalutamide, but those can be overcome with just increasing dosing. Other considerations, both apalutamide and darolutamide are not approved in the metastatic CRPC setting, so that could be an intriguing path forward for those two drugs.
And lastly, if you look at the patent expiration, enzalutamide does come off patent in 2027. So they're all got the different pros and cons. The way we've designed the phase 2 dose escalation study is really to focus on allowing one or more AR inhibitors. The protocol actually allows all three if we wanted to. So we don't have to really pick our AR inhibitor of choice until, you know, second half of next year, where we're kind of planning for that potential of phase 3 registrational studies.
Got it. And anything more you want to say about strategy? Just when thinking about that neither apalutamide or darolutamide has mCRPC in their label, and then with the enza patent expiration, how do you think about that as well?
I think it all just fundamentally comes out that any of those three drugs would be phenomenal drugs for us to combine with. And I think if you talk to clinicians, they tell you that each of the all three of those drugs have done really well by patients on the efficacy front, on the toxicity front. So we don't have a preference.
Got it. And for phase 3, for the Pfizer phase 3 studies that they're gonna start, anything that you get from the strategy there based on those study designs, and could that be leveraged at ORIC?
All they've said thus far is some high-level commentary at their Innovation Day, which is that they're green-lighting two different phase 3 studies in metastatic CRPC. One is in a post-abiraterone population, and then also a treatment-naive population. Collectively, that's a $10 billion addressable market opportunity. And Roger Dansey's commentary during their Innovation Day was that they can build a wall of data across the prostate landscape here with this program, just like they did with enzalutamide, and that this is, they view that as only the start of their phase 3 studies and development program for that, for that mevrometostat, their drug.
That's as best as we know right now, Maury. We wouldn't be surprised if they go into an earlier line setting as well, eventually. So a hormone-sensitive setting, that would make a ton of sense. But we'll see.
Could you guys pursue an accelerated approval path somehow in this setting, or?
Well, I'm hesitant to talk about accelerated approval paths in the prostate setting, just 'cause it's a, it's a little more unprecedented in prostate. It's obviously probably far more relevant for ORIC-114, our lung cancer drug. But if the signal is here, is as strong as we think it may be, you know, we'd pursue all paths available to us to try to go fast to market.
Got it. Makes sense. And, let's shift gears to ORIC-114, your exon 20 TKI. A lot of focus on this drug. You had data at ESMO 2023, which looked good. Can you recap those data and provide your latest thoughts on inclusion criteria for patients with active CNS metastases in your study versus competitor studies, and talk about what investors should focus on for this topic now, given that this is gonna become more important with the ongoing in future studies, as well as the commercial opportunity?
Sure. I think the first-order analysis we hear of the EGFR exon 20 space and even HER2 exon 20 to some extent is that it's crowded. There's a lot of drugs. I think that's absolutely true. There are a lot of drugs, but there's a lot of suboptimal drugs in the space. I think what strikes us, and should strike others, is that the only approved drug for EGFR exon 20 today is amivantamab from Janssen. That drug is good, but it has a lot of room for improvement, both on the toxicity side and, most importantly, on the CNS activity side. So the drug does not have CNS activity. The leading agents in development that are ahead of us timeline-wise in the space also do not have CNS activity.
And while many of those agents have minimized wild-type EGFR toxicities, as we have with ORIC-114, they have quite a few off-target toxicities. So I'd encourage people to look at the kinome trees of those drugs and really stare at the AE tables for those drugs, 'cause you will see a lot of off-target toxicities, like QTc prolongation. You'll see anemia. You'll see bilirubin increases. You'll see CPK increases, all kinds of things that you don't wanna have as part of your tox profile. So those are the areas where we think we can differentiate. The ESMO update we gave last year was in a heavily pretreated population. 81% of the patients had had a prior exon twenty inhibitor before coming on to our study.
86% of the patients had brain mets at initial presentation, and even in that population, we saw multiple examples of RECIST responses. And we saw multiple examples of CNS activity in patients with active brain mets who had not been treated with surgery or radiation before coming onto the study. One of the patient anecdotes that we spent quite a bit of time on at that time was the perfect example of the promise of ORIC-114, which was a patient, 55-year-old lady, who had been struggling with non-small cell lung cancer, EGFR exon 20 mutation, had been on chemo, had progressed, went on to amivantamab, actually did quite well on amivantamab. She was on amivantamab for almost a year in response and then progressed exactly where you'd expect someone would progress with a non-brain-penetrant compound, which is in the brain.
She had 4 small lesions that developed in her brain. Because she had had amivantamab, she could not have qualified for any other trial of any other drug in the space, 'cause they disallowed patients who had had prior exon 20 inhibitors. She also, because her brain mets had not been treated with surgery or radiation, she would not have qualified for any of those trials because those trials disallowed patients whose brain mets had not already been treated with surgery or radiation. Our trial allowed both of those patient populations, so she came onto our study, and within 2 cycles, had a complete response in her lungs and a complete response in her brains and in her brain, singular. And the only tox was grade 2 tox that she had seen.
At the time of ESMO, she was on for nine months and ongoing. That's exactly the kind of example that we're hoping to build more of in as we differentiate versus the other compounds in the space.
Got it. And for your study, the expansion cohorts are pretty interesting. At ESMO, there was discussion around whether it could be difficult to enroll the exon 20 inhibitor-naive frontline cohort. But you said there was a lot of investigator interest in this. Can you talk about this, provide any status update on this cohort, and also contextualize the importance of the frontline naive cohort?
Yeah. I guess it was in May, we did announce that we had selected the provisional recommended phase 2 doses, 80 mg and 120 mg, once a day, and that we are moving forward. We started dosing in 3 expansion cohorts, and those patients included EGFR exon 20 patients. These are patients that are exon 20 naive, so had not seen a prior EGFR exon 20 inhibitor. We also are recruiting HER2 exon 20, and then the EGFR atypicals. You are right. There was a strong interest in the first-line treatment-naive patient population, so we are enrolling that as well. Listen, Maury, if you look at the first-line setting, you know, what's used now is chemotherapy and obviously amivantamab in combination with chemo. Those are not CNS-active agents.
We've talked about the prevalence of CNS activity being pretty high here. 35%-40% of these patients do present with baseline brain mets, so it is an underserved patient population. So it's demonstrating CNS activity in that patient population would be very, very helpful for us.
Got it. And, doctors typically use the stereotactic radiation to proactively control the disease prior to systemic therapy. How is that going to impact your ongoing dose expansion cohorts and then potentially the pivotal study enrollment with patients who have active brain mets at baseline?
Yeah, the short answer is it won't impact us. The reason, Maury, your statement's absolutely correct. Doctors typically use stereotactic radiation, but they use that in the absence of a CNS-penetrant drug. So when you don't have a CNS-penetrant drug, you give stereotactic radiation. If you do have a CNS-penetrant drug, you give the CNS-penetrant drug. That's why. So we got asked a question earlier today in our one-on-ones, you know, how, in a phase I study, were we able to enroll patients with active brain mets who had not already had surgery or radiation? The reason is simple: It's because at that time, the preclinical package was so compelling that clinicians understood that this was likely to be a CNS-penetrant drug, and so they enrolled patients onto the study, even who had not had surgery or radiation. That's in a phase I setting.
Now that we've actually generated the clinical data that further shows that and demonstrates it, it's not gonna be a problem to enroll those patients. Because if you think about it, you know, if you as a patient have an option to either get radiation, which comes with a ton of morbidity to it as well, or you take a small molecule pill that you swallow, and that small molecule pill can handle the CNS mets in your brain, you would much rather do path two. As a clinician, there's a lot of reasons why you'd rather give a small molecule pill rather than stereotactic radiation. You know, even aside from the toxicity of stereotactic radiation, you have to keep in mind that SRS can only handle a small number of brain mets.
If patients have lots of brain mets or they have micrometastases, you don't, you can't give radiation for that kind of a situation. That's where you need a small molecule. The other thing is, a small molecule can prevent the eventual development of brain mets. So there's a lot of reasons why you would opt for a small molecule that is actually brain penetrant and not radiation.
Yeah, makes, makes a lot of sense. And you talked a little bit about the expansion cohorts for this study. Maybe set expectations for the phase 1b data updates in the first half of 2025. Which cohorts are enrolling better and are further along, and how many patients could we see from each of these cohorts?
Yeah, I'll keep it at a very high level there, Marty, which is we don't give sort of interim enrollment updates or timing. Other than I'll just suffice it to say that, you know, the three expansion cohorts Dominic mentioned are of primary importance to us, which is EGFR exon 20, HER2 exon 20, and then the EGFR atypical mutations. We should have enough patients in each of those three to report first half next year publicly as to how those look, and then also, more importantly, to make decisions on how many of those three we would greenlight for further development. Further development being second half 2025 next year, the start of pivotal studies.
So we could be in one, two, or three pivotal studies, in the second half of next year, depending on just how the signal stacks up there. Those would be standard—your, your typical, you know, long playbook. You asked about accelerated approval earlier, in the context of the other program. This would be your, your typical, TKI playbook, which is, in a second-line population, post-chemo, single-arm accelerated approval, design starting in second half 2025 next year. And, and because the timelines there are quite fast, the NDA filings would be in second half 2027, so really fast.
Got it. And just for what you have to show in those cohorts, is there anything more that you're saying on that? What's the bar for success?
Well, I think the bar for success for all of those systemically, if you have, it's obviously specific to the cohort. So, you know, in the EGFR exon 20 space, drugs seem to be vectoring to call it roughly the 35%-40% ORR range. You know, tox profiles that have minimized wild-type toxicity, but obviously quite a bit of off-target toxicity that you see there, so we think we ought to have an advantage there. And then total lack of CNS activity. So we think any CNS activity we can show there is the differentiating factor for the drug in the EGFR exon 20 space.
In the HER2 exon 20 space, you know, I think there's perhaps a slightly less developed competitor data set right now, but it looks like drugs are vectoring again to that kind of 40%-45% range in terms of response rates. And then atypical seem to be about the same, even with the latest updates that came out of ASCO just a few days ago. So they're all kind of in that, that general range. Obviously, in the front line setting, the, the numbers I just said go up in terms of response rates.
Got it. Maybe one other question just on dosing. You've selected the two provisional recommended phase 2 doses at 80 and 120, but you further dose escalated since the last cut at ESMO. What's driving the decisions around dosing, and do you expect longer-term follow-up from the dose escalation cohorts at some point?
Yeah. What's simply driving the decision is wide therapeutic index. So, you know, folks will remember at ESMO, the lowest reported dose at which we had a RECIST response was 40 mg daily, and the two provisional RP2Ds that we're taking forward to satisfy Project Optimus requirements are 80 mg and 120 mg daily. So 2x and 3x, the dose levels at which we saw the first RECIST response. So that should speak to the very wide therapeutic index of the compound. And the safety profile that we've seen at 80 and 120 aren't meaningfully different than what we've already shown people, as part of the ESMO update.
And then the reason to take forward the two doses, obviously, is just to satisfy, you know, Project Optimus requirements, where you need to get different exposures at the two different doses that you take forward for optimization. I think one thing that should give people further comfort there is at ESMO, we said that, you know, at that time, 75 mg was the highest that we had dosed, and we said that that would be a perfectly great RP2D to take forward, given the strong activity we saw there systemically and in the brain, and good tox profile. What I did not know at the time at ESMO was seventy-five gonna be the top RP2D dose, and we'd pick a dose lower than that, or, you know, or how that was all gonna play out.
We were obviously able to dose quite a bit higher than that, and so 80, which is effectively the 75 dose, is coming out as our lowest of the two RP2D doses that we're taking forward.
Got it. Interesting. And also wanted to briefly ask on ArriVent, furmonertinib. They're gonna have frontline pivotal data next year, but before we see that, they're gonna have PACC mutation data in the second half of this year, which has some overlap with your atypical setting too. What are your latest thoughts on the furmonertinib's clinical profile, and what should investors focus on in their data updates?
Yeah. So with regards to firmo, they obviously it's an approved drug in China for T790M. The drug is being repurposed for EGFR exon 20. They are doubling and tripling the dose. They had shown some activity at World Lung last year. Their response rates looked to be in line with lazertinib and amivantamab in the second-line setting. They claim to be CNS penetrant, excuse me. They haven't shown that data just yet. And with regards to atypical, as you said, they're gonna present some data in the second half of this year. At ESMO this year, we did profile ORIC-114 versus both afatinib and furmonertinib, and we seem to be more potent in vitro.
So again, we'll have to wait and see what data they put out later this year and what the data we show first half of next year.
Got it. Yeah, makes sense. And, I don't know if there's anything else you want to say about development path and potentially pursuing the frontline non-small cell lung cancer setting. You talked about some of the bars for the other cohorts, but...
Yeah, both to satisfy FDA requirements, but also just in terms of, you know, the unmet need in the various populations. We're already thinking about what the first-line strategy looks like. So, you know, I mentioned the various second-line single-arm accelerated approval cohorts. We would be looking to start second half of 2025. We'd be looking shortly thereafter, so call it 2026, to start the frontline confirmatory study, 'cause obviously you need to have a confirmatory study as well. In the case of EGFR exon 20, there's two flavors of those confirmatory studies. It's to go head-to-head versus chemo, and there's a couple compounds that have done that. The other flavor is to combine with chemo and then compare yourself to chemo. So both paths are under discussion right now by us as to which of those would be interesting.
There's also a third path, which is actually pretty unique and interesting and probably only open to us as a brain-penetrant TKI, which is you could potentially combine with amivantamab. You could do an amivantamab plus ORIC-114 combination. You'd have to figure out what your comparator arm is there, but that would be, you know, akin to the Enhertu tucatinib combination or the amivantamab-lazertinib combination. There's a lot of reasons to think why, in the EGFR exon 20 space, that could be a pretty unique, opportunity that again, is only available to a brain-penetrant TKI like ourselves.
Got it. Yeah, makes sense. We're pretty much out of time, so just to close out, if you can comment on your cash position. I don't know if there's anything you're saying on BD strategy for the rest of the year, and then just highlight key catalysts investors should be focused on.
Yeah. So, cash, we ended $331 million at the end of the first quarter. Our cash runway gets us into late 2026, and that does assume full success for both 114 and 944, so that assumes we're starting registrational studies in the second half of next year. With regards to BD, you know, we do have a two-pronged approach to building our pipeline, both external in-licensing as well as internal research and discovery. We have this two-pronged approach. We've used it. We continue to do it. If we think about our areas of focus right now, it's small molecules, really focused on prostate and lung and breast, again, something that's about 6-12 months away from the clinic.
Regarding catalysts, the next update on 114 will be the first half of next year, as we discussed earlier today, and lastly, the program update on 944 midyear.
Got it. Thanks so much for joining us today.
Thank you, Maury.