All set? Okay. Hi, everyone. My name is Maury Raycroft , and I'm one of the biotech analysts at Jefferies. I'd like to welcome our guests today from ORIC. We've got the CEO, Jacob Chacko, and the CFO, Dominic Piscitelli. Thanks so much for joining us today. We're going to do fireside chat format. Maybe for those who are new to the story, if you can give a one-minute intro to ORIC.
Happy to. Thanks for having us, Maury. ORIC stands for Overcoming Resistance in Cancer. In a nutshell, that's the mission of the company. We're focused specifically within oncology on small molecule drug development in solid tumors. Obviously, as based on our lead programs, that's primarily focused on prostate cancer and lung cancer. Both programs are in dose optimization right now. Both are headed towards the start of pivotal studies, phase three studies next year in 2026. Happy to chat about either of them.
Great. Yeah, it's a great intro. Let's start off with the ORIC-944 program. Last week, you just reported data. It was encouraging dose escalation combo data for the ORIC-944 plus apalutamide or daralutamide combos. The PSA waterfall plot looked impressive. Based on what you've shown today, do you think that ORIC-944 can yield the same or better results on RPFS relative to Pfizer's Mevrometostat?
Yeah, I hesitate to make those kind of forward projections or guesses at this point. What I will say is, based on the data we've shown thus far, we see the same types of efficacy, if not better, than what Pfizer has shown with Mevrometostat in combination with their AR inhibitor. As folks know, we're dosing with the other two big AR inhibitors. One of those is daralutamide from Bayer. The other is apalutamide from Johnson & Johnson. We see very good PSA 50s, very deep PSA 90s, and a very good safety profile with either combination drug. I think in particular, and we can get into some of the pharmacokinetics here, I think where the key differentiation for the compound is going to come is from the fact that our compound, ORIC-944, has a 20-hour half-life, whereas Mevrometostat, Pfizer's compound, looks to have about a five-hour half-life.
That being the case, what it means is that we can cover CMIN. This is an epigenetic modifier. So we can cover CMIN for a 24-hour period without having too high of a Cmax, which essentially is where the toxicity is coming from. That is where long-term we think the differentiation will be on the safety front. Because this is prostate cancer, safety differentiation often leads to efficacy differentiation as well in the form of PFS.
Got it. Okay. Yeah, it's helpful. And you showed compelling ctDNA clearance in 59% of the patients. Talk about the significance of this data and how the correlation is even stronger with RPFS benefit.
Sure. You mentioned the data update we gave last week had three new patients' worth of data in it from the perspective of PSA 50s and PSA 90s. It was really just the finishing up of the dose exploration, most of which we had updated in May of this year. I would say that there was not a whole lot new to learn in terms of PSA 50s or PSA 90s. The really substantial part of last week's update was the ctDNA. For folks that track ctDNA, for folks that understand its significance, I think you'll find that last week's update was actually pretty profound from that perspective. What I mean by that, Maury, is, as you've alluded to, in the prostate space, you've increasingly seen ctDNA being used as an exploratory endpoint.
The reason for that is literature suggests that even more so than PSA 50s and PSA 90s, ctDNA tends to correlate with, so the ability to clear ctDNA correlates with long-term durability measures like PFS and with OS. Just to put things in context, in what we showed last week in the patients that had ctDNA at baseline entering into the study, first of all, close to 90% of our patients had ctDNA at baseline coming into the study, which is far higher than you see in these other studies, which means it's effectively a sicker patient population. Then close to 60% of the patients had complete clearance of the ctDNA. To put that in context for you is we've looked at other phase three studies in the prostate space where they have looked at ctDNA as an exploratory biomarker.
You tend to see on the order of 30%-40% clearance of ctDNA for studies that have hit for positive studies. We specifically, in the update last week, called out two of those studies in particular, mainly because they gave the cleanest look in a comparable population at the ctDNA clearance rates for enzalutamide alone and for chemotherapy alone, the relevance of those two being that those would effectively be the control arm, a physician's choice control arm in a potential phase III study for us. In the case of whether it was enzalutamide alone or chemotherapy alone, they show between 10%-30% rates of ctDNA clearance. If you average across the two, it's basically a 20% rate of ctDNA clearance.
For context, we had a 60% rate of ctDNA clearance, which again should give some sense of the de-risking for the potential phase III trial design that we'd be embarking upon next year.
Got it. Maybe talk about the kinetics of the ctDNA clearance and activity across AR mutations. How does this data inform your strategy with patient selection going forward?
Yeah, what we saw, the ability to clear the ctDNA across a broad variety of mutations within, obviously, these are a heterogeneous patient population. You see a whole host of different mutations. It didn't matter what the mutation was in terms of our ability to clear the ctDNA. We measure ctDNA after the first cycle. It is basically cycle two, day one. You see those profound reductions in ctDNA quite quickly. Everything points to very good, well-behaved drug properties, very good, well-behaved pharmacokinetics. Importantly, from a patient selection strategy, there would be no patient selection strategy, my point being that because you can see this activity across a whole variety of mutations, it means that we can take an all-comer population.
Got it. Okay. Since Pfizer is using ctDNA as a secondary in MEVPRO-1, their phase three study, would you anticipate they are seeing a signal on ctDNA as well? How much emphasis is FDA put on ctDNA as a correlative biomarker? Would it be possible to leverage these data for your pivotal study?
I can't speak for what Pfizer may or may not be seeing. They are measuring ctDNA as an exploratory endpoint. I assume that they're seeing similar good activity like we are, but we haven't seen those data from them yet. I can't comment on that. In terms of being included as a potential correlative biomarker in a potential phase III study that we would do, yeah, we would certainly include it. I think the gold standard continues to be radiographic PFS in terms of the primary endpoint that you're trying to hit. Correlative measures are good, but at the end of the day, radiographic PFS is what's going to matter.
Has FDA commented on ctDNA at all for any other studies?
As far as I know, it's been an exploratory endpoint in all the other studies.
Got it. Okay. Safety looked good overall in the 20 patients with only one grade 3 event of diarrhea. Pfizer's pivotal dose of 875 mg b.i.d. with food improved versus without food, but still had multiple grade 3s, including 7% grade 3 thrombocytopenia and 7% anemia. Do you think these AEs are on-target effects or specific to the drug? How important is the safety profile of future development plans and differentiation?
Let me go and reverse on your question. I would say that the safety profile is incredibly important for the future development considerations. The reason being that the name of the game here in prostate, you're looking for radiographic PFS. You don't want patients to progress radiographically. You also don't want patients dropping off the regimen because the tox is too much for them to handle. Historically, as you compare across different oncology indications, I would argue that within prostate, there has historically, based on the trials, been less of a tolerance for toxic regimens, especially as you go to earlier and earlier lines. While initial development would likely start in the castration-resistant prostate cancer setting, we have every intention to move earlier lines.
A setting like CSPC, castration-sensitive prostate cancer, that safety profile, so having an exquisitely clean safety profile, is going to be even more important. As you think about a PRC2 inhibitor, you should expect two major classes of on-target toxicity from a PRC2 inhibitor, which would be GI tox, so in the form of diarrhea. You should also see heme tox, various types of heme tox. Obviously, we do see those two types of on-target toxicity. We see them in a lot lower frequency and severity than what Pfizer is showing, as you alluded to. The other thing is we do not see things at all like alopecia, which is, as best we can tell, an off-target toxicity that is showing up in the Pfizer profile. Overall, I think it's pretty easy to see.
While I can't, I mentioned earlier, I can't comment yet on our PFS because our PFS is obviously not mature enough to try to make those side-by-side comparisons with Pfizer. What I can definitively comment on is that the safety that we're seeing at any potential RP2D for ORIC-944 is clearly differentiated from Pfizer in terms of, like I said, a lower incidence rate and a lower severity rate. That should bode well for us in terms of the long-term comparability between the two. Now, at the end of the day, you might ask yourself, is safety alone enough to lead to a best-in-class profile? As I've mentioned several times already in this talk, absolutely the answer is yes. All you have to do is look at the three big AR inhibitors. Enzalutamide was the first AR inhibitor that was developed and approved.
That's Pfizer's drug now, which they acquired from Medivation. It was approved in 2012, does $6 billion a year in sales. The second and the third AR inhibitors, which were approved six years later and seven years later and have better safety profiles, are themselves multi-blockbuster drugs many years later. The point being that daralutamide, which is a third to the party from Bayer, is already a $2 billion a year drug, growing over 50% a year. That is largely based on its safety differentiation from the other two.
Got it. Yeah, good perspective. What might be the reason that you see higher PSA 50s and PSA 90s and lower AEs in Pfizer? Is it related to your drug targeting EED versus Pfizer targeting EZH2, or is it the drug properties or something else?
Yeah, I'd be hazarding a guess in all of these situations, but I would tell you it's almost certainly not a mechanistic difference between the two. I mean, we've interrogated this every which way preclinically and looking at the various clinical data sets. What I would tell you is that if you have two drugs that are trying to attack the PRC2 complex in different ways, one's an EZH2 inhibitor, one is an EED inhibitor, which is exactly the case. Pfizer's is an EZH2 inhibitor, and ours is an EED inhibitor. If the potency of those drugs is exactly the same, if the drug properties are exactly the same, they should be equally effective at initial inhibition of that PRC2 complex.
Where we think the difference is really coming out here comes back to the drug properties, which is that if Pfizer has a five-hour or shorter half-life and we have a 20-hour half-life with ORIC-944, it's not just the convenience that the pitch, in other words, is not the convenience of QD dosing versus b.i.d. dosing. What it really comes down to is the ability to cover target. From an epigenetic modifier's perspective, you want to be able to cover CMIN for 24 hours in a day. What you want to avoid is Cmax-driven toxicity. As you can imagine, Pfizer with a five-hour half-life is running into issues of trying to cover that CMIN effectively for the full 24 hours of the day without running into Cmax-driven toxicity. You don't take my word for it.
Pfizer themselves said at ASCO GU earlier this year that their toxicity, they believe, is coming from Cmax. The reason why they have been playing around with the dose that they took into phase three and they're trying to dose with food is because, according to them, that gives them the same exposure but a lower Cmax, which they think should lead to less toxicity. Empirically, it looks like it does lead to less toxicity, at least based on the results that they presented a few months later at ASCO. The other way that you can get that better behaved profile is by having a 20-hour half-life, which is what we have with ORIC-944.
I do think that that ought to benefit us in terms of the source of that safety differentiation versus Mevrometostat ought to come from the pharmacokinetics, in other words, the longer half-life of ORIC-944. One thing I said earlier, which I do not want to gloss over here, is keep in mind these are combo regimens. I am very confident that with ORIC-944, we have a better profile, a better behaved drug than Mevrometostat for all the reasons I just articulated. The combo regimen involves combination with an AR inhibitor. Enzalutamide, Pfizer's drug, apalutamide, Johnson & Johnson's drug, and daralutamide, Bayer's drug are all phenomenal AR inhibitors. If you ask any physician who has got experience with all three of those drugs, they would tell you that the clinical efficacy is the same for all of those drugs, identical, undistinguishable between the three.
What is different is on the safety profile, which is that every physician will tell you that daralutamide and apalutamide are better tolerated than enzalutamide. It's not that enzalutamide is poorly tolerated, but if you had to force rank those, daralutamide and apalutamide get the nod over enzalutamide. Because those are the drugs we're working with, we have an opportunity to differentiate the combo regimen not only with a better behaved PRC2 inhibitor, but also with a better tolerated AR inhibitor.
Got it. Makes sense. For the alopecia, does that come up with enzalutamide ever, or is that no?
Not that I'm aware of.
Yeah. Okay. You are going to have a data update first quarter of next year with dose optimization data. You have guided to having 20 patients-25 patients' worth of data across recommended phase two doses for one of the AR combinations. Can you walk through what we should expect to see in this data update?
Yeah. So that update, as you said, will be 20-25 patients' worth of data across one of the combinations, so the combination with apalutamide or the combination with daralutamide. That will be across the provisional RP2Ds that we're testing. For the daralutamide combination, we're testing 4 and 600. And for apalutamide, we're actually testing three doses. So it's 6, 8, and 1,200. What you should expect to see there is obviously PSA 50s, PSA 90s, safety, tolerability. This will really be the first look at the durability as well. It is way too early for a PFS outlook on this. This is way too immature for that. What you should expect here is a landmark analysis, like a three-month or four-month landmark analysis.
Got it. That's helpful. Your protocol allows assessment of both metastatic CRPC cohorts, post-abiraterone, and also post-androgen receptor pathway inhibitors. Are you still enrolling in both CRPC patient cohorts?
Yes, we are.
Okay. Okay. What is the data set you're going to be taking to the regulators in early 2026 to get alignment on what a pivotal study would look like?
We will take the dose optimization data to the regulators to get sign-off on what we believe to be our go-forward phase III dose. Obviously, we may show the regulators the full set of data that we are enrolling, which, as you alluded to, is two different populations within CRPC. One is post-abiraterone. The other is post-AR inhibitor. It does not necessarily mean that we will show all those data publicly. We will probably focus the public disclosure in Q1 on whatever is going to be our first phase three study.
Got it. Okay. Do you expect your first pivotal to mirror Pfizer's study design, or would you potentially need a larger sample size to satisfy the safety database?
Those are two different questions or two different topics, but I would say that we don't need a larger sample size to satisfy the safety database, for one thing. On the question of where, because there's obviously different populations within prostate cancer that we can go develop this compound in, we haven't said yet what that first study is going to be. To the extent that it is the same as Pfizer's MEVPRO-1, then I would anticipate that the study design, sizing, timelines, everything would be quite comparable to what Pfizer has outlined. To the extent that we go in a different direction than that MEVPRO-1 population, then I wouldn't be able to comment on how it compares to Pfizer.
Got it. What are some of the drivers to making that decision of what the direction is going to be? Are you going to wait to see what Pfizer's MEVPRO-1 top-line data are and potentially start the pivotal after that in case you have to make adjustments based on that phase three readout?
We are not waiting for anything, Maury. We are pedal to the metal running to that first phase three study. I should maybe clarify. We know exactly what that first phase III study is internally. We're just not talking about that publicly for competitive reasons at this point. I would tell you, we're not waiting for anything. We're not waiting to see Pfizer's phase III data. We're not waiting to see our own mature PFS data because any of those outcomes, waiting for any of that means we're just losing more time of getting to the finish line. At this point, the name of the game is get this drug approved as quickly as possible. We're going to start that first phase III first half next year.
We're going to have the primary readout from that first phase III, second half 2027, and we'll be off to the races after that.
Got it. We have talked a lot in the past about picking daralutamide or apalutamide. What goes into this decision to choose the optimal combo partner for your phase III?
The great news is that with apalutamide and with daralutamide, we see the same efficacy, the same safety profiles. There is nothing that has differentiated one of those drugs versus the other in our hands thus far in the dose exploration activity and the early dose optimization activity, which I think is great because we basically have our choice between two phenomenal blockbuster drugs that have done great for patients in the prostate cancer space. I think as a small biotech, as you kind of figure out what the next step is for us in the phase III development in terms of combo partners, it is great to have two combo partners and two combo companies that we have worked so well with historically. I am agnostic is the short answer.
Got it. Okay. Maybe talk about the market size. You had provided some numbers earlier just around the individual AR inhibitors, but how do you see the market size and do you need to have a differentiated profile versus Pfizer?
Yeah, great question. This is prostate cancer. Obviously, this is a large commercial opportunity. When you look at the metastatic CRPC setting, there's approximately 50,000 patients across three different groups of patients. The way we kind of look at it is there's the post-AR inhibitors, there's the post-AVI, and then the ARPI naive. The two patient populations that we're currently enrolling in the dose optimization are the post-AVI and the post-AR inhibitors. Each of those, if you just did the simple math, is about a $3.5 billion TAM in the U.S. alone. Obviously, this is a significant market opportunity. With the second question regarding the need to be differentiated, the simple answer is no. If you look at any historical analogs, you're second to market. Even with an undifferentiated profile, you're going to gather about 35% of the market.
Given the opportunity here, this is just, it's a billion-dollar opportunity on its own. Now, obviously, as Jacob kind of highlighted, there is room for potential differentiation both on safety and on PSA responses that we've seen already. Obviously, if our profile continues to remain better, that could obviously represent a larger opportunity as well. The perfect analog for this really is the AR inhibitors. If you look at it today, as Jacob said, it's an $11 billion opportunity. I was at Medivation. We launched that in 2012. That's doing $6 billion. APA came six, seven years later and is doing $3 billion in sales, so.
Got it. That's helpful. For the data updates that you get, the one that you just had, do you share that with Bayer and Johnson & Johnson? I guess maybe talk about just the relationships there with those two companies.
The relationships are strong to very strong. We have a very good dialogue with both of them and, for that matter, with a number of other pharmas that follow the prostate space closely. Obviously, we want to keep all of these potential future partners up to speed on the program, and I probably will just leave it at that.
Okay. Understood. You have presented compelling preclinical data on the potential for PRC2 in oncology indications outside of prostate. Can you remind us which of these are of most interest to you guys?
Yeah. I mean, this is an area that we're spending a lot of time kind of flushing out the roadmap forward, Maury. As folks know, in August of last year, we made the tough decision to stop some of our discovery research work working on new programs because the company had internal discovery capabilities. We actually retained a core group of that discovery team so that we could continue to do quite a bit of work on the preclinical justification of taking ORIC-944, a PRC2 inhibitor, in combo with various other standards of care in areas outside of prostate cancer. As you alluded to, there's been a significant amount of evidence, third-party literature that has suggested that a PRC2 inhibitor could be combined with standards of care in hormone receptor-positive breast cancer, could be combined with KRAS inhibitors in lung or CRC.
We're flushing out some of that preclinical evidence today because while probably those kinds of trials or studies are too far off from the perspective of lots of folks in Wall Street, I can tell you those are right in the sweet spot of how pharma likes to think about these programs. We're absolutely flushing out those preclinical rationales and then trying to figure out what might be the next step clinically to further interrogate that.
Got it. Okay. Let's shift gears and talk about ORIC-114, your other pipeline asset. The non-small cell lung cancer program updates expected at ESMO Asia in December. We're expecting a comprehensive data update from your four cohorts. You've got two oral presentations and one poster. What should we expect for this update?
Yeah. That will be a pretty, as you said, a pretty comprehensive update. As you remember, we're doing three cohorts in the second line or later patient population. This is the EGFR Exon 20, HER2 Exon 20, and EGFR atypicals. For each of those cohorts, you'd expect around 25 patients' worth of data. We also moved up one of our earlier milestones. This will give you a first look at first-line EGFR Exon 20 as a monotherapy, and then we'll have about 10 patients-15 patients' worth of data.
Got it. Okay. That's helpful. Earlier this year, you updated strategy to focus on frontline only where durability and high response rates are important. How do you expect potential better safety and CNS activity to translate to durability for ORIC-114?
Yeah. If you look at the history of drug development within the targeted therapy space within non-small cell lung cancer, there's been a truism there, which is that CNS-penetrant drugs end up developing longer PFS outcomes for patients than non-CNS-penetrant drugs. The reason being that so many of these patients, about 35% at initial presentation in early lines, have brain metastases already. The brain is often the very first site of progression for these patients. What ends up happening is if you look at the Kaplan-Meier curves and the hazard ratios for these non-brain-penetrant drugs, what you will find is that there's a profound difference in the PFS for the patients with versus without brain metastases. The drugs that are brain-penetrant, which ORIC-114 is brain-penetrant, where they end up really differentiating is not on things like ORR.
Their ORR profiles often look the same as other well-developed drugs that are not brain-penetrant. What ends up being dramatically different is the PFS. That is because you do not have this huge discrepancy in the PFS for patients with versus without brain metastases. We would absolutely expect that to be the case with ORIC-114 given its CNS activity. That ought to lead to longer PFS, longer durability outcomes for our patients than what you would see with these drugs that are not brain-penetrant.
Got it. That's a good segue to the next question. Just if you can give an update on the combo with amivantamab, how that's going, and set expectations for the data update in the middle of 2026, along with the atypicals.
Yeah. The combination is going well. Just to clarify, I think when you look at what people are doing in the first-line EGFR exon 20 space, most people are doing one of two approaches, either monotherapy or a combination with chemo. We're actually doing monotherapy, as I talked about. We'll have an early look at that data next month. We're also doing a combination with amivantamab as well, which is kind of a differentiated approach. That is going on. That's going well. We'll have that data mid-next year. We'll kind of take a look at that as well. I think when we think about the bar there, it's about an ORR about 65% in that first-line setting. We also show the first-line atypical EGFR, and the bar there is around 50%.
Got it. Okay. How are you feeling about the pivotal plan for ORIC-114? Are you still planning to start pivotal in the second half of 2026?
Still planning to start in the second half of 2026. Obviously, assuming the data plays out as we expect it to play out over the next six to seven months from both ourselves and from competitors. In terms of what that design looks like, it will be very data-dependent. We are nothing, if not a data-driven company in terms of the way that we make decisions and how we think about the development plans going forward. The treatment arm might be monotherapy of ORIC-114, might be a combo with chemo, might be a combo with amivantamab. It will all depend on how our own data shake out.
Got it. Okay. This has been a great conversation. We're out of time. Maybe to close out, if you can just comment on your cash position and runway assumptions for the pivotal studies.
Yeah. We ended the third quarter with $413 million in cash and investments. Gives us cash runway into the second half of 2028. That does assume we start the phase three study for ORIC-944 in the first half and the ORIC-114 study in the second half. The good part of that is it gets us cash runway basically past top-line data readouts for both phase three studies, both ORIC-114 and ORIC-944. It actually gets us about 9-12 months past the top-line data readout for ORIC-944 as well.
Got it. Okay. Thanks so much for joining us today.
Thanks for having us, Maury.