Global Healthcare Conference for the next session. We are very excited to host the team of ORIC. Representing ORIC, we have Jacob Chacko, Chief Executive Officer and Dominic Piscitelli, Chief Financial Officer. Gentlemen, thank you so much.
Thanks for having us.
Maybe we can start with a quick introduction about the company and the key priorities for you over the next one to two years.
Sure. I am happy to start.
First time doing this?
First time at a fireside chat, sorry. ORIC stands for Overcoming Resistance in Cancer, which, in a nutshell, is the mission of the company. We are most focused on two programs that are in late-stage clinical development at this point. rinzimetostat, which is our PRC2 inhibitor that is being developed in combination with a couple of different androgen receptor inhibitors in prostate cancer, right now, specifically in CRPC.
enosartib, which is our brain-penetrant lung compound, is for two different targeted therapy populations within non-small cell lung cancer, primarily within the EGFR family of mutations, but specifically EGFR exon 20 and EGFR atypical mutations. rinzimetostat, our PRC2 program in prostate, has recently entered its first phase III study, HIMALAYA-1, which I am sure we will discuss. enosartib is about to have a lot of data that is presented at ESMO for atypical EGFR mutations.
If all goes according to plan, we will start the first phase III study for that program next year. A lot going on.
Okay. In the minds of investors, one topic is really at the top, MEVPRO-1, which is Pfizer's phase III, because it has implications for your program as well. I guess during the last earnings call, Pfizer disclosed some important updates regarding what they expect in terms of control arm performance and how they see the event rate, and that they expect the trial to read out in 4Q. What was your high-level take on some of those commentary and updates?
Yeah, I'm always a little hesitant to comment on other companies' assumptions or to make predictions on what's going to happen, but obviously, this is probably the most common question we've been getting over the last couple of weeks, ever since their Q2 quarterly call.
I think by Pfizer narrowing their guidance for when the MEVPRO-1 readout was coming to Q4, I think it probably fed into a lot of folks' event-driven analyses as people are trying to predict when would the events come in that MEVPRO-1 trial. What does that imply about treatment arm versus control arm performance?
I think you put out, obviously, a very thoughtful analysis on that as well, and I think the net conclusion of that for us is pretty much the same conclusion you came to, which is that, in general, a Q4 readout for MEVPRO-1 ought to be a positive signal in terms of how that trial plays out, and in general, the later, the better within Q4 itself.
We've done everything internally to stress test all the big assumptions you can on an event-driven analysis around that trial, namely things like control arm performance, composition of the physician's choice control arm. So in other words, what percent of patients get chemotherapy versus get enzalutamide? What is the performance of the chemotherapy subportion of the control arm? What's the performance of the enzalutamide subcomponent of the control arm? Things like dropout rate. When was enrollment completed?
Which I know is a hot topic of debate, and I think the bottom line is you sort of have to lay out a whole bunch of different scenarios under all those different assumptions, and I think you generally see a skew to the positive. So that's probably the conclusion we come to as well.
I think maybe just taking a step back from that, Prakhar, where we get comfort is obviously in seeing how our own data have developed in two different populations within CRPC, so in the post-abiraterone CRPC population as well as post-AR inhibitor within the CRPC. You've got a couple different phase I data sets from Pfizer. You've got a randomized data set from Pfizer. You have another data set from another PRC2 inhibitor called igermetostat.
So at this point, I think the preponderance of evidence is that the mechanism of a PRC2 inhibitor in combination with an AR inhibitor is, in fact, synergistic, and I really think now it just comes down to trial stats and whatnot to try to figure out, is it going to be positive or not?
Okay. And I guess for you, what are the possible scenarios from MEVPRO-1 that are positive, negative, and what will be the implications for your phase III program after that?
Yeah, look, we've always been pretty simplistic in the way that we think about how those scenarios might play out. At a high level, you can have MEVPRO-1 with a big win, a small win, a bare miss, or a big miss. I think the conclusion of the analysis, the very good analysis you did and that others have done, I think at this point, especially with the Q4 readout, pretty much takes the big miss scenario completely off the table.
It's almost statistically impossible at this point for that trial to have a big miss. Now you're left with those other three scenarios, and I would argue that certainly the first two are, in general, better read-throughs for us, which is that they have either a big win or a small win.
But even in the small miss scenario, it doesn't necessarily change our base case plan given what we already understand to be the key differentiation of our compound versus theirs, which really comes down to the drug properties and then how that translates into the safety of the compound. If you think about the ways that they could potentially have a near miss, we've scrutinized that every which way possible.
You can look at things like trial design, and in that sense, you would look at things, for example, like do you somehow have an unexpected enrollment of patients in the control arm more heavily weighted towards chemotherapy, for example? That's one of the ways that could pressure the trial stats, so to speak.
Now, what we've heard, kind of anecdotally, and I think in some public Pfizer statements that they've made, is that there was nothing unexpected in terms of control arm performance that they're seeing. That would suggest to you that it probably enrolled the expected percentage of chemo versus enzalutamide in the control arm, and that things are performing as expected in the control arm.
Then you go to other things that could go wrong, and for the most part, those all seem to be very much drug-specific. What I mean by that is if for some reason they end up with too much in terms of safety signal and that causes them to have to dose reduce patients to deal with that, and patients get a lower dose intensity of their regimen, that obviously would compromise the therapeutic efficacy of that regimen.
They obviously are going with a slightly different regimen in this phase III than what they've done previously. It's a fed regimen at a lower dose than what they did with the randomized results. While there was some data suggesting that those two regimens were AUC-matched and exposure matched, anything can happen as you move into a phase III.
Clearly they have a DDI with enzalutamide because enzalutamide is a CYP inducer, and any time you up dose your drug to overcome something like that, you can get more interpatient variability. There's a number of those factors that could come to play in the scenario of a near miss, none of which are relevant to us because with rinzimetostat dosing with darolutamide, we don't have a DDI. Darolutamide is not a CYP inducer.
We're obviously using a quite low dose of rinzimetostat in the grand scheme of things, 400 milligrams once daily, and that's because of the potency of rinzimetostat. That's because of the fact that it's got a 20-hour clinical half-life as opposed to the four or five-hour half-life of mevrometostat, and the good properties of darolutamide. I think in any of the scenarios that I've outlined, I think it's still pedal to the metal in terms of HIMALAYA-1, which is our own phase III study, which we just kicked off.
Okay. I guess as you think about the efficacy or maybe even safety, what's clinically meaningful in this setting in terms of PFS hazard ratio, medium, or PFS? Pfizer has made some comments. What's your take on that and what does your research say?
Yeah, it's interesting. Anytime you talk about what's going to be meaningful, there's different ways to cut that. You think about what's going to be meaningful from a regulatory perspective. In other words, what's going to hit your stats, your trial stats? Sometimes that's the same as what's going to be actually clinically meaningful to clinicians and patients, and sometimes it's not the same. I think this is one of those scenarios where the two line up quite nicely.
What I mean by that is if you look at the protocol for MEVPRO-1, which is obviously quite similar to our own protocol for HIMALAYA-1, the stats are pretty straightforward, which is you're assuming roughly 50/50 enrollment in the control arm between chemotherapy and enzalutamide that leads to or yields a performance, an expected performance in the control arm of about 6.75 months PFS.
I should have mentioned, the sole primary endpoint for Pfizer, for us, is radiographic PFS. The assumption is 6.75 months of radiographic PFS at the median for the control arm and then just over 10 months in the treatment arm. That is all intended to yield a 95% powering for a 0.66 hazard ratio. So those are the stats, just keep that in mind.
Pfizer's own commentary recently talked about a 30% improvement over the control arm being clinically meaningful. If you just want to use very simple, what I call caveman math, and you think about the control arm doing about seven months, if the treatment arm gets anything approaching double digits, so call it 10 months just to make the math easy, any of that would hit the trial stats.
But more importantly, then you get to the second question, is that actually clinically meaningful? Do clinicians care about that? There I would tell you wholeheartedly that would be an outstanding outcome for those patients and for those clinicians. The reason being, you think about what else can those patients receive in that setting.
So post-abiraterone CRPC, you can certainly do an AR switch, an androgen receptor, so give those patients an androgen receptor inhibitor like enzalutamide, apalutamide or darolutamide. Those you should get about five to six months in that case. You could give those patients chemotherapy. They could get about seven to eight months of PFS in that case.
You could give those patients PLUVICTO, and while there is no perfect exact PLUVICTO population to do like for like, you can merge between the two different PLUVICTO populations, basically come up with about 9 months PFS for PLUVICTO in that population. PLUVICTO is obviously an incredibly successful and helpful drug for patients in the prostate cancer setting.
It has its own set of distribution challenges, its own set of toxicity challenges. This is an all-oral regimen that, in theory, is going to be better tolerated than any of the things that I just rattled off. If you have anything approaching a double-digit PFS, you not only have better PFS than all those other options, you also have a drug, like I said, or a regimen that is all oral and well-tolerated. So it is a no-brainer that that would be clinically meaningful.
Okay. Maybe some people are concerned that if Pfizer shows extremely positive results, let us say 0.6 hazard ratio, which is not unrealistic because they showed 0.5 in phase II, that it raises the bar for rinzimetostat. What is your take on that?
I think that would be a wonderful problem to have. I hope that they can drive that hazard ratio as low as possible because what it means is a better therapeutic option for patients. Ultimately, it means that rinzimetostat's going to be able to do the same thing, if not even better. There are two things we should talk about there.
One is just the like for like comparison of rinzimetostat with our regimen with mevrometostat, Pfizer's regimen. I mentioned earlier, as you just look at just back to basics of drug development 101 and look at the pharmacokinetics of the two drugs. They have about a four or five-hour half-life for mevrometostat. We have a 20-hour half-life for rinzimetostat. The two drugs have fairly equal potency.
What is going to come down at the end of the day, what's going to matter as a difference between the two is the half-life. That's one component. The second component is the other part of the combination regimen. Pfizer, of course, is combining their drug with their AR inhibitor, enzalutamide. Enzalutamide is a great drug.
At the end of the day, though, enzalutamide is a CYP inducer, so it will push down the exposure of other drugs you combine with it. That plus the relatively short half-life of mevrometostat is why Pfizer is dosing 875 mgs BID in the phase III study, almost 1.8 g of drug per day. That leads to Cmax-driven toxicity.
That is not something that we face to the same extent with rinzimetostat because, of course, we're dosing 400 milligrams once a day because while the two drugs are equipotent, we have that much longer half-life. We also don't have a DDI with darolutamide because darolutamide is not a CYP inducer.
On top of all of that, if you stack rank darolutamide and enzalutamide right next to each other, what you're going to see is efficacy of those two AR inhibitors is the same, but darolutamide's got better safety. That's widely acknowledged amongst all the physicians. All of that kind of goes in the favor of the rinzimetostat-darolutamide combination that we're studying. If Pfizer can get a phenomenal hazard ratio with mevrometostat plus enzalutamide, we are cheering them on because we should be able to do that and better.
Okay.
The second piece is, right now we've talked a lot about post-abiraterone CRPC.
Yeah.
As folks know, Pfizer's got a second study and a third phase III study ongoing, including the third phase III is in castration-sensitive prostate cancer. The lower you can drive that hazard ratio here in the later line, the better it's going to bode for de-risking the other opportunities for Pfizer and for us.
Yeah. MEVPRO-2 is an interesting trial because they don't even have a chemo arm there. Maybe if MEVPRO-1 is positive, what are the implications of that trial to the different settings, especially MEVPRO-2, which actually should be reading out soon as well?
Yeah. That's an interesting thing because as part of the Q2 update they gave where they talked obviously quite a bit about MEVPRO-1, they also mentioned that the MEVPRO-2 phase III readout, according to them, is coming within 12 months of that Q2 call. I think the part that maybe went underappreciated by folks there is the clinical and the scientific PTS of MEVPRO-2 is even higher than MEVPRO-1, if you think about just the populations in which they're being studied and the fact that the control arm in MEVPRO-2 is enzalutamide alone.
There is no physician's choice. There's no chemotherapy that's part of that control arm. You don't have to go through all these analyses of what percent of the patients are going to get chemotherapy versus enzalutamide in the control arm. It's all enzalutamide in the control arm.
If you believe that this PRC2 mechanism on top of an AR inhibitor actually adds something and is synergistic, the likelihood that MEVPRO-2 is positive is quite high. The hard part of MEVPRO-2 was just that's in a population that's known as treatment-naive CRPC, and one of the challenges of that population is it's hard to find those patients, certainly in the U.S. these days.
In other words, the real difficulty of that trial was can you enroll that trial successfully? The fact that Pfizer has said that they'll have the phase III readout for that trial in 12 months implies that they have been able to enroll that trial successfully. That means that the chances are you're going to see a positive MEVPRO-2 study whenever that comes out, assuming that that's next year according to the timelines that they talked about.
MEVPRO-1 helps de-risk MEVPRO-2. The two together obviously help de-risk the CSPC study in the even earlier line. Back to your earlier point, the more de-risking of the mechanism you can have, the lower the hazard ratios you can have. All of it is very good for this class and ultimately for patients.
I think, Prakhar, one of the things is there's been a tremendous amount of evidence at this point generated from Pfizer, both in single-arm setting as well as randomized data setting. You have a lot of evidence from ORIC at this point in two different single-arm settings within CRPC, all of it pointing to the synergy of a PRC2 inhibitor on top of an AR inhibitor.
I think the one challenge for folks to wrap their minds around thus far, which is a completely valid critique, has been that PRC2 inhibitors don't, on their own, have profound single-agent activity. Really where you see the synergy is by putting them.
They're epigenetic modifiers, and when you put them together with AR inhibitors, you're seeing this very strong synergy. That type of a mechanism of action, obviously folks want to see more and more randomized data, and that's why as you start to see this cadence of randomized phase III readouts, it'll be very important for just continuing to de-risk this mechanism.
Okay. You have guided to a program update for rinzimetostat later this year, so what will that entail?
Yeah. As you know, we gave our guidance earlier this year, and we were very deliberate, very intentional on how we described it as a program update. That could constitute a number of different things. That could be just an update on HIMALAYA-1 study on how things are going and where we are. Two, it could be our thoughts on a potential second phase III study for prostate cancer.
Or it could include some additional data from some of the data we presented earlier this year. So it's a little bit TBD on that, but that doesn't automatically mean it will include data. We'll kind of see what we want to do in the second half of this year. One point we did think we'd provide some color on MEVPRO-1, but now we don't know when that's actually coming out. Again, we'll have to wait and see what makes sense.
Okay. Regarding your own phase III, HIMALAYA-1, any similarities or any differences versus MEVPRO-1? Or cap and chemo arm performance there to make sure that the control arm behaves in a reasonable benchmark?
Yeah. There's not a lot of differences in the design between the two different studies. They're both in the castration-resistant prostate cancer setting. They're both in patients who had all experienced prior abiraterone and who could have had up to one prior line of chemotherapy. All of the inclusion/exclusion criteria are quite similar in that sense.
I think one, if you want to now go down the minor differences route, we don't allow ECOG status two in our phase III study. I believe Pfizer did allow ECOG status two. Then what you called out, which is it does not seem that they've got a cap in their protocol around the physician's choice in the control arm. In other words, it could skew either direction.
In our case, we have capped the control arm at 60% for either of the choices, meaning whether it's AR switch or chemotherapy, neither one is going to go higher than 60%. That way you know that the two options in the control arm, as classes, are essentially going to be between 40% and 60%, and you won't get a skew one way or the other. That's about it.
Okay. What are your plans outside of this trial?
A lot of plans outside of this trial. The analogy is sort of the duck looking calm on the water while they're paddling furiously underneath. That's what it feels like internally because while everybody sits around and debates Pfizer trial stats, we've got a company to run, and we've got trials to get going. HIMALAYA-1, obviously we just started.
We want to make sure that that gets going incredibly well. That's a global study at hundreds of sites around the world in 2 dozen countries. There's a lot that's focused on that. But at the same time, we're actively thinking about what is going to be HIMALAYA-2, what's going to be HIMALAYA-3. Because we want to get at least one of those started next year in a different setting within prostate cancer.
Obviously, there's a lot of contenders in terms of what that might be. We certainly like castration-resistant prostate cancer in the post-AR inhibitor setting, which is a second population that we've been studying and on which we presented data earlier this year. That obviously our data in that space looks quite promising, and we've gotten to continue to see the follow-up of those data. If that continues to look good with longer and longer follow-up, that might be a space that we would go pursue.
There's currently not a MEVPRO study, a phase III study in that particular setting. In castration-sensitive prostate cancer, which I talked about earlier, as large as these indications are. First of all, the CRPC indications on their own are multi-billion dollar markets in the U.S. alone, any one of them. But even larger than that is the CSPC indication.
The more data points that we can get from ourselves and from others to just continue to de-risk the mechanism, the more confidence we would have going into an earlier line setting like CSPC. Those are all under active consideration as to what would be HIMALAYA-2 and what would be HIMALAYA-3. Certainly one of those is we intend to get started next year.
Maybe that's a good segue to the commercial side. How big is the opportunity in, let's say, in the setting that HIMALAYA-1 is testing in the U.S. and ex-U.S., and maybe even if we go beyond that and just, let's say, a setting where MEVPRO-2 is being tested, how many addressable patient population is there?
Yeah. When you look at MEVPRO-1, same population we're studying in HIMALAYA-1. In the U.S., that's around 17,000 patients. If you look at any duration, assume a 14-month duration, and the average price for an AR inhibitor, that's about a $3.5 billion addressable market in the U.S. alone. If you look at any analogs for prostate cancer, the ex-U.S. market is pretty much the same as the U.S.
Call it globally, that's a TAM of about $7 billion. The second indication that we're considering is the post-AR inhibitor. That's about 20,000 patients. That also is about a total market of about $7 billion globally. Those are huge markets just in the CRPC setting. As you move up to the CSPC setting, then it's just next level.
Obviously, you got about 33,000 patients in where MEVPRO-3 is playing today, and the duration for those studies, I mean, XTANDI alone, AR inhibitors alone, which is the control arm, is doing about 48 months. That is a multi-billion dollar opportunity as you get earlier lines as well.
Right. One question on commercial. We always hear from investors that abiraterone usage is declining in the U.S. ex-U.S., we don't know. What's your feedback been?
Yeah. I love that question because the analogy that I always tell people is it's not a shrinking ice cube, it's a shrinking glacier. What I mean by that is if you just look at the scripts for the ARPIs. The ARPIs are the 800 or 8,000-pound gorilla, if you want to call it that, in prostate cancer therapy today. Abiraterone and the three big AR inhibitors.
Those collectively have done phenomenally well for patients in prostate cancer. You would be hard-pressed to find anybody with prostate cancer in the U.S. who has not had one of those therapies. Half of the scripts are abiraterone, and the other half are the other three AR inhibitors. That 50% that is abiraterone has been very steady for the last five years.
I think what people are referencing is that increasingly the AR inhibitor part of the pie is growing over the course of time that you've seen. Abby is still one of the preferred agents, and that's as evidenced by the fact that it's 50% of the scripts because it's been well-used. Physicians are comfortable dosing Abby. There's also not only the comfort level, but there's also plenty of evidence, the Kalof paper and others, that suggest that AR inhibitor after abiraterone does better than the other way around of AR inhibitor and then abiraterone.
For all those reasons, Abby continues to get a lot of scripts. Even if that 50% part of the pie starts to shrink slowly over time, it is still such an enormous part of the treatment paradigm today that it makes all the sense in the world to go after that population.
We should also talk about enosartib, which is the-
We should definitely talk about enosartib.
second child that never gets any attention. Maybe, on the ESMO update, just talk about what are you going to present there. What should be the investor expectations?
Yeah. At ESMO, we do have a poster with the atypical patient population. We're super excited about this program, I'd say. What we said we'd have is about 20 - 25 patients worth of data. We'll obviously have systemic response, CNS response, safety, tolerability, as well as durability. When we look at the competitive landscape here, we'd say the benchmark kind of resides from a systemic response rate, resides in that low to mid 60% response rate.
The second thing is CNS response rate. We think that's equally important. The interesting thing about the competitive landscape, there seems to be a big gap between the systemic response rate and the CNS response rate.
The reason that's important is if you're truly a CNS active drug, there should be some difference, but it shouldn't be 20 or 30 points, what we're seeing with some of these competitors as well. The other thing we think people should focus on is the off-target toxicities. A lot of these drugs obviously have on-target toxicities, which you'd expect, but they're also plagued with some off-target toxicities. Excuse me, such as QTc prolongation, elevated liver enzymes, and anemia.
That's something else. It's really when we look at the benchmarks, we look at across the three areas, the systemic response rate again, which is in the mid to low 60s, CNS response rate, and then on the off-target toxicities as well. We're super excited about that program. You look at the patient population there in the U.S. alone, it's about 6,000 patients alone. We think that TAM for atypicals alone is about $2.5 billion in the U.S. alone.
Okay. For the EGFR exon 20 setting, phase III frontline, I guess what combination—I guess we have an option of monotherapy, or you can go after a chemo combo. How are you thinking about it internally, and what will drive that decision? We have some competitor updates coming as well from Erivedge as well as Cullinan's compound, which tested in chemo combo. Maybe just talk about that.
Yeah. Prakhar, you know us pretty well. We're very pragmatic, very data-driven. As you mentioned, we're exploring all three options. We're exploring the monotherapy, we're exploring the combination with chemo, and lastly, we're doing the combination with amivantamab. We're the only ones that are doing that. We will be data-driven.
Obviously, the benchmarks will be obviously influenced by the data we see from Cullinan in combination with chemo, with their drug, as well as the Erivedge data that I guess is expected at some point this year as well. But we've always said in order for us to move forward to a phase III program, we need to have a differentiated profile. The key area for us is really the CNS aspect of it.
The reason that's so important when you think about these patient populations is these patients present with about 35%, 40% of these patients present with baseline brain mets, and it's also the point of first progression in the number of these patients as well. If you look at historical data sets like mobocertinib, even with amivantamab in combination with chemo, you see this big divergence in the PFS benefit of patients with and without brain mets. If you have a CNS active drug, that should translate into a longer PFS benefit as well.
Okay. You have two assets, rinzimetostat and enosartib, big undertaking. I guess, how are you thinking about the different strategic options for both assets to maximize the value for the company?
Very carefully. Look, I think the good news is prostate cancer and lung cancer are key areas of focus for lots of large pharmas. Prostate is obviously massive indications, as we've talked about. So, there's a lot of ways that we can think about a potential BD collaboration at the right time, assuming it's the right terms. But look, we understand the value of rinzimetostat and what that is eventually going to be.
So we'll be very thoughtful about how we think about a BD collaboration there as well, in order to maintain an equal partnership status. In case of enosartib, look, for anybody that's got a targeted therapy franchise amongst the pharmas, strategically, it makes all the sense in the world to keep thinking about adding more pieces of that targeted therapy pie.
So, we'll have all the right discussions at the right time and keep our minds open. One thing that we're very pragmatic about, as Dominic mentioned, is we never are sort of just path dependent and dogmatic about this program. Program X must be partner, program Y never partner, things like that, I think.
So we'll always entertain conversations and just think about what's the right way to continue to de-risk the programs, what's the right way to continue funding the programs, and that funding doesn't just have to come from the equity markets obviously.
We can think about creative ways, either on the royalty side of things, we can think about creative partnerships with pharmas. We can think about other sources of capital that are just more non-traditional as we think about getting the right set of capital to help us do everything we want to do for both programs.
Okay, and maybe last question, the current cash on hand, what does that cover?
Yeah, we ended the second quarter with $388 million in cash and investments. That gives us cash runway into the second half of 2028. That is a fully burdened number. That does include, obviously, HIMALAYA-1. That also assumes we're starting a phase III study for enosartib in the first half of next year. And the important thing here is that cash runway takes us past the expected top-line data readout from HIMALAYA-1, which is in the first half of 2028.
All right. I think that's all the time we have, but thank you, Jacob and Dominic, for a great conversation.
Thanks for having us.