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, Jacob Chacko and Dominic Piscitelli. Jacob is CEO and Dominic, CFO at ORIC. Thanks so much for joining us today. We're gonna do a fireside chat format. So, for those who are new to this story, maybe give a one-minute intro to ORIC.
Sounds good. Thanks for having us, Maury. So ORIC stands for Overcoming Resistance in Cancer, which, in a nutshell, encompasses the mission of the company. We have three different small molecules that are in phase I studies right now. One of those is for EGFR exon 20 and non-small cell lung cancer.
Another is for PRC2, which is a target that is highly relevant to prostate cancer, and then finally, a CD73 inhibitor, which is relevant to multiple myeloma, at least the way that we're studying it. A couple unique things about the way we've put together the pipeline. One is that it's sourced from both our internal discovery as well as opportunistic business development.
I think it's pretty rare in oncology these days to find pipelines that are from both of those sources, which really gives us a chance to be, very focused on the target. So, we start with the target first and figure out, you know, where there's, where there's areas of high unmet need. Second thing is, just the team's expertise. So, the team's got a lot of deep expertise in lung, prostate, and breast. Those are, generally speaking, the tumor types that we are most focused on, and then, as I mentioned, small molecules.
Got it. Great intro, and, there's a lot of focus on your exon 20 oral ORIC-114 recently, since you had data at ESMO, which looked encouraging. Although there are caveats with cross-trial comparisons, can you contextualize the data versus competitor programs and approved agents and talk about how ORIC-114 profile is differentiated?
Sure thing. I think, Maury, targeted therapies in lung cancer are, at this point, well understood. The biology is easy to understand, that once you've got a target, it is a validated oncogenic driver. And so, at that point, it's really a question about getting a selective molecule and importantly, getting a molecule that is brain-penetrant. So, as you look at the EGFR exon 20 space, the number one critique you'll hear from investors looking at the space is that it's a crowded space. I think that's a first-order analysis.
I think for those who do a second-order analysis and really understand the nuances of the programs will quickly come to understand that nearly every single one of those programs is not brain-penetrant. And the problem with that is that 35% of patients at initial presentation have brain metastases.
Every patient is gonna eventually develop brain metastases if they're on a drug for long enough, and so you need a drug that is brain-penetrant. So in the data that we presented at ESMO recently, we started to demonstrate that we have a brain-penetrant drug, while others obviously have not been able to show that because they haven't been designed for that brain penetrance.
And so, while early, we were highly encouraged by the data that we showed, including the first-ever documented complete response in the brain for a patient that was dosed with an exon 20 inhibitor, and that's a patient who had not had previous therapy, either surgery or radiation, for that brain metastasis. So literally just the small molecule drug getting in and doing the job it's supposed to do.
That patient also, by the way, had complete response systemically in their lungs, and it's a patient who had previously had chemotherapy and progressed, previously had amivantamab, now the only marketed therapy for exon 20, and progressed.
Got it. Yeah, good, great summary of the ESMO update. And it's important because about a third of patients have brain metastases at baseline, at initial presentation, and yet many of the studies in this space only enroll patients if the CNS metastases were treated and stable versus enrolling untreated active metastases. Can you help me better understand inclusion criteria for CNS metastases in your study versus some of the competitors out there, since there are some critical variables involved that could impact interpretation of whether the drug is CNS active or not?
Absolutely. So you sort of nailed it right in your introductory comments, Maury. So, as you look at the EGFR exon 20 space, nearly every single other drug in the space severely limits the enrollment into their studies on two main criteria. Number one, they don't take patients who have had a prior EGFR exon 20 inhibitor. We do. Number two, on the CNS mets front, nearly every other drug excludes patients from the study who have not already been treated for their brain mets.
So, in other words, the patients have to have had surgery or radiation before coming onto those studies. We don't require that. So, we will take patients onto the study who have brain metastases that have not been treated with either surgery or radiation, and that's a big, big difference.
Every now and then, you'll get one of those competitor programs that will highlight an example of a patient where they saw some reduction in a brain metastasis. What they are not as open about is the fact that those patients had already had surgery or radiation for that brain metastasis. We're one of, like I said, one of the only drugs in the space that will take patients with untreated brain mets.
Got it. And maybe talk about unmet need in this space, too. We've spoken with Kael Walls, who say that they use stereotactic radiation to proactively control the disease prior to systemic therapy. So, what's the unmet need, and why does it make sense to start with the CNS treatment upfront?
Totally. So stereotactic radiation is used right now in the space because the other drugs don't have brain penetrance. So, if you don't have a drug that can handle the brain metastases, the only option you've got as a clinician treating your patient is, like I said, either surgery or radiation.
So, you can use stereotactic radiation, but if you, if given the choice between doing that or giving a small molecule oral drug that has brain penetrance and can treat brain metastases, 10 times out of 10, the providers are gonna take a drug that or give a drug that can handle brain metastases. The analogy I would use, it's a crude analogy, but I would tell you, if you think of brain metastases as cockroaches, okay? So, bear with me for a second. You know, the...
Here's the issue. So, if you've got cockroaches, let's say if there's... You can either stamp them out physically, which is what stereotactic radiation is doing, or you can fumigate, which is what a small molecule is able to do. So, think about cockroaches. The issue is if there's too many of them, so if there's too many brain metastases, stereotactic radiation is not a helpful modality. You really can't use it if there's too many.
Second, cockroaches, you got to be able to see them to stamp them out. So same thing with stereotactic radiation. Keep in mind that a lot of these patients have micrometastases that you literally cannot see on imaging. So stereotactic radiation is not going to be good for those patients, whereas a small molecule oral drug is going to be.
And then the third part of my rather crude analogy is, if stereotactic radiation, so stomping on a brain metastasis is going to lead to side effects for the patients as well. You're stomping on the brain, and that's not the case with a small molecule oral drug. So, I think, like I said, 10 times out of 10, if you've got the choice between a small molecule oral drug, you're going to do that rather than stereotactic radiation.
Yeah. Yeah, it's an interesting analogy and, yeah, definitely fumigate rather than...
Yeah.
S tomping on them, for sure. Makes sense. And let's see. And how do you anticipate current standard of care is going to be, will impact enrollment for a potential pivotal study with 114, that's aiming to show benefit in patients with active brain metastases as a baseline?
Yeah, you're referencing, I assume, the PAPILLON study from amivantamab. So PAPILLON essentially confirmed amivantamab's accelerated approval, so I think everybody is assuming at this point that amivantamab will be approved for the front line. Importantly, again, I will note, just as in my opening comments, amivantamab and the PAPILLON confirmatory study excluded patients with active brain mets. So, unless they had been treated with surgery or radiation, they could not come onto that study.
Secondly, amivantamab, even with that criteria of excluding patients with active brain mets, if you dig into the New England Journal of Medicine paper that J&J put out concurrent with their updated ESMO for that PAPILLON study, it'll show you that the patients with brain mets had worse outcomes, dramatically worse outcomes, than the ones without brain mets.
So, as we think about standard of care and how that shifts, amivantamab is likely going to move in the front line. But for those patients with brain mets, it's still an issue. And so, for us, we in our ESMO update, like I said, showed activity in the brain.
We also showed activity post-amivantamab, and right now, we're the only drug that's been able to show those two things. And so, I think it sets us up much better than other drugs in the space, in this new paradigm of amivantamab moving to the front line. Sets us up to be the obviously de facto drug of choice to come right after amivantamab. And then, ultimately, you look, the ...
We made a case at ESMO for why we can come after amivantamab, we can come in combo with amivantamab, cause, again, it doesn't have that brain penetrance. And then finally, you know, the bigger opportunity, which we're very focused on, is that we come instead of amivantamab. So eventually, we move into that front line, and we displace amivantamab.
Yeah. Maybe talk more about that, just getting into treatment-naive patients and how you could enroll those studies into the dose optimization phase of your study. And do you envision any, any challenges to enrolling these patients?
Yeah. So, one of the questions we got from investors after ESMO, after our ESMO update, was that, you know, the data are good, but with amivantamab moving in the front line, can we enroll patients who are naive to a prior exon 20 inhibitor?
The answer is absolutely yes, we can. And the reason comes back to, I'll sound like a broken record, it comes back to the brain penetrance of the drug, of ORIC-114, and the safety profile of the drug because it, it looked like it had a very well-tolerated safety profile. And I can tell you from the investigator perspective, we were very pleased that after the ESMO update, we got a lot of investigators asking to be part of the trial and asking to put patients on who are exon 20 naive.
In fact, we have investigators asking to put patients on who are treatment naive, who have not even had chemotherapy. That's something we'll have to figure out how we navigate at this point with a drug that, you know, is obviously still investigational, but quite a bit of interest from investigators in both of those settings. So, treatment naive, fully treatment naive, and then also exon 20 inhibitor naive. I'm very confident we'll be able to enroll those populations.
Got it. And would these patients have baseline CNS mets, do you anticipate? Would there be...
I would anticipate with and without. So, we'll, we'll continue to enroll patients who have baseline mets. We'll also enroll patients who don't have baseline mets. In that very first update at ESMO, what you'll have noticed, and others will have noticed, is that 86% of the patients who enrolled in the trial had brain metastases at baseline.
That is dramatically higher than any other drug has enrolled. So, the others, the other drugs very consistently enroll about 35% of their patients at baseline have had brain mets, which is exactly right on top of what the epidemiology would suggest, because 35% of these patients have brain mets at baseline. The reason why we were dramatically higher than that at 86% is obviously because clinicians believe that the drug is brain penetrant.
All of that being said, we fully intend that in future studies, we will enroll both populations with and without brain mets because this is a drug that is good for all of those patients. So one thing I want to be really clear on is the drug is clearly good for patients who have brain mets, mets at baseline.
But there's two other groups that it's good for as well, which is there's a second group, which is patients who have brain mets, and nobody knows they have brain mets because, like I said, the mets are too small to show up on imaging and too small to cause symptoms in the patients. That group, clinicians also want to give a drug that is brain penetrant because it'll help treat those brain mets that nobody is aware are there.
And then there's a third group, which is the ones that don't have brain mets, but like I said, will develop brain mets eventually on these other agents that don't have brain, brain penetrance. And so, it is now dogma. Look, I was at Ignyta before, before ORIC, and at Ignyta, we developed a drug that is now approved, which was a brain-penetrant ROS inhibitor.
Back then, five, six, seven years ago, there was a debate about whether you wanted a drug for the lung, for lung cancer or targeted therapy to be brain penetrant or not. Today, it's dogma amongst clinicians that the drug needs to be brain penetrant. And so, I think for all patients, whether they have brain mets or not, the drug ought to highly benefit them.
Where that ought to show up eventually is in the PFS. So, for example, if you look at alectinib in ALK non-small cell lung cancer, it's the... it was the first brain-penetrant, selective ALK inhibitor. Even though it was third to market, alectinib is now close to a $2 billion a year drug, and it's taken the vast majority of the share in that space. The reason is, if you, if you go dig into the dat, the response rates are not dramatically different for alectinib versus the other, the first and the second drug that were approved in the space. The PFS is dramatically different, and where that comes from is the fact that the drug is brain-penetrant.
Got it. Yeah, it makes a lot of sense, and I think those are good reference examples. Maybe talk about how you envision use of a CNS-penetrant drug in the treatment paradigm. Would it be in second-line post-amivantamab plus chemo or frontline potentially in combo with amivantamab? And anything more you can say about how you're thinking about a combo strategy.
Yeah, the answer to your question is yes. It's, it's really both settings. So, you know, just in the spirit of just normal walk before you run drug development, obviously we'll be starting in a second-line setting, not post-amivantamab, but really post-chemotherapy. So, with exon 20 inhibitor-naive patients, but eventually the goal would be to move into the frontline, into a treatment-naive setting. And in that treatment-naive setting, we... L ike I said, we can either go it alone, as a single agent or think about combining with amivantamab.
Got it. Based on the data from the phase 1b, how does the safety profile for 114 compare to other current approved and development-stage drugs?
Really, really well, is the short answer. So there's basically two aspects of safety you have to think about with an EGFR exon 20 inhibitor. One is avoiding EGFR wild-type toxicities, so that's essentially rash and GI toxicities, and we showed a profile that, on that front, looks as good or better than the competitors.
And then the second piece, which you don't hear a lot about from competitors, is off-target toxicities. What I mean you don't hear a lot about is the other, the competitors have a lot of off-target toxicities because they've got dirty kinome trees. I think we showed, and have many times said at ESMO and, prior to that, have a very clean kinome tree with ORIC-114. So, we did not expect to see significant off-target toxicities. We did not see significant off-target toxicities.
With competitors, you will see things like bilirubin increased, you'll see liver enzyme increased, you'll see CPK increase, you'll see anemia, so a lot of off-target toxicities that are problematic, and we didn't see any of that with 114.
Got it. And we've been asked recently about Arvinas's furmonertinib, which is mostly being developed in China and was relatively under the radar. It was designed for EGFR T790M mutations and not in the EGFR exon 20. How do you view this drug relative to yours?
Yeah, look, I think furmonertinib is a very good drug for T790M, but like you said, it's been repurposed into EGFR exon 20 at 2x or 3x the dose that they're approved for T790M. That leads to a lot of toxicities that are, you know, I think, somewhat problematic. And then, again, back to my broken record or soapbox, or whatever you wanna call it, is it, they have not shown brain penetrance or brain activity in an exon 20 population, and that's a big liability again.
Got it. And you also showed some data on HER2 exon 20. Maybe talk briefly about that and, and how you could see this competing within HER2.
Sure. Yeah, we've talked a lot about EGFR exon 20 as an opportunity for ORIC-114, and I'll tell you, EGFR exon 20 alone is a population that is bigger than ROS1, it's bigger than RET. And so that population alone would be worth us pursuing. But the other thing that we showed at ESMO, in fact, even more responses in HER2 exon 20, with the, with this drug, ORIC-114.
HER2 exon 20 is a space that has Enhertu approved, as you mentioned, Enhertu has not demonstrated brain activity in that HER2 exon 20 population, and the other thing it, it has demonstrated is a lot of toxicity. And so, there's a lot of Grade 3 toxicity from Enhertu in that HER2 exon 20 population.
In fact, Enhertu has a greater rate of interstitial lung disease than we have total Grade Threes. And so, I think there's a big opportunity there for this drug in HER2 exon 20 as well, and it's one that we're certainly excited about pursuing. And, you know, so we've talked about EGFR exon 20 a lot. We've talked a little bit about HER2 exon 20.
The piece that we haven't talked about is atypical EGFR mutations, and that's one where I would tell people to stay tuned because at ESMO, we presented preclinical data that showed that ORIC-114 is even more potent against atypical EGFR mutations than we are against EGFR exon 20 or HER2 exon 20.
So, the fact that we've already shown good responses in EGFR exon 20 and HER2 exon 20 ought to be translatable, we think, to atypicals, and that's a population that we have just started to enroll. It's a population that is bigger than EGFR exon 20. When you start to add up these three populations, you know, EGFR exon 20, HER2 exon 20, and the atypicals, you now are looking at a population that is larger than ALK and RET combined. And so that's where we think that there is a lot of opportunity for ORIC-114.
Got it. Makes sense. And you mentioned first half of 2025 for dose expansion completion. Could we see longer follow-up from the dose escalation cohorts earlier in 2024?
Potentially. I think for now, we're just kind of, focused on the next public milestone as being first half 2025.
Got it. And, you've got two other upcoming milestones, including ASH data for 533, and then, early 2024 for 944 data. Maybe set expectations for the number of patients, dose cohorts, and measures you expect to report for each of these programs.
Yeah, sure. I'll take that, Maury Raycroft. I guess short answer is this is again, this is dose escalation data. This is the first in-human data that we'll present. We said about 15 patients at clinically relevant doses for both of these, both of those studies, the ORIC-533 and ORIC-944. And again, we'll have ORIC-533 data at ASH and ORIC-944 in Q1 of 2024. Being its early data, this will be focused on safety, PK, PD, and any early anti-tumor activity.
Got it. Makes sense. And you've got a differentiated strategy with your CD73 inhibitor 533 in multiple myeloma. Maybe talk about the rationale there and execution.
Yeah. Yeah, we definitely do. As you know, Maury, most of the, most of the competitors with CD73 inhibitors are looking at combination strategies with IO agents and solid tumors. We, for a number of reasons, didn't think that was the best path forward for us. For one, we don't have a PD-1. The second reason, the results in combination with IO agents in solid tumors has been mixed. And third, those studies are typically large, expensive studies for a small biotech to kind of take on. So, we kind of looked for a different alternative.
This is back when we were a private company. We had a top shareholder that has known Ken Anderson from Dana-Farber for, you know, 20-plus years. Ken is kinda, you know, known as the godfather of multiple myeloma. He knows the space well.
He was exploring CD73 inhibition in multiple myeloma. So we actually entered into a collaboration agreement with Ken, and basically, he had a patient-derived ex vivo patient assay, and in this assay, we saw three things.
We saw reversal of immunosuppression, we saw good T cell activation, and we saw lysis. If you look at the same assay, and you look at the current approved standard of approved drugs in multiple myeloma, we looked favorable to those drugs as a single agent, so that's kinda what got us excited, and we put this into a phase 1b study in multiple myeloma, and again, we'll have data next month at ASH.
Got it. And maybe talk about the relationship with Pfizer for this program, and what would you want to show with 533 in order to opt-in for...
Yeah. So, late last year, we did enter into kinda two, two agreements with Pfizer. They made a $25 million investment in ORIC at a significant premium. And the second part of that is actually probably more interesting. We signed a collaboration agreement with them for a phase 2 study. The phase 2 study would be a combination of ORIC-533 plus their multiple myeloma drug, elranatamab, which is currently approved.
And the beauty of this is we gave up no economics. It doesn't restrict us from doing anything with anybody else. Basically, we would use their infrastructure. They would operationalize the study for us and supply the drug. So that's basically the leverage there, and again, this is totally at our discretion if we wanted to move forward.
As we think about what would be—what it would take to move forward, is obviously a couple things here. There's obviously strong biological rationale for the combination. Second thing is safety. When you think about multiple myeloma, it's all about, you know, combining drugs. So having a drug with a clean safety profile is key, and then some level of clinical activity. Now, that could be in the form of responses, that could be in the form of a decrease in paraprotein in the blood or the urine, so that's kinda the criteria there.
Got it. Makes sense. Wanted to talk about your PRC2 inhibitor 944, where there's growing interest with that program, also as it relates to Pfizer's program and study. It's in prostate cancer. It's a challenging population with tumor heterogeneity. How should we think about 944's potential as a single agent in enzalutamide-resistant settings, and what kind of biomarker data are you collecting from these patients?
Sure. So as with all our programs, we're starting ORIC-944 as a single agent in dose escalation studies. The promise here, as I think you alluded to in your commentary, is eventually to combine, so to combine with an AR modulator, and that's the data that Pfizer showed with their PRC2 inhibitor in combo with an AR modulator that was so profound earlier this year, and they'll have an update on that next year.
As a single agent, we're looking at an all-comer population, and the goal really is to find an RP2D and establish a profile where we can see what other PRC2 inhibitors thus far haven't been able to prove, which is literally just good drug properties. So, if you look at the PRC2 inhibitor space, they all are plagued by short half-life.
So, you know, you're talking one-to-three-hour half-lives, CYP liabilities, where they get autoinduction. You'll get phenomena like dose-dependent decreases in exposure. Literally, the more drug you give, the less exposure you get. And so, these are all problems, obviously. And this drug was one that we, excuse me, acquired from Mirati. Mirati made the drug and essentially optimized for the drug properties and optimized for the in vivo activity, and we think that it's a drug that's got better drug properties than what's come before it. So, from the phase 1 study, we're primarily looking to see the things I just mentioned.
Obviously, any single-agent activity would also be quite welcome, but folks have to sort of keep in mind, there's never been a PRC2 inhibitor, including Pfizer's, that has shown single-agent activity in prostate cancer. Really, the biology would suggest that you ought to combine with an AR modulator to show the profound activity. That's what Pfizer has shown right now.
Got it. And can you talk about Pfizer's ongoing open-label, randomized, controlled study, which is also expected to read out in 2024? How should we contextualise your initial 944 update relative to Pfizer's 1497 monotherapy data, and then alongside their controlled combo data?
Yeah, so, there's a lot in your question there, Maury. I try to be brief here is really just Pfizer earlier this year presented a data set, which, while it was single arm, was profound in what they showed. So, they combined their PRC2 inhibitor in combo with enzalutamide, an AR modulator, and in a setting where they would have otherwise expected to see about 5 months of radiographic PFS, they got 17 months of radiographic PFS.
In a different setting, different population, where you would've expected to see two to three months of radiographic PFS, they got 8.7 months of radiographic PFS. So, in both settings, they're getting dramatically higher radiographic PFS than what they'd otherwise expect in combo.
Now, they haven't presented a lot of monotherapy data, so for our own update, like I said earlier in my commentary, you know, the goal is really to show the good drug properties of ORIC-944, the combinability of ORIC-944, and then shortly thereafter, to get started on combo studies with ORIC-944, so combos with an AR modulator. There's obviously two other billion-dollar-plus AR modulators that are out there, Janssen with apalutamide, and then Bayer with darolutamide.
Both have the exact same mechanism of action as enzalutamide from Pfizer, and you know, those would both be you know, fantastic combo agents for us to think about combining with ORIC-944 in that population.
Makes sense. Do you have any preliminary evidence that 944 could have synergy or added benefit with other AR modulators?
Yes, we do. I'll say that we, we've already obviously studied this preclinically, I should say, with a big caveat. Preclinically, we've looked at it, and we do have that evidence. Pfizer has also, by the way, shown evidence preclinically of the mechanistic rationale, the synergy of combining a PRC2 inhibitor with an AR modulator.
Like I said, we have our own evidence showing that as well, so we, we believe it. We believe the mechanism that they've shown, and more importantly, they've now shown clinically that you get that synergy with an AR modulator combined with a PRC2 inhibitor. So, we are believers in the mechanism.
Got it. And if successful, what are next steps for 944 , and what patient populations would you pursue initially, and could there be a biomarker-based strategy?
Yeah, I think initially, you know, the good news of this is with the Pfizer data was a unselected population. They, they took all comers. They weren't selecting, and mechanistically, that makes sense, and we would probably pursue the same type of strategy. So, so if the population they were most focused on and their... You know, you referenced it, their open-label randomized study, and I really emphasize the open-label nature of that.
So, it's a randomized study, but it's open label. They, they know how it's going, so when they are talking about this program and their excitement for this program, I think people ought to pay attention. In some ways, it's hiding in plain sight, in front of Wall Street.
What I'd say is, the combinability of an AR modulator with a PRC2 inhibitor in that prostate population, which is post-abiraterone, but pre a second-gen AR modulator, so pre-enzalutamide, pre-apalutamide, pre-darolutamide. If you combine with one of those second-gen AR modulators, I think that's the case that they're making, and that's a population that we'd be most focused on.
First things first, we have to finish our single-agent dose escalation study and prove out the things that I just mentioned to you, but assuming that we can prove that we have those good drug properties and the combinability, we would think about combining with one of those second-gen AR modulators next year. So, we'd have to do some dose finding, obviously, in combo with those. And then, as early as 2025, we could be talking about registrational studies for this program.
Got it. Well, we're pretty much out of time. It's been a great conversation. Maybe in closing, recap your milestones ahead and what investors should be focused on.
Yeah, so the near-term milestone obviously is ASH, which is next month. We'll present the initial data for 533, followed by 944, in Q1 of next year, and then we'll have an updated phase 1b data for 114 in the first half of 2025. Thank you.
Thank you, guys. Thanks.
Thanks, Maury.