All right, welcome to this next fireside chat with ORIC Pharmaceuticals. I'm Michael Schmidt, Senior Biotech Analyst with Guggenheim, and I'm really pleased to welcome Dominic Piscitelli, CFO, and Matt Panuwat, Chief Business Officer from ORIC. Welcome, thanks for joining us.
Great, thanks for having us at the conference.
All right, exciting times for ORIC. And before we go into Q&A, Dominic, perhaps just give us a quick overview of the company and the key value drivers, and then I'll jump right in.
Sure. So ORIC Pharmaceuticals is a clinical-stage oncology company. Our name encapsulates our mission, which is to overcome resistance in cancer. Given the team that we've assembled, we really have three areas of focus, which are prostate cancer, lung cancer, and breast cancer. And again, due to the team that we've assembled, as well as the capabilities, we do have a two-prong approach to building out the pipeline. So if you look at our pipeline, it's comprised of both internally discovered programs as well as business development opportunities that we've been licensed as well. We currently have two lead programs in the clinic. The first is ORIC-114. This is a brain-penetrant EGFR/HER2 exon 20 program that we're studying in various forms of mutated non-small cell lung cancer. And the second program is ORIC-944.
This is an allosteric PRC2 inhibitor that we're studying in prostate cancer in combination with AR modulators. Looking forward, we've got a total of seven data readouts in the next 18 months or so, so pretty busy schedule ahead of us. So I'll stop there, and we can jump into the more detailed questions.
Awesome, thanks. So maybe just jumping right into ORIC-944, your PRC2 inhibitor, just again, stepping back, what is the rationale of combining this mechanism with AR antagonists in prostate cancer?
So PRC2 inhibitors have been studied in prostate cancer for many, many years. If you go back to GSK, Constellation, Epizyme, the play here is all about combinations. No one's really shown any robust single-agent activity. But again, the issue that the first-generation PRC2 inhibitors had is really short drug, poor drug property, excuse me. This could be in the form of short half, clinical half-life. They had some of these CYP autoinduction issues, poor in vitro activity, and poor in vivo activity. So those are the issues that the first generation have. Pfizer has a second-gen asset, which they've shown some pretty interesting data. They've improved upon a number of the issues that the first generation have had. So the play here is basically as you treat patients with AR inhibitors, it would have been a great treatment option for patients with prostate cancer.
Over time, these patients gain resistance. What basically happens is the prostate cancer transitioned from an AR dependent state to an AR dependent state. So with these epigenetic modifiers like ORIC-944, like mevrometastat from Pfizer, you're pushing them back to the AR dependent state and reactivating the ability of these AR inhibitors like enzalutamide, apalutamide, and daralutamide.
Okay, super. And so as you mentioned, there's a number of those out there. I think the most relevant data has been generated by the Pfizer program on their EZH2 inhibitor. We've seen some single-arm data in phase 1 data so far. They had, I think the most recent one was at ASCO last year. And then we have now randomized phase 2 data coming up at ASCO GU next week. And so first of all, in your opinion, how much validation do we already have on this class of drugs? And then what additional level of activity, I suppose, could further validate this concept as we look to some of those data readouts?
I'll start and Matt, you chime in. But I just had Pfizer put out some data back in 2023 and 2024, basically in two patient populations. The first are patients that had failed abiraterone, and then they could have seen up to one round of chemo. And the second group of patients are patients that had failed Xtandi and then got onto the combination. What they showed in the first cohort of patients, the post-abiraterone patients, this is the caveats, n=12 single-arm data, they showed a radiographic PFS of 17 months. What you typically would expect to see with the Xtandi alone in that patient population is somewhere along the lines of five months. So they saw a three- to four-X increase in radiographic PFS.
In the second cohort of patients, again, these are patients that had failed Xtandi and then got onto the combination of mevrometastat plus Xtandi, they showed a radiographic PFS of 12 months. Again, here you'd expect to see about three to four months of PFS here. So they show a three to four time increase in the radiographic PFS. So that's obviously super interesting data. The two caveats, it's single-agent data, and the second, it's relatively small N. As you mentioned, they do have some data that they're presenting on next week at ASCO GU. I think the presentation was on the 13th of February. So here they're randomizing 80 patients. These are patients that had failed abiraterone. They could have seen up to one round of chemo.
And then they're being randomized 40 patients to the Xtandi arm as the control, and the experimental arm is Xtandi plus mevrometastat. What we do know is the study is powered with a hazard ratio of 0.5. So I think that's what everybody's looking forward to see what that looks at. The key thing here is that is an open label study. So Pfizer has seen this data already. What we do know is Pfizer has already started two phase 3 studies that they announced in the second half of last year. They're referred to as MEVPRO-1 and MEVPRO-2. MEVPRO-1 is basically the patients that had failed abiraterone and then they're going on to the combination. And then they're starting an even earlier line study, which is patients that had failed ADT that are treatment naive.
So they had not seen an AR inhibitor. And then most recently, Pfizer did announce that they're starting a third phase 3 study. They did this at a conference last month in the castration-sensitive prostate cancer setting. So obviously we haven't seen the data. Pfizer has seen the data and they've decided to move forward into three large phase 3 studies. So obviously we can't comment too much on the Pfizer data since we haven't seen it, but we'll wait to see what happens next week.
Right. And so as you mentioned, they obviously saw some caveats around the phase one, but obviously the post-Abi, Enza combo was the better data set and that's what they're moving forward into phase three now. Is there a particular reason why this mechanism works better in one combination versus the other? And how does that relate to your own studies, perhaps?
I wouldn't necessarily say one is better than the other. I think it's just different patient populations because one has seen an AR inhibitor and one hasn't. But maybe you want to talk about why it could play better in earlier lines or not?
I think so. The data we'll see from Pfizer, I think as Dominic said, it's post-ARPI, it's post-abiraterone. So they are launching a phase three study in that population. We do know that. The second study will be an ARPI-naive. So they are moving essentially earlier line than the data that they have generated. And then the more recent study in the castration-sensitive is even earlier than that. So we do know they are moving forward. I think from a conceptual standpoint, it is what we've seen preclinically in the mechanistic hypothesis is that you can reverse this transition from prostate cancer cells moving into an AR-independent state. And so doing that after a tumor has already seen an ARPI is one way to do that. We think the Pfizer data might validate that from a mechanistic standpoint.
Moving earlier into prostate cancer, I think that has been essentially the trajectory of almost all drugs in prostate cancer always moving to earlier lines and having a better response there. Mechanistically, you should be able to prevent the resistance basically before it starts. And so starting a patient on an ARPI inhibitor for the first time and essentially make sure that the prostate cancer maintains its AR dependence so that the ARPI inhibitor can work longer, you might see a much more added benefit. And so I think that's the rationale that Pfizer is pursuing.
Right. But it sounds like you think it doesn't matter if it's post-Abi or post-Enza as long as they've seen one AR antagonist or so.
I think that's a good question. I think the data will tell us. I think one, the study that we're doing, we're allowing patients that have failed an ARPI. So we are enrolling patients that have failed abiraterone, that have failed enzalutamide. We're allowing daralutamide and apalutamide. So we'll be looking at that data coming in. What we've seen from the Pfizer data, again, similar to the data they presented, it is dose escalation data. It's the phase one. It's not randomized. But in their subset of patients that had failed Xtandi, many of those patients also had abiraterone as well. Many of those patients also had chemotherapy, but they still did see an interesting PFS there. It was 11.7 months, which is interesting. Again, not in a randomized setting.
From what we can tell, Pfizer is not pursuing that as an indication, but that is an interesting, I think, piece of data that is out there.
Sounds like that cohort may have been more advanced, basically.
Potentially, it could be more advanced. That's right.
We actually like that. That's something that for when we think about phase 3 studies, we definitely like the post-Abi setting, but we also like the post-ARPI setting as well. We think people would love to keep patients off of chemo as long as possible. So providing an option to do that could be an interesting play as well. And in KOLs that we've spoken to, they like that option a lot as well.
So that makes sense. T here was another data point from another product from Ipsen that was recently at ESMO that didn't look quite as convincing. Is there a view on that and impact of that data set to the space in general?
I think the short answer is that if you look at tazemetostat and you go through the list of items, the drug has poor in vitro potency. It showed poor in vivo efficacy. It has a very, very short half-life, two to three hours, and it also has this concept of CYP autoinduction where they actually self-metabolize. So they're actually decreasing their exposure with repeat dosing. I think it's not fair to look at that data set. I think honestly, if you would have put maybe mevrometastat in that data setting, I think the experimental arm would have done much, much better. It wasn't a matter of the control arm overperforming. It was more of a matter of the experimental arm underperforming because it's just not a good drug.
S o great. And then maybe just moving to your own phase 1 study, which you have now, I think you've completed the monotherapy, correct? Maybe just talk about takeaways from that. And then you recently started the combination with apalutamide, daralutamide as well. We saw some early data a few weeks ago. So maybe just bring us up to speed on where you stand with your phase 1 and quick takeaways from that.
So the phase 1 data, this was monotherapy dose escalation. And the objective here was really just to look at drug properties and really demonstrate that we have potentially best-in-class drug properties. So we showed good PD, good PK. We showed we had a clinical half-life of 20 hours. And overall, from a safety perspective, it was pretty clean on target tox at doses up to 900. So that was the objective of the phase 1 data we presented in January of 2024. We did start the combination dosing. We'd started combination dosing with both apalutamide and daralutamide in mid-2024. Matt was able to secure clinical supply agreements from J&J for apalutamide and from Bayer on the daralutamide. So we started dosing in mid-2024. And then what we did show last month was some very early data on the combination of apalutamide.
Big picture, guys, this is early data, N of six, so we don't want to overstate it in any way, but with the N of six, we did see that three out of the six patients, so 50% of the patients, did have a PSA 50, a confirmed PSA 50 at week 12, and then two out of the six patients, so a third of the patients, had a PSA 90 at week 12 as well, so early data, but promising. If you go across, and again, with the caveat of cross-study comparisons, if you go back and look at historical benchmarks here, this is well characterized, you'd expect to see a PSA 50 of, call it 20% here, and you expect to see a PSA 90 of 5% or less.
On the safety side, primarily grade one and two, and we'd expect on target with a PRC2 inhibitor or an AR inhibitor, so you think of hem, GI, and fatigue. So overall, looks interesting, but obviously there's a lot more work to do and get in a bigger patient population.
And then, remind me what else you're doing in this phase one and what do you need to see before making a phase three go decision?
So with regards to next steps with 944, what we've said is we're going to continue to dose escalate on both the APA combination as well as the Dara combination and do some more dose exploration. We'd like to select the recommended phase two dose, provisional RP2D, i.e., in Q2 of this year, and then start the dose optimization. And the goal is to provide an update either Q4 of this year or first half of next year. Our goal is to start one or more phase three studies in early 2026. So the goal would be to select that provisional RP2D, actually the RP2D, as well as which AR inhibitor we want to start with sometime in the second half of 2025. So a lot to get done, but that's our current plan and timeline.
Okay. Maybe just a quick follow-up. So you said you went up to 900 monotherapy. Was there a monotherapy go forward dose or, and these two initial doses where we saw combination data a few weeks ago, at what dose level was that and what's your anticipated RP2D, I guess?
You want to take it?
Sure. So from the single agent, we always expected that we would be moving forward in combination. So single agent RP2D is a little bit of a misnomer, but we did want to understand the drug as a single agent from a safety PK/PD standpoint. What we had basically observed from the phase one data, we think 600 milligrams once daily is that so-called RP2D. That was an effect where we see really nice PK, where we're getting the exposures we think we need to achieve based on preclinical modeling. We saw a very nice safety profile, no grade three adverse events. We saw really nice PD activity. And so we feel like that's the right dose. That was the dose we wanted to target when we moved into combination.
So our combination studies are starting at 600 milligrams QD of our drug in combination with the. Are that full dose of the AR antagonist? Full labeled dose of the other ones. Exactly right. I think a couple of the nuances. I think Dominic had mentioned the preliminary phase one combination data that we shared last month. That was the first two cohorts of our combination with apalutamide. And so with apalutamide, it is an inducer of CYP3A4, so there is likely drug-drug interactions with any drug. And so we will continue to dose escalate that drug. We are also doing a combination study with daralutamide. We did not show that data yet. That one's a little bit earlier.
We had mentioned we're in the second dosing cohort of that. Daralutamide is well known to actually have a different metabolic profile than apalutamide. It tends to not have drug-drug interactions with other drugs. It will likely be a different dose on the go-forward dose in combination just based on the profile of the other molecules, but those are all under consideration as we generate data.
Okay. Helpful detail. And then would you expect different clinical outcomes between the two combinations?
We actually would not for a couple of reasons. Obviously, the data will be more telling. I think what we've seen preclinically, the molecules are essentially indistinguishable. They both work extremely well. When you look at the clinical data of both molecules as a single agent, they both have overlapping labels. They've done very similar type studies, hazard ratios, PFS, overall survival. Generally, it's consistent. They both are extremely commercially successful as well. And so we don't really see a difference there from a mechanistic standpoint or anything that we would expect. And so I think we view both as relatively interchangeable other than obviously the dose might be a little bit different of the drug that we use going forward.
Sounds good. Okay, perfect. So then it sounds like additional data disclosures by the end of this year. Is that correct?
We said Q4 of this year or first half of next year. We're being a little vague. Obviously, we're still in dose escalation, so I don't want to get ahead of ourselves. Obviously, we want to see what type of data Pfizer puts out next week as well. So we'll provide a little more clarity on that later in the year, but we haven't given any specific guidance on number of patients or what exactly we're going to show there.
Sounds good. Great. Okay, cool. And then maybe switching over to ORIC-114, which is your EGFR/HER2 exon 20 inhibitor. I know you're running a number of dose expansion cohorts, and you did say you'll provide updates of those throughout the next 12 or 18 months. And so just maybe remind us where you are with the program first, and then we can jump into some questions.
So we put out some early data in 2023 on dose escalation data. Since that time, we started the dose expansions, as you mentioned, Michael. And here we're looking at three patient populations. These are second-line patients or later. This is EGFR exon 20, HER2 exon 20, and then the EGFR atypicals. And what we've said from a guidance standpoint is we expect to have an update for the EGFR exon 20 and HER2 exon 20 in the first half of this year, and then the atypicals will be in the second half of the year.
Okay, and then.
Sorry.
Go ahead.
Just a little more color, a little more guidance we've given on that. We said for each of those cohorts, obviously we're exploring two provisional RP2Ds. The two doses that we're exploring is the 80 and the 120. So we said we'd have about 30 to 35 patients in each of those cohorts. So across the three cohorts, you're talking about 90 to 100 patients worth of data. And the decision here is whether to determine it's a go or no go with the program. Assuming it's a go, the plan would be to start a registration study in the second half of this year. This would be a single-arm accelerated approval registration strategy. Because of the CNS activity, the unmet medical need, we do think there's an accelerated approval path here as well.
Could you help us then maybe just provide a little bit more context? Obviously, in the exon 20 EGFR space, there is amivantamab approved now, a few TKIs in late-stage development, and then in the atypicals, I would say maybe some emerging data. H ow do you think about the context of the treatment landscape for your drug in each of these settings and also through the efficacy bar as you think about making a phase 3 go decision?
Y ou're right. There's obviously amivantamab approved both in the second line as a monotherapy and in combination in the first line setting. And then there's obviously a number of other readouts that'll happen this year and next year in both the first line and second line setting. I think for us, our key distinguishing areas are safety and tolerability. I think the second-generation EGFR inhibitors have done a good job of dealing with on-target tox, but some of these agents do have some significant off-target tox in the form of increased bilirubin, elevated liver enzymes, QTc prolongation. So there's room for improvement on that front. And then I think more importantly is the CNS angle. If you look at these patients, a third of these patients, if not more, present with baseline brain mets.
If you look at the previous data sets, and mobocertinib did a good way of showing this, and then you see it in the PAPILLON study as well with amivantamab . If you have a history of brain mets, those patients seem to progress much, much sooner. There's a significant unmet need here. We think hopefully, if the data supports it, that is our area of differentiation there as well. With regards to benchmarks, just go through them quickly. I think in the second line EGFR exon 20 setting, we're saying the benchmark has to be a 35% ORR or better, as well as we need to continue to see CNS activity, as well as a good safety and tolerability profile. For the HER2, this is somewhere north of that. We're saying it's about 50% or better.
Lastly, for the atypicals, this is still, I'd say, evolving. Let's call it. That's also about 35% or better in that setting as well. In the second-line setting. I know we saw some first-line data last year from one of the companies, but this is in the second-line setting.
Okay. Super. And I know you've announced some work that you're planning with amivantamab as well. Can you just talk about that?
Mind you, I'll take that.
We're actually really excited about that. So we just announced we're doing a clinical collaboration with Johnson & Johnson to study amivantamab, which you mentioned is the approved therapy for EGFR exon 20 right now, in a combination with our ORIC-114. So I think just from a mechanistic standpoint of why we're looking at that, it is very complementary why those two might actually work really well together. You would get dual EGFR inhibition to really cover the broad landscape of the EGFR mutations is one. Amivantamab is active on potential resistance mechanisms to a TKI, which would be c-MET, potentially EGFR C797S. So it gives us nice coverage there. Obviously, we're bringing to the table CNS activity, which seems to be probably not optimized with amivantamab. So I think it makes a lot of sense strategically and for us to pursue that.
The other thing is that other people are looking at the phase 3s that are ongoing right now are in combination with chemotherapy or as a single agent, so nobody is pursuing a combination with amivantamab yet. I think we and Johnson & Johnson are excited both by the fact that amivantamab, when they combine with an EGFR TKI in other settings, seems to do extremely well, and so amivantamab has demonstrated extremely great data with the classical EGFR mutations in combination with lazertinib. They have also studied their molecule, that combination in the atypical EGFR mutations as well. They're seeing really nice response rates, really long duration of therapy, and so I think that gives us the proof of concept that 114 plus amivantamab might work really well.
Lazertinib is not very active in EGFR exon 20, so we think that obviously fits in Janssen's portfolio in the lung cancer landscape. And so we will also be focusing only on first-line patients. So patients that haven't been treated yet, that is a potential phase 3 option for both companies too.
All right. And I think you said the monotherapy exon 20 and HER2 exon 20 cohorts will be the first news we'll see in the first half, correct?
That's right.
The HER2 exon 20 study, does that allow prior Enhertu? What should we expect? How patients have been receiving prior treatments there?
That's a good question. I think one, our study does allow for it. And so we're generally accepting of other therapies to really prove our molecule works. And that was the case in the update that we presented at ESMO 2023. What's somewhat interesting, at least in the data we've presented earlier, what we're hearing is that there's actually not a lot of Enhertu in the lung side, certainly not like it is in the breast cancer space. And so we do allow it. It's hard for us to tell how much will be there, but we do allow for that. So that's one. And that obviously is approved. They got accelerated approval and is now in a phase three confirmatory study on the HER2 side.
On the EGFR exon 20 side, do you allow prior AMI or is it AMI naive patients?
No, that is just post-chemo right now. So what we wanted to do here was to be more comparable to what others have shown here. You remember the data set we showed at ESMO 2023, 81% of the patients had seen a prior TKI and 86% of the patients had baseline brain mets. So this is a more apples-to-apples comparison to what others have done. These are patients that had failed chemo, had not seen an EGFR inhibitor, either AMI or another TKI. The only difference I'd say is we're actually allowing patients with active brain mets. And as you may recall, a lot of the other agents, if not all, excluded patients with active brain mets, which I think is, again, a key area of differentiation for us as well.
Cool. Gotcha. And then lastly, on the atypicals, I know there's different types of atypicals. There's PACC mutations, there's others. What do we know about your drug's activity in that context and what are you allowing in your study?
I think first, just from a preclinical standpoint, I think one thing that got us excited by it is the data that we've put out. The molecule is designed for exon 20, and that was the original clinical study. We had gotten a lot of feedback. There's a lot going on in the space of looking at molecules and the atypical side. We have profiled our molecule and somewhat serendipitously, it's actually more potent on the atypical mutations than it is actually for EGFR and HER2 exon 20. So the preclinical data is pretty compelling. We have studied it across different atypical mutations, including PACC mutations. We see it's a highly potent molecule preclinically. So with that being said, our phase one study allows for both. So we are enrolling a broad type of activity.
I think others have taken somewhat of a different approach based on the preclinical profiling they have, but we're allowing it, and obviously, we're excited to see the activity across the atypical mutations.
All right. Great. Well, with that, our time's up. So looking forward to a number of updates here, starting with Pfizer data soon in a couple of weeks and then your exon 20 data in the first half. So thank you, Dominic and Matt. Really appreciate it.
Great. Thank you for having us.