STIFEL 2026 HEALTHCARE CONFERENCE - ORIC PHARMACEUTICALS INC

Hey everyone, thanks for joining us this afternoon. I'm here with Auric Pharmaceuticals. I have a CFO, Dom, and Matt, CBO. So it's been quite a year for PRC2. I think we've all been waiting for this MEVPRO1 data set that has continuously gotten pushed out. So maybe a good place to start is, I guess, a brief introduction to the company. And then my first question will be, you know, how are you guys reading this Pfizer push-out of MEVPRO-1? Yeah, sure. First of all, thank you for having us here at the conference. So at a high level, Oric is a clinical stage oncology company. Our name really encapsulates our mission, which is to overcome resistance to cancer. We've got two late-stage clinical programs. The first one is RINC-Z-Metastat. This is an allosteric PRC-2 inhibitor that we're studying in prostate cancer in combination with AR inhibitors. We initiated our first Phase III study early this year, which is known as Himalayas I, and that timeline, we're expecting top-line data in the first half of 2028. The second program, inozertinib, this is an EGFR TKI that we're studying in two distinct patient populations in non-small cell lung cancer, both EGFRAtypical and EGFXon20. We did present some data at ESMO earlier this year. which we'll talk about, and then we'll have some additional data in the Exxon 20 patient population mid-2027 as well. So we're looking to start our first Phase III study on the atypical patient population in the first half of next year. So looking forward to next year, we should have two ongoing Phase III studies. I think this is the first time I've ever heard you say we have two late-stage studies going on. So, as has become expected, let's talk about Mepro1, which is actually not our drug, it's Pfizer's drug. So, I guess taking a step back in our view on the timeline shifts from Pfizer, I think taking a big step back is first and foremost, there's been a lot of datasets recently from Pfizer from other competitors as well of ourselves, that has shown the benefit of combining a PRC2 inhibitor with an AR inhibitor. I think the most compelling dataset that we've seen, obviously, is the randomized data we saw from Pfizer back at ASCO 2025. This is an 80-patient study. It was a randomized study. The treatment arm showed a 14.3-month benefit, PFS benefit. The control arm showed about a six-month benefits, so pretty profound results in this patient population. This was post-Aboradarone patients that could have seen up to one round of chemo. So from a high level, this is highly validated from a biological standpoint. Pfizer started their study MEVPRO-1, which is in its exact patient population. It's a 600-patient study. They're showing the combination of mevrometastat, I should say, in combination with enzalutamide versus a control arm of physician's choice between AR inhibitor and docetaxel. They started this in late 2024. they had originally had their primary completion date as of call it mid-2026 so i think we were expecting it around that time since that on their q2 earnings call in early august they shifted that guidance to q3 q4 of this year and then on a q3 earnings call they just shifted it again to first quarter of next year i think they said february of 2027 so at a high level obviously it's a blinded study we don't know any more than you guys do but as you guys can imagine a number the street analysts investors as well as ourselves we've done a lot of an event-based modeling to try to predict what the potential scenarios are relating to this delay at a high level we kind of looked at this in four quadrants right the the big miss scenario the slight miss the slight win and the big win i think based on again all the data that we've seen so far with this mechanism based on the event modeling we've i think we feel pretty comfortable that that big miss is very low probability if not off the table so the small you know there's always a possibility of a small miss and we obviously don't know what that would be we think again the biology makes a lot of sense so if there is a miss maybe it's regiment related maybe that's something to do with their safety profile or high discontinuation rates but in a scenario there's a small win or a big win where the study is positive obviously we think that's a strong validation for the mechanism kind of a read-through to rinsy as well yeah i mean just you know to contextualize a little bit what the control arm could be capable in a study like this you know you have arpi switching you have chemo um it doesn't seem like anything in the control armor to warrant maybe you know six to eight months do you think that's a fair assumption yeah um i think if you look at the again the control alarm just to clarify is is ar is enza or docetaxel so if you Look at kind of the benchmarks out there i think I think you'll see docetaxel in this patient population will be, like you said, seven to eight months. The AR inhibitor in the post-Avistatin will probably give you five to six months. We don't know what that distribution is. Assuming a 50-50 split, that gets you close to 6.75 or seven months of durability. Could that inch up a little bit? That's possible as well. But we think kind of an outlier there would be unusual. Pfizer has said, I think on their Q2 earnings call, they kind of said they expect the control arm to be somewhere in the five to eight month range. So obviously they're closest to the data. That's kind of the latest data that we have. Matt, anything else you'd add to that? No, I think just, you know, the study has been delayed. So I think there's obviously multiple ways you could look at that. I think in general, people have gotten comfortable. That might be a good signal. I think that's kindof what Pfizer's signaling. That's the way we interpret it as well. And I think it's just because the control arm of docetaxel ARPI switching has been so well studied in phase three studies, And it's been replicated in multiple studies by different parties that I think people generally feel good that enzalutamide switch should give you about a five to six month RPFS, docetaxel in multiple phase three studies should give You seven to eight. And so anything within that range, I think Pfizer has signaled that is their expectation as well. And And so, again, if you kind of assume the control arm is doing what it should do, then, you know, we think, again the study being delayed so-called that their expectations due to less events occurring seems to be that could be driven by the treatment arm. Yeah. I think, you know, one thing that's come up in conversations with investors recently that I think is very well appreciated by some and, you, know, maybe not broadly enough is that both doctors and patients are going to be blinded to psa levels um you know in some cables we talked to suggested that you know maybe psa level is not budging or going up a bit in phase one where some of the reasons why you know studies like yours or you know visors in early stage have early drop-offs um do you guys think this could you know may be help out with a pfs like endpoint or an rpfs like endpoint yeah i think your point is a good one i think in early prostate cancer studies like phase one studies the primary input of those studies are typically pk and safety they're not blinded so patients physicians investigators are aware of what the psa response is so for some reason if the psa is not going down or up a little bit they may just decide to come off the study that is very different than what you see from an operational perspective in a phase three study where the the patient and the you know the the doctor the physician is blinded to that information and all that information is done centrally. So they don't have that insight. So you would expect that kind of discontinuation to kind of go away in a phase three study. And again, this isn't just applicable to Pfizer's data set or our data set. If you look across phase one studies in prostate cancer, you see this early discontinuation rate in these early studies for the reason you just articulated. So we do think that risk goes away in the phase three setting. Yeah. It was kind of interesting seeing that ESMO data for meprometastat monotherapy in that poster, where there was almost no PSA response, but nine-month PFS. Have you guys talked internally about that or kind of trying to read into that? I know it was small patient numbers, but it's certainly a very interesting signal that I think was unexpected to many. Yeah. I mean, Matt, you want to talk about the science behind the PSA? Yeah, in some ways it's not unexpected. I would say the target and mechanism is different. So this is an area that we have spent at least the last five years trying to understand this mechanism the best we can, which is different than anything else in prostate cancer. It is an epigenetics target that basically modifies gene regulation. One of the effects that we Have seen preclinically, and now I think the Pfizer data kind of replicates this in the clinic, what it actually does is it increases KLK3 expression, which drives PSA responses, and so the way the mechanism works, a PRC2 inhibitor essentially reverses the resistance in prostate cancer cells. It will make a prostate cancer cell look more like an early stage prostate cancer line, so with that, it actually increases AR signaling and things like that. We've kind of put out a lot of data within that, and what the Pfizer data show is actually you might actually see an increase in PSA as a single agent, and again, somewhat of a confounder of that you know usually other AR directed therapies reduce PSA. I think a couple things with that they still sell relatively long you know RPFS of almost nine months as a single agent which is actually a pretty good outcome. It's a small end and it's you know single arm study but somewhat intriguing is just you can see that with just single agent where you really see the profound clinical or the profound synergies pre-clinically and so I think this is again a lot of our data suggests this, others as well, is you see strong combination synergy pre-clinically when you combine a PRC2 inhibitor with an AR inhibitor. And so I think that just the clinical data they have shown is basically replicating what you see pre-clinically. But it's something I think what we feel comfortable with within the Pfizer randomized data, the primary endpoint there was RPFS, which is the regulatory endpoint. Andso I think a lot of people in prostate cancer therapies tend to look for PSA responses. It's an early surrogate endpoint. It doesn't have any regulatory bearing, but it's always interesting to see it's just with our mechanism, there's confounding, you know, influences. So our mechanism hasn't really been driven by PSA responses. And it's more of just getting long-term, you clinical benefit. And so that's obviously why we're excited by the target, but yeah, interesting data kind of under the radar. They're not pursuing single agent development, but an interesting signal, you don't know the last. Absolutely. And you've seen this before, Laura. You've seen other targeted agents, or other agents I should say, that have shown really profound PSA benefits that haven't translated into durability. And with Pfizer, you've see good PSA responses, 30%, 40% consistent with what we've seen, and you've this profound benefit from a PFS standpoint. And to Matt's point, that is the regulatory endpoint. You can't get approval on a PSA endpoint. I've also kind of seen some very deep, exciting PSA data that didn't translate as well. But I guess maybe this is a good segment on the topic of ESMO and whether or not PSA is a good biomarker. There was the J&J RIPTAC data at ESMO that drove a lot of hype. Many comparing to PSA response levels to your data and to Pfizer's data, which we now have discussed maybe isn't the best marker here of success. but what were your thoughts on that data and just broadly of the emerging competitive landscape as it relates to PRC2? Yeah, I mean, one, I think it's really exciting data. For sure, it's a brand new mechanism, and so it's different modality and also going after a different target. So I think there's a lot of excitement whenever you see something new, and I think the early clinical activity is very impressive. I'm sure they're gonna do a great job developing the drug and kind of exploring that across different lines and combinations. So it's definitely something kind of watch in the landscape um i think a couple things you know when it's still early data and so we don't know what those early psa responses what they'll mean for long-term durability i mean i think that remains outstanding uh and then of course like any other therapy what is the long term side effect profile but yeah uh at the very least i think couple things i think one you know just with the prc2 inhibitors we just know from the pfizer data that you can get really long clinical benefit and be relatively well tolerated and i think our early data supports that as well And then two, there's also strong rationale on why you might combine the two mechanisms as well. And so again, we'll see kind of both programs, COPRC2 inhibitors, and I'm sure there'll be plenty more RIPTACs in the future as well of just how they'll both develop. But the other thing is just prostate cancers are such a huge patient population. It's a significant unmet need. It is an area of oncology that is just underserved with the current therapies. And so I think there's room for multiple new therapies where J&J, other folks as well, presented T-cell engager data. That's obviously exciting. There's plenty of opportunity for that. We think obviously PRC2 inhibitors we're combining with standard of care regimens that are approved across the whole spectrum of prostate cancer. So we obviously have plenty of white space to go after as well. So more therapies are needed for sure. Absolutely. So I'm just going to be clear that what I'm to say is the street what the street has been expecting not what auric has guided but there's been this expectation that this prc2 update that you guys would have um in the back half of this year would be in response to mev pro one um are you guys still on track to have this update or should we you know maybe hold on for yeah it's a great question it's one we've been getting uh you know recently um and just to remind everybody we we gave guidance at an investor conference earlier this year and what we do is we typically set the guidance for the next 12 months and one of the one of the milestones was to provide a second half program update and we intentionally left that as a program update we didn't promise specifically data and what that what we said that could include would be an update on himalayas one and where we were at that study or it could be our thoughts on a second phase three study in prostate cancer and you're right the the premise So the premise of that guidance is always predicated that MevPro1 would be out, which we anticipated it being out. And we could provide kind of our color and our perspective on that. And the third piece, it could be some incremental data in one of the two cohorts that we shared with you guys early this year. So the guidance still holds. As of now, we've definitely discussed the concept of does it make sense to push out post-MevPro 1. But as of today, the guidance is a second half update. We'll keep an eye out for your next disclosure. So you guys moved into your own Phase 3 trial, Himalaya's one, which some perceive to be kind of ballsy ahead of getting the MevPro1 readout. What gave you guys the conviction to move forward here before the biological de-risking from, or clinical de- Risking, Phase 3 clinical de Risking from Pfizer? Yeah, good question. So we started our first Phase 3 trail this summer, and it's going after patients with mcrpc previously treated with abiraterone and so i think there's the level of evidence for that we think is very strong i think one we've kind of already talked about it but pfizer already has presented randomized phase two data there i think in some ways that gives us confidence that mechanism seems to be relevant in that patient population that's probably first and foremost secondly all of the data we've presented so far again not in a randomized setting and a little bit uh not as um not as many patients as Pfizer, but everything we've seen so far seems to be everything is tracking, you know, very consistently, potentially with a much better safety profile. So we like that aspect as well. We have presented so much preclinical head-to-head comparisons on basically any metric that we can see, and it seems to perform very consistently, if not a little bit better in most comparisons, and we've kind of published a lot of that too. So, we feel, you Know, very confident of that, let alone there are other competitor PRC2 numbers in development that have put out little data sets here. All of them are basically replicating, you know, the same type of theme of just it seems like you can get very long clinical development with these programs in combination with an AR inhibitor. So I think the totality of the data, both our data is giving us conviction. The Mevrim metastat data, all Pfizer has put out multiple data sets in addition to their randomized phase two. Allof them are supportive. And even some other molecules that might be, you now, inferior to Mevrometastat and Rinzumetastat are all kind of pointing us in the right direction so we felt we had pretty good conviction to launch that first phase three study and uh are there any powering differences between this and the pro one that are worth noting and maybe in the future you know if maybe this you know near miss or you know slight win situation plays out you know could you guys readjust powering um to to maybe set yourself up better for success yeah that's that's a good question um i think what i would assume is that our protocol is very similar to Pfizer's as I said and again that's power to show a hazard ratio of 0.66 with again the treatment arm doing 10.2 and the control arm doing around 6.75 months I think your question is a good one I think you have to just think through how much information Pfizer will give us at various points so we've started enrolling Himalaya's one already assuming the top line data comes out in you know it's called February of next year you'll probably the more detailed color because they're not going to give us too much detail based on their historical precedence of how they release top line data so that may come i don't know mid-2027 i don t know how much how helpful that would be again we have high conviction on the mechanism we think you know the potential risks associated with their drug their regimen i should say not necessarily the biology could be the safety and tolerability as you know they started at a 1250 BID dose in a fasted state, they kind of took it down to 875 in a fed state, and, you know, they were able to kind of reduce some of the on-target toxics. So with that, but it's still there, right? It's still not even close to what we've shown. So we still differentiate significantly from what they've shown on the safety and tolerability side. So is there, if there's a near-miss scenario, if it's safety-related, I don't know if they provide additional color on that i mean the one incentive that they have to potentially provide a little more color is they do have two more phase three studies ongoing with mepro2 and mepro3 so if there's something to encourage you know physicians or something to kind of continue with that then it would be in their best interest to do so but it really depends on what they say around the top line data absolutely and in the event of a mepro1 when um you know would this maybe be a trigger event for you to move into perhaps the castration sensitive setting or you know you have kind of toyed with the idea previously of another phase three in prostate for this asset yeah the two you know so pfizer's first first we talked about my pro one which is their first their second phase three studies my pro two that's also in the metastatic crpc setting that's an arpi naive setting, and then they have Mepro3, which is in the metastatic CSPC setting. So our view is, and we think about what a potential next phase three study would be, we like the post-AR inhibitor patient population, and Pfizer back in 2023 showed some pretty compelling data here. Early this year with our data update, we showed some Pretty Compelling Data here, and the interesting thing there is Pfizer is currently not developing a phase three in that, studying a phase 3 in that setting as well. So we like that patient population, and we do like the, you know, obviously the earlier CSPC setting for obvious reasons. It's a much larger patient population and patients who are on drug for, you Know, multiple, multiple years, four to five years on that. So yeah, obviously that is definitely something we're thinking about on which one of those would be our next phase three study. And as far as, you have the setting you're currently going after, should we expect that at some point you will show us updated RPFS data? Yeah, that's, again, the guidance is what it is at this point, so we'll leave it at that. The second half program is intentionally left broad, so that could include some incremental data. Okay. And do you guys believe the bar is non-inferiority versus mebrometastat and that a differentiated safety profile truly could drive clinical differentiation or commercial differentiation? You want to take that, Matt? Yeah, we actually do, and prostate cancer is a little bit different, but patients are on therapy for a long period of time, And I think the best analog for us is just to understand the market today. And so there's four ARPI inhibitors approved. They're all essentially indistinguishable from an efficacy standpoint. There's no head-to-head comparisons, but they've all ran very consistently similar phase three studies. All of them have been generally in the same ballpark in hazard ratio, PFS, and overall survival. And I Think the market research, our discussions with KOLs, they would all tell you they're indistingishable from an advocacy standpoint. There are some nuances on the safety profile. What is very interesting to us is the fourth one approved is darolutamide. That's currently the market leader in the U.S., and so that was actually approved seven years after enzalutamide and abiraterone, number one selling ARPI in the US in their indications. And so we think that is only differentiated on safety. And again, the benefits of that, it does not have drug-drug interactions, and so patients, older men with prostate cancer often are on other medications. is a great fit for them. It also has a better side effect profile. Technically, it doesn't cross the blood-brain barrier. So you're better on side effects like fatigue and some of these other things that are associated with enzalutamide. And so the market has told us that in prostate cancer, safety can actually have a huge benefit. All of those drugs are successful, but safety can be very meaningful. I think, as Dominic said, one of the biggest opportunities is in the metastatic castration sensitive setting in that enzalutamide is one of the standard of care PFS is 48 months on that and so patients are on drug for years and so if you can improve fatigue if you can improved diarrhea if you could have proofs you know improve some of these side effects it is you know well reflected I think in the in the commercial market yeah we only have conducted no sorry to throw we have conduct our own independent market research and you know we disclose this back at our data update like if you just put it together assuming no difference on efficacy so same efficacy uh and just the differentiation comparing our profile versus a competitor profile uh it was large majority i think it was over 70 of the the you know physicians basically said that they would prescribe this and again it's so important because at the end of the day these are elderly men you know 65 70 years old and as matt just said that their own therapy for not weeks or months they're on there for years so So dealing with grade one or grade two diarrhea is not fun. So I think that's a huge differentiation for us. Yeah, absolutely. So fireside chats have gotten a lot harder because now we have two phase three trials to discuss. And I want to make sure we get time to talk about the EGFR program. So maybe pivoting into that, Edesmo was a busy conference for a lot of people. So I want make sure people are aware of the data and the CNS activity, which I think is a real point there that you guys are trying to stress as far as de-risking moving forward. So if you could just very briefly recap the data and the phase three design that you've come to alignment with the FDA on. Yeah, obviously we're very excited by the data. I think, you know, a couple of things, the program, this is a program we brought into work, you know many years ago, you know and really looking for a targeted lung cancer therapy. The real differentiating feature is it's highly brain penetrant. And so it was designed to be that way from the beginning. And so we've set, you have very strong preclinical support on why that was the case. Our view, it was somewhat of a crowded space back then, to a lesser extent it is now, and we always felt what was missing from everybody else that was developing drugs in spaces, there wasn't a truly brain penetrant drug. Why that's relevant in lung cancer, we know that from multiple studies, a lot of research is just most patients actually have, about a third of patients will have some form of brain mets on diagnosis, let alone will develop brain metastases over the course of their disease. If you look at a lot clinical studies, most patients actually progress in the brain is obviously a common site of progression. And so it's very highly relevant in lung cancer. And so that was what our molecule designed to do. We had shown some earlier studies and so some really nice proof of concept. We designed our studies to actually allow patients with brain mets into our study. You could come into our with untreated brain mets, which is very unusual in this space. Those are very difficult to treat patients. So no radiation before? And no radiation, yeah. You just literally have brain mets you can come into out study. And so, that was the criteria. we showed really nice proof of concept at ESMO Asia about I think 18 months ago. And so that was kind of the proof of the concept. What we announced here at ESMOS was one of our prioritized indications, which is atypical mutations, also frontline. And so we went into a treatment naive setting and then also at our recommended phase three dose. And so this was, I think a really nice data set to show what the drug can do at the go forward dose. We're very excited by the data, but essentially we've showed it in kind of multiple ways to cut the data. but about an 84% ORR by investigator, 80% blind and independent review. So obviously one of the higher response rates, if not the highest, I think, that we're familiar with in this space. So really nice ORR, most patients are still responding. Majority, all patients had reduction in systemic lesions. And then secondly, the CNS activity. And so because our drug is brain penetrant, because we have this broad enrollment criteria, over 60% of our patients had some form of brain mets coming to our study, a majority of those were untreated. So again, very challenging patients. Within that, 70% of those patients had a resist response in the brain, as well as systemic responses. And then we looked at a more stringent renal criteria, similar concordance there of 67%. We had patients with complete responses in the CNS. We had patient with responses with untreated brain meds. So no confounding activity. I think it was very clear to people your drug is brain you know brain penetrant and doing a great job at doing that so um we're very excited by it by that data um and obviously we're moving forward into a phase three study there yeah i think the one thing i just want to emphasize is the patient population that we enrolled and it wasn't a function of us trying to enrich for it but you know 65 of the patients had baseline brain mets as matt said a number of patients had untreated brain mets when you look across you know the comer you know the the real world it's about 35 so we had almost double that amount and if you If you look at competitors, you've seen that some of these competitors have actually enrolled much less than that. So we were not trying to be selective, and we were able to put up these pretty impressive systemic response rates and CNS response rates in a much more challenging patient population. And if you look across other targeted therapies, what really distinguishes, you know, you see some like electinib, you look like ocimertinib. Where they really distinguish from kind of the first generation about EGFR inhibitors and ALK inhibitors is really on the CNS activity. And what that does, it translates into longer PFS benefit for patients and obviously longer commercial opportunity for companies as well. So we're really excited about that data set. We're looking to start that phase three study in the first half of this year. Again, I think we want to talk about the study design a little bit, but we're, you know, that's definitely. And then for just real quickly on the EGF or Exxon 20, we said we'd have an update in mid-2027. And there again, we're kind of taking a three-prong approach. we're studying it as a monotherapy we're setting it in combination with chemo and then we're doing something that no one else is doing we're combining with amivantamib as well so the approach there is let's look at our data mid-2027 let's looking at the competitive landscape if we show true differentiation like we do feel like we have for a typical patient population then we could potentially start a phase three study in that patient population as well yeah so trial design is it's going to be a randomized study in over 300 patients. They'll be randomized to inoxertinib, monotherapy, 80 mg QD, versus a physician's choice control arm of osomertinab and afatinib. And both of those drugs, again, aren't really approved for the atypical mutations. There's some nuance there, is that afatinab technically is approved for three mutations, three very specific mutations, based on a retrospective analysis of their data. They have three mutations in their label. Osimertinib is not approved for atypical mutations. There are a couple kind of single-arm studies. They're actually in the treatment guidelines. So there's two drugs that are available therapies. Neither of them actually work very well in this patient population. And so we feel kind of very good about that choice. What has been reported with the fatinib? It's kind of a 60% ORR. And I think, again, the nuance is there that's only in three specific mutations. I think two, in their studies, it is not a brain penetrant TKI. so they excluded patients with brain mets from their studies, and it's not very well tolerated. It is a pan-EGFR inhibitor, so there's a lot of DGFR-related side effects, and so significant treatment discontinuations. It's the only drug that's really available technically approved for these mutations, so it does get some use, but a lot OF patients can't tolerate it is kind of one, and if patients have brain mets, then physicians use osomertinib for those patients. Osteomertinib does not work as well in atypicals as it does the classical mutation. So relatively low bar, a completely significant unmet need. We estimate it's about 3% or so of lung, so it's bigger than ROS, it's bigger than RET, it is bigger than a lot of the targeted therapies. And so it is a really nice commercial opportunity. And what we have seen from other data sets, which we think, you know, with some potentially inferior type molecules than what we have, there is potential to see really long duration of therapy. And again, we haven't reached a median PFS yet, but what we have seen is a majority of our patients are still in response. They're still responding. We had about an 11-month follow-up at the time of our ESMO data. So it looks like it's tracking to be very durable as well. And I think one thing we learned from your competitor, one of your competitors this week, is that it's unfair to compare data sets that have different mixes of CNS metastases because the PFS can look very different in these patients. So, when we think about, you know, your phase three and ultimately longer follow-up for your data, you noted enrichment in phase one for CNS metastases of baseline. Should we expect a similar type of enrichment in the phase three, just to happen naturally? Yeah, it's possible. Obviously, that's something we want to think about as well. We're definitely not looking to do that prospectively to enrich for it, but when you have a good drug and, you now, investigators are seeing good results, it just naturally happens. So it's something we need to think through as well. And then will patients with brain mets at baseline enrolling in your Phase III getting osomertinib be allowed to get radiation before going into the trial, or will they also need to be untreated? So we're not limiting it only to untreated patients. We're allowing both treated and untreated patience, just like we did. So it'S not exclusive to just untreated. Sounds good. Well, we're out of time. All right, great. It goes by pretty fast, especially with two phase three trials. Great questions. Yeah.