GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - ORIC PHARMACEUTICALS INC

So thanks everybody for joining us. My name is Paul Jang. I'm a biotech analyst with Guggenheim. And our next presenting company is Oreck Pharmaceuticals. And I'm very pleased to be joined by Dominic Piscitelli, CFO, and Manthew Panuwat, Chief Business Officer. Welcome. Thanks for having us, Paul. Good to see you. All right. So maybe just to kick things off for those that might be newer to the story, could you provide a quick overview of Oreck and your two late stage programs that are in the clinic right now? Sure. So ORAC Pharmaceuticals is a clinical stage oncology company. Our name really encapsulates our mission, which is to overcome resistance in cancer. As Paul said, we have two late stage clinical programs. The first one, RINC-Z-Metastat, this is an allosteric PRC2 inhibitor. We're studying in prostate cancer in combination with AR inhibitors. And that study, we actually started our first phase three study earlier this year, which was known as Himalais 1. The second program is inozertinib. This is an EGFR TKI. We're targeting two distinct patient populations, both EGFRA typicals as well as EGFX on 20. We had some data in the atypical patient population at ESMO earlier this year, which I'm sure we'll talk about. And we expect to start our first phase three study for that in the first half of next year. All right, fantastic. So maybe beginning with brinzimetastat. So I think it's fair to say all eyes on the space or on the MEVPRO1 upcoming readout for Pfizer's mevrometastat, which will be a possibly defining readout for the class. So maybe just to start with, can you talk about how RINC-E and Mevro differ fundamentally in terms of target, pharmacology, and how that might translate to a potentially different clinical profile? Sure. Yeah, a couple of things on the nuances there. I think both are PRC2 inhibitors, so we're actually going after the same target. We're doing that in a little bit of a different way. So we are actually binding a separate binding pocket on the PRC2. And so as Dominic said, we call it an allosteric PRC1 inhibitor. So we're binding what's called the EED subunit, whereas other molecules before us, the earlier generation molecules, inhibit EZH2, which is the catalytic subunits. So what we've seen from, you know, based on a number of preclinical research, it seems to be very similar pharmacology. You're basically having the same impact on genetic signaling, very similar potency. I think us and Mevrimetastat, very high potency, much higher than earlier generation molecules, very strong in vivo data. And so what we're doing, we're actually inhibiting the target differently. And the main advantages we've seen preclinically is that you can actually have much better molecules binding to that pocket. And I think what I mean by that is just the drug properties are much improved. and being an EED inhibitor in rinzumetastat. And I think everything that you come to select for a molecule, improved solubility, the potency, bioavailability, all of those drug properties that you really want from a preclinical standpoint, that's really where our drug stands out. And so what we've seen in the clinic, I think, for example, is our recommended phase these three doses, 400 milligrams once daily. We've seen really nice PK profile at 24-hour half-life, so it's an easily once-daily therapy. What we've seen from the earlier generation molecules, including Pfizer's mevermetastat, is a very short half-Life. I think we estimate mevernetastat's probably in the three or four-hour half- Life. They have to dose with a very significant amount of drug. The randomized phase two dose was 1,250 BID in combination with enzalutamide. So again, high doses, very frequent dosing. So they're able to kind of have target coverage. And I think with that comes a lot of safety advantages from what we've seen from our earlier data. The data we presented so far from an efficacy standpoint seems to be generally consistent is what we have shown. But where the differences really differ is on the safety profile. And i think a lot the data that other people have reported is a lot is the safety adverse events are really CMAX driven. And so you tend to have those issues when you have a short half-life molecule that is dosing frequently and high doses, whereas we have a much more sustained profile. So at least so far, it seems like we have a much better, more tolerated regimen. And I think we feel comfortable with that so far. We hope, either one, that could play out to patients staying on drug for a longer period of time. Obviously, safety is always helpful. And then two, what we've seen commercially in prostate cancer is that there are a nice analog with AR inhibitors. There's three approved. enzalutamide, apalutemide, and darolutamide. Darolutamid is our combination partner of choice. But interestingly, when you look at that as a commercial analog, that was the third AR inhibitor approved. Indistinguishable on efficacy, very different safety profile. You know, that is now the number one selling, you know, ARPI and approved indications in the U.S. And so I think that's a good example of safety can kind of matter pretty significantly in prostate cancer. But again, our data will you know continue to mature. Yeah and maybe just to add to that Paul as Matt said that we're combining with darolutamide, Pfizer is combining with enzalutamide. Both enzulutamid and apalutemide are acipid users so you have that DDI impact which does require you to increase the dose in order to maintain the exposure. So that could also be driving why we have a better safety profile is what we've seen so far and more or less intrapatient variability. Sure makes a lot of sense. Then, I guess, sticking with the read-through from MEPRO1, the advisor sort of recently sort of honed the timing to February of next year. You know, any thoughts first on that fine timing, and how do you think about the range of scenarios around study success or failure that you're contemplating ahead of the readout? Yeah, so there's been a lot of movements, I guess, with the timing of that study. I think the original primary completion date that they had on clinicaltrial.gov was mid-2026. Then on their Q2 earnings call, they did say that that data would be in Q4. And as you pointed out, on the Q3 earnings call they kind of shifted that to February of next year. The first thing is, if you take a step back, there has been a lot of data of seeing PRC2 inhibitors with combination with AR inhibitors showing some pretty interesting data. Pfizer had, you know, about four or five data sets. We saw another competitor, iGrametastat, that showed some pretty interesting data as well. You saw our data as well. So from our standpoint, there's a lot of good biological rationale and got a lot good clinical data supporting the rationale of combining a PRC2 inhibitor with an AR inhibitor. When we think about scenarios, historically you kind of broke it down into four buckets. There was kind of the big miss, the small miss, small hit, and the big win, let's call it. I think based on the timing and based on event-based modeling, you know, we've done as well as a number of analysts, I think most people would say that the kind of the big miss is probably off the table. And obviously, if we think about what we would want, we'd want them to hit, we think it's further validation for the mechanism. Now, is there a scenario where there's a near miss by Pfizer? It's possible. Obviously, we have to see what that rationale was. One thing to consider, as Matt said, is the safety and tolerability of the regiment. Remember, they started at the 1250 BID dose in a fasted state. They went to the 875 BID in a fed state. There was an improvement on the overall safety and tolerability, but it's still not as good as what we've seen so far. So is there a scenario they saw something that led to more discontinuation? That's possible as well, a scenario where there's a near miss on them, where it still makes sense for us to obviously move forward. But yeah, we're obviously encouraged by the data that they've presented. Most importantly, I think the randomized data they presented at ASCO-GU in 2025, where they They showed the treatment arm did for about 14 months, and that was Mevro plus Enza compared to Enza alone where it did six months, so pretty impressive data for that patient population. All right, so then maybe sticking with the landscape discussion, there was a recent readout at ESMO from J&J that spurred a lot of discussion about upcoming competition, perhaps in the prostate cancer space. Any thoughts on the data and would that mechanism with the Riptac compete with RENZ for the same patients or perhaps be more complementary? Yeah, I think that's a great question. I think, I guess to summarize it real quick, I it's a little bit of both. I think anytime there's a new mechanism, a new program in prostate cancer, there is some competition built in there of just competing for the same patients and things like that. So really promising data. I we're excited to see more. I when generally when somebody announces new data with a new mechanisms, it does tend to have a spotlight on it. So I think it's It's a very promising molecule that obviously J&J will be investing in very aggressively. And so, you know, I think our fundamental view, a couple of things. I think one is just the prostate cancer market is so substantial that there are room for multiple players. And I think it's one of those areas that's just the number of patients that are out there, the approved therapies that are up there. There's such an unmet need across all lines of prostate cancer. So we think, you Know, we've always fundamentally believed there's just a room for multiple players in this market. And I think there's a lot of active mechanisms. And so I think the future in prostate cancer is obviously pretty bright, and I think there's room for a lot different modalities. I think that's one. And then I think two, at least for what we've seen for PRC2 inhibitors so far, especially the mevrometastat data, our emerging data, is that it seems like you can get very long, durable clinical benefit. And I the Pfizer randomized phase two data has really shown people what that mechanism is capable of. I'm not sure if there's another data set that shows patients and previously treated ARPI patients having a long-term PFS of 14.3 months in that study. Obviously, we are looking forward to that validating in a phase three study, but being able to treat patients for a very long period of time, have long durable benefit, we feel confident that there's a very substantial role for PRC2 inhibitors across all lines of therapy. And again, the mechanism is essentially making patients more sensitive to AR inhibitors, which is kind of the longstanding backbone of prostate cancer across all lines of therapy. So we like the promise there. But then three, I think the future of prostate cancer, there is going to be a lot of combination regimens. You can see a lot different modalities are exploring early stage combinations essentially across the field. Obviously, PRC2 inhibitors could be combined with other things beyond AR inhibators. And I I think combining with RIPTAC could also be complementary as well. So I think there's multiple ways to kind of develop each program individually and together. Okay. So your Phase 3, Himalayas 1, has begun as of this summer. So can you sort of briefly remind us of the design of the study, how enrollment is tracking, and your line of sight to a top-line readout? yeah so the the Himalayas one study is very very similar to Pfizer's first of three studies right they have member one two and three member one just reminder when it's metastatic CRPC and these are patients that had seen post post abiraterone patients so we're basically the same patients same patient population our studies around 600 patients Pfizer study just to use it as a reference that studies the treatment arm is expected to do around 10 months The control arm is about 6.75 months, so it's a hazard ratio of 0.66. The controlarm there is physician's choice between AR inhibitor and docetaxel. So for the most part, those studies are pretty much the same as theirs. I'd say the one difference that we're aware of, we did institute a cap on the usage of the control arm between AR inhibitor and docotaxel, so either AR inhibiter or docetoxel can't be more than 60% in our study. just something we did we don't know if Pfizer has done that or not so that study did start early this year so a little too early to tell you any specifics on enrollment and we do expect you know 16 month or so enrollment period and we expecting top-line data let's call it in the first half of 2028 so that puts us about a year and a half or so behind Pfizer okay great and then you've also talked about a potential second phase 3 study that you could initiate perhaps next year. So how do you think about the setting that you might want to go into for this additional phase three study? Yeah, so Pfizer, as I said, is doing three phase three studies. The first one we just talked about, MedPro2, is ARPI-naive metastatic CRPC setting. We do like that patient population, but it's not high on our priority list. And then they have MedPro3, which is the metastastic CSPC setting, which obviously is a very large patient population and a large commercial opportunity. The two that we're kind of focused on right now in determining what the next one would be is both the CSPC setting, similar to MEVPRO3, and then the post-AR inhibitor metastatic CRPC setting. We did show you guys some data early this year, and that data, based on the early data that we've seen there from a clinical perspective, was tracking very nicely. So that's something we just want to see more mature data on to determine if that makes sense. So those are the two that we're kind of thinking about moving forward to. So it would either be the post-ARR inhibitor patient population with Pfizer is not doing phase three study or the metastatic CSPC setting. Now, when you think about the metostatic CSBC setting, obviously it's a larger opportunity. And that's where we really think we could potentially differentiate even more so because these patients are on patients not for 14 months or so, but they'll be on therapy for five years or so. Okay. And you've referred to a possible program update for RINCY in the second half of this year. What do you expect that we could learn at that time yeah so at a conference in every January what we typically do is kind of lay out our milestones for the next call it 12 to 18 months so one of the milestones was a program update in second half of 2026 we intentionally left that broad that could encompass you know many things that the one thing that we expected it to encompass was kind of our view on the mephro one data because we anticipated it in 2026 obviously that shifted into 2027 but so the update could include an update on Himalayas one and kind of where we are a little more details on enrollment could be an update where we thinking about the next phase three study so Himalay's two whether it's the post AR inhibitor patient population or it's a csvc or it could be some incremental data so we haven't committed to anything at this point so it's little bit of TBD okay great so then maybe shifting gears to your second late stage asset and was there any of the EGFR TKI. So this one had some recent data at ESMO in atypical EGF-R mutant non-small cell lung cancer. So maybe can you walk us through the highlights of that data and how you think of positions you compare to others perhaps in the space? Yeah, we're obviously very excited by that data. I think a couple things. So I think one, you know, what exactly what did we present and I think from that is the first line, patient population in EGFR atypical mutations, you know, at our go-forward and now our recommended phase three dose. And so, I think that's a very nice data set, you that really shows, you how our data compares to the landscape. The highlights of it, you extremely high response rates. I think, that's something that people generally look to first for an EGF-R inhibitor, but we're essentially, you 80% response rate or 84% by investigator. So, we feel very good about that. That, I I think, is one of the highest reported response rates we've seen systemically. So we think that that was a nice benefit. The real dramatic improvement that we see, and really the differentiator from the molecule, what has always been exciting to us is that it is a highly brain penetrant molecule. And so we have always seen that preclinically. It was designed to do that. And then from our early clinical studies, we had early signs that that that was the case. And so now I think that's been validated in more patients. But we looked at several different criteria there. but essentially our CNS response rate was 70% by investigator. We also looked at that from a different metric by Raynaud criteria, also essentially highly concordant, pretty close to 70% CNS ORR. And to be clear, that is like ORR activity in the brain as opposed to the way some other people present. It could be systemic response in patients with baseline brain metastases. So this is actual bona fide treatment responses in the brain. Most of our patients actually had untreated brain mets. And so there is no confounding that some patients might have had radiation that could be attributable to CNS activity. And we feel very good about the CNS activity of the molecule. We think that that was very well demonstrated. And I think that got a lot of headlines from KOLs, ourselves, potential investors, and things like that. So we think that is the, you know, one of the biggest differentiator of the molecule. It's very important in this population because the very least about a third of patients present with brain mets just at baseline before even treatment, let alone develop brain metastases over the course of their disease. So a very substantial unmet need that doesn't seem to be well served with other therapies out there. And then thirdly, you Know, safety and tolerability, you Now, looks extremely well tolerated. We had 0% treatment discontinuation rate, very low rates of grade three adverse events, so a very strong profile for an EGFR inhibitor. So we're obviously very excited by that data, and we have already took that data to the FDA and have a phase three trial design that we'll execute next year. So we are very, very happy with the data. Yeah. Sorry, one more thing, Paul. To everything Matt said, I think all the impressive response rates that we saw, we saw a very, I'd say, heavily challenged patient population like as Matt said you typically expect about you know a third of the patients to have baseline CNS mess we actually had 65% of the patient said so other companies you've seen somewhere from 12 to 30 percent we've had 65 percent of our patients had baseline brain mats and again Matt articulated the the responses that we saw both systemically and in the in the brain so I thought that is definitely an important factor as well and it's not like we tried to enrich the study for patients with brain I think it's just a factor of when investigators are seeing good results, they seem to put more patients on the drug with brain mets. Sure. And, Matt, as you alluded to, the data were supportive of a regulatory discussion and a possible phase three design and initiation in the coming future. So can you sort of walk through how you're thinking about that design, Redwood One, the control arm, and when you could kick that off? Sure. is pretty interesting, and it's somewhat similar to another competitor that seems like they're developing it in a very similar way than we are. But it'll be a randomized study, and so it'll be single-agent inazertinib at 80 milligrams once daily versus a physician's choice control arm of osimertinab and afatinib, and we can come back to that in a second. We do have the possibility for accelerated approval, andso this is based on Project Frontrunner. And so it is a randomized study with the opportunity for an interim analysis based on ORR and DOR. And so there is the possibility to get approval on that. And then the study will continue for a PFS primary endpoint that will come after that. We will be enrolling patients with PAC mutations in addition to classical-like mutations. So that's a little bit different than some of the way that other folks are preparing their phase three study. We'll be enroling patients with active brain metastases. And so we'll be enrolling basically all patients, but you can come into our study with untreated brain mets, history of brain mets and no brain mets all qualify for our study. And so, we're obviously looking forward to that. And that will be against the control arm of osomernib and afatinib, which we think, again, those are the available therapies that are used today for atypical mutations, relatively a low bar for success there. As we think about afatinab, technically, that's the only drug approved. It has on label for atypical mutations, but it is only three specific mutations where there is a whole host of potential mutations there. It haves a reasonable response rate of about 66%. Duration of therapy is relatively short, and it's not known to have CNS activity. And so those are major shortcomings with the drug. The other alternative is osomertinib, which is actually not approved for atychicals. It is recommended in the treatment guidelines, mostly because it's a little bit better tolerated than a fat nib, and it's known to be CNS active, although the responses and the level of evidence for data in atypicals is definitely not as good as osomertinib in other areas, and potentially, you know, less than a FatNib. And so, again, we, you know—the data that we've shown so far, we think are superior than what's been reported for both of those potential choices in the control arm. And what do you think about the split that you could see in the control on between Afatinib and OC? Yeah, I think that's a great question. It is probably, I mean, it's hard for us to tell, but it'll probably be biased for Afatinab. That is the approved regimen. There is more data to support Afatinob and atypicals than Osimertinib. And most people seem to be more comfortable with that. The problem with it, it is not well tolerated. Significant treatment discontinuations, a lot of AEs. So a lot of patients probably will not opt to take that. And then two, I think where physicians somewhat have the choice is Afatinib is not known to be brain penetrant. And as I mentioned, you know, a lot of patients come to, you know, come to use Osimertinib because of that. And so, again, they're left with the choice of using a drug that's less effective, although it does have CNS activity. So it's a difficult choice. But we think the bias would probably be Afatinab just because the response rates are a little higher, potentially two-thirds to one-third. But obviously, we'll see how that goes. Okay, makes sense. And then the other side of the non-classical EGFR coin is Exxon 20 insertion, which is obviously a much more crowded space. But you guys are taking a strategy to look into combinations as well as monotherapy. So what can we learn from those data you're generating in the forthcoming update next year? Yeah, so we've sent a lot of data sets in the Exxons 20 space over the last 12 months. We saw some single agent activity from one competitor. We saw a chemo combo that, again, showed some pretty impressive top line data, but did come with a lot of grade three treatmentally adverse events, I think it was like 80%. And then obviously we saw another drug that was doing a monotherapy approach that unfortunately failed. So we're actually taking kind of a three-prong approach here. We're doing it, we're studying it as a monotherapy. We're studying in combination with chemo, and then we're doing a third, which is in combination with imivantamab, and we have a clinical supply agreement that Matt was able to execute with J&J and what we've said here is you know we're gonna run all three out we'll have an update mid next year obviously we see which one of those three cohorts look the best and how that compares to the competitive landscape and then at that point make a decision on whether it makes sense to move forward into a phase three study so a little bit of TBD I think when you think of kind of the benchmarks here as a monotherapy I think you need to be around 60% I think obviously in a combination you want to see something higher than that but it's not just the CNS response right you need to have the not just a systemic response I should say you want to see good CNS response rate as well and obviously good safety and tolerability as well so a little bit of TBD on what we expect on what the landscape looks like at that point in time okay so maybe with the last minute can you remind us of your cash runway and summarize the key upcoming milestones for the company yeah so I think we cover the milestones for the most part but I think from a cash perspective we ended q2 with 388 million in cash and investments that gives us cash runway into the second half of 2028 that runway does assume obviously the himalayas one study in prostate cancer that we initiated earlier this year and it also assumes that we start a phase three study for um for you know certain called redwood one in the first half of next year so next near-term milestones obviously i guess i hate to say it but it is going to be the biggest one is probably the pfizer update for mepro1 and q1 we'll We'll have a second half update as well, a program update on RIN-Z, and then we have the mid-2027 update on ENO on the XM20 patient population. All right, fantastic. So I think that's a good place to stop, but I wanted to thank you guys again for joining us. Yeah, thanks again for having us. Thanks a lot.