Thanks for joining the Oppenheimer Conference. Super excited to do a fireside with my next company, which is ORIC Pharmaceuticals, which I cover the Outperform rating. Perfect timing here. Jacob Chacko, CEO. Let's talk about the MEVPRO abstract that came out last night, I guess unexpectedly from it's going to be presented later this month at ASCO GU. Obviously, you have a program, ORIC-944. It's a PRC2 inhibitor. A lot of overlap between MEVPRO and tazemetostat. You know, the data from Pfizer clearly was better than we had expected. Basically doubled rPFS, 80 patients, randomized control arm enzalutamide performed exactly as expected. Drug is clearly active, although it does have PK liabilities, which I think yours corrects, at least from the data we've seen.
Yeah, I mean, walk us through kind of your, like, high-level impressions of the Pfizer abstract and kind of what the read-through should be to your program.
Thanks for having us, Matt. I'm joined by Dominic Piscitelli, our CFO, as well. The Pfizer MEVPRO randomized data have been long awaited by ourselves and several others, I think, because of the strong read-through to our own program, ORIC-944. Both programs target the PRC2 complex. The PRC2 complex, of course, has been implicated as one of the therapeutic potentials is to combine a PRC2 inhibitor with an AR inhibitor. Pfizer's now demonstrated the first meaningful proof of concept there, showing that that's possible, and like you said, in a randomized setting. I think what's important here is even before this abstract was released yesterday, I think all of Pfizer's body language was pointing to quite a strong signal effect that they must have been seeing.
As folks probably know, they started two different phase three studies with this program, MEVPRO -1 in Q3 of last year and MEVPRO -2 in Q4 of last year, and then at JPMorgan earlier this year, they said that they're going to start a third phase three study, MEVPRO -3, in the castration-sensitive setting, those first two studies being in the CRPC setting, but a third study in the castration-sensitive setting that they intend to initiate first half of this year. The reason I mentioned that is because obviously the body language is quite strong from the phase threes that they had committed to, and then if you're going to go into CSPC, that probably means you're seeing a strong signal, and I think we saw in the abstract yesterday, our impression was the same as yours, Matt. It was better than anything we had expected.
H onestly, going into this update that, and we'll certainly see more details on Thursday, you know, at ASCO GU beyond, you know, just what was in the abstract, but what was in the abstract alone was far beyond our upside case, and what I mean by that is we were hoping to see a 0.65 or 0.7 hazard ratio on PFS or better. The way we get to that is you look at recent prostate cancer drug approvals. They're 0.65 or better on PFS hazard ratio, but even more directly, folks may not know this, but Pfizer has powered MEVPRO -1 and MEVPRO -2, the two phase 3 studies, for a 0.66 PFS hazard ratio. You can find that in their clinical protocols, which are available on the EU equivalent of clinicaltrials.gov, and TALAPRO-2, another big prostate phase 3 study for Pfizer, is powered at a 0.69 hazard ratio.
I n other words, everything kind of in that 0.65-0.7 range that we've been talking about, we were hoping to see better than that. When we looked at the abstract, you know, frankly, Matt, before seeing the abstract, I was a little worried. What if their number is, you know, 0.63 or 0.64, something that would be viewed as on the cusp? And is there going to be a big debate about it being on the cusp? So I thought ideally they can creep into the 0.5s, like 0.59 or something. And instead they're at the bottom of the 0.5s. They're at 0.51. It is a really strong effect they're seeing. And on top, the next area of focus for us was how did the control arm perform? Because you've seen one example, at least with Tazemetostat of a really anomalous control arm.
We didn't want the control arm to dramatically under or overperform what you'd expect. In this post-abiraterone population in which 45% of the patients had prior chemotherapy, you'd expect about five to six months of PFS from enzalutamide. And they were, they nailed it. They were right at six months. And so then you look at the, so nothing anomalous with the control arm. And then you look at the treatment arm. And the treatment arm got 14.3 months of PFS, radiographic PFS, which is just astounding when you try to do. So a couple of different benchmarks there is, as I mentioned, enzalutamide should do about five to six months, five to six months of PFS in that setting. They got six months.
Of course, in a phase 3 randomized study, you are going to need to allow, and MEVPRO -1 is designed this way, and we would design our phase 3 in this setting the same way, which is you're going to need to allow chemotherapy as well as a physician's choice in the control arm. And chemo obviously can do a little bit better than enza in that setting. Probably you'd expect seven months, maybe eight months if chemo does quite well. What they've done here, and I'm not sure people appreciate it, is they've given themselves so much buffer that they could be an entirely chemo control arm. So, you know, enza in that setting should do six months. Chemo does seven or eight months.
In that physician's choice, they could literally have 100% of physicians choose to give chemo, which is obviously not going to happen, but they could choose 100% of physicians to give chemo. You could, chemo could outperform. You could have an eight-month PFS, and they still have half a year of buffer with their treatment arm above and beyond that. It's just astounding, and then the other kind of frame of reference we do here is just a sanity check. You know, look at Pluvicto. Pluvicto has obviously been a successful drug. It's done quite well commercially. Pluvicto, people will remember in the pre-chemo setting, so pre-chemo, it got 11.6 months of PFS, and in the post-chemo setting, it got 8.7 months of PFS. So Pfizer here with a 45% chemotherapy-experienced population is giving 14.3 months.
It just, it knocked it out of the park in every different way we might want to see. On the safety side, the safety looks fine for a late stage, you know, late-line prostate cancer population, you know, diarrhea, dysgeusia were things that were noted in the abstract, which we've already known about. They did note, they note sepsis in the abstract as well. Obviously, you know, all of the abstract AEs they listed were treatment emergent AEs, not treatment-related AEs, so hopefully we'll see on Thursday whether they're able to do some attribution of those AEs, and bottom line is we look at that as potentially another area where ORIC-944 could differentiate. Because as you alluded to, we have better PK properties. We've got a 20-hour half-life, whereas they have a four-hour half-life, so we're dosing QD, whereas they're dosing BID.
The randomized data we just saw were 1250 BID, two and a half grams of drug per day. That obviously alone, the drug load alone can lead to some GI effects. So we think that, you know, there's plenty of ways that we can differentiate. And the bottom line, and then I'll stop with my monologue here, is that this is such a large indication you're talking about. I mean, just the two CRPC studies that Pfizer is doing in MEVPRO -1 and MEVPRO -2 collectively is a $5-$10 billion TAM that you've got the perfect analogy there that we don't have to be better than their drug. We just have to be as good. But there's actually lots of reasons to think that we might be better. And the perfect analogy I'm alluding to, of course, is look at the AR inhibitors.
Enzalutamide, apalutamide, daralutamide collectively do $11 billion a year in sales. And they have undifferentiated efficacy between those three drugs. And yet Daro, which is the third one to market by many, many years, last year did $1.6 billion of revenue, growing 70% a year. So my point is our goal now is it's game on. With the 0.51 hazard ratio, we need to just go pedal to the metal, close the timeline gap with Pfizer as much as we possibly can so that, you know, we're something like 18 months behind for our phase three intervals. And the other thing, Matt, I should just note, sorry, one other note is I'm also not sure people are appreciating that the size of these trials is actually quite manageable and small in the grand scheme of things.
Pfizer's already said for MEVPRO -1 and MEVPRO -2 collectively, those two phase three trials in CRPC are 1,500 patients. That's exactly how we would size those trials. Although I'd say those trials, given this effect size of 0.51 hazard ratio, are clearly overpowered for what they're trying to achieve. And so, you know, to run two trials, 1,500 patients total across the two trials is $200 million. It's eminently doable, certainly for Pfizer, but even for a small biotech like us. Let me pause there and see if Matt wants to add anything.
I would agree with everything you said. I mean, I think the two main pushbacks that I've been getting this morning, one on the safety, you know, the nausea, vomiting, diarrhea, you mentioned it. I agree that I think given their grams of dosing, that some of this could even just be caused by the excipient. On the neutropenia, you know, we've seen this with other epigenetic modifiers like tazemetostat. It might be on target. Do you have any, maybe, I mean, if you look back at your phase 1, do you have any data to kind of suggest any differentiation there? Or if not, I mean, maybe it's not, you know, it's not like neutropenia is like super dose modifying. So I don't know if you had any thoughts there.
For PRC2 inhibitors in general, and you can, folks, go back and look at the Tazemetostat label, you know, you can see this as well. There are two major classes of tox you would expect to see. One is various forms of heme tox, of which neutropenia would be one, because obviously you do have an effect on the bone marrow. And then the second major category would be GI tox.
And clearly you see both of those things in Pfizer's data. You know, in our own single agent experience, you know, we saw both categories of tox. Although, you know, I think as folks probably are well aware, the vast majority of our single agent tox experience was grade one and grade two. We had to push dose, you know, 50% past kind of the go forward dosing level to get to the grade three AEs.
Even then it wasn't much. It was really around, there was some heme tox there without grade three diarrhea. We do think there's ways to continue to differentiate versus Pfizer there. You know, again, at the end of the day, this is oncology. This is, you know, late-line prostate cancer patients. You know, heme tox and GI tox are kind of, they're par for the course.
I agree. The only other pushback.
You put that in the context of, you know, the tox that you see with some of these other, you know, great modalities that are out there for the same prostate cancer populations, and, you know, obviously you would take heme tox or GI tox any day over something like CRS.
And Matt, you know that the doses here in the randomized phase 2 study was 1250 BID. The doses they're using in the phase 3 is 875 BID. They did have some commentary in the abstract that they got the same exposure with food with 875 than they did at 1250 on an empty stomach, and they had better safety as well. So that's just something that we're obviously going to hopefully see some additional data on Thursday. And lastly, you got to think of the fact they're starting three phase 3 studies. And, you know, one is in the post-abi setting, which is the same data set that they, same patient population that they just shared. And then the other one is actually in earlier lines. This is patients who had failed ADT, had not seen, you know, an AR inhibitor.
Then lastly at JPMorgan this year, they announced even an earlier one in a castration-sensitive setting. So I think there's just a lot more to learn on the safety side. I think there's a lot of vagaries in the disclosure today. So we'll wait and see what happens on Thursday.
That should be exciting. The only other pushback that I do get from maybe just some of the non-believers in epigenetic modifiers and the mechanism of action is really the only thing maybe that I could point to is that the PSA50s are a bit low. Now, the counterargument to that is that the PSA50s like doubled since the phase two, but they still are in the combo like around 35%. And I think people will automatically compare PSA50s from something like Pluvicto. I remember when I covered Ambrx, 50% PSA50 was the bar.
I s there something mechanistically going on where maybe we're not seeing as robust PSA responses, but we're still translating to really nice improvements in radiographic PFS?
Absolutely, Matt, which is without maybe boring folks on the nitty-gritty of the biology. You mentioned PRC2 is an epigenetic modifier. One of the genes it modifies is called KLK3. KLK3 has a direct impact on PSA levels. So it pushes up PSA levels. And so any PSA effect that they or we are able to see is despite the mechanism essentially pushing up PSA levels. You're basically overcoming that confounding. And so it's not a surprise to see PSA50 levels that apples for apples might look lower than, you know, PSA50 levels of other active therapies that aren't having that same impact on the KLK3 gene.
Then at the end of the day, I always kind of say, look, if you've got a mature PFS in a randomized data setting, and that is the regulatory endpoint for the FDA, that's the regulatory endpoint for Pfizer's phase three studies, I probably wouldn't, you know, get too twisted up on the PSA50s. For what it's worth, because, you know, at JPMorgan about a month ago, we presented two cohorts' worth of patients very early on in our dose combo dose finding work. The reason we presented a PSA waterfall plot there was obviously because we're only a couple quarters into our dose finding work, and we don't yet have anything that's a mature PFS. And so kind of to your point, to see if PSA could be a proxy here of just showing some level of activity.
In those first six patients, we had three patients that achieved at least a PSA50 that was confirmed at 12 weeks. Two of those were PSA90s. And one of those PSA90s was ongoing at 38 weeks and counting at that time. And so, you know, just a level set for you, you know, in that post-apalutamide population, you'd expect that apalutamide alone would get about a 20% rate of PSA50s and a less than 5% rate of PSA90s. So obviously we're not trying to make more than it is, you know, on an N of six data set, but we should have had to enroll 20 patients just to get one PSA90, and we had two in the first six.
Totally agree.
Another point or two, Matt, on the PSA response. Obviously, it's a little tricky comparing against cross-trial comparisons, but I think you had mentioned Pluvicto. Them having a 50% PSA response rate, I think that was in the pre-chemo setting. So obviously, the data is a mix of post-chemo and pre-chemo. So I think that's one point. If you look at Pluvicto in the post-chemo setting, I think the PSA responses are a little bit lower. And then plus that was Pluvicto in combination, you know, with standard of care. So I think a couple of things to look for there. And I think what's usually most important is having PSA responses. I think one are confirmed. And so I think they give us that, which not everybody cites confirmed responses. And then two, it's always the durability of the PSA responses. So we'll see if we see anything there.
But I think as Jacob said, having a really nice durable radiographic PFS, which is the key regulatory endpoint, you know, is pretty promising there.
T hat makes sense. Walk us through kind of expectations for further data disclosures this year from that phase one, either monotherapy or in combo. I know, you know, as part of the JPMorgan package, you had these first two cohorts. But, you know, what are you thinking in terms of dose escalation? Have you reached an MTD yet? You know, what's the current status of this and when are we going to get more data from it?
T he big picture roadmap here, Matt, is at some point in Q2 here, we would like to have selected our provisional recommended phase 2 doses. As you know, for Project Optimus, you need two provisional RP2Ds. At some point in the second quarter here, we hope to have that in hand for both of the combos that we're running. So as folks probably remember, we're doing a combo with apalutamide that is supported by Janssen in the form of free drug from Janssen. And then also a combo with daralutamide, which is Bayer's AR inhibitor, which is supported by Bayer as well. And, you know, we'd like to have our provisional RP2Ds for both of those combos at some point in Q2, then spend the rest of the year basically doing dose optimization at whatever those two dose levels are in order to satisfy Project Optimus requirements.
So, our next data milestone update here is that ideally by the end of this year in Q4, otherwise in first half next year, we would have the next data update for our combos of 944 with those two AR inhibitors. The ultimate goal from a big picture perspective, Matt, is to have picked one RP2D and one AR inhibitor that would be our chosen horse, so to speak, such that in the first half next year, we would start one phase three study in the CRPC setting, or potentially a second one as well. We'll have to see. We really like that post-AR setting in which Pfizer is studying. Obviously, it's the randomized data set we just saw with the super strong hazard ratio. That's also the setting in which they're doing their MEVPRO -1 study.
It's kind of a TBD as to where our second CRPC study might land.
Got it. I'm getting quite a few questions. By the way, if you want to ask a question, you can email me at matthew.biegler@opco.com. One is on tazemetostat, which you mentioned had that wacky control arm. I don't think tazemetostat's a very good drug. You've done preclinical head-to-head studies and you've shown it, but just to maybe quell anybody else suspicious out there, why did that tazemetostat study not work?
T he tazemetostat study, I mean, tazemetostat is in many ways a poster child of poor drug properties. It's got a two-hour or less half-life. It has CYP autoinduction. And so, you know, effectively, you know, Epizyme actually showed this data. They were kind of famous for this of showing a PK chart where they have dose-dependent decreases in exposure. The more drug they give, the less exposure they get, because basically the drug, you know, has an interaction with the CYP enzymes that then metabolize the drug. So there's a lot of reasons why tazemetostat was not a great experiment. And then the really funky control arm that you saw out of the randomized data set they presented last year, I think is less about maybe the tazemetostat properties, more about the patient population they enrolled.
They clearly enrolled a very indolent population because their control arm alone was over a year in PFS.
So Pfizer, 50% taxane exposure. Everyone had prior Apalutamide. I mean, this is clearly much, much higher pretreated. And the fact that they got that six month, I mean, that's very consistent with PSMAfore and ARPI switching and everything else we've seen in the past.
Exactly what you'd expect. Yeah. And sorry, Matt, you were going to Matt Panuwat, you were going to add something?
No, I was just going to say just on the preclinical profile in general, if you kind of go back and look at tazemetostat, it wasn't really designed for prostate cancer. They were really going after the EZH2 mutant in follicular and DLBCL. And so much more sensitive cancer than prostate. But we've seen both on the data we've published and both on the data that they presented, their in vitro potency is very low in prostate cancer. And so us and mevrometostat are much more potent PRC2 inhibitors than tazemetostat. I think that's one. I think Jacob touched upon all of the PK issues that tazemetostat has that Pfizer fixed several of them that we believe we fixed as well. And then if you look at what tazemetostat has shown in vivo, they have almost no in vivo activity with tazemetostat in prostate cancer models.
That's very different, I think, than what we've seen preclinically and what Pfizer has shown with mevrometostat preclinically. I think different molecule for sure. Then I think we've pulled out the trial design tweaks, you know, kind of nuances there too.
There are some questions on, you know, how long do you think it will take to develop this drug? I mean, I think you touched on it a little bit earlier with MEVPRO -1 and 2 being collectively 1,500 patients. You know, there's questions on whether you would, you have the bandwidth to run these trials on your own, or would you ideally seek out a partner? You've already got clinical trial supply agreements in place. And also just kind of a question on kind of where does your cash take you right now? And after I answer these, I want to go to the Exon 20 program, which I also think is pretty cool.
Definitely. Matt, I could start out there and then Dominic can talk about cash runway and whatnot. So just to kind of level set for you on, you know, sanity checking what we're saying, which is that these trials ought to go quite quickly. You know, we're trying to start, like I said, one or two CRPC studies, phase three studies in the first half of next year, first half 2026. And we would anticipate that in the second half of 2027, we would be in a position to submit NDAs to the FDA. And the way you can sanity check that is you look at Pfizer. So Pfizer's MEVPRO -1 study, which started Q3 last year, has a primary completion date of end of this year, end of 2025.
MEVPRO -2, which started in Q4 of last year in that treatment naive prostate cancer setting, has a primary completion date of mid 2026. They've already been on record saying that for MEVPRO -1, they intend to launch, not file, launch in 2026. And then we're assuming that based on the timelines they've laid out, that for MEVPRO -2, you know, with a primary completion date of middle of next year, that they'd be anticipating launching in 2027. So these are fast trials, and especially with the signal effect size that they showed, you know, quite doable. Certainly for us, Matt, we fully anticipate, because like I sized it for you, 1500 patients at any reasonable cost of per patient, you know, in this CRPC setting, you'd be assuming about $200-ish million, just or just over $200 million to run both phase 2 CRPC studies.
That's something that is clearly from a financial and operational point of view with 1,500 patients total across two phase 3s, you know, in our purview as a small biotech. In fact, our head of clinical development at ORIC was the head of clinical development for Aragon that developed apalutamide. And we know every prostate KOL out there in the business, including Charles Sawyers and Rich Heyman, who are two of our founders. So the short answer is yes, we can do the two CRPC studies ourselves. You will not see ORIC announce a CSPC study like MEVPRO -3 that we're going to apply ourselves.
That, in other words, that's where, you know, for something like that is certainly where we want to partner on board like a Bayer or a Janssen, or frankly, Merck, Novartis, AZ, Roche, anybody with a big interest in prostate that doesn't have their own AR inhibitor. So any of those parties could help us do that. Then Dom, you want to talk about just the cash runway?
So at the end of Q3, we had $282 million in cash investments. Our guidance is till late 2026. So it does get us through all the catalysts, seven catalysts, and we'll talk to you about ORIC-114 shortly. But that's an all-in number, Matt. So that assumes that we're involved in multiple registrational studies for ORIC-114. That does assume we're starting one or more phase three studies for ORIC-944 as well, all the associated CMC costs. That's not a risk-adjusted number. So we've got a good runway. We've got a number of catalysts ahead of us that we'll talk through as well.
Okay, cool. Let's talk about 114.
One quick detail, I think, to kind of round out Jacob's comment on just the speed and the size of these studies. One of the major things that Pfizer has going for them in their phase 3 studies is the primary endpoint of rPFS. And so that is a big advantage. When you look at the recent studies that Merck has initiated or Amgen has initiated, the phase 3s in prostate, a lot of those have a co-primary of overall survival. And so again, an overall survival endpoint has to be much bigger, much longer. But Pfizer is able to kind of keep these studies to rPFS. And so that's kind of how they have these pretty aggressive enrollment kind of approval launch timelines, much better than what we've seen for other programs in prostate cancer.
Makes sense. 114, brain penetrant, Exon 20. I mean, the main pushback I get is that it's a crowded market. It's not a huge indication. But I kind of feel like this could be a sleeper program here. And the reason is because you have recently announced that you have a clinical trial collaboration with J&J to pair this thing with amivantamab. And I think that's really interesting because we know amivantamab is not brain penetrant. We know from Mariposa that it needed the CNS activity from lazertinib to beat osimertinib. It seems like a similar strategy here that you're going for Exon 20, and you could potentially go front line. Is that right?
That's right, Matt. Yeah, you nailed it. So, you know, amivantamab, Janssen. Janssen has obviously made a big deal with amivantamab combos with lazertinib in the classical mutations, as you talked about the Mariposa studies, and then also for atypical mutations. Both of those populations are places where lazertinib has CNS activity and also has good potency. Lazertinib does not have good potency for EGFR Exon 20. So Janssen wanted to do the same kind of combo approach with the brain penetrant TKI that was potent for EGFR Exon 20. You alluded to it. This is a crowded space. I think people should take a step back and think, why did Janssen choose to partner with ORIC-114 to do that combo and not one of the many other drugs in the space?
I t speaks to the profile that we continue to see with 114, which is that the drug is well tolerated, doesn't have the off-target toxicities of lots of these other drugs, has done a nice job of minimizing EGFR wild-type related toxicities, and then most importantly, has shown CNS activity. And we've done that in a very pretreated population. So as we kind of roll forward, Matt, to the first line strategy, you know, every drug in the space, in the EGFR Exon 20 space, has done one of two strategies. It's either, you know, you go head-to-head with chemo for your confirmatory trial. Obviously, mobocertinib tried and failed. There's a couple of other companies that are trying that now.
Or you combine your drug with chemo the way that amivantamab did and, you know, one other drug in the space is doing, and then you compare to chemo. Either of those would be an interesting path forward to us. But a third path that would be super interesting if this dose-finding work with amivantamab shows that you can combine the two safely would be to combine it with amivantamab, where you get broader mutation coverage with the two mutations. You get the brain penetrance of 114, and then you get the MET coverage from amivantamab, which is obviously a resistance mutation for EGFR Exon 20.
Yeah.
Then on the population side, Matt, I would just say folks should do their work on more than just EGFR Exon 20. Atypical EGFR mutations is clearly; it's a bigger population than EGFR Exon 20, and it is a less crowded population than EGFR Exon 20. That is definitely on our radar as well as another high, high area of interest for us with ORIC-114.
Matt? This is the atypicals, yeah.
J ust to round that out, I think, Matt, just the clinical collaboration we have with Johnson & Johnson, that is focused on front line, first line patients only. And so that is the focus of that combination.
Right. We got a minute left. Jacob or Dom, if you guys want to just maybe run through catalysts for this year, and then we'll wrap it up.
S o first half of this year, we have the second-line EGFR Exon 20 and HER2 Exon 20. That's the first half. Second half of the year, we have the second-line atypicals as well, EGFR atypicals. And then first half of next year, let's just go through. They got monotherapy, first-line EGFR Exon 20. And then mid-2026, we have the combination with amivantamab in the first line we just talked about and the atypical first line as well. So, and then for 944, as Jacob mentioned before, the data readout on that, the next data update would be either Q4 of this year or first half of next year. So we've got a full slate of catalysts over the next 18 months.
All right. And we're out of time. That was awesome. That was like rapid fire. Thank you so much, guys. It's always fun.
Thanks, Matt.
Thanks.
G reat seeing you. Thank you.