All right, excellent. Well, thank you, everybody, for joining us this afternoon. We've got Olema here. We're very excited to talk about both recent and upcoming data- Sure. and the ER space in general with you. So maybe before we dive into the nitty-gritty, why don't I give you a minute or two? What's coming up next, and how you feel you're positioned coming into the end of the year as well? Yeah. Right. That. Great. Thanks, Sean, and thanks for the opportunity and for people in attendance to learn more about Olema. So, you know, obviously, we're a biotech focused on women's cancers, and the lead asset, the one everyone pays attention to, it's not our only one, is our only clinical one is palazestrant, which is a complete estrogen receptor antagonist. And so we've recently, late October, at ESMO in Madrid, presented a pretty large 80-plus patient phase 2 monotherapy data set, which I think was extremely encouraging. Favorable tolerability, daily dosing, good exposure, all that confirmed, but really showing the efficacy potential to differentiate. That's important for our second/third line study, which is a phase 3 study, which is starting this quarter. we presented the data, and relevant to that, with, you know, 7.2, you know, 7.3 months in ESR1 mutant median PFS, which has really not been seen in this field. What that sets us up for and what's coming is combination with CDK4/6 inhibitors, to enable a first-line, trial in ER-positive, HER2-negative breast cancer to begin next year, late next year. So at San Antonio Breast Cancer Symposium next week, on Thursday, we will present a phase 2 data set, evolving phase 2 data set, I would say, of palazestrant with palbociclib, Ibrance. And we'll also present our initial phase 1b data, dose escalation data, with palazestrant plus ribociclib or Kisqali. So PK there is very important. Others in the field have had difficulty with drug-drug interactions, tolerability, both showing that there's no super additive toxicity, but also that there's not a PK effect that leads to poor tolerability and dose modification. And then with, for palbo, we'll get kind of some fairly initial efficacy data. For ribo, it's sure what we have, it's pretty immature, but you will see the ribo PK tolerability from the dose escalation. And then, I mean, to some extent, the punchline is out for that because we have communicated that we're doing the phase 2 expansion with ribociclib, with the full dose of palazestrant 120, with the full dose of ribociclib 600. And I think that's really of interest to the field because palbociclib is not the standard of care anymore. It's ribociclib, and so it creates this really unique opportunity to, to a first-line trial with the CDK4/6 inhibitor of preference, with full dose of both, et cetera, et cetera. So, that's going to be exciting for us. Yeah. All right. Very exciting. Now, there's a lot in just that brief recap to dive into. There is. Let's start with the ESMO data. Mm-hmm. And let's start with how to position that relative to other ER, we call them ER general modulators. Obviously, you're an antagonist, not a degrader. But how do you position your Yeah Response data, your PFS data? You, you cited a particular mutant subpopulation, which is very relevant here. Right. But for you, I think maybe a little less, Maybe. Right. So the way and this, we get asked this a lot. So what is the gold standard? What should you be judged by? And our answer, pretty consistently, is the EMERALD study with Orserdu and their ESR1 mutant subset. And the reason I'm going to tell you how we compare, it's not how we compare that gives us that answer. The reason we give that answer is because what you're all asking is: people who don't work for one of these companies who have evaluated this, what was significant to them? And that data set, 3.8 months median PFS versus 1.9 months in their control arm fulvestrant or an AI, led to approval, right? Right. The FDA looked at it and said, "Hey, this is benefit- Barely a scanning interval. Yeah, right. So there were some caveats in the... But their hazard ratio is 0.55. Right. Which is quite respectable, in fact. And so the FDA approved it, the EMA approved it, right? So you've had these objective experts approve it, and. They're private, so we don't have their sales data, but we can follow scripts. And it looks like they've done quite well in the first 6-ish months of their launch, and so I think that means that prescribers in the United States, which is where the only place it's available now, are using it, right? So you've got a whole bunch of people saying, "This means something to me." Now, in their wild type population, where they didn't really show any effect, they didn't get approval. So we use that 3.8 ESR1 mutant. When you go and look at what we had, we have to be careful with our populations. We do better than 3.8 in our overall trial, but we had 40% fourth-line or later patients. They wouldn't have gotten on to EMERALD. So we took the 50-ish patients that had, 49, I believe it was, that were second-, third-line, ± chemotherapy. That would be eligibility criteria for EMERALD. What you saw in that population was a 7.2-month median PFS. And CBRs and a six-month PFS really consistent with that larger magnitude of benefit. Interestingly, you then go into the subset, that ESR1 mutant there, and you get 7.3 months. So what's interesting there is a couple things. One, obviously 7 months is a lot more than 3.8 months, so that's fairly straightforward and really an opportunity to show greater efficacy in this population because we're a complete antagonist, not a partial agonist-antagonist SERM. The second is the 7.2 versus the 7.3. So that means with the wild type patients in there, where they saw a 2.8-3.8, we didn't see any difference. And what that probably indicates is, with a complete antagonist, you have the opportunity to show activity in wild type patients, which ORSERDU does not have in their label because of this data. So I think that's probably the best way. We, in our IR, compared to a variety of... Tried as best we could, prior CDK4/6 treated, to do comparison to show favorably across a number of agents. But really, it's ORS ERDU that's crossed the finish line. Mm-hmm. Mm-hmm. I, I wanna dive into that, wild type versus ESR1 mutant population a little bit more. Yeah. Because looking at your Kaplan-Meier curves, it does look like there could be some difference there, but obviously it's early and small- Yeah. -numbers. Is there a mechanistic reason we should expect your, Yeah. You know, to have no difference or a lesser difference relative to a modulator? Yeah, that's great. I think there are two answers to that. So what we saw, we pulled out our wild type subset, and it was 5.5 months, which obviously does well compared to 3.8, a little less than the 7.3. Mm-hmm. You're saying, "Well, wait a minute, it was 7.2, I thought." We have some unknown in this, so it's a different. I think you have two things going on there. One is, 5.5 is certainly better than the 1.9 in wild type that ORSERDU saw. It's less than 7.3. What you're seeing in wild type is some of those patients probably have become truly endocrine resistant. That means that they're using a pathway to promote the growth of the tumor other than the estrogen receptor. So it probably doesn't matter in that subset, what you do. But clearly, it's better than what was seen with ORSERDU. That's complete antagonism. OP-1250 palazestrant, when it binds the estrogen receptor, wild type or mutant, locks the estrogen receptor in a completely inactive conformation. Now, in the wild type setting, in those patients whose tumors haven't developed escape pathways, you'll block estrogen binding, and you'll stop that signal. In the mutant, they're always on because these are activating mutations, so it's now not again regulated. So you lock it into an inactive conformation from a constitutively active conformation. In mutant patients, where it's a driver, you lock out. Yeah. In wild type, where some patients, it's still a driver- That's exactly right. You lock out. Okay. I wanted to ask, in the phase 2 readout, you know, you have this second-line, third-line patient population carved out. Could you put that into context, your inclusion/exclusion criteria for phase 3? Because- Yeah. -you have a no- It's a little different. Yeah. It's a little different. Yes. Excellent. So the, as I said, the gold standard that we felt for comparison is ORSERDU ESR1, right? That's the only thing that's been approved. Now, one of the things that Menarini has done really well for the field is publish on retrospective subset analyses of these EMERALD data. They've said, you know, "What happens if you pull out fulvestrant only?" Because everyone's like, "Well, fulvestrant is better than AI." In this setting, it made no difference. 80% of their patients were on fulvestrant. The median was 1.9 in the control arm. If you took the 20% with AI, added them, it was the same. It just doesn't work in this setting. One of the things they pulled out was: What happened to patients who had had prior chemotherapy in their previous treatments? They did very poorly, regardless of what you gave them. And so in our OPERA-01 trial, which is informed quite a bit by EMERALD, I will say, we took that learning from EMERALD, and we excluded the chemo previously treated subset. Other than that, the criteria are quite similar to EMERALD. And we have to get more detail on this question, we have on that same day, I didn't bring this one up, a Trials-In-Progress poster at San Antonio next week on the OPERA-01 trial. So we'll share with folks more detail about that. Great. Um. One thing I will point out, of course, is that AstraZeneca just got approved. With capivasertib. Capivasertib. In a very narrow label. Yes. Yeah. How does that change the standard of care and the like? Yeah, I really don't think it does change much for endocrine therapies. Sure. Right? If you look at how you treat PR-positive, HER2-negative breast cancer, you always have a backbone of endocrine therapy. Your targeted agents may switch in and out, right? Mm-hmm. In the first line, the standard of care is ribociclib- Mm-hmm. with an endocrine therapy, usually an AI, 'cause fulvestrant can do better in that setting, and it's an all-oral regimen. When you progress on that, you continue with endocrine therapy, right? You're trying to keep off chemotherapy as long as you possibly can. So you may give the endocrine therapy alone, you know, currently switch to fulvestrant. If you're ESR1 mutant, you might go to ORSERDU. Or you may say, "Look, I'm gonna switch my endocrine therapy and add a new targeted agent, mTOR, PIK3CA mutated. That was the other class. Yeah, yeah. PIK3CA mutated, and we have alpelisib combo ongoing, too. PIK3CA mutated, we're gonna go over to a PI3 kinase inhibitor. You know, AKT, maybe you consider capivasertib. The point is, you're always keeping an endocrine agent there. Their trial was with fulvestrant, which really I think is a bit of a older standard of care. Older now, not at the time that they started their trial. But I think that that label was also a bit narrower than some of us expected, than some of the data showed. So it'll be interesting to get the approval summary from the FDA, 'cause I'm guessing they had some tolerability issues, and they probably looked at subsets that the company wasn't allowed to look at, 'cause it wasn't part of their pre-specified analysis plan. But would that... They also achieved seven, around seven-month PFS. Does that change your bar, what you want to see in phase three or, yeah? No, I think to be able to treat someone with a single agent regimen, with much less toxicity and get that, it's just a very clear advantage that you wanna be able to do that if you can. One would also ask: What would capivasertib do with palazestrant? Right? Because we know that we have this opportunity to be better than fulvestrant, as ORSERDU is in the ESR1 mutant subset. So I don't think these targeted agents and endocrine agents compete with each other. I think there's actually... You want to have, and I will do a butcher job of it, 'cause Dr. Nancy Lin was asked this question at ESMO and gave this really wonderfully elegant answer, which I will not nearly reproduce presently. But her point was, you, you want options so that as you're looking at the patient's history, the progress of their disease, you're always gonna want an endocrine therapy. Do you have options for endocrine therapies? You want the-- you're going to want different targeted therapies. What have they seen? What do I think they'll tolerate? You're going to want to have options there. And then, obviously, the objective is to push off that chemo as long as you possibly can. Well, maybe that's a good segue to talk about trial slate and development plans from here. Yeah. You mentioned OPERA-01, obviously. But- Yep. If we're thinking about combos, moving up in lines of therapy, replacing fulvestrant in combos with targeted agents. Yes. Where are you most excited to go next? Yeah. We're most excited to go into the first-line setting and do that with ribo, ribociclib. The data that we're generating, you know, we just expanded the ribociclib combo trial in collaboration with Novartis. And, you know, a little bit... First, we've already said this publicly, but foreshadowing what you're going to see at ESMO, we're in the phase two at the full dose of ribo and the full dose of palazestrant. So you kind of have an idea of what we saw PK tolerability-wise to be able to enable that. The objec- Maybe to put that a little bit into context. Yeah. Ribo obviously becoming standard of care now. That's right. U.S. data, but combinability has always been a bit of a challenge. It has been a bit more of a challenge. It doesn't cause as much neutropenia. Yes. But it has a QT prolongation signal. And palazestrant has no QT effect in the clinic through 300 milligrams daily, which was the highest dose we tested. We never identified an MTD, and no DLTs, and it has no hERG effect. So we give full doses of both. But if you are going to increase the exposure to ribo, you worry about arrhythmia. You mean, because you have a drug-drug interaction- That's right. or a metabolic issue? That's right. That's right. That's exactly right. But yeah, the first-line setting is where we wanna go. We would be enabled to do that with ribo, late next year. Mm-hmm. We do need some more capital in order to be able to do that. The OPERA-01 trial, the second-, third-line, we have all the money. We're gonna finish that one out and go past our top-line readout with our current cash, but we do not have the cash to do that, so we will be seeking partnership and some sort of, Can you talk a little bit about what the partnership opportunities would look like? Yeah. And what are you most focused on? Obviously, in a single tumor type, it's tough to carve out indications and stuff. Yeah. So, what kind of a partnership are you thinking of? Yeah, we wouldn't do an indication carve-out. It would be, it would be... You know, actually, I think the Arvinas Pfizer deal is one example. It's not an unusual structure where, where, you know, you have to keep enough that it's not a cheap acquisition, right? Mm-hmm. You have to keep upside for Olema shareholders. That's our responsibility to them. And they have been a patient group, by and large. So we feel quite strongly about that responsibility. So, you know, you can do things like share profits, but book sales and keep U.S. sales and co-promotion and things like that. So there are ways that you can carve these sorts of- Co-development. Co-development. Co-development, maybe, you know, joint governance, sharing costs. Sure, sure, sure. You know, some upfront, that profit sharing down the road with questions about how do you book sales? How do you promote together? There's some obvious, you know, choices there, obviously. Yeah. Yeah. Yeah. Yeah, I mean, so there are some obvious choices. I mean, everybody goes to Novartis because they don't have a program. They don't have a CERAN and endocrine therapy program. They actually have a pretty good CDK 4/6 program- Yeah which is thriving. So, and they're our partners, so we interact with them a lot. But, you know, any company that... Yeah, you know, that second, third line market is $5 billion plus in the United States. Got it, yeah. If you get, particularly if you get the wild type, right? You add in another probably $10 billion plus if you're in the first-line setting. Any company that needs a multi-billion-dollar market opportunity- Many of those, You know, maybe before the end of the decade, it probably helps if you're in oncology, you know, second largest cancer diagnosis in the world. They could all be potential candidates. Makes sense. As we're running out of time at the end here, final thoughts, what else do people really need to be focused on as we come into, well, San Antonio next week, obviously, but coming into 2024, what should we be on the lookout for? Yeah. I mean, in San Antonio, you're gonna see data from a number of things. You've got to be very careful with who are these patients? What are the doses being given? What's the tolerability profile here? Because you can't do something in phase 2 and then not do it in phase 3 and say, "Oh, this, we're reading this through to that." That's important. For 2024, KAT6, we got a pipeline, so very excited to update people on that. We could have a development candidate nomination fairly soon, and that'd be- Of course, Pfizer has a program there as well. Yes. Obviously we'll be. Yep, yep ... looking very carefully. We're looking to differentiate. Their data at ASCO was quite interesting, I have to say. Well, excellent. Lots of news coming and a very exciting set of data recently announced. So thank you so much for joining us and going through it. Thank you, John.