Thanks everyone for joining us today. My name is Anthony Yu. I'm an executive director in Morgan Stanley's healthcare team. I'm joined here on stage with the President and CEO of Olema Oncology, Sean Bohen. Thank you so much for being here today. Thank you. It's a privilege to host you, so why don't we just jump in and get into some questions here? Sounds great. Starting high level, with Orserdu now in its second year of U.S. commercial launch, and- Right The continued accumulation of real-world data around the switching of CDK4/6 inhibitors that have been on the market for some time now, how do you view the evolving treatment paradigm for ER-positive, HER2-negative breast cancer? And, you know, sitting here today, how would you describe the patient need? The treatment paradigm has really not changed from the standpoint of the paradigm. I think what's changed is the options, right? If we go through that treatment paradigm, it's pretty simple. If you're diagnosed with advanced or metastatic breast cancer, you get CDK4/6 plus an AI. That CDK4/6 now is Kisqali, it's ribociclib, based on the survival data, unless you have a contraindication, which is a small percentage of patients. When you progress on that treatment, that treatment is unfortunately not curative, so patients will progress. What comes next is not a regularly defined standard of care. It's more like a menu, right? A lot of factors go into choosing what the options are, and there's always an endocrine therapy. That's the backbone. Sometimes it's given alone, right? No one wants the shots. If you have a mutation, no one wants the shots. Not particularly effective. Mm-hmm. For the mutation-positive patients, Orserdu, it is an option. Uh-huh. Combinations are also options, and you'd like to give the best endocrine agent with a combination agent. Could be another CDK4/6, although the data doesn't indicate any efficacy- No, no- for CDK4/6 after CDK4/6. It's really kind of mediocre failed trial after- Yeah ... failed trial. Palazestrant monotherapy maybe looks better than CDK4/6 after CDK4/6 data. So there's a huge need for more treatment options as you go into that- Mm-hmm - progressed post-CDK4/6 population, because what you really want to do is keep off chemotherapy as long as possible. It has a lot of side effects. It's not good for quality of life, and frankly, once you've started it- Mm-hmm It doesn't go in a good direction for the patients. You want to keep an oral targeted therapy as long as possible. So there is an ongoing unmet need, both in terms of- That's what you get. ...monotherapy options, which will be endocrine, but also combinations with targeted agents, which is why we're doing the everolimus combo- Mm-hmm right now. And then the need for more agents, which is why we have the KAT6 inhibitor, OP-3136. So that's- Yeah That's the paradigm. Got it. Maybe just on the first line specifically- Yeah The opportunity is quite significant. And as you mentioned, aromatase inhibitors are used here with CDK4/6 inhibitors. What are the limitations of the AIs? And, you know, those were originally approved in the nineties. How do you see the new class of SERDs, you know, being able to overcome some of those limitations? Yeah. So the important part about palazestrant is not being a SERD. I don't think the SERDs really do overcome the limitations because they're for two reasons, primarily. One, they're not complete antagonists, many of them. And the other is they don't combine well with the CDK4/6, right? So you have two things you have to do. You have to shut off the estrogen receptor completely, which AIs don't do. AIs don't, in fact, bind the estrogen receptor at all. What they do is they decrease the peripheral conversion of progestins to estrogen, so they help suppress the production of estrogen in the body. But a couple things happen. One is you can develop, obviously, an ESR1-activating mutation, and then that is now not a ligand-regulated transcription factor. And so you need to bind that and shut that down. The AIs don't do that. For those wild-type patients who progress, we're seeing evidence. We see it from palazestrant in a wild-type post-CDK4/6 with a 5.5-month median progression-free survival. In a monotherapy data, there's a subset of those patients who are still endocrine dependent, but the AIs aren't completely suppressing that. So there are multiple opportunities to beat the AI in combination with CDK4/6, but you have to bind and completely shut off the receptor, both wild-type and mutant, and you have to be able to combine with CDK4/6, not only palbo or Ibrance, but ribo, which is tougher, because if you increase exposure to ribo, you're going to not only get neutropenia, you're gonna get QT prolongation. And we've demonstrated very clearly we get none of that. Got it. At full doses, by the way, of both agents. One more question on the landscape, the treatment landscape, before turning to your pipeline. What are your thoughts on the next generation CDK4 and CDK2 selective agents? You know, are those, in your perspective, incremental or meaningful changes relative to the current CDK4/6 inhibitors? Yeah. So CDK4 is pretty interesting, right? It's very clear that the neutropenia is primarily a CDK6 targeted effect, and that you can dial that out to some extent by decreasing CDK6 and increasing CDK4. The evidence is that doesn't do anything for efficacy. It actually may hurt you, right? Why do I say that? Well, Verzenio is basically abemaciclib, is basically a CDK4. It's given continuously. There's no dose holiday for neutropenia. Neutropenia is a small component, but it's very seldom a dose-limiting. It's not a dose-limiting toxicity for that molecule. So biologically, you can see that it's dialed out the neutropenia, the CDK6, and yet the survival benefit is from Ribo, which is a little more CDK4 selective than Ibrance, but not that much and still has neutropenia, the dose holiday, things like that. You have to recognize that there is no less neutropenia pathway to approval in cancer. You have to have better efficacy. Mm-hmm. I think it's very risky to think that you can dial out CDK6 and preserve that efficacy, particularly with three of three trials with survival as the bar. You go against CDK2. Just really haven't seen any data to indicate... Obviously, if you're gonna do CDK2, you have to do it on top of 4/6. Mm-hmm. So there's a tolerability question. So we watch that space carefully. We certainly, you know, one of palazestrant's great attributes is its combinability. So if something's coming through, we want to combine with it. But at the same time, we'd like to see some evidence of activity. Everyone's gonna go after this. You mentioned it before, Anthony. That first-line market is greater than $10 billion. You know that 'cause you can take the current CDK4/6s and say that's what it is. Yeah. Yeah. Yeah. It's just gonna grow from there, so it will attract attention. Got it. Okay. That's really insightful to kind of hear- Sure the distinguishing factors there. So zooming in on palazestrant then, you continue to build the body of evidence around the molecule, in advanced and metastatic, ER-positive, HER2-negative breast cancer, you know, both as a monotherapy in the later settings, and in combinations with CDK4/6 inhibitors for the frontline. You know, and you mentioned the combinability, but what other characteristics of the profile, you know, that the data is bearing out, are you particularly excited about? Yeah, I mean, I think ultimately the molecular attribute is a complete antagonism. Unfortunately, the field has been misguided by the whole degradation part, which goes back to fulvestrant. Degradation is an attractive idea, right? Something is bad, and you make it go away. It's an almost toddler-like view of the world. The only problem is it doesn't work because the degraders do decrease the amount of ER, but not substantially. You go from a 40-fold excess to a 10-fold excess, ER-positive, PR-positive. Not a real thing, and we've seen that play out. So you have to bind the receptor and lock it in an inactive conformation. If you think about the concept of a significant proportion of the receptor being there, right? In vivo, it's about 50%. If that's mutated, it's just signaling like crazy 'cause it doesn't even need estrogen. So complete antagonism is absolutely a key, but then, as I mentioned, you have to occupy the receptor all the time, so you have to have good oral bioavailability. We have an eight-day half-life. We have a very high exposure. The challenge you get with that is then if you have any drug-drug interaction, any significant CYP, any QT effect, you limit your ability to combine, so you have to have that too. And I think what's emerged with palazestrant is it is truly unique, in that you give full doses, high exposure palazestrant. You give full doses of ribociclib, full doses of palbociclib. We're still working on alpelisib and everolimus. They're further behind, but we'll continue those. And so those attributes are vitally important, and then it's really well-tolerated. You don't want... you want this as our Ribo data. It looks just like MONALEESA-2. It looks like the label with letrozole from a tolerability standpoint. The efficacy, it's early, but looks better, and that's really what you're shooting for. So you mentioned the study in palazestrant in combination with multiple other targeted- Right - agents. You know, can you share a little bit about the strategy of building out that broad clinical data set? Yeah. You know, how would that be relevant in some of the later line settings? You know, knowing that you've got the monotherapy OPERA-01, phase III, you know, ongoing and just so that contextual? Yeah. I mean, the point is that you have two things going on. One is, you wanna give the treating physician and the patient options because one thing that... Remember, this isn't a curative treatment. So one thing that's considered, obviously, is efficacy, and it always should be, and that's the pathway to approval. But in the real-world setting, quality of life is a big consideration, so tolerability. So for instance, we see, you know, breast cancer is a disease of age. As you will see, most the median in trials is mostly in the sixties, low sixties, median age. In the real world, it's higher than that 'cause a lot of those people don't get on to trial as they age. We've seen in the first-line setting, the use of CDK4/6 in the first-line setting drops above 60 and above – certainly above 65. They get monotherapy endocrine agents in the real world. So if you think of a second-line setting where the patients have had more therapy, monotherapy still plays a place. In other patients, if they look like they don't have comorbidities, they're able to tolerate more, the physician and the patient will want to be more aggressive. They may include everolimus in there. They'll test for PIK3CA and AKT mutations, and they'll tailor therapy there. If we can move OP-3136 forward, you know, KAT6, particularly that ability, again, to combine with palazestrant, the superior endocrine agent, we give another alternative down there. And then for some of these patients, they go through multiple lines of therapy. If you look at the Pfizer monotherapy, KAT6 data, their median lines of treatment in that patient population, prior treatment, they're all post CDK4/6, so that's one. Their median was five. So these patients are getting multiple treatments as they go through, because if they will tolerate them and benefit from them, the physician and the patient want to put off chemotherapy as long as they can. Yeah. And I'll circle back to the KAT6 in a bit here. Sure. But you know, OPERA-01, I'm excited about it, so I'm- Yeah. Certainly a topical phenomenon as of late. OPERA-01, it's a large trial enrolling, you know, targeted enrolling 510 patients. Yep. How is that progressing? And can you remind us of some of the timing of events or milestones to look forward to? Yeah, it's enrolling very well. It is a randomized, you know, bigger. You don't get any interim kind of. I'll explain that in a second. You don't get any interims. We've guided that it will read out in 2026. And as we get closer to that, we'll refine the timing of that. The enrollment's going great. It's a global trial. You know, the sites are activated. Enrollment's going quite well. Excuse me. The thing about the interim there is, recall, The fulvestrant control arm is basically gonna be two months. It's been two months median PFS across multiple trials and then post CDK4/6 population. You know, we saw 5.5 months in the ESR1 wild type, 7.3 in ESR1 mutant in a similar population. Actually, we have a little better population here because we don't allow prior chemotherapy. So when you have such a short time to progression, you really don't have time to do an interim. So you just do a final analysis. Mm-hmm. There's really no time difference between the two. So, it'll be the final readout that we share. Got it. Okay. 2026, got it. Obviously, we think the probability of success in the ESR1 mutant is way above generic. The opportunity here is to get the wild type as well. Mm-hmm. Our data looks better than anybody else. Right. Better than our Orserdu in the mutant population. Mm-hmm. And what's great about that is you don't have to do the test. You don't have to wait. You don't have to tell 50% of the patients, "Oh, guess what? You don't get it. Mm-hmm. So it's a massive opportunity, not just to simply expand the market, but to differentiate meaningfully- Yeah for all patients. Definitely. Okay. And then on the ribo combo data, obviously, we're looking forward to the update there- Yeah ... which could be very differentiating. Any updates you can share just on the combination trial there with ribo and then palazestrant, you know, how are preparations for the phase III pivotal study that you've talked about? Yeah ... previously going? Yeah. So the Phase II, more than fifty patients at one twenty completed enrollment at end of Q1. So that's going well. There's no more enrollment. It's just follow-up. We'll refine, you know, later this year or early next when we will update again. We updated in May at ESMO Breast. I think what you saw there was very compelling tolerability at full doses of both agents. We showed the lack of PK interaction. Those things won't change. It'll be a slightly expanded data set. The tolerability was about fifty patients, so it was large. The efficacy, because this combination is so active, you really can't do Kaplan-Meier, probably for a while, which is a good thing, but you can do CBRs, right? Use a six-month milestone. So that was above 80%, right? Wild type or mutant, didn't matter. They were almost all post CDK4/6, which is really not been seen. That was 13 patients, though. That's the denominator. So we have an opportunity to expand that, you know, a fewfold at least. We just have to. We have to- we don't do things in 8-Ks, and we don't do things in quarterly announcements. Mm-hmm. We do them at scientific meetings, so we have to look at the data and get an abstract accepted. Yeah. It could be as soon as the end of this year, but, maybe next year, depend upon how the data matures. Got it. And along those lines, can you remind us of sort of, you know, the timing of some of those updates, presentations, and publications that we should look forward to? Yeah. I mean, the one that we know now that we can share is at the ENA meeting in Barcelona in October. We will present an expanded data set on OP-3136, the KAT6 inhibitor. Preclinical efficacy, we'll show it as a monotherapy, but very interestingly, in combination with endocrine agents, and you'll see why our enthusiasm for the palazestrant combo is so high. We also have the Pfizer molecule. We've presented monotherapy data before in ENA last year with the Pfizer compound. We had the compound throughout the selection of OP-3136. We started that in 2020. So, we have chosen a molecule to differentiate. Mm-hmm. I think at this point, everyone agrees that the target is validated. I don't think fulvestrant did anything in the combination, so I think you can see what happens when you use a really good endocrine agent, and then that IND will be filed before the end of the year with FDA to start- Got it. Shortly thereafter. Certainly, by early next year, we'll see what we can do. Again, with the Ribo combo, it depends on. We'll look at data cuts and see when we can do it, when it's mature enough. Mm. It's really an efficacy update, and we want it to be meaningful. So we'll guide on that when we have a meeting, and we have an abstract accepted. Very consistent sort of data on that so far. Yes. So something to look forward to. Yes, absolutely. And I think you hit my questions on the KAT6 in terms of, you know, what was, you know, promising about the preclinical data set and timing to look forward to an update there, so. Yeah, the update's in October. I think one thing that probably people should understand is that we do not agree with what was presented at ASCO about the mechanism of KAT6. It, like degradation, which isn't the mechanism of CERAN, doesn't use that. It shuts off the receptor. Decreasing ER expression is not the mechanism of KAT6. It does do that, but it doesn't again, like degraders, doesn't do it enough. But what it does is it affects all of the downstream genes for growth and proliferation. That alone has a profound effect on the ER signaling pathway, but if you combine it with a really good endocrine agent, you have an opportunity to double down. So I think there is some mechanistic refinement- Mm-hmm ... to be done on what's been communicated. Got it. it. Something to look forward to, for sure. Yep. I think that wraps it up. Thank you, Sean. Great. It seems like there's a lot of momentum building at Olema, and you've got now a product pipeline with OP-3136 following palazestrant, so a lot of exciting updates to look forward to. So thank you very much- Yeah. and wishing you the best as you continue to execute. Great. Thank you, Anthony. It's great to have the opportunity. Great. All right. Good. Is that it? It ended. All right.