Hello, everybody. Thank you for joining us at the Wells Fargo Healthcare Conference. I'm Jessica Boardman. I'm a member of the biopharma banking team here. It's my pleasure to be introducing Olema Oncology. Olema is developing novel therapeutics for solid tumor indications with an initial focus on breast cancer. Speaking more about that, Sean Bohen, CEO. Thank you, Jess. Thank you, everyone, for taking the time. We're gonna spend about 25 minutes going through our presentation and leave plenty of time for questions, should you have them. Oh, also here in the front row is Shane Kovacs, who is our Chief Operating Financial Officer. So, if you give really hard questions, I may drag him up here, and then we'll let him answer those. As Jess mentioned, we are a company focused on targeted therapeutics for the treatment of breast cancer, specifically ER-positive, HER2-negative breast cancer, which is really the vast majority, 70% of the breast cancer indication. They're forward-looking statements. You can look at that whenever you like or don't. So as we overview the company, we have a lead asset, which is palazestrant. It targets the estrogen receptor, which is the key driver of growth and proliferation of ER-positive, HER2-negative metastatic breast cancer. It is in a first-line trial with the CDK4/6 inhibitor of preference, that's ribociclib or Kisqali. And that trial is ongoing. It's partnership, collaboration with Novartis. And in the second/third line metastatic breast cancer trial as a monotherapy, that trial will actually read out in the second half. It reads out earlier. That'll read out in the second half of next year. We also have a second clinical stage asset called OP-3136, which targets a novel target called KAT6. This is involved. It's an epigenetic target that is involved in gene regulation for ER-positive, HER2-negative breast cancer. It's a validated target. There's a Pfizer program that's a little bit ahead that has validated this target, and as with all targeted therapies in breast cancer, the KAT6 inhibitor ultimately will be combined with an endocrine agent, and our data indicates that the most promising endocrine agent for this combination is actually the top molecule, palazestrant. So it's a really good portfolio fit, these two assets. Combination of these assets provides us access to a very large market potential, $15 billion-$20 billion in aggregate if you look at the two assets and also across the lines of therapy. So as we mentioned in the first line, this current standard of care, CDK4/6 plus an aromatase inhibitor. That is a $10-$15 billion market opportunity, and we are uniquely the only next-generation endocrine therapy that is combining with Kisqali or ribociclib, which is the CDK4/6 inhibitor of preference. That was a fairly recent change in the standard of care. Previously, it was Ibrance from Pfizer, but what happened was the survival data for the CDK4/6 inhibitors matured, and it turns out that ribociclib had very compelling overall survival benefit, whereas palbociclib was unable to generate a survival benefit in those trials, and so that has really led to a shift in the standard of care, and we're taking advantage of that in our first-line trial, again, as I said, in collaboration with Novartis. Second/third line setting is interesting. If the objective of therapy in ER-positive, HER2-negative breast cancer is to use targeted therapy to put off chemotherapy as long as possible. Obviously, that's to extend PFS, that's to extend survival, but it's also to preserve quality of life, right? You don't want the side effects of chemotherapy. You don't want the inconvenience of having to be tethered to getting chemotherapy, getting infusional therapy. And in the case of all of these treatment paradigms, you're dealing with one or two pills taken orally once a day. So that's very favorable for the quality of life of the patients. Obviously, they can go about their normal life. They don't have to spend time in an infusion center or going to the doctor's offices often. That second/third-line setting, I'll talk about it a little bit, that we believe that's $5 billion +. There's actually two places to differentiate here, that there are two populations, the ESR1 mutation-positive. Mutations in estrogen receptor are the most common resistance mechanism to CDK4/6 + an AI, and then the wild type, the patients who have progressed on a prior CDK4/6 but mutation. We believe we have the opportunity to have better activity in the mutant but also have activity in the wild type, which has not yet been demonstrated by others. And then OP-3136 gives a novel target to prolong the use of targeted agents, to put off the use of chemotherapy, to give an oral regimen as we go into the post-CDK4/6 setting as well. So with palazestrant, it's molecularly differentiated. It is a complete estrogen receptor antagonist. When it binds the estrogen receptor, wild type or ESR1 mutant, it completely suppresses the transcriptional signal. So the transcriptional signal is what is primarily driving these tumors. The way you think about that biologically is this is a growth and proliferation signal for the breast tissue. Everyone is familiar with what it does in normal physiology. When a girl enters puberty, the ovaries start producing estrogen, a variety of tissues respond to that. One of them is the breast, so this leads to normal breast development. ER-positive, HER2-negative breast cancer does what cancer generally do, it hijacks a normal growth and proliferation signal, in this case, the estrogen receptor, to grow and proliferate inappropriately as a cancer. So if you have ER-positive, HER2-negative breast cancer, whatever your treatment is, you want part of it to be shutting off the estrogen receptor, and that's what palazestrant does. Again, it's in phase III, as we mentioned. It does have a Fast Track designation from the FDA. Interestingly, we have a lot of milestones coming up in the near term for this. In this case, the OPERA-01 trial, which is the second/third-line I mentioned, we'll go into it. That will read out second half of next year. That will be our first pivotal trial for this molecule. We will initiate the OPERA-02, which is the first-line ribociclib, this quarter, so we got a few weeks left to be able to do that. And then our next data presentation is that combination data from phase II that in the post-CDK4/6 setting, we're gonna present at ESMO in about six weeks, and we'll be able to show you more mature data there. That data is unique. We've already shown less mature data, which shows that we get a year plus of PFS after patients have already been treated with one or two prior CDK4/6 inhibitors. And again, the objectives that we have here are this prolongation of PFS. Those are the approvable endpoints. We will follow for OS. That takes a long time to mature, but we have the opportunity to go in these sequential lines of therapy. In addition to the complete antagonism, the other ways to differentiate are pharmacological. So palazestrant has a very long half-life, eight days, so this oral daily dosing gives a very high exposure that's necessary to keep the receptor occupied and turned off all the time. In addition, a challenge that others in the class have run into is combining with targeted agents. Two problems: One, drug-drug interactions, the classical, stabilizing or inducing the clearance of the partner molecule, CDK4/6, PI3 kinase inhibitor, mTOR inhibitor, you know, KAT6 we'll look at, or enhancement of toxicity, and those have led to dose reductions in one or the other agent. We have combined with palbociclib, ribociclib, alpelisib, everolimus, and we'll talk about we're going to combine with another novel agent in a newly announced collaboration with Pfizer, atirmociclib, which is a CDK4 selective inhibitor. With the first four, we've generated data and shown that we can give full doses of both agents without a PK interaction and without enhancement of toxicity, and so that's unique. Again, I mentioned how we differentiate in this first-line setting. One is the combination with ribociclib at full dose, so you don't... Doctors, the other two agents that are combining in the first line is a molecule called giredestrant, which is from Roche. That's combining with palbociclib. They had to reduce their dose because of bradycardia. There's another molecule, camizestrant, which is from AstraZeneca, also combining with palbociclib. That molecule is the most toxic of the group, but has the lowest exposure, and that's visual toxicity and cardiac toxicity, as I described before. As I mentioned, we'll talk about the median PFS. We'll show updated data in October at ESMO, and we really think that that's gonna support our objective of prolonging PFS at least six months in this first-line setting, and then opening up a really extraordinary market potential here, $10 billion +. This relies on a very well-trodden path in targeted oncology, which is if you have a dominant resistance mechanism, if you have a mutation that occurs in a target that you can turn off, and it occurs frequently enough, just by doing that, you can improve the therapy from the first-line setting. So the example we give here, probably the best known, there are many actually, but is Tagrisso. So if you'll recall, Tagrisso, EGFR inhibitor, but it does something very interesting. In the wild type, the non-mutated, activated EGFR, it's just like the first-generation molecules. It's just like Iressa or Tarceva. But there was a common resistance mutation, which is T790M, single point mutation, which occurred in 40% of the cases, and Tarceva and Iressa didn't inhibit it. So the first approval we got at AstraZeneca, when I was CMO there, was from the AURA study. It was in the T790M population. They had already progressed on the first-generation agent. What we saw was about a six-month increase in PFS there. Now, based on this, we then went into the first-line setting, so we think we can get even more and improve outcomes in all patients. Even though the T790M mutation isn't there yet, it will arise, and when it does, we're gonna stop it.... And so that was the FLAURA trial, and what you can see is we went from about six months to about nine months prolongation of PFS. That ultimately became a survival benefit. This is the exact we're using now with the estrogen receptor, ESR1, and activating mutations there. When those mutations arise in the control arm, the letrozole ribociclib arm, those tumors will grow. When they arise in the presence of palazestrant and ribociclib, those clones won't be able to grow, and so those patients will be progression-free for longer. Now, eventually, as was the case here, the tumor finds another way around, but it takes a while longer, and that's exactly what we're shooting for, and what we're feeling very comfortable with our ability to get at least a six-month benefit because we have, as I mentioned, over a year in the second-line resistance setting, and when we go into first-line setting, we see the potential for that to even expand further. This is that trial design. It's pretty simple. It's big. It's a thousand patients. Simple design. Current standard of care, ribo plus letrozole versus ribo, but now giving the better endocrine agent, palazestrant. This looks more at the concept of combinability. I'm just gonna highlight the top. I talked about the other combinations we've done. This is a new collaboration that we announced yesterday. Pfizer has a very active pipeline in breast cancer. They do not have a novel endocrine agent in their pipeline. Their lead molecule is a molecule called atirmociclib. Atirmociclib is a CDK4 selective inhibitor. What is known about the CDK4/6 inhibitors is their primary toxicity, because of hitting CDK6, is neutropenia. So what Pfizer has done is they've dialed back that CDK6 inhibition with the hope that by hitting CDK4 harder, because you can from a tolerability standpoint, you will increase the ability to control the tumor's growth, and that's what they're testing. They have an ongoing phase III trial in the first-line setting of atirmociclib versus, + an AI, versus the physician's choice. It'll mostly be ribociclib of CDK4/6 + an AI. But they also have had an interest historically in next-generation endocrine therapies. Initially, that partnership was with Arvinas. That molecule didn't combine well, and so they have now moved on, and we've started a partnership to generate combination data in their lead asset with palazestrant. This is a great fit for us because our primary first-line strategy is the existing standard of care, CDK4/6 ribociclib. But we wanna have a life cycle beyond ribociclib, right? What's going to replace that in the first line, and atirmociclib is a possibility. So we will generate data very quickly with this combination. We're putting it into an existing trial, the trial that was used to test ribociclib, alpelisib, and everolimus, and so we'll get data very quickly on that combinability. This is the market opportunity in the second-line setting. This will be our first readout, OPERA-01. We'll read out in the second half of next year. Our. Again, here, this is a place where our phase II data is very encouraging. Our phase II data is in the post-CDK4/6 setting, which is exactly where we're gonna be doing this trial. What you expect from the control arm, fulvestrant, or exemestane, is about two months median PFS. They're not very active. There is proof of concept in the mutant setting from elacestrant and Orserdu and vepdegestrant from Arvinas, which is filed now for approval. But it's really just a mutant setting, and it's two to four months, so it's a two-month improvement. What we saw in the ESR1 mutant setting in our phase II experience was seven point three months, so quite a bit longer in the mutant setting, and in the-- there was no activity of these other agents. We saw 5.5 months, so we think there's a very. There are two ways to differentiate here. One is to have superior PFS in the mutant setting, but then also to capture those, you know, 50%-60% of patients that are ESR1 wild type and give them a single-agent oral alternative, and that would be a very meaningful differentiator from the existing options. And again, this is a $2-$5 billion market opportunity. Why the range? That's approximately 40-45% of patients who are mutant only. If you add in the other patients who are wild type, then you get to the $5 billion. And again, this is not very far off for us. This looks at what others in the class have seen in monotherapy. In this setting, I mentioned in all comers, we saw 7.2 in just the wild type, truly unique to see over 5 months. The others have not been able to demonstrate activity there where they have shared it. So we think there's a extraordinary potential from this trial. Oh, yeah, this is a trial design. We did have a little Project Optimist part in this. That's part one, is selection of a dose. 90 mg was that go-forward dose, so we are actively enrolling the second part of the trial. Again, later this year, with more enrollment data, we'll be able to refine the time of readout in the second half of next year. But for right now, we're just keeping that broader time frame. Again, 3136, KAT6 inhibitor. This is a novel target. There are no approved agents. Again, this against this target, it is a epigenetic target. KAT stands for lysine acetyltransferase. The lysine primarily that's being targeted here is on histone H2. And so what this does is when the lysine goes on the histone, it relaxes the heterochromatin, and it gives transcription factors more access to promoters for genes that promote the growth and proliferation of the tumor cell. If you inhibit the acetyltransferase, then the lysine is not transferred, and the heterochromatin remains wound tight. There's less access. So to some extent, what you're doing here is you're doubling down on the transcriptional targets mediated by the estrogen receptor and then expanding that as well. It is in phase one as a monotherapy. It is still in dose escalation, and that started at the end of last year. We just started dosing patients in combination with fulvestrant. All these targeted agents are given, as I said, with an endocrine agent, and so fulvestrant is what, Pfizer is using in their second-line trial with their CDK4/6 inhibitor. Our preclinical data indicates that while fulvestrant enhances the activity of KAT6, palazestrant does it much more, and so that combination will start before the end of the year. It'll start very soon, and we think that that's another way to differentiate in addition to higher potency and greater selectivity, which we have in OP-3136. We anticipate being able to present data from monotherapy and combination by the middle of next year. So again, another catalyst for us. And again, a couple interesting things about this. One is it seems to be agnostic to the underlying mutations. So there are some therapies after CDK4/6 that you can give if you have particular mutations, right? If you have a PI3 kinase activity, a PI3 kinase mutation, you can give Piqray, alpelisib, or capivasertib. If you have AKT, you can give capivasertib. It doesn't matter what your mutational status is here. It looks like there's activity in without any of those mutations or in those mutations. So that, again, opens another meaningful alternative to stave off chemotherapy, and we think not only the molecule but the combination with palazestrant are potential differentiators. Again, another substantial market opportunity, particularly for a small company. This is basically where we are with this. We are continuing the dose escalation. It's going quite well, as palazestrant will start in the very near future. And then, there is the possibility, depending upon the tolerability profile, that you could actually do a triplet therapy and have a CDK4/6 in there. It's too early for us to know if that will be something that we would be able to approach. And again, a look at our milestones and our corporate priorities. I'll remind you, this is a big execution year. There will be data coming in October from the combination, which we think will increase conviction around the OPERA-02 trial with ribociclib. There are external catalysts, so in that case, probably the big one people will watch is the Roche pivotal trial in first line with palbociclib. That's called persevERA. They reiterated in their recent quarterly call that that will by the end of this year, so not very far off. That will be particularly a positive. It will be read through to the proof of concept of being able to do this. We again have superior data than what they have shown, so we think we have an even better possibility. We also are combining with the CDK4/6 of preference, so nice differentiation points. There will be the OP-3136 data coming by midyear next year, both alone and in combination for the KAT6 inhibitor, and in the second half of next year, our first pivotal trial, OPERA-01, the monotherapy and second/third line. That trial, if positive, will enable filing and subsequent launch, and then we're pointing to OPERA-02 in late 2028. Obviously, we'll get that going and enrolling and get events going and be able to refine that. That trial takes longer to mature, right? In the first line setting, the control arm should do about 24-25 months, median PFS, 'cause CDK4/6 + AIs are effective therapy, most effective with ribociclib, so that's our summary. Definitely happy to take questions from people. I left more than 10 minutes, so questions, thoughts? If you just wanna yell 'em, by the way, it is webcast. I'll just repeat the question so everyone can hear it. I just want to give you this mic back suddenly. Little brief break. You can put that on. Okay. Okay. Thanks. All right, I blew out the mic. That's perfect. Not you. He says it's not me. No, there's [crosstalk] a lot of rooms. Don't believe him.... Questions? Just quickly on the wild [inaudible]. Yeah, wild type population. The market doesn't really understand it. What are you doing to communicate? What will you show going forward? Yeah, I think that's right. Jess's comment and question are the phase. It goes to the wild type population post CDK4/6. This is the two populations that will be assessed in the OPERA-01 trial. The phase II data looks compelling, that's the 5.5 months median we have shown. But as she's pointing out, the market does not seem to be valuing it, i.e., does not seem to be convinced that that is a possibility. I think there are a couple things going on there. One is a bit of fatigue, right? We do have a group of true believers who really go into the data and believe that this is meaningful and actually value it. But I think a lot of the market just lumps everything together, so there are a couple things. We remind people of what the data is. We also remind people of something that seems to have been lost. Every phase III readout in this space has been perfectly predicted by the phase II, right? Elacestrant didn't work in mutant, or didn't work in wild type, worked in mutant. It's exactly what they saw. That giredestrant didn't work in wild type, worked in mutant. It's exactly what their phase II data said would happen, so the hypothesis hasn't been tested. Now, why is that the case? Those are not complete antagonists, so we have to go back mechanistically, so I think there are two things. One, you have to look at the differences in these molecules because they're not the same. And the second thing is, you know, it's kind of the classic, the likely outcome, and it's not done until it's done. I get it. But the likely outcome in phase III is that it looks like it did in phase II. And so I think people just, you know, have to see that. We are gonna do one other thing with our data at ESMO. Now, that's the combination post CDK4/6, but there is a belief that there's no activity in the wild type population with these molecules. We're gonna show the wild type and the mutant, and I think people are gonna get a sense that, yes, while there's compelling activity in the mutant, and we know that, we know that from monotherapy, we know that from other drugs. In this case, you see something interesting in the wild type, too, and I think that that should help, as well. Ultimately, I think people are going to read a lot into the persevERA trial. I hope Roche succeeds. I think their dose is lower than I would like. One hundred gets exposure about like ours, thirty is a third lower, not surprisingly. It's still better than the other molecules. It is a complete antagonist. So, I'm reasonably hopeful for that outcome, but, you know, that will be important as well. Yes, ESMO, October, Berlin. Need an excuse to go to Berlin, there you go. Nice in October. Any other questions? There we go. All right. Well, thank you. Thank you, Jess, for hosting us. Thank you all, for your time and those of you, on the webcast who joined. Thank you.