All right. Good morning to the intrepid four people who are here on day three of the conference at 8:00 A.M. Thank you. And anybody online? Thank you as well. I'm going to talk about Olema, our company. I'm Sean Bohen. I'm the President and CEO. Olema's mission is to improve treatment options for people living with breast cancer. I'm going to talk about the progress, significant progress we have made doing that, focusing on our two clinical stage programs. The lead is palazestrant. This is a complete estrogen receptor antagonist, which is uniquely capable of completely blocking the estrogen-driven growth and proliferation signal in breast cancer, and also uniquely able to combine, at least so far, with every other targeted agent that we have attempted to combine it with. The second program is currently in phase I, sort of phase II, as we're starting to combine with other endocrine therapies. It's OP-3136, which is a KAT6 inhibitor. That's the disclaimer. Pretty standard. Again, just reminding you the two programs, palazestrant. Palazestrant is in two phase III trials that are ongoing. A first-line trial called OPERA-02, which recently initiated enrollment, and a second, third-line trial called OPERA-01. In the first-line trial, we are in combination with ribociclib versus ribociclib and an AI, the current standard of care in first-line metastatic ER-positive, HER2-negative breast cancer. In the second, third-line trial, OPERA-01, we are a monotherapy. This is post-progression on that first-line therapy, CDK4/6 plus an AI. You could have had another endocrine therapy in that metastatic setting and be eligible for this, the control on this is fulvestrant or exemestane. As I mentioned, OP-3136 in the phase I/II setting. Monotherapy dose escalation is ongoing. We have not defined an MTD yet, despite escalating through multiple dose levels. We have initiated the fulvestrant combination and will shortly initiate the combination with our lead CERAN palazestrant. What we are addressing is a major unmet medical need. In the course of this year, there will be about 320,000 breast cancer diagnoses in the U.S. Of those, the vast majority will be estrogen receptor-expressing, ER-positive, and not expressing the HER2 oncogene. ER-positive, HER2-negative, that's about 70%. As a result, this represents as well not only a very large unmet need, but a very large market. It's about $20 billion. This is not a market forecast. This is the amount of money that is spent on pharmaceutical agents to treat this disease now. The majority of that is in the first-line setting, not so much because that's more prevalent. It is actually less prevalent. However, the treatment duration is quite long there. Right now, the AIs plus CDK4/6 have a median PFS in the at least in the two-year range, maybe a little bit longer. Second, third-line setting, patients, unfortunately, this is not curative therapy. Patients will progress to need other therapies. The objective here is to put off chemotherapy as long as possible to stay on targeted therapies, preferably oral targeted therapies, and both the agents I talked about are oral daily pills, palazestrant and OP-3136. That also represents about a $5 billion market. This market's more complicated because it is split diagnostically between estrogen ESR1 mutant, so estrogen receptor mutated, and ESR1 wild type, about 60/40, 60% the wild type, 40% the mutant. Then 3136 again. There are a variety. In addition to being a complete estrogen receptor antagonist, meaning having the molecular properties to turn off the growth and proliferation signal of the estrogen receptor completely, which not all of the third class can do, there is a massive importance to pharmacology in this indication. Pharmacology, really, in this sense, means a couple of things. One is you have to have enough drug present to be able to block the receptor all of the time. This is a ligand-regulated transcription factor. If it signals, its signal is massively amplified. You have to have enough drug present to block the receptor 24/7. Beyond that, while monotherapy with endocrine agents is viable and a used treatment option, the ideal is if you can combine with other targeted therapies. Endocrine therapy is the backbone. You do not give other targeted therapies alone. You always give them with an endocrine therapy. There is a challenge, however, pharmacologically. Other agents have had difficulties combining, either due to drug-drug interactions or to enhancement of toxicity. We have not seen that with palazestrant. Again, the real opportunity here is not only better activity, but to differentiate in terms of being able to be used in multiple lines of therapy with multiple targeted agents. Because once you make it, obviously, the first line, that's a CDK4/6 inhibitor. In the current world, it is Kisqali; it's ribociclib based on the survival benefit that's seen there. We know that that will evolve over time. There are other companies—we aren't doing this right now—testing agents to try to displace CDK4/6s in that first-line setting. You want to change if you progress, you want to change to another targeted therapy, either based on a mutation such as PI3 kinase, AKT, or if those mutations are not present, to a broader mechanism of action like KAT6, but you will always keep the endocrine therapy going. Recently, we presented some data at ESMO. This was last month. This is from our phase II trial of the combination of ribociclib plus palazestrant. There are a couple of things that we're doing with this. The most obvious is supporting the rationale for believing that in the first-line setting, in the OPERA-02 trial, ribociclib plus palazestrant will beat the standard of care, ribociclib plus AI. The way you can think about this, we do have some naive patients on the left side. You can see we had a median PFS of 15.5 months, which is unprecedented in this setting. That includes some treatment-naive patients, treatment-naive in the metastatic setting. Those patients will tend to do quite well. The data from those patients, in fact, is not mature. The mature data is from the right-hand panel, which is the patients who had progressed on a prior CDK4/6 inhibitor plus an AI, in some cases two CDK4/6 inhibitors. They will have gotten usually fulvestrant, another endocrine therapy. Here, again, you see a remarkable treatment benefit. Twelve months. I'll show you what other drugs have gotten in this context. The standard is a trial called Maintaine, which was ribociclib plus fulvestrant or exemestane post prior CDK4/6. The PFS benefit seen there was five months, so considerably less than half of what we're seeing. Others, the newer third class, have done better, but really, seven or eight is the most that's been seen. We also in a second see we break out by wild type and mutant to show you that we are exceeding this standard, not just in the mixed population, which is here, but in each of the individual populations. The way to think about this when you think about OPERA-02 is in OPERA-02, we give the drugs an even better chance to prolong PFS because we treat from the beginning so that palazestrant will be present when the ESR1 activating mutation or any other resistance mechanism arises. Here, the resistance mechanisms not only arose, but they were there long enough so that those clones grew, and you saw them as new tumors or an increase in the size of the tumors on a radiographic study, which led to the progression. There we get 12 months. The bar, by the way, for the first-line setting, the bar to show that you are really bringing additional benefit to these patients is six months. Practitioners, regulators, payers will reward you, will change their standard of care if you're able to take the current about two years and take it to the 30 months +. We think we are set up to do much better than that. This is now breaking out, and we can't compare it to others' data because no one's done this. This is breaking out by mutational status of the ESR1 gene, the gene that encodes the estrogen receptor on the left. You will see the CDK mutant subset. There we get 14 months. It is very clear that palazestrant is able to take this driver of resistance and completely obliterate the growth and proliferation signal. That's why you get that extraordinary benefit. We see that we exceed quite compellingly the target that we're shooting for, even in the context of the wild type. Now, in the wild type, post-CDK4/6 is a very different biological setting than the wild type patients, which are the vast majority, 95% range in the first-line setting because in the first-line setting, they're all endocrine sensitive. In this situation, they have progressed on one or two prior endocrine therapies and the CDK4/6. They have evolved other resistance mechanisms, which are not mutations in the estrogen receptor. Yet, still, going back to the same MLA, CDK4/6, and adding in a better endocrine agent in the case of palazestrant, we get a significant benefit at nine months. This, with all the dangers of cross-trial comparisons, which is what this is, this sort of shows what others in the field have seen. The main cane down at the bottom, that's really the randomized standard of care. That was five months, as I mentioned. That was ribociclib plus exemestane or fulvestrant, mostly fulvestrant, post prior CDK4/6. The phase II data sets from other next-generation endocrine agents are shown below. You can see eight months is about as well as anyone does. No one gets a year except us. The second, third-line setting, remember here, the objective of therapy is to put off chemotherapy as long as possible, to stick with oral targeted therapies, and prolong freedom from progression, preserve quality of life for these patients living with breast cancer. In this case, there are more patients in this category because, as I mentioned, metastatic breast cancer therapy is unfortunately still not curative, so patients will progress. The reason that this is $5 billion as opposed to $10 billion-$15 billion is that the treatment duration is shorter. Now, obviously, if you have a more effective therapy and you are prolonging the treatment duration, you have the potential to increase the size of this market for your drug. This is what we've shown to support the OPERA-01 trial. This is monotherapy data. This was presented a couple of years ago at ESMO in an oral session. Again, we break out by mutational status. Unfortunately, what we are seeing amongst primarily investors, not investigators, but a half of our two largest audiences is a desire to lump all of these next-generation endocrine therapies together. That is a mistake. The reason is that the data indicates that they're not all the same. In particular, palazestrant has shown activity consistently in the wild type setting. This is a place where others, most recently, was the data from Roche that was everolimus with their next-generation SERD giredestrant. That showed a nice compelling benefit in the ESR1 mutant subset with everolimus, but no activity in the wild type subset with regard to PFS. Here, what we see is that we see activity in both. You have more activity in the ESR1 mutated population. You get 7.3 months in a population, second, third line plus or minus chemo. This is comparable to the patients treated in EMROB, which led to the approval of our SERD. They saw four months in that population over two months, the control arm. Interestingly, in the wild type setting, we see five months. We see 5.3 months. Again, evidence of this wild type activity, the evidence you saw in combination just a moment ago from our phase II with ribociclib. This is ongoing in the OPERA-01 trial, enrolling very well. We will have data in the second half of next year from that trial. That trial is designed to specifically test these questions. There is no intent to treat. That is an exploratory endpoint. The primary endpoints are PFS in the mutated and in the wild type because that is really the regulatory pathway to getting this broader label. It is also the question of greatest interest to oncologists, to patients who are in this particular situation, which is, "Do I have an oral option if I am wild type post my progression?" The bar here is relatively modest compared to the first line. Two months' improvement in PFS will lead to approval and use. That is exactly what we are seeing with our SERD. That is exactly what we are seeing with beptagestrant in the VERITAC-2 trial, what we are seeing with imlunestrant. In number three trial, in all cases, again, seen only in the ESR1 mutant setting. Now, that is a big subset. That is 40%-50% of patients. That does mean that the remaining 50%-60% of patients are without an oral endocrine treatment option. That is what we are trying to address. This, again, with the caveats of cross-trial comparison, is showing what has been seen as monotherapy in the various trials. You can see pretty much you go from two months to four months. We saw 7.2 in the mutated setting. For those that shared wild type, you did not go anywhere. You went from two or three months to two or three months, again, 5.5. We will test this soon. Like I said, at second half, that's obviously a big range, six months. We think that later this year or certainly early next, we'll be able to refine that a bit for people, basically because the enrollment is going very well and we'll be able to forecast better when the readout will be. I should add for OPERA-02, the first-line trial, the readout timing is dependent much more on the rate of progression. It's 1,000 patients. It'll enroll relatively quickly. As I mentioned, the control arm is 24-25 months median PFS. You watch patients for a long time. They do benefit significantly from the standard of care. This, unfortunately, for patients is not the case for OPERA-01. As you can see here, the timeline is dependent largely on enrollment. The control arm performs pretty poorly. The majority of patients will be, or about half of patients, will actually go off to therapy at the first assessment, which is at eight weeks. We really can't predict the readout from the enrollment timeline. Obviously, with a pivotal trial readout coming in about a year, we are preparing to commercialize. I think our probability of success in the mutant is extremely high. Our probability of success in the wild type is, I would say, higher than generic. We need to be ready to address these significant markets. The mutant only is probably about $2 billion in the U.S., adding in that extra group of patients that if the wild type goes to the $5 billion range. That is partly due to the annual incidence. We are doing the commercial planning right now. The manufacturing process is already set up to enable launch. The launch would obviously not be next year, but could be as early as 2027. This is an oral daily tablet. It is a very simple medication to take. Unlike fulvestrant, which is two large volume painful intramuscular injections, this is simply an oral daily pill. In the first-line setting, the way that you change the standard of care is you switch out one oral daily pill, the AI, for another oral daily pill, palazestrant. You give the CDK4/6 you always wanted to give, which was ribociclib or Kisqali. In the second-line setting, you avoid the large volume injections, and you give an oral daily pill. This is KAT6. Interesting mechanism of action. This has been validated, excuse me, by the Pfizer program. Pfizer is currently in phase III with their KAT6 inhibitor. They've shown significant efficacy in the context of combining with fulvestrant. Like all targeted agents, this is not given as a monotherapy. It's given with an endocrine agent. What we have done is we've made a more potent, more selective KAT6 inhibitor. KAT6 is an epigenetic target. What you're doing is you're modifying the acetylation of lysines on a variety of proteins, but primarily the target we're looking at is histones. When you don't acetylate the histones, the chromatin remains tightly wrapped. The promoters for these growth and proliferation genes are hard to access, so their transcription goes down, their gene expression goes down. You're sort of doubling down on this transcriptional growth and proliferation signal. The initial place this would go would be that post-CDK4/6 setting. What's interesting here is that we would combine with fulvestrant to show the potential of OP-3136, the KAT6 inhibitor. The real potential we see comes from the data we've seen in the preclinical setting where OP-3136 plus palazestrant, actually the Pfizer molecule even plus palazestrant, shows a significant enhancement in efficacy both from the context of shutting off transcription with the KAT6 inhibitor, but also by using the best CERAN and completely shutting off that estrogen receptor-mediated signal. Again, our focus in this year, what remains of it is execution. Next year, in the latter part of the first half of next year, we'll show our first OP-3136 data. I think if you look at our share price, we're probably undervalued just based on this program. Obviously, in the second half of the year, we'll have that first pivotal trial readout for palazestrant with the opportunity to hit both the mutant and wild type subsets as monotherapy. Product approval and launch filing will be in 2027. We are hoping that we can launch in 2027 dependent on the review timeline. In 2028, we'll refine this later, but that's the earliest possible time we could get readout from the first-line OPERA-02 trial. We are hopeful that in this timeframe, we're also executing the first pivotal program for OP-3136 and then the supplemental filing depending upon OPERA-02 when that readout occurs. We'll follow shortly thereafter. Again, thank you very much for getting up early and learning about Olema and palazestrant OP-3136. I will take questions, which I think you can enter virtually if you want. Anybody in the room, please pipe up. Yeah. Next year we're going to get the first trial study of the next year. That's correct. We're also looking at that three or four studies coming next year. Correct. Based on what you've seen of those itself, you said either of them might work in the first line. My second question is, what are your rates of ready product off-sale rates for palazestrant? Nice. Okay. Yeah. I'm going to repeat them for people online. The first question that was asked, and then I'm going to try to remember the second question, but I may ask you. The first question was about two others in the SERD class, next-generation SERD class readouts that are projected for next year. Those are persevERA and SERENA-4. Just reminding people what those trials are. persevERA is a first-line trial of giredestrant. I showed you some data from giredestrant. There was data from giredestrant showing nice effect in the wild type or in the mutant subset, I'm sorry, in the second-line setting with everolimus. Giredestrant is from Roche. The persevERA trial looks very much like OPERA-02 or maybe the other way around. The difference is it's palbociclib as a CDK4/6. It was designed a while ago. At that point, Ibrance ruled the world. The survival data had not come out yet from Kisqali. So it is palbociclib plus AI versus palbociclib plus giredestrant. And that we are told when OPERA was announced, Roche updated their timeline, pushed it out a bit. We are told we will read out in Q1. The question was, what do we think about the potential outcome of that trial? I think, persevERA, giredestrant clearly has not shown the activity that palazestrant has so far. The acelERA, second, third line trial failed. I think it failed in the mutant mostly because of study design issues. There was pretty clear evidence of effect. In the wild type, it did not show much. Giredestrant has a problem, and it goes to your second question. The problem is that it has enhanced toxicity with palbociclib. Roche started out saying, "Here's our recommended phase II dose, it's 100 mg." I showed you the PK slide. If you have 100 mg of giredestrant, the one that was several pills below us, but still the highest is giredestrant. If you give 100 mg, it looks just like palazestrant, actually. And it is a complete antagonist. Molecularly, it's a very potent molecule. The problem is when you reduce threefold, you fall out of that range where you're inhibiting all the time. They clearly have compelling activity in the mutant setting. I think it's reasonably likely that that alone can drive the effect, suppressing that mutation because it is so prevalent, 40%-50%. And the effect on the mutants is pretty profound. I think they put their probability of success, Roche does, at 50/50. I don't think that's unreasonable. I think that range is reasonable. They have a reasonable likelihood of being successful in persevERA. We want them to be successful because all the investors will then go, "Wait a minute, palazestrant looks better. It's with ribo, which is what everyone wants to give anyway. This is going to be great." That's true regardless of what happens to persevERA, but people will want to lump them together. We're reasonably optimistic. I think the data supports that. I mean, they're saying it. I think it's quite credible. We feel looking at their data exactly the same. SERENA-4. SERENA-4, let's just say it's very similar trial design. It's for camizestrant, which is the AstraZeneca molecule. That's a very toxic molecule. That's the most toxic of the crew here. They have not been able to get above 75 mg. Now, if you go and look at our PK slide, the one way down at the bottom by fulvestrant, that's camizestrant. That's problematic. Again, more treatment options is good for patients. We would like it to be successful. We think giredestrant has a better chance. The readout, I should say, for SERENA-4 is currently forecast by AstraZeneca as second half. The next question that was asked was about our incidence of bradycardia. Our bradycardia is in the low single-digit range. It doesn't matter if you give it. We give full dose all the time. We don't dose reduce. Our dose is 90 milligrams, and you'll see that. We have also studied 120. The exposure is the same and much higher than anybody else. It's in the low single-digit percentage. It's grade 1. We do not get an enhancement of QT prolongation with ribociclib. That's a big deal. Ribociclib is harder to combine with than palbociclib. Obviously, rate of bradycardia is why Roche reduced their dose. Not as a monotherapy. They did quite nicely with 100. It's well tolerated. In combination with palbociclib, they saw an enhancement of bradycardia through an unknown mechanism. Bradycardia is really not much of an issue for us alone or in combination. I should say today at full dose, we've combined with palbociclib, ribociclib, alpelisib, everolimus. That data we haven't presented yet, but we can, but it's all done. It combines fine. We're ongoing, as I mentioned, in combining with our KAT6 inhibitor, OP-3136. Interestingly, we will start very soon the dosing in a combination with the Pfizer CDK4 selective molecule, atirmociclib, which is a recent collaboration we announced, and we'll be able to generate data from that. Probably not for public consumption yet, but for ours and Pfizer's within the first half of next year. Yeah. Thank you so much for the presentation. I just had a quick question about the KAT6 update next year. Yeah. An exciting new asset and target. Right. Maybe what are your expectations on that data? Right. It is going to be mostly phase I data. It will be mostly monotherapy and monotherapy dose escalation. Very clear PK to be shared, tolerability. Reminding you that the primary toxicities that were seen with the Pfizer molecule were kind of an unusual one, not for epigenetic targets, called dysgeusia. That is an alteration of taste. It can be a nuisance for the patients. It tends not to be dose limiting. The other that they saw was cytopenias. More so from the standpoint of cytopenias, what we are hopeful for is to mitigate that somewhat by dialing out KAT6 and 8. We will have data to be able to share around that. The single-agent efficacy was not all that impressive. They were in the single digits, high single digits in breast cancer. We will show what we have. Interestingly, I think something that people will find interesting is that our monotherapy is not just breast cancer. We do have ER-positive/HER2-negative breast cancer, but we also have castration-resistant prostate cancer and lung cancer because we have seen activity preclinically in those indications. We've also seen great activity in ovarian cancer. Standard of care is so complicated there, we've decided we will put that off if we decide to go there. We do have those two other histologies. We will present on that as well, the data, the patients that we have. Fulvestrant is ongoing, right? We do not have an MTD yet, but we were able, we've done enough dose levels. What Pfizer saw was a kind of high single-digit response rate just in breast cancer. When they went in and added fulvestrant, it went to high 30s, right? It'll be early for that data that just started recently, but we'll see. We'll certainly present what we have. I don't think we'll have much from the palazestrant combo yet. That's just starting right now. Five months or six months isn't very long, but we will present what we have. Okay. Any other questions? I don't have anything coming online, so. All right. Thank you, everyone. Have a wonderful day and the rest of the conference.