All right, good morning, everyone. Thanks for joining us, joining us for Jefferies healthcare conference, in London. My name is Clara Dunn. I'm one of the Biotech Analysts here at Jefferies. Sitting next to me, I'm joined by President and Chief Executive Officer Sean Bohen from Olema Pharmaceuticals. Welcome. Thank you, Clara. Thanks for the opportunity to talk about Olema. Great. Maybe just to kick things off, can you give us a brief overview of Olema, your lead asset, and, you know, your vision in breast cancer? Sure, absolutely. Olema is a company that is focused on bringing better treatment options to people living with breast cancer, and we do this by our intense focus on the primary subtype of breast cancer, estrogen receptor positive, HER2 negative breast cancer. That's about 70% of breast cancer. The primary growth and proliferation signal in that type of breast cancer is signaling through the estrogen receptor. We target that signaling with our lead molecule, palazestrant, which is a complete estrogen receptor antagonist, which means it has the ability to completely shut down that growth and proliferation signal by occupying the receptor and turning off its transcriptional activity. That molecule is in two ongoing phase III trials, pivotal trials, the first of which, OPERA-01, is in the 2nd/3rd-line setting. That's as a monotherapy versus the monotherapy standard of care. That's after patients have progressed on a prior CDK4/6 plus an AI. That trial will have its readout in the 2nd half of 2026. It's about a year from now. The 2nd trial, which is also ongoing, not quite as far along, is OPERA-02. That's in the 1st-line setting, the 1st-line metastatic setting. This would be the first treatment patients are receiving for their diagnosis of metastatic or advanced estrogen receptor positive, HER2 negative breast cancer. It is in combination with ribociclib or Kisqali, which is the CDK4/6 inhibitor of choice. The control arm, comparator arm, is the existing standard of care in that line of therapy, which is Kisqali plus an aromatase inhibitor. That trial will take a few years longer. The earliest possible, possible readout would be late 2028, but we will have to update on that as time goes on based on both the enrollment, which we expect to be, to go quite quickly, but then the accumulation of events. We do have another clinical asset, OP3136. It's a KAT6 inhibitor. It's in a phase I trial as a monotherapy and in combination with endocrine therapy, both fulvestrant and palazestrant, enrolling right now. In the monotherapy, it's also being studied in addition to breast cancer in castration-resistant prostate cancer and in non-small cell lung cancer. The first readout from the phase I portion of that will be presented in, probably late in the 1st half of 2026. I'm gonna start things off by talking about the data from Roche yesterday. Mm-hmm. Obviously, there was a lot of excitement on the data. Maybe can you just talk about what does it mean? What, what, what's the, you know, the implication from that data to the overall space and to Olema as well? Yeah, you're referring to Roche's announcement around the LIDARA trial. The data we have not yet seen, I think, I think it's gonna be a few weeks. I think it's San Antonio Breast Cancer Conference. First, I think it's important to talk about what that trial is. So that's a trial of their next generation anti-androgen or anti-estrogen therapy called giredestrant in the adjuvant setting. It's the moderate to high risk adjuvant setting. And that's as a monotherapy versus the monotherapy endocrine standard of care would be AI or tamoxifen. As I said, we haven't seen the data yet, but what they did announce is that the trial is positive. They see improvement in disease-free survival with giredestrant and that that occurred at an interim analysis. A bit surprising in that respect. We did not really have that, that about a year from now, we were expecting to hear about LIDARA, but here we have it, yesterday. As I said, we have not seen the data. Usually, interim analyses do not get allocated a whole lot of statistical power, which means that the efficacy boundary tends to be quite high in order to meet those endpoints. It is my presumption that that is exactly what the trial design was like. We will get more insight to that, hopefully at the San Antonio Breast Cancer Symposium. You asked about implications. I did not do that. The implication here is this is an interesting population. It is the wild type ESR1, so non-mutated estrogen receptor, endocrine sensitive population. This is very similar to the population you would treat in, for instance, the OPERA-02 trial, right? These are patients who have not demonstrated progression on an endocrine therapy or endocrine therapy plus CDK4/6. What it says is that the ability of these next generation SERD CRAM molecules to have an effect is really quite great in the wild type setting in that endocrine sensitive context. Then, you recently also presented some data at ESMO, your updated phase I to Ribo combo data. You did show, you know, activity across both ESR1 mutant subset and ESR1 wild type population as well. Maybe just walk us through, you know, the key findings from that data and then what have you heard from, you know, the physicians, investigators at ESMO as well? Yeah. We have a guest, I guess. That we did see, so what that was is that's our phase II data in the context of the ribociclib combination. This is the combination that is being tested in OPERA-02. However, in OPERA-02, as I mentioned, that's the 1st-line setting. That's the endocrine sensitive 95%, possibly plus wild type. In the setting we tested for ESMO, hopefully they can do that a little louder. In the testing, in the setting we tested for ESMO data, that was post progression on a CDK4/6 inhibitor. That's a mixture of wild type and mutant. As well, that wild type population is different because they've demonstrated relative endocrine resistance. What we were able to show is something quite interesting. It's really the best data that's been seen in that setting. Overall, we saw about a year of progression-free survival. In the ESR1 mutant, it was a bit better. It's about 14 months, but what we saw was over nine months, almost 10 months in the ESR1 wild type. That compares very favorably with data presented to date. The data presented at that same meeting from Roche was the Avera data, everolimus plus fulvestrant. What they saw was about 5.5 months. In the wild type setting, they saw the nine months, but only in the mutant. 5.5 months was what the control arm showed. Their effect was only in the mutant. Even there we saw a better effect in the mutant than they did. I hope I cut that, you know, with all those noises, but. Yeah. Maybe at ASCO, the, another relevant data set from Roche, you just mentioned. I mean, maybe just share some of your perspective on that as well. What really differentiated your SERD? Yeah. Like, since you would be able to show activity in both populations. Yeah. Yeah. That's a great question. I think that Roche is having a meeting in the next room, so they probably don't want me going out with this right now. My former employer. The distinction for palazestrant is in part from a lot of the next generation SERDs molecular. It is a complete estrogen receptor antagonist. Palazestrant or SERDU is not. Epigestrant is not. Giredestrant, the Roche molecule, is a complete estrogen receptor antagonist. However, they were not able to maintain their full recommended phase II dose. That was 100 milligrams per day. Why did they reduce the dose to 30? Because they saw an increase in bradycardia with palbociclib. Palbociclib is their combination CDK4/6 in their 1st- line seed. I got right to the important point and I came back, in that Persevera trial, which is their 1st- line trial with palbociclib. Now we are able to give our full dose, 90 milligrams, with full dose of numerous molecules, palbociclib, ribociclib, that's the OPERA-02 trial, alpelisib, everolimus. We are in the process of testing the Pfizer CDK4 molecule, atirmociclib. And we're moving on to OP3136, our KAT6 inhibitor. The complete suppression of the growth and proliferation signal from the estrogen receptor is coming, we got a phone now. It is coming both from that CERAN property, but as well that very high exposure and receptor occupancy all of the time. Obviously Roche is reading out their frontline data in the 1st quarter of 2026 as well. Maybe just talk about the implication of that data and what, you know, what could be the reason to Olema as well? Yeah. I mean, I think the LIDARA data reads through positively to Persevera and OPERA-02 because of this wild type endocrine sensitive population. I think it's very important to think about this, the opportunity that we're looking at in that 1st-line setting, right? Right now, globally, the CDK4/6s are about $15 billion market. You can anticipate 2030, around the time that we get data, start to launch in the 1st-line setting. It could be $15 billion-$20 billion. This is a very large market opportunity, very large unmet need. As I mentioned, both Persevera, the 1st-line, and the adjuvant setting are the wild type endocrine sensitive population. Roche has said, I think they have a very, very compelling reason to state that they believe LIDARA increases their probability of success for Persevera. We would say that our probability of success for OPERA-02 is quite high because of the data you mentioned from ESMO. We get more than a year, six months is the bar, more than a year after you have progressed on one or two prior CDK4/6 inhibitors. I think some proof of concept from another molecule in the space adds even more confidence as we move forward. Now, as you mentioned, Persevera will read out, they are forecasting in Q1, January 1 through March 31. We do not have any idea where in there, but we think a positive readout there would further support. Yeah. Okay. I think I'm gonna stop talking about Roche and hopefully the noise will stop. Let's focus on your pivotal trial, the monotherapy first. The readout is coming soon next year. Maybe just help us define what the success looks like next year and what supports your confidence. Yeah. Yeah. I thought that was working for a 2nd and that was really, but now I'm convinced it's a LILI meeting. In the OPERA-01 trial, what we're studying is we're studying, again, this post progression on CDK4/6, plus an AI, right? There, as I mentioned, we have several things, right? The tumors have displayed an endocrine resistance. Now, what's the most common mechanism that tumors use to do that? They mutate the estrogen receptor and they turn it on. That's the ESR1 mutant subset. We know that this class has established activity in that subset. We think based on our seven month, 7.3 month PFS in that population or phase II data where others see only four or five, we have a real opportunity to do better with our complete antagonism and better exposure and occupancy. That will be tested in OPERA-02. In addition, the way we've designed our trial is not to study intent to treat, but to study ESR1 mutant and ESR1 wild type separately. That is what's relevant. That's how regulators and prescribers will look at this. In the ESR1 wild type, we would be unique in being able to show monotherapy benefit here. Based on the 5.5 months we saw in phase II, remember, nobody sees any activity in this population to date. We think we have a great opportunity of achieving the at least two month increase in progression-free survival that you need to have, in that setting. Okay. I hope I caught that part. So are the mutant and wild type populations independently powered for regulatory considerations? The statistical design, because we have them both as primary endpoints, is capturing adequate power for both of those. Okay. And then maybe turning to your frontline combo, OPERA-02, what's the rationale of the combo partner you are using? I mean, obviously this for CDK4/6, there are three approved drugs on the market right now. Yeah. We, so obviously we studied palbociclib Ibrance first, and we presented that data, and we combined very well at full doses without enhancement of toxicity. What happened at the same time, we were studying ribociclib in collaboration with Novartis, and what happened was the whole standard of care shifted. It shifted because the MONALEESA trials, as well as the PALOMA trials, the MONARCH trials started to read out their survival endpoints. It was really only ribociclib that demonstrated not only statistically significant survival benefit in three of three trials, but about one year absolute survival benefit, which is obviously an extraordinary benefit for patients. The standard of care has shifted. It is actually in the process of shifting with new starts to Kisqali. We are seeing that shift in the standard of care, decided to deprioritize the palbociclib combination and go with the ribociclib combination. Now, of course, that's greatly facilitated in OPERA-02 by our ongoing clinical trial collaboration. Supply agreement, Novartis supplies all of the ribociclib. For now, I'm getting a call, so I don't know who, for this OPERA-02 trial. You also have another clinical trial collaboration and supply agreement with Pfizer with their CDK4. Can we just talk about that as well and what drove that collaboration? Yeah. I mean, from, I'll, I think the driver for the collaboration is different but complementary for the two participants in the collaboration. I'll start with us. For us, we are constantly looking at the potential life cycle of palazestrant. Where is the standard of care going to go? Right now it's CDK4/6, it's really Kisqali, and we're set up well for that. The question is what's next? We really have felt like atirmociclib, the CDK4 selective molecule from Pfizer, has a decent shot at transforming that standard of care. The thesis there is that by dialing out CDK4/6 and dialing down neutropenia, which they have demonstrated they do, you can hit the CDK4 target harder and potentially get better efficacy. They recently presented data at ESMO, not a huge data set, but it looks quite interesting in that respect. For us, it was interesting to say, where's it gonna go in the life cycle of palazestrant? For Pfizer, they have demonstrated over the years an interest in the next generation of endocrine therapies. They previously had an agreement with Arvinas, which has dissolved. Now with their lead asset, atirmociclib, they're moving on to palazestrant, which has shown favorable combinability. We would like to demonstrate that with the atirmociclib. That enrollment is ongoing. Data not for everybody, but for the collaboration will be available in the 1st half of next year. We are very hopeful, depending upon what we see, that could generate yet another 1st-line trial opportunity to extend the life to the new standard of care. Since you have pivotal trials in both frontline and 2nd line, maybe just like, let's talk about the market opportunity in breast cancer in those two settings and for Olema specifically. Right. As I mentioned a bit before, the market opportunity currently in the 1st-line setting is about $10 billion-$15 billion globally. We anticipate that that will probably increase somewhat over time. The main reason for that increase would be in order to succeed, you have to have a longer progression-free survival. That is to say, the patients will stay on therapy for longer. Of necessity, obviously that means that there will be a bigger market. The 2nd/ 3rd-line setting we believe is about a $5 billion market opportunity in the United States alone. That's split, right? Right now there are a couple of drugs approved in the 40%-50%, which are ESR1 mutant. We think that's about a $2 billion opportunity. There's no one in the opportunity as a whole with the wild type. That's the opportunity we have with the 2nd half of next year readout of OPERA-01 to potentially access that full $5 billion opportunity. Great. I also wanna quickly touch on your KAT6 inhibitor. Maybe just give us a little bit of background of your KAT6 inhibitor and how is it different from Pfizer's KAT6 degrader? We have seen some data presented from them recently as well. Yeah. So, credit to Pfizer here. They really are the first to go after this one in the clinic and really have validated the target, KAT6. KAT6 is an epigenetic target. Our molecule's called OP3136. The similarities are that both our molecule and the Pfizer molecule target KAT6A, KAT6B, and KAT7. At the exposures that Pfizer achieves, they are also inhibiting KAT5 and KAT8. We have dialed that back. We don't, in our preclinical model, see that as important efficacy. We think it could potentially be contributing to toxicity. Now, toxicity here takes two forms: dysgeusia, which is a taste alteration, which is an inconvenience for the patients, not dose limiting, and cytopenias. And those can be dose limiting and obviously also limit potential combinability. It is our hope that maybe by dialing down KAT6 and KAT7, we will be able to mitigate that somewhat. That is a clinical question. I think that is one of the things we will be able to shed some light on, late in the 1st half of next year when we present the data. Just add, these, like all targeted agents, are given with an endocrine therapy. You do not give them alone. You combine them with an endocrine therapy. The current endocrine therapy, the standard of care that Pfizer is using, is fulvestrant. This is a large volume injection. We know it has limited activity primarily due to its poor pharmacokinetics and bioavailability. Our preclinical data says a good targeted agent, including the Pfizer molecule, does better with the best endocrine agent. Palazestrant significantly enhances the activity. Now it is Pfizer. We are the only company that's able to do that combination, KAT6 and palazestrant. That enrollment is actually ongoing in the phase I/II trial right now. Just in terms of the data you mentioned next year, maybe just help us frame the expectation here. What should we expect to see from the data next year? Yeah. It'll mostly be phase I dose escalation data. That's going well. There's a lot of interest. It's enrolling well. We don't have a maximum tolerated dose yet. You'll see PK, you'll see some preliminary monotherapy efficacy. You'll obviously see safety data at multiple dose levels. It gets to the question you asked before about differentiation, particularly cytopenias. I think with fulvestrant, we may have some data to present. How do we combine maybe very early efficacy and early cohorts? palazestrant, I think we're just getting going. I think that'll probably be pretty limited. That'll be for a later update. I think the drug-like properties, early tolerability will be pretty robust. How should we think about the overall opportunities for KAT6 and, and then, any other indications you will be considering as well? For the path forward, how fast, like after the phase I data, will you think you move the program forward? Yeah. I'll divide that into two: positive, HER2 negative breast cancer and other indications. For positive, HER2 negative breast cancer, where it's a validated target, right? The Pfizer molecule with fulvestrant saw about a 38% response rate post CDK4/6 plus AI progression, right? That's impressive. I think what we would wait for is really the palazestrant combination safety and preliminary efficacy, because that could be a significant differentiator, being able to combine with palazestrant. That would lead us to a decision. Where would you position that? The therapeutic objective in positive, HER2 negative metastatic breast cancer is to put off chemotherapy as long as possible. Ideally, you do that by giving oral targeted therapies because that's really good for the quality of life of the patient, right? With palazestrant, which is an oral daily pill, OP3136, which is an oral daily pill, we give the opportunity to do that as opposed to a fulvestrant combination. It would be post CDK4/6, and hopefully, OP3136 plus palazestrant. In the monotherapy part of the trial, we are testing two other histologies. We are testing castration-resistant prostate cancer and non-small cell lung cancer because we saw activity in those tumor types in preclinical efficacy models, not mouse xenograft models. We will see what signal we generate in the phase I to decide whether we want to continue there. Obviously, if it were prostate cancer, it would be now a combination with an antiandrogen, very similar to the approach we take with an endocrine therapy in breast cancer. Non-small cell lung cancer, we will have to see. We are not quite sure what that would be. We also saw activity in ovarian cancer. Now, the standard of care there is very complicated, so we chose not to include it, but it could be, if we go outside of breast cancer, that it could be in the life cycle of 3136. Great. A lot of exciting milestones next year, and we're all looking forward to it. Thank you very much, Sean, for joining us. Thank you to all the audience for joining us today. Apologies for all the noises, but enjoy the rest of the conference.