Good afternoon, everyone. Very sorry for the delayed start here. I got a forced dual restart right when the session was supposed to begin. I'll have to thank TD Cowen's IT department for that one. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thanks again for joining our Seventh Annual Oncology Innovation Summit. This session, very excited to have with us Dr. Sean Bohen, the President and Chief Executive Officer of Olema. Sean, apologies for the delay, and thank you very much for joining us. Thank you, Tyler. We'll do our best to be efficient with the questions, but you guys can go ahead and vote via the portal, and I have a dashboard. Why don't we go ahead and start with the KAT6 inhibitor this time, given your guys' recent update and the data coming ahead of us this upcoming weekend. Sean, it would be great if you could start with the program, why it's differentiated, and maybe the high-level takeaways from the abstract. Sure. The program is centered around our lead molecule, OP-3136, which is progressing nicely in phase I. The poster will focus on the monotherapy dose escalation portion of the trial. Obviously, a lot of tolerability data, PK, pharmacodynamic data from histone acetylation. As well, our early efficacy data, both in terms of a waterfall plot showing decreases in tumor size, but also an early swimmer plot showing time on therapy. Reminding everyone this is a validated target. The Pfizer program is in phase III, showed clear activity with fulvestrant in breast cancer after CDK4/6 plus AI. Quite a bit of toxicity. The minor toxicity limiting dosing or dose intensity was cytopenias, neutropenia in particular. We have had a hypothesis that that is due to the relative lack of selectivity. The molecule hits KAT5, KAT6, KAT7, KAT8 at the exposures that are achieved with the 5-milligram daily dose. What OP-3136 does is it dials down the inhibition of KAT5 and KAT8. It is a potent KAT6 and KAT7 inhibitor at the exposures that we are achieving. I think what you're going to see in the poster is clear evidence of anti-tumor activity. That anti-tumor activity is in breast cancer, post CDK4/6, where you would expect it, but also in prostate cancer, post a number of therapies. Prostate cancer and lung cancer were allowed on the trial. We didn't specify numbers of patients, we do have a fair number of prostate cancer patients, obviously the majority are breast. The early efficacy looks good in the abstract. We'll get more details on that just to summarize, there's also going to be a lot more on the efficacy front, to be clear. Yeah. You'll see swimmer plots. You'll see all our patients that had measurable disease. I'm sorry, waterfall plots. You see all our patients that had measurable disease, and you'll see the majority of them had some amount of tumor shrinkage, actually. Remembering you're dealing with early phase I data. You have multiple dose levels over a huge range, actually 2 mg- 45 mg. You'll have maybe max a half dozen patients at any given dose. What you can see is that you'll see with the PD marker that already the target engagement occurs at the 2 mg dose, and is maintained throughout, but you'll also see anti-tumor activity over a variety of dose levels. Importantly, I think it's hard to do these cross trial comparisons, but I think what you're going to see is an indication. There are no DLTs, there's no MTD yet determined, and we are still dose escalating. I think what you're going to see is the beginnings of potentially a better tolerability profile. Got it. That's quite exciting. Now, I should add the fulvestrant and palbociclib combinations in breast cancer are ongoing right now. No data in this poster. Too early. We are enrolling patients in those combinations now. As we announced today, the combination with NUBEQA will start in the not too distant future in prostate cancer. Yeah. Just to be clear, I guess mechanistically, the improved safety and tolerability versus Pfizer's program makes sense, and we've seen, obviously, from the abstract a little bit on that and look forward to seeing more. Yeah. Do you believe as a monotherapy that you all could be differentiated on efficacy as well? Is it really people should really think about the ability to differentiate with the combo? Well, I don't think these drugs are going to be given as monotherapy. They're growth inhibitory, although again, we do see tumor shrinkage, so we definitely see decrease in tumor volume. I think that the majority of therapy in this space is combinations of targeted agents. In breast cancer, you always combine with an endocrine agent, right? An estrogen receptor targeting agent. That's why the fulvestrant and palbociclib combinations are ongoing. Preclinically, the palbociclib combination looked pretty extraordinary. We're very excited about that. I think what's a bit new here was monotherapy activity in prostate cancer, mechanistically you go back and do something very similar, right? Breast cancer is an estrogen-driven tumor. Prostate cancer is an androgen-driven tumor. You use basically the same playbook, which is inhibit the KAT6 pathway, try to keep this growth and proliferation transcriptional program locked down, but then also go back and inhibit that endocrine driver of the tumor. That's what NUBEQA's about in prostate cancer. Okay. Do you all also plan to explore lung cancer moving forward? Maybe you could elaborate on that a bit, or? Yeah. You'll see we have one patient on the trial, so I don't think you're going to get a whole lot of lung cancer information. We are still enrolling. Lung cancer is, again, is an included histology for eligibility in the trial. I think we'll have to decide over time whether we want to explore that. It's not quite so clear mechanistically what you would combine with in lung cancer. IO, maybe, probably. It's not biologically pathway-wise quite as clear. We included it because the pre-clinical data was indicative of potential there in lung cancer xenograft models, and so that's why we included it. Got it. Okay. Again, you mentioned this briefly, but just the fulvestrant combo, the abstract had some very early details on that. Can you elaborate on that a bit? Yeah, I would just say right now it's ongoing. There's no data on the combos in there. The soonest we could possibly, I think, be sharing that is end of year. I wouldn't commit to it. First half of next year for sure. The fulvestrant combination for us is basically strategically we hope just a comparator data set, right? Because it looks pre-clinically like the palbociclib combination is much more potentially powerful. That's really our primary focus. Again, we're uniquely able to do that. We have a KAT6 inhibitor, which is clearly active, we believe may be differentiating, and we have a combination agent in palbociclib that no one else can combine with. We're uniquely positioned there. That's really our primary focus in the breast cancer combinations. Got it. Would the pala combo data come as the same time as the fulvestrant combo data, or would we get fulvestrant first? Yeah, we'll just have to see. It is a little bit behind because remember with pala and OP-3136, you're combining two novel agents. You end up from a safety standpoint, there's nothing that we've seen that's concerning, but you end up approaching it a little bit more conservatively than when you're combining with fulvestrant, which is obviously a very, very well-established agent as a monotherapy and combination that you can do more quickly. That makes sense. You're obviously excited about the pala combo because the pre-clinical data were striking. I guess the reason that the pala combo with KAT6 looked better is the same rationale as you all are discussing in the ongoing OPERA trials, right? I think it's the same rationale as to why we believe the ribociclib combination looks better than with AI or fulvestrant or other endocrine agents, [YV]. Everolimus, we haven't shown the data. We think that that also is very exciting as a combination. Monotherapy, again, we believe looks better, and that'll be tested in OPERA-1 with readout in the fall. The concept here is that what you're doing is you have this transcriptional program, and you're shutting it down through two pathways. One is preventing the histone acetylation, which is the PD marker, so that you're keeping the heterochromatin tightly wrapped. That decreases access to these growth and proliferating genes promoters, and then you're also shutting them down by completely antagonizing and shutting down the estrogen receptor. Great. Just to wrap up the KAT6 discussion, ultimately where do you see KAT6 inhibition falling into the standard of care for ER-positive, HER2-negative breast cancer? Well, the obvious space is after CDK4/6 plus AI, right? Because we need more targeted agents. The objective is to put off chemotherapy as long as possible, control the disease. Remember, just remind everyone, OP-3136 is a daily oral pill. What you'll see in the poster is it has a 12-hour half-life approximately. What you have is two daily oral therapies. People can just take these pills once a day. That's a great quality of life benefit. Obviously you avoid the more intense toxicity of chemotherapy, be that standard chemo or an ADC like Enhertu. That's the objective. Now, with a more favorable tolerability profile, it does raise the question, could you combine it with a CDK4/6? I think that that is an interesting question, it's more a down the road question. The first step is to combine with the endocrine agents, and that's ongoing. Sure, that makes sense. At ASCO, we will also get the persevERA data, which people are excited to see. Maybe you could discuss your expectations for that, if there's a particular or specific kind of numerical benefit that you would like to see that would increase overall confidence towards the potential for frontline combinations with SERDs and any additional detail you might feel worth discussing? Right. I think the most important point for us is that we designed palazestrant to be better than giredestrant. We think our phase II data indicates that we are well on the way to achieving that. The reason we can achieve that is because we don't have to compromise on our exposure and our dose. They had to go from 100 to 30 because of bradycardia with palbociclib. We don't have to do that. We give the full dose of 90 with full dose ribociclib. That's another differentiator, which more has to do with time, which is combining with Kisqali, which is the standard of care now, rather than Ibrance. We really believe OPERA-02's probability of success is based on our data with palazestrant and ribociclib, which we showed 12 months plus post-CDK4/6 inhibitor progression-free survival. That's being tested in OPERA-02. I do think a more favorable hazard ratio does suggest that the AI is inadequate, right? To some extent, giredestrant has shown that in the AI versus giredestrant setting in lidERA. Now, though, they're in the combination with CDK4/6. There's nothing in particular we're expecting. We actually don't think it has anything to do with the activity of palazestrant, which we see as superior. We are very interested in the trial data, though, because one of the things we've been doing is we've been making assumptions about the performance of the control arm. If those assumptions are wrong, then we may need to change the trial design and specifically change the number of patients included. 25 months is what in PALOMA-2, approximately what palbo plus AI showed. We know in oncology these things get better over time frequently. That may have been the case here. It's really useful to have a more contemporaneous data set, and we have time to change OPERA-02. To us, that part of the trial is very exciting and we look forward to seeing the data. Okay. That's helpful. That makes sense. What about SERENA-4, that readout later in the year? Do you think that has a higher probability of success than persevERA, or what should expectations for that be? Yeah, unfortunately, I don't think it has a higher probability of success. It's the same combo, right? It's palbociclib, not ribociclib, and the exposure is much lower. We know that from the 75 mg dose of camizestrant. Again, that's due to tolerability issues. Now, there are other aspects that may help the probability of success of SERENA-4. Remember, persevERA, OPERA-02 are about 1,000 patients in their design. SERENA-4 is almost 1,400. It's a much larger trial, and so the same hazard ratio could be positive in SERENA-4, where it was negative in persevERA. Obviously, I don't want to talk too much about OPERA-02 because we can change it. It might not be 1,000 once we're finished with it. I do think that's interesting. The other thing of interest to us is if AZ is able to stick to their timeline of second half, we could potentially actually wait for SERENA-4 as well to get a look at the performance of the control arm and incorporate both as we make our assessment of how to potentially change OPERA-02. Okay. Since you mentioned OPERA-02, can you talk about where you're at in terms of enrollment and how long you expect enrollment of 1,000 patients to take, and when we could see data? Yeah. Enrollment's going well. It is active. It is enrolling, and it's enrolling robustly. We're on target for our timeline. We had previously communicated as soon as potentially 2028. I'm getting a bit more hesitant about that in particular. If the control arm outperformed, that will push out the whole trial. I think it's very likely later than 2028, and I think our time to update on that is probably after we see this data from persevERA, maybe from SERENA-4, and see if we should change the trial design. Obviously, changing the patient numbers, changing the assumptions about the performance of the control arm will change the timeline for the trial. It doesn't change the fact that we have the confidence in palazestrant-ribo combo because of what we've seen in our phase II data set, that 12 months. Great. Now moving to the other OPERA-01. 01, yeah. A big data readout coming in the fall. Maybe you could walk through what you expect to report there, what you might need to show to be differentiated in the mutants, then also how you're thinking about expectations for the wild type setting or perhaps ITT and the overall analysis there? Yeah. In the mutant, I think the current standard of care, elacestrant, now imlunestrant, vepdegestrant coming, they're all about two months, right? You go from about two months median PFS in the control arm to about four in the treatment arm. Obviously, if you achieve that, you can get approved, but you're possibly not differentiated. If you double it, that should be something meaningful. It'll go maybe from around two to six, get four months. Now, in the wild type setting, there's nothing, right? There's nothing there, and that's a huge opportunity. If we are able to duplicate what we saw in phase II, again, the bar there would be a two-month delta in PFS, two to three months in the control arm, four to five in the treatment arm, and you give an oral monotherapy option to that 50%-60% of patients who are ESR1 wild type following their progression on CDK4/6 plus AI. The readout will occur in the fall, and that we're still on track for that. The trial is designed to analyze wild type and mutant. ITT is in there, of course, as an exploratory analysis, but that's not how the treatment paradigm or regulatory authorities look at it now. They look at it as two separate populations, and biologically, that's probably accurate. What are your latest thoughts on the overall market opportunity for palazestrant monotherapy? Well, we think the overall is about $5 billion annually, and that would include wild type and mutant, right? It's about $2-ish billion in the mutant. Again, though, with multiple entrants, right, as you pointed out. There you would want to differentiate based on some factor, efficacy being the best. The wild type is alone, right? That about $3 billion opportunity, if we are able to access it, we will uniquely be able to offer patients a treatment option there. Cool. We're approaching time here before the next session. My apologies for us having to be a bit more efficient here. You did a great job, Sean. Maybe a final question. What do you believe is the most underappreciated aspect of the Olema story by investors right now? Yeah, it's funny, as I look at we're a bit below $1 billion in enterprise value. Look at the poster on Saturday. I think we're undervalued for OP-3136. The irony is you can buy us for OP-3136 if you believe that thesis, and you get a phase III asset with a $5 billion market opportunity readout in the fall with great phase II data behind it and a $10 billion plus opportunity coming down the road in the OPERA-02, and you get that for essentially free. To me, I think the investor thesis here is pretty compelling, but I also have my biases. That's great. Sean, thank you so much for your time. Really appreciate it. Thank you, Tyler. I will see you in Chicago. See you there. Bye. Okay. Bye-bye.