Great. Good morning, everybody. We have the pleasure of hosting the Olema management team for this fireside chat. Thank you for taking time out of your schedule to stop by. Maybe before we get started, to more detailed questions, Sean and Shane, for those in the audience that are maybe not as familiar with the Olema story, can you please give a brief introduction of yourselves and the company at a pretty high level? Sure. I'm Sean Bohen, I'm the CEO of Olema. We've both been there a little over five years. Took the company public in November of 2020. My background is clinical development. I'm an oncologist and biochemist by training and worked at Genentech for about 13 years, was head of early development. CMO of AstraZeneca for about five years, and then went to Olema as CEO. I've been with Olema a little over five years as COO and CFO and spent the last 25 years across investment banking and a variety of operating roles in biotech. The company, Olema, is focused on breast cancer, particularly ER -positive, HER2-negative breast cancer, which is 70% of breast cancer, right? Breast cancer is the most common malignancy diagnosed in women, but the most common cause of cancer death in women. Our lead asset, palazestrant, is in two phase II trials right now. The one to initiate first was OPERA-01. It's in the second, third line setting. It's a monotherapy. That will actually read out in the second half of next year. We have a very news flow-rich period over the next 12 to 18 months. The second trial, and there are really important opportunities to differentiate there. There is proof of concept for anti-estrogen in that setting in the ESR1 mutant population, 40%- 50%. Nobody's been able to show improved efficacy over fulvestrant or exemestane in the wild-type. Our phase II data indicates we have better activity in the mutant, and we have activity in the wild-type. That's because palazestrant is a complete estrogen receptor antagonist with very good exposure. Those are the opportunities to differentiate, and the readout will be, as I said, second half of 2026. That's, I should say, a $2 billion- $5 billion market opportunity. We have the first-line trial initiating before the end of this month called OPERA-02. That's a combination with ribociclib versus ribociclib plus AI, the current gold standard first-line standard of care. That trial will take a few years to enroll and mature. That's a $10 billion plus market opportunity. We are updating on our combination phase II data in about a month at ESMO, in October. We had shown that combination data post CDK4/6 inhibitor, we have more than a year of median PFS, which is pretty unprecedented. The bar in that first-line setting is to improve upon the ribociclib plus AI by about six months. We think this bodes very well. We are going to update on that data. We are actually going to do something else interesting, which is split out the wild-type and the mutant because many observers believe there's no activity in wild-type. I think we are going to help people understand why we're so enthusiastic about it. We have a second clinical stage program. It's in phase I, phase Ib, which is a KAT6 inhibitor, OP-3136. That is enrolling very well. It's continuing to dose escalate. We don't have an MTD in the monotherapy setting, and we've started dosing a combination with fulvestrant. Remember, all targeted agents are using combination with an anti-estrogen. We've started combining with fulvestrant. Before the end of the year, we believe we'll start the palazestrant combination, which looked very promising from a preclinical standpoint. That's basically the company. Okay. I guess we'll hit on most of these as we kind of go through, pick through all your programs. As investors are, you know, looking at Olema, what should they focus on in the near term, and also what are you focused on in the near term? Yeah, I think in the near term, the first thing probably to focus on is the data that we've generated from phase II with palazestrant. The easiest way to predict the outcome of a phase III trial is to see how the molecule in that trial has performed in phase II. That seems obvious, but it's really largely not what's happening in this field. The SERD class, which is unfortunately named because degradation is not the mechanism of action, SERD class is getting all together. Our data, both as monotherapy, where we showed over seven months in the ESR1 mutant setting and in the overall population post CDK4/6, and over five months median PFS, which is unprecedented in ESR1 wild type, distinguishes itself. That's the data that predicts O-01. The update that we present at ESMO next month is the one that will give confidence in OPERA-02 going forward. We will also present mono and combo data in the first half of next year for the KAT6 program. For KAT6, I want to emphasize a couple of things that are interesting. Obviously, the primary indication for us is ER -positive, HER2-negative breast cancer. There's proof of concept there from the Pfizer program, which is in a pivotal trial. The monotherapy has non-small cell lung cancer patients and castration-resistant prostate cancer patients in it because the preclinical data indicates good likelihood of activity. That will be interesting as well. We will be opportunistic there based upon what we see. There is external data that I think people will be watching. The Roche program, giredestrant, also a complete antagonist. It is dosed a little lower than we would like because of toxicity in combination with palbociclib, bradycardia. Roche has reiterated that top line data from their persevERA trial will be made available before the end of this year. I think people will look at that data as particularly positive as a proof of concept for the approach. Yeah, certainly a big event for the cause. Yes. Yeah. Now maybe digging specifically into Olema. The OPERA-02 phase III in combo with ribociclib, can you just talk about the therapeutic rationale behind a CDK4/6 combo in metastatic breast cancer? Right. There are two elements I think that I'd like to talk about. The one is ribociclib, really. OPERA-02 is the only trial of a novel anti-estrogen in the first-line setting that uses ribociclib as the CDK4/6 inhibitor. The persevERA trial I mentioned before from Roche uses palbociclib. The SERENA-4 trial, which is quite a bit delayed, it's into 2026, which is a camizestrant AstraZeneca trial, uses palbociclib. That's a historical thing. Those of you who followed this will realize that IBRANCE pretty much ruled the CDK4/6 world for a while. Something interesting happened a few years ago. The overall survival data started to mature with these agents. Just kindly, ribociclib really declared itself as the agent with, you know, three of three trials with survival benefit, with the benefit being about a year. Obviously, that's extremely significant. That then switches the standard of care to ribociclib. We were generating data at that time when we were able to switch our strategy to include ribo. That's the CDK4/6 part. Now the CDK4/6, all the targeted therapies, CDK4/6, PI3 kinase, AKT, KAT6, everolimus, so mTOR, you need the endocrine therapy backbone, right? What we're doing here is we know that AI is effective with CDK4/6, but we also know a couple of things. One, the most common resistance mechanism is an ESR1 activating mutation. Aromatase inhibitors have no activity against that, really noted as fulvestrant. Palbociclib has very clear activity against that, 40%- 50% of mutations. The core hypothesis is we will suppress that very common resistance mutation. It's exactly what TAGRISSO did in EGFR-mutated non-small cell lung cancer with T790M. The thing that we're going to show you, and so that's a very compelling hypothesis. I think the thing that we're going to show at ESMO is it's not just that, that there is more activity to be had in the wild-type setting too, right? Those patients will be post CDK4/6 plus AI. About 30% of them will have had two prior CDK4/6 inhibitors. You're going to see what happens when you use ribociclib and palbociclib in that setting. Got it. Now, you hit on this a little bit earlier, but what kind of activity do you need to, or do you expect to see, rather, in ESR1 wild-type tumors relative to the mutant tumors, given that it's, you know, we're talking about a frontline? ESR1 mutant is not really a consideration in the frontline setting. The percentage of patients who will go into the OPERA-02 trial with an ESR1 mutation is low single digits. It's probably about 3%. The mutation arises in the context of the selective pressure of CDK4/6 plus AI. We'll show you the data as to what we saw in the mutant versus the wild type. It is absolutely true that there is more activity in the context of the ESR1 mutant. That's probably in part because the ESR1 mutation is not only the target, but it's declaring that the tumors are estrogen receptor dependent. It's a more homogeneous population. In the first line setting, again, we saw more at, or I'm sorry, second, third line setting post CDK4/6, we saw more activity in the mutant, 7.3 versus 5.5 months in the phase II experience. We expect that to play out in OPERA-01. That gives the two ways to differentiate. The current benefit that's seen in ESR1 mutant is essentially two months. It was two to four months in EMERALD, which led to the approval of Imlunestrant, VERITAC-2, Vepdegestrant, pretty similar. Going to seven range, if we can do it, six or seven would be a significant benefit. Obviously those failed in the wild type. Being able, if we could recapitulate five months, that would be compelling. That is how you're thinking about the potential efficacy bar? For OPERA-01, yeah, the efficacy bar is pretty straightforward. You have to have two months over the control arm. You have to have one radiographic assessment period, which is eight weeks. That's, we know that for palazestrant in the mutant, we believe vepdegestrant will be approved in that same population based on VERITAC-2. If you see that wild-type or mutant, you have a basis for approval. Yeah. Now, beyond metastatic breast cancer, are there any other indications where the combination with palazestrant could make sense from your perspective? I really think our focus is on advanced metastatic breast cancer. It is reasonable to believe that a better endocrine agent would have activity in the adjuvant setting as well. We have not embarked on that, but at the point where we were to establish a collaboration or have a partnership, it is a discussion that would occur. It's a little complicated in two ways. One, the adjuvant standard of care is really actively evolving. The existing adjuvant trials and Roche, AZ, and Lilly all have ongoing adjuvant trials. They actually don't use the current standard of care, because it's evolved. I think that's one challenge. The second is those trials take a long time. Yes. Got it. On the collaboration point, you recently announced an agreement, with looking at palazestrant in combination with Pfizer's CDK4, in a phase Ib/II trial. Can you talk a little bit around the agreement to the extent that you can share and also your rationale for pursuing the combination as well as the potential you see in eventual pivotal trial in the frontline setting? Yeah. Yeah. We announced this last week. This is a clinical trial collaboration and supply agreement. The objective here is to combine palbociclib, which is Pfizer's CDK4/6 selective molecule That molecule is in the FALCON-3 trial, an ongoing first-line pivotal trial versus physician's choice of CDK4/6 inhibitor, right? So it's [ibrance (palbociclib) plus] AI versus physician's choice CDK4/6 plus AI and PFS endpoint. Pretty standard. The idea behind what Pfizer is doing with palbociclib is we know that the neutropenia caused by CDK4/6 inhibitors is primarily due to the inhibition of CDK6. If you dial that out, you should be able to hit 4 harder, provide greater inhibition of CDK4 activity without having this limiting toxicity of neutropenia. Their data presented to date suggests that they have successfully dialed it out and reduced the neutropenia. It is really a FALCON-3 trial that tests the hypothesis. Does that lead to greater activity from the PFS standpoint? So control of disease. Obviously, they're going with AI, the existing standard of care. However, they and we believe that the endocrine standard of care will evolve. From a lifecycle standpoint, it makes sense from their standpoint to combine their lead molecule with what may be, we believe will be, the next generation endocrine standard of care. For us, it makes sense to be prepared when OPERA-01 or even before OPERA-02 reads out to be positioned with what may be the CDK inhibitor standard of care. We do think palbociclib has that potential. We're generating data in a phase Ib/II trial, a total of about 35 patients, to show combinability, which has been challenging. We know with palbociclib, vepdegestrant, the previous SERD that Pfizer was partnering on had trouble. We haven't had any trouble. We've combined very favorably without DDI or toxicity with palbo, ribo, alpelisib, everolimus, and now we'll test [palbociclib], and very soon we'll also test our KAT6 inhibitor. Could you share a little bit around, before we get into the combination rationale a little bit further, around what you announced in terms of the agreement itself, any economics? Yeah. What we've said is it's supply provided to us of palbociclib to do a phase Ib/II up to 35 patients in combination. There aren't any economics. We have worked very hard to preserve the global rights to palazestrant. Palazestrant is wholly owned by Olema, with no royalties, no global rights committed to anyone else. That includes Novartis in our ongoing agreement around ribociclib in OPERA-02. Novartis provides the ribociclib for that. That as well is carried into the IBRANCE agreement with Pfizer. With respect to that, there aren't economics, right? You don't give an upfront, no financial rights, no future revenue. What we really want to do is generate data to show the viability of that combination. We're hopeful because palazestrant is combined so well with all of the other agents. What that does is that then sets up a discussion about where do we want to go with this? Do we want to go into the first-line setting in a pivotal trial context? Got it. The great thing is we have existing trials ongoing. We have a combination trial where Sean said we've tested multiple of the combination, U.S. sites, Australia sites. We're going to drop that convoy, and we'll dose patients and generate data with [ibrance] very quickly. Yeah, that accelerates the ability to address this important question. It sounds like this is a collaboration that really furthers your potential as a best-in-class backbone endocrine therapy in metastatic breast cancer. Yeah, that's right. For a small company our size, the $2 billion- $5 billion monotherapy is very attractive. If you look at the future of this disease, the biggest market opportunity, the biggest opportunity to help patients is in combination. That's why we have been testing these various combinations. I will add, that's another place where we really believe we're best in class. Other agents either do the classical DDI or enhancement of toxicity have been challenged. Yeah. Now, just one more point on Pfizer. How are you thinking about their ongoing phase III trial, the FourLight-3, in combination with letrozole in first-line ER -positive, HER2-negative metastatic breast cancer, and any potential read through to your palazestrant combinations? I don't think we have any data for that to be available in time to read through. It is fundamentally not about the endocrine agent, right? It's about the testing of this very interesting hypothesis that more profound inhibition of CDK4 enabled by dialing out CDK6 will actually translate into better tumor control. We think it's a fascinating experiment. It's very important for understanding first-line therapy and how does CDK4/6 really work. To be honest, I don't think we're going to have data in that timeframe. 2029, I think is, okay, that's on contrast. Now touching briefly on something that folks are probably more familiar with, which is OPERA-01 in second, third line ER -positive, HER2-negative breast cancer. Can you provide just a general update on the program and your efforts to accelerate enrollment ahead of the potentially ahead of the top line data in H2 2026? Yeah, it's enrolling very well. It is a global trial. We will update on that timeline and refine it a bit, probably around the end of the year, and that'll be based on more enrollment data. The trial is about 500 patients in total. The timeline for readout is really dependent on enrollment in this trial. It's a little different than OPERA-01 and the other first-line trials where it takes a while for events to accumulate. Events accumulate quickly in this second, third-line setting post CDK4/6. The control arm, fulvestrant or exemestane, will have a median PFS of two to three months, we predict. That's been confirmed by, you know, that was what was in EMERALD, but really, if you look at VERITAC-2, which recently read out, very much the exact same. We've seen this consistently. It's really enrollment that drives that. We are confident in saying it will read out before the end of 2026, but I think over the coming months, we'll be able to narrow that a bit for people. Got it. Maybe could we talk around palazestrant's best-in-class potential as a single-agent endocrine therapy in the second-line setting? Yeah, that is really related to molecular properties, related to being a complete estrogen receptor antagonist. Just to give you a contrast, elastastin and vaptogestrin, we've published on this, are partial agonists, partial antagonists. They're SERMs. In the wild-type setting, they're weak antagonists. In the wild-type setting, they're weak agonists. In the mutant setting, they're weak antagonists. In the mutant setting is where that antagonism, estrogen-activity, you don't ever want to turn on this receptor in a breast cancer patient because it drives the growth and proliferation of the tumor. That agonist activity is a liability there. Palazestrant is a complete antagonist. It shuts off all transcriptional activity, both in the mutant and the wild-type. In order to do that, you also have to occupy all the receptor all the time. The eight-day half-life, the very high exposure we get enables that, and so with a single oral daily dose. That is really the fundamental, molecular and pharmacological basis for this. As I mentioned before, it translated into very promising phase II data, over seven months in aggregate. The trial and regulators won't look at the data in aggregate. They'll look at mutant and wild-type separately. They're all with 7.3 and 5.5. We're reasonably confident. Of course, we'll see when the data reads out. Got it. Since you brought it up, maybe we can talk a little bit around the dose selection. Since we're talking about targeted coverage and PK, you recently aligned with the FDA on dosing for all palazestrant trials, including OPERA-01 and OPERA-02. That's right. Can you speak to the dose selection criteria and how the FDA decided on the 90 mg daily dosing regimen versus 120 mg daily? Yeah, I can describe the process. The unblinding was for the IDMC and the FDA. I can't really describe the data. I can also describe why we're confident that 90 is a good dose to move forward. The story here is that the OPERA-01 trial is a little unusual. It had a part one dose selection component, which was a little gift of the Project Optimus program. We had previously dose ranged 120 mg and 60 mg. Both active doses, actually, but that was done in a randomized phase II setting. We agreed with the FDA that 60 mg was not the right dose. When we started OPERA-01, they said, "What about 90 mg?" The basis for this is that 90 mgs exposure is completely overlapping with 120 mg. You are getting the same receptor occupancy in both situations. We randomized 40 patients to the control, 90 mg and 120 mg. The data was unblinded for safety and efficacy for our IDMC to interpret. They recommended 90 mg. That then went to the FDA, who concurred. We never had a problem with 90 mg because the exposure of the pharmacogenetics are so favorable. That's what proceeds forward in the part two, the completion of OPERA-01. As you said, it also is the selected dose for the OPERA-02 trial in the first-line setting. It is really that PK. We've shown it before. We'll update on that and give people confidence on 90 in combination with ribociclib when we present at ESMO as well. Great. Thank you. With the last few minutes, let's talk about your KAT6 program, at OP-3136. There's been an enormous level of interest around KAT6 inhibition as a mechanism over the past year, particularly with some clinical updates from other programs, including Pfizer, around the potential for the drug class. Can you please provide an update on your OP-3136 program? Sure. The potential in metastatic breast cancer and beyond? Yeah, there has been a ton of interest in KAT6. Let's talk a little bit about the mechanism here because this is a bit unusual. This is an epigenetic target. KAT stands for lysine acetyltransferase. This molecule is an enzyme that puts lysine on amino acids on proteins. When you do that, you create a steric interaction where the protein has an inhibition for interacting with other targets. In this case, the targets most interesting is the histones. If you put a lysine on histones, then the DNA interaction relaxes and the heterochromatin opens up and the promoters that are wrapped in that heterochromatin become more accessible to transcription factors. Inhibiting that means you keep the heterochromatin tightly wrapped and the promoters are less accessible. From the standpoint of ER-positive, HER2 negative breast cancer, what you're doing is you're doubling down on turning off this transcriptional growth and proliferation program. The target is validated. Really, the only clinical data comes from the Pfizer program, right? They are in phase III right now in the second, third line setting with fulvestrant. They showed interesting low levels of clinical activity as a monotherapy. When they added in fulvestrant post CDK4/6, they got into the high 30% response rate, fairly long PFS in that setting, about 10 months, a little over 10 months, actually. That led to the interest. We had been working on KAT6 for years prior to that and started the actual clinical program late last year. Right now, the monotherapy dose escalation continues to be ongoing. We don't have a maximum tolerated dose, but we have a lot of clinical data. I feel confident that this is a drug-like molecule, drug-like PK, drug-like tolerability, and we've already started the combo. Fulvestrant combo is ongoing. A couple of things to distinguish from Pfizer: a more potent molecule, more selectivity. We don't hit KAT5 and KAT8 as hard. We do hit 6A, B, and 7 as they do. The other thing is preclinically, we saw that while fulvestrant enhanced activity, palazestrant was much more potent as an endocrine partner in patient-derived xenograft models. We will move to initiate that combination before the end of the year. We'll be able to update on both by the middle of next year, both the combo and the monotherapy. The other thing that we saw, and again, we've shared this in publication, is we saw activity outside of breast cancer. We saw in xenograft models, we saw prostate cancer, we saw non-small cell lung cancer, we saw ovarian cancer. Ovarian cancer's got a very complicated standard of care. In our monotherapy, we're doing prostate and lung as well. We'll be opportunistic about following whatever we see there. Sure. Can you touch on the enrollment, how in the phase I and provide an update? Just ongoing dose escalation as a monotherapy. It started in the fulvestrant combo. You go down a few dose-wise from where your monotherapy is, and then you follow behind, but that accelerates the process of hitting the combination palazestrant. We'll do that exact same thing. It's hard to give a timeline for phase I when you don't have a dose-limiting toxicity or an MTD. You keep going, and that's where we are. We can give the timeline for presentation of data by mid-year next year. That gives monotherapy update relative to OPERA-02 next month or a combotherapy update relative to OPERA-02 next month at ESMO. Persevera outside U.S., which is always a little nerve-wracking, by end of year. The KAT6 mono and combo first half of next year. OPERA-01 monotherapy phase III pivotal trial readout second half of next year. Got it. Now, you hit on this earlier. I think one of the more interesting things about Olema is how OP-3136 could be very synergistic with palazestrant. Can you expand on that a little bit? Yeah. Again, it goes to this concept that these targeted therapies, as monotherapies, are just not very active molecules. Remember, what's the goal of treatment in ER -positive, HER2-negative breast cancer in the metastatic and advanced setting? It's to push off chemotherapy as long as possible. Now, the first chemotherapy to be used in this setting now, it is in HER2. You want to push that off as long as possible when a targeted oral therapy preserves quality of life, allows the patients to go about their daily lives as uninterrupted as possible. In the case of the KAT6 combo, it's two pills daily one time. It's a pretty low treatment burden in that respect on the patient. What's been interesting and is consistent with our hypothesis that endocrine therapy needs to evolve further is that data has been indicating that we're leaving efficacy on the table with AIs and fulvestrant. I think palazestrant OP-3136 combo shows this in the preclinical setting very clearly and is a great differentiator, right? Pfizer has a KAT6 inhibitor. They're combining it with fulvestrant. They can't combine it with palazestrant. We're the only ones who can do that. That just offers another differentiation opportunity. Got it. Any key questions that you think still need to play out in the KAT6 arena? I think there are two, right? One is if you combine with a better endocrine agent than fulvestrant, can you even unlock more activity from this already validated target? Maybe three. Another one is by looking at the different spectrum of KAT target inhibition, can you change the therapeutic index, keep activity high, and perhaps improve tolerability? I think the next part is really, as I mentioned before, is this just the breast cancer target, or are there opportunities in other solid tumors? Got it. Last question. You've had a really robust track record, especially over the past year or so where you're pursuing strategic partnerships and clinical collaborations as you advance your pipeline. How are you thinking about your business development and strategic partnership efforts going forward? Yeah. We're always obviously open to discussion where it makes sense. What we've done so far is mostly agreements that allow us to combine with molecules that we think are very important to advancing the standard of care, to unlocking value, to palazestrant. I think that most certainly the scope of business development will switch post OPERA-01, right? That's a registrational trial. We do not believe that we are going to be marketing palazestrant globally. We will need to seek a partner at that time. Great. Sean, Shane, thank you so much for your time. Enjoy the rest of the conference. You too, Rick. Thanks, Rick.