Alrighty, let's go ahead and get started. Welcome, everybody, to the JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the Senior B iotech Analysts here at JPMorgan. I'm joined by my squad: Priyanka Grover, Malcolm Kuno, and Ratih Pinhay. Our next presenting company is Olema, and presenting on behalf of the company, we have CEO Sean Bohen. Alright, thank you, Anupam. And thank you, squad, as well. Thanks for everyone in attendance here and for your interest in Olema. Olema is making great progress in our mission, and our mission is to advance transformative medicines for breast cancer and cancers beyond breast cancer. This is our forward-looking statement. You can find it on our website for your reference if you need it. So how are we doing this? How are we executing upon this mission? We really are quite a focused company. We're good at breast cancer, and so we really focus ourselves on that. Our lead asset is a complete estrogen receptor antagonist, palazestrant. We'll talk about how this molecule differentiates from others in the class. Some of that is molecular. Some of that is pharmacological. Some of that is combinations. Some of that is how we develop the molecule. This molecule is in phase III. It will soon, in mid-year, enter a second phase III, currently in the second third-line setting. We'll enter the first-line setting in HR-positive, HER2-negative metastatic breast cancer. We entered our second pipeline molecule into the clinic recently. We are recruiting to our phase I trial for OP-3136. This is a KAT6 inhibitor. This is a novel and now validated target. It is a target that is engaged in combination with an endocrine therapy, and with palazestrant, we have what is emerging as the best-in-class endocrine therapy to combine with. Then we are working to further expand pipeline opportunities, again, with our focus being primarily cancers in women. This is an overview of our pipeline. As I mentioned, with our recent collaboration with Novartis and our recent IPO in the latter part of last year, we are now enabled to execute OPERA-02, our first-line combination study with palazestrant, combined with the CDK4/6 inhibitor of preference, which is ribociclib/Kisqali. The second- and third-line monotherapy trial, OPERA-01, is ongoing now. It will read out in 2026. We'll be able to refine that readout time as we progress our enrollment on the trial. And our single-agent data from phase II indicates that this should be a highly differentiated molecule in this setting, both by virtue of greater activity in the ESR1 mutant subset, but also the ability to actually improve upon the standard of care endocrine therapy in the ESR1 wild-type subset. Obviously, combinations are very important with endocrine therapy. Remember, endocrine therapy is the backbone of treatment for ER-positive, HER2-negative breast cancer. It is given alone or very often in combination with other targeted therapies. So the CDK4/6 ribo combo, we showed really encouraging and differentiating data at SABCS. We will update on that data sometime later this year. You will see that we had encouraging data, but we're not yet mature for PFS with a median of one-year follow-up. We previously presented the palbociclib combo data, again, giving both agents at full doses with no enhancement of toxicity. Alpelisib for PIK3CA mutated is ongoing, and we are to expand our combinations, enrolling a combination with the mTOR inhibitor, everolimus. At the bottom is this beginning of our OP-3136 KAT6 inhibitor phase I trial. Our main focus there is ER-positive, HER2-negative breast cancer, where this is a validated target. Preclinical data suggests that there is broader efficacy. So also in our dose escalation, we have included castration-resistant prostate cancer and non-small cell lung cancer. These are our milestones achieved in 2024, anticipated in 2025. For 2025, as I mentioned, advancing the accrual in OPERA-01 and the ability to update when we will unblind that trial in 2026. We'll initiate in mid-year the OPERA-02 phase III pivotal trial. We'll present more non-clinical data for OP-3136. We anticipate the clinical data first presentation will likely be in 2026, and then the mature data from the palazestrant ribo combo phase II. We anticipate our first commercial launch to occur in 2027. That will be based on the outcome of the OPERA-01 trial. So palazestrant, reminding you, breast cancer is the most common cancer occurring in women. 70% of breast cancer is ER-positive, HER2-negative. This is a very large unmet need, a very large indication. We're focused on the advanced metastatic setting. While there's been great progress in therapy, these treatments are not curative. And so unfortunately, most women who have advanced metastatic ER-positive, HER2-negative breast cancer will ultimately succumb to that cancer. So more treatment options, better treatment options are desperately needed. The current standard of care is focused on a backbone of targeting the estrogen receptor, which is a key growth and proliferation driver in this cancer. We know that the existing endocrine therapies are inadequate. They do not fully turn off the estrogen receptor signal. And that's where a complete estrogen receptor antagonist with favorable PK, oral daily dosing, eight-day half-life, high exposure, ability to combine at full doses without enhancement of toxicity is needed. Those properties so far describe only palazestrant. Reminding you the underlying molecular differentiation here. The existing ER-targeting therapies are SERMs. When the wild-type estrogen receptor is bound by estrogen, it is converted to an active transcription factor, binds target sites on the DNA, and modulates transcription of genes that promote the growth and proliferation of the cancer. A SERM partially inactivates this and partially leaves it active. So they bind the ligand-binding domain. They block one of the two transcription domains, AF2, but they leave AF1 exposed. AF1 is phosphorylated by many pathways activated in cancer. And so in that case, you have a partial agonist, partial antagonist. And that describes really many of the therapies that exist right now, both approved and in investigation. So tamoxifen, lasofoxifene, vepdegestrant, elacestrant, Orserdu. In contrast, palazestrant, when it binds the estrogen receptor, completely inactivates both transcriptional activation domains. And that is the objective here, right? You need to have all the receptor bound by an antagonist and turned off completely. It is also a potent degrader. However, there's so much estrogen receptor remaining that the tumors are still ER-positive. So you need to keep that significant remaining receptor completely turned off in order to control the cancer. As I mentioned, these are our two phase III clinical trials, OPERA-01 ongoing, OPERA-02 planned to start mid-year. These are significant market opportunities. Again, this is a large unmet need. So we anticipate a $5 billion plus market in the second/third-line setting, particularly if you are able to get both the ESR1 mutant and ESR1 wild-type subsets. OPERA-02 in the first-line setting in combination with the CDK4/6 of preference, ribociclib is more than $10 billion market opportunity. As I mentioned, there are several factors of palazestrant that differentiate it. In the monotherapy data, we saw extraordinary efficacy in our phase II setting. In the second- and third-line, plus or minus chemotherapy, we had 7.3 months median PFS in the ESR1 mutant setting. That's as opposed to four months, which was seen with Orserdu in the EMERALD trial. 5.5 months in the ESR1 wild-type setting in this line of therapy, again, differentiated more than what was seen even with the mutant with Orserdu, also certainly more than was seen with wild-type where there was no activity with two months. That's a result of the favorable pharmacokinetics in addition to the CERAN molecular activity. And this drug is very well tolerated. It's oral, daily, very well tolerated as a monotherapy and also in combination. And here are the Kaplan-Meier curves that support that. I'll ask you to focus on the lighter pink lines, which are the second- and third-line setting. We had some very heavily pretreated patients, but that's where we show you the 7.3 months in the context of the EMERALD comparable population and 5.5 in the wild-type. As we move on and look across what others have seen in this treatment setting post-CDK4/6 inhibitor plus AI, you can see that this is a really outstanding result that we see. Over seven months, most drugs are in the really the four-month range where they see median PFS, and so I think that we have a great opportunity in OPERA-01 to confirm and extend on this effect. This is the OPERA-01 trial design. You can see it has two parts. There is a dose selection Project Optimist component. 90 and 120 are the palazestrant doses. They have equivalent exposure. They both exceed our target exposure defined from maximum activity from highly resistant preclinical xenograft models. We actually are not particularly concerned about which dose is chosen. We would be happy with both because we achieve our exposure target. Once that dose is selected, we will resume enrollment and complete the trial. Again, later in the year, we'll be able to refine from a full year, 2026, for the readout to give a more specific timeframe for when we'll have the primary readout in 2026. PFS is the primary endpoint. That That is the approvable endpoint. Again, as I mentioned, we have the combinations that are ongoing. All of these at this point show the very favorable combinability profile of palazestrant, again, without compromising dose levels of these different agents to give the full dose. And the most recent data and probably most relevant because it is going to be the experimental arm in OPERA-02 that we presented was an update of our phase II ribociclib combination data that was presented at SABCS in early December and again shows that palazestrant now in combination with the CDK4/6 inhibitor of preference distinguishes itself with great tolerability, ability to give full doses of both agents, and resulting excellent efficacy. The six-month PFS rate we reported is mature. Every patient on the trial has had, at 120 and 600, the ability to have six months of follow-up. And I'll show you in comparison, but over 70% six-month PFS in all patients. In the prior CDK4/6, the harder to treat patients, about 20% of these patients had had two prior CDK4/6 inhibitors, and yet we maintain this very strong six-month PFS at 68%. Not surprisingly, lots of activity in the ESR1 mutant setting, 81%, but still very, very strong activity in the wild-type where others in the class struggle. There's no drug-drug interaction. Extremely important. There are two forms of drug-drug interaction that have limited the ability of others to fully saturate the receptor. Some are the classic. You induce the metabolism or inhibit the metabolism of the partner drug in some form, and that makes you alter the dose or exposure. The other form of drug-drug interaction is enhancement of toxicity, which leads you to lower the dose of one of your agents. As I will show you, we don't have any of that. And this is exactly that data. On the left, below the purple are the treatment emergent adverse events. Again, this is all the adverse events. It's not filtered by the attribution of the AE to palazestrant or ribociclib. Similarly, on MONALEESA-2, we have that data. MONALEESA-2 is relevant because this is the current standard of care in the first-line setting. Because of its survival benefit with ribociclib, Kisqali, letrozole plus ribo is emerging as the most common and preferred first-line therapy. It is also the control arm in OPERA-02. So that tells us what we can expect from a tolerability standpoint. As you can see here, I can't go through it in detail. They're very, very comparable. The really important things to look at are the primary toxicities of ribociclib. They are neutropenia and QT prolongation, which you'll see is further down here. The important point here is that the MONALEESA-2 data and the palazestrant ribo data are very comparable. So we do not expect the distinction in tolerability. To get greater efficacy here, all you do is substitute one oral daily endocrine agent, palazestrant, for another, letrozole. These are the Kaplan-Meier curves that result. With a median follow-up of 12 months, the median PFS is not yet reached. We do not know yet what our median PFS will be, but we will report on it this year when we have time to follow the 30 patients who remained on study at the time of this November data cutoff and do eventually reach a median. Now, you will see there is a crossing of 50%, but there aren't enough patients at risk at this time to actually call that the median. It is unstable. It can push out further as the patients who are censored continue to follow up. Interestingly, you do not see much loss of activity. So I should say that about a quarter of these patients are actually treatment naive, and they're in the all-patient subset. So as we go out and take the 16 patients out who are treatment naive and go into the prior CDK4/6, again, with many of those having two prior CDK4/6 inhibitors, we see not much decrement in the activity here. And that is extremely encouraging because this is a difficult-to-treat patient population. I'll show you some comparison in a moment. Again, favorable activity in both the ESR1 wild-type and ESR1 mutant setting. What you will have seen is that the SERD class has already demonstrated compelling activity in the ESR1 mutant setting. These are tumors driven by the estrogen receptor, driven by those mutations. So turning off or partially turning off the receptor is a powerful mechanism. However, to get at the wild-type receptor, you really need to have high exposure. You need to be a complete antagonist, not a partial agonist, and so you see, unlike others, evidence of activity in the wild-type setting as well. Again, median's not reached here. We will update. For comparison, these are the six-month PFS rates of ribociclib combinations from other trials. Our 68%, this is all again in the post-CDK4/6 setting. Our 68% compares favorably with MONALEESA. That's fulvestrant or exemestane plus ribo post-progression on CDK4/6. There's a small study MORPHEUS that Roche did with giredestrant and ribociclib. Again, we do quite a bit better, and then you really see it in the PFS curves. We have SERENA-1 here presented at SABCS. That's camizestrant with ribociclib, and again, we don't know where the top of this bar on the right will be. We put it at 12 months. That's our median follow-up. But later in the year, we'll be able to actually tell you where we ended up. This is the OPERA-02 study. It's pretty straightforward. It's first-line metastatic or advanced ER-positive HER2-negative breast cancer. Pretty simple trial. Everybody gets ribociclib, the CDK4/6 of preference. It will be, in fact, the only trial using ribociclib in the first-line setting, which is already a differentiator in addition to that favorable efficacy that we have seen. For endocrine agent, you'll either get letrozole, the existing standard of care, or you'll get palazestrant. It'll have a PFS primary endpoint as is typical. It's 1,000 patients. It's a bit overpowered for PFS. You need to have some power dedicated to OS in the first-line setting as well. And this will start in the mid-year. I should add we are fully resourced to do this trial. We have the capital. We have the drug supply that we need, and so we're planning based on OPERA-01, the readout in 2026 for our first U.S. commercial launch in the second/third-line setting, and I should add this is wrong. It's following a positive OPERA-01 trial in 2027. Our second pipeline program, very exciting, is OP-3136. It is an oral KAT6 inhibitor. The attributes that we have now, this is a validated target, right? Pfizer has an oral KAT6 inhibitor. It's a bit ahead. Presented some very compelling data in combination with fulvestrant at ASCO and updated it with even better efficacy at SABCS. OP-3136 is a highly potent selective inhibitor of both KAT6 A and B. It's orally bioavailable. We anticipate daily dosing. It's got high free drug exposure. Importantly, it synergizes both with palazestrant, has activity with fulvestrant too, but as we showed at ENA in October, really intense enhancement of activity when combining with the SERD with palazestrant. Also, synergy with CDK4/6 inhibitors. We presented triplet data, palazestrant and ribociclib. The IND is cleared. Phase I trial is currently recruiting patients. The mechanism here is interesting. It's complex. KAT6 is lysine acetyltransferase. We inhibit that. When it's active, the lysine acetyltransferase acetylates multiple targets, but one is histones. And what that acetylation does is it relaxes the heterochromatin on the target histones, target promoters. And that increases the access of transcription factors to those target promoters. Many of them overlap the growth and proliferation genes that are stimulated by the estrogen receptor in ER-positive HER2-negative breast cancer. So what we're doing is we're really doubling down on shutting off that transcriptional growth and proliferation signal. This is the Pfizer data from their publication in Nature Medicine that was released at the time of the ASCO release and just shows you the level of activity they're seeing post-CDK4/6 when they use their molecule combined with, in this case, endocrine therapy is fulvestrant. Interestingly, it doesn't matter what your ESR1 mutational status is. It's also active in both PI3 Kinase mutant and wild-type. And the update is in all patients at San Antonio. They were at 38% overall response rate. So this is most definitely a validated target. This is preclinical data that we presented. And what I'd ask you to look at is the dark orange versus the kind of light blue gray. This is equivalent exposures of OP-3136 in the orange versus the Pfizer compound in the kind of gray. There's definitely activity with these molecules. I will say, however, that we think there's incremental benefit from the higher specificity of OP-3136. But where you see things really get enhanced is when you add in endocrine therapy. So fulvestrant definitely enhances the activity for both molecules. Again, more so for 3136. But in both cases, it's palazestrant that really shines in combination, both with the Pfizer compound and with OP-3136. So getting through the single agent and getting into combination with palazestrant in the phase I experience is a very high priority for us. And so that will occur as part of the ongoing trial. We think the ability to combine with palazestrant and have both of these molecules in our portfolio allows for a unique opportunity to present a new treatment option. This, again, is an outline of the study design. Obviously, we're dose escalating as a single agent. We will then move into combinations quickly to establish safety, combination with fulvestrant, combination with palazestrant, and then palazestrant and ribociclib. And that is very exciting. We will then dose expand in monotherapy and in combinations as well. As I mentioned, for the first part of the trial, we have included metastatic castration-resistant prostate cancer and metastatic non-small cell lung cancer based on the preclinical activity. We'll see what we get there and decide what we might do as next steps with those tumor types. So, as you can see, we have a compelling pipeline, a compelling late-stage opportunity, a phase III program preparing for readout in pivotal trial next year with commercial launch to follow and the opportunity to significantly expand that opportunity and move it earlier with a collaboration with Novartis and financing to enable us to execute the OPERA02 first-line trial. That's basically all described here. I will add that as a result of that financing, we are well capitalized over $430 million, and that is really what's enabling us to execute this program, but also at the same time, the cost avoidance of about $275 million by virtue of not having to buy Kisqali on the market, but rather having it supplied by our partner. With that, I thank you, and I'm going to move on to Anupam here. Thanks, Sean. I just want to remind folks, there's three ways to ask the question, right? So raise your hand and do it the old school way, and I'll call on you. You can submit your question through the portal, and I will get it here, or you can email me. But I will start out with the first question. It's actually an email question that I got, which is, "Investors seem to be generalizing the results from the SERD class to all the compounds. What are your thoughts on this, and would you push back?" Yeah, I would push back. I don't want to. I'm not trying to be pejorative here, right? The way that you forecast how a compound will perform in subsequent clinical studies is by looking at the data from that compound in prior clinical studies. That seems like a simple concept, but I think your observation or the emailer's observation is unfortunately correct, that people are saying, "Well, the EMBER-3 result was disappointing, and therefore this class doesn't work." But it is very clear that that is specific to imlunestrant and to some extent the EMBER-3 trial design. And so I really think if you're going to handicap what's going to happen with palazestrant, just look at our data. I showed it to you. And I think, Anupam, we have to figure out how to communicate better. So we're continuing to work on that. I wanted to dig in just a little bit more on this topic here, which is there is this debate on the street on the potential of oral SERDs in ESR1 wild-type patients, right? And would it work in this population? What are your views on that? Yeah. So first of all, again, I think the way that you do this is you take data from the molecule that you're studying and you ask, "Does it look like it works?" And I've showed you both post-CDK4/6 in the wild-type, 5.5 months median. That's better than people see in the mutant, right? We do even better in the mutant. I also think, and then of course we showed the combo post-CDK4/6, extremely compelling data even in the wild-type. The wild-type, there was a mixture, but we'll have time to update later, but compelling activity in the wild-type and in the mutant. I think there's another thing that's happening that's a little bit, unfortunately, investors are somewhat confused. ESR1 wild-type is not the same across lines of treatment, right? If you are a first-line patient, you have not seen advanced or metastatic therapy before. We know what happens when you get a CDK4/6 plus an AI. The majority, the most common resistance mechanism is you turn the estrogen receptor on, right? You get the ESR1 activating mutation. So in that setting, having activity against the mutant only may actually help you prolong PFS because in the AI arm, those mutated clones will progress. In the SERD arm, and even more so with palazestrant, the growth of those will be slowed or suppressed, right? Which eventually there will be progression, but you will prolong the disease-free interval. Now, it's a separate thing that happens post-CDK4/6 AI progression, right? The ESR1 mutants are telling you two things. One, that they are dependent upon the estrogen receptor. And two, that you need to have something that binds and actually inactivates, or in the case of something like our SERD, partially inactivates that receptor to help prevent progression. Now, in the wild-type setting, you're going to have a mixture of things. You're going to have some patients who are truly resistant. They've mutated other pathways. And an endocrine therapy won't help those patients, but you'll have a significant number of patients who are still relying on that wild-type receptor. And what you need to do then is you need to bind it completely with a complete antagonist, not a molecule that partially turns it on, and you have the opportunity to get to 5.5 months in that setting. I just want to hit on another topic that I think some folks on the street are talking about is how you think about the probability of a success of a CDK4/6 plus a SERD in a head-to-head study versus CDK4/6 alone. I think there's some views out there. Oh, plus an aromatase inhibitor. So those two combos against one another, I think there are views on the street that like a CDK4/6 plus palazestrant couldn't beat that combo. Yeah. Yeah. So first of all, I think what you can see from the activity in so there's two situations here. One is minimally, if you just have activity in the ESR1 mutated setting, you have a good chance of beating the AI, and the reason for that is a little bit what I talked about before. The wild-type patient that you go in that hasn't seen prior treatment in the advanced metastatic setting, when they are on the CDK4/6 AI arm, about 40%-50% of the time, about 40%-50% of those patients, at some point, an activating mutation in ESR1 is going to arise, and that mutation is going to turn on the receptor without any estrogen present, and AIs do absolutely nothing for that, so as we have seen in progression post-CDK4/6 plus AI, 40%-50% of those patients will progress with an ESR1 activating mutation. If you are able by using a SERD or even better, a CERAN, and keeping that full dose of the CDK4/6, those clones can't grow in the experimental arm. We did this at AstraZeneca in a similar situation with Tagrisso. Tagrisso isn't any better against non-T790M mutated EGFR than Tarceva or Iressa. But it shuts down T790M, which is 40% of resistance. When that arises in Tarceva or Iressa, they have no activity. And so it just advances. And you saw a significant increase in PFS as a result of that one activity. Now, that only works if your prevalence of your targeted mutation is high enough, right? But 40%-50% is more than high enough. In addition, we just have the opportunity to be a much better inhibitor even of the wild-type. So I think there will be actually additional activity to add on top. Questions from the audience? We have another email question. Is there any plans to develop palazestrant in the non-metastatic breast cancer setting, perhaps with an aromatase inhibitor? Yeah. So that's an adjuvant question. Not presently. That's an evolving landscape, obviously, right? As you all know, Novartis very recently got the NATALEE approval. So in a high-risk population, we see Kisqali there. Verzenio has been there for a while, a slightly different population. I think if we were to do it, we'd actually combine with a CDK4/6 inhibitor. But at present, our focus is on advanced or metastatic. Those are smaller trials. A thousand is not small, but they're smaller. They're more rapid to mature, and I think that they more rapidly address an unmet need, but also from the standpoint of getting therapy to patients and getting return for our shareholders, that should be the focus. Questions from the audience? Maybe a final one from me. Sean, if you had to post-SABCS just last month, if you had to boil it down to your top one, two, or three most misunderstood points about palazestrant, the clinical data and/or the development program by the street, what would they be? Yeah. So the first one was something you touched on right away, which is all the drugs in this class are not the same. That should be obvious because the data generated from them isn't the same. But yet, it is a complex space, and we do see a significant group of investors saying, "I'm going to correlate them all," in spite of the fact that the data indicates that that's not correct. So we have some educating to do around that. Another thing is it's not the sexiest, most flashy part of drug development, but pharmacology is really, really important. Being able to get really high exposure, to engage a target completely, to shut it off completely. Remember, this is a transcription factor. This thing, if it binds a target gene that is causing the tumor to grow, it's a massively amplified signal. The mRNAs come out, the polyribosomes form, lots of protein is formed that goes on for a while. You have to shut this thing down completely. Then finally, if you aren't able to give a full dose, you can't do any of that. These pharmacological aspects, which are designed into palazestrant, actually turn out to be real, we know now from the clinic, are a big part of the superior data that we're seeing. Maybe not to, I don't know, maybe to just supplement, not impact the PK of your combination agent. Yeah, I think that's right. Drug-drug interaction, but also enhancement of toxicity, right? You want to be able to keep these things in there. Look, the objective here is to keep patients on a very well-tolerated therapy for a very long time, and so feeling good while you're taking it, not having to go get high-volume injections, having oral daily regimen is a really important aspect to helping patients, and that's ultimately what's going to make us successful. All right. Sean, thank you so much.