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Thank you all for coming today and coming to the Morgan Stanley Healthcare Conference. My name is Ruck Byun. I'm head of West Coast Healthcare Investment Banking for Morgan Stanley. I have the pleasure of hosting Sean Bowen, CEO of Olima. I think as we, you know, as we kind of think about, kind of just to jump right in, And, you know, the market keeps lumping every oral CERD together. But, you have to forecast a molecule by its own data. And from my standpoint, palisesteran doesn't look like everyone else's CERN. Why is treating this as one monolithic class the core mistake that investors are making? Yeah, so thank you, first of all, for the opportunity and the people here for listening to the Alema story. I think that there are a number of reasons why lumping these molecules together is a mistake. I mean, beyond an oversimplification. First of all mechanistically, there are key differences. So palazestrin is a complete estrogen receptor antagonist, binds and shuts off the estrogen receptor signal, growth and proliferation signal completely. That's true in the context of the wild type receptor where it competes for estrogen, but also the ESR1 mutated receptor, which is turned on without estrogen needed. Some molecules are serms. They're agonists in some contexts, and you do not want to turn on the estrogen reactor in these cancers. In other cases, it's really got to do with exposure and pharmacology, right? You need to have a high level of drug to force receptor binding and keep the receptor off all the time because estrogen receptor is a transcription factor, so its signal is highly amplified, and we have by far the best exposure within the class. And then finally, combinability becomes very important. I mean, our first phase three to read out in Q1, OPERA 1, is a monotherapy trial. But the larger opportunity with this class of drugs is in combination with other targeted agents. And we have found uniquely that we are able to combine with multiple different modalities without having to compromise our dose and without enhancement of toxicity. Why do investors do this then? Why do they lump it all together? Well, I think the simple answer is it's complex. But if you decide to do that, then you decide to ignore some very important data that can distinguish the molecules. Got it. Thank you. Maybe just since it's topical on the Serena 4, it seems like, you know, from my perspective the first line misses are about exposure and dose, not necessarily mechanism. and chemisestrin carries, as you said, the lowest exposure of all the oral SIRs because of its tolerability ceiling. Isn't that the very problem palisestrine designed out from the very beginning? It is. It's one of the many. So when the founders of palisesterin really took this on a little less than 10 years ago, other companies were working on this. And by the way, they were addressing as well that they had also gotten to the concept that you want a complete antagonist. Camazestrin molecularly is a complete protagonist. Girodestrin, the Roche molecule, is a completely antagonist, so they had made that observation as we did at Olima. But in looking at those molecules, it was seen that there were these liabilities, that they didn't have high enough exposure. They had tolerability problems, and then those tolerability programs are exacerbated in combination. And so the objective in designing Palo Sestrant was let's address all these things. We have successfully achieved that. That's all demonstrated. But one of the obvious conclusions of wanting to address those things is also saying, hey, look, these liabilities are going to turn into limitations when you test these things for efficacy. Now, we don't know what the data is from Serena 4. All we have is this cryptic, numerically different for PFS. We do know what the data is from Persevera, from the Roche compound in its first-line phase 3. And that data clearly indicates that there is better activity of an oral CRAN than an aromatase inhibitor. They had a five-month delta in PFS, they had a clear trend for hazard ratio, but didn't quite make statistical significance. and that in spite of some design flaws. And so I think those molecules demonstrate two things. One, we're leaving efficacy on the table with AIs, and we can improve upon it. And two, these liabilities in terms of exposure and combinability are turning into liabilities when you look at achieving a clinically meaningful outcome. Got it. Thank you. Since you mentioned it, Persevera, what folks may flippantly call a negative trial, still delivered about a five-month PFS delta while they were carrying about 10% endocrine-resistant patients, which diluted some of the treatment effect and efficacy signals. Now, in terms of your own trial, OPERA2, can you tell us about how you've thought about patient selection exclusion and also your decision to run a ribocyclic backbone? You know, I guess as we're looking at, you know, what happened with Persevera and Amos Serena 4, you know, a competitor miss may actually potentially raise your confidence given your trial design and some of these molecule differentiations, but would love to hear your perspectives. Yeah, so there are multiple questions in there, which are all good ones. So the first one has to do with the patient selection. I must say, OPERA O2 is not the unique trial in terms of how we've defined our patient population. That is to say, the endocrine-sensitive patient population, what that looks like in these first-line trials is for the patients who have had prior adjuvant therapy, in order to be eligible for OPERO2, you have to have completed your adjunant therapy and had at least one year of treatment-free interval without recurrence of disease, and that's the clinical definition of endocrine-sensitive, and so that's what we do in Opro2. By the way, that's exactly what was done in Serena 4 as well. AstraZeneca used the same criteria. The unique thing was that Roche decided, for some reason, to include patients who had progressed within that year of completion of adjuvant. As you said, it ended up being about 10%, but that was after they stopped that in their First Amendment. So it must have been much higher at the beginning of the trial. They did very poorly, right? So this is a trial where you had 28 months in the control arm, letrozole plus palvo, 33 months, that's the five months you were talking about medium PFS, gerodestrin plus palbo. If you go to that subset of patients that had that shorter treatment-free interval, the controlarm wasn't 28, it was 19. The gerodestrin arm wasn't 33, it was 14. They did very, very poorly. And so this actually not only diluted the treatment effect, it actually fought the treatment affect in terms of the hazard ratio. So this is a really big, I would just say, mistake to include those patients. Serina 4 didn't do that. We haven't seen the data. I think Serina 5 is very well designed. The challenge with serine deforest, camozestin, is not it's got the lowest exposure. I think it's Got limitations as a drug. Both of those trials, as you mentioned, used palbocyclin as their CDK4-6. Now, that was not a mistake. At the time those trials were designed, eye brands totally dominated the first-line market. and that continued to be the case until overall survival started to read out from the CDK4-6 inhibitor of pivotal trials and what happened there is the standard of care got flipped on its head. The third most used drug was Kiskali, ribociclib, but it had three out of three trials positive for overall survival. The delta, the improvement in overall survival is about a year. That's significant, obviously, for these patients. And so oncologists did what oncologists do. It's very simple. I am one. It's not being pejorative. They just follow data. And so when they had a survival benefit, they said, okay, this is it. We're switching our new patients onto this. We designed OPERA-02 with that knowledge in hand. We actually had done the PALBO combo first. We thought that was going to be an IBRANTS trial. But we were able to capture that change in standard of care. Thank you. Now, gear of death strength, going back to that, my understanding is that they cut from 100 mg to 30 mg such that they can manage bradycardia with palbo. You have an eight-day half-life and high exposure. And so I guess as, you know, others may have had to make some tradeoffs on the exposure versus tolerability equation, you think based on kind of your PK, looks like you have what seems like a durable moat. Can you elaborate on kindof that a little bit more? Yeah. So it turns out our half-life, and we'll publish on this, our half life is even longer. That's about 14 days. Oh, okay. And so our steady-state exposure is even higher than we have published. And, you know, that 14-day half-Life really allows us with daily, once-daily dosing to achieve this very high exposure. Again, the objective with this treatment modality is to shut this signal off completely all the time. and the way you do that is by forcing the binding of palzesterin onto the receptor. We had predefined the exposure threshold we felt we needed, right? We weren't first. We saw liabilities in the others and we thought, okay, this isn't worth doing these phase three trials if you can't address those liabilities. We're able to easily cover 24-7 that exposure threshold. now the the gerodestrin had pretty nice exposure not as high as ours at 100 milligrams and that was their original recommended phase two dose the problem was they combined with palvo and they found as you said they had this this this increase in rate of bradycardia and they decided that that was not acceptable and so by mitigating their dose going down to 30 three-fold decrease in exposure as you might expect, that they did actually control the bradycardia problem. We think, however, they sacrificed their receptor occupancy. And that is the kind of flaw that we were seeking to address. Yep. I mean, even a great degrader leaves plenty of receptor behind. And so, you know, what controls the tumor is really keeping the residual receptor completely silenced, and I believe that's what you set out to do with designing and developing palozestrin. So, now, does that reframe the next-gen CER debate away from the degradation depth? It should. So, unfortunately, we have, it goes actually back to fulvestrant, this sort of red herring that degradation could be a mechanism of action. Look, if you could absolutely eliminate all the receptor from the cell, probably that would be a reasonable thing to do. But in the very best circumstances, you still have 20% intact receptor. Now, remember, this is a protein versus the DNA binding sites, the promoters. It is in massive excess to its binding sites. So going from estrogen receptor positive to estrogen receptor positive is not a significant therapeutic effect. And that's what happens with the degraders. Look, palazestrin is as good a degrader as anything. It's just that there's all that receptor remaining. You have to turn that receptor off. And that's the exposure, that's the complete antagonism that really adds up to what is the formula for doing this successfully. Thank you. Now, talking about going to APRO-1 dosing choice, you know, it seems like your dose selection is almost like a non-issue for you. Your 90 mg, 120 mg have equivalent exposure and both clear your preclinical target um can you talk a little bit around what drove and guided your dose selection and uh how investors should feel about um that yeah so i can so the first thing that you said is right when you when you look at when we show everybody our exposures at 90 and 120 they far exceed the threshold even with the 14-day half-life, and the newer PopPK data, it's even more than what we had previously said with both doses. So 90 and 120 are essentially, from an exposure occupancy standpoint, the same. It's a great question as to what drove the dose selection. What I can tell you is how the dose was selected. I cannot tell you what drove it because we didn't decide. Our independent data monitoring committee, which was unblinded to the Part 1, 90, 120 data, decided, and then that data was provided to the FDA, who concurred with their decision. But they were provided both safety and efficacy data at 90 and 120 from this 40 patients on each dose arm in order to make this assessment, made the recommendation of 90. We had felt comfortable with 90 all along because we knew the exposure easily achieved our objectives. And, you know, the FDA concurred with that decision. But as to the specific factors within safety and efficacy, I can't actually share what that was. Talk about your ESR-1 wild-type activity that you've seen, 5.5 months, which I believe is even competitive with your competitors' posts in the mutant setting. yeah and I think that's really the part that the street might be not paying focus on can you talk about kind of write the condition that you have right right so so so I mean I think there's an underlying principle it gets a little bit to your question at the beginning about comparing all the members of this class I think this is such an obvious thing to say but it does seem to need to be repeated the best way to predict the future outcome of a of a drug or a regimen is to look at the past clinical outcome of that drug or regimen now look at a different drug a regimen look at that drug in that regimen so if you if you look at palazesterine compared with the others in the class we have outperformed in our phase two no one has really seen any evidence of activity in the wild type. We had 5.5 months. Again, this is uncontrolled. It's phase two, admittedly. We had over seven months in the ESR1 mutant. Again five is about the best people do. It is usually more like four. So again in both cases it seems like they are superior. In the ribocombo post-CDK4-6 we had over a year, which again really stands out. So of course the question here is, and what we're answering in our clinical trials more approximately APRA 01 is, do we duplicate the Phase II experience in the Phase III randomized setting? That is always a risk. I will say the APRA 1 patients are somewhat less heavily pretreated than the Phase 2 group were. If we are able to duplicate that effect, then we really have a chance of being differentiated in the mutant subset by greater efficacy and being successful in the wild-type subset where no one has been. But that's the question, right? That's the risk that we're bearing as we go into that trial, and it is tested to answer those specific questions. Thank you. Can we talk a little bit around your pallet esterans' unique combinability at full doses without drug-drug interaction and the fact that your is the only first-line trial on ribocyclib. Now, you know, how have you thought about kind of your, you know, maybe going back a little bit on your backbone choice, but also, you know, you haven't compromised on dosing to be competitive in a first line setting yeah so so it's interesting some of this is a structural some of it is is preclinical screening so so you there are some there is some testing you can do in um in preclinal both metabolism testing and and in combinations to look at risk of drug drug interaction it's not perfect It was, I think, done more extensively than some of the other molecules. There's then an empiric component where you have to go in to the clinic and see what happens in terms of exposure and what happens in termsof tolerability. And we have combined at full doses of palazesterin with full doses of palbocyclib, ribocyclid, everolimus, alpalysib, a termocyclib, which is the Pfizer CDK4 selective molecule, and OP3136, which is our CAT6 inhibitor. And we find that we are able to do this without enhancement of toxicity with preservation of good exposure. Yeah, so that was an objective. It is unique within the field. and we do think it conveys a very significant potential efficacy benefit by virtue of being able to maintain this exposure and thereby complete estrogen receptor antagonism either in the monotherapy or while combining with all these various targeted agents. So OPER1 reads that this year, later this year. No, Q1. Okay, Q2. Q127. Yep, and then can you talk a little bit around the read-through to OPERA-O2 and how people should be thinking about the value inflection to expect from O1? Yeah, so the first thing that's really interesting is, and this is, again, something that's easily confused, ESR1 wild type is not the same throughout lines of therapy. So ESR1 wild type and OPERA-O2 is endocrine-sensitive. So OPERa-O-2 is the only endocrin-sensive first-line trial in combination with ribosicletin. As I mentioned, one of the things we thought we knew before but was proven in Persevera is that in that first- line setting, the endocrino-resistant population doesn't do that well. They need a bigger switch in therapy. We exclude them, as did Serena 4, from APRA-O2. Now, when you get into the APRA O1 setting, the second, third line setting, those patients are, by definition, including the SR1 wild type, endocrine resistant. They progressed on CDK4-6 plus AI, right? So that biologically is a different population. So the thing that predicts the outcome of OPERA-O2 is actually the Phase II combination data from RIBO and PALS-Estrin. OPERa-O1 has relatively little correlation with OPERа-O3 because they are biologically different. That said, OPERα-O13 opens up a potentially very large market opportunity. The wild type is a $2 billion annually market opportunity. I'm sorry, the mutant is $2 million. The wild pipe, which is probably about 60%, is about $3 billion, right? So there are two ways to really access significant opportunities here. One is to differentiate for efficacy in the mutant. Get more than this two-month Delta and PFS that has been seen. In the wild type, just showing efficacy is a meaningful differentiation because everyone's failed, so you're alone there. So this is what our first readout does for us. It gives us this market opportunity. It validates that this increased exposure with a complete antagonist is a Meaningful Differentiator. I think separately, we know that, for instance, molecules that really failed in the second, third-line setting, like gerodespirant, which failed in Axolera, clearly show a signal for activity in endocrine-sensitive patients in first-line. So OPPO2 is really built on that first- line endocrin-sensitivity data set. Got it. Okay, well, let's shift gears to CAT6. Yeah. I think, obviously, Pfizer has been pioneering the field. Now, you've engineered out some of the Cat5, Cat8 liabilities, and obviously there were probably some learnings from seeing Pfizer develop and progress into the clinic ahead of you. Now, what do you think is kind of the unique differentiation for your Cat6 molecule versus the field? Because I think it's an evolving field, and people are trying to understand kind of which Cat6 family may or may not matter for various things. Yeah. So I think you're exactly right. So what we did was we made a more potent and specific CAT6 inhibitor in OP3136. Now, from the standpoint of level exposures we're achieving, like Pfizer, who really did pioneer the field, they validated this target for ER-positive HER2-negative breast cancer. Our hope was, and our early Phase I data suggests that possibly we're doing this, is that by dialing out CAT5 and CAT8, we would preserve the efficacy of inhibiting 6 and 7 and maybe dial back toxicity, particularly the cytopenias caused by this class of agents. And it seems like we might have done that, particularly based on the breast cancer patients. the way to differentiate within that obviously is tolerability and then the other thing that we saw this is from pre-clinical xenograft data is that the endocrine partners weren't always the same certainly with the cat sixes you you as with all targeted therapies and breast cancer adding an ER targeting agent fulvestrant enhances the efficacy what we found pre-clinically was that happened but if you added palazestrin you had a much more profound increase obviously we are the only company that come combined with palestrine we're the only company other than pfizer that has clinical data from cat6 inhibitor that we've shared that palazester combo in addition to fulvescent is ongoing right now And so we're hopeful that one way to distinguish from the whole class is that by having the better endocrine agent combination, you get better efficacy, which is the main driver. We also are hopeful that as we expand this experience that a favorable tolerability profile emerges and is preserved. We did one other thing in our phase one trial, which was based on our preclinical data, which we included castration-resistant prostate cancer. pfizer had done this as well in their phase one experience they did not see activity they did not continue um we saw monotherapy activity in the castration resistant prostate or prostate cancer cohort and so we we subsequently the logical thing you do then is you combine with an androgen receptor inhibitor and so in looking across that landscape which is complex we We identified Nubeca, darolutamide, the Bayer androgen receptor inhibitor, as the most desirable. It has the best side effect. So you perceive that as the best in class. It's the best-in-class, and it's based on its side effect profile. Side effects often translate into efficacy. So obviously, talk to the people at Bayer. They have an amazing prostate development team. They were interested and so signed this clinical trial, supply agreement, collaboration. Q4, we will start the dosing of that prostate cancer cohort. So that's a new area for us as a breast cancer-focused company. The Cat6 opportunity in breast cancer alone is $5 billion plus a year. I would argue that right now, if you look at the Olima valuation, we are undervalued just for Cat6, not even considering the Pallas Estrin opportunity. We haven't valued prostate yet. It's new to us, but that will come out in the billions of dollars a year as well. in non-small cell, I'm sure. We have one patient whose tumor did get smaller. I don't know what that means. We're still evaluating what to do with that. It's not quite so clear what the development pathway is in non small cell lung cancer. It probably involves immunotherapy at some time. but we're deciding whether or not we think we should explore that more. Yeah, I think in any event, I'd think on top of breast, where having a very tolerable cat sex agent giving you the combination flexibility and having palazestrin to your point, And that plus, you know, potential indications to think about, I think, is important. Now, let's talk a little bit around your runway, financial position, and your upcoming catalysts and timing. Yeah. So our cash on hand at the end of Q2 is about $461 million, in that quarter burning a little bit north of $40 million within the quarter. And that gives us runway into the second half of 2028. Obviously, we have a lot of catalysts coming in that period of time. As we talked about Q1, we had the Opera 01 readout, Mutant and Wild Hut. And we have CAT6 data coming in, as I said, maybe some fulvescent data by the end of the year. We'll have to see as that data matures. Certainly in the first half, we'll have combination data in breast cancer with 3136, with our CAT6 inhibitor, to be able to share. OPERO2 is enrolling very, very well. It won't read out in that timeframe, but certainly is progressing nicely. It's a very large market opportunity. And then, you know, as we get the prostate cancer enrolling, we'll update on when we'll have a catalyst there or some data to share, but definitely should be in the timeframe of our runway, so quite a few things. And I should say that runway includes OPERA 01, OPERa 02 execution. It also includes the spend needed for commercial to enable the registration, the filing, and the launch of PAL's estimate based on OPERа 01. So all of that stuff is incorporated into that runway forecast. Thank you. Now, if you had to leave the investors here and listening in, with one thing about Olima, what would that be? Yeah, I mean, I think we are a leader in ER-positive HER2-negative breast cancer, which is a big unmet need and a very, very large market opportunity. And I think that the important thing to do as you assess us and handicap our ability to firm that space is to look at the data we have generated with our molecules because that's what tells you what our potential is. And I think when you do that, you're going to see a company that's undervalued because it's over-associated with other molecules in the class, with a molecule that has designed to and has been shown to be differentiated from the others in that class. and then a further pipeline opportunity in CAT6 that complements the lead molecule palazesterin but also diversifies us in risk into another MOA and more recently now, even into another tumor type and becoming a prostate cancer-focused company as well. Great. Sean, thank you so much for your time. Thank you. and hope you have a good rest of your busy day with investor meetings. Thank you. Thank you very much, and thanks, everybody.