Welcome, everyone, to the 44th Annual JP Morgan Healthcare Conference. My name is Anupam Rama. I am one of the Senior Biotech Analysts here at JP Morgan. I'm joined by my squad: Priyanka Grover, Joyce Zhou, and Rathi Phinnai . Our next presenting company is Olema and presenting on behalf of the company we have CEO Sean Bohen. Sean?
Thank you, Anupam, and thank you, everyone, for joining us and your interest in Olema. Our objective at Olema is to improve treatments for patients living with ER-positive, HER2-negative breast cancer and address the significant remaining unmet need in this very common cancer indication. Should I do that for a second? Normal disclaimers, as you would expect. Consistent with the objective I described to you, we have two programs in the clinic: one in two phase III trials, one in phase I, phase IB. Our lead asset is palazestrant. Palazestrant is a complete estrogen receptor antagonist. We believe the properties and the data generated to date indicate that palazestrant could be the best endocrine therapy for ER-positive, HER2-negative breast cancer. Remember, endocrine therapy is the backbone of treatment of this disease because the estrogen receptor is one of the primary drivers of the growth and proliferation of this tumor.
Palazestrant is in a first-line trial in combination with ribociclib, the only first-line trial of a CERAN in the endocrine-sensitive wild-type ESR1 wild-type setting. It's also in a second third-line trial, OPERA-01, which is ongoing as a monotherapy. These are patients who have progressed on prior treatment with a CDK4/6 inhibitor plus an AI. This trial is enrolling very well and will read out in the second half of the year. We also have a KAT6 inhibitor, OP-3136. That molecule is continuing dose escalation in phase I, but we have also started combination studies with endocrine agents, both fulvestrant and our own palazestrant. This is a large disease. This is a large unmet need. ER-positive, HER2-negative breast cancer is 70% of all breast cancer. Breast cancer is the most common malignancy in women in the world, the second most common cause of cancer death.
If we look at the market opportunity that results from this, it is also very large. In the adjuvant setting, market opportunity for new agents would approach $20 billion globally. We do not yet have an adjuvant trial, but it is certainly something that is being evaluated and under consideration. For OPERA-02, our first-line trial that I described in combination with ribociclib, that is a $10 billion-plus market opportunity in first-line. The OPERA-01 trial, which will read out this year, can access a potentially $5 billion market opportunity in the later lines of treatment post-CDK4/6 inhibitor plus an AI, the current standard of care. OP-3136 in breast cancer alone, I'll talk about potential for other indications as well. Also, a $5 billion opportunity would be a targeted therapy to be given in combination with an endocrine agent in that second, third-line setting as well in breast cancer.
I won't go through this in great detail, but it is very important to understand that in addition to the molecular properties, which are key to making the best endocrine therapy, that specifically being binding the estrogen receptor and turning off all transcriptional activity, all of the transcriptional function that promotes the growth and proliferation of the tumor, that is complete estrogen receptor antagonism. That is a property that palazestrant has, but in addition to being potent, it has a long half-life, eight days. So you have to have the drug able to occupy the receptor all the time to keep this signal suppressed. And what you can see here in the middle is the favorable PK we have. The top two purple lines are our 90 and 100 milligram dose. You can see there's really no difference in exposure.
This is versus the other agents that are currently being tested, which are below. There is also degradation of the receptor. It is not profound enough to actually be the primary therapeutic mechanism, but we just demonstrate here that we degrade as well as anything else in this respect. But it's really the antagonism which gives us the best-in-class potential. This is a little more detail here. I won't go through it thoroughly, but just to tell you why this market potential is so large in the first-line setting, this market potential is not theoretical. So just to remind you that if you look at the CDK4/6 class, the three molecules that are there, you are currently in the $10 billion range for the size of the market, with those molecules losing exclusivity around the end of the decade in the early 2030s.
So the potential here, obviously, is to improve the endocrine therapy that they are combined with in that setting. That trial is now enrolling OPERA-02. We anticipate top-line data possibly in 2028 that would lead to an approval that would be our second approval subsequently in 2029. Our data supports this best-in-class potential for palazestrant, both as a single agent and in combination with ribociclib. I'll point you particularly to the right side panel here because this is what allows you to compare what other agents have shown in combination with ribociclib. These are patients in the prior CDK4/6 treated settings. This is the second and third line. Not the indication we will see in OPERA-02, but the kinds of patients you get in a phase II setting.
You can see that in patients who have already radiographically progressed on a CDK4/6 inhibitor plus an AI, about 30% of these patients then got a CDK4/6 inhibitor plus fulvestrant and progressed again, so the tumors have not only developed resistance, but resistance and growth to the point where you can see them radiographically, and even with this, when we go back with another CDK4/6 inhibitor, ribociclib, and we do it in combination with palazestrant, we get a year of median progression-free survival beyond that. We think this reads through very favorably for the probability of success of OPERA-02. One of the holy grails in this space has been to be able to demonstrate activity in the very hard-to-treat endocrine-resistant wild-type setting. This is different than the adjuvant setting where those patients are almost all ESR1 wild-type. They're endocrine-sensitive. The first-line setting, again, almost all ESR1 wild-type and endocrine-sensitive.
In this setting, post-CDK4/6, they have shown growth of the tumor on an endocrine therapy plus CDK4/6. They are endocrine-resistant. We see remarkable activity in the mutant setting. That is not terribly surprising. It's 14 months, but nine months in the ESR1 wild-type setting with ribociclib is differentiating. Recognizing the caveats of cross-trial comparisons, these are other agents in the class combined with ribociclib and the data that they have generated. Again, in these phase II trials, they're treating patients who have progressed on a prior CDK4/6 inhibitor. You can see, again, this 12-month median PFS is differentiated. Looking now at our first phase III trial, our first readout that will occur potentially viable, which is OPERA-01. This is the second, third-line setting. So these patients will have received a CDK4/6 inhibitor plus an AI. They have to have progressed on that treatment.
They can have received one additional endocrine therapy and progressed on that and be eligible for the trial. They get palazestrant as a single agent. The control arm is fulvestrant or exemestane in the current standard of care in this setting for endocrine monotherapy. As I said, in the fall of this year, we will have the top-line readout of that trial, the PFS readout. This trial is designed to specifically examine the ESR1 mutant and the ESR1 wild-type populations separately. There is not an all-comers analysis because there is significant remaining unmet need in both cases. In the case of the mutant, as I'll show you in the data, we have the opportunity to have better benefit than has been seen with other agents. There are other agents that have been successful here. In the case of ESR1 wild-type, nothing has been successful in this space.
So we have a real opportunity to provide a targeted therapy to patients who don't have a targeted oral option for endocrine therapy now. With positive trial later this year, we would file an NDA next year and potentially launch late in the year in 2027 in the United States. This is the data that supports success and best-in-class potential in that population. Specifically, if you look at the pink lines, those are second, third-line patients, patients who've had prior treatment similar to what are being enrolled in OPERA-01. You can see these are ESR1 mutant and wild-type subsets here in the ESR1 mutant subset. Seven months is what we see. The existing agents that are filed or approved show a two-month benefit over standard of care here. This would be more like four to five months benefit.
No benefit has been shown in the wild-type setting, and here we show 5.5 months. As I said, that's around the range of what you get in mutant or the other agents if we are able to reproduce it in the OPERA-01 setting. And again, caveats of cross-trial comparisons. These are the other agents in the post-CDK4/6 setting as monotherapies and the data that they have generated, both in the all-comers experience where you really see about four months where we see seven, and then in the ESR1 wild-type experience where, as I mentioned, there isn't any agent that has demonstrated efficacy over the standard of care. And they're all about two months. We have this opportunity to exceed five. Obviously, clinical trials are great. This is the way you get to filing. This is the way that you get to commercialization.
But the way that you get the drug in the hands of the patients that need it is to successfully launch and commercialize that drug. And so we are planning that right now because, obviously, that launch is less than two years away, we anticipate based on the OPERA-01 trial. So we are planning to market palazestrant ourselves in the United States and to seek a collaborator for the rest of the world. Again, just to remind you, the market potential here is $3 billion-$5 billion. Why the range? The range depends upon if you get ESR1 mutant only or if you're able to capture that 50%-60% of patients who are ESR1 wild-type after they've progressed on a CDK4/6 inhibitor plus an AI. Moving on to OP-3136. This is a fascinating target, KAT6. It's an epigenetic target. The mechanism of action I'll show you in a minute.
Again, the population here is not dissimilar to the OPERA-01 population that we're looking at. The difference being now there is a need for further targeted therapies to go beyond the CDK4/6 inhibitor, to go beyond PI3 kinase, to go beyond AKT, and to obviously give another therapy to patients who don't have any of those mutations as well. The objective, just to remind you, in the treatment of ER-positive, HER2-negative breast cancer, one of the major objectives is to put off chemotherapy as long as possible. This is both a quality of life issue and, obviously, the ultimate objective to extend life. But again, you have about a $5 billion global market opportunity just in breast cancer. I'll talk about other indications, as I mentioned. The phase I is now enrolling both monotherapy in combination with fulvestrant and palazestrant.
The initial results, mostly of monotherapy, we anticipate presenting late in the first half of this year and then have an opportunity to update on that subsequently. And we anticipate we would start a phase III trial in breast cancer probably in 2028. Again, this is the pipeline just to summarize for you: OPERA-01, OPERA-02, and the ongoing OP-3136. Just to remind you, we were able to successfully raise money in an offering late last year. We're in a very favorable cash position. We have more than $500 million now that carries us into the second half of 2028 with these phase III trials with the advancement of OP-3136. Again, this is a very busy year for us. We have our first phase III readout in the second half of the year and OPERA-01.
We have our first data that we anticipate sharing with OP-3136, which we truly think has the opportunity to be the best-in-class KAT6 inhibitor, both from the standpoint of efficacy, from the standpoint of tolerability. Just to remind you, the monotherapy portion of that trial has castration-resistant prostate cancer and non-small cell lung cancer patients being enrolled in it in addition to breast cancer. We are looking forward to approval and launch of palazestrant. That's in that OPERA-01 second, third-line setting next year. We think that OPERA-02, the first-line setting with ribociclib, could readout potentially as soon as 2028. With that, I will thank you all for your attention, and we have plenty of time for questions, Anupam.
Yeah, yeah. Thank you, Sean, and I'll ask the first couple of questions, but then I'll also ask for audience questions. Just feel free to raise your hand, and we'll call on you. I wanted to ask a couple of broad questions first. What about the lidERA update from giredestrant? You were at San Antonio. Did you sense any KOL perceptions changing around the third CERAN class or?
Yeah, absolutely, so I would say that from the standpoint of the attendees of the meeting and the people that we interact with, there really are two schools, right? There was one school that already believed that this class had the potential, particularly the CERAN aspect of it, to differentiate from the existing endocrine therapies, really AI and fulvestrant, right, and so I think those individuals felt this is expected that there would be a benefit. I do think that the magnitude of the benefit was impressive to everyone who saw it. For others, there was skepticism. There was skepticism that you could actually achieve a meaningful clinical benefit by better suppressing the estrogen receptor growth and proliferation signal, and obviously, the data was compelling.
And so we saw a lot of people say, "Wait a minute, there's a lot of potential here, and we need to see where else, right? This can make a difference for patients." And obviously, that works ongoing, both our work, but then there's the persevERA readout coming in a few months from Roche with palbociclib in the first-line setting.
And so where else can it work on that question that you just posed, right? From your perspective, post-lidERA, how are you thinking about any read-throughs to persevERA , which is, I think, expected at the end of the quarter or early next?
Yeah, right. So let's talk a little bit about the settings in which you're using these agents. So as I mentioned in the talk, in the adjuvant setting, you're treating patients who have never seen an ER-targeting therapy, right? This is their initial diagnosis of breast cancer. It's limited stage. They get treatment for that limited stage, and then they get adjuvant therapy afterwards to try to decrease their risk of recurrence of their disease. Those receptors are almost all ESR1 wild-type because there's been no selective pressure for the mutation for resistance. And obviously, they're endocrine-sensitive because they haven't had any prior treatment. So that's the lidERA setting. That biologically is quite similar to the persevERA or the OPERA-02 setting. In the metastatic breast cancer setting, again, the vast majority ESR1 wild-type.
Because of the way of the patients who are enrolled, so patients have had about 70% of patients who've had prior adjuvant therapy, they have to have completed it and had one year off of it disease-free to be eligible for these trials. They remain endocrine-sensitive. About 30% of the patients are actually naive to treatment. That's metastatic breast cancer that the initial presentation, it's de novo metastatic, was metastatic disease. They never received prior treatment. With those biological similarities, we believe that activity in that adjuvant ESR1 wild-type endocrine-sensitive adjuvant setting has significant read-through to the first-line ESR1 sensitive wild-type setting.
Question from the audience? Feel free to raise your hand. In your presentation, Sean, you stressed that in OPERA-01, you were doing the wild-type and ESR1 mutants analyses separately. How are you thinking about win scenarios in both? You kind of commented on it a little bit, but if you could expand.
Yeah, right. So yeah, so the statistical design of the trial is that there are analyses of these two separate populations. And that's going to happen anyway, right? That's how regulators, quite rightly, are going to analyze this data. The advantage of doing it that way is you actually can describe and design around the statistical characteristics of the two different analyses. The win criteria have been pretty well established. You need a two-month additional PFS benefit in order to be successful. And that's been seen by a few drugs in that ESR1 mutated setting, which is 40%-50% of the patients' post-progression on CDK4/6 plus an AI. The criteria are the same for the wild-type setting, the difference being that in this ESR1-resistant wild-type disease, it's never been achieved. And again, I showed you the data, the 5.5 months in that setting.
We really think we have an opportunity there. Right now, the current labels are all restricted to ESR1 mutant. And I think really, if you look at the data for things that are about to be filed, even combinations, we anticipate that's going to stay that way. So it is a significant unmet need giving another alternative to the wild-type patients. In addition, with two months being the bar, if we're able to duplicate the range of the seven that we saw in the ESR1 mutant setting, that would be a significant benefit over the current standard of care.
Then you talked about that 5.5 months in the wild-type setting, right? Mechanistically, with palazestrant, what gives you the confidence, right, that you can replicate this or be in and around this?
Yeah. So from a mechanistic.
Or even decrease a little bit, and you'll still be above it.
Yeah. So there's several things. That's true. It's true. There is a little room there. There are several things that when we think about going from that phase II experience to the OPERA-01 experience that give us confidence. I mean, one of the molecular properties of the molecule, and that's the complete estrogen receptor antagonism. It's the very robust exposure that we see to keep the receptor growth and proliferation signal suppressed, favorable tolerability in that context. And so those things are very important. The other thing to recognize is that probably the population in OPERA-01 is a little more favorable to response to treatment than the ones that were in the phase II because in the phase II, we allowed prior chemotherapy. We don't allow that in OPERA-01.
In the phase II, we allowed people to go on palazestrant who had progressed within six months of the start of their last endocrine therapy. Those patients are excluded from OPERA-01. So we're hopeful that those properties may actually enrich for patients who are more likely to benefit from a single-agent endocrine therapy.
Questions from the audience? In the back?
You mentioned ex-US. You're going to have a commercial partner. What do you think the timing on that might be? Can you comment?
Yeah, that's a great question. I mean, I think to some extent, I will say that it'll be a partner. So the timing is somewhat dependent upon the partner's timing as well. I think if you think about when to seek a partner, I think the overall objective is you want to make sure that that partner is there and involved at a time where you can maximize the impact of regulatory filings in these different regions, setting up for a good commercial launch in those different regions. So I think it has to be sooner rather than later is the way I would put that. You certainly don't want to get too close to the U.S. filing and launch to have the partner identified because you run the risk that you aren't maximizing the benefit and the ability of that partner to influence the rest of world launch.
I was wondering if we could get an update on sort of the Pfizer combination study and that collaboration?
A tumor sequencing.
Yeah.
Yeah. So let me back up for a second. One of the key attributes of palazestrant, again, with its pharmacology, is its combinability, right? Endocrine agents are given as single agents as a very common and viable. It's really the only targeted agent in neoplastic breast cancer that's given as a single agent. But very often, what you want to do is target another pathway that's driving the cancer. So the most common we all know about is CDK4/6, right? Ribociclib plus an AI right now is the gold standard in the first-line setting. We combine very well at full doses with the variety of targeted therapies we've tried, which are palbociclib, ribociclib, everolimus, the mTOR inhibitor, alpelisib, PI3 kinase inhibitor, but we're expanding beyond that. Atirmociclib is a CDK4 selective small molecule inhibitor that Pfizer now has in phase III.
And I think their objective is to say, "Look, we think we can do better than CDK4/6s, which are limited by their toxicity in the inhibition of CDK4 by dialing out the neutropenia associated with CDK6 inhibition and being able to hit CDK4 harder." They've presented some encouraging data at ESMO in October. From our standpoint, with the potentially best endocrine therapy, we want to be positioned for the future evolution away from CDK4/6 inhibitors to better targeted therapies. And we think that atirmociclib is a good candidate for that. So between the two of us, we decided it's worthwhile to see if we can create something interesting by combining these two. That's a clinical supply agreement with Pfizer. There's really no economics. There's no read-through to palazestrant or atirmociclib from us. We co-own the data. And that combination is ongoing in the clinic now.
Questions from the audience? I've got one more. Yeah, go ahead.
Thank you for taking my question. I've got a question on the competitive positioning. So in terms of the timing for phase III readouts, so Roche will be the first, and AZ is probably the second to the market, and we're probably the third. And just wondering what's your strategy for kind of improving our positioning in that context?
Yeah, it's a great question. I think there are several aspects to that strategy. Some of them have to do with the properties of the molecule, right? So I'll give an example. Oncology is an interesting space, right? Because there's definitely advantage to being first to the market, but there's a much bigger advantage to having better data. And we saw that in the CDK4/6 space, right? Based on the original PFS readouts, palbociclib, so palbociclib Ibrance, abemaciclib Verzenio, ribociclib Kisqali looked pretty much the same. You got two years plus a little bit median PFS benefit, definitely a huge advantage over AI alone, which was the prior standard of care. Ibrance was first, really dominated the market for a long time. Then the survival data came out. Kisqali was the only drug that was able to clearly demonstrate a survival benefit.
Not only that, the survival benefit was about a year, which is a very long time for these patients, and what you have seen over the course of the past about year and a half is a complete switch in the use of these drugs. Kisqali was number three. Kisqali is number one and still growing, and that's based on the data, and so while being first is valuable, being best is more valuable, and so we think there are really two ways to get at that. One, again, is the property of the molecules. If we are able to duplicate something in the range of a year, which we saw in phase II in the OPERA-02 study, we believe that'll be truly differentiating and that that will drive patient and physician behavior. There's one other thing that's interesting here, right?
And it's more has to do with that CDK4/6 situation I described. Occasionally, there's an advantage to not being first. And in our case, that advantage is we were able to go with the partner molecule CDK4/6 that is the global gold standard because it changed. So when AstraZeneca and Roche did their trials, Ibrance was it. It was by far the leader. And that's what they went with. And that makes perfect sense at that time. We, however, came later. Remember, our first combination studies with CDK4/6 were done with palbociclib. At that time, we thought that's what we were going to be doing. We did ribociclib as well. We had other hypotheses that were interesting to us, but it positioned us very well to be, we are the only company with a phase III trial in the first-line endocrine-sensitive setting.
And so we think that just by virtue of being able to say, "Give the CDK4/6 inhibitor you want with this better endocrine agent," that will be a differentiator.
Maybe final question for me, just switching gears a little bit to the KAT6 here, OP-3136. Just talk to us about the size and scope of the data that we're going to be getting mid-year. And just given the competitive landscape, what would be an encouraging update for you?
Yeah. So, talk a little bit about our approach to KAT6 here. This is now a validated target. Pfizer, very much to their credit with 8144, their lead molecule, has demonstrated that in ER-positive, HER2-negative breast cancer post-CDK4/6, KAT6 plus fulvestrant has pretty impressive activity. And they have an ongoing phase III trial in that space. They do have some tolerability challenges. So the main toxicities are dysgeusia, a taste alteration, in some cases being so bad that people don't eat enough to maintain their weight. Losing weight is not a good thing for cancer patients. The other main toxicity is cytopenias, is cell count decreases, mainly anemia and neutropenia. Obviously, that can be dose limiting, but beyond that, that limits combinability outside of the endocrine agents. When we designed OP-3136, the KATs are a family of lysine acetyltransferases.
KAT6 is what's talked about and targeted because it's amplified in some tumors. So that was what led to the identification of therapeutic target. But truthfully, what we're targeting with most of these agents is KAT6A, KAT6B, and KAT7. And that's what we do with OP-3136. We dialed out KAT5 and KAT8, which are hit by the Pfizer molecule. We do not significantly inhibit them at the clinical exposures we get. And so our hope is that we may, one, have a better tolerability profile as a result of that, particularly around the cytopenia aspect of this. And so that data will be part of this. It'll mostly be monotherapy dose escalation data. Obviously, there will be a lot of tolerability data in that, a lot of PK.
There will be some clinical activity data presented as well to the extent that we have it as a monotherapy. I don't think you're going to get. You might get a little bit of fulvestrant combo. You might not get any palazestrant. I don't think it's ongoing, but I don't think we'll have enough data maturity yet. Obviously, there's an opportunity to update on those things either later in the year or possibly early next, 2027. The other thing I think that people will want to look at is, as I mentioned before, we have other histologies based on what we saw preclinically, so we have non-small cell lung cancer. We have castration-resistant prostate cancer.
So there's an opportunity to see potentially as well. Is there an ability to expand with this mechanism of action, particularly with a different inhibition profile outside of just positive, HER2-negative breast cancer and into another indication?
All right. Thank you, Sean.