All right. Good morning, everyone. Thanks for joining the H.C. Wainwright 28th Annual Global Investment Conference. My name is Emily Bodnar, and I am an Equity Research Analyst at H.C. Wainwright. I will be doing a fireside chat with Sean Bohen, CEO of Olema Pharmaceuticals. Maybe to start off, if you can walk us through the background of Olema, your lead asset palazestrant, and how the transforming landscape in ER-positive, HER2-negative breast cancer has been in the last couple of years.
Great. Thank you, Emily. Good morning. Thanks for the chance to talk about Olema. We have been working on this problem for over a decade. The problem underlying is that the most common malignancy in women is breast cancer. The most common subtype, about 70%, is ER-positive, HER2-negative breast cancer. The disease has been known for decades to be primarily driven by the estrogen receptor growth and proliferation signal. Obviously, inhibiting that signal, turning off the estrogen receptor, is a key therapeutic modality in this cancer. We have also known for decades that we are not doing that optimally. Our lead asset, palazestrant, is a complete estrogen receptor antagonist with very high exposure, favorable tolerability, and a unique ability to combine with other targeted agents at full dose without pharmacological PK effects and without enhancement of toxicity.
We are testing that in two phase III trials right now. The first is OPERA-01. It is a second, third-line trial, so these are patients who have progressed on the first-line standard of care, which is a CDK4/6 inhibitor, now specifically KISQALI or ribociclib and an AI, and then are looking for alternative therapy after that. That trial will read out in Q1 of 2027. It is fully enrolled. At this point, what we are doing is we are really waiting for the assessment of progressions, the radiographic outcome, and sort of maturation of that data to be able to read out the trial. There are two relevant subsets in that patient population. About 40%-50% of the patients, their tumor will harbor an ESR1 activating mutation. That is the gene that encodes the estrogen receptor.
There is some demonstration that the next generation endocrine agents have better activity in that population. The remainder of the patients do not have a mutation, and they are a wild type genotype of their estrogen receptor. That is a place where no alternative therapy really has been successful, again, in decades. We, based on our phase II data, have some confidence that we should have an opportunity to address both populations, and that is being tested in the OPERA-01 trial. The second phase III trial is in the first-line setting. The first-line standard of care for metastatic ER-positive, HER2-negative breast cancer is pretty standardized. It is KISQALI or ribociclib plus an AI now based on the survival benefit shown by that regimen. We are testing the combination with KISQALI and palazestrant, which had, again, very promising phase II data.
We had over a year median progression-free survival in the post-CDK4/6 progression environment, including about 30% of patients who had actually had two prior CDK4/6 inhibitors and now going on to their third CDK4/6 inhibitor with KISQALI and combined with palazestrant. We think that's very promising. That's enrolling very well now. Again, a place where other agents in combination with IBRANCE, not KISQALI, have not succeeded. We have a second clinical asset, a KAT6 inhibitor called OP-3136. We presented that data at ASCO as monotherapy, but we have the combinations in breast cancer ongoing. Interestingly and uniquely, we also saw activity in castration-resistant prostate cancer. That combination with the androgen receptor inhibitor NUBEQA will start in Q4.
All right. Maybe going back to the phase III oral SERD trials. We've seen three read out so far. They've all been positive, but as you mentioned, mainly have benefit in the ESR1 mutant population. What is giving you confidence that palazestrant could be different based on its mechanism and the phase II data that you've had?
Right. Mechanistically, it's the complete antagonism. It's the ability to completely turn off the growth and proliferation transcriptional signal of the estrogen receptor. The first of the molecules to be positive was elacestrant or ORSERDU. That's a SERM. It's a partial antagonist, partial agonist, so it's turning the receptor on in some situations. You don't want to do that. Now, in the context of a ESR1 mutated receptor, that receptor's on all the time anyway. The normal biology of the estrogen receptor is it's a ligand-regulated transcription factor. It is inactive if estrogen isn't present. But these mutations, they're point mutations in the ligand binding domain. They actually turn it on without estrogen, and ORSERDU partially turns that off. That led to activity in the ESR1 mutated setting. But as you said, nothing has succeeded in wild type.
Our confidence comes from complete antagonism, very high exposure. This is a monotherapy trial, so the combinability isn't really as much of a factor. Then in our phase II data, in ESR1 wild-type setting, we saw 5.5 months median PFS in phase II, and that's more than anyone's seen, even with a mutant, in that second line setting. The question, of course, in OPERA-01 is can we reproduce it in the phase III?
Yeah. I guess with that, do you think the 5.5 months, if you did see that in OPERA-01, would that be sufficient for a statistically significant PFS?
Statistically, for sure. The important part in this line of therapy is clinically significant. Clinically significant is kind of generally agreed to be a two-month prolongation of PFS. The control arm should be two to three months median PFS. That's been seen in multiple trials in this post-CDK4/6, progression setting. If you see two to three months, obviously if we reproduce something like 5.5, you're more than two months. Imlunestrant was approved based on a 1.6 month prolongation of PFS. It's not hard and fast that it's two months, but that's really the range. Again, the question I think is not, was what we saw in phase II, if reproduced, clinically significant, but just can we reproduce it?
Hmm. Yep. What would be the next steps for palazestrant monotherapy based on different outcomes of OPERA-01 as if you did hit only ESR1 mutant patients, or if you hit on both? Would you still file an NDA with only ESR1 mutant patients?
Yeah. There are a couple things to consider. One is that the overall second, third line market opportunity is about $5 billion a year, so it is very significant. If you divide that up, it is probably slightly more wild type than mutant, so it is kind of like $2 billion and change in the mutant, I am sorry, and about $3 billion in the wild type. If you get the mutant only, you are still in a significant market. The complexity there, as you mentioned before, is that it is competitive because there are other agents there. We think we have an opportunity not only to have an effective therapy there, but also to differentiate, and that differentiation would be a greater than two months prolongation of PFS. Every agent that has been successful there has been two months.
We saw 7.3 months in our phase II in the ESR1 mutated setting, and that again is unique. Then the question is, if we are able to reproduce that in the phase III, in OPERA-01, then that would be differentiated by efficacy, and that would be a significant opportunity.
Maybe moving to the combo side, you mentioned that you are evaluating palazestrant with ribociclib, and you have had phase II data, where you showed a 15.5-month PFS, in all patients evaluated. How does that compare to some of the other combo studies that have read out data with the oral SERD and CDK4/6 combos?
Yeah. Again, it is quite favorable. I think the most relevant population to be able to compare is actually the 15.5 included a mixture of patients, I should say. It had treatment naive in the first-line metastatic set. That is the first-line metastatic setting, and it also had the patients who had progressed on prior CDK4/6 inhibitor. To be able to compare to the other agents, it is most useful to use that second population. In that second population, other agents were more in the six-month range of median PFS, when combined with ribociclib, six to seven. We, again, were 12.2, so quite a significant difference. The other thing to note is that there have been two clinical trial readouts in the first line setting, persevERA from Roche and SERENA-4, most recently on Friday from AstraZeneca. We know both are statistically negative. We have actually seen the persevERA data.
We have not seen the data from SERENA-4, so it's a little hard to comment. But the persevERA data show clear evidence of activity of the regimen. It just didn't hit statistical significance for hazard ratio. PersevERA, unfortunately, has some flaws in its trial design which may have contributed to that, so it's a little hard to tease out. SERENA-4 is not terribly surprising. It's negative. That drug camizestrant is the most toxic and also the lowest exposure in the class. Excuse me.
Yeah. I guess with that, what are you looking to see in the naive patients in your phase II trial that will get you to be more confident in first-line success?
Yeah. I think, first of all, we're confident based on the post-CDK4/6, right? If you think about the post-CDK4/6 progression situation, it's basically the first-line situation, but you waited to the most extreme resistance. You did two things. One, you took the patients who you knew were going to progress because they did, and two, you waited until the tumor volume was large enough to actually be able to measure it as a progression. So we think that's the most unfavorable situation, and yet we were able to get a year of median PFS. The clear win in that setting is a six-month prolongation of PFS. If you get less than that, there's still a lot of room for use. So for instance, the point estimate that persevERA showed was five months.
If they had been significant for their hazard ratio, that's fileable, that would get used, that would get approved, that would get used. So we feel quite confident that we have a good chance to get six months, and if it's somewhat less than that, but still statistically significant, there is opportunity as well.
Yeah.
I should say that's a $10+ billion market opportunity.
Yeah.
That's very large.
Have there been any protocol changes to OPERA-02 following persevERA results?
No, not yet. No, but I caveat, right? We would love to see the SERENA-4 data. We do not care about the camizestrant arm. We care a lot about the control arm.
The reason for that is when we designed OPERA-02, as when Roche designed persevERA, as when AstraZeneca designed SERENA-4, we are using pretty old data for our estimate of the activity in the control arm. Not unique to breast cancer, it is common in oncology that a regimen or a drug gets better over time. Oncologists are very good at managing toxicity, and as they develop that, they do make the drugs more effective. We would like to have a more contemporaneous estimate, and the best one is SERENA-4, mostly because the patient population that AstraZeneca enrolled did not include these endocrine-resistant patients. It is very much like the OPERA-02 population. So what would we do to OPERA-02? What might the changes be?
The simple thing is, if the performance of the control arm has evolved positively, we might want to put more patients on the trial in order to accumulate the necessary events more quickly. We will communicate that later. But obviously, as I said, we have the top-line readout from Friday. The trial was negative. We do not care. We are looking at the control arm. But we have not seen the data yet.
Okay. You also have a clinical trial collaboration with Pfizer's atirmociclib.
Yes.
The CDK4 inhibitor. How do you think about the differences between combining with CDK4 versus CDK4/6, and when might we see data from that trial?
Yeah. That's a phase II trial. It is combined with atirmociclib, and that's fully enrolled. It's a collaboration, so we have to see when the data matures. We have to also talk to our collaborator about when we might present it. I don't have other than be able to tell you it's fully enrolled, so we know we can give the combination, and we're following the patients. We don't have a timeline yet. We usually communicate when we have an abstract accepted. How does it fit into the life cycle? What we were doing with that is we're trying to look at where might the standard of care evolve. The first place where we were able to look at that was ribociclib versus palbociclib, IBRANCE versus KISQALI. IBRANCE was the dominant, by far, CDK4/6 inhibitor for years.
However, as the survival data read out from those registrational trials, ribociclib, KISQALI, had positive survival data in 3/3 trials of significant prolongation one year, and the standard of care shifted, and based on when we were timing the start of OPERA-02, we were able to shift our start able to shift our combination from palbo to ribociclib, and so we're really using the standard care CDK4/6. I should add, ribociclib's harder to combine with. It has a more complex metabolism and toxicity profile, but palazestrant is able to do that. Similarly, we're wondering where are things going to go next, and really the most promising agent under development as a targeted agent for the first line is atirmociclib, which also has a somewhat better tolerability profile. In particular, the neutropenia is dialed down by the CDK4 selectivity.
Pfizer's running phase III trials, registrational trials with AI for atirmociclib, but we, in collaboration with them, feel like we wanted to anticipate what might be coming next.
Yeah. With our last few minutes, maybe we'll transition to OP-3136.
Your KAT6 inhibitor. You mentioned you had initial phase I data at ASCO this year.
That's right.
Walk through that data set a bit more in detail and how that compared to Pfizer's KAT6 data in breast cancer specifically.
Yeah. There's multiple dose levels there, and what we present is a bit of an aggregation. What we think we're seeing in the earlier data is that there's possibly a better tolerability profile, in particular, the frequency and severity of cytopenias, of myelosuppression being more favorable. Which was the dose-limiting toxicity for the Pfizer molecule. The other thing that we saw that's distinct from the Pfizer molecule, we saw single agent activity in ER-positive, HER2-negative breast cancer that is not distinct from the Pfizer molecule. They saw that as well. They really validated the target in breast cancer. They did also study prostate cancer and didn't see a signal that encouraged them to continue on. We saw clear single agent activity in castration-resistant prostate cancer. We are continuing on with that development.
In that case, in combination with an androgen receptor inhibitor, the molecule we've chosen is NUBEQA darolutamide. We're doing that as a collaboration with Bayer, who makes NUBEQA.
Yeah. Maybe talk about what the opportunity could look like in prostate cancer and that combination.
Yeah. The concept with prostate cancer is this concept of androgen inhibitor resistance, right? The degree of refractoriness of prostate cancer tends to be defined by its resistance to androgen receptor inhibitors, and castration, which is deprivation of androgen. It's very similar, actually, biologically to what's going on in ER-positive, HER2-negative breast cancer, where you define endocrine resistance based on estrogen receptor. The thing that happens here, in both cases that's a little strange, is you define the resistance by the standard of care therapy. Standard of care therapy has liabilities. You may not actually be resistant, you just aren't giving a great therapy. We think there's an opportunity to redefine androgen inhibitor resistance by combining with an agent that compensates for some of the resistance mechanisms, and we think OP-3136 has that possibility.
That is exactly what will be tested when we combine with NUBEQA.
Yeah. On the breast cancer side, what are the next steps there?
Yeah. So that's a combination again, right? What we saw pre-clinically was something that you see all the time. Targeted therapies in breast cancer are never given alone. They're given with an endocrine agent, with an ER targeting agent. Post CDK4/6 plus AI, right now that's fulvestrant, which we know is inadequate. It's also really inconvenient to give. It's an intramuscular large volume injection. We have the combinations with fulvestrant, but also in our preclinical data, the much more potent combination was with palazestrant. That was true pre-clinically, both for the Pfizer molecule and for OP-3136. Obviously, we're uniquely able to combine with palazestrant. So those combinations are ongoing right now. We will definitely have data in the first half of next year on the combinations. Possibility that we might have some on fulvestrant by the end of the year, but it's really tough right now.
Perfect. Maybe to close out, just sum up for us upcoming catalysts and milestones that investors should be looking for.
Yeah. The big one obviously is OPERA-01 readout in Q1. The other proximal one is the combination data that you talked about, fulvestrant and palazestrant with OP-3136. Again, OP-3136, that is a $5 billion market opportunity in the breast cancer space alone. We really haven't estimated prostate cancer yet, but it is billions annually as a market opportunity. Then there will be enrollment around OPERA-02, whether we change that trial, those things will also be communicated.
Great. Thank you so much, Sean. Thanks everyone who has been listening in. Hope everyone has a great rest of their day.
Thank you.