Hi, everyone. Good afternoon. Thanks for joining us at the HC Wainwright BioConnect Conference. I'm pleased to introduce Sean Bohen, who's the Chief Executive Officer of Olema Pharmaceuticals. I am Emily Bodnar, Equity Research Analyst at HC Wainwright. Sean, maybe to start off, if you could walk us through a bit about the background on Olema, your lead asset, palazestrant, and the transforming landscape in the ER-positive versus negative breast cancer space.
Sure. Great. Thank you, first of all, for the opportunity to have this chat with you. Olema is a phase three pivotal trial oncology company really focused on breast cancer, in particular hormone receptor positive, HER2 negative breast cancer. Our lead asset, palazestrant, is a complete estrogen receptor antagonist, or a CERAN. The ongoing phase three trial is a monotherapy trial in the second, third line setting. That will read out top line next year. We are also, in the second half of the year, starting a first line trial, also in metastatic ER-positive, HER2 negative breast cancer. That trial is called OPERA-02. It includes ribociclib, right? The standard of care in that line of treatment is really ribociclib plus aromatase inhibitor. We are going head to head with ribociclib plus palazestrant in that trial.
We also have a second clinical stage asset, which is in phase one dose escalation, which is OP-3136. That is a KAT6 inhibitor. That's progressing nicely there. One of our objectives is to, as quickly as possible, initiate combinations with endocrine therapy with that molecule. Those will include fulvestrant. Our preclinical data suggests that really there's a great enhancement of activity by combining the palazestrant.
Great. Maybe we could start with palazestrant. There's obviously been a lot of movement in the oral SERD landscape recently. We've had three phase three trials. We are kind of seeing now the majority of them have only shown benefit in ESR1 mutant patients. How do you kind of interpret this? Where do you think palazestrant could differentiate amongst the others?
Right. In OPERA-01, I think there are really two ways to differentiate. As you say, the activity in the ESR1 mutant setting is, I think, at this point extremely well established. I guess, why confine to the mutant setting? There are different reasons. The first to do this, actually, the only one that's currently approved is elacestrant, or Sirtu, from memory of the Stemline. That molecule, as well as camizestrant from Arvinas, those are SERMs. Those are not complete antagonists. They're partial agonists of the wild type. You do not want to turn on the receptor. They're partial antagonists of the mutant. We have seen the data, obviously, from EMERALD, where Sirtu went from two months in the control arm to four months in the treatment arm for the ESR1 mutant setting, had no activity in the wild type.
From a SERM, that's really what you would expect. We haven't seen the data yet. We'll see it at ASCO. VeraTac2 from camizestrant, their top line announcement suggests something similar. That molecule is a SERM, and that's what we would expect. It's also consistent with the phase two data that they had previously disclosed. EMBA-03 is more complicated. A part of it is more complicated because the trial design is extremely complex and difficult to interpret. I think also you have to realize that while EMBA-03 molecularly is a CERAN, the molecule has poor PK, and so they really can't get any more exposure than they have. We think it's about—it's significantly below our exposure. We think it's about a third of what they would really need for optimal activity.
When you have an exposure problem, one thing you have to recognize is these ESR1 activating mutations occur in the ligand binding domain. One of their effects is to activate the receptor. They turn it on in the absence of estrogen. Another effect is they decrease the affinity of the receptor for all ligands. If you have an exposure problem, then it's going to be enhanced in that setting. I think that probably explains the disappointing results. The two opportunities that exist there are in the Emerald comparable population in ESR1 mutant. In our phase two, we saw a 7.3 month PFS. Obviously, that's considered more than four months. We saw 5.5 in the wild type, which is more even than our surgery saw in the mutant context. We think there's two great opportunities to differentiate.
Great. So maybe walk us through a bit more on the OPERA-01 phase three trial design, which has a primary endpoint of PFS.
That's right.
As you mentioned, the PFS rate is on phase two. Do you feel confident that you could potentially see a benefit in the ITT population?
Yeah. So interestingly, we don't test the ITT population formally because it's not relevant. You may recall for elacestrant, then elacestrant, and EMERALD did test the ITT population. They said it was significant. The FDA went out and did the scientifically driven thing. They separated out the mutant and the wild type. Since the real activity was confined to mutant, and that's what drove the ITT, they gave approval only there. With that precedent, what we decided to do is actually test mutant and wild separately. When you do that, that allows you to write your statistical analysis plan with design characteristics that really help you to test those two questions. We do think there's a significant opportunity based on our phase two data to be better in the mutant than what has been seen and to be positive in the wild type.
That's at least half of the patient population. It also means you don't have to do the test and then not be able to treat a significant fraction. With regard to VeraTac2, again, we haven't seen it. The top line that Arvinas shared was that they met their objective in the mutant population. They did not meet the intent to treat.
Okay. Maybe moving on to the combo approach for palazestrant and ribociclib, which you currently are evaluating in a phase one phase two trial. You've presented some very encouraging PFS results there for 13 months. How does that compare to some of the other oral SERD and CDK4/6 inhibitor combos that you've seen?
Yeah. Again, it compares very favorably. Probably the gold standard was a large randomized phase two called MAINTAIN, which was ribociclib plus fulvestrant, or exemestane, mostly fulvestrant after prior CDK4/6 plus an AI. You had about five months there. You definitely saw a treatment effect. It was not something that would drive a change in the standard of care. Obviously, 13 months is considerably better than that. Others have looked at ribociclib plus their SERD. What we've seen from Roche and AstraZeneca is in the seven- to eight-month range more in that population. A bit better than what was seen across trial comparisons, of course. A bit better than what was seen in MAINTAIN. Again, we really think that this is favorable and will bode well for the OPERA-02 trial, which is, again, the first line setting.
Treatment naive in the advanced or metastatic setting, comparing ribociclib plus AI to ribociclib plus palazestrant. That will start the second half of this year. We should, in the not too distant future, be able to announce our dose selection. That's really the rate limiting step for us to start OPERA-02 right now.
Given the majority of the patients you've evaluated so far have been second line, third line patients, how do you kind of get more confident in the first line potential? You do have some CDK4/6 naive patients in your trial. What should we be expecting to see from those patients?
We will update, and it'll depend upon the level of maturity, whether we include those patients. We will update before the end of the year, in the second half of the year, on the phase two data set, which is 70-ish, 70-plus patients with palazestrant with ribo. As you say, most of them are post-CDK4/6. We do have, later in the trial, a cohort of investigators enrolled treatment naive. We do have a cohort of those patients. We anticipate it'll take a while for that to mature. Those patients should do pretty well with this treatment. Remember, ribo plus AI, the median PFS was about 25 months. That's a little different patient population, but we expect them to do quite well.
The confidence in having efficacy in the first line really comes from the concept that if you've had a CDK4/6 and progressed, you then switched palazestrant plus ribo. The way you can think about it is that whatever led to your progression, we should be able to stack our benefit on top of that by just starting with the superior therapy. Now, adding 13 months would be a lot, obviously, to 25. What we think is the bar is really, if you were to get a six-month PFS extension by using palazestrant instead of letrozole with ribo, that that would be a clinically meaningful difference in the kind of thing that should support regulatory approval, should support physicians, oncologists using palazestrant rather than letrozole.
Can you walk us through a bit more about the OPERA-02 trial design and your clinical trial collaboration with Novartis?
Yeah. So the design is pretty simple, actually. It's first line advanced or metastatic. In the advanced or metastatic setting, these patients will not have had any therapy. Now, they may have had some prior therapy, right? Because many of those patients are first diagnosed with limited stage disease and get local therapy, adjuvant therapy, and usually complete that and have some disease-free interval. Then they're diagnosed with metastatic disease. At that point, they're first line metastatic. The randomization is fairly straightforward. Everybody gets ribociclib. Half the patients get letrozole. Half the patients get palazestrant. The primary endpoint is progression-free survival. Overall survival is a key secondary endpoint. That will be followed as well. Again, about 1,000 patients. We expect the performance in the control arm to be consistent with something like MONALEESA-2, 24-25 months.
We're looking for 30 months plus in our treatment arm. Now, obviously, one of the things I just said is there's 1,000 patients, and all of them get Kisqali, ribociclib. This, by now, I think many of you know, this is the CDK4/6 of preference in that setting. The reason is it's the only one to show consistent survival benefit. Survival benefit was about one year, which obviously is extremely meaningful. It's the category one NCCN CDK4/6. Obviously, all of these patients will be getting Kisqali and some of them for a very long time. That's a lot of Kisqali. The Kisqali is being supplied by Novartis through a clinical collaboration. I think we've disclosed pretty extensively what they get. They don't get any rights to palazestrant, but they do get some negotiating rights for partnering. That's all been disclosed pretty extensively.
Okay. Great. Maybe if you could tell us a bit more about expectations for the data update you plan to have from that study later this year.
Yes. The update is from the phase two combo trial. Basically, what we're doing is we're able to see greater maturity, certainly in the post-CDK4/6 setting, right? 13.1 was what we were able to present as a median. There is still some maturation to go on there. I think we can also then start to look at, interestingly, in the post-CDK4/6 setting, it's an unusual population. About 30% of the patients actually had two prior CDK4/6 inhibitors. They're very heavily pretreated. We'll be able to update that, but also potentially look at wild type versus mutant, other subsets. We'll tell everybody when and where that's going to happen once the abstract is accepted. We do have some other good catalysts this year. There's possibility we'll update on OP-3136, 486, the monotherapy dose escalation, possibly before the end of the year.
There are external catalysts. Persevera, which is a Roche trial of ribociclib plus camizestrant versus palbociclib plus AI, is expected to read out before the end of the year. Obviously, if that's positive, that would read through very positively the class.
Okay. Great. Maybe for the last couple of minutes, we can talk about the KAT6 program. Obviously, that's been an interesting target with the new concept data from Pfizer's asset. Maybe you could give us a bit more detail on how OP-3136 differs from the Pfizer molecule.
Right. CAT6 is a very interesting target. It's essentially an epigenetic target. It's a lysine-acetyltransferase. One of the places where these lysines are acetylated is on histones. When you acetylate the lysines, it creates a steric interaction that the histones relax the heterochromatin. What that does, that gives greater access to promoters. The CAT6 spectrum of genes overlaps considerably with steroid hormone receptor responsive genes. Again, it's a little bit like doubling down. Obviously, if you inhibit the CAT6, you're stopping that acetylation. You're keeping the heterochromatin tightly wound. You're reducing access to the promoter and downregulating the genes. By the way, it is not downregulation of estrogen receptor that is the primary target here. There are a lot of other genes that are involved as well. We inhibit the estrogen receptor very effectively just with palazestrant.
What Pfizer showed is a pretty impressive response rate post-CDK4/6, 38% in the SABCS presentation in combination with fulvestrant. OP-3136 is a bit different than that molecule. It's more potent for KAT6A and B. That molecule hits KAT7 and so does OP-3136, but it also hits KAT5 and A. We don't think those contribute to efficacy, but they may contribute to adverse events. We have dialed that out. We will see in the clinic how does that play out. We presented last year at ENA in October. What we've shown is that actually both for the Pfizer molecule in animal breast cancer models and for OP-3136, if you add in palazestrant, you get much enhanced activity. A very high priority for the OP-3136 program is to get that combination going as quickly as possible because it's unique for us to be able to do that.
I think Pfizer and also you preclinically have shown potential to have benefit in other cancer types besides breast cancer. Maybe also talk a bit more about the phase I trial and indications you're looking at there.
Yeah. That's right. One of the interesting things, and as I mentioned, this is an epigenetic target. There are a lot of genes affected. So one fairly logical set of models, and we presented this as a late-breaking abstract at AACR in April, was castration-resistant prostate cancer. Obviously, that's a progesterone-driven tumor. We saw activity there. We, interestingly, also saw non-small cell lung cancer and ovarian cancer, ovarian cancer again, and estrogen-driven. Non-small cell lung cancer, obviously, neither of those. Interesting. Our phase one dose escalation obviously has HR positive, HER2 negative breast cancer as a tumor type. We include also castration-resistant prostate cancer and non-small cell lung cancer. We're using that as an opportunity maybe to generate some data across that broader spectrum of tumors.
We're going to be able to decide if we want to expand into those tumor types when we get a dose select.
Maybe some timelines around when you might open up to other indications, also potential combinations like you mentioned.
Yeah. I mean, yes. Hard to do. It's a little hard in dose escalation to know when you're going to stop dose escalation. It depends upon when toxicity shows up, if it does, if you get dose-limiting toxicities. So we're hoping that it's possible that we can present monotherapy data by the end of the year. Maybe, maybe not. Certainly next year, we're going to be able to get into that later next year. I think the combination certainly with Fulvestrant and palazestrant. I think it depends upon the data that we generate whether we will do expansions in the other types as well.
Okay. Great. I think that's all the time we really have. So thank you so much, Sean. Thanks, everyone, for listening in.
Thank you. Thanks a lot.