Olema Pharmaceuticals, Inc. (OLMA) Earnings Call Transcript & Summary

All right. Excellent. Well, thank you, everybody, for joining us this afternoon. We've got Olema here. We're very excited to talk about both recent and upcoming data [indiscernible] and the ER space in general with you.

So maybe before we dive into the nitty gritty, why don't I -- I give you a minute or 2, what's coming up next? And how you feel you're positioned coming into the end of the year.

Yes. Right. Great. Thanks, John, and thanks for the opportunity and for people in attendance to learn more about Olema. So obviously, we're a biotech focused on women's cancers. And the lead asset and the one everyone pays attention to, it's not our only one is our only clinical one is palazestrant, which is a complete estrogen receptor antagonist. And so we've recently late October at ESMO in Madrid presented a pretty large 80-plus patient Phase II monotherapy data set, which I think was extremely encouraging. The favorable tolerability, daily dosing, good exposure, all that confirmed but really showing the efficacy potential to differentiate. That's important for our second third-line study, which is a Phase III study, which is starting this quarter, and we presented the data and irrelevant to that with all comer 7.3 months in ESR1 mutant median PFS, which has really not been seen in this field. What that sets us up for and what's coming is combination with CDK4/6 inhibitors to enable a first-line trial in ER-positive HER2 negative breast cancer to begin next year -- late next year. So at San Antonio Breast Cancer Symposium next week, on Thursday, we will present a Phase II data set -- evolving Phase II data set, I would say, of palazestrant with palbociclib with IBRANCE. And we'll also present our initial Phase Ib data, dose escalation data with palazestrant plus ribociclib or KISQALI. And so PK there is very important. Others in the field have had difficulty with drug interactions. Tolerability, both showing that there's no super additive toxicity, but also that there's not a PK effect that leads to poor tolerability and dose modification. And then with palbo, we'll get kind of some fairly initial efficacy data. For ribo, show what we have, it's pretty immature, but you will see the ribo PK tolerability from the dose escalation. And then I mean, to some extent, the punch line is out for that because we have communicated that we're doing the Phase II expansion with ribociclib with the full dose of palazestrant 120 mg with the full dose of ribociclib 600 mg. And I think that's really of interest to the field because palbociclib is not the standard of care anymore. It's ribociclib. And so it creates this really unique opportunity to do a first-line trial with the CDK4/6 inhibitor preference with full dose of both, et cetera, et cetera. So that's going to be exciting for us.

Yes. All right. Very exciting. Now there's a lot in just a brief week have to dive. Let's start with the ESMO data and let's start with how to position that relative to other ER -- we call them ER general modulate. It's obviously you're an antagonist, not a degrader. But how do you position your response in your PFS data. You cited a particular mutant in some population, which is very relevant -- but for you, I think, maybe a little less, so.

It may be right. So the way -- so -- and this we get asked us a lot. What is the gold standard? What should you be judged by? And our answer pretty consistently is the Emerald study with ORSERDU and their ESR1 mutant subset. And the reason I'm going to tell you how we compare, it's not how we compare that gives us that answer. The reason we give that answer is because what you're all asking is people who don't work for one of these companies who have evaluated this, what was significant to them. And that data set, a 3.8 months median PFS versus 1.9 months in their control arm fulvestrant or an AI led to approval, right? So the FDA looked at it and said, "Hey this will benefit...

Scanning internal.

Right. So there were some caveats and -- but the hazard ratio is 0.55, which is quite respectable in fact. And so the FDA approved it, the EMA approved it, right? So you've had these objective experts approve it. And they're private. So we don't have their sales data. But we can find those scripts. And it looks like they've done quite well in the first 6-ish months of their launch. And so I think that means that prescribers in the United States, which is where the only place it's available now are using it, right? So you've got a whole bunch of people saying, this means something to me. Now in their wild-type population where they didn't really show any effect, they didn't get approval. So we used that 3.8 ESR1 mutant. When you go and look at what we had, we have to be careful with our populations. We did better than 3.8% in our overall trial, but we had 40% fourth line or later patients. They wouldn't have gotten on the EMERALD. So we took the 50-ish patients that had 49%, I believe it was, that were second, third line plus or minus chemotherapy. That would be eligibility criteria for EMERALD. What you saw in that population was a 7.2-month median PFS. And CBRs and a 6-month PFS really consistent with that larger magnitude of benefit. Interestingly, you then go into the subset that CSR1 mutant there and you get 7.3 months. So what's interesting there is a couple of things. One, obviously, 7 months is a lot more than 3.8 months. So that's fairly straightforward and really an opportunity to show greater efficacy in this population because we're a complete antagonist, not a partial agonist, antagonist. So the second is the 7.2% versus the 7.3%. So that means with the wild-type patients in there where they saw a 2.8% to 3.8%. We didn't see any difference. And what that probably indicates is with a complete antagonist, you have the opportunity to show activity in a wild type patients, which ORSERDU does not have in their label because of this data. So I think that's probably the best way we and our IR compared to a variety of tried as best we could prior CDK4/6 treated to do comparison to show favorably across a number of agents. But really, it's our survey that's across the finish line.

I want to dive into that wild-type versus U.S. over mutant population a little bit more -- because looking at your Kaplan-Meier curves, it does look like there could be some difference there. But obviously, it's early in small numbers. Is there a mechanistic reason we should expect your -- to have no difference or a lesser difference relative to a modulate?

Yes, that's great. I think there are 2 answers to that. So what we saw, we pulled out our wild-type subset and it was 5.5 months, which obviously does well compared to 3.8%, a little less than the 7.3%. And then what you're saying, well, wait a minute, was 7.2%. We thought we had some unknown in this. So it's different. I think you have 2 things going on there. One is 5.5 is certainly better than the 1.9 in wild-type that ORSERDU saw. It's less than 7.3%. What you're seeing in wild-type is some of those patients probably have become truly endocrine resistant. That means that they're using a pathway to promote the growth of the tumor other than the estrogen receptor. So it probably doesn't matter in that subset what you do. But clearly, it's better than what was seen with ORSERDU that's complete antagonism. OP-1250 palazestrant when it binds the estrogen receptor wild-type or mutant locks the estrogen receptor in a completely inactive confirmation. Now in the wild-type setting, in those patients whose tumors haven't developed escape pathways, you'll block estrogen binding and you'll stop that signal. In the mutant, they're always on because these are activating mutations. So it's now not ligand regulated. So you lock it into an inactive confirmation from a constitutively active confirmation.

So in mutant patients where it's a driver, you lock out, in wild-type where some patients is still in...

That's exactly right.

Lock out, okay. And I wanted to ask, in the Phase II readout, you have this second line, third line patient population carved out. Could you put that into context your inclusion exclusion criteria for Phase III because you have a [indiscernible].

It's a little different. Yes, excellent. So -- so the -- as I said, the gold standard that we felt for comparison is ORSERDU ESR1 mutant, right. That's the only thing that's been approved. Now one of the things that Menarini has done really well for the field is publish on retrospective subset analyses of these EMERALD data. They've said, what happens if you pull out fulvestrant only because everyone is like well fulvestrant is better than AI. In this setting, made no difference. 80% of their patients were on fulvestrant. The median was 1.9 in the control arm. If you took the 20% with AI added them, it was the same. It just doesn't work in this setting. One of the things they pulled out was what happened to patients who had, had prior chemotherapy in their previous treatments. They did very poorly regardless of what you gave them. And so in our OPERA-01 trial, which is informed quite a bit by EMERALD, I will say. We took that learning from EMERALD and we excluded the chemo previously treated subset. Other than that, the criteria are quite similar to EMERALD. And we have to get more detail on this question, we have on that same day, I didn't bring this one up, our trials in progress poster at San Antonio next week on the OPERA-01 trial. So we'll share with folks more detail about that.

One thing I will point out, of course, is that AstraZeneca just got approved.

With capivasertib and a very narrow label. Yes.

And how does that change the standard of care and then led.

Yes, I really don't think it does change much for endocrine therapies, right? If you look at how you treat ER-positive HER2 negative breast cancer, you always have a backbone of endocrine therapy. Your targeted agents may switch in and out, right? In the first line, the standard of care is ribociclib with an endocrine therapy, usually in AI because fulvestrant can do better in that setting and it's an oral regimen. When you progress on that, you continue with endocrine therapy, right? You're trying to keep off chemotherapy as long as you possibly can. So you may give the endocrine therapy alone currently switch to fulvestrant. If you ESR1 mutant, you might go to ORSERDU -- or you may say, look, I'm going to switch my endocrine therapy and add a new targeted agents, mTOR, PIK3CA mutated.

Well, that would be the other class.

Yes, PIK3CA mutated. We have alpelisib combo ongoing to PIK3CA mutated, we're going to go over to a PI3-kinase inhibitor. AKT, maybe you consider capivasertib, the point is you always keep an endocrine agent there. Their trial was with fulvestrant, which really, I think, is a bit of an older standard of care older now, not at the time that they started their trial. But I think that, that label was also a bit narrower than some of us expected than some of the data showed. So it will be interesting to get the approval summary from the FDA because I'm guessing they had some tolerability issues, and they've probably looked at subsets that the company wasn't allowed to look at because it wasn't part of their prespecified analysis plan.

But would that -- they also achieved 7 -- around 7-month PFS. Does that change your bar, what you want to see in Phase III or?

No. I think to be able to treat someone with a single agent regimen with much less toxicity and get that. It's a very clear advantage that you want to be able to do that if you can. One would also ask what would capivasertib do with palazestrant, right? Because we know that we have this opportunity to be better than fulvestrant as ORSERDU is in the ESR1-mutant subset. So I don't think these targeted agents and endocrine agents compete with each other. I think there's actually -- you want to have -- and I will do a butcher job of it because Dr. Nancy Lin was asked this question at ESMO gave this really wonderfully elegant answer, which I will not nearly reproduce presently. But her point was you want options so that as you're looking at the patient's history, the progress of their disease, you're always going to want an endocrine therapy, do you have options for endocrine therapies. You want -- you're going to want different targeted therapies. What have they seen? What do I think they'll tolerate. You're going to want to have options there. And then obviously, the objective is to push off that chemo as long as you possibly can.

Well, maybe that's a good segue to talk about trial fleet and development plans from here. You mentioned OPERA-01, obviously. But if we're thinking about combos moving up in lines of therapy, replacing fulvestrant in combos of targeted agents. Where are you most excited to go next?

Yes. We're most excited to go into the first-line setting and do that with ribociclib. The data that we're generating, we just expanded the ribociclib combo trial in collaboration with Novartis. And a little bit -- first, we've already said this publicly, but foreshadowing what you're going to see at ESMO we're in the Phase II at the full dose of ribo and the full dose of palazestrant. So you kind of have an idea of what we saw PK tolerability wise to be able to enable that...

To put that a little bit into context, ribo, obviously, becoming standard of care now with less data, but combinability has always been a bit of a challenge.

It has been a bit more of a challenge. It doesn't cause as much neutropenia, but it has a QT prolongation signal. And palazestrant has no QT effect in the clinic through 300 mg daily, which was the highest dose we tested. We never identified an MTD and in DLTs, and it has no herd effect. So we give full doses of both. But if you are going to increase the exposure to ribo, you worry about arrhythmia.

You mean because you have a drug-drug interaction, right. Metabolic issue.

That's right. That's right. That's exactly right. But yes, the first-line setting is where we want to go. We would be unable to do that with ribo late next year. We do need some more capital in order to be able to do that. The OPERA-01 trial, the second, third line, we have all the money that we're going to finish that one out. We can go past our top line readout with our current cash, but we do not have the cash to do that. So we will be seeking partnership and some sort of...

Can you talk a little bit about what the partnership opportunities would look like? And what are you most focused on? Obviously, in a single tumor type, it's tough to carve out indications and stuff. So are you -- what kind of a partnership are you thinking of.

Yes. We wouldn't do an indication carve out. It would be -- actually, I think the Arvinas Pfizer deal is one example. It's not an unusual structure where you have to keep enough that it's not a cheap acquisition, right? You have to keep upside for Olema shareholders. That's our responsibility to them, and they have been a patient group by and large. So we feel quite strongly about that responsibility. So you can do things like share profits, but book sales and key U.S. sales and co-promotion and things like that. So there are ways that you can carve these...

Co-development.

Co-development. Co-development, maybe joint governance, sharing costs some upfront that profit sharing down the road with questions about how do you book sales, how do you promote together.

Yes, there's some obvious choices there.

Yes, I mean -- so there are some obvious choices. I mean, everybody goes to Novartis because they don't have a program. They don't have a CERAN, an endocrine therapy program. They actually -- they have a pretty good CDK4/6 program, which is thriving. So -- and they're our partners. So they -- we interact with them a lot. But any company that -- that second third-line market is $5 billion plus in the United States. If you get particularly if you get the wild-type, right? You add in another probably $10 billion plus, if you're in the first-line setting. Any company that needs a multibillion-dollar market opportunity maybe before the end of the decade, it probably helps if you're in oncology, second largest cancer diagnosis in the world, they could all be potential candidates.

Makes sense. As we're running out of time at the end here, final thoughts, what else do people really need to be focused on as we come into, well, San Antonio next week, obviously, but coming into 2024, which would be on the lookout for future?

Yes. I mean in San Antonio, you're going to see data from a number of things. You got to be very careful with who are these patients? What are the doses being given? What's the tolerability profile here because you can't do something in Phase II and then not do it in Phase III and say, "Oh, this we're reading this through to that. That's important. For 2024, KAT6, we got a pipeline. So very excited to update people on that. We could have a development candidate nomination fairly soon. And that...

Of course, Pfizer has a program there as well. So obviously, we'll be very careful.

Yes. Yes. And we're looking to differentiate their data at ASCO was quite interesting. I have to.

Well, excellent. Lots of news coming and a very exciting set of data recently announced. So thank you so much for joining us and going through it.

Thank you, John. It's been terrific.