Good morning, everyone. Thanks for joining our healthcare conference. I'm Matt Biegler. I'm the covering analyst for Olema, and I'm really pleased to have President and CEO Sean Bohen with us today. Sean, pleasure as always. You know, I think a lot of people know the story, right? When it comes to the SERD class, now, I think we've learned a lot in the last year, right? We know from lidERA that they work in adjuvant setting. I think we always knew that they work in a ESR1 positive mutant setting in later line cancers. We definitely know they work in combination across all comers. You know, we'll get data from persevERA that'll tell us if it works in combination in the kind of a more frontline setting.
I guess as we stand here in 2026, you know, has kind of the class shaped out or is shaping out as you had kind of expected it would?
Yeah. First of all, thank you, Matt. It's great to have a chance to talk about this and talk about Olema. You know, I think that we, a couple of things I would say here. First of all, I think that we've known for a while that we were not adequately suppressing the estrogen receptor-mediated growth and proliferation, signals in these tumors, in ER-positive, HER2 negative breast cancer. You know, tamoxifen is a SERM, so it's a partial agonist, so it's turning it on in some contexts, not suppressing it completely in others. You then move on. We get the AI, AIs, which don't really actually interact with the estrogen receptor at all, but they do decrease, though do not eliminate, peripheral estrogen.
You get fulvestrant, which should have the potential to be a complete estrogen receptor antagonist, but it just doesn't have good pharmacology, right? Molecularly, it's really interesting. Clinically, pharmacologically, it's really flawed. This led to this massive effort to do better.
Yeah.
it turns out, however, that this is a really tough target, a ligand-regulated...
Right
... transcription factor. It's not just the molecular properties. You need a complete antagonist. It is also the pharmacological properties. You have to have exposure all the time. You have to be able to turn the receptor off, occupy it all the time. You have to be able in, you know, not in the lidERA context, but in really the broader context, to be able to combine with other drugs, right?
Mm-hmm.
Without drug-drug interactions, be that toxicity or DDI. I think what's been confusing to people is they saw. You know, when we started, palazestrant, then OP-1250 in the clinic, there were ten drugs in this space.
Yeah.
It was fairly predictable that many of them were badly flawed.
Mm-hmm.
Now you're really down to a handful or less, and I think that, I think that that's, that attrition led people to say, "Oh, this doesn't work.
Mm-hmm.
Well, as you said, in the last year, it's very clear it does work.
Mm-hmm
... if you do it well.
Mm-hmm. Yeah. Yeah. How does palazestrant differ from these other ones as a, as a SERM versus some of the others that are out there?
Right. Broadly speaking, you do have a few in the class that are complete estrogen receptor antagonists or CERAs, palazestrant amongst them giredestrant is as well.
Mm-hmm
as is camizestrant. Drugs like elacestrant and fabtuzastrant are not.
Mm-hmm.
They're SERMs. That's the first major molecular distinction. Even if you have that molecular property, you have to have really good exposure-
Mm-hmm
... and palazestrant has, by quite a bit, you know, a 2-fold at least above giredestrant and even more above the other agents, superior exposure. Then there's this combinability issue, where you need to be able to combine at this full dose, get that full exposure with other drugs like CDK4/6 inhibitors, everolimus, PI3 kinase inhibitors, if you want to go in that direction. You know, more recently interesting, you get the KAT6 class.
Yeah. Yeah, you know, as I kind of said earlier, you know, Roche got that win with giredestrant in the lidERA trial in the adjuvant setting. That was head-to-head against an aromatase-.
Yep
... inhibitor. I think it kind of dispelled this notion that a SERD cannot beat an AI head-to-head persevERA , also from Roche, it's going to read out at some point this year. That's effectively the same thing, except now you're metastatic, and now you're combining with a CDK4/6. I mean, is there any reason why that trial wouldn't work?
Yeah, I mean, I guess I would put the outcomes in probably more like three categories than two.
Mm-hmm. Sure.
There's obviously the top line, the thing you'll see in a press release. Roche's guidance has been, "This is more like a month or two-
Mm
... that we should get the top line result from this. Probably not see the data, but see a press release." The top line is going to be binary, as you say. It's going to be, you know, this trial is positive, met primary PFS endpoint, or no, it didn't.
Mm-hmm.
I think as you go and look at the data, when we're able to see it, there's more subtlety than that.
Mm.
Within that, no, it just really didn't seem to have much treatment effect at all.
Yeah.
I think, as you say, post-lidERA, that seems very unlikely.
Yeah.
We know these drugs are better than an AI.
Mm-hmm.
That's the comparator. I think that there is some possibility you get a trend, but you don't meet the statistical bar.
Yeah.
Um-
I guess my question was also, like, does adding the CDK4/6 in some way change the biology? I mean, is giredestrant combinable well with the CDK4/6? Does it have to dose down, you know, whereas you don't?
I mean, I think historically, First of all, I'll do the second one first, then we'll go to the biology.
Yeah.
They did dose down, right?
Okay.
They dosed down from 100, which was their original recommended phase II dose, which had exposure, you know, pretty comparable to palazestrant at 90. They dosed down to 30, which is the dose they're using in persevERA. I think, you know, going in, and you and I had talked about this, I thought this dose down was a real risk, that you would.
Yeah
compromise the activity of the SERD to the point where you wouldn't be able to see it.
Yeah.
Well, 30 of giredestrant is what was used in lidERA, okay?
Yeah.
It's the same dose in both trials.
Yeah. I see, okay.
Do I think they may have not been able to maximize their efficacy? I still think that's true. At the same time, they clearly have activity. The LIDERA result was not subtle. It was compelling. I think going to the biology question, you know, the biggest biological difference that I look at as an unknown here is, right. The other question people had doubts about was, these things work in ESR1 mutant. Everyone finds that quite compelling. Even if they aren't very good drugs, they still have some activity. What happened with LIDERA is you went into an ESR1 wild type population, right?
Yeah.
You saw this tremendous effect. The thing about that is that there are different kinds of ESR1 wild type. There's endocrine sensitive, and there's endocrine resistant.
Yeah.
Right? where previously, the other drugs in the class. We'll see what happens with palazestrant.
Yeah
... from OPERA-01, where they had not worked in endocrine-resistant wild type. People had generalized all wild type, and that's not biologically what you should be doing.
Yeah.
Now we go into lidERA, which is endocrine-sensitive wild type, and you see there's very clear efficacy.
Yeah.
The difference in the persevERA population, the first-line metastatic, is that the majority of those patients, probably about 70-75%, will have seen adjuvant therapy before.
Mm-hmm. Mm-hmm.
They're endocrine sensitive wild type, but they are also endocrine experienced, whereas the adjuvant setting is endocrine naive. They don't have a high percentage of ESR1 mutations, so what is the biology of that? We don't really know. I should say, the remainder of the 25% or 30% remainder in PERSEVERA would be de novo metastatic. They would also be endocrine naive.
Yeah
because that's their first diagnosis. We don't know how that plays out.
Yeah.
The idea that the palbociclib is gonna dilute the effect, I have difficulty with. You know, you need to give endocrine agents-
Yeah
... with these targeted agents. CDK4/6s on their own have very modest therapy.
Yeah.
It's true of all the targeted agents. You add in even a not optimal endocrine agents, like AI or fulvestrant, you see great potentiation. I think that there's plenty of opportunity for an even better endocrine agent to further potentiate.
Yeah. Yeah, I'd agree with that. I mean, it's an interesting position for you, right? You're kind of beholden right now to how our persevERA does, and I personally think giredestrant looks like a pretty good drug, but palazestrant looks better. You know, you could have this outcome where the trial misses, but let's say it trends in the right direction. You are running your own front line trial, OPERA-02.
Right.
We should be clear about that. Like, does the outcome of persevERA change anything in terms of, like, your ability to want to continue to fund OPERA-02?
No. We're not beholden to persevERA at all.
Okay.
It's of interest.
Yeah.
Let me tell you the most interesting thing about it. It's actually not the giredestrant.
Mm
... + palbociclib arm. It's the palbociclib + AI arm.
Yeah, you want to see how that goes.
Because-
Yeah.
Yeah, because we're looking back at relatively old trials-
Yeah
... when we use our prediction, when we design a trial of how the control arm will perform.
Yeah.
We know that in oncology, a given regimen over time often performs quite a bit better.
Mm.
That's probably in part, the oncologist becoming.
Thank you.
... with how to use.
Yes, sir.
Yeah.
Yeah.
They keep the dose intensity. They don't discontinue or pause as often. They don't dose reduce as often. Then, of course, there are positive changes to care overall. Having a more contemporaneous control arm is really useful. What may change about OPERA-02, right, which is our ribociclib plus AI versus ribociclib plus palazestrant ongoing Phase III trial, is we have the opportunity to change the design.
Mm.
If we see something from that control arm in persevERA, and we can even wait for SERENA-4 in the second half of the year, if we see something in those control arms that makes us think, "Oh, you know, we need to revise our assumption." We can go back and do that. We can look at what we would like to now use as an assumption for performance in the control arm. We know what we want in the treatment arm, which is, it's not the minimal efficacy that would.
Yeah
be positive or make a difference. If you hit six months, you're going to change the standard of care. No question.
Yeah. Right.
everyone will adopt it, and it will get approved easily. you know, We had a year post CDK4/6 in our Phase II setting, and mostly in wild type patients.
Yeah
... post CDK4/6. We're quite confident. I do think that, you know, getting the trial design right is a really big deal, and we have this great opportunity to be better informed and change the trial if that's appropriate.
Yeah, it's a really good point. I didn't really think about that, but you're right. I feel like we haven't really had a lot of contemporaneous.
Yeah
... arms to kind of judge what our statistical assumptions should be. It's good to know that you can always go back and kind of change that, increase the sample size or whatever you need to do.
Exactly.
Let's talk about your combination data with Ribo. It's the emerging standard of care. It seems like other drugs can't really combine with Ribos, and many have tried. There's a lot of DDIs. What is it like the molecularly about palazestrant that allows it to combine with Ribo?
Yeah, I mean, one thing that happens, and it's just kind of combinability in general, because we've combined with palbo, ribo, full doses of all these drugs.
Mm-hmm.
Alpelisib, everolimus. Atirmociclib is ongoing. That's the Pfizer CDK4 selective molecule. KAT6, OP-3136, our KAT6 inhibitor is ongoing as well. I think the first thing is tolerability profile, right? You have to have no overlapping toxicity, no enhancement of toxicity with the agent you're combining with. It was, in fact, tolerability that led to the dose reduction for giredestrant. It was bradycardia, rate of bradycardia. We just have found that we don't have any overlapping toxicity, and we don't have any enhancement. I think beyond that is kind of how you interact with the molecules that metabolize these drugs, and are you inducing a CYP?
Are you inhibiting something that metabolizes the drug such that you alter the PK? We've just found that, you know, we don't have.
Yeah
... significant PK alterations in combination.
You want to kind of put your combo data that you've had...
Sure
... with Ribo in the second line, just kind of into context of what we saw?
Yeah.
I don't even know the best comp here, maybe EMBER-3, the imlunestrant combination.
Yeah, Imlunestrant was abemaciclib. A few of the other drugs have done small combinations with ribo.
Mm-hmm.
Again, their doses are always lower than, you know, I think is optimal, which leads to lower exposure. Pretty much the best we've seen is around eight months in the, in those, data sets of median PFS.
Mm
... in a post CDK4/6 treated population.
Yeah.
Right? what we saw is one year-
Yeah
of medium PFS. Again, where you anticipate the most activity from these agents is in the ESR1 mutant in that post CDK4/6 setting. We had a predominantly ESR1 wild type population, and beyond that, we... Right? We broke them out, and we saw that we got nicely over nine months in that wild type only, and almost 14 months.
Yeah
... in the mutant. This, again, this treatment effect, this is preserved, you know, independent of the whether the ESR1 mutation is one of the mechanisms of resistance.
It kind of begs the question of why don't we keep the CDK4/6 backbone.
Yeah
... after we've already failed the CDK4/6, right? I know it puts you in kind of a tricky spot because you've got your pivotal trial OPERA-01 that is going to read out this year. That is a monotherapy. I think that that's very much when you designed the trial, where the field was, you know, we started getting data from postMONARCH read out, three, read out. You know, physicians that I talked to-
Maintain
... were like, "Yeah.
Yeah.
Yeah, it kind of makes sense to kind of keep the CDK4/6 backbone. How do you kind of view where you are strategically, right? I think OPERA-01, it's obviously important to get the drug approved and labeled-
Yeah
to also maybe have the ability to combine in the future, like, what are your plans to kind of, like, adapt if that is the emerging standard of care here?
Yeah. A couple things about that, right? While the data that has been generated on CDK4/6, post CDK4/6, it's, it has not been wildly encouraging, right?
Yeah.
You saw some effect of Ribo+ fulvestrant over fulvestrant in MAINTAIN. It wasn't statistically significant, but there was clearly a trend there. You know, Clearly, when you added abemaciclib imlunestrant, you saw a potentiation of the activity. I don't think it was earth-shattering in the end, but it was definitely better, again. What we know is that in practice, physicians very frequently do exactly what you said, which is keep a CDK4/6 on and change the endocrine agent. you know, we didn't, when we did OPERA-01, we didn't have the data that we presented at ESMO, the Ribo-Palbociclib combo data.
Yeah.
We are evaluating, is it worthwhile, to go out and do another, second-line trial and have it be ribo plus Palbociclib versus some other doublet, like maybe everolimus fulvestrant?
Mm.
Because you know, it, remember, the objective of therapy here is one of the objectives is to put off chemotherapy as long as possible. Sometimes physicians or patients will want a monotherapy endocrine therapy because maybe it's the tolerability, maybe it's comorbidities. Other times they don't. They want to try and get some sort of combination. We are evaluating whether enabling that is a worthwhile thing to do. I will say, OPERA-01 has a real opportunity to differentiate.
Yeah.
One, by having much better activity than what is seen. Two months is what you see, two months increase in median PFS in the existing agents in the ESR1 mutant post-CDK4/6 setting. We think we can do better than that.
Yeah
... setting. In addition, if you capture the wild type population, that is completely unaddressed.
Right.
Right?
Right.
There was some, again and again, people say, "Oh, you know, we're gonna address it with abemaciclib and imlunestrant." No, abemaciclib and imlunestrant is filed for mutant.
Right.
We're gonna address it with everolimus/verodegastat from Arvinas." No, the FDA accepted that application for mutant. The reason is, you didn't design the trial well to do wild type. OPERA-01 is designed specifically to address that wild type question.
Yeah. Let's talk about OPERA-01 and kind of some of your assumptions, you know, into it. I mean, I think it's ultimately going to be the adjudicator of this idea of in a patient population that's much less endocrine sensitive, if you have a very selective SERD, can you get a benefit there? You know, I think the argument in favor of it is, like, elacestrant obviously is not a CERAN. It's a pretty decent molecule, it's not the best. Did show a trend there. Now the question is: can we get to, like, that 0.7 hazard ratio, right? That's ultimately for the wild type setting, what you're trying to get.
Yeah, you're trying to get two months increase in medium PFS, right?
Mm-hmm.
Back to our assumptions, Matt. Our assumption is that control arm, which is fulvestrant or Exemestane, it's mostly gonna be fulvestrant. All these trials that have used, that's about 80% fulvestrant. That will be 2-3 months in its median, and that's been seen repeatedly. Your objective is to get two months beyond that. Now, imlunestrant was 1.7, so clearly there was room for doing a bit less than that, but we don't think you could go much below that, right? One is that is a significant benefit in this population where you're trying to push off chemotherapy or a harsher regimen.
The second aspect of it is, remember, there is advantage to the patients in terms of they aren't getting these two large volume injections every 28 days. You are offering them their therapy with an oral daily pill as the mode of delivery. If you can get that treatment benefit, there are other benefits that come with having an alternative. That's really what we're designed to demonstrate.
Yeah. I mean, regardless of how you do on the wild type, you know, this thing's gonna work on the mutant, so you're gonna...
I hope so.
you're gonna get the drug approved. Yeah, of course, knock on wood, but you're gonna get the drug approved. Well, I guess a better way to ask it is, like, where are you on the build-out of a sales force and marketing-
That's correct.
... this drug?
Yeah. We are going to launch, obviously, assuming a positive trial, as you said, be it mutant only or mutant and wild type. Obviously, the approval of the drug is valuable in all sorts of ways because, you know, one, the mutant only is a $2 billion a year market.
Yeah.
For us, that is, that's significant. It's more crowded.
Yeah
We have to get in there, but certainly we feel like we have this opportunity to have a better PFS benefit. An opportunity to go out and have a differentiated profile. The wild type is a bit of a game changer, right?
Yeah.
It's a $5 billion plus market, and that wild type portion is unaddressed.
Yeah
I would say, at this point in time. Now, if you go and do the Ribo combo, if you take that five, six months of the monotherapy and go to a year, simple math, right? It becomes a $10 billion plus market. This is a significant, unmet need and market opportunity.
Yeah.
We believe that there's great value with data that supports a launch of, you know, either of these scenarios is of great value in the near term, but then certainly down the road. In terms of where we are with the build-out, we have started the hiring of commercial expertise, and really are developing a strategy around that. Now, I should say that commercial effort is in the U.S. only.
Okay.
Right? We are, we do not have aspirations or capabilities. It would be a terrible distraction-
Right
... to try to do, this globally. The other thing that we will need to do is seek a collaborator who has that global capability, to be able to work with us in getting this drug to as many patients as we can.
Makes sense. Got like 5 minutes left, probably a good time to shift to the KAT6.
Okay.
that's gonna be more.
Yep
Topical this year.
Yeah
It's kind of funny, you know, you guys had, this program's been on your pipeline for quite a few years at this point, and up until maybe two years ago, no one ever heard of KAT6. Kudos to you guys for getting behind novel targets that are in breast cancer. I definitely owe that up to you and your CSO. Yeah, I mean, the number one question is, like, how do you differ from Pfizer? There's quite a lot of debate over, well, do you want to hit KAT6 and 7? Do you want to hit the alpha versus the beta isoform of KAT6?
Like, where do you stand on that debate, and why do you think your drug can be better than Pfizer's and some of the other novel ones that we have coming up in the pipeline?
Yeah, we do hit KAT6A, KAT6B, and KAT7. We've dialed back, you know, severalfold the inhibition of KAT 5 and KAT 8.
Mm-hmm.
Based on the things that we looked at, there are a couple of things. We felt like you had to hit KAT6A and KAT6B. There is some data, it was published about a year ago, in a mouse knockout model, that KAT6B overexpression rescues KAT6A deletion. There's very clearly an ability of KAT6B to compensate for the absence or inhibition of KAT6A. We had seen that in different experiments very early on and decided we needed that. The KAT6, 7 question is a bit unanswered. It they're very similar, and so it's hard to target KAT6A and B specifically, and we don't.
We're a little more selective, for KAT6 than KAT7, but at the levels of exposure that are going to be achieved here.
Yeah
... they're both inhibited. 5 and 8 are interesting because, you know, there are two primary AEs occurring with this class. One is dysgeusia, which is this taste alteration...
Yeah
... which is pretty broad with epigenetic targets, in fact. If it's not too severe, it is an inconvenience for patients, but ends up not being unmanageable. What you want to avoid is having a severity where people are reducing their caloric intake, and then you've got cancer patients losing weight.
Mm-hmm.
That is not a good thing, right? The real thing we are looking at is the cytopenias, right? That's really where you get a dose-limiting.
Mm
... exposure-limiting situation. We'll present our first data in Q2 of this year. It'll be mostly monotherapy data, but you'll get a very clear
Mm
of the tolerability profile. The levels of exposure we're getting will show you what efficacy data we have. I'll just add that it's not just an ER-positive, HER2-negative breast cancer. There's also castration-resistant prostate cancer and non-small cell lung cancer, 'cause our preclinical data suggests those are potential diseases that could be.
All right, what did you say the third indication was? HR-positive, castrate-resistant prostate, what was the third?
Non-small cell lung-
Non-small-cell
NSCLC. Yeah.
Yep.
Yeah. I think that this is what we're testing. It's very interesting that Pfizer in January announced that they have a second KAT6 inhibitor. They're moving into the clinic, and it's a KAT6, 7.
Mm.
Well, that's essentially what.
Mm
... 3136 is. It's just about a year and a half ahead.
Mm.
Plus, we can combine with Palbociclib, which no one else can do, and the preclinical data indicates.
Mm
... that you significantly increase-
Mm
... the potentiation of effect with Palbociclib versus just using fulvestrant.
Interesting. Pfizer definitely needs to resuscitate their franchise now, with palbo getting its lunch handed to it by Ribo and trying to make atirmociclib work. My last hard-hitting question is, if you're gonna get taken out, who is, who's the best suitor for you, right? You've got kind of like ongoing collaborations with Novartis. You know, you're trying to kind of cover the ground here. Could certainly set up for a bidding war, who do you see as maybe the best fit?
Well, I mean, first of all, I don't spend much time thinking about it. We have collaborations with Novartis and Pfizer. Novartis, obviously, the OPERA-02 supply collaboration is the largest of those. I don't spend any time thinking about it. Our objective is to get better therapies to patients with ER-positive, HER2-negative breast cancer who have a very clear unmet need. We think palbociclib can do that. As OP-3136 emerges, we're extremely optimistic, and they work together, which is extremely exciting, and that's being tested in the clinic now. That is really where we focus. Now, obviously, you know, investors wonder, "Well, what does that mean?" Well, look, if somebody says, "This is something we want in our portfolio, and we'd rather not collaborate, we'd rather own it," we will entertain it. That's our job.
We will do it, but that's not what we do day to day.
Yeah. Always fun to ask you the hard-hitting questions, Sean. I appreciate the time.
Yeah. My pleasure, Matt. Thank you.
Yeah. Looking forward to a really, really pivotal year for you guys. It's been fun-
It's an interesting year.
watching the story.
Yeah, for sure.
Yeah.
Very exciting.
Thanks so much, everyone, for joining. Thanks, moderator.