Good afternoon. How are you? Thank you for joining us on the next panel discussion here. I am very fortunate to have the CEO of Olema Pharmaceuticals here, Sean Bohen. Sean is continuing to work on developing and executing on his breast cancer drug, palazestrant. Obviously, we just came away from ASCO and continue to learn more about the developments in breast cancer. I would love, Sean, maybe just to give a snapshot view. Here we are in the middle of 2025, just, you know, sticking first with Olema. You guys are enrolling in a phase III program. You're starting a first line study. Tell us about where Olema is in your development, and then we can talk about how that will all fit in with all of the other programs going on in the landscape coming away from ASCO. Tell us about Olema first. Where are you?
Okay, thank you. Thank you, Mike. Thank you, everyone. Good morning. Yeah, so where Olema is, so our lead asset, palazestrant, is a complete estrogen receptor antagonist with a variety of distinguishing characteristics. It has excellent PK, a week-long half-life, oral daily dosing, very high exposure, combines very well with other targeted agents, including CDK4/6 inhibitors, PI3 kinase, everolimus, mTOR, and is in phase III, as Mike said. That first phase III, OPERA-01, is a second, third line trial as a monotherapy versus fulvestrant or exemestane. Interestingly and uniquely, we have shown two ways to differentiate from others in the third class in that one is better activity in the ESR1 mutant subset, which is about 40%-50% of patients post-CDK4/6, post-progression on CDK4/6 plus an AI, based on our phase II is 7.3 months in second, third line plus or minus chemo.
Then the opportunity to capture that wild type population. Others are not doing that because they are SERMs. They are not complete antagonists or they have poor PK. We saw 5.5 months in that setting, again, both uniquely active. We are also starting OPERA-02, which is a first line study. The first line study is obviously advanced positive, HER2 negative breast cancer that has not received treatment in the metastatic setting. The standard of care there is pretty straightforward. Right now, it is ribociclib plus an aromatase inhibitor. That is the control arm. We are testing palazestrant in that. What we have seen, palazestrant with ribociclib is very favorable tolerability, give full doses of both agents. Post-CDK4/6 plus an AI, so already with progression, we saw 13 months, 13.1 months median PFS, which is remarkable. The real standard there is maintained, which was about 5.5.
A really marked difference driven by palazestrant. We have the CDK4/6 inhibitor, which is in phase I, dose escalation. That is going very well. We have a priority there to start combining with the endocrine agents. They really obviously enhance activity as they did with the Pfizer molecule with fulvestrant, but we see that even more so again with palazestrant. That is a high priority.
You know, if you took a step back, you could see that palazestrant, your SERD, has shown great data in phase I, phase II as a monotherapy, great PFS in both ESR1 mutants and wild- type. In addition, you have combination data with ribociclib. That data has been presented. That's important because ribociclib is expected to be and is already standard of care. You're kind of like the only one that is running, well, you are the only one that will be running a phase III first line study with ribociclib. Now, while that's all super exciting and promising, the market seems to be quite confused because other SERD studies have been reading out and they seem to be kind of like saying different mixed messages. VERITAC-2, you know, read out, I wouldn't say that's a big surprise, but that just read out at ASCO.
Then also EMBER-3 from Lilly that read out six months ago at San Antonio. That, you know, seems to be confusing for people because Lilly may or may not even file for that, you know, whole thing. Here we are at ASCO and SERENA-6 read out and everyone's like, huh, I don't understand it. Can you tell us, based on what we've been seeing, what gives you confidence that a front line study is going to work based on what we saw from SERENA-6, which seems to be a seven month PFS? How is that going to translate into a huge PFS? EMBER-3, which was like a 10 month PFS, how is that going to translate? Market seems to be confused. What can you help us out with to tell us that it's wrong?
Yeah, I mean, I think that this is, I'm going to state something that should be relatively obvious, and I don't mean for it to be pejorative, but the way that you predict the outcome of a particular experimental agent in a clinical trial is to look at the previous outcomes for that agent in prior clinical trials.
Seems like a reasonably good start. Look at prior data.
Yeah. If we start there, then everybody says, well, that's obvious. That is not what the markets are doing with this class right now. They want to put them all together. If all the data that was generated with these agents were all the same, that would probably be okay, but it's not, right? In our case, we specifically designed these aspects of palazestrant because we saw weaknesses in the other molecules in the class and we sought to and have successfully addressed them. The VERITAC-2 outcome was completely predictable from the phase II data with vepdegestrant as a monotherapy. It showed no activity in the wild type. It did look like it had some activity in the mutant. What they saw in the mutant was two months in the control arm, going to five-ish months with vepdegestrant.
I believe that will lead to approval in that mutant subset. It doesn't distinguish it a whole lot from elacestrant, but both of those molecules are SERMs. They're agonists, right? They showed no activity in the wild type setting. Again, we had in the EMERALD comparable, right? EMERALD in the mutant, two months to four months; in the wild type, two months to two months, no effect whatsoever. We saw 7.3 in the mutant and 5.5 in the wild type. That is what gives us confidence going forward. I really think it's important for people to look at the data we've generated, the data we've shared, and then use that to handicap the ongoing trials. EMBER-3, yeah, a bit more complicated. That molecule is, we think, significantly underdosed. It doesn't have as non-proportional exposure. The trial design is very confusing.
This is the Lilly compound.
Yeah, yeah, Lilly imlunestrant. And that trial is very confusing, right? The monotherapy was versus, you know, what is an arguable standard of care for fulvestrant, but then they get into a combination, they're comparing their experimental agent. It's hard to see how that creates a regulatory pathway. I think people are rightly confused with what does this mean. I think the important part is it didn't distinguish itself again. And SERENA-6 is a completely different.
Talk about SERENA-6. You know, this, first of all, it was a quote unquote positive study.
Yes.
You have a very nice hazard ratio of 0.44.
That's right.
You know, that tells you that the overall shape of the Kaplan-Meier curves are, and we saw them, impressive. Now, the absolute delta of around seven months progression-free survival by swapping to a SERD upon molecular progression of ESR1 mutation, you'd say, yes, that looks really good. You know, ESR1 mutation is about 1/3 or higher, given, depending on what you think, of a first line study. If 1/3 of the group is going to get that seven month benefit, what is the other 2/3 group going to see in an overall first line population? They're not going to get an ESR1 mutation, and therefore they may not have as much benefit. 1/3 might get seven months benefit. The other 2/3 of the group may not make much of a benefit.
How good could a first line study be? That's what people are saying.
Right. I think it is confusing. I think the whole challenge that we have there, first of all, camizestrant is dose limited. It is toxic. I do think.
They did not use a super high dose.
75.
The dose that they used is a lower dose than they used in the monotherapy studies.
No, it's the same, but they don't have any monotherapy studies that were pivotal. Right? SERENA-2 is their only monotherapy phase II study. It was dose limited. The reason it's dose limited is enhanced toxicity, bradycardia, and visual changes with palbociclib.
They, meaning that if you go back to the design of camizestrant, they went up and up and up, but they were hitting AEs, and therefore the exposure is not as good as you could be because they had AEs.
That's right. That's right. The higher dose, higher exposure, it was not adequately tolerated to move.
By the way, we have a chart, right? The exposure of that drug is much lower at that dose.
We do.
Than what palazestrant is showing. Fair?
That's exactly right.
That's important.
That's exactly right. I think there's a very interesting scientific proof of concept in SERENA-6, right? The idea is, hey, it's more like 40%-50% of the time when patients progress on a CDK4/6 plus an aromatase inhibitor in their first-line setting, they're doing it with a driver mutation. That driver mutation is an activating mutation of ESR1, the gene that encodes the estrogen receptor. These mutations turn the receptor on without any estrogen. They make it a constitutive transcription factor instead of ligand regulated. We know it's that percentage because even if you take VERITAC-2, truly second line, the percentage of patients who entered into that who had an ESR1 activating mutation was 43%. Forty-eight, that number, that's kind of where you land, right?
What SERENA-6 said is, wait a minute, we know these mutations are there before we see a bigger tumor on a radiograph. Let's see if we can find them earlier and switch out the aromatase inhibitor, which we know does not do anything in the context of these mutations, for a molecule that might have some activity in them and see if that suppresses the tumor growth and progression. That is what they did. The answer is yes, it does somewhat. The seven months, the 0.44, all the things that you rightly quoted. The challenge is that people are equating that to what happens if you start with this, right? In which case the ESR1 mutation may not be there when you start therapy, right? This is what OPERA-02 as well, SERENA-4 coming later for AstraZeneca, Persevera for giredestrant with palbociclib.
They're saying, wait, we're going to start with this, right? The mutation isn't detectable very often in first line. It's less, probably 5% or less, right? But you know, a lot of those patients are pre-mutation. They're going to get it. You put the better drug in and you suppress it from the very beginning. The way that cancer therapy works is you give your best agent at the very beginning and you get more benefit from it. SEREANA-6 isn't doing that. You're starting out with what is.
It's like 1.5 line.
It's like 1.5 .
By the way, more than 60% of the patients had been on their therapy for more than six or 12 months, as I recall.
Yeah, actually over half were more than 18%.
I think more than 50% of them were tested positive for ESR1 as soon as they got the first scan.
Yes.
That was interesting.
Yes, but the point is that these patients weren't followed from the start of their CDK4/6 plus AI. If you look at the median time on CDK4/6 plus AI for those patients who were positive at their first test, it's 21 months. The median progression-free survival for these agents is 24 or 25.
They're already well in there.
Right there.
By the way, the seven month PFS, right? That was the difference. They progressed. I can't remember what was it, was it nine? I can't remember, nine, nine months in the control arm. Yeah, they were towards the tail end of their therapy is the point. You want to give the drug 21 months earlier.
That's exactly right.
You know, before all of these things are going, which includes other mutations, other escape mechanisms that could be developing.
That's exactly right. That's the first thing. The second thing is, as I mentioned before, having better activity in the wild type setting, right? Which, as you point out, is the majority, even at the time of progression.
How do you feel about that pool of patients?
We have shown activity in the wild type. You want to be able to contribute to better benefit for the first line patients through both mechanisms. We are positioned to do so. That shows up right later. The patients who we got 13.1 months, they are mostly wild type post progression, right?
How much was the PFS?
13.1 months.
13.1 months.
For our phase II data set, we'll update it again later this year. We are post progression, right? It is not a test, it is a scan. Your tumor got bigger on your CDK4/6 plus AI. We then say, okay, take Ribo, which might be a switch, might not, plus palazestrant and the median PFS is 13.3.
You're in 13 months in second line with Ribo plus palazestrant.
Right.
That was, okay. What about the two studies coming up? While you are executing, in the next six months, a company named Roche is going to put out phase III first line breast cancer data called Persevera. This is a very big study.
Thousand.
People's expectations are actually quite low, but we do want to see it work. I would like to see it work.
Love to see it work.
I'd like to see it. What's going to happen? Because people just say, see Mike, there's a first line study, it didn't work. Is that bad for Olema? Or what are the things that could come out? What are the scenarios and why could it be risky?
I mean.
It could be risky for many reasons.
Yeah, it can be risky for a lot of reasons.
For that drug, giredestrant.
Giredestrant has much better exposure than camizestrant, even at the 30 mg dose, which is a little lower than where they were originally headed, which was 100 mg.
Just to be clear, you think it has a higher probability of working in Persevera than SERENA-4? Is that where you would think in your science?
I do actually. I mean, if you look at the exposure, it's better. Giredestrant is a very potent SERD. I would have liked them to continue at 100 mg. That would have been a really impressive exposure, actually higher than ours. I do not think 30 mg is bad. They did in Accelerate and monotherapy, they showed what looked like a nice level of activity. This is again, post CDK4/6 progression in the ESR1 mutant subset. Certainly, it was not powered and designed to be pivotal or registrational. It did not get registered. I think that their proof that they are getting an exposure that is active was there. Now they are going and they are testing that paradigm that we just discussed. It is palbociclib, not ribociclib. That is an artifact of time. Ibrance was the standard of care when they started that trial.
They are now doing it from the very beginning, as I mentioned, and trying to suppress both the wild type and the arising of these ESR1 activating mutations. I think it has a very reasonable probability.
What do you think the probability is that that study works?
I don't know. 60%-70%.
60%-70%. Okay.
Yeah.
Astra study a little bit lower.
I think it is lower. Their exposure isn't as good. I don't think that their activity at the 75 mg dose was as good. I don't think it's zero. Everybody talks about the seven months. Hey, if you start at the very beginning, which they do in SERENA-4, which is their pivotal trial, you may see more activity than you saw in SERENA-6. We just don't know. I mean, and I think our probability of success is higher. We get greater activity post CDK4/6.
The reason I ask is because, look, in the next six to 12 months, we are going to get two major phase III readouts for the breast cancer landscape. These are going to be big presentations, I'm sure. Roche could be at San Antonio and SERENA-4 could be at the next year ASCO associated in Chicago for that one. They're both coming. These could be positive studies that say SERDs work in first line. The market seems to be very bearish. We talked about the risk for it is because Roche's exposure is lower and they dose down to 30 mg, although it's decent exposure.
It's decent exposure.
AstraZeneca has their phase III in the first half of 2026 for those that are keeping track. You think it's a little bit lower probability, mostly because of exposure too?
I think that's it. I think it's the toxicity limiting the dose.
You have significantly higher exposure of your drug. You can see the Jefferies exposure chart, which got some of that data from you guys and others, but also that you have just better data that you should.
That's right.
That comes from your OPERA studies, which you presented showing much better PFS in ESR1 mutants and wild type in monotherapy and then in combination. You've shown that all.
Yep. We will update the combination again later this year. I do think you make the point, right? I said you should use the data from the molecule to predict the future performance, but people do like to lump these things together. If one of these comes out positive, as you were saying, Mike, just to reiterate, if one of these, Persevera or SERENA-4 or both come out positive, people are going to say this whole thing works. We would love to see that happen. It just makes our lives easier.
Right. Right. Going back to you, where are you with your, obviously, whatever the data shows, we're going to see where the cards may fall. We'll see where the chips may fall. Let's take a look at what happens. It doesn't matter because you're going to completely run your studies. We're going to see these out.
That's right.
It's not like we're stopping. If they're positive or negative, we'll see what happens. You need to finish your monotherapy phase III study. Let's get that. That is an equivalent.
We don't next year.
You're going to VERITAC-2, which is the Arvinas one, which obviously, well, I would say there were no major surprises in that study.
No, there weren't any surprises.
What do you expect? Where are you with your study? What do you expect is going to happen? Because that data is next year yourself. Your own phase III data.
Right. We had a dose selection part in our study, a project optimist thing, that's done. We have 90 mg in our monotherapy dose. It's also the exact same dose we use in combination with full dose ribociclib in OPERA-02. That study is enrolling. We anticipate it's about 500 patients in total. About 120 of that 500 have already enrolled. We anticipate a top line PFS readout next year. That's OPERA-01. That's the second, third line monotherapy study, as I mentioned.
How does that work? You're enrolling now that you've hit 90.
Yeah.
How long does it take to enroll that study?
Yeah, we'll see. We'll update later in the year on that. We were enrolling very well when we had to stop enrollment for the dose selection. We are hopeful we can get it going very quickly. We have all the sites open and activated. Later in the year, we'll be able to update based on actual enrollment data. We are anticipating that we will have the data readout next year. Where in the year is something we can refine as we continue?
PFS of the two arms you can kind of handicap from the other studies. Basically, Fulvestrant is a few months.
Yep, two to three.
Two to three.
Yep.
We just saw that from VERITAC-2.
Yep. Yep. It was exactly predictable. Yep.
Your drug should add, you know, hopefully more than three to four months delta on ESR. We'll see what kind of benefit in wild type. Do you think you're actually going to see something more than zero? Because Arvinas didn't show anything. They showed zero in that. Actually, it was slight hazard ratio 1.1.
1.1.
We won't give them a 1.1.
Yeah, we'll call it one. We'll call it one.
We'll call it similar. You think that you could have a positive hazard ratio, meaning less than one. Therefore, you could have maybe a month or something on the wild type.
You think more than that.
You know, your control, your drug arm could be four or five months. Again, that should complete later in second half based on the time of the completion.
Yep.
Do you believe then that if that's the case, would you get a differentiated label? Because obviously, Orserdu is approved. It's on the market. It's got an ESR1 label. Pfizer, vepdegestrant, based on what we're hearing from our Pfizer analysts, you know, it's 1/3, 1/3, 1/3, or 50/50 that they're going to push forward and commercialize it. They could be on the market with a, actually, our breast cancer doctor said slightly better hazard ratio and one month better PFS than Orserdu in ESR1s. Maybe Pfizer gets more market share because it's Pfizer. If you have an ESR1 label, would it be differentiated other than the numbers? Could you get wild type in your label?
No. Yeah. I mean, I think that's what we saw, 5.5 months. Obviously, looking back on what happened with elacestrant, and you mentioned what happens there. Let's just think in the ESR1 mutant, right? Elacestrant was two to four, right? So two was the control. Four is what they got, what they got approved on. Yes, a little more in VERITAC-2, two to five. Now, the patient population was a little different too, though, right? Excluded prior chemo, was truly second line. You know, there's other things going on there. Again, in a more EMERALD-like patient population, second, third line plus or minus chemo in the mutant, we saw seven. That I think will be interpreted as meaningfully different. In the wild type, we saw a little over five, five and a half, which is better.
I'm trying to actually go back. I think like if you actually, because you said, just go look at prior data. Prior data generally lines up to phase III. If you go look back at the vepdegestrant data, did their ESR1 mutant and wild type data kind of fall right in line with VERITAC-2?
Yes, they did, actually. Yes. Now, they didn't present them as Kaplan-Meier curves, but you can put Kaplan-Meier curves together because they did put all the information in the form of a Schwimmer plot.
Right. You could calculate it out and that was pretty much similar.
You can go and have a feel for that.
You know, while phase IIIs do not always replicate phase IIs, Sean, you feel confident that you will have good PFS that's closer to your PFS numbers you've shown, which are pretty good.
Right. Exactly.
Okay. We'll get that. That's a big result. Where are you with the Novartis one? You got to, now that you did the project optimist, Novartis is supplying ribociclib.
Right. Basically, that's correct.
How long does it take to complete the enrollment of that study?
We think it's going to enroll fairly quickly. Now, it depends, if you go look at Persevera, if you go look at, it was a little bigger, SERENA-4. Those were kind of 18-month timelines, you know, some a little longer. We are hopeful we can do it faster. We don't have as much competition as they did, right? There was a study called AMIRA-5, which was contemporaneous at that time.
I'm not actually sure what major phase III studies are enrolling in first line right now.
Yeah, there's not a whole lot.
Not a whole lot.
There's not a whole lot.
Pfizer just stopped theirs with.
Yes. They're not, yes, they're not proceeding. Yeah. It is a big unmet need with a bit of a paucity.
All right. Now, also in the next 12 months, that's my estimate, we could have SERENA-6 data.
Oh, we will.
If I'd like to shift in the next last two minutes.
Yes.
One of the other major important developments at ASCO was at the, you know, we have camizestrant monotherapy, Pfizer drug showing that. Some monotherapy in combination with that. It's definitely showing strong activity.
It definitely is.
Of like 38% response rates in a small molecule pill.
That's right.
How does your Cat 6 look like? Is it better? Are you dosing? When will we get data on your Cat 6?
Yeah, we're in single agent dose escalation in phase I right now. Yep. There is an outside possibility we could present some of that before the end of the year, but definitely next year. We have a very high.
Now, you could present data later this year at San Antonio?
It's possible. Depends upon how, you know, single agent dose escalation. Ours is going as quickly as you can. It depends upon how many dose levels you have to do.
Okay.
Right?
People would just say if you do, it must be great. If you don't, it must not be great. That's what people.
No, that does not have anything to do with it in phase I. It has to do with how many dose levels you need to give one. No, you are dosing to toxicity. When do you see that? The other is, of course, we have, like everybody, exposure targets. How much do you want to engage the target? I agree with you. The Pfizer data is very encouraging. It is definitely proof of concept. It definitely says that while there is some single agent activity, adding the endocrine agent enhances it, right? That was fulvestrant in that case. What we have seen with our molecule preclinically is that sure, fulvestrant enhances 3136 activity, but palazestrant does it much more.
Can I? When you look at the Pfizer data, are you implying that fulvestrant has synergistic or just one plus one equals two? Fulvestrant has like 5%, some 10% response rates of the 38%. Are you saying there's synergy or no? Because in monotherapy.
It's definitely more than additive.
It's more than additive.
It's definitely more than additive.
For monotherapy data, we should not be expecting 38%.
No, I think Pfizer definitely validates the target, right? It is very clear, and this is what they are doing. They know what they are doing. It is very clear that the endocrine agent enhances significantly, right? It is about a four-fold difference.
Right.
It's a lot. Those are all post-CDK4/6 patients. 38%, that's quite a response rate.
Right, right, right. At their higher doses with more five, so when you put your dose escalation up, 10%-20% at the initial, at the lower doses is reasonable.
They didn't see 20%.
They didn't see 20%.
We have to see what our exposures are. The point of this is the priority is to get it combined with endocrine agents. We are going to do fulvestrant, but we're also going to do palazestrant. We think that's a real distinguisher.
Thank you very much, Sean. Appreciate it. We are continuing to track all of this. It's exciting times.