Thank you, everyone. Welcome back to the afternoon sessions. Michael Yee at Jefferies, Senior Biotechnology Analyst, and very pleased to have up on the stage with me members of the management team of Olema Pharmaceuticals. Importantly, while there's been a lot of controversy around the SERD class, Olema has been executing and reporting data, and we'll get to it in a second because you have an important data set coming up at San Antonio Breast Cancer Symposium. I would like to offer the opportunity for Sean to talk about his enthusiasm for his drug, palazestrant, because I'll repeat again, the market seems to be, I'd say, confused or maybe bearish on the class, and you guys remain quite bullish. Please tell us why you guys are bullish on your product as monotherapy and as combo, and what is the opportunity for an oral SERD?
Great. Thank you. Thank you, Mike. Thanks for having us here. As Mike said, our lead asset, palazestrant, is an oral SERD. Perhaps more importantly, it's a complete estrogen receptor antagonist, right? So it not only degrades the receptor, but that very significant amount of remaining intact receptor is bound by palazestrant and locked into a transcriptionally inactive conformation, meaning that it cannot activate the growth and proliferation program that drives the inappropriate proliferation of positive, HER2-negative breast cancer cells. Our monotherapy data was presented about a year ago. We really think very compellingly demonstrates the proof of concept and the potential, right, in the ESR1 mutant subset where the receptor is turned on by the mutation.
We found in a later line setting over seven months of median progression-free survival, even in the wild type, where ORSERDU has demonstrated proof of concept, though it is not a complete antagonist. I'm sorry, in the mutant is where it did proof of concept in the wild type, it didn't have activity, and that's because it's not a complete antagonist. Palazestrant showed over five months median PFS, where four months is the ORSERDU bar set in the mutant setting. So what we are presenting at San Antonio in about three weeks' time is the first line opportunity. So the monotherapy data enabled the ongoing OPERA-01 phase III trial, which is proceeding nicely according to plan, data readout in 2026. That's the post-CDK4/6 setting monotherapy versus fulvestrant or exemestane.
In the first line setting is an extraordinary opportunity, which is to replace the AI with a better endocrine agent in the context of the CDK4/6 inhibitor of choice, which over the course of the past year has emerged to be ribociclib, Kisqali, because of its survival benefit that it demonstrated. So we're going to present a unique data set at San Antonio, more than 50 patients' worth of safety and efficacy of full dose Kisqali with full dose palazestrant. We presented the safety data ESMO Breast in May. It was very favorable. It looks essentially like ribociclib plus letrozole, and we'll expand on that. Don't expect much change, but the efficacy was early then. So we have six months more of follow-up that we will be able to present at San Antonio to show that potential to beat ribociclib-letrozole in the first line setting.
So let me expand upon these two opportunities because this is in the near term. First, in your combination study, in the data you presented at ESMO Breast earlier this year, there was, help me out, like 30 patients, 20?
There's 50 evaluable for safety.
Okay, right.
But really, in terms of the efficacy, we were more in the teens.
And so when you reported that result, very clean safety, very important. And then on efficacy, you looked at CBR, and there was some discussion around how you guys cut your CBR versus others. But yet you looked at CBR numbers around 80%, which is quite strong, and people were like picking at that. What are our expectations when we go into San Antonio? Because people are going to be looking at efficacy. Some people say, "Oh my gosh, have you not looked at Arvinas's compound because Arvinas and Pfizer shows like 11 months PFS, yada, yada, yada." And you guys are going to show something. You're going to be like, "Oh my God, Olema doesn't have any PFS. They don't have any Kaplan-Meiers. They had 80% CBR." Can you set our expectations on what we're going to see?
Yeah. So there will be CBR again. The CBR methodology we use, one of the, and this is legitimate. Investors have challenges with CBR because there isn't an established methodology, and sponsors aren't always clear about how they're measuring it. We base it on RECIST criteria because what you're doing with that six-month milestone, that landmark analysis is you're trying to predict where is PFS going to go because PFS is the approvable endpoint, right? That's where the regulators go. That's really where the treating physicians go when they're looking at this. So we had the same thing with our monotherapy, and then we presented the mature PFS, and they were almost the same, and everyone said, "Wow, this looks good." And we did the same methodology.
Now we're going to be in a position where we can show a different kind of methodology, which is six-month PFS, and that's done by RECIST criteria, which are very well defined. We'll, of course, show CBR again so that you can look, but then the data set goes from teens to, you know, dozens, the 50 range. We'll also be able to give people some better idea of where things are looking in terms of the overall population and the efficacy that we're seeing in terms of time without progression or death, which is what a PFS curve would have. The other thing we'll do is we have an interesting population. It's mixed. We have a quarter of our patients are actually treatment naive.
CDK naive?
CDK4/6 naive in the first line. So first line in the advanced or metastatic. The other three quarters have had one or two prior CDK4/6s. So we'll be able to take that CDK4/6 previously treated, which really enables a comparison across other agents.
Sure.
We'll be able to show that as well. Of course, there's ESR1 mutant and wild type. You'll be able to see and look at, and I think it's going to be important for people to look at the wild type because there's also a thesis that this isn't going to work in the wild type setting. That is incorrect. That's based on the.
We'll get to that in a second because obviously Lilly has some data as well as Arvinas.
Yes.
So going back to this important update at San Antonio, safety tolerability could be dozens and dozens of patients, could be around 50. And what should people expect a potential PFS number to try and compare to Pfizer? No, because that's not the right way to look at it, or you're only going to look at people past six months. Can you just remind us what you're looking at?
The trial, a completed enrollment in the end of March. Okay? Obviously we're presenting in December. You kind of go two and a half, three months before you do a data check. You don't want the PFS curve to be mature at this point in time, okay, because you want people to be remaining on therapy. What can be mature are things like six-month PFS because you get that minimum of six months follow-up on everyone, and that allows.
This is PFS on all the patients who've crossed over six months of therapy.
That's correct.
Okay.
That is accurate.
How does that account for people who have not made it out or have dropped out or were fast progressors? That's not relevant? I don't know.
No, the fast progressors will be in that number, right, because they've progressed.
Okay.
Right? They're gone. The people who've not made it past that number, it's by RECIST criteria. You censor them because you can't assess further out. So you see this when you see Kaplan-Meier curve.
They haven't gone to the first. Did they get to the first scan?
Everybody. If you've been out six months, the scans are everywhere.
No, no, no. To be in the denominator, to be eligible.
Yeah.
You've been on drug and you've made it past six months.
We'll give all of these.
I'm sure there's a lot of great patients there.
We'll give you all of these criteria. You're going to find that it's very standard. It's resistant. It's a larger data set. Importantly, it's at doses that you can use in phase III, full dose ribociclib, full dose palazestrant at 120. And so you had mentioned the Arvinas data set. People look at that as a benchmark, and we're okay with that. The problem is it'll never be repeated because there's 40% grade four neutropenia because of the PALBO exposure increase. We've shown this before. We don't have a drug-drug interaction with PALBO or RIBO. We don't have an enhancement of toxicity. So we're able to give these full dose both agents in combination.
All right. Looking forward to that. In addition, at San Antonio, there will be a presentation of a large phase II/III data set of another SERD, SERENA plus CDK4/6, and this is the largest combination study that I'm aware of that's going to report out. Obviously, Roche and others are in it, but those are phase III and still going on, and this is sort of a mixed first- and second-line population, but important to show what could a SERD CDK4/6 show versus fulvestrant and also versus monotherapy SERD. What do you expect us to learn from that, and how important is that as a read-through to you?
Yeah. So this is the number three study that Mike had mentioned before from Lilly. The trial is 800 patients in total, although there are a lot of subsets. So it's going to be interesting to see how they'll present that. A significant number of the patients are not previously treated, as you said.
I heard up to 40%.
Yeah, that's what we've heard as well. Now, those patients will not be considered by the FDA for a second, third line label. We know that, that the FDA says you have to have progressed on a CDK4/6 plus endocrine therapy in order to be second, third line. So the important part is the 60. It's the post-CDK4/6, and then you're going to have a control arm of existing fulvestrant, we think predominantly endocrine therapy as a monotherapy, and then sequentially.
Yeah, they can't get a first line label because the control arm is not like a relevant control arm.
That's exactly right. The relevant control arm would be a CDK4/6 plus an AI.
Since it didn't directly compare against that, that's not a relevant regulatory bar for first line. So in the 60% second line, but also in the overall intent to treat, first start with that. I would like to say in the overall intent to treat, you expect strong results of the combo and the mono versus the fulvestrant.
Yeah, certainly in the ESR1 mutant population for the mono, we expect our result to be comparable to our SERD, maybe better.
Okay.
We don't know. Better would be great. We like data that validates this mechanism and gives people more confidence. Don't know about the wild type.
Right.
And then they did their abemaciclib imlunestrant combination as well.
Okay, tell us about that.
And so we'll see what that looks like. We would anticipate, as we anticipate with our own RIBO combo data, that you get some additional activity by adding in the CDK4/6, even in those individuals who have seen it before. So we'll have to see if that brings in the wild type population then as well. Now, the one thing we know about this combination that will be seen and what we'll look for it, whether it's repeated, they presented the phase II data from the abemaciclib exemestane combination last year at San Antonio, and there was a predominant toxicity. 95% of the patients experienced diarrhea. 12% of them were grade 3 or greater. So that's quite a bit of toxicity and a quality of life impact. So we'll see whether or not that carries through to this population as well.
So, if the combination arm of a CDK4/6 plus their SERD shows that there is added benefit over monotherapy SERD, including if you had failed a prior CDK4/6, which is a standard of care, then that would suggest that there is an opportunity for SERDs to be combined with CDK4/6 in second line, and that would increase the market opportunity from just where ORSERDU is today, which is pretty narrow because it's only in ESR1 mutants. And so we could go from whatever a billion or whatever number you want to pick to many billions because of second line therapy. And another thing that's relevant about this is if you had failed a CDK4/6, it's probably going to be nearly all failed PALBO, which is kind of a relevant thing initially because there's a lot of people who have failed PALBO. And so how does that read through that what?
That you and RIBO could be a second line situation too or what? What's the read-through?
That's absolutely correct. So recall that in that second line setting right now, the existing bar is a trial called MAINTAIN, which is a randomized phase II trial in the post-CDK4/6 setting because of the timing, mostly PALBO, as you said, CDK4/6 plus AI. And that was fulvestrant or exemestane, mostly fulvestrant versus RIBO plus fulvestrant or exemestane. And their median was 5.4 months, about 43% six-month PFS. And that was versus, you know, not quite three months as the monotherapy. So if you could add on to that, that would be important. And then, you know, the interesting thing is for us with our ongoing OPERA-01 trial, if you get approved in the second, third line setting with the endocrine monotherapy, physicians can then, if they choose, prescribe it with a CDK4/6.
What they need to do that is they need to have data that indicates to them that they can do that safely. You don't need a full phase III trial. And so there is then this opportunity in patients in whom you'd like to use a monotherapy and not have the CDK4/6 to do that, or if you'd like to add in a CDK4/6, do that.
All right. So we expect that there will be positive results out of EMBER-3 in the combination. If there's added benefits of the combination in a real world situation, which is post-CDK4/6, then that would suggest that those two agents should be combined and could be combined in a second line label. Presumably, they may and could try and file for that because they want to get sales of abemaciclib and their SERD up, and they want that to be a new second line regimen. Would you agree with that? They want that.
Yeah, I think they would, and I think it's a very large market. It's a large unmet need, and obviously, these patients, what you want to do is recycle or cycle through different targeted therapies and put off chemotherapy as long as you possibly can, so more alternatives to do that is of value.
Yes. We hosted many breast cancer doc calls. Look, in HER2 is great, but the idea to have an oral therapy certainly has taken place. ORSERDU does have hundreds of millions of dollars of sales despite a narrow label. Before people go to ADCs, they would like to try these other oral agents. I'm sure Lilly would push that thesis as well.
Yeah, I think they absolutely would and should the data support it, obviously.
Okay, so then tell me about this Arvinas data set. Is there anything to read out of that? Because another phase III readout from a competitor is coming. My question to you, without directly commenting too much on them, is, you know, they may also file for approval.
Yeah.
Okay, so they're going to be, they could be on the market, and also they may, through Pfizer, announce that they're going to go forward with the CDK4 combination, and they're also pushing forward, and they think that that's going to be a more relevant standard of care five years from now.
Yeah, so there are two separate things in there.
That's what they're saying.
One is with regard to VERITAC -2. This is a trial that they are now guiding will read out in first quarter.
Early, yeah.
Yeah, first quarter.
First quarter.
Just 2025.
2025.
Yeah. And that's a monotherapy post-CDK4/6 second line trial. Based on what we've seen for the monotherapy, we think it could look like ORSERDU again. Would it have a better point estimate? The trials are different. They don't include the third line. So we'll see. But we don't think they'll get wild type. They really haven't shown activity there. So it's another validation. It's another entry, probably again with this narrow label. So then how do you get to the first line, which is where people want to be? What you want to do is have that first line therapy go as long as possible, right? They can't do it with PALBO. At least they can't do it at the full dose, certainly. And they haven't announced moving forward. In addition to that, people don't want to use PALBO.
They want to use RIBO because of this one-year survival benefit that's been demonstrated with Kisqali and an AI. So, you know, can you beat that with a CDK4? Completely unclear. We haven't seen any combo data from them. We haven't seen any data from CDK4 that says it's going to be more efficacious.
So the idea that their CDK4 is going to be clinically meaningfully better than ribociclib is a stretch.
It is a stretch.
So don't worry. That's their only angle because they don't have a next generation CDK4/6. There is, let's try and do CDK4. But who's to say that's going to be so much better than ribociclib is your point?
Yeah, we just haven't seen data to address it. Now, on the other hand, we are uniquely positioned next year to start a trial with ribociclib, the CDK4/6 of reference, palazestrant, which we believe has demonstrated, and you'll see the update in December, you can make your own judgment, the best endocrine therapy profile. The abemaciclib imlunestrant combination is not relevant there. There is no first line trial being run by Lilly with that combination. We don't know why, but maybe the toxicity, maybe the diarrhea. And as you mentioned, with regard to Arvinas, there isn't a trial now. There are PALBO combo trials. So persevERA, we think Roche with giredestrant, palbociclib, we think we'll read out in the first half of the year.
Wow, that's first half of 2025?
That's what they're guiding to. So we'll see.
50/50 chance that that works?
I don't know. We don't have that much.
Higher.
We don't have that much data.
I would love to see it work.
Yes, I would love to see it work. I'm not saying what I'd love to see. I'm saying what we have basis for. And then there's a larger trial with camizestrant, the AZ molecule, and again, palbociclib called SERENA-4. And that we don't have, we think 2026, we don't have a readout really from them on when that will be. But we feel like we're uniquely positioned to be in that first line setting with ribociclib at full doses.
So there's no doubt that over the next few years, all of these studies are pushing forward, and we're going to get some answers, but there's huge opportunity if these studies work. And that's why you're excited about the opportunity for your SERD, Sean, because there's a reasonably high probability that these could work. And we're talking huge blockbuster sales, and the market cap is $600 million or so. So that's the same opportunity. So how are you going to do that? Because running a phase III frontline study, and I'll even gloss over the phase III monotherapy study, because I think pretty much people understand that's plausible and will come. But we want to know how you're going to run a combination, which we just spent 20 minutes talking about. How are you going to do that?
Absolutely. We would have to raise more capital, which is what you're alluding to. It's a 1,000-patient trial. It uses a lot.
Raise capital, that's one way.
Yeah, you have to have access to capital. So you can.
Do you have access to capital?
Not that we've announced yet. But we do have data coming out in three weeks. So that's a helpful aspect, both in terms of initiating and completing FDA interactions, right? So you need the regulators on board. But also in terms of the different potential options and how we'll actually do that. I'll just hand over to Shane. Now, we're going to look at what the possibilities are and what the best one is for us and for.
So one is raising capital.
One is raising capital. Others are non-diluted. There's partnership. There's.
Why doesn't pharma, all of them are here? Like, why don't they look at this and say, "Sean, we see that." Now, in many cases, Lilly's probably not going to be relevant because they're their own thing. Obviously, Pfizer, who's here, would say, "Well, we're tied up." So they're kind of, they've got their game plan. Obviously, Roche has their playbook ready. Many do have their playbook. There's about seven others that don't either have a CDK4/6, but do not have a SERD. So why don't these people see what you're seeing and engage?
You should ask them since they're here. I think that's a really good question. Tell me what you're seeing.
Are they engaging? Yeah, please.
Like what we would say is we're fully funded today in running the OPERA-01 second, third line trial. The front line trial we've articulated costs about $500 million. Half of that is the cost of the Kisqali and half of that is to run the conduct, the trial. That $500 million is incurred over about a five-year period with actually the data, the PFS data coming about midway through that.
Okay. To get your answer right away.
We will not move forward with that front line trial independently. So we will not just go and only raise capital to effect that study. So we will only do it in conjunction with a path forward.
Right. Just to be clear, I don't think it's plausible to raise $500 million. So you could raise capital and continue to push forward. But just to be clear, you would not start the study unless there is a complete visibility to complete the study?
Completing the study is going all the way to a survival endpoint, which is years.
Can you run the study if you have visibility on $250 million, which is the cost to run to get to a PFS endpoint?
And drug somehow coming in. Yeah, I think that's the kind of range you could go, right? That would be in the $500 million range that Shane just mentioned. About half of that is Kisqali. Right? And so if the other half is executional.
Right. So if Novartis provided that, that's an easy one way to solve that. That solves it. If it was a different way, if you had hundreds of millions of dollars in visibility, plus you were able to predict that you'd have revenues from the label from, I guess that's what you were saying from that, you could run a plan that you would be able to get to the PFS endpoint.
Right, and the data is what facilitates, I think, really exploring some of these possibilities more broadly. And then it's what we have access to to execute this that then helps us decide what's the.
And you'd be open to a global partnership. That makes sense.
Yeah, we're open to it. Sure. We're going to look at what the possibilities are. There are certainly, as you mentioned, multiple companies that are going to lose billions of dollars of revenue before the end of this decade. And we're going into a potentially $15+ billion market. So that's attractive.
That makes sense. I agree that a global partnership, certainly at this market cap, would create value because now we have visibility to get huge upside if it works. So that's upside from here, not in my opinion, not downside from these levels. So that would be great. Full strategic situation in terms of M&A is even greater. And I might add there's also KAT6 opportunities, which we don't have time because that can be explored in the one-on-one meetings. But KAT6 is another opportunity because multiple people.
IND before the end of the year.
Yep. IND. And that's a wholly owned asset and moving into clinic next year.
Yeah, it's partnered with Aurigene, small royalty, but it's ours.
Very good. Thank you guys very much. I appreciate the discussion and look forward to San Antonio.