Excited to have a hybrid presentation and fireside chat with Olema Oncology. It's my pleasure to introduce Dr. Sean P. Bohen, President and CEO of Olema. Sean, it's a privilege to have you here. Thanks for joining me. I'll hand it over to you for the presentation.
Great. Thank you, Tyler, and thanks for the opportunity. Thank you everybody for attending. I'll spend about 10 minutes doing a bit of an overview, then we'll switch to the more Q&A format. Sorry, forward-looking statements and disclaimer, it's also on our website. At Olema, we are focused on transforming the standard of care for patients with ER-positive, HER2-negative breast cancer, we're doing that. Our first asset is palazestrant. It's a complete estrogen receptor antagonist in the metastatic setting. It is in two clinical trials. One, OPERA-01, is in the second/third line setting as a monotherapy. That trial will read out in the fall of this year. That will be our first pivotal trial readout for palazestrant. We also have an ongoing first-line trial, OPERA-02.
That's in combination with ribociclib, or Kisqali. That's a Kisqali plus AI, which is the gold standard of care in the first line setting versus Kisqali plus palazestrant, and that is enrolling. We have a second asset, which is in a phase I/II setting, which is OP-3136. It's a KAT6A/ B, and VII inhibitor. Our first monotherapy for that drug will be presented in Q2 of this year. We are also, I should add that's in not just breast cancer, but also castration-resistant prostate cancer and non-small cell lung cancer. That trial is also enrolling a fulvestrant and palazestrant combination in breast cancer. All right. Oh, I hit the wrong button. Just to give you an idea of what we're talking about, this is the vast majority of breast cancer.
70% of breast cancer is ER+/HER2-. It is divided by line of therapy. The objective of treatment in this disease is to put off chemotherapy as long as possible. There's treatment in the adjuvant setting. First line, that's the first metastatic diagnosis should that occur. That is not curative treatment. There will be subsequent progression. You can get in the second line setting there. Endocrine therapy, which palazestrant is the backbone of therapy. It's used in every line and with every combination until such time as you have to switch to chemotherapy. Collectively, this is a tens of billions of dollars market opportunity. $5 billion in the second/third line, that's our first trial. $10 billion+ in the first line. Adjuvant can be even larger than that.
OP-3136, in breast cancer right now is in the second or third line setting, could be in combination with palazestrant. We're exploring this possibility of other indications. The properties of palazestrant that make it unique are in addition to its complete antagonism, binding and turning off the estrogen receptor completely and stopping that growth and proliferation signal, are the ability to combine very well with other agents. It's an oral daily pill with an eight-day half-life. It has a very high exposure. The interesting thing is it's uniquely able to combine with other targeted agents like CDK4/6 inhibitors, PI3 kinase inhibitors. The KAT6 we're trying now, we're doing the CDK4, atirmociclib with Pfizer at the full doses of both agents. We don't have to dose modify the drugs. I won't go through this.
This is just to show you these are the data that we have generated to show this distinguishing characteristic. The PK in the middle is probably most interesting. The top two lines are the exposure at steady state of palazestrant at 90 and 120 milligrams. What you can see from there are the others in the class, so that you can see that we get much better exposure, particularly if you look at the trough exposure that we get at the steady state. That allows us to bind and completely occupy the receptor, and that keeps the receptor turned off. Again, the OPERA-01 study, as I mentioned, it's our initial opportunity to enter the market. What you'll see is that this population is really divided into two subpopulations. The first is the ESR1 mutant subset.
The most common resistance mutation to a CDK4/6 plus an AI is to actually develop an activating mutation of the ESR1 gene, the gene encoding the estrogen receptor. This turns the estrogen receptor on without estrogen being present. It goes from a ligand-regulated transcription factor to a constitutive transcription factor. What you want to do is bind that receptor, push it into the inactive conformation, and keep that signal off. That's 40% to 50% of patients. There is proof of concept there from other agents. Although our phase II data at 7.3 months showed more progression-free survival, longer delay of progression than others have seen. The open opportunity there is the wild-type setting, the remaining 50% to 60% of patients, because none of the SERD class have worked in that population so far.
We saw 5.5 months median PFS in the second/third-line setting in wild type. This is being tested in the OPERA-01 trial too. Two opportunities there to differentiate. As I mentioned, in aggregate, the whole population is a $5 billion+ market opportunity. This again is the data that I was speaking about that supports this. It's the pink lines really that you wanna look at, where we saw in the second, third-line setting, ± chemotherapy. It's actually more heavily pre-treated patients than we're treating in OPERA-01, 7.3 and 5.5 months in mutant and wild type respectively. This gives you some idea. These are cross-trial comparisons, caveat with that.
What others have seen in this population, showing that we are distinguishing in the amount of activity we have seen in the mutant, but also by virtue of seeing activity in the wild type. We'll try to validate this with OPERA-01. We're beginning the process of building a commercial presence. Our objective is to be a fully integrated company going from research all the way through marketing in the United States. We'll have to seek a collaborator for the rest of the world. We do not have an aspiration to be a global marketing company. We execute our trials globally, but we don't plan to promote and sell globally. This goes on to OPERA-02. This is an ongoing enrolling trial, about 1,000 patients planned.
Again, relatively simple design, Kisqali plus AI versus Kisqali plus palazestrant with the PFS primary endpoint. Again, this is a much larger market opportunity, primarily because the duration of treatment is so much longer for these patients, right? The pivotal trials for Kisqali were 27-28 months median PFS, you know, as opposed to the 2-3 months we expect for the control arm in OPERA-01. Again, that's enrolling now. The soonest it could read out is 2028. Obviously, it'll depend upon the event rate, so it could push beyond that. This is the data we showed in October. These patients are different. They're post CDK4/6 inhibitor, and they're not first-line. They're post-progression. We see something unique here. The overall population had a 12-month median PFS.
When you break it out into the mutant and the wild type, again, you see a really profound treatment effect here, almost 14 months in the mutant and over nine months in the wild type. This wild type activity is better than other combinations have been seen, even in the mutant setting, and nobody's seen over a year in the mutant. We see great promise for this treatment to suppress progression when we start with it right at the time of the initial first-line treatment when all the patients actually are ESR1 wild type. It's really the mutation arising under selective pressure. Again, this shows you comparably what in the post CDK4/6 setting, what others have seen in combination with ribociclib.
Once again, you see that we distinguish a 50%+ increase in PFS. For OP-3136, again, this is like all the KAT6 target has been validated. It's validated by the Pfizer program, which is in phase III right now. That program, however, runs into a situation where it has quite a bit of toxicity, both cytopenias and dysgeusia, which is a taste alteration. We see that by dialing out KAT5 and KAT8, by making our inhibitor more selective, we're hopeful that we'll get a better tolerability profile. You will see that data in Q2 when we present it from the monotherapy dose escalation. You'll also see the PK. You'll see what efficacy we have in those patients.
What we anticipate doing just in the breast cancer setting is going into the second-line setting with yet another targeted agent and doing that in combination with an endocrine agent. Hopefully, palazestrant, where the preclinical data showed that that combination was much superior to the fulvestrant combination. That palazestrant combination is enrolling right now in the clinic. We have patients on treatment, but, you know, we'll continue to do dose escalation. Maybe at the end of the year, we'll have data from those combinations, not in Q2. Again, this is a $5 billion+ opportunity. Could be more than that if we get a significant increase in progression-free survival because duration of treatment is a big component to the size of the market opportunity in this indication.
We anticipate that we could be starting a phase III trial in 2028 for that. That, again, in a second, third-line setting would mature relatively quickly. This is just a snapshot of what we have coming up. I mentioned to you that we will have OP-3136 data in Q2, our first pivotal trial readout in OPERA-01 in the fall of this year. As we get closer and have more events, we can refine that timeline a bit for everyone. That should could lead to launch potentially as soon as next year in the second, third-line setting. As soon as 2028, having potentially the OPERA-02 readout in the first line in combination with ribociclib.
Just to mention, we'll report our annual results soon, but we end the year with about $500 million on the balance sheet. You know, nicely positioned to execute on this through multiple data readouts through that period. With that, I thank you for your attention, and I'll move on to Q&A with you.
Great. Thanks for that presentation, Sean. You showed the clinical data that's been reported, and appears differentiated versus others in the class. Maybe you could start by just highlighting what stands out about palazestrant compared to the rest of the SERD and CERAN class, especially including giredestrant, just the important kind of molecular properties.
Yeah. I mean, I think that there are two ways we really stand out. One is being a CERAN, a complete estrogen receptor antagonist. If you take the molecules that are more SERMs, tamoxifen, obviously vepdegestrant, lasofoxifene, those are partial agonists. They turn the receptor on in some contexts. They have shown some activity in the mutant setting where they partially turn it off, but in the wild type, they don't see anything, and it's probably that molecular property. Giredestrant is a CERAN, molecularly it is a complete antagonist. The challenge giredestrant has is that it could not be combined at their first recommended phase II dose with palbociclib. It was 100 milligrams, and they had the dose reduced to 30. That.
With that dose reduction got about a threefold reduction in exposure. That said, giredestrant is the next highest exposure to us, although still a few fold lower. It is really that extra exposure that we get, the ability to force the occupancy of the receptor, which turns it off completely. That really distinguishes us by being able to give the full dose of both agents. That said, giredestrant specifically has activity at 30 milligrams. We know that from the lidERA trial, right? Where it beat AI in the adjuvant setting, you know, pretty soundly a good clinical result.
Great. Last year at this conference, our first question was about the negative sentiment in the SERD/CERAN class.
Yeah.
Things have changed quite a bit in 12 months.
Yeah.
Maybe you could elaborate on that. Clearly the lidERA data, really led to a significant increase in excitement for the class in recent months. Maybe you could talk a little bit about what you think the lidERA data signifies for the class, and the space, you know, even regardless of the metastatic opportunity.
It's absolutely true. I would say it's about six months that the sentiment has changed. I, you know, I think some of the investor sentiment had to do with when palazestrant first went into humans was in 2020 and there were 10 molecules in the space. As is often the case in oncology and targeted oncology, there are a lot of efforts at getting at a validated target. We learn a lot and some of them aren't very good, and they fall by the wayside. That certainly has happened here. I think that with those falling by the wayside, a lot of investors said, "Oh, this approach doesn't work. You can't beat an AI or fulvestrant." The biology never changed. It's just that the molecules were getting better.
I think that the ability to do that was validated in lidERA. People went back and said, "Wait a minute, you can beat these molecules." There was also a bit of a misunderstanding, which is in the second third line setting, the other molecules, for reasons I described, showed no activity in the ESR1 wild type. People say, "Oh, they only work in mutant, they don't work in wild type." The problem is equating endocrine sensitive ESR1 wild type and endocrine resistant ESR1 wild type. lidERA is endocrine sensitive ESR1 wild type. The other thing that happened is people started to now make that distinction and say, "Okay, they have trouble.
It's harder to work in the endocrine resistant wild type, but there is activity in the ESR1 wild type when you're endocrine sensitive. I think the lidERA data helped people realize that.
Do you think the lidERA data increase the probability of success for Roche's persevERA and OPERA-02? How are you thinking about that readout since it's coming here very soon, I believe potentially later this month or next month, right?
Yeah. They've said late March or early-
Yeah.
April. First of all, going to OPERA-02. The best way to handicap the future performance of a drug or a combination is to look at the past performance of that drug or combination. Our enthusiasm for OPERA-02 comes from our data with ribo plus palazestrant. One year median PFS post-progression on a CDK4/6 plus AI. Actually, 30% of those patients had two prior CDK4/6 inhibitors. That is a really encouraging result. Usually when you go earlier in a line of therapy, you do better than you do treating later after the resistance has developed but also the tumor's grown to a certain size that you can measure it. We really think that the read-through from persevERA is limited because our data looks better.
On the other hand, I think you have to feel that lidERA does increase the probability of success of persevERA because they're both ESR1 wild type endocrine sensitive populations. They're a little different because in the first line setting, many of the patients will have seen endocrine therapy before, though they're not resistant. We don't know what that means. Of course, you're with palbo in one case versus as a monotherapy in the other. I think there has to be an increase. Look, if persevERA is positive, everyone's gonna do what they did with lidERA, which is say, "Oh my God, these things work." My only point is. Our confidence comes from our data. We don't need persevERA for that.
Obviously, we're combining with ribociclib instead of palbociclib, which I think is important as well.
Yeah. You know, I guess, giredestrant is obviously a CERAN like palazestrant. As we think about the persevERA data potentially reading through, are there any key differences between palazestrant and giredestrant, just to elaborate on a bit?
Yeah, I think the exposure is the primary one. That exposure difference is because of tolerability, right?
Yeah.
When palazestrant combined, or I'm sorry, when giredestrant at 100 milligrams combined with palbo, they ran into a bradycardia.
Yep.
... as a tolerability issue. What Roche did is they elected to dose reduce to 30 the other dose they... Threefold dose reduction. I have to say, it did seem to address the question about the bradycardia, but obviously reduced the exposure threefold. One of the things that's interesting about the ESR1 mutations, not only do they turn on the receptor without estrogen present, they also decrease the affinity of the receptor for ligands. They occur in the ligand binding domain of the receptor. If you had an exposure challenge, that thing gets amplified in the context of the mutation. With that being the primary resistance mechanism, I think that exposure becomes extremely important in that context.
Some have pointed to the PARSIFAL trial with fulvestrant to suggest that CDK4/6 dilutes the benefit of a SERD or potentially even a CERAN. What might be wrong about this comparison or read-through, and why do you think the CERAN class might be a little different as well?
Just fulvestrant's a bad drug. It's got a very, very low exposure. I mean, we're multifold. Much of the dose period were tenfold or more better exposed, by the way, than the peak of fulvestrant exposure, not the trough. I think really AIs and fulvestrant are essentially equivalent. You put two drugs that were about the same, and you got about the same result, and that you can't really interpret much from a negative result.
Okay. Moving to OPERA-01, the monotherapy second/third line phase III reading out in the fall. For the, I guess, in the ESR1 mutant population, what do you believe that palazestrant needs to show in order to be differentiated versus what others have reported?
Everyone's shown about a two-month increase in PFS over the standard of care, which is fulvestrant or exemestane. It's mostly been fulvestrant, and that's what we'll get is two to three months median PFS in that setting. They've gone four to five, depending upon. I think if you get two more months, right? If you can get four, it's quite distinguishing. You've doubled it. I think that, you know, based on what we saw, we have an opportunity to even potentially do better than that, but we'll see soon. What it does set though is what the bar is for success in the wild type, which is two months. It's one scan interval. Nobody's been able to show any signal really in that wild type setting.
I think that's a enormous opportunity for us.
I know you talked about the prior palazestrant data being most important as you think about predicting future success. As we think about the wild type population, again, do you think the lidERA data improve the probability of success in the wild type population?
I guess, I think that endocrine sensitive wild type is a different underlying biology than the endocrine resistant. I mean, we've always known that these things can engage the wild type receptor very effectively. We also have raised the concern that the 30-milligram dose of giredestrant is underexposed for their potential. You know that said, in the endocrine sensitive population, the lidERA result is outstanding. It's going to change standard of care. It's going to help a lot of patients. I think that's great. I don't think it reads, I think its read-through to persevERA is interesting. I don't, in acelera, they didn't really see any activity there. It was the same dose, and I think that's probably the endocrine resistant wild type setting.
Understood. Let's move to OPERA-02, the combination. Can you elaborate on how enrollment there is progressing and how long you expect the enrollment of a 1,000 patients to take?
Yeah. We haven't done a forecast at that out yet. Again, we've said the earliest readout could be 2028. It may very well push out. I mean, the standard of care arm does very well, right? It's probably 27, 28 months. We'll get an update on that when persevERA reads out and SERENA-4. Unlike, unlike the OPERA-01 setting, where the timeline of the readout of the trial is very much dependent on enrollment, in the OPERA-02 setting, it's very much dependent on the rate at which events occur. It will take us a while before we can update on when the readout will be.
What improvement on the 27, 28 of the control arm do you think you need to show in OPERA-02 to be successful?
Six months is kind of a slam dunk, right? It's interesting, right? The way the trials are designed, the way you read them out is by hazard ratio. You use the whole shape of the curve. The way clinical significance is determined is much more by the prolongation of the median. Six months, I think, is very clear approval changes use patterns. Doesn't mean if you got, you know, five a lot, you could. A lot of people would say that's meaningful enough, and they would move, but I think six months is a clear win.
You, or Olema presented the palbociclib data at ESMO in the second line, which you elaborated on-
Yes.
...during the presentation. Very impressive. Can you talk about the second line setting combinations? How are you guys thinking about that currently? Obviously, there's no formal plans, but looks like a slam dunk if you decide to start a trial. What are your thoughts there?
Yeah, it's interesting. We are considering it. We certainly. The first thing we do usually is we go to our investigators and we kind of ask them, 'cause obviously they're the ones with the patients making the treatment decisions, and they seem enthusiastic about it. It's an interesting thing to consider. There are two opportunities there. If we're unfortunate, not successful in the ESR1 wild type with OPERA-01, it gives you another shot at that market opportunity. I think the thing we're evaluating also is, for instance, if you go from four to six months, which is a $5 billion market opportunity, if you go to a year, you actually double it. That all of a sudden becomes a $10 billion market opportunity. That is very significant.
It's great for the patients, obviously, but it's also very significant. I think the thing that's strange about it is that the data on CDK4/6, after CDK4/6 to date hasn't been very impressive.
Mm.
This is different. The thing is we know that doctors use it. They cycle CDK4/6s. The question is, how do we fit into that current treatment pattern? That's what we're thinking about.
What about plans for the adjuvant setting following lidERA?
That's a different question, right?
Mm.
I think, the second line setting with ribo is something that we can find the capital to be able to execute. The adjuvant setting would probably have to, in the future, right. lidERA was monotherapy versus monotherapy, AI versus giredestrant. At the time that that trial was started, that was absolutely appropriate. CDK4/6s weren't in the adjuvant setting yet. It's not appropriate now. Now you would probably have to combine with a CDK4/6, and that is a much longer, possibly bigger trial. That would be in the $1 billion+ range. That's not something we're ready to take on right now.
Fair enough. Let's move to OP-3136, the KAT6 inhibitor. What should we expect for the initial data midyear, and then also, if and when we eventually get the combo data, which could come maybe at the end of the year or next year?
Yeah, that's right. The first data's gonna be monotherapy. It's gonna be our dose escalation. I think you'll get a pretty clear idea about the tolerability that we're generating with OP-3136. We'll show the exposures, so you'll see that we're hitting the target well, and then what efficacy we have, we'll show. Again, that'll be not just the breast cancer patients, but what prostate and lung cancer patients we have on the trial. Yeah. I mean, for breast cancer, the combination we think is really all the targeted agents really are enhanced in their activity by the combination with an endocrine agent. If we take the Pfizer KAT6 lead molecule, for example, it's monotherapy wasn't all that impressive.
It had a 9%, I think it was, overall response rate when they combined with fulvestrant, so not even a great endocrine agent. Went to 38. You can see that they really, there's this super additive effect. We're hopeful we can even add on top of that with palazestrant, which is what we saw in the preclinical setting. That's why we have it, we've accelerated it to get it going right now. Hopefully we'll be able to share that soon.
You think there's the potential to have differentiated, safety, versus the Pfizer compound?
That's what we're shooting for. I mean, obviously that's something that's demonstrated in the clinic. Our hope is that by tuning out the KAT5 and KAT8 that Pfizer is hitting at their 5-milligram dose, certainly that perhaps the cytopenias and or dysgeusia are mitigated.
How do you think about the eventual positioning of a KAT6 inhibitor in the breast cancer landscape and the market opportunity?
The way that what's happening with ER positive, HER2-negative breast cancer is, you know, once diagnosed with metastatic disease, the treatment is not curative. You're trying to delay progression as long as you can. You know, in the case of Kisqali in the first line, also prolong survival, which is fantastic. You're also trying to push off chemotherapy as long as you can, both from a tolerability standpoint and also that the outcome then tends not to be very good. You want more targeted therapies, and the targeted therapies obviously require an endocrine agent. KAT6 gives us the opportunity both to use palazestrant and also to have an yet another targeted therapy that physicians can choose to cycle through and push off that chemotherapy as long as possible.
Great. With that, we're up on time, but, to wrap up, Sean, maybe I'll ask you, what do you believe is the most underappreciated aspect of the Olema story by investors right now?
Yeah, I mean, I think going back to what I have said before, it really, I would say handicap our future performance based on our past performance. I think when you, when you look at that aggregate data set, it should give confidence. Obviously, there's more people paying attention because, as you mentioned, lidERA helped people say, "Wait a minute, there's room to improve here." That's definitely the case, but I think if you look at our data set in aggregate, you'll see the potential that we're generating.
Wonderful. Sean, thank you very much.
Thank you.