All right. Mic is on. All right. Good morning, everyone. Welcome again to day three of TD Cowen's 45th Annual Healthcare Conference. My name is Tyler Van Buren, Senior Biotech Analyst here at TD Cowen. For our next session, I'm very excited to have a hybrid presentation with Q&A discussion with Olema Oncology. And it's my pleasure to introduce Dr. Sean Bohen, the President and CEO, and Shane Kovacs, the Chief Operating Officer and Chief Financial Officer of Olema. Sean and Shane, it's a privilege to have you both here. I'll hand it over to you, Sean, to start with the presentation.
Great. Thank you, Tyler. Thank you for the opportunity to talk about Olema. This is everyone will see as our forward-looking statements, if you'd like to review that. Olema's mission is to advance the treatment options for people suffering from breast cancer. Our lead program is palazestrant. Palazestrant is a complete estrogen receptor antagonist. Endocrine therapies are the backbone of the treatment of estrogen receptor positive, HER2- negative breast cancer. Palazestrant is our, we believe, and I'll show you some data, best in class endocrine agent, both as a monotherapy and in combination with CDK4/6 inhibitors, in particular ribociclib, Kisqali. We have a second clinical program. Palazestrant's in phase three. It's a monotherapy in second, third line. The first line, phase three, will start later this year. We have another clinical, OP-3136, which is a KAT6 inhibitor.
That molecule entered the clinic end of 2024 and is advancing through phase one right now. KAT6 is a validated target. I will show you some data that shows that not only is it a validated target, but the addition of palazestrant to this target from our preclinical data suggests that this would be an optimal regimen, that palazestrant is the optimal endocrine agent. We have a pipeline behind that in the research stage. One thing I just want to remind everyone of is we are in a strong capital position. We have over $400 million in cash, which enables us to execute on all of these programs. 2024 was a great year for us. We continued the progression of the second, third line trial, which is called OPERA-01. That is the monotherapy trial. I will show you nonclinical data from the KAT6 inhibitor that we presented.
We have been able to advance now into the first line trial, one, because of data that I will show you of the ribociclib palazestrant combo, but also because of the resources we were able to get access to. A pipe of $250 million in capital in November, and then an up to $275 million collaboration for drug supply of Kisqali with Novartis as our partner to enable the execution of the OPERA-02 trial. We presented the palazestrant ribociclib data at SABCS. I'm going to present an update today of that PFS data at SABCS. We had favorable tolerability, but we had not reached a median PFS yet. We had a median follow-up of one year. We did have some confusion amongst investors by not having a median. I'll show you that our median is very favorable, 13.1 months in the prior CDK4/6 treated setting.
I mentioned OP-3136 started. This year, we have important news coming. We definitely have continued OPERA-01 recruitment that will allow us, we believe the top line readout of that will be next year. We'll be able to narrow that as we find out later in the year how our recruitment is for OPERA-01. We'll initiate the OPERA-02 first line trial. We have more preclinical data for the OP-3136 KAT6 program actually outside of breast cancer, and we'll present that later in the year. Just to remind you, these are very large opportunities. The second, third line trial is a $5 billion plus global market opportunity. As I mentioned, that trial's ongoing. That will be our first readout in 2026 with launch potentially in 2027. The first line market is even larger. It's not more patients, but they remain on therapy for quite a long period of time.
$10 billion plus. Reminder that breast cancer is the most common cancer diagnosis in women in the world. ER- positive HER2- negative breast cancer is about 70% of that. This is a very large oncology indication. This is the design of the OPERA-02 study. Again, this is first line advanced or metastatic ER- positive HER2- negative breast cancer. The current standard of care based on the survival data shown with Kisqali is ribociclib plus an AI, usually letrozole. That is our control arm. The experimental arm is to replace that AI with palazestrant, with a CERAN at a very high exposure, with the ability to better suppress the growth and proliferation signal of the estrogen receptor, both in the context of the wild type, but also in the context of the most common resistance mutation, which is ESR1 activating mutations.
The tumors turn back on the estrogen receptor by mutating it. This is the updated PFS data that I mentioned. This is from our phase two experience with going from now a median of 12 months to 15 months of follow-up. On the left is all the patients at our full dose, 120 mg of palazestrant daily. That's orally as a tablet. You can see in that population, we have a median PFS of 13.8 months. Some of these patients in this are first line patients. They haven't seen a CDK4/6 inhibitor. That is the less mature of the data. They came on later in the trial. We focus on the CDK4/6 previously treated because we can compare to other data sets that way. Also, this is the more mature of the data sets. You can see we now have a median.
The median is 13.1 months. I'll show you that in comparison. We have a six-month PFS of 68%. That is mature at this point in time. We are still following these patients. There will be an update later this year. There are 15 of these 40 patients who are still on trial. They get not progressions, but they get censored by virtue of how long they're on. We look forward to updating later in the year. We do think there's a good chance this could even further improve beyond 13 months. We believe this is truly distinguished as best in class data for an endocrine agent. Here are some relevant data sets for comparison. The existing gold standard is probably MAINTAIN. MAINTAIN was a randomized trial of ribociclib after progression on prior CDK4/6 plus an AI. The control arm was just mostly fulvestrant.
Some patients had exemestane. The treatment arm, which did show benefit, was fulvestrant or exemestane plus ribociclib. What you saw there was 41% six-month PFS, 5.3 months median PFS. Better than the endocrine therapy alone, but really did not change the standard of care. What we are seeing is, again, 68% as the six-month and 13.1 months as the median, very significant difference. Some other companies have looked at this combination. Roche did a giredestrant-MORPHEUS combo, again, post-CDK4/6. SERENA-1 had camizestrant plus ribociclib. That is the AstraZeneca molecule. You can see they do better actually than the MAINTAIN ribociclib arm. Palazestrant is doing significantly better on top of what they have shown. One of the things that we have run into is that people are equating the molecules in this third space. They really are not the same.
They aren't the same from the standpoint of mechanism, pharmacology, combinability. As I've shown you, and we'll show you with monotherapy, they aren't the same in terms of data. The best predictor of the future performance of a molecule is its past performance in the clinic. We think that that puts palazestrant in a very favorable space. In addition to being a complete estrogen receptor antagonist, we have a higher exposure than the other molecules do. That's because of favorable tolerability. That's because of a long half-life with oral daily dosing. Most importantly, favorable tolerability in combination with other agents. We've shown palbociclib data that was favorable. We've shown ribociclib data shown here as efficacy, but also safety that is favorable. Everolimus and alpelisib are ongoing. It's very important that you are able to maintain the full doses of both agents to get maximal efficacy.
This is our ongoing phase three trial called OPERA-01. This is now in the second, third line setting post-CDK4/6 inhibitors. It's fairly similar to the EMERALD trial, similar to the EMERALD trial that led to the approval of Orserdu or elacestrant. The difference being, we think we have better activity in the mutant than the SERM elacestrant had, and also evidence of activity in the wild type where elacestrant failed. This trial has a bit of Project O ptimus in it. It has a dose selection that's enrolled. We're in the process of following and processing the data to choose the dose, 90 or 120. The exposure is the same. We really actually don't feel strongly about which dose this is. We will continue the enrollment, and PFS will be the primary endpoint. Fulvestrant or exemestane is the control arm.
I'll show you here our phase two data in the second, third line plus or minus chemo setting. This is the elacestrant EMERALD population. You can see post-CDK4/6 what others have. This is now a mixture of the wild type and mutant population, which is taking everybody here. You can see again, palazestrant at 7.2 months far exceeds what was seen in the overall population, 2.8 months in EMERALD. Also the other relevant monotherapy data sets, we do much better. Again, it's this pharmacology, it's complete estrogen receptor antagonism. As I mentioned, we're planning for the palazestrant commercial launch based on OPERA-01 in 2027. That population, there are about 40,000 patients a year in the U.S., will start working this year. I'm planning that commercial launch with top line readout from the trial in 2026.
We think our probability of success in the mutant is extremely high. We think we have a decent probability of success of truly differentiating by having activity in the wild type. That leads to a U.S. market potential of $3 billion to $5 billion. Again, some of what's going on here is which label do you get? Do you get all comers or do you get only the mutant? That is the summary of palazestrant, our lead asset. I also want to talk a little bit about the KAT6 inhibitor. This is an exciting validated target. Pfizer has a KAT6 inhibitor. There are some differences. Ours is more selective and more potent. They definitely have proof of concept with that molecule. I'll show you some of that. The molecule is highly potent. It's another molecule that's a tablet oral daily dosing.
This will ultimately be given with an endocrine agent, as all targeted therapies are in this setting. I'll show you that palazestrant will be the endocrine agent of choice. We also have data with CDK4/6 inhibitors, ribociclib. I'll show you some of the data we presented in October of 2024. As I mentioned, this phase one trial is currently recruiting. This is the data that we presented in October. I'll try to orient you a little bit. On the left, you have the single agent data. The relevant clinical exposure is the kind of gray in the middle for the Pfizer compound. The orange next to it is the dose range that we're looking at in clinic for OP-3136. You can see that you do get more tumor growth inhibition than you did with the Pfizer compound.
Pfizer compound had about a 10% response rate as a monotherapy. Definitely active. They then showed updated data at SABCS in combination with fulvestrant, and that went to 37%. Obviously, these molecules benefit from the endocrine agent. You can see that here. Both the Pfizer compound 8144 and OP-3136 benefit from that fulvestrant. The purple is the most interesting. This is what happens when you combine either compound with clinically relevant exposures to palazestrant. You can see the strong enhancement of activity, particularly with OP-3136. Our ongoing trial quickly incorporates combining with not only fulvestrant, but with palazestrant to maximize the activity of this combination. Of course, we're uniquely able to do this. No one else can combine with palazestrant, at least until it's approved and on the market. This is the study design.
It's a standard dose escalation, safety, and dose finding as a monotherapy. Interestingly, and I talked a little bit about the data that we'll share later this year outside of breast cancer. ER-positive, HER2- negative breast cancer is in this dose escalation, but so is metastatic castration-resistant prostate cancer and non-small cell lung cancer. Once we have defined that dose, we will go on to combination. We will do fulvestrant, palazestrant, and then sequentially palazestrant plus ribociclib. This is our pipeline. I've mentioned these things to you. The top is our collaboration with Novartis OPERA-02, the first line trial to start later this year. OPERA-01 is ongoing, the second, third line monotherapy. Importantly, our cash runway takes us well past that top line readout of OPERA-01 in 2026, including with the execution of all of this pipeline.
We have our combinations ongoing, as I mentioned, and then the phase one trial of OP-3136. I won't repeat that. This is the summary here. I think everything that's on here I have talked about already. I think, Tyler, now we can go ahead and go to the Q&A.
Sounds great. Sean, thank you very much for the presentation. You're joining me on the phone.
Over here.
Yeah, yeah.
Yep. I want to start at a high level with palazestrant and the SERD/CERAN class that's out there. Just the EMBER- 3 data at San Antonio Breast towards the end of the year. On one hand, it disappointed, which would be great, you would think, for other competitors in the space. I think some people might also be taking that and using it to read through to other agents. Curious to get your reaction to that data and how you think people should perceive it.
Yeah. I mean, I think I commented on this a little bit. I think your summary of the reception is exactly right. I think, one, there was some disappointment. I think there was a lot of confusion because the trial is so poorly designed and so hard to analyze as a result of that. I think one thing that I think is a mistake that people are making is equating all of the molecules in this class. One thing you do not want to do is take the SERMs and the CERANs and put them all together. We are not the only CERAN. The SERMs, like Orserdu, vepdegestrant, those are not complete antagonists. They will have some agonistic activity. They are partial antagonists of the mutant. As happened with elacestrant, we think they will have activity in that mutant setting.
When you go into the other molecules, I think you do run into problems where they don't combine well with CDK4/6 inhibitors, either due to toxicity or standard drug-drug interaction. We know that immunestrin, the Lilly molecules, underdosed. It has nonlinear PK. If they dose higher than what they're dosing, they don't get any higher exposure. They have another pharmacological liability, and we don't have that. I would ask that people look at the data generated from the individual molecules in order to try to handicap where that molecule is going to go and how it will perform in the future. I think we come out pretty well with that.
Great. The updated data, 13.1 months to 13.8 months, that's a stellar result by any metric. Were you surprised to see that small of a difference between those previously treated with CDK4/6 and overall?
I think the problem is that the first line are not mature there. The way that this trial enrolled is kind of interesting. Something I didn't point out in the presentation, in the 40 patients I showed you that are prior CDK4/6, they're all prior CDK4/6 + AI, and they've progressed. About 25% of them had two prior CDK4/6 inhibitors, which is unusual. As we were enrolling this trial, we saw our investigators putting on these patients post-two prior CDK4/6 inhibitors. We asked them to stop doing that. They had two responses. One, fine, we'll limit it to one, but we see activity as a third. The data that we showed at San Antonio indeed shows that there is significant activity. They then moved to one prior CDK4/6 inhibitor. That's the bulk of what you see in those 40.
Now, the other 16 patients came on later in the trial. They now started to switch to first line. They treated palazestrant plus ribociclib as the first line standard of care. What that means is that subset is less mature. I think that will push out.
They're being censored, and in an update, it could go longer.
Okay.
Right.
We will get an update on that later this year.
Later this year.
Okay. As we think about the OPERA-02 trial with ribociclib, I mean, clearly, this is very encouraging data, especially if the front line patient median PFS gets extended. What do you need to achieve in that trial to be successful? Do you, assuming this extends, you just need to replicate it, or what's the bar for success?
Yeah, it depends upon how you look at this. One way we look at this is that if you were, for instance, to say, okay, these patients are starting at the point that the progression occurs, right? If you look at the median PFS of ribociclib plus letrozole, it's about 25 months, right? What we think you need to achieve to be clinically significant, statistically significant, and provable is around five to six months. Get to 30, 31, okay? If we take this group of patients, we're starting at that progression, and we go 13 months longer. Many of those patients were treated previously with ribociclib, by the way. This would even be their second time with ribociclib. Clearly, palazestrant, ribo together are doing something different. We handicap this very positively as we look at going into that OPERA-02 trial.
I will point out that the agreement, the collaboration with Novartis providing the drug and the pipe were signed the week of Thanksgiving. A couple of weeks later, the data presented, not the 13.1 months, we did not have it yet, but the 12-months median follow-up without a median PFS. Very clearly, there were a group of people who responded very positively, including our partner.
Yep, yep, for sure. The OPERA-02 trial, it's about 1,000 patients.
1,000 patients.
How long might that take?
Yeah, it's a good question. We think enrollment will go fairly quickly. Now, remember, the median in the control arm, we think, is about 25 months. If you take the whole thing overall, it's probably three-plus years to the primary readout. It is a bit overpowered for PFS because in that first line setting, regulators want power dedicated to the OS, which reads out much later. It's not the provable endpoint, but it's important. Obviously, in the life cycle of the CDK4/6 inhibitors, that became extremely important, right? Because Ibrance, palbociclib, ran everything. Then the OS started to read out in Kisqali three of three trials, a year of overall survival really shifted the standard of care.
Yeah. I'm going to work my way back to OPERA-01, I promise, and the monotherapy opportunity. In between one and two, there's the potential for combinations in the second line.
Yes.
Some of your competitors are talking about that more lately.
Yes.
Curious to get your thoughts on that.
Yeah. I mean, I think there are a couple of things going on. One, I think you've seen data here that supports that.
Yeah, they're great.
Right? And we know, I will say, we were a little surprised to watch investigators going for a third. We did not predict that. We did not think we needed to write that in. But they were right. There is activity. I think there are two opportunities here. We do not think it is necessary to do a registrational trial in that setting. We think that the safety data is very clear. We think that if investigators or oncologists want to use the combination, getting approval in the second, third line setting will enable mono or combo. You cannot promote on it, but they have the information that they need for it. There is a need for other targeted agents, though. You want to keep chemotherapy away as long as possible. KAT6 fits very prominently there for us.
With, again, that unique opportunity that palazestrant can be the endocrine combo.
That's a great point. Yeah. You have a unique opportunity to do that combo there versus your competitors. OPERA-01, can you just talk? You reiterated data next year. Can you talk about where you are at in the trial in terms of enrollment and how that's progressing?
Yeah. You saw the part one and the part two. This is a Project Optimus gift. 90 and 120 have the same exposure, which we've published on. From our standpoint, it's not a really meaningful dose finding exercise, but we did it because it was required. That is enrolled, and we're in the process of processing the data, and we'll meet with regulators, choose the dose, and then move forward. We'll have to meet with regulators, but because the data I just showed you with ribociclib combo was done at 120, the higher of the two doses, we do have an expansion in 90 to about 50 patients. It's further behind. It's why we're not showing it. It'll be at least as well tolerated, right? We figure the single agent dose is going to be the ribociclib combo dose.
That will then get incorporated into start of OPERA-02.
Okay. As we think about those results, I think anyone who has looked at your data would be shocked if you guys don't hit in the ESR1 mutant population.
I would be, but.
Wild type is really kind of the differentiator here. I mean, obviously, you're going to be comparing your data against the data sets that have been produced by others.
Yeah.
No one's hit in wild type yet. We'll see what happens here in the near term with the VERITAC- 2 trial. Why might PALA be more effective in wild type versus the others?
Right. Really, the only time I think this was tested was probably EMERALD so far. VERITAC-2 will test it, right? Between veptigestrant and elacestrant or Orserdu, those are both SERMs. So they have estrogenic activity in the setting of the wild type. They turn it on. And veptigestrant is based on lasofoxifene. Lasofoxifene is approved in Europe as an estrogen. Those molecules, though, are also partial antagonists in the mutant setting. I think that's why EMERALD was successful in the mutant. I would predict VERITAC-2 will be successful in the mutant as well, just looking at their phase two data. They are partial agonists in the wild type. There was no activity of Orserdu, right? It was two months, exactly like the control arm in the wild type. I agree that the probability of success is higher for us in the mutant.
We've definitely seen something in the wild type. The question is going to be, is that going to be strong enough to basically get to the four months to enable that label? We know from the regulators that they're going to analyze the mutant, and they're going to analyze the wild type separately. We designed our trial that way because it's going to happen regardless. This business of assessing wild type on its own is what's going to happen.
Okay.
One other thing, Tyler. The majority of the data that Sean presented on the combo is actually wild type patients, second line wild type, not mutant.
That's right.
That's a good point.
That's right.
One more palazestrant question before we get to KAT6 because we need to get to it. But the Orserdu launch, kind of establishing the monotherapy second line, third line market early on, any brief observations there? Obviously, more agents will expand it, but that's only the mutant wild type could.
Right.
How do you think about wild type expanding that as well? What do you think the overall market opportunity is?
Yeah. We put globally that we think it's $5+ billion . We kind of took that by saying, how many patients do you have there? That was all of them, right? If you take a subset of that, if you're the mutant only, and then also based on our data, how long do you think they'll stay on the drug? That was the opportunity. I think getting the all-comers is a really big differentiator, right? You don't have to do the test. The test is a blood test, okay? I'm not saying it's that arduous. If you think about what happens in the clinic, you bring the patient in, you say, "Hey, there's this injection, there's this pill.
I'd rather give you the pill, but you got to take the test. 50% to 60% of the patients, you bring the patient back a week or two later and say, "Oh, guess what? You don't get that pill. You don't qualify for it." Others get it. Doctors and patients would much rather just say, "Okay, we're going to switch it to this other pill, and this is it, and we're just going to give it to you now." Might still do the test because they may be curious what's going on. Just don't have to wait. I think that extremely expands the market, more than doubles it. That's obvious. I do think there's another differentiation, though, which is if we're at 7.3 months, which is what we saw in the mutant versus four, which is what our Orserdu saw, I think that's a potentially meaningful differentiator.
We'll have to see how it plays out, right? That's big extrapolation, and we're doing the trial. I do think there are two ways to differentiate there.
Okay. That's helpful. OP-3136, the KAT6 inhibitor. I was just looking at the waterfall plot you had up on the slide, and there's a lot of data there, but you go to the right, and it's pretty striking, right? Everything's dropping with the palazestrant OP-3136 combination. When could we get a data update from that study?
Yeah.
How do you think about safety potentially versus Pfizer's program?
Right. There is the potential late this year that we could have some monotherapy. I think next year is for sure, right? We'll be able to update on monotherapy phase one data. Obviously, once we get that, we'll very quickly start those combination arms that I told you about. Thinking about the, and again, I agree, if we are able to recapitulate, and by the way, the palazestrant data in animals has recapitulated in people very nicely. If we are able to recapitulate the palazestrant combo, that is a very unique differentiation opportunity. If we think about what Pfizer's program saw, they saw two main toxicities, dysgeusia, taste alteration. This was not a DLT, but it definitely happened. We do not know whether that is on target or off target. Animal models really are not very useful there. That is a clinical question for us. We will just have to see.
The other was some cytopenias. Again, they didn't have a DLT, but there were some cytopenias. I think the question there becomes not so much a question of, can that be tolerated? It was. Could you add in ribo? And would that be tolerated? I think that's going to be a clinical question. Animals, it was fine, but that doesn't necessarily read through. That's what we'll be watching for. We are hopeful that because we hit cat six and cat seven as they do, but avoid cat five and eight, which they're going to hit at their dosing, that maybe we do have a tolerability difference. It's going to be a clinical question.
Okay. That's very helpful. We're over time.
Okay.
I want to round out the discussion by asking you what you believe is the most underappreciated aspect of the Olema story by investors right now.
Wow. I have to say, I think investors are pretty excited about KAT6. They aren't valuing it in the share price, but I think they are. They're pretty aware. I think this approach of equating the third class is really leading to a massive underappreciation of palazestrant. It outperforms every time we look at it. Every time we do another data cut, it gets better. It further differentiates. This is a massive unmet need in potential market.
Great. Shane, Sean, thank you very much for your time.
Thank you, Tyler.