Great. Thanks very much. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much again for joining TD Cowen's Sixth Annual Oncology Innovation Summit. For our next session, we have a Q&A and discussion with Olema, and it's my pleasure to introduce Dr. Sean Bohen, the President and Chief Executive Officer. Sean, it's a privilege to have you here. Thank you very much for joining me.
Thank you, Tyler, for giving me the opportunity and for the chance to talk about Olema and the progress we're making.
Of course. Before we get started with the questions, for those of you in the audience, feel free to email me questions at tyler.vanburen@tdsecurities.com or cowen.com. Again, that's first dot last. We'll do our best to get it asked before the end of the discussion. Naturally, Sean, we'll start with palazestrant. It's been over a year since you initiated OPERA-01. Maybe you could talk about the stage of trial activation and enrollment that OPERA-01 is currently at, and if we're still on track for data in 2026.
Yeah, great. Yeah. Reminding everyone, OPERA-01 is our trial of palazestrant, which is a complete estrogen receptor antagonist in the treatment of second and third line ER+/ HER2- metastatic breast cancer. That is versus fulvestrant or exemestane. That phase III trial did start enrollment over a year ago. Reminding you, it has a dose ranging part we call part one. In the first part of the trial, we randomized about 120 patients, 40 mg - 120 mg of palazestrant daily, 40 mg- 90 mg daily, and then 40 to the control arms, fulvestrant or exemestane. That data then is used to choose a dose going forward, our sort of final dose of palazestrant, 90 or 120. The enrollment for that portion actually was completed late last year.
We waited some time to collect data and really are getting toward that process of making that dose selection. When that's done and announced, we'll go on to part two. Part two is just a one-to-one randomized, really the same design, but with one palazestrant dose, 90 or 120. In part two, we kind of enroll the remainder of the trial, 390 more patients, which leads to our final PFS endpoint. Yes, we are still on track for top line data in 2026.
Okay, perfect. Will you be able to narrow the timelines later in the year for when we might get data in 2026, potentially?
Yeah, I think so. Sometime in the second half of the year, we will be able to. Obviously, we didn't remain idle during this period of data maturation for the dose selection. We activated more sites and more countries, et cetera, et cetera, to try to position ourselves to accelerate enrollment once the time to start part two came. We are hopeful that later this year, we'll be able to use the actual enrollment and reiterate and/or refine our top line data readout timing.
Okay. You all will be presenting a trial in progress poster at ASCO this upcoming weekend. I think typically investors will kind of tend to overlook trial in progress posters, but curious if there might be any updates there that people should be paying attention to?
Yeah, that poster will be really focused on the part two portion of the trial. I think it simplifies things a little bit, and that may be of interest to investors. You know, I think your point is a good one. The audience for those posters from our standpoint is really investigators, potential investigators to some extent, potential subjects who may be interested or wish to enroll in the trial and/or breast cancer advocacy people who are looking for opportunities for patients to access clinical trials. That's the primary audience. For people who are wanting to learn about Olema and about palazestrant, I think it's useful as well.
Okay. May we get some information on the potential dose you guys might be using in part two?
It'll be a wait and see.
Got it. Okay. We had the EMBER-3 data presented at San Antonio Breast at the end of last year. VERITAC-2 data from the Arvinas-Pfizer trial is going to be presented this weekend at ASCO. Curious how you're thinking about those in terms of the potential to recalibrate pal's potential for success in the eventual OPERA-01 trial.
Yeah, I mean, what we've seen from those trials for VERITAC-2, I should say, as you stated, Tyler, the data itself comes out over the weekend. We'll be very interested in seeing it. The top line that they've shared makes it look a lot like EMERALD, like the ORSERDU pivotal trial in terms of outcome, but we'll get much more detail. Again, with EMBER-3, very confusing trial design. If you focus on the post-CDK4/6 prior treatment monotherapy population, you get what the others so far have looked like, which is there's no activity in the ESR1 wild-type setting. There's modest activity in the ESR1 mutant setting, all kind of two months or less increase in median PFS. This just, I think, to some extent adds more molecules without any real differentiation to that landscape.
As a result, we're the only opportunity left through the OPERA-01 trial to differentiate, I think, in two ways. One is to show a meaningfully better improvement in PFS for the ESR1 mutant population. We saw in our EMERALD comparable population in phase II, 7.3 months, which is quite a bit longer. And then in the ESR1 wild- type, we saw over five months, which again, it is quite distinguishing if we can replicate it, shows activity in the wild-type where others have not seen it. I think to some extent, obviously, it's dependent on the differentiation from the data and the outcome of the OPERA-01 trial, but there are very meaningful opportunities remaining in this landscape.
What would you expect the OPERA-01 control arm to do? Would you expect it to be similar to what we see with VERITAC-2?
VERITAC-2, I don't expect it to be terribly dissimilar. Our OPERA-01 is a little closer to EMERALD. EMERALD had a two-month median PFS in the control arm. What is similar about OPERA-01 is we do allow second and third line patients. Everyone has to have progressed on a prior CDK4/6. That's true of VERITAC-2 as well. That's the relevant population in the second line setting. We, like EMERALD, allow another endocrine therapy prior to going on to the trial. It is second and third line. VERITAC-2 didn't do that. They only allow the one prior CDK4/6 plus an AI. You don't have prior fulvestrant. Their control arm is fulvestrant. Both of us don't allow prior chemo, and we require six months on prior endocrine therapy.
In that respect, we may be a little better than EMERALD, and VERITAC-2 may be a little better on that. I would not think they are going to be all in the two to three months in the control arm. We will see. We will see on the weekend with VERITAC-2.
Okay. That's helpful color. I guess just in terms of OPERA-01 trial success, not just in the overall population, but in wild-type patients, maybe you could review some of the molecular characteristics and differentiation for pala versus vepdeg, imlunestrant, or ORSERDU, especially for those who are maybe less familiar with the Olema story.
Yeah, sure. We believe the key palazestrant molecular characteristic is that it's a CERAN or a complete estrogen receptor antagonist. The class gets called SERDs because it was discovered decades ago that fulvestrant led to a decrease in the steady-state level of the estrogen receptor. It's a decrease, but there's still a lot of intact receptor present, plenty to do the signaling. We don't think degradation is the primary mechanism of action. We think it's an epiphenomenon. Binding that remaining receptor and locking it in an inactive conformation to stop the estrogen and estrogen receptor-mediated growth and proliferation signal is vitally important. That's what palazestrant is designed to do. In the context of the molecules you mentioned, vepdeg and/or ORSEDU are [SERMs]. They are not complete antagonists.
They turn off the AF2 activation domain, which overlaps the ligand-binding domain, but they allow activation of the AF1 domain. They have estrogenic activity. In that respect, it's not terribly surprising. They're partial antagonists in the mutant, but they can be partial agonists in the wild-type. Indeed, they don't show activity in the context of the wild-type. Imlunestrant has a little more complex situation going on. It is molecularly a CERAN. It is a complete antagonist. However, we believe it has inadequate exposure. It doesn't have dose-proportional pharmacokinetics or increase in exposure above its single-agent dose. That is due to its PK properties. It's got a lower exposure than we see with palazestrant. We think inadequate to really maximize that antagonism.
Okay. That's great. Hopefully OPERA-01 will allow you to fully assess the hypothesis of max CERAN or activity. Okay. Let's move to the pala-ribo combo data. At our conference in March, you all updated the data with a very impressive median PFS of 13.8 months in all patients and 13.1 months in the prior CDK4/6 population. Could we see more mature data from that combo data set at a Medical Conference later this year? When might that be? Could we see the median PFS get even longer with 15 patients still ongoing?
Yeah. I mean, I think both of those, yeah, the answer is yes to both of the questions. Medical conference would be the second half of the year, obviously. The conferences that are relevant here tend to be in the fourth quarter, actually. We can't really announce specifically until we get an abstract submitted, accepted, et cetera. That's when we communicate that. There is the opportunity for greater maturity in that data. There are a significant number of patients that were still on treatment, as you mentioned, at the time of the data cut that we presented at the Cowen Conference. There is an opportunity for the PFS to refine. It's probably not going to change a whole lot. Could go up or down a bit, but I think we can get greater maturity.
The other thing, and I don't know if we'll have it later this year, is there are not a significant number of first-line patients that enrolled on that trial. That'll be an interesting patient population to look at. The thing with those patients is that can take a while to mature because they do tend to do well on ribo plus an endocrine therapy. That is something we'll just keep an eye on.
Okay. Other than more mature data from the full data set, are there any other learnings that you guys are looking forward to seeing perhaps with respect to ESR1 wild-type versus mutant patients with the combo? Is that going to be informative or?
I think it's interesting. I think in part because, for instance, if you look at the recent update to the EMBER-3 data post-CDK4/6 with the combination of imlunestrant and abemaciclib, it looked like there was more activity of the combination in the wild-type than the zero activity seen with the monotherapy. We have some evidence of activity, as I mentioned, with our monotherapy. It'll be interesting to see what does the combo do in those two populations. I don't know if that will be mature at the time that we present, but I think it is an interesting question to ask. It's not all that relevant, actually, to the first-line setting, though. Remember, in the first line, ESR1 mutation is very uncommon. It's like single-digit percentage. They're all wild-type because the mutation arises as a response to the selective pressure of CDK4/6 plus an AI.
While suppressing the mutation is a very relevant mechanism of action for increasing PFS in the first-line setting, it's not so clear how that data from second line will read through. Interestingly, some data that we will see at ASCO that I think is certainly of scientific interest is the SERENA-6 data, right, where AZ does a higher sensitivity test for ESR1 mutation in the first-line setting. For those patients who have the mutation but haven't progressed radiographically, they randomized continuing the AI or switching to their molecule, their SERD, camizestrant. They've said top line that that trial is positive. We will get a chance to see that. That could be a scientific proof of concept for suppressing the proliferation of mutant clones as a way of delaying progression.
Okay. Yeah. I wanted to follow up on two of the topics you mentioned. Just on the rationale for SERDs improving efficacy in the front line versus AI when mutation rates are so low. It's because even though these mutations are not showing up on a test, these patients likely still have at least single clones. And obviously, if you treat a patient with these clones earlier as opposed to when it's able to grow out, it's going to be easier. Is that a working hypothesis?
Yeah. That's one of them, right? There are a couple of ways to win in that setting. The first thing is when you think of the second line or the post-CDK4/6 setting, we really do think of these two populations, ESR1 wild-type and ESR1 mutant. I think in the context of the first-line setting, you can think of the patients as a significant subset of them, 40%-50%, are pre-ESR1 mutant, right? When they get that CDK4/6 plus an AI, they're going to have a mutant clone grow, and that will be their mechanism of progression in the CDK4/6 plus AI treatment setting. If you start with a molecule that doesn't allow that to happen, then that set of patients will not have that clone grow. We believe that that will lead to a prolongation of PFS in the overall population.
That's what the OPERA-02 trial will test.
Okay. Since you mentioned SERENA-6 data at ASCO, I guess, obviously, it was positive. If we see the data and they are really, really compelling and you see a meaningful separation in PFS2, does that give you that much more confidence in the front-line trials and OPERA-02 working, or how are you going to interpret that?
I think it does read through probably to actually all of the front-line trials, right? PersevERA, which is the Roche trial of giredestrant with palbociclib. SERENA-4 is the more standard front-line trial design that AstraZeneca is running with camizestrant, also with palbociclib. Obviously, OPERA-02, now the CDK4/6 landscape has changed. It is ribociclib that is the CDK4/6 of preference based on its survival benefit. That is the one where we are the only company doing a first-line trial with ribociclib. I think depending upon the strength of the data, as you said, from SERENA-6, it can read through, I think, to all of them, to the whole class.
Okay. I guess from the persevERA trial perspective, if that's positive, that just gives you a lot more confidence that pala plus ribo combo will look even better, right?
I think that's right. I think that's right. Again, that's a place where in acelERA in their kind of phase II experience, randomized phase II experience in the ESR1 mutant, it wasn't powered adequately, but they had some indication. They had a point estimated hazard ratio of 0.6. They had some indication of activity in the ESR1 mutant setting with giredestrant at their current 30 mg dose, which is also in persevERA. The question will be, does that carry through to a PFS benefit by suppressing the growth of those mutant clones? I think SERENA-6 does modify the probability of success at that.
Okay. The current guidance is to initiate the OPERA-02 trial at some point this year. How close are we to that announcement, and what might the gating steps be?
Yeah, it'll be the second half of the year. I mean, obviously, one thing that we need to have in order to start OPERA-02 is a dose from part one of OPERA-01. That's an important gating step. Obviously, there's the completion of regulatory interactions to finalize that decision and also the trial design. I think we have plenty of data, the data we talked about from our phase II ribo palazestrant combination, where that was mostly at 120. We do have patients at 90 as well. The point is you saw no enhancement of toxicity. It looks very much like ribociclib and an AI and some encouraging progression-free survival from that trial.
Okay. Can you use some of the sites from OPERA-01? How many do you plan to activate, and how long do you expect enrollment of 1,000 patients to take?
Yeah. We haven't gotten into that timing yet. We can use some of the same sites because it's a different patient population, right? These are non-overlapping. The patients that will go on to OPERA-02 will be treatment naïve in the advanced or metastatic setting, whereas OPERA-01 had patients who had at the least progressed on a prior CDK4/6 plus AI. We will have some overlapping, and we'll also have some new sites too, but we haven't really gotten into the details of that. At some point, probably in the not-too-distant future, we'll start doing trials in progress of OPERA-02 as well. We are on track to start that trial in the second half of this year.
Okay. Perfect. I want to get to the KAT6 inhibitor and the time we have remaining, but maybe just quickly, what's the latest thoughts on the market, both as a monotherapy in the second, third-line setting, especially if you have positive wild-type data, and then also the front-line opportunity as well?
Right. We think in the second, third line, with the wild-type, it gets to about a $5 billion market opportunity just based on the high prevalence. To some extent, how large that market is depends upon how long your PFS is, right? How long do patients stay on the therapy? If you get a significant, if you get our phase II data seven and five, then you have a pretty robust treatment duration. That's another factor in it. Obviously, if you can capture the mutant, if you can be better in the mutant than the existing therapies, and we'll get more data on that this weekend, there's an opportunity to differentiate there. Certainly, it's very meaningful to be able to show activity in the wild-type and potentially get a label there.
Okay. KAT6 inhibitor program, there was a slide I saw the other day from Pfizer. It's like you guys and Pfizer leading the pack. Obviously, exciting new mechanism. Our KOLs just the other day said they were just excited to see a new target and a new pathway that they can go after in a large indication like breast cancer. Maybe you could start by describing some of the preclinical differences between yours versus Pfizer's drugs, and some people may not be familiar with that.
Yeah. KAT6 is an epigenetic target. It's a lysine acetyltransferase, and one of the things it does is it acetylates histones. If they're acetylated, that relaxes the chromatin. Basically, you can think of it as opening up the chromatin and making the promoters more accessible to a variety of transcription factors, including estrogen receptor, progesterone receptor. You inhibit KAT6, and you stop that acetylation. That keeps that heterochromatin tight. You're kind of doubling down on the pathway. Pfizer has definitely demonstrated proof of concept, right? It's 30, I think 38% with fulvestrant in the post-CDK4/6 setting response rate, which is pretty impressive and also, interestingly, agnostic to the underlying mutational status. The Pfizer molecule is an inhibitor of KAT6A and B as we are, of KAT7 as we are. They have more activity against KAT5 and KAT8. We've kind of dialed that out.
We think that might contribute to toxicity. We don't think it's part of anti-tumor activity. We're a bit more potent, and then we also have a little bit narrower spectrum. The other thing that we've seen in preclinical animal models, and we presented this last fall, is what anti-estrogen you combine with is important. Fulvestrant clearly enhances the activity, but what's interesting is palazestrant does it to an even greater degree. Actually, it's true with the Pfizer in combination in preclinical models and with OP-3136. Obviously, we're uniquely positioned to be able to explore that combination. That's a high priority. We're currently in single-agent dose escalation. That is going very well. Obviously, that's needed to determine a recommended phase II dose. Also, that safety data is needed to start the combinations, fulvestrant and palazestrant. That's a high priority.
Is it possible we could get data by the end of the year?
It's possible. On the monotherapy dose escalation, it depends upon. It's going quickly, so that's great. I think the question is, what do we see? How many dose levels does it take? I think we can update on that maybe in the coming months. Certainly, next year, we will have data, but it's not impossible for us to do it before the end of the year.
Okay. Yeah. With the various combinations, you'd see tumor reductions preclinically, but with 3136 and pala, it goes negative, right? Like it's strikingly different. Why is that? Why is there the improved synergy?
I think it's just a complete estrogen receptor antagonism and the fact that as a monotherapy, we saw palazestrant tumors where fulvestrant could only slow their growth. I think when you take the KAT6 combination, you just see that amplified by the combination. We think it's both the superior pharmacokinetics combined with the potent complete antagonism that we see in it. That's obviously very interesting for us to test in the clinic. It's another differentiation opportunity for 3136 because at least until hopefully OPERA-01 reads out positively and we are able to file and get to market, we're the only one who can combine these two molecules to really optimize targeting these two mechanisms of action.
Okay. Great. We're running out of time here, but just outside of breast cancer, what other solid tumors are you most interested in from the KAT6 perspective?
Yeah. In [ACR], we did a late-breaking abstract. It presented and we showed activity in non-small cell lung cancer, castration-resistant prostate cancer, and ovarian cancer. The ovarian cancer standard of care is pretty complicated. In the monotherapy dose escalation in our 3136 trial, we do allow non-small cell lung cancer and castration-resistant prostate cancer. We are exploring that, and we'll see what we get and decide, is there a path forward for those tumors as well?
Okay. Great. To wrap things up, maybe Sean, I'll ask you a question I often ask, which is, what do you believe is the most underappreciated aspect of the Olema story by investors right now?
Yeah. I mean, I think the investors want to lump this whole class of drugs together and just say, "A SERD is a SERD is a SERD." I think what we're finding as more data comes out, and probably we'll see it again at ASCO, is it's not true. These molecular properties, being a CERAN, having better combinability, having an ability to get high exposure with full doses in combination, these are meaningful differentiators. I think in that respect, if you really dig deeper, you'll see that palazestrant very much distinguishes itself. Beyond that, we're a breast cancer-focused company, and we actually have a pipeline. KAT6 is an extremely exciting target and fits perfectly with palazestrant. I think we're very well positioned.
Wonderful. With that, Sean, I thank you for your time, and thanks to everyone for logging in and attending. I hope everyone has a great evening.
Yeah. Thank you, Tyler, and I hope to see you at ASCO. Everyone, have a good week and a good meeting if you're joining us at ASCO.