All right. Thank you, everybody, for joining us this afternoon. We've got Olema Oncology with Shane joining us this afternoon. I really appreciate you taking the time to sit down and chat with me.
Thanks for having us.
All right. Well, obviously, we'll start with palazestrant. That seems like the relevant place here. The oral SERD space has had some ups and downs, I think, in the market this year. It's no exaggeration to say. But you've been very active in trying to differentiate on mechanism versus some of your competitors in the broader space. So can you remind us, in your eyes, what the key differences are between the various next-gen SERD that are in development here and how we should interpret those differences when we look at clinical data?
Yeah, sure. So the SERD space is interesting because we characterize our mechanism and our activity slightly different. We characterize it as a complete antagonist, also a degrader, but so we call ourselves a CERAN and SERD. And while the SERD space broadly, I think, fell out of favor potentially with investors over the last few years, I think the momentum's coming back. And there's going to be a lot of activity probably starting next week.
Since San Antonio, a lot of the insurance is coming.
Yeah. And then the first frontline phase 3 studies are going to start reading out next year, the first one being persevERA with giredestrant Roche. So I think the momentum is coming back to our asset class and the potential to really transform standard of care in metastatic breast cancer. In terms of our mechanism of action and how do we really differentiate from some of the other in our class, I think when you think about what are we drugging, what are we targeting, and that is the estrogen receptor. And the estrogen receptor, I think you know, is the primary growth and proliferation signal for the vast majority of breast cancer ER+/HER2- is about 70% or so of breast cancer patients. And it's the estrogen receptor as well at the heart of it that's driving that tumor growth, at least initially and early in the disease.
Endocrine therapy and the estrogen receptor has been a target for decades now. But it's sort of been incomplete in the way some of the historical therapies have been able to try to shut down the ER activity. This is where with the breakthrough that we're on the cusp of with this new class of SERD to kind of do better than tamoxifen did, do better than the AIs, to realize the ultimate potential that people thought was going to come with fulvestrant. Fulvestrant looks great in an in vitro experiment, but in the clinic, it's limited by exposure. How did these drugs work and what's the real differentiating factor? If you think about the structure of the estrogen receptor, three domains, two different activating domains, and a DNA binding domain.
The ligand binding domain is the early on signal for the ER. And all of these targeting agents, these so-called SERDs bind that ligand binding pocket, outcompete estrogen. And in the case of a wild type estrogen receptor that's already off, they keep it off or they try and keep it off. In the case of an ESR1 mutant receptor, which has got a mutation that turns that receptor on in the absence of ligand, it binds that same ligand binding pocket and shuts it back off. Okay? However, there's another way to turn this on, and that's called AF2, the second activating functional domain of the receptor. And some of these molecules don't affect AF1. They only bind and keep AF2 off, but they don't also shut off AF1. And for us, that is the key differentiator between what we call a complete antagonist versus a partial antagonist, partial agonist.
Depending on which molecule you look at, that's the first thing about how do you differentiate. Do you shut off AF1 and AF2 or just the ligand binding domain AF2? Then it goes beyond that to going into the clinic. That's where pharmacology comes into play, where we also differentiate from some of the other CERANs. Other CERANs are giredestrant, camizestrant, and imlunestrant. Okay? We differentiate from those other molecules from Roche or AZ or Lilly around clinical pharmacology with half-life, good drug-drug combinability, which is what we're going to present next week with our ribociclib update combo.
Yeah, so looking forward to San Antonio next week. Obviously, you've got ribo combo data. We'll see EMBER-3 from Lilly. Even Arvinas Pfizer have some data.
A little bit.
A little bit. So we've got multiple data sets.
And KAT6 data too.
KAT6 also data as well. We'll get to KAT6, I'm sure. But when we think about those positive combo data sets especially, what should we be on the lookout for that in your mind sort of highlights those differences between the programs?
Yeah. So one, if you go back to Olema's monotherapy data in a second, third line patient population, we presented data at ESMO last year, 2023, and what did we show in a monotherapy activity was about seven months of median PFS in ESR1 mutant and about five and a half months of median PFS in ESR1 wild type. So where do we differentiate in that monotherapy data versus our competitive landscape? Deeper, stronger activity in the mutant patient population than some of the competitors, but actually also showing good activity in wild type patients where others have kind of failed to show separation, really differentiation versus the current standard of care.
So I would say look for some of that to repeat itself for that underlying thesis about how does palazestrant differentiate now in a second, third line patient population, but in combination with ribociclib in both ESR1 mutant patients and ESR1 wild type patients. Okay? Furthermore, I think if you look at the precedents, there's this idea, can you add the CDK4/6 in a second line patient population, switch out the endocrine therapy? There's the PACE study, which was around palbociclib being repeated. There's the MAINTAIN study, which was a very robust study, 60 patients per arm, which was ribociclib in the second line setting post prior CDK4/6. In the MAINTAIN study, you saw median PFS go from monotherapy, it's pretty well recognized two to three months, up to about five and change months in MAINTAIN.
One scan, two scans.
Right. You add an extra couple of months. If you look at postMONARCH, it's the same thing. Median PFS with abemaciclib in the second line is six months. And if you look at a small study that came from Roche, giredestrant in combination with ribo in that patient population, they got about closer to seven months, 15 patients, so it was a small data set. But most of this says if you add the CDK4/6 in a post CDK4/6 patient population, second, third line, you get from what's monotherapy two, three months to more like five to six and change months. And so that's the comparator, I think. And then looking at not only in the mutant population, but look for activity in wild type.
Sure. So I would love to talk about, well, we'll get back to that wild type population because I have a bunch of questions about that. But let's talk more then about the update next week at San Antonio. How much follow-up are you going to be able to show? Number of evaluable patients? How is that going to change from the earlier data set? And at this stage in development, where do you think the key durability comps are? Obviously, we just talked a little bit about median PFS. But when I look at these PFS numbers, to me, sometimes it's tough to tell the difference between five, six, seven months if it's all two scans. Are those meaningful differences when we're trying to put these assets next to each other?
Right. So in terms of our data next week, I mean, stay tuned. We enrolled over 60 patients.
If you could tell us your data next week now, that would be great.
We enrolled over 60 patients in combination with ribociclib. The vast majority of those were our full RP2D of 120 milligrams of palazestrant in combination with the full 600 milligrams of Kisqali or ribociclib, and the way we enrolled that study, we started off three patients at 30 milligrams of pala, then three patients at 60 milligrams of pala, then three patients at 120 before then later expanding. Most of the expansion that happened started in September of 2023 and continued through the end of the first quarter of this year, so when we're doing a data cut and what we'll present next week, and we have our actual IR event is on the Tuesday morning at 8:00 A.M. Eastern. Every patient will have a minimum of six months of follow-up, so any type of six-month landmark analysis should be feasible.
We're talking about Arvinas Pfizer have a 70% six-month PFS landmark. Is that the comp?
It's interesting. I think, again, the right comps to look at are MAINTAIN, maybe postMONARCH. I think you have to look at a protocol and a drug regimen that's repeatable. I think there's questions. It's been about 18 months since that data was presented, then that study still hasn't started. I think there might, I don't know if there's issues about getting that combination to work.
You mean the palbo combo for Arvinas ?
Right.
Sure. When we think about first line, how do we translate all these results into the expected combos in first line setting? When are you going to have clarity on that first line design and push forward into the places where I think market assumes these regimens will end up?
You may not have seen our announcement from yesterday.
Oh, that's right. It just came out.
Right? We had a real major milestone for our company. We announced yesterday a new clinical trial collaboration supply agreement with Novartis to supply the full 1,000-patient frontline study of palazestrant in combination with ribociclib. It's called OPERA-02 . Right? And we also announced in combination with that a $250 million equity private placement with some really star investors. And how much of that, how much does that cover into that phase III, the big phase III?
I think we've been very consistent to say that the frontline study, 1,000-patient study, where if you look at MONALEESA, the control arm does about 24-25 months. So we'll enroll 1,000-patient study, one-to-one randomized, 500 per arm. We anticipate the control arm will be about 24-25 months. We hope to extend PFS when palazestrant in combination by up to a year. Okay? We're going to start that trial mid next year. We're now funded to do that with the announcement from yesterday.
Funded to begin the study, but presumably not then to finish reading it out with that size.
So we announced at the end of September, we had about $215 million of cash on the balance sheet. When you pro forma adding $250 million from the financing, that puts us well into the 400s. That finances Olema probably about a year past the readout of OPERA-01. OPERA-01 reads out in 2026. Then we would prepare with a positive trial. We would file for an NDA for a U.S. approval and think about launching late 2027.
Makes sense. All right. Well, then let's talk about potential combos beyond even the CDKs. So you brought up KAT6 just a moment ago. I'd love to talk about the data we've seen there from Pfizer, your preclinical work that you showed earlier this year. But there are other potential combo agents here as well. We've seen the PI3K alpha space starting to heat up as well. Have you considered combos with the PI3Ks or even beyond the KAT6s that you got?
Yeah. So one thing in the treatment of metastatic breast cancer positive, HER2 negative, you always need to be shutting off estrogen receptor activity with an endocrine therapy. So you always have an endocrine therapy and then you add on other targeted agents, a CDK4/6, PI3K, could be AKT, et cetera. Might be KAT6, right? So what we've done with the palazestrant clinical development to date is we're trying to show that it is combinable and works synergistically with multiple other targeted agents to your point. So we've already done a 60-patient palbo combo trial. We've done a 60-patient ribo combo trial. We also have ongoing trials with alpelisib, the Novartis PI3K. We haven't updated on that data yet, but we will probably at some point in time. We're doing a combination with everolimus, right, which is also used commonly in combination with endocrine therapy.
We'll look to do other potential combos. There's a couple of interesting mutant selective PI3Ks. They all need an endocrine therapy partner. Right? There's other things looking at CDK4, for instance. Maybe in the future we'll consider those types of combinations. KAT6 is a very likely combination for palazestrant. And we showed some really incredible preclinical activity or data back in October showing that not only does palazestrant combine well with our KAT6 inhibitor, but when we compare it with fulvestrant in the KAT6, the palacombo looks much stronger than a fulvestrant combo.
Now, that same meeting, Pfizer showed some early clinical data from their KAT6. Is it too soon to do a little compare and contrast between your program and theirs?
Well, look, we're absolutely tracking the Pfizer clinical updates as they come in KAT6. The data they presented at ASCO about six months ago were really telling. This is clearly an active new target. We'll see where it ultimately gets used. Is it in combination with a CDK inhibitor or is it relegated to second line TBD? I think the jury's out. They both have neutropenia associated with them as a primary toxicity. Based on our preclinical data, we look at the KAT family and what kind of specificity do you have against KAT6ab versus hitting KAT 5 or KAT 7 or KAT 8, and we believe based on our preclinical activity, we have stronger potency and specificity on KAT6ab. We'll see how that plays out in the clinic.
We've publicly said we will file the IND by the end of 2024 and look to initiate clinical development in early next year.
Well, maybe that's a good segue to talk about clinical milestones both for palazestrant and for KAT6 and the various combos thereof. You mentioned the ribo phase III. Obviously, that's going to take a while to fully enroll and read out. In the meanwhile, where are the key combo readouts, milestones that you expect to be showing?
Yeah, I think that from an investor's perspective, there's a lot of drivers of Olema that could create value, both direct announcements and updates coming from Olema as well as from our landscape. What comes directly from Olema? Obviously, I think we have a very important announcement next week, okay, updating on what is the biggest, this is the biggest data set that's been shown with ribociclib in a second, third line setting in combination. There might be an opportunity to further update on that data set and present at a medical meeting in 2025, depending on how the maturity is of what we're showing next week. And then maybe allowing additional maturity to develop.
With a year of follow-up with.
Exactly. Obviously, we're going to initiate our KAT6 program. So at some point, we'll have KAT6 monotherapy data. And we're going to quickly try and get into combinations with both fulvestrant and palazestrant. So there'll be KAT6 single agent data and then combination data present publicly.
Given KAT6 trials starting in monotherapy and escalation beginning of next year, fair to say we could start seeing initial data from early cohorts end of next year, beginning of?
It's going to be, we're going to have to see how, you know, with a dose escalation trial, you have to see how you go with each dose. So I can tell you we anticipate the starting dose could be at an efficacious level. So we'll see where we go with timing for that KAT6 data. The OPERA-01 study reads out in 2026. In addition to that, I think we're going to see news flow from our competitive landscape, including EMBER-3 next week. We'll see an update on the KAT6, I think, from Pfizer next week. I think a very important landmark study coming out of Roche, Giredestrant, persevERA sometime in the first half of next year, I believe, is when it's anticipated. I think that could help with a lot of perception on can you really beat the aromatase inhibitor in front line.
Fair enough. Maybe in our last couple of minutes, a couple of thoughts on BD beyond the Novartis collaboration. Obviously, as you mentioned, the clinical supply agreement for phase three is excellent, private placement excellent. Are there other places that you want to see BD for palazestrant or for KAT6? Other potential collaborators that are front of mind for you?
Look, we are now fully enabled to advance palazestrant in front line. We have our second, third line trial ongoing right now. We're very well positioned, I think, from a clinical development over the next 12, 24 months with palazestrant. We'll see where BD interest goes over that period of time. The KAT6, same thing. I think it's an exciting new target as more and more data develops. I got to imagine that anyone that wants to be in breast cancer is going to be interested in that target. For now, we are fully enabled to advance our KAT6 program in through phase one, two, mono and combination. We'll present data as we go. I think we're in a very good spot.
We continue to evaluate other opportunities to bring assets in that might work in combination with our mission, which today is really focused on breast cancer, so I would say stay tuned on what we do from a licensing BD perspective.
Makes sense. And maybe as we run out of time here, I would love to return to the topic of ESR1 wild-type patients. Obviously, we see divergent results there across the SERD space for reasons that I think make sense to everybody. But insofar as it's possible to show benefit from these molecules in the wild-type patient population, are we really looking at a subset of those patients who are going to benefit, who remain estrogen responsive despite being failed on AIs and still being wild-type? Or is there a potential for benefit across the ESR1 wild-type population?
Yeah, great question. I think the first is to differentiate between a frontline metastatic patient that's no prior treatment in the metastatic setting that's wild-type. That patient is different from a post-CDK4/6 AI patient that is still wild-type. What I want you to think about next week is look at those patients that are wild-type and look at potential benefit from a pal/ribo combo in a second line post-CDK4/6 remaining wild-type. Can you show activity across the board in all those wild-type patients? I think it remains to be seen. And there may be other mutations within those patients. Maybe they're all PI3K mutant or maybe they're AKT mutant, right? So you have to think about the mutations that exist in that patient population. But broadly, I want you to consider that wild-type activity.
Makes sense. All right. Well, thank you so much, Shane, for joining us. And we are out of time, but wish you the best at conference here.
Thank you. Thanks for having us.