Good morning, everyone. Thanks for joining us at the HC Wainwright 27th Annual Global Investment Conference. My name is Emily Bodner, and I'm an Equity Research Analyst at HC Wainwright. I'm pleased to introduce our next fireside chat with Olema here with Shane Kovacs, the Chief Financial Officer of the company. Maybe Shane, start for those a bit less familiar on Olema. Can you give us some background on your lead asset, palazestrant, and also the transitioning, transforming treatment landscape in hormone receptor-positive HER2-negative breast cancer?
Sure. Thanks for having us. Sorry for running a little late and back-to-back investor meetings this morning. Olema Pharmaceuticals, we are a clinical stage company focused on advancing treatment for metastatic breast cancer. We've got two clinical stage programs. Our lead program is palazestrant, which we'll expand on. It is a complete estrogen receptor antagonist. It is a once-daily oral tablet that combines the estrogen receptor and completely shuts off its transcriptional activity. We also have, advancing quite quickly in clinical development, a CDK4/6 inhibitor, which we can talk about. Palazestrant, we are in two Phase 3 trials today. We entered the clinic about five years ago and fairly rapidly went through both monotherapy and combination therapy with palazestrant.
Today, our two Phase 3s, we are about to initiate a frontline metastatic breast cancer study combining palazestrant with Kisqali or ribociclib and comparing the control arm, which is an aromatase inhibitor with Kisqali. That's about a 1,000-patient trial, randomized one-to-one, about 500 per arm. We'll be presenting actually next month at ESMO in Germany some Phase 2 data that really should support the frontline thesis about not only do we combine well with Kisqali and we have great activity in the ESR1-mutant in combination, but also in, again, in ESR1 wild-type patients. We also are running a second, third-line metastatic trial. That trial actually reads out next year in the second half of next year. That is called OPERA-01, and that's about a 500-patient trial randomized, again, one-to-one palazestrant monotherapy versus standard-of-care monotherapy.
Yep. Maybe we could start with the landscape, particularly a second-line, third-line setting. Obviously, now we've had three positive Phase 3 trials in the oral SERD space, but essentially have only really seen benefit in ESR1-mutant patients so far, which makes up about half of the population. How do you interpret this and how do you believe that palazestrant could potentially be differentiated or show efficacy more broadly?
You're right. I think part of the issue we've had with some of the oral SERDs is that they are incomplete in terms of their activity and their ability to completely shut off estrogen receptor signaling. One of the great things about palazestrant, and we saw this preclinically, we've seen this now in the clinic, is we really are a very potent binder and completely shut off both activational domains of this estrogen receptor. We've seen that both in the ESR1-mutant and ESR1 wild-type settings preclinically and in the clinic. When you look at elacestrant, which is an oral SERD, and that trial that led to its approval a couple of years ago was called EMERALD. As you said, they showed about a two-month improvement over standard-of-care, which was mostly fulvestrant in a second, third-line trial.
They showed about a two-month benefit in ESR1-mutant, and that led to their approval, but really had no activity in ESR1 wild-type patients. We saw that similarly, I think, in the VERITAC II trial with giredestrant, which is now under review as a PDUFA date next year and should lead to its approval, again, in ESR1-mutant. We believe Lilly may be under review as well and potential approval. We could have three oral SERDs approved in ESR1-mutant, all with about a two-month benefit in that subset versus standard-of-care. What we're really trying to do in our OPERA-01 trial, which will read out in the second half of next year, is to repeat what we showed in our Phase 2 trial. At our 120 milligram dose in our Phase 2, we showed in ESR1-mutant patients, we showed about a seven-month benefit.
In the wild-type subset of patients, we showed about a five-month benefit. There's no doubt that you show greater activity in ESR1-mutant patients. Part of the reason is if in later line patients where they've been suppressing estrogen receptor activity for so long that when the mutation occurs, what the tumor's telling you is it's using the estrogen receptor still to drive its growth and proliferation. By binding it and shutting it down, even if you're incomplete in its inactivation, you're still going to show activity in that mutant setting. If in a later line setting, if the patient is still wild-type, it means it may be more endocrine resistant or it may have mutated other pathways that are also driving that tumor.
There is no question that there's probably a subset of later line ESR1 wild-type patients that are now truly endocrine resistant and you're not going to be able to show monotherapy activity with an endocrine agent like oral SERD. We believe, and our data shows, that there still is a good subset of endocrine sensitive ESR1 wild-type patients that will respond and show activity to a complete antagonist. We showed that in our monotherapy Phase 2 data. We are going to show that next month at ESMO when we combine with Kisqali in later line ESR1 wild-type patients. We are the only oral SERD or complete antagonist that continues to demonstrate not only great activity in the mutant setting, but also wild-type activity.
Yeah. That 5.5 months ESR1 wild-type median PFS that you demonstrated, do you believe that would be potentially sufficient to show a PFS benefit in your OPERA-01 trial?
Yeah. You know, the FDA I think has been very clear, one in the approval process of our SERD where they showed about a two-month benefit or about one scan. The patients come in for scans every eight weeks in these trials. The FDA also gave some guidance at San Antonio Breast in December, both 2024 and 2023, where they talked about they will evaluate these oral SERDs in later line populations. They'll split it up and they'll look at mutant and wild type separately. The bar for approval is really to show about at least a one scan benefit or about two months over the control arm. We believe that's the bar for approval and that will be evaluated in each of mutant and wild type. The primary endpoint in our OPERA-01 study isn't about ITT in mutant, it's about wild type in mutant.
Can you talk a bit more about the OPERA-01 design? Obviously, initially you were looking at two different doses, now you've selected 90. Just kind of set out where you are with the trial and upcoming guidance.
Yeah. It's very similar actually. If you look at both the EMERALD trial and the VERITAC II trial, we're about a 500-patient trial. It's one-to-one randomized control arm versus our experimental palazestrant. We looked at, and we're sort of a hybrid between where probably VERITAC II was and EMERALD. EMERALD didn't allow prior fulvestrant and took second, third line patients. We do the same. We take second, third line patients, we allow prior fulvestrant. Whereas VERITAC II was really second line only and no prior fulvestrant. Their control arm was only fulvestrant. We allow fulvestrant or we do allow exemestane. We anticipate we'll get mostly fulvestrant in the control arm, but it may be a little bit of a mix. Where we differ and are more like VERITAC II is that we don't allow prior chemo.
There was prior chemo allowed in the EMERALD study and they showed in a post-hoc analysis that those patients tended to do worse. We don't allow prior chemo in the study in the advanced or metastatic setting. This was also a post-hoc analysis done by EMERALD that I think was incorporated in VERITAC II and we've incorporated is minimum of six months on your last endocrine therapy. If you only saw four, six in an aromatase inhibitor in frontline metastatic, but you progressed within the first six months, you won't be eligible for OPERA-01. Seemingly, if you're a third line patient and you had fulvestrant second line, you had to have been on it for at least six months to be eligible to then get into OPERA. We're trying to enrich for those patients where we still think there's endocrine sensitive.
Yep, makes sense. Maybe jumping to your combo trials, you obviously discussed that you're going to have an update in the palazestrant plus ribociclib Phase 2 trial, and you've announced median PFS of 13 months in that study. How does that kind of compare to other oral SERD and CDK4/6 inhibitor combo studies that we've seen to date?
Right. If you think about hormone receptor-positive HER2-negative metastatic breast cancer, you always have an endocrine therapy backbone. You always need to be shutting off the estrogen receptor signaling no matter what. You think about other targeted agents on top to hit and turn off other signals that may also be going on. Our strategy from a clinical perspective is to show we can safely combine with all these other targeted agents. The first one, of course, is to go to the CDK4/6s, which are standard-of-care frontline. We've now combined with both palbociclib and ribociclib. In addition, before I go to some of your other questions, we've also now combined with alpelisib, a PI3K inhibitor. We've combined with everolimus. We're about to initiate very soon our CDK6 combination. We announced last week we're going to be combining now with atiraciclib from Pfizer.
We want to show that we are combinable safely with all these. Other SERDs in the space have also tried to combine with the 4/6s and have had some type of issue that has led to dose modification. We saw that with giredestrant when they tried to combine their 100 milligrams with palbociclib. They had increased bradycardia, and as a result, they dose reduced the giredestrant down to 30. We saw that with camizestrant from AstraZeneca when they were combining with palbociclib. They ended up at their lowest dose of 75 milligrams of camizestrant. We saw a DDI issue arose with Arvinas' bavdegalutamide combining with palbociclib, which led to significant increases in palbociclib exposure, which you can't do. What we've been successful at doing is showing that palazestrant is very combinable with other agents, which is great. No drug-drug interaction. We did that with palbociclib. We did that with ribociclib.
We dosed full dose 600 milligram ribociclib with our full dose 120 palazestrant. We've shown now last year at San Antonio Breast that safety, that there's no increase. The major adverse event associated with 4/6s, at least with palbociclib and ribociclib, is grade 3/4 neutropenia. They've had no increase. All the AEs seem to look pretty good. We had early efficacy last year that was immature. The PFS curves had not crossed a median. We gave a short update at the Cowen conference last March that showed that we had now crossed north of a year across in post-CDK4/6 patient population. That was still maturing. The median, all of the patients haven't crossed that median yet. We're going to update that at ESMO next month.
What we're going to show is probably the biggest data set, certainly that's been shown in combination with Kisqali and probably even if you look at the other SERDs that combine with palbociclib because we dosed over 70 patients in aggregate. There were some frontline patients where that's still maturing because those patients are going to do very well. I expect that those PFS curves hadn't crossed medians. In the post-CDK4/6 patients that are now getting palbociclib and ribociclib after already progressing on an aromatase inhibitor and CDK4/6, we showed we got over a year in aggregate. We're going to split that out. We're going to show you, and I think investors think these SERDs are only active in the mutant setting. There's no question you get better activity in mutant and wild type. When you combine, you get synergy there.
We're going to show, again, here's the mutant subset of palbociclib and ribociclib. We're also going to show you the wild type, later line wild type, palbociclib and ribociclib and show that it's not just driven by the mutant. That should also further support the frontline thesis where we need to beat the aromatase inhibitor. You need to beat the aromatase inhibitor in frontline. Standard of care does it 24 to 27 months. We need to win in frontline by about six months. Yet we're showing we can get 12 months in aggregate in second line patients combo.
In terms of the frontline patients that you have in that trial, is there any early data that we might see at ESMO from those patients? I guess when do you think we may be able to see some more mature data?
Yeah, that takes the front. We enrolled, you know, I think it's 15 or so frontline patients in combo with ribociclib. That data is going to take a couple of years to mature. I don't know what we'll show on those because I don't think people gain a lot of value to show curves where that's just sort of a line going out and you're not seeing anything cross. That data really does take some time.
Okay. You mentioned briefly the new combination trial that you're planning to start with Pfizer's CDK4 inhibitor. Can you just talk a bit about what drove the interest in that trial and how do you kind of view CDK4 inhibitors relative to CDK4/6, which obviously is the standard-of-care currently?
Right. Frontline metastatic breast cancer, standard of care today is a little over two years. There's about an annual incident. It's about 40,000 women a year in the United States are frontline positive, HER2 negative metastatic. Today's standard of care is about two years. That's about 80,000 patient years. I think what we want to do is continue to extend PFS in frontline. We'd love to take it from two years to three years and add an extra year. That would take up the size of that commercial market from a pharma perspective from 80,000 patient years to 120,000 patient years. It's a very big opportunity. The CDK4/6s, it's interesting to see how that commercial market has evolved, right? Palbociclib was the first one approved. It was perceived to be the easiest one to give from a tolerability perspective. It was about a $5 billion drug for Pfizer.
They all got approved on PFS and OS comes out years later. The OS came out from all these trials a couple of two to three years ago. What we saw was Kisqali hit in three for three. That survival benefit was about a year on four. One year survival on four going from four to five is very meaningful for patients. It is now NCCN number one Kisqali. You've seen the CDK4/6 commercial market flip over the last couple of years, where now Kisqali is the number one prescribed CDK4/6 in the advanced metastatic setting. They just actually got the adjuvant on the label. Novartis now guides to, I think, Kisqali coming in an $8 billion drug. CDK4 is potentially going to be the next generation. By dying out the six, which leads to the neutropenia, maybe you can hit CDK4 harder. Pfizer's got a CDK4 called atiraciclib.
They're running a Phase 3 with an AI to see if they can beat the 4/6. I think they want to see if they can be with a next generation SERD. I think they tried that with a different partner and it didn't seem to, we're not sure what happened, but we're going to test it with palazestrant. It behooves us to see not only should we work with the 4/6, but can we also safely combine with the 4? If that works, we could consider going to that into a frontline trial.
Maybe for your OPERA-02 trial, which you're initiating very soon, can you just talk a bit about, I guess you did mention some expectations already, but we also have Roche's first line trial reading out this year. How do you kind of expect that to potentially inform indirectly for your success?
Yeah, we have been talking about the thesis of winning in frontline metastatic for a number of years now. There's really three frontline oral SERD 4/6 combination studies. The first one to come is the Roche study called PERSEVERE. They're guiding to the end of 2025. We're really looking forward to seeing if giredestrant can beat the aromatase inhibitor when combined with palbociclib. The second one is called SERENA-4. That's coming from AstraZeneca next year, and that's their camizestrant with palbociclib versus the aromatase inhibitor/palbociclib combo. We're the only ones that are combining with ribociclib, which is now the new standard-of-care. That trial is going to take longer to read out. We're very hopeful to see proof of concept that yes, we can indeed beat the aromatase inhibitor in the frontline. This will be the first trial. Giredestrant is a great molecule preclinically. We love it preclinically.
In the clinic, they dose reduced from 100 to 30 because of some very increased bradycardia they had when they combined with palbociclib. We haven't seen, I don't think, any 30 milligram clinical data from the Phase 2 in combo with palbociclib. The question is, do they, you know, is that the right dose? We're looking forward to seeing the result from that trial.
Yeah, maybe last few minutes, if you could touch on the CDK4/6 inhibitor, how that Phase 1 trial is going. Obviously, you're looking at different indications there. What's kind of the thesis for CDK4/6 working in indications like prostate cancer, lung cancer?
Yeah. CDK4 is probably the most exciting new target in breast cancer. The Phase 2 data presented from Pfizer at ASCO 2024 showed that they had response rates in the high 30% and median PFS. This is in second line post CDK4/6 patients where standard-of-care does two months median PFS. They got response rates less than 5%. They got close to 40%. It's an exciting new target. We started with our CDK4 inhibitor in the clinic late last year. We are rapidly moving up the dose escalation as a monotherapy. We have not yet hit MTD. We're continuing to go higher, but we've already initiated the combinations because you do need an endocrine therapy backbone with CDK4. They absolutely synergize and Pfizer showed that. We've recently initiated combinations with fulvestrant. We're about to start later this fall in combination with palbociclib.
We'll present the first mono and combo data by mid-year 2025 next year. We like where it's going. In the monotherapy, we're also enrolling prostate, prostate and lung. The mechanism of action says that it may have activity in prostate and that could be very interesting. I would say stay tuned for that. It's sort of an epigenetic regulator. The CDK4 enzyme loosens the chromatin on the histones to allow promoters to come in and have transcription and then translation. By inhibiting the CDK4 enzyme, which is what we do, you keep the chromatin tightly wound around the histones so that the promoters can't get in there and lead to transcription. You're hopefully downregulating some of that growth and proliferation signal that's happening in the tumor.
Great. All right. Thank you so much, Shane. We're kind of out of time now, but great speaking to you. Thanks everyone for listening in, and please enjoy the rest of the conference.
Thank you.