Okay. Great. Thanks, everyone, for continuing to join us here at the Guggenheim Healthcare Conference, our second annual Healthcare Innovation Conference, I think is the full name. My name is Brad Canino, Senior Analyst here. Very happy to have on the stage for the next fireside Olema. We've got Shane Kovacs, the CFO, and Naseem Zojwalla, the CMO. Thank you so much for joining us.
Thanks for having us, Brad.
I guess, can we just kick off? If you can introduce Palazestrant, your oral SERD, CERAN, and talk a little bit about the most recent data that you presented at ESMO.
Right. Big picture, I think we're seeing a lot of evolution of the oral SERD, or in our case, the CERAN/SERD data come in, more and more support that this is going to be the next generation of endocrine therapy backbones for the treatment of metastatic breast cancer, and maybe early breast cancer as well. With Palazestrant, we recently presented some more data supporting at ESMO, supporting what we believe is that we've got the best-in-class agent coming along. We're currently, I think you know, enrolling and have data in 2026 from our first pivotal phase III trial called OPERA-01 that's in the monotherapy second, third line setting. We recently initiated our frontline pivotal trial in combination with Kisqali.
The data that we just presented at ESMO, which is our Palazestrant-Ribociclib combination data, in a second line post-CDK4/6i setting, we had a median PFS of a little over a year. That compares incredibly favorably versus A, current standard of care, or even B, what other combination agents have shown in that setting. We then further broke that out into both the ESR1 mutant subset and the ESR1 wild-type subset. In the mutant subset, where we tend to see better activity across this asset class, we got about 14 months. That compares versus sort of six to eight for the class. I think very uniquely, in ESR1 wild-type patients, we showed about a nine-month benefit. Why is that so important? Because few have shown activity in ESR1 wild-type patients that are more refractory second line post- CDK4/6i .
These are patients that sequentially just failed an AI +CDK4/6i and now come on to the Palazestrant-Ribociclib combo. Even if they're wild-type, they get nine months. If they're mutant, they get 14 months. That gives us incredible confidence in the potential success of our frontline study.
Okay. Let's talk about that a bit more, because you're seeing this differentiated clinical data emerge in combination. We've seen a lot of data sets from other oral SERDs. How closely related or dissimilar do you think Palazestrant is compared to the suite of oral SERDs and estrogen receptor antagonists that are out there?
Yeah, I mean, I think the important thing to remember about Palazestrant is it's a complete estrogen antagonist. And some of these other competitors, elacestrant, for example, is not a complete antagonist. It's a partial agonist. Imlunestrant is a complete antagonist, but the exposure level for that is not as high as what we see with Palazestrant. Camizestrant, also partial agonist. So, you know, I think the actual mechanism of action is different. Even though they're all categorized as SERDs, some are actually selective estrogen degraders, while we are a complete estrogen receptor antagonist.
Yeah. Furthermore, I think, Brad, on top of that, mechanistically, when you think about pharmacology and the exposure that we get, when you think, first of all, we're all trying to beat Fulvestrant in that second line setting. Fulvestrant is limited because it's an intramuscular injection once a month, right? And you get 500 ml injection. You get two injections every month. You get the, from a plasma drug exposure, Fulvestrant's peak is about 25 nanograms per ml. We get over 10x, 10x-15 x the exposure of Fulvestrant with a once daily oral tablet. We've got a half life of about a week. We get really nice, high, steady state exposure. We're always binding that receptor and locking it in an off position. I think that's a massive advantage for Palazestrant.
Yeah. Maybe to expand on that a little more, because there are two oral SERDs that are in frontline development now that have readouts potentially next year. We at least know the Roche one coming in Q1. You mentioned AstraZeneca's Camizestrant and how that compares to Palazestrant. How about giredestrant? How do you think the giredestrant compares to Palazestrant in patients as well?
I think Shane just talked about it. I think the, you know, the mechanism of action of giredestrant is similar to Palazestrant. However, in their phase I to two studies, they had challenges increasing the dose and the exposure due to toxicities. They had some bradycardia. Also, when they were combining with the CDK4/6i inhibitors, there were some toxicity issues. We do not have that. We are able to dose to full dose our drug, as well as give full doses of the CDK4/6i inhibitors. The difference with giredestrant is they were not able to achieve as high exposures as we have.
Okay. Now you talked a little bit about your data at ESMO. There were a couple other oral SERD updates at ESMO as well. What were your takeaways from those? How does it inform your view of the potential for Palazestrant or not?
I think the one that people focused on was the Roche evERA study that read out, which was a second line in combination with everolimus. Number one, I think what you saw with evERA was when you combined giredestrant with everolimus, you get synergistic activity. Now they did split out and show that in the ESR1 mutant was where they drove a lot of the benefit. They had about a 10-month PFS versus the control arm was about five and a half . In the ESR1 wild-type subset, they did not really show a significant benefit, at least on PFS. They had better ORR. They showed a bit of a trend on survival, and we will see how that plays out. Overall, you do get synergistic activity in combination with even everolimus. We think the better combo is with a CDK4/6i, even in the second line setting.
You see that driven in some of our data. We have tested and enrolled a cohort with everolimus, and at some point, we'll be able to update the palazestrant-everolimus combo. I think what we really are investing in is the CDK4/6i combo with the SERD. It wasn't entirely surprising to us in terms of giredestrant having good activity in mutant and not necessarily showing incremental activity in wild-type, because they didn't show any wild-type activity as a monotherapy, right? That's where we continue to differentiate is our phase II data mono says wild-type, our phase II data combo says wild-type activity.
Got it. Let's talk about the phase III development program then for Palazestrant. What is the status for those two different trials? What are you seeing in terms of enrollment expectations and when you think you can reach data endpoints?
Both trials are currently enrolling. The OPERA-01 is our monotherapy trial, a second, third line trial post-CDK4/6i in patients who had received up to two prior endocrine therapies and no chemotherapy. That trial we have announced publicly will read out second half of next year. Enrollment is going well. It is a global trial. The OPERA-02 is a first line trial in combination with ribociclib, and that has just begun enrollment. You know, we expect that to also enroll well. There's been a lot of investigator interest in that combination. There's not a lot of competition now in that space, in the first line space. There are not, no other CERANs or SERDs have been able to combine with ribociclib in the first line setting.
Yeah. On the monotherapy phase III, can you talk a little about how you've designed that relative to, I think, the six other now phase II or threes that were randomized against an endocrine monotherapy? What are the key features that you've implemented that you think sets it up for success?
There was a couple of factors. We do allow patient, we, sorry, we select patients who have had at least six months of endocrine therapy, helping to make that population more endocrine sensitive. You know, some of the other trials did not, earlier trials did not have that inclusion criteria. Also, we do not allow prior chemotherapy, which also could increase the endocrine sensitivity of that population. I think those are two factors for the trial. The statistical design we have not publicly announced yet. However, I think the important thing, and this has been with the FDA feedback for the other trials, is that you have to distinguish the ESR1 mutant and the ESR1 wild-type populations in your analyses.
If you look at the prior, what I'll call oral SERD trials that you referred to, some of them had sort of mixed inclusion/exclusion criteria. That was true originally for Amcenestrant with AMEERA-3, AMEERA-5. That was true for the Roche giredestrant. That was also true in EMBER-3. They did not require prior CDK4/6i. We know that FDA wants those as considering a second line trial. The only really good comparator trials are probably the EMERALD study with Orserdu and the VERITAC-2 trial. When you look at and compare those two, they're really nice, well-designed, well-controlled trials. I would put our OPERA-01 in the same category as those other two. In terms of the inclusion/exclusion criteria, I would say we're somewhere in between in terms of how we've refined versus EMERALD, but not gone all the way that VERITAC-2 did.
Got it. Okay. Now you've mentioned the differentiation in your clinical data around ESR1 wild-type activity. I think the question that stems from that is, why do you think there could be Palazestrant activity in that population that's thought to really not be driven by an ER-dependent biology?
Meaning in the second line setting or the first line setting? In the second line setting. I think, you know, there are patients that are still endocrine sensitive in the second, third line setting. Our exposure is also much higher than what we've seen with some of the other drugs. That could overcome some of the resistance, as well as the fact that we are the only people that have actually shown monotherapy wild-type data. If you look at our monotherapy phase I to trial, we had wild-type in the EMERALD eligible subset, we showed a PFS of 5.5 months. I think all of those features combined, we have confidence that, you know, we do have the ability to hit wild-type in our monotherapy phase III trial.
There's no question that the second line plus post-CDK4/6i patients are more refractory. If they're ESR1 wild-type, they tend to be more endocrine resistant on average, certainly more than frontline, right? Again, as Naseem said, our monotherapy data says we have wild-type activity. The data we just presented at ESMO in second line refractory wild-type patients with Palazestrant-Ribociclib says nine months. We're achieving wild-type activity even in those refractory wild-type patients.
Okay. I guess maybe the question that stems from that is then, why don't you consider the Palazestrant-Ribociclib combo to also be worthy of development in the post-CDK second line population, given that activity you've gotten?
It may be worthy. It may be worthy for us to consider a second line pivotal trial of the combination. Part of the question would be, what would the control arm be? Because the CDK4/6is are not on label in the second line setting. We have had some discussions internally. What would a second line CDK4/6i Palazestrant versus what would the control arm be? It may be an everolimus fulvestrant control arm, just like evERA, which is kind of five and a half months. If we could go and repeat our 12 months that we just showed versus five and a half, that would be a killer trial. Part of it is capital and timing for us, but it is something that I think we think about.
Okay. For the monotherapy readout, you know, a couple different scenarios could take place depending on whether or not you hit on wild-type, which is independently powered, as you said. Shane, as you think about the sales opportunity on those two different outcomes, what do you expect Palazestrant could achieve under those scenarios?
We think about the number of the incidence of frontline metastatic ESR, ER+/ HER2 -, about 40,000 a year, plus or minus, in the United States. I'll just focus on the U.S. market. The majority of those patients will progress to second line and then to third line. Obviously, some patients you will lose along the way. ESR1 mutant is about 40%-50%, and ESR1 wild-type is 50%-60%. If you're, if you were restricted to an ESR1 mutant only patient population, that's still 20,000 + potential patients a year. If you look at where the pricing is today for Orserdu, where Lilly just launched, the WAC price is about $22,000-$24,000. You can take a gross to net, and you can annualize that to put a duration on how long patients are going to be on therapy in that setting.
All it is to say is we believe that the mutant only opportunity in the U.S. is a couple billion dollars a year. If we're successful getting wild-type, that's probably more like a $5 billion opportunity, okay? We believe even in for ESR1 mutant only in OPERA-01, we have an opportunity to drive better activity from a PFS and from a hazard ratio perspective than the existing incumbents. The existing incumbents have achieved about a 0.55 to a 0.6 hazard ratio and really only about a two-month benefit over the control arm. Our, if we're successful in repeating our mutant only activity in the pivotal trial, we should be able to get a four or five month benefit and drive a hazard ratio that's stronger. That could lead to probably a half a billion dollar peak sales opportunity just in mutant.
Now, if we successfully achieve wild-type, now you don't have to test and get prior authorization from that ctDNA. Now you are the go-to oral SERD CERAN in that market. We think that drives something that's probably closer to a couple billion dollars of peak sales.
Yep.
That sets us up really well for then when our OPERA-02 reads out a couple years later, and we file a supplementary NDA, expand the label, and then launch into frontline.
Yep. Great. Let's move on to talk a little bit about the frontline trial that's enrolling, OPERA-02. Can we start just by outlining the collaboration you have with Novartis to conduct that trial?
Yeah. Novartis does not give out Kisqali to a lot of collaborators. One of the reasons is it is actually very challenging to combine with safely and tolerably. We showed that we could do that effectively in our phase I to early collaboration with Novartis. We spent the better part of last year, 2024, actually negotiating what was a pretty unique collaboration supply agreement with Novartis. They are now going to be, today we are already, we have the drug, we have initiated the trial, we are enrolling patients in OPERA-02. The value of that supply agreement to Olema and Olema shareholders and the patients we are enrolling is incredibly high because it is 1,000 patients, all 1,000 patients get Kisqali. They will be on that, they will be receiving Kisqali for two to four years or longer over the course of that trial.
We lead the trial, we lead the operations. Naseem and her team are very busy with that. Obviously, we collaborate with them, we share the data, we jointly own the IP. As part of that collaboration, you know, they have an eye into a potential future collaboration with us around Palazestrant. To the extent next year OPERA-01 reads out, we decide, hey, we're going to go and find a global partner to work with us as we commercialize Palazestrant. The first phone call we make is to Novartis saying, hey, we're ready to go, let's take a look.
Got it. Okay. While that trial is enrolling and you're working with Novartis, you also started early stage development work combining with Pfizer's atirmociclib, the selective CDK4. I guess why did you decide to do that while you've got the Novartis frontline study ongoing? How are you planning to incorporate this new combination into your development strategy?
Growing up in Canada, I played a lot of hockey and we're always looking at where the puck is going. Today the puck is with CDK4/6i Kisqali, right? We started off with both Palbociclib and Ribociclib as the market moved. The earlier movers went with Palbociclib in their pivotal trials. We were a little bit fortunate to be coming from behind and we're the only one combining with Ribociclib. Today Ribociclib is where you want to be in the frontline. Where's the puck going? It may be going to CDK4 selective, right? There is a number of CDK4 selectives out there in early development. Atirmociclib is the lead in that race. We had interest and we had enough of our stakeholders say, hey, you guys should think about combining with a CDK4. We said, you're absolutely right. We were in dialogue with a number of potential CDK4s.
Pfizer originally had a different SERD partner, right? There probably was not originally a lot of interest. That changed earlier this year. Now today we are combining with the atirmociclib. We will see where that goes. The big thing we need to find out in that phase I to that we are combining with the atirmociclib is can we safely combine with no DDI, no PK interaction? We will know that very quickly.
Okay. Now I mentioned the, we're all expecting the Roche frontline giredestrant Palbociclib data in Q1 of next year. I want to ask you, will you look at the result of that trial as the definitive test of oral SERD class in frontline? Why or why not?
The definitive? Probably not the definitive. It's certainly going to be the very first indication of can this new class of drugs dethrone or beseat the AIs in combination with the CDK4/6i. There are three trials in frontline. The first one coming is Roche, right? It's coming in the next three months or so. We are very hopeful for persevERA and Roche because we think people, I think the market will say, if Roche and giredestrant can win in frontline, then the Palazestrant-Ribociclib is absolutely going to win. I think people understand and believe and look at the data and say, we have the best combination. Our data is head and shoulders the top. If that one wins, we absolutely win. Now, if it just misses, will people still say and say, I think the Palazestrant-Ribociclib can win? I think so, right?
It's not like the be-all and end-all in terms of persevERA, but it certainly will be a positive indicator for this new SERD class to come. Of course, we got SERENA-4 currently guided to second half of 2026. And then our data is going to be a little bit longer in duration. I don't know if you have any addition on this, Naseem.
No, I think you summarized it well. You know, it will definitely help the whole landscape if persevERA is positive. You know, just faith in the class and in the first line setting, as he mentioned.
If that study is successful, what can you do at Olema to close some of the timelines gap?
You know, I think either way, our Ribociclib trial is going to enroll quickly. Again, there's not a lot of competition in the first line. No one else is combining with Ribociclib. There's a huge interest in investigators and participating in this trial. It's well tolerated. Our phase II data, as we've already talked about, is very compelling and robust. I don't, it may be able to enroll even faster, but we're not concerned about enrollment even right now. For a monotherapy trial, you know, at that point, if we're expecting top line results at the end of next year, that will almost be enrolled. You know, I don't think that will be affected so much. I just think in general, as Shane already mentioned, there will be just a huge interest in the class and then first line setting.
The confirmation that it does really work in the first line setting. Most patients in the first line setting are wild-type.
What we can do is enroll quickly. The issue we're going to have is the patients are going to do really well. That's going to extend the PFS and the timeline for data. The good part is, is we've got IP and exclusivity till the early 2040s, right? We're going to have about 10 years of marketing exclusivity. That's enough time to generate ample sales and cash flow and return for shareholders.
Got it. Okay. Maybe to close out, just one or two questions on the KAT6 inhibitor that you have in the pipeline as well. I'm interested in how you think about designing that first KAT6 study to one, show the properties of the drug itself, but two, also show what the potential combination potential can be with your own internal pipeline with Palazestrant.
Currently the trial's in dose escalation and we have planned for a combination with Fulvestrant and Palazestrant. I think the uniqueness of our KAT6 is we do have Palazestrant in our pipeline so we can combine with what we think is the better complete estrogen receptor antagonist where, you know, other companies who have KAT6 do not have that option. Our plan is to do monotherapy expansions in breast cancer as well as combinations with Fulvestrant and Palazestrant, with the focus being on the optionality to move forward with Palazestrant in combination.
The preclinical data says monotherapy is active. Combo with Fulvestrant synergistically has much better activity. Then when you throw the Palazestrant in instead of Fulvestrant, way better. We will see how that plays in the clinic, but the novel, novel opportunity is something that I think today at least is unique to Olema.
Got it. Would you expect the KAT6 inhibitor alone to have any differentiating features versus Pfizer? Is it more about the combination potential that's the novel approach for Olema?
It's both. Our KAT6 inhibitor is more potent and more selective for KAT5 and KAT8, which could distinguish the safety profile of the drug. The activity we've seen in the preclinical data in combination with Palazestrant is much more robust than you see with Fulvestrant.
Okay. Shane, close us out with the state of the balance sheet and current runway through Catalyst.
We just reported today $329 million at the end of September. I think we run an incredibly tight ship. We stretch the balance sheet as far as we can. The current runway is into mid 2027. We've got a lot of big value driving catalysts, I'd say in 2026 that are coming that I think can help drive us.
Okay. Thank you so much for joining us and thanks everyone for listening in. Appreciate it.