Hey, good morning, everyone. Thanks for joining the OpCo virtual conference. I'm here for my next fireside, which is with Olema Oncology. We've got CFO Shane Kovacs. Shane, welcome.
Hey, Matt. Thanks for hosting.
Totally. Start with the elephant in the room. EMBER-3 seems like there's some skepticism around oral SERDs right now. Do you just maybe want to address that trial and kind of how you think palazestrant is different?
Yeah, absolutely. I mean, look, Matthew, big picture, what's exciting about palazestrant, what gets the team at Olema up and out to work every day, is that we are working to bring a new class of medicines to patients, broadly referred to as SERDs, and in our case, CERAN SERDs. We have the opportunity to really change the treatment landscape for a form of cancer that affects, unfortunately, so many individuals. As you know, one in eight women will be diagnosed with breast cancer in her lifetime, and over 40,000 women are diagnosed with metastatic breast cancer every year in the United States. What we know is that there's broad enthusiasm for this new class of medicines on the part of the oncologists that are treating these patients.
And our goal is to demonstrate that palazestrant can outperform the old line standard of care meds, like fulvestrant and the aromatase inhibitors. And despite the mixed results from Lilly's EMBER- 3 trial late last year, which many, I think the consensus is, was driven both by a very poor trial design and the patient population and the baseline demographics of who was enrolled in that study, but also, as we've discussed, about the insufficient drug exposure that they get at 400 mg of imlunestrant. And I think what we need to remember is that our single agent activity at Olema is, at least we believe, without question, the best among the class. And our combination data with ribociclib, which we updated last December, is incredibly strong and clearly supports the path forward that we're pursuing from a clinical development strategy perspective.
We've got an incredibly potent drug, great PK, the longest half-life in the class. Our steady state exposure is above our target that enables complete binding of that estrogen receptor, locking it in an inactive position, shutting off its growth and proliferation signal, and that's normally driving those tumors. Our data indicates we've got very good activity across the board in ESR1 wild type and in ESR1 mutant settings. It looks synergistic with CDK4/6 to extend that PFS even further. And this looks like it has the potential to be highly differentiating in this new class of drugs for metastatic breast cancer.
Yeah, so it's amazing.
We're going to have two late-stage pivotal phase III trials running palazestrant, and we're working incredibly hard to deliver value.
So it sounds like the main pushback is this kind of belief that oral SERDs can't work outside of the ESR1 mutation. And it sounds like your counter to that is that you have a novel class here, a CERAN. It's different than elacestrant. It's different than Arvinas's degrader. Can you talk about maybe some of the differences and then use the data that you've generated to support that you think you can actually hit an ESR1 wild type?
Yeah, I mean, number one, so an ESR1 mutant versus an ESR1 wild type patient in a later line metastatic setting is different from what we'll consider an ESR1 wild type patient that's still highly endocrine sensitive coming into frontline metastatic, right? And so how a patient's going to do in a monotherapy SERD in a later line setting if you're wild type is different from how patients will perform in a frontline metastatic trial where you're combining with the 4/6 in a very endocrine sensitive patient population. What we're talking about in these second, third line patient trials is we see most activity for this class in the mutant patient population. And the reason is because if the patient's gone and mutated the receptor to keep that tumor going when it's previously being suppressed with an AI or an AI and a 4/6, right?
And now it mutates the receptor, and that's driving the tumor. So if you're ESR1 mutant in the later line patient population, it's almost telling you, I'm still using the estrogen receptor. Now I'm using a mutated estrogen receptor to drive my growth. That's what the tumor's doing. Whereas if it's wild type, and yet it's averted the AI, then it may still be using the estrogen receptor for part of that growth, but it's probably also using some other signal as well. And so the question is, is by shutting off all that wild type activity, is that enough to slow that tumor growth? And in some cases, the answer is yes, because we've demonstrated that. But what you need is great pharmacology, long half-life, really high exposure, and mechanistically hitting both AF2 and AF1.
Got it. We'll get back maybe to EMBER- 3 and whether you think it changes the landscape. But first, I just want to talk about what the current landscape is and kind of how it's changing now with Orserdu, i.e., elacestrant on the market. I think people sometimes lose sight of how big this market is. Do we have any insights into sales from Orserdu?
Unfortunately, both Menarini and Radius are private, and so we don't get reported quarterly sales. We track a little bit about the royalty streams, which get reported through DRI Capital, and you can kind of track that in their quarterly reports. I think there's a lag every quarter, but you do see a great trend upwards in their royalty revenue. Now, it's not clear if the royalty rate is ticking up as sales go up, but either way, it would indicate that the drug is performing well. I think we're now, this is the second year, right? They got approved around February 1st of 2023. So we should have just wrapped up two years of commercialization for Orserdu. Our understanding is it's very well tolerated.
So where the label indicates, which I think is an ESR1 mutant only in later line patient populations, that it's probably having good uptake, and at least in the United States. I don't know what the exact sales are.
Okay. Does Lilly get the combination of imlunestrant plus abemaciclib approved? Because EMBER- 3 did hit on all comers, but it was, as you mentioned, kind of a wacky trial design with certainly a lot of holes, and right now the overall survival is not looking great.
I think we'll have to see where they get to with their regulatory interactions. I believe Lilly indicated that their plan to file for ESR1 mutant, where they had close to a two-month benefit over the control arm and a hazard ratio that was stat-sig, and I think it was around 0.65. So actually, the data in that patient population wasn't as strong as the EMERALD data for PFS trend. I think the consensus is that the wild type missed, and so they're unlikely to get that. And then in terms of the combination data, you know the nine-month combo data with abema, definitely looks interesting for that patient population. A lot of the pushback that we've heard is, is it the right control arm? And so is that at risk in terms of being able to file and get approval in the combo or not?
Our understanding is they're waiting. You know, the OS data was quite immature. There weren't that many events from what they presented at San Antonio.
I kind of want to get back to this idea of combinations because you have one with ribociclib and you have ones with some others. But in your kind of doc checks, talking to KOLs, is there excitement for keeping a CDK4/6 backbone? Obviously, postMONARCH was considered a success, but the delta was pretty low. And now we also have EMBER-3, which, I mean, frankly, I thought the nine-month did look pretty interesting, albeit with the holes that you mentioned. So what is your kind of thinking for how this late line population could potentially change, and how would you confront that?
We know that certainly in the United States, that there are many centers that like to use combination therapy in second, third line setting for those patients that can tolerate the combination. There are certain patients that might not be able to tolerate the combination, and they might use a monotherapy agent. Clearly, we're running today a monotherapy phase III trial. We're enrolling patients, and the enrollment's actually gone quite well for OPERA-01. So we know absolutely you can enroll, and that physicians will put patients on a monotherapy. In the United States, we know there are a lot of centers that like to keep the CDK4/6 on in the second, third line setting. The data from our data, right, that we presented 62 patients in combination with ribociclib, 12 months median follow-up, and still hadn't hit a median PFS yet. It's looking great.
Yeah.
Right? We've now got over 75 patients enrolled in that combination study. We will update on that ribo combo data later this year. And we'll see how far we get with respect to how well the patients do. But clearly, the combination that we have, ribo with pala, is looking great in later line patients.
Yeah.
So we'll see how that plays out commercially. We know, for instance, the label for the CDK4/6 is in front line, right? The labels for the CDK4/6 don't say, use the 4/6 after prior CDK4/6. And yet it's being used in that setting, and it's being reimbursed in that setting in the U.S., right?
Interesting.
Not on label. So I think investors miss that. So when we get approval, we hope to get approval on the basis of our OPERA-01 study. We hope to hit not only the ESR1 mutant, but the ESR1 wild type that would lead to a broad label. Today, with Orserdu, right, it's ESR1 mutant only. That means the insurance reimbursement is going to have a prior authorization of getting that Guardant Health test to prove that you are mutant before you can get it. If you have the broad label, we believe that's an incredible advantage commercially because you no longer need the prior authorization to confirm your ESR1 status.
Yep. Let's talk about that, actually, because there is some debate with Arvinas' VERITAC-2 coming out with the intent-to-treat, intent-to-treat basically being all comers. Your view from your interactions with the FDA is that you need to hit stat-sig on the ESR1 wild type subset in order to get approval. Is that correct?
No question.
Okay.
No question. We had that direct feedback. We put it into our trial, right, that we're testing both wild mutant and wild type, not ITT. And if you look at the summary basis of approval that the FDA presented at San Antonio in December of 2023, and those presentations are available, they talk about the approval of not only Orserdu, but also AZ's capivasertib. And in both of those, they pulled it apart and they evaluated both mutant and wild type independently. So regardless of what a company pre-specifies in their trial design, we highly believe that FDA in evaluating a label is going to evaluate each group independently.
Yeah, with OPERA-01, I think you are the first that actually has co-primary endpoints of basically separating ESR1 mutant and wild type, whereas everybody else that's designed these trials had made co-primary endpoints of the all-comer ITT and then a co-primary of ESR1 mutant, right?
I believe that might be right, but we listen to the feedback.
Yeah.
We look forward, you know, we're aware of how other drugs have gotten approved.
It sounds like you're very bullish that you have the best chance as a SERD in ESR1 wild type.
Look, we think the probability of success in mutant is higher than wild type, no question.
Yeah.
Right? But the opportunity, who has the best opportunity to also hit the wild type? We believe it's palazestrant.
Yeah, so the idea is OPERA-01 is a success. I mean, when do you think top line readout will be? Sometime in 2026, right?
It'll be 2026. Obviously, we're going to be picking our dose, 90 or 120, enrolling part two, and then you wait for events to accumulate. So as we get closer, we'll be able to narrow that window. Today, our guidance is 2026.
When you have picked the dose to comply with Project Optimus, you wouldn't present data from that, right? I mean, that's just going to be like a press release that says we've selected dose, I don't know, 120.
Yeah, I don't know. The data from the first 120 patients, whichever dose, because it's 40, 40, and 40. We enrolled 120 patients, 40 per arm, including the control arm. Two-thirds of that, whichever dose we select and the control arm, will go into the final analysis, so it won't be unblinded.
Got it.
There won't be any presentation of that data, and it actually will be immature. To be quite honest, we're really a bit indifferent if it's 90 or 120, because if you look at the PK drug exposure, they're incredibly overlapping.
Right. So basically, the idea is to get a best-in-class oral SERD on the market with OPERA-01 in the late line setting and then let physicians prescribe it in combination with whatever they want to do because you've already generated that data and there will not be any reimbursement.
You know, so we've enrolled over 75 patients in our ribo combo study, right? We've already seen the behavior on the part of the oncologists enrolling frontline patients, patients with no prior treatment in the metastatic setting, right? They're not giving them AI ribo. They're giving them pala ribo. So I think that speaks volumes, actually.
Yeah. Let's talk about the Holy Grail, really, front line. I'll say a bit later behind, but you've already kind of disclosed the OPERA-02 design. Do you want to just kind of walk through that? Or maybe start out with ribociclib as kind of the new standard of care here. They have an OS advantage based on MONALEESA. Pala, abema don't have that. Clearly, we're seeing physicians switch in the front line setting. You recognize that early. You were one of the first to combine with ribociclib, and I thought you have some really compelling data. So.
It's not that we're only one of the first to combine, but we're actually the only ones to have this collaboration agreement, right? Kisqali is now very quickly becoming one of the top-selling products at Novartis. They recently updated over $8 billion at peak sales. Now they're moving into adjuvant. It's an incredibly important franchise for Novartis. And so they partner with us in what's a very unique collaboration agreement, right? They're going to supply. So the OPERA-02 trial, which we're actively preparing to initiate now, our teams are very busy. It's going to be about a thousand patient trial. It's much more straightforward than actually the second, third line study. Because in the front line study, it's no prior treatment in the advanced or metastatic setting. It's about a thousand patients, very similar to persevERA, the Roche study that's coming later this year.
AI plus ribociclib versus pala plus ribo. So we're really effectively testing pala versus AI, you know, both in combination with ribo. We think we can very easily outdo AI. For only one real reason that you need to be able to beat it in is what's the most common resistance mutation that occurs to current standard of care that causes those patients to progress? They go and activate the estrogen receptor. They turn it on independent of the lack of estrogen being around in that cell. The AI just starves the cell of estrogen. It keeps the wild type receptor off. As soon as the tumor goes and mutates that receptor, it starts growing again, and the AI is ineffective. And that, we know from all the data, is about 40%-50% of the reasons why these patients progress in first line.
Solely by beating the ESR1 mutant and suppressing that mutation when it arises, whereas the control arm with the AI does not suppress that mutation. In the AI arm, those patients progress. In the experimental pala ribo arm, they don't progress. Now, eventually, they'll progress because of some other mutation.
Yeah.
But it's going to take longer. And we keep referring to the FLAURA study that was done in EGFR mutant lung with Tagrisso, where Tagrisso was no better than Iressa or Tarceva until that T790M mutation popped up.
Right.
And that's where Iressa and Tarceva fell down because they didn't suppress that mutation, but Tagrisso did. And it led to a longer PFS. It's the same playbook.
Do you have any concerns commercially over some of the switching trials that are out there, which effectively take an AI and then they monitor ESR1, and then when patients?
No, we don't. We don't.
An academic trial.
The trial that's doing that is SERENA-6. Our understanding is they ran that study to get a head start on the real study that matters for AZ, which is SERENA-4.
Okay.
The reality is you don't monitor patients constantly in the front line on AI and then switch as soon as the mutation pops up.
It's a little academic experiment, but it's practical real life.
Yeah, I think that's hard.
I actually got a question about the Novartis collaboration. By the way, if you want to ask questions, you can email me at matthew.biegler@opco.com. Did Novartis receive any preemptive rights in relation to commercialization of OP-1250 as part of its agreement with you?
Let me tell you something. Last November, we signed what is a new and a very unique collaboration agreement with Novartis. You know, we concurrently raised $250 million of equity in a private placement with a very strong syndicate of institutional investors that are big believers in the opportunity for more. We are now very well positioned, well capitalized to now execute this OPERA-02 trial. We just said that's obviously frontline metastatic of palazestrant plus ribociclib.
I don't believe that Novartis has had any other kind of these kind of agreements.
This is incredibly unique. Novartis.
It's working for PI3K. That's it.
That's it. Yeah.
Yeah.
So they're supplying all of the Kisqali for this trial, something they value at nearly $300 million. Drug supply at this scale is something they have not done historically. Clearly, they're excited about it. They put OPERA-02 on their pipeline. So they're paying attention. And that makes sense because if we're successful, this will positively impact patients that are on Kisqali longer, right, in front line.
Yeah.
Right? We hope to take the two-year median to closer to three years. That means you're on Kisqali 50% longer.
Yeah.
It's a unique, but I'll tell you from a business development perspective, from a strategic perspective, we're in an incredibly strong position because, one, we're well capitalized to execute. And today, we maintain 100% of the commercial rights to palazestrant and to KAT6.
We'll talk about KAT6.
I think that's a lot of optionality as we go forward.
Yeah. Maybe now is a good time to switch to KAT6. It's funny, we spent the first, I'd say, two-thirds of this fireside talking about palazestrant, but arguably the bigger near-term catalyst would be KAT6. Do you agree?
We love KAT6. KAT6, you know, is clearly a very validated target based on the data from ASCO at Pfizer from ASCO last year. It is probably, without question, the most exciting target that might have the opportunity to really change breast cancer treatment in the future. We think it's far more exciting than PI3K and mutant selective.
Right.
The data shows that.
Yeah.
So we are now in the clinic dosing patients with our KAT6 program, right? The trial starts as monotherapy dose escalation. We are going to very quickly be going in combination with an endocrine therapy because you clearly see synergy. We see synergy preclinically. Pfizer has seen synergy in the clinic, right? They're testing with fulvestrant. We're going to test fulvestrant combo, but what we saw preclinically and what we're going to do in the clinic is test palazestrant KAT6 combo.
That's interesting. Why fulvestrant? Why not just go straight to pala? It's a better drug.
Yeah. I mean, look, fulvestrant is the approved drug today. Palazestrant is still experimental, so we want to actually show and make sure that the path forward for our KAT6 program can be used independent of pala or in combo with pala.
Okay. There's yeah, maybe somewhat of a misperception in the market where people think that like a KAT6 can cannibalize an oral SERD, but as you mentioned.
No, they're used in combination.
Yeah, very clear that.
You always have to suppress with a SERD or an endocrine therapy. And then you add other therapies on top. So never forget that these new SERDs or CERAN SERDs are always the backbone entirely. You might add on top a CDK4/6. You might add on top a KAT6. You might add on top a PI3K or AKT, but you always have the endocrine therapy.
Yeah. I just got another question about who are the potential suitors for you in terms of an acquisition. And people always ask me if Novartis is like really the only one that would buy you, but when I hear that, my first reaction is I think Lilly bought Scorpion. Novartis had the same agreement with Scorpion that you do, so.
Yeah, I obviously don't comment on our business development interactions. But what I'll tell you is we've got two late-stage pivotal phase III trials ongoing for the largest one of the oncology market, breast cancer. We've got an exciting second asset in the clinic, one on probably the best new targets in breast cancer. So I think what we have, and what's kind of unique is that these two assets work synergistically in the clinic is the expectation. And we're going to test that. So we're in a very strong position, I think, at Olema. And we're well capitalized with the financing that we did late last year.
That gets you into a runway that is certainly through OPERA-01 top line, right?
Oh, yeah. I mean, probably at least a year past OPERA-01, to be quite honest.
Okay. So back to KAT6. Again, I mean, the discussion at ASCO, I'm not making this up. She said it was the best phase I data that she'd ever seen.
I hope we update again at ASCO this year. We'll see.
Okay. That's good to know.
So we've got a number of catalysts in 2025, I think, that will drive the opportunity with Olema. Some are internal Olema. I think the update that we do later this year on our ribo combo data, we're going to hit a median at some point, right? We're already way past any of the competitors in that combination setting. So stay tuned for when we update on that. But I think that's an important update. And it's, you know, we've now enrolled over 75. But then you're going to see, obviously, VERITAC-2 we like. You know, I'm hoping that trial reads out positively. I think the expectation is it will hit mutant. It's a very well-controlled and designed study, unlike, you know, EMBER-3. We've got the perSEVERA study coming from Roche in the fourth quarter, it looks like.
But earlier on, we got the evERA study, which is their everolimus combo in second-line patients. And I think that's important for Roche and giredestrant. So there's two Roche studies coming. There's the Pfizer-Arvinas study coming. We've got our own data coming.
Yeah. So basically, some of these other SERD readouts could maybe reinvigorate, you know, enthusiasm for oral SERDs.
Oh, I think so.
They don't have the messy design. The drugs arguably look better than imlunestrant and Verzenio, so that makes sense to me. Maybe just quickly on KAT6 again, just in terms of your differentiation from Pfizer, right? That drug had some tox liabilities. Is there a certain way that you're hitting it? The different isoforms.
Preclinically, we look at activity in IC50s or IC80s on KAT6A and B, but also KAT5, KAT7, KAT8, right? It looks like vis-à-vis what we believe on 8144 that we have higher specificity on KAT6AB versus the other KAT family members. Now, how that plays out in the clinic, I think we're going to find out. We don't know the answer, but hopefully, the higher specificity should drive good activity without, well, that's TBD.
Yeah. It's still a very emerging space. I think Ideaya is now coming out and saying that KAT6 might be a target that you also kind of want to tickle. So I'm not sure.
Yeah. Everybody tickles it a little bit.
Yeah. Yeah.
And even if Pfizer does so.
Got it. That makes sense. And maybe just closing remarks, just as you think about the valuation here, you're basically trading at cash. As you mentioned, you've got a lot of milestones coming up.
It's really surprising.
And external. The KAT6 data, will we get KAT6 data this year?
I think it's TBD, you know, the timing. We're absolutely generating data. We'll present it as soon as we can.
Yep.
You know, dose escalation, you see how you go. You see how many, we don't know if we're going to end up with four cohorts or eight cohorts. You kind of see as you go. We're looking at the exposure. You do modeling from preclinical to clinical. We'll see. So we'll see how those cohorts go. We will present it at some point. We haven't yet guided if it's at the end of this year or if it's going to be pushed into 2026.
Is the trial design similar to Pfizer in that you're just looking at HR-positive patients that have been pretty extensively?
Oh, no. You know what? So we're enrolling breast, prostate, and lung. Very similar, actually. Pfizer did the same thing.
Okay.
So then the expansion at Pfizer was in breast. And clearly, we're going to expand in breast. We'll see if we get a signal in prostate or lung and if that warrants expanding in those indications.
Makes sense. I think those were all my questions. Shane, thanks so much. It seems like.
Thanks for hosting.
Yeah.
We appreciate it.
Compelling value proposition right here.
Oh, yeah.
All right. Thanks, everyone. Talk later.