All right. Excellent. Well, thank you guys for joining. Super excited to have the management team from Olema Oncology. I feel like it's been a blockbuster year in the SERD space. And for many investors, they didn't necessarily see it coming. So, looking back, a lot of people are pleasantly surprised to see all the investments you guys are making in OPERA-01. So could you remind us, where things stand? What are the top priorities for you? And has a lot changed on your end, the way you see the world, or, the world just sees it differently?
Yeah. So thank you, Umar. Yeah, I'll just briefly introduce Olema Oncology to people. So we're a breast cancer-focused oncology company. I'm Sean Bohen. I'm the CEO of the company. And our lead asset is palazestrant. It's a complete estrogen receptor antagonist and SERD, selective estrogen receptor degrader. And it's in two phase III trials. OPERA-01, second- and third-line trials and monotherapy that will read out in the second half of next year. OPERA-02 is a first-line trial, the only first-line trial in ER-positive HER2-negative breast cancer combining with ribociclib/Kisqali, the standard of care. And that's ribo AI versus ribo palazestrant. And that's enrolling now. It will take a few years to read out.
Then we have a second phase I/II program, KAT6 inhibitor, OP-3136, which we're doing as a monotherapy and also in combination with fulvestrant and palazestrant enrolling now. It has been an interesting year. I think what's gone on is, you know, there've been numerous agents in this space and many people have felt that their results have been disappointing.
Correct.
And I think that disappointment is really a result of the evolution of the understanding in the space. We are more recently we see advancement in the space, which came actually from Roche, right? lidERA, their adjuvant trial, they announced a couple of weeks ago, is positive in an interim. And that data will be presented one week from today at the San Antonio Breast Cancer Symposium. And I think what we had seen for a long time was the ability to improve upon AIs and fulvestrant with better estrogen receptor targeting agents was really, we thought, pretty obvious from the limitations of those existing drugs, but it hadn't been demonstrated clinically. And I think lidERA now does that, and it has read through to, we're gonna do this on the fly.
This is a total Olema standard operating procedure here.
We'll get you a 10.
This is Shane Kovacs. He's the Chief Financial Officer of Olema, and so that has read through, and I think what has happened is that has given investors confidence in that.
I feel like, Sean, what might be really helpful for folks, because for a while folks were looking at SERDs and they kind of moved on. Now they're looking, coming back. And this is an exercise I've been doing with Shane recently as well. Could we just slightly linearly go through some of the key trials by indication where drugs have worked or failed? And then we can get into how they're similar or different. Perhaps we can start with super late line and work our way backwards to the adjuvant and what's missing in the middle, and we can talk about persevERA. But let's start with late.
Yeah.
What has worked, what has failed, and we can go step by step.
Right.
Late line, let's start there.
Yeah. In the late line, the first one that worked was a trial called EMERALD. The drug is now Orserdu. It's the first to launch oral SERD. And that's a Menarini second-line drug. That was a trial in the second, third-line setting. So these are patients who've progressed on a CDK4/6 inhibitor plus an AI, may have had another endocrine therapy. And so.
Mucin or not? Just.
A combination of the two.
Okay.
Right? So, the trial had a combination of the two. Its effect was only seen in the ESR1 mutant subset.
Correct.
So in that, in that setting, one of the most common resistance mechanisms is the ESR1 activating mutation. Essentially, what the tumors do is they turn the estrogen receptor on with the mutation. AI doesn't do anything there. And so 40%-50% of patients, 50% in EMERALD had these mutations, and they saw an effect there that led to the approval. But in the wild type setting, they saw nothing. Why? Because it's not a complete antagonist. This molecule is a SERM. So in the wild type receptor, it's a partial agonist. In the context of the mutant receptor, it's a partial antagonist, partially turning off the receptor, and that's why they saw an effect.
Got it. So that was that. Also in the post-CDK4/6 setting, if we could maybe speak to the recent trial from Roche.
So the post.
Or sorry, you can go linearly.
Yeah.
You can go step by step.
Yeah. So I think the next one would probably really be VERITAC-2.
Yep.
Which is vepdegestrant. This is also a SERM. Basically showed the same results, slightly different trial design. That's an Arvinas drug at that point partnered with Pfizer. And showed exactly the same result, not being a complete antagonist. That's not surprising. If we go back historically, there was a drug trial acelERA, which was a Roche giredestrant trial. That was a very different trial. It had frontline patients as well as second, third-line patients. It showed some effect in the mutant. It didn't show an effect in the wild type. Again, that's a case where the drug is a complete antagonist, but the dose is much lower. They had to reduce their dose from 100 - 30 milligrams. They don't get complete occupancy of the receptor. And that led to limitations there. That didn't lead to an approval.
In the interim was a trial called EMBER-3, again, a very confusing trial from Lilly, which studied Imlunestrant or Imlunestrant plus Abemaciclib. Again, Imlunestrant showed activity only, I'm sorry, in the ESR1-mutant setting in the second- and third-line. That led to approval again. There was this general, and this may be where you're going, Umar, there'd been this general reticence to believe that these agents could have activity in wild-type estrogen receptors.
Correct. So could you remind us then in this, evERA would fit in this, in this broader category?
It definitely would. So the.
So that's the Roche trial.
It's a Roche trial that was presented at ESMO in October. This is again the second, third-line setting now with a combination. The combination is Everolimus, Everolimus plus giredestrant versus Everolimus plus fulvestrant. And in this case, once again, the Everolimus/giredestrant combo shows interesting activity in nine months versus 5.5 in the context of the ESR1 mutant. It doesn't show a benefit over fulvestrant in the wild type. A couple of things going on here. One is we had previously shown our data phase II monotherapy, also more recently at ESMO, phase II combination therapy, ribo plus palazestrant in the second, third-line post-CDK4/6 setting. And in both cases, we saw evidence of activity in the wild type setting. And the reason there is because we have higher exposure and we are a complete antagonist.
There is an opportunity in the second- and third-line setting to have activity in the wild-type endocrine-resistant population. One thing I think that confused investors was they were mixing the wild-type endocrine-resistant second- and third-line population with the wild-type endocrine-sensitive adjuvant in first-line population.
I see.
Which I think.
When you say they, you're referring to evERA right now?
No, I'm referring to investors.
Oh, sorry.
Yes.
Okay.
They had said, well, this doesn't work in Wild Type, and there are two different biologies, and they were conflating them. What lidERA, the adjuvant trial that recently had a top-line press release, no data, again, data comes a week from today, but it read out positively at an interim. This is a moderate to high-risk adjuvant population, giredestrant versus the existing standard of care, Tamoxifen or an AI, and read out positive for prolonging disease-free survival. That has been having investors go back and go, wait a minute, this is a different population. This is a different way of targeting these drugs, and it does work.
Right.
And so they're now reading through, obviously, to adjuvant, but also to the first-line setting where patients have metastatic disease, but they remain endocrine sensitive because they have not progressed on a prior endocrine therapy or have never seen a prior endocrine therapy if they're de novo metastatic.
On this, Shane, I remember this conversation with you some time recently. Could you remind us the Sanofi trial? To what extent was it endocrine sensitive or not? But also the construct and its prior data was not as strong. But could you just expand on that?
And the AMEERA-3 and AMEERA-5?
Yes.
This, the Sanofi, the AMEERA, which was the second line was the AMEERA-3 and the AMEERA-5 was the front. The Sanofi trial, the AMEERA-3 enrolled a mixture of patients as well, just like the Roche acelERA study did.
Correct.
So they enrolled about half were actually frontline patients and half were post-CDK4/6 patients. So it was a mixed population that they enrolled. The issue with the Sanofi amcenestrant drug was a few things. Number one is a monotherapy had a very short half-life of six to eight hours. That meant by the time you got to the, before you took the next dose, you were already three half-lives short or four, three to four half-lives down. So they had a very low exposure as a result of the short half-life. Furthermore, when they combined with the CDK4/6 palbociclib, they had a 60% reduction of polbo exposure at their RP2D of 400 mg a day. So what did Sanofi go and do? They did a monotherapy study at 400 milligrams, but when they combined with polbo in their frontline study, they dropped the dose down to 200.
When they combined 200 with palbo, they still reduced the palbo exposure by 25%, so you're tying both hands behind your back in your frontline study trying to fight the Al 4/6, which is full dose, full dose, so of course it was set up for failure, so the probably amcenestrant never should have advanced in the clinic, and we've got a seven-day half-life. Compare that with six to eight hours, night and day.
Got it. Also, could you just remind us, we went through acelERA and evERA for Roche broadly in the same setting, I would argue.
There were some first-line patients in acelERA. There were not in evERA. Yeah.
Some first-line patients. But was the dose used the same?
It was.
Okay. And could you remind us, 'cause I remember going through this, some of the cardio challenges on the Roche molecule and why they had to drop the dose. Do you think the dose they're using is sufficient or is it still not fully optimized? Because I'm trying to use that to then get into your data sets.
Yeah. My opinion is that there is the potential that there's efficacy left on the table with their current exposure. The original recommended phase II dose was 100 milligrams as a monotherapy. They then combined with palbociclib. Ibrance was the dominant CDK4/6 at that time. And they saw a rate of bradycardia that they were not comfortable with. So they dropped the giredestrant dose, their drug down to 30 milligrams, so a threefold decrease. And they didn't see that problem anymore. And so they continued as monotherapy in combination with the 30 milligrams. Now, so that's about threefold, maybe a little more below our exposure at our 90 milligram dose. That said, giredestrant has the next highest exposure to ours.
It's a bit higher than some of the others like camizestrant for AstraZeneca or imlunestrant. It's quite a bit higher than camizestrant, significantly higher than imlunestrant.
Got it. Got it.
But one other thing that you should know, the adjuvant patients and the frontline patients are all endocrine sensitive.
Right.
By definition, they've never progressed on an endocrine therapy. The later line patients are all endocrine resistant mutant or endocrine resistant wild type. You may need more dose in the more endocrine resistant patients where their 30 milligrams failed. But in the endocrine sensitive adjuvant, in the endocrine sensitive frontline, the 30 milligram monotherapy and adjuvant or combo with 4/6 and frontline might be sufficient to really show the separation versus standard of care.
Got it. Makes sense. I wanna do, I wanna spend the last few minutes now on first your phase III, which could have data next year, I believe. Correct?
I can read out second half.
Second half next year. And then secondly, I wanna spend some time on the Roche data, which precedes that. So I wanna spend time on each. Let's start with your trial. So I understand there were two doses and one of them has been chosen to move forward into the full trial.
Yeah.
How was that decision made?
Yeah. So this was a bit of a gift from Project Optimus. The approach that, so we had previously done two doses, 60 milligrams and 120 milligrams in a randomized phase II setting and chose 120 milligrams. One of the things that we had seen, and we've published this, the 90 milligram, 120 milligram doses overlap very much in terms of almost completely in terms of their exposure. So FDA was interested in seeing 90 milligrams. So we ended up doing the trial OPERA-01 with a run-in part one with a control arm, 90 milligrams and 120 milligrams, 40 patients in each. And that was used for a dose selection. Now, the dose selection was done by unblinding 90 and 120 for our data monitoring committee, who recommended 90, and that then went on to the FDA who agreed with that.
That's what's moved forward. That's our dose for everything going forward.
Right.
We were agnostic because the exposure's the same. That was the most important thing to us, and that's because of this very long half-life that Shane mentioned, so that trial will end with about 500 patients, second, third-line setting, and a PFS endpoint, so the control arm is Exemestane or fulvestrant, and all of the patients will have had to progress on a CDK4/6 plus an AI.
Right.
Some of them may have had another endocrine therapy, and that will read out in the second half of next year. We may in the next month or two be able to refine that timeline with more.
Sean, do you know how one dose was chosen over the other?
No. I mean, that's the point.
DSMB knows.
they do.
Okay.
Yeah. So they got efficacy and tolerability data. Again, the exposures are, we were pretty agnostic. Exposures were similar. My only statement was you probably get better tolerability with a little less, and the exposures are about the same. And so that's all I can think about.
Right, and I guess.
I don't know.
How are you guys thinking about what percentage of patients would be endocrine sensitive in this trial?
Yeah. So it's going to be none truly endocrine-sensitive, 'cause the way it's defined is if you've progressed on an endocrine therapy, you're endocrine-resistant.
Sure.
But they get divided then into two things, right? One is the ESR1 mutant, which you know why they're endocrine resistant. It's because they turned on the estrogen receptor. And you can turn that off with a high exposure antagonist. The interesting population is the wild type. We have a high likelihood of doing well in the mutant. In the wild type, we saw 5.5 months, which no one has seen in our phase II data. If we can replicate that, that will be a unique benefit. No one has had activity in the wild type in this setting. And so we would capture this whole market, potentially $5 billion market in the U.S. And so that's being tested as independent endpoints in this trial, mutant versus wild type.
Got it. Okay. And I think at this point, it might be, it might be helpful to perhaps spend some time then on thinking about the Roche data coming up. I realize it's not your trial, but I also think, one of the points that's come up in some of our conversations is that may almost matter perhaps as much, if not even more than your OPERA-01 study. So could you just expand on that? And could it form the basis of you starting a first-line study right then?
We have a first-line study ongoing.
Okay.
It more reads through to what's likely to happen. The trial that's gonna read out in the first quarter for Roche is persevERA. persevERA is a first-line trial, and it is palbociclib plus AI, the standard of care at the time they started the trial versus palbociclib plus giredestrant at their 30 milligram dose. You know, what's being read through is this lidERA adjuvant data, wild type, endocrine sensitive reading through to the first line, wild type endocrine sensitive. If persevERA is positive, then people are, I think quite rightly, going to go, going to surmise that OPERA-02, our first-line trial, is very likely to be positive.
What, any differences in the trial design between?
The biggest difference is that we use Kisqali, the current CDK4/6 standard of care. And Roche used the then standard of care, which was Ibrance, right? Palbo. So we use ribociclib.
Oh, interesting.
So, I think that is the major difference. The other difference is that our combination data looks better in the phase II setting than theirs has. So, we do think we have a higher, even if their trial is not successful, we have a reasonable likelihood of being successful in OPERA-02.
Right.
but I do think the positive trial would read through, positively to us.
Remind me, I should know this. Did lidERA work? This is a Roche study.
Yeah.
In adjuvant setting. Did that work on an interim? Correct?
It did.
It did.
It did. Yeah. It read out on an interim. So the challenge with reading out on an interim is we don't know a whole lot about the statistical criteria. We're gonna learn them on Wednesday.
Right.
It is looking at.
If lidERA was fully recruited six months later than persevERA, I realize these are separate settings, different endpoints.
Yeah.
IDFS versus PFS. You know what I'm working with this?
I do know.
Do you think an interim has happened on this one? Do we, is there a buzz out there?
Yeah. On persevERA.
Yeah.
Yeah. I think it most likely has. I don't know what the, we don't know what the performance characteristics will be. It's interestingly, none of the first-line trials had run out, had read out on interims, right? There are a whole bunch of 'em. They're MONALEESA-2, PALOMA-2, the MONARCH trials, all these things that led to the approval of the existing CDK4/6s, all read out on their final analyses. There are other adjuvant trials that have read out at interim. NATALEE read out at interim. So it may have something to do with the very large number of patients you put on the, the adjuvant.
By the powering.
Yeah.
Okay. Got it. Okay. That makes a lot more sense. Then PFS is the endpoint, obviously, in persevERA, but we do wanna see an OS encouraging signal, kind of like the type of language they use to describe the adjuvant study.
Right.
Correct?
Right. Yeah. So these trials are powered to some extent for overall survival. That's a regulatory requirement. It takes a while to mature. We've seen how this plays out, right? Remember the Verzenio, Ibrance, Kisqali all had about 25, 27 months of median PFS in their trials that led to approval. They really looked undifferentiated. You then wait for the overall survival readout, and Kisqali is really differentiated. It shows a statistically significant benefit in three of three trials with a delta for survival of about a year, which is obviously very clinically significant. So that leads to a late shift in the standard of care away from Ibrance and Kisqali.
Fantastic. My last question, just as we start to wrap it up, your OPERA-01 and OPERA-02 both are using, obviously, the tablet form, right?
Yes.
The dose in OPERA-02 is 90 milligrams?
Everything's 90.
It's what?
90. Everything's 90.
Everything is 90 or 40. Okay. The one thing I wanted to confirm is some of the phase I, phase II data we spoke about. Was that all done on tablet form?
No. Some of it actually was done on a capsule formulation. The bioavailability is overlapping. So it's really, it's not a.
Okay. Have you guys analyzed responses by tablet versus capsule? And if there's,
The PK is completely overlapping between the two.
Okay.
With an eight-day half-life, absorption is not what determines your exposure. Clearance determines your exposure.
That makes sense. Yeah.
There's really no difference in the exposure that patients get with the two formulations. There does seem to be some difference though. The difference is that upper GI tolerability is better with the tablet than with the capsule formulation. That may just be a local GI irritation effect of the tablet dissolving more slowly versus the capsule, which just releases all the palazestrant into the stomach relatively quickly.
Got it. Fantastic. Did we miss anything, Shane? Is there anything else we should touch up on? Maybe like 30 seconds on the market side.
This week we've got persevERA and Q1. We've got our own KAT6 data coming probably mid-year next- year. There's three arms to the KAT6 study, monotherapy followed by fulvestrant combo, followed by palazestrant combo. We're really excited for the novel, novel.
They're all enrolling right now.
They're all enrolling now. The novel KAT6, or we call it OP-3136 with palazestrant. And of course, we're also testing a combination, a novel combo of atiramisiclib with palazestrant. And we'll share some of that data. We'll have some of that data in the spring.
Got it. Excellent. The DLTs seen with all the fulvestrant combo on the Pfizer molecule, are they well understood by the field along with the taste issues?
The KAT6, the Pfizer, it's not particularly well understood. I think most of the toxicity that leads to dose limitation has been cytopenias. It's not the dysgeusia, which is the taste alteration issue.
Right. Excellent. Fantastic. Sounds like a busy 2026 ahead. So looking forward to being in touch.
Yeah. Absolutely. Thank you for the time.
Thank you guys. Thank you again.