All right, good morning. It is my pleasure to introduce Shane Kovacs, COO and CFO of Olema as our next speaker. Shane, welcome.
Thanks for hosting us.
Yeah, this is my second time hosting Olema at the Goldman Sachs Conference, so absolutely enjoy having you back. Before I kick off with the Q&A, I'm going to turn it to you for opening remarks.
I think we're at a very interesting time for Olema. As you know, drug development takes some time, and now we're, over the next 12 months - 18 months, we're going to be generating a lot of, I think, very important clinical data. We're coming off hitting a lot of milestones, I think, in 2024. Over the next 12 months, later this year, we'll be presenting some updated data on our phase II ribociclib-palazestrant combination. Most of that data was at 120 mg, but we did enroll a good cohort at 90 mg of palazestrant in combination with the full 600 mg ribociclib. We'll be updating on that data later this year. Our KAT6 program has been going very well for us. We're in the phase I dose escalation, and we'll be rapidly moving towards combinations both with fulvestrant as well as with palazestrant.
Potentially could have data as early as this year. We'll see how the rest of the escalation goes. Of course, in 2026 is the readout of our first phase III trial called OPERA-01. That's our monotherapy second, third line pivotal phase III trial. That could, if successful, lead to a filing in late 2026 or early 2027 and an approval and commercial launch in late 2027. Continuous with all of that going on, of course, we signed a very significant agreement for us with Novartis late last year, raised a big private placement that helped to enable the initiation of what we call OPERA-02. OPERA-02 is our frontline metastatic breast cancer study in combination with ribociclib versus an aromatase inhibitor with ribociclib. We are very much looking to initiating that study very near term.
A lot of the pre-startup is ongoing now. That is a longer trial. We anticipate the control arm is probably around two years, median PFS, and we hope to achieve at least a six-month benefit over that. That is probably looking for data in late 2028 or in that time frame.
Fantastic. Like you said, this year's mostly execution for you guys. What should we expect in that clinical update for the phase II, the ribo-combo study? What do you hope to present then? When should we expect to see it?
I think if you look across this asset class, which people broadly characterize as SERDs, and we talk a little bit about mechanism being a complete antagonist and shutting off both parts of that receptor. I think if you look across our landscape, monotherapy data, we believe we've shown best-in-class data not only in the mutant population, but also in wild type. In combination with CDK4/6, where I think every other agent has had to dose modify due to drug-drug interaction, we have not. We are able to dose patients full dose palazestrant with full dose ribociclib or previously full dose palbociclib. The data that we presented at San Antonio Breast last December was still immature in terms of efficacy. As you may recall from those PFS curves, had not yet achieved medians.
We updated in early March with a February data cut where we are still maturing data, but achieved a post-CDK4/6 patient population of about 13 months, median PFS, which I think when you look at the landscape again, when they have combined with CDK4/6, they have achieved seven-eight months. We truly believe we have a best-in-class molecule here. We will be updating. That should be fully mature data at one of the medical meetings towards the end of the year.
Oh, fantastic. I know when you guys presented the data, you did not have much data on that 14-patient treatment, i.e., patient.
Yeah.
Should we expect to see something there? Do you think there's a pretty good redo in terms of how palazestrant can perform the potential in frontline?
Yeah, so we enrolled in that ribociclib-combo trial. It was interesting how the enrollment went. We've now enrolled about probably 75 mg or so patients in combo with ribociclib. The majority are at the 120 mg, and a good sized cohort are at the 90 mg. When we enrolled in the 120 mg, interestingly with the sites, initially we had a good cohort of patients that had two prior CDK4/6s. This is the third time they were receiving a CDK4/6. We actually saw responses in that patient population. When you think about that, that's a patient that had an AI plus a 4/6. Maybe they then received fulvestrant plus a different 4/6. Now they're coming onto palazestrant plus ribo and seeing nice activity. As I think the investigators got comfortable with that trial, we started to move to what we more anticipated, which was patients with one prior 4/6.
Probably more true second line patients with one prior 4/6. Now this is the second time they're getting 4/6. Very interestingly, and we allowed in the inclusion and exclusion criteria, they started to put frontline patients. As you said, we had about 14 patients, I think it might have been now up to 16 patients or so frontline patients at the 120 mg dose. When we presented at San Antonio, those patients were enrolled late when we enrolled them. That data was immature. You would anticipate we might be able to break that out going forward.
Fantastic. Okay. So besides.
We did, by the way, show the subset of the post of one prior CDK4/6, which was the 13 months.
Right, right, right. Besides providing ribo to your phase III studies, and I think some of your ongoing phase II studies, is Novartis advising or contributing to your phase III trial sites or initiation or execution?
Yeah, so they're obviously a collaboration partner. We lead on the execution of the trial. We lead on the regulatory interactions. They had certain rights to participate. They give us feedback. We share data. If we're going to meet with the FDA, like we recently did, we share, say, the briefing book with them. They're able to comment on it. They're absolutely involved where we take the lead on the execution of the trial and the data. They share the data, the results. They'll be able to use the results if they choose to, for instance, in the ribociclib label. I think, as you know, as part of that agreement, we gave them certain rights potentially around partnering in the future of palazestrant and on other strategic activity if that were to unfold.
I see. Okay. Let's talk about Olema stock price for a little bit and what it has been through. Last year when we hosted you around this time, the stock price was around $13-$14. We were still waiting for more mature data from, like you said, your phase II ribo-combo study. It was also unclear how you would fund the phase III frontline ribo-combo study. Fast forward to today, you guys presented very impressive data. You have clarity over the funding for your phase III frontline study. With all that positive development and achievement, your stock price is now below $5. A lot of it was due to your competitors reporting worse than expected data and the market applying negative redo to palazestrant. These include EMBER-3, VERITAC-2, SERENA-6.
Before we dive into some of those trials and what that means and the redo from those, should investors see this as a greatly dislocated buying opportunity, or are they justified to believe that the risk is now much greater based on all your competitors' data and that the risk is much greater than what we believed a year ago?
Yeah. Yeah, there's a lot packed into that. I mean, yeah, if you look at where we are today as a business, as a company with our development program versus a year ago, I would say we've created a significant amount of value. With our OPERA-01 trial, a year ago, we were enrolling part one. We finished that enrollment late September, early October time frame and had to pause, let that data mature, go and meet with the FDA, choose a dose. You may recall we enrolled three different groups, the control arm, 90 mg and 120 mg. We've recently announced we had successful interactions with the FDA, post-NDMC meeting, and selected 90 mg going forward. We're now enrolling the part two portion of that, and we're that much closer to the top line data in OPERA-01.
With the KAT6 program, we were wrapping up IND enabling studies a year ago. We successfully finished that, filed the IND, and we're now well away along the way into the clinic with our KAT6 program. There was uncertainty on the path forward for how we were going to execute OPERA-02, the big frontline trial. We were obviously at that point in time, we were in discussions with Novartis about that path forward, but we announced that. We raised the capital. Today we're on the cusp of initiating that trial, which we think will be very, has the potential to be very impactful for frontline breast cancer patients. I think we've done a significant amount of value creation. Yet, yeah, you're right, the stock price is at a much lower price. We're probably trading around cash, plus or minus.
We have had readouts from the landscape, I would say, mixed perceptions about the success or failure of them. We anticipate we will see approvals coming for both the ARV-471 vepdegestrant as well as potentially for Lilly with imlunestrant. Likely restricted in the ESR1 mutant-only patient population was not a surprise to us really in terms of the results. I think as you know, we have some of the first frontline trials going to be reading out over the next 12 months.
Right. So we already debated the details of EMBER-3, I think back in December after San Antonio. I highly recommend anyone who missed that to review our discussion. I think that was back then with Sean. I would like to hear your thought about what we saw recently at ASCO for VERITAC-2 and also SERENA-6. Why don't we kick off with VERITAC-2 and what are your thoughts? Anything that surprised you there?
I mean, for us, it wasn't a big surprise. We knew they had good activity in the ESR1 mutant patient population, and that's where they were stat-sig. I think their hazard ratio was about 0.57 on a BICR analysis. I believe they're filing or have filed for approval with that patient population. When we had previously looked at their activity in a later line patient population that was still wild type, we hadn't seen activity there. It wasn't a surprise, I think, that both they didn't break. They only showed the ITT, I believe, in the ESR1 mutant. They didn't actually show the wild type subset. I think that they were sort of the fulvestrant arm and the vepdegestrant arm were on top of each other. The hazard ratio was 1.1, but I think the curves likely didn't really separate.
That wasn't a big surprise to us. I think that they're still finding a path forward for their combination studies, whether or not they can do that in combination in the second line or in the frontline. With SERENA-6, for us, SERENA-6 is really a preview to SERENA-4, which is the 1,400 or so patient study from AstraZeneca that's anticipated to read out next year. The SERENA-6 was a bit of a peculiar trial design where they're doing serial ESR1 mutant ct DNA testing on frontline patients to determine when they go from wild type to ESR1 mutant. They randomize patients to either stay on their current AI and CDK4/6 or to switch over to camizestrant plus the same CDK4/6 that they were on. They didn't enroll all patients at baseline.
Patients were allowed to go into screening with a minimum of six months, but there was variability on when patients enrolled, how much prior time they had been on their 4/6 and AI. You look at the overall results, the hazard ratio, I believe was 0.44 or 0.43, depends on the presentation or the publication that you look at, which is a very strong hazard ratio. If you look at the milestones, they have really nice separation versus patients that stay on the AI. I think there was a little bit of disappointment that the seven- to eight-month separation that they saw, people were hoping for another, I think another month or two, maybe towards 10 months.
If you look at the 75 mg camizestrant data, it's actually fairly consistent with their second line combination data when patients, say, to progress on a prior 4/6, where I think it was SERENA-1, one of the SERENA-1 subsets, that they got about eight months. Right? So it's kind of consistent with their prior phase II data, combination data. We'll see if the frontline SERENA-4 can get a bigger separation or when they're enrolling all patients who are still highly endocrine-sensitive, right? Frontline patients are going to be highly endocrine-sensitive that they enroll. And it's a much bigger and pretty well-powered study. We're looking forward to seeing the SERENA-4 results. We're looking forward to seeing the PersevERA results when they come later this year.
Both of those drugs are in those frontline studies at the lowest, really the lowest dose they tested in the clinic because I think they had some issues around cardio tox or retinal tox. I think, again, we differentiate because we are at a very high exposure. If you look at the plasma drug exposure of palazestrant at 90 mg or 120 mg, it averages north of 300 ng/ mL at steady state. You know, I think we have about a seven to eight day half-life. Others have a 24 hour-48 hour half-life. We get at steady state, really nice, high consistent exposure, much higher drug plasma exposure than really any of the competitors. We think that's a significant advantage, the PK exposure, the compatibility at full dose, full dose, the fact that we're a complete antagonist and shut off both activating domains of the receptor.
It all comes together into a really nice package that we think delivers a best in class opportunity with palazestrant.
Okay, fantastic. Let's go back to VERITAC-2 a little bit. I think they did show some wild type look worse than ORSERDU in that population. That was a little surprising because when you look at VERITAC-2's design, they excluded any prior fulvestrant use. That was one, I think one change, one difference between their trial and also your trial. Is there any redo from to palazestrant? I know you guys were confident that you guys can hit the wild type. Any concern just looking at how VERITAC-2 turned out and any redo to palazestrant ability to show benefit in the wild type in OPERA-01?
Yeah. If you look at the VERITAC-2 study and you look at the ORSERDU study that got their approval, which is called EMERALD, both were very good, we think, well-designed, well-controlled studies. Slightly different inclusion-exclusion criteria. VERITAC-2 required no prior fulvestrant and no prior chemo and a minimum of six months on their last endocrine therapy, which is a slight variation from the EMERALD study. I would say our OPERA-01 trial is somewhere in between. We are allowing second and third line patients, we're allowing prior fulvestrant, but no prior chemo similar to VERITAC-2 and a minimum of six months on your last endocrine therapy. I would say three of the trials are very similar in terms of design, inclusion, exclusion criteria. We like those two trials.
We'll probably have a slightly more patient population slanted towards EMERALD versus VERITAC-2, given we're allowing prior fulvestrant. If you go to, again, how does the phase III data show up that then gives you guidance into what the phase III might look to? Again, we saw good activity in ESR1 mutant with both of those assets or those candidates, but not really much in terms of wild type. I think that's where you really differentiate with palazestrant. We have great activity in ESR1 mutant, and we have very nice activity in wild type patients. If you look at our, we enrolled, I would say, about 80+ patients at 120 mg. About 60% of those met the EMERALD criteria. And in the ESR1 mutant subset, again, that's a bit of a post hoc and a single arm trial, so all the caveats that go with that.
We got about a little over seven months in ESR1 mutant and about five, five and a half months in the wild type patient population. You look at for the approval and what you need to see for separation versus the control arm is probably about one cycle or one scan, which is every eight weeks or call it two months. We know or we believe that we are going to evaluate in our OPERA-01 trial both ESR1 mutant and ESR1 wild type patients separately. For approval, we think we need to show about a two-month benefit over the control arm in each subset and a hazard ratio that is clinically meaningful and statistically significant.
Fantastic. Okay. I know you're also in the six a little bit earlier. Some investors saw it as a potential redo for how a more potent SERD could improve over AI and de-risk the frontline opportunity. Just to be honest, I actually didn't see it that way. I mean, the trial was obviously biased toward ESR1 mutation. The first line includes all patients, not just ESR1. I also didn't get how this trial could provide any more redo learning than your phase II rival combo trial, but all patients already progressed on frontline on a CDK4/6 and many times, multiple CDK4/6. I never saw how the trial's relevant or the opportunity being real since switching patients to a more potent endocrine therapy while they have not yet progressed in 1L may not have any benefit over putting them on a more potent SERD after they progressed.
That's the PFS2 question. That's still immature.
Right. We did not really publish much on SERENA-6 and did not really feel the need to do so. Did I miss anything in terms of any useful redo? Maybe just like, did any of that help de-risk the way that you think about frontline?
Look, they did have nice separation, right? People were, I think, were hoping for more separation. Similar to EMBER-3, I mean, clearly in combination, the combo agent in later line patients looks stronger than the monotherapy imlunestrant. If you look at our rival combo in a second line post CDK4/6, where we're achieving about 13 months, you know, 12+ months, that looks good. Those are patients that were on the AI CDK4/6 and progressed. And then effectively you switch out the AI and give them palazestrant instead, and now they get another 12+ months. In a later line population, we believe if you come earlier in frontline, you should achieve that or potentially more, right? That is the hypothesis we're going to test in OPERA-02. We will see what happens with some of our competitors in their frontline studies.
Again, we're hoping that they do well because it'd be great for breast cancer patients to have an improvement over aromatase inhibitors. Aromatase inhibitors have been out for about 30 years now and are still sort of frontline standard of care. We do need innovation in this space. We know there's limitations with how they're dosing their drugs.
Right. I asked a question at the late breaker at ASCO, and I'm going to ask you the same question. Based on what you saw for vepdegestrant.
I heard that, by the way. I remember you on that.
Based on what you saw for VERITAC-2 and also for EMBER-3, do you see any differentiation for imlunestrant or vepdegestrant compared to ORSERDU as these drugs are gearing for their NDA filing?
Yeah.
How do you think these drugs will be used compared to ORSERDU in a commercial setting?
It's a good question. I mean, look, so I think they're either under review or will be under review soon. I'm not sure where Arvinas is with their submission. We'll see what the lead looks like. I think on the surface of it, each of those assets seem to achieve about a one cycle or one scan, about a two- to three-month benefit over the control arm. There isn't significant, and they all seem likely to be ESR1 mutant only in terms of the label. It doesn't seem to be significant differentiation in terms of the efficacy. The hazard ratios are all in a similar spot. We'll see from a tolerability perspective if there's differentiation there. Commercially, that could affect the uptake. I think more drugs on the market maybe can help increase penetration into this group for physicians.
We know that if you can safely use them in combination, that seems to be good for patients now. Vepdegestrant seemed to have a DDI with palbociclib, so maybe you can't safely do that. We know that fulvestrant is very often, at least in the United States, being used in combination with the 4/6 in a second line setting. Some of the primary market research that we've done has shown that elacestrant or ORSERDU is being used according to label. Just as a monotherapy and ESR1 mutant only, but maybe with more approvals with these drugs, the overall penetration into that market will get bigger as well.
Got it. Let's expand that discussion to palliative. What do you think palliative needs to achieve in OPERA-01 to be considered best in class at this point and then succeed commercially over these drugs because you guys will come after the potential launch of these drugs? What is the bar for commercial success?
Yeah. I think if we're successful, what we will hope to do is to repeat what we showed in our phase II study. If we can achieve seven months versus a two- to three-month control arm in OPERA-02, that would lead to a better profile in the ESR1 mutant patient population. That would lead to a stronger hazard ratio versus the control arm. Doing better in ESR1 mutant with a better agent. In addition to that, and this is the big one, is also achieving activity to get the wild type on label. If we're successful in doing that, then it means there's no prior authorization. Today, there's a prior authorization with the Guardant test. You have to take the blood test, send it off to Guardant, confirm whether or not you're ESR1 mutant or not. If you're mutant, you get ORSERDU.
If you're not, you get fulvestrant. If you're successful in getting the broad label, then from a commercial perspective, there's no more prior authorization because you don't have to check for it. That's a massive advantage commercially.
Right. Okay, so let's move on to future trials. The next trial reading out was Roche's giredestrant. Giredestrant is a SERD just like palazestrant. Their phase III frontline combo study with palbociclib will be reading out soon. The trial basically will test if, for the first time, we'll see if a next-gen SERD can beat an aromatase inhibitor in a frontline setting. What are your thoughts on this one in terms of the readout if the trial succeeds or fails? Any caveats there? Because we saw we did not see giredestrant having success as a single agent in the earlier line study in both ITT and also even for ESR1 patients.
Yeah. So you know if you had asked us five years ago when we were sort of entering the clinic with palazestrant, you asked our scientific founders which of the competitors' SERDs they like the most, they would have told you giredestrant. It's got great potency on the target. You know, as they went through their early clinical development, they chose 100 mg as their go-forward dose. At the time, the CDK4/6 of choice was palbociclib. They went and combined with Palbo and they noticed that they had a DDI similar to others. As a result of that, they dose reduced. They wanted a single dose, is our understanding, across monotherapy and combination. So they dose reduced from 100 mg down to 30 mg. That's a threefold reduction.
If you look at the exposure that they get, now their exposure is sort of below where we think the target exposure is at 30 mg. At 100 mg, they would have been well above it. We think that may have been a bit of a liability for them in terms of not having the right pharmacology in the monotherapy trial that they did, Axelera. If you look at Axelera, they came very close to hitting the ESR1 mutant subset. I think the hazard ratio was 0.6, but because it was not well powered in a post CDK4/6 patient population, it was not stat-safe. They have an active drug. The question is, is 30 mg enough in the monotherapy setting? It was not, clearly, or at least it was not powered enough in a post. It was a bit of a trial design issue.
For PersevERA, when you combine with the full 125 mg, because they're combining with full palbociclib, hopefully there's enough synergy there to show activity and to beat the aromatase inhibitor combination. We will see. It's a 1,000 patient study, similar in design to our OPERA-02. If we had to handicap it, that's the one risk we would highlight is, is the 30 mg in combo with Palbo enough exposure? We hope they win. We hope they show good activity vis-à-vis the AI. We'll see. Hopefully we'll see that by the end of this year. It would be, I think, a big win again for the patients living with metastatic breast cancer, as well as I think it would imply success towards our OPERA-02.
I would say that our OPERA-02 trial design, again, going back to our phase III combination data, we're the only one combining with ribociclib. Obviously, the CDK4/6 market today is very different than it was three or four or five years ago. We're now, I think almost any physician you would talk to in the United States would say that ribociclib is their go-to CDK4/6. We're the only one running a phase III frontline trial with ribociclib. Our phase III data looks, in our belief, head and shoulders better than anybody else's combination data.
I see. Every time I see your competitors reading out the trials, I can't help but be nervous about the implication to Olema stock price because it has not been correlating well.
Yeah.
Should investors apply a redo if these trials succeed, fail, or show results? Your hypothesis is that palazestrant is differentiated by being a SERM and able to show them both AF1 and AF2 activity of the estrogen receptor, while SERDs such as ORSERDU, vepdegestrant as a degrader can only target AF2 and not AF1. In some cases, it only turns on AF1 even more. Do you think palazestrant is fundamentally different from giredestrant or camizestrant since these are all SERMs?
You're absolutely right that if we can consider the SERMs, SERDs like vepdegestrant or ORSERDU, that in the wild type setting, they can activate, they can actually turn on AF1. And we have preclinical data to demonstrate that. You're also correct when you say that imlunestrant or giredestrant and camizestrant are complete antagonists. They shut off AF1 and AF2 molecularly. When you get into the clinic, they have all been limited by getting enough exposure. From a pharmacology perspective, what is the plasma drug concentration they can achieve? They're at their lowest doses, 30 mg for giredestrant. They wanted to be at 100 mg. Seventy-five milligrams for camizestrant. They tested 300 mg in SERENA-2 and had to drop it because of toxicity. They also tested 150 mg and ended up at 75 mg. They're at their lowest dose. We think we are differentiated from the other SERDs.
Combine ability of full dose, full dose. It makes a difference. Pharmacology matters. We think that's going to play out in the clinic. I say be patient. From a value perspective, in Olema, you've got two clinical assets. KAT6 is coming fast and furious. We think it's the most exciting new target in breast cancer. Pfizer's got very strong data. We'll see their path forward in the clinic towards a pivotal trial. We're very much looking forward to presenting some of our data, certainly within the next 12 months, potentially by the end of this year.
Got it. Going forward in the randomization portion of the OPERA-01 study, you guys will be using 90 mg instead of 120 mg.
Yeah.
Any concern there as not being the full dose or instead the full dose?
No. You know, if you look at 90 mg versus 120 mg, it's not that much of a difference from a PK exposure. If you look at our plasma drug exposure at 90 mg, 120 mg, they're effectively close to overlapping. Both are well above our predetermined exposure target based on our most difficult to treat preclinical xenograft model. Our 90 mg is well above our target exposure. It's well above the 30 mg giredestrant, certainly above the 75 mg camizestrant in terms of plasma drug levels.
Got it. So my final question back to you for concluding remarks is that why is Olema a good investment at this time?
Look, I think we've got two great, I think, drug candidates in clinical development generating, you know, we're enrolling patients every month. We're generating new data. I think the next 12+ months are going to be pretty interesting for the company. Breast cancer is obviously the largest cancer affecting women. Breast and lung are the two biggest oncology markets. You know, we're going after formidable competitors with Roche and AstraZeneca and Eli Lilly. You know, you've got little Olema. I think it's a great opportunity.
Fantastic. Shane, that's all the time we have. Thank you for coming. We appreciate hosting you today and Olema for the second time at our conference. Before we say goodbye, I'll turn it to you for a final remark.
No, thanks for having us. It's good to be in Miami. This is sort of the last, I think, conference before there's a bit of a summer break and we gear back up in the fall.
Great.
Thank you.
Thanks again.