Everybody, welcome to the Jefferies Healthcare Conference. My name is Dennis Ding, SmidCap Biotech Analyst here. I have the great pleasure of having Sean Bohen, CEO of Olema Pharmaceuticals here. Welcome.
Thank you, Dennis.
What a time to be alive in breast cancer, right?
It's exciting.
In terms of all the progress made in the space and all the different mechanisms, and just coming out of ASCO as well. Before we get to persevERA and just some of your thoughts, I'd love to talk a little bit more about CDK6. I think it deserves a lot more airtime. Maybe just remind us of what you guys presented at ASCO for CDK6 and the path forward there?
Thank you, and thanks for the opportunity to share that. We had a poster on Saturday, a very well-attended poster on our phase I single-agent dose escalation for OP-3136. This molecule inhibits CDK6 A, B, and also KAT6 at the exposures that we are achieving. What we saw, I think quite encouragingly, was single-agent activity in ER-positive, HER2-negative breast cancer, heavily pretreated patients at multiple dose levels. In addition, and differentiating from an efficacy standpoint, we saw clear monotherapy activity in castration-resistant prostate cancer, and that obviously presents a significant therapeutic opportunity. There's another differentiation opportunity, which is tolerability, and in particular, the cytopenias that are caused by some in the class. The lead molecule from Pfizer at their 5 mg dose, which is in phase III, has 50% of patients dose reducing because of cytopenias.
What we saw was a considerably lower rate and also lower grade of cytopenias in breast cancer. We saw 22% grade 3. We saw no grade 4 toxicity of any kind, no DLT. We don't have an MTD yet up through 60 mgs daily, and that's about half of the grade 3/4 toxicity that Pfizer saw, in addition without any grade 4 toxicity. What that presents potentially is an opportunity to expand from the doublets, which are ongoing with fulvestrant and palazestrant, into triplets. To add in CDK inhibition into the endocrine therapy and the CDK6, which would be unique and really an opportunity to possibly stop three mechanisms of the advancement of the cancer.
We also, the week before, announced a collaboration agreement and a clinical trial supply in collaboration with Bayer for Nubeqa, their androgen receptor inhibitor, to be combined with OP-3136 in prostate cancer. That will start in the not-too-distant future.
Perfect. To be clear, this is dose escalation from two mgs to 45 mgs. Also what's differentiating here is prostate cancer as well, which I believe Pfizer does not have any responses there. Also on safety, I think the nuance there is that even though when you compare the safety table side by side with Pfizer, your levels were numerically higher, but maybe that's because of prostate cancer, right? When you back that out-
They aren't for neutropenia. For neutropenia, they're lower.
They're lower.
Ours is 33, and theirs is 44.
Yeah.
It is true, though, that when you back out breast cancer, you go down to 22, and we think there are a few reasons for that. One is the prior treatment. Prostate cancer patients tend to get a taxane, docetaxel. About 70% of the patients had had prior chemotherapy. There's also a treatment modality that gets used in prostate cancer that just isn't used in breast cancer, and that's radioimmunotherapy, Pluvicto, which targets the tumors primarily in the bone in prostate cancer. Obviously you're now targeting a radioisotope to the bone, which has marrow effects, and so those patients are probably more predisposed to cytopenias.
Got it. Okay. In terms of the PK data that you guys presented.
Yeah
It doesn't seem like you guys have hit any dose-limiting tox, right?
We have not yet.
You continue to dose escalate. I guess, how high do you think you'll need to go?
That's a good question.
How will you make that determination, whether it's PK or PD data? Can you talk a little bit about that and when you think you'll be able to make that decision?
Yeah. That's a great question. So far at least, the old-school way of dose selection, right, which is you dose up until toxicity that's intolerable, and then you go the dose below, which is the maximum tolerated dose. That doesn't seem to be working, and we do have exposure targets that we've set based on the hardest-to-treat xenograft models in animals, and we're far exceeding that. We really exceed it starting at six mgs. With the 60 mg dose, data was not presented, but that's enrolled. We're tenfold above that. We see, I think, pretty compelling activity. We see activity at all dose levels, but at 20 we see pretty compelling activity. I think there are several factors that will come in. First of all, with Project Optimus, you're going to expand at two dose levels. That's part of it, so we have to choose those.
Probably 20 and something above. The other thing we want to factor in is combination activity. We have fulvestrant and palazestrant. In breast cancer, you don't give these targeted therapies as monotherapies. You always give them in combination with an endocrine agent. Our preclinical data suggests that palazestrant should be much more potent in combination than fulvestrant, not only with 3136, but we also tested the Pfizer compound, and it had the same effect there. That's ongoing in the clinic. With fulvestrant, we're just a little bit behind. The 45 mg cohort is enrolling now. We're, because it's a novel combination, a little bit further behind with palazestrant. Ideally, we'll be incorporating that data plus expansion at doses. I would guess it'll be next year before we're really certain of what dose we're going to move forward.
We do have the opportunity, I think, potentially as soon as the end of this year, to present the first combination data with the endocrine therapies. If not, certainly in the first half of next year, we would share that.
Okay. Again, for KAT6, the eventual profile of this product is not as monotherapy. It's going to be in combination, right?
Yeah. None of the targeted therapies that are used in breast cancer are given as monotherapy. If you think about CDK4/6's, PI3 kinase inhibitors, Akt, mTOR, all of it, you always have a backbone therapy, which is an endocrine therapy. In the second, third-line setting right now, that's a pretty poor one, which is fulvestrant. The opportunity here is to improve the targeted therapy by using a novel mechanism with a better agent, differentiated agent, but then also to incorporate a superior endocrine therapy in the combination.
Got it. For those combo studies, what are we looking for, or what are you looking for as you dose escalate? What's considered promising to you?
It is a place where in combination, you can use response rate, which is interesting in this disease because the mechanism of these particular targets is primarily not cytotoxic, it's cytostatic. You slow the growth and proliferation of the tumor. What we know from the Pfizer program is while they had a modest response rate as a monotherapy, when they combined with fulvestrant in the second-line setting, it went into the 30% range, high 30% range. That gives us an indication that as we start to advance dose and expansion of the combinations with 3136, we should be able to use response rate. The responses don't all come right away. They do take time.
Sure.
You have to follow the patients for a little while to really get a good estimate of it. That is a useful marker.
Okay. Presumably, that's in combo with fulvestrant, but what about for palazestrant, in terms of.
Yeah, I think we would use the-
Same
Exact same thing hopefully, see some differentiation there. Remember, palazestrant is able to differentiate from fulvestrant really in two very significant ways. One is if the preclinical data is recapitulated in people, there should be superior efficacy. Beyond that, patients don't want two large volume intramuscular injections every 28 days. They're painful. They don't provide a whole lot of exposure to the agent in fulvestrant. If you are able to advance KAT6 plus palazestrant, you have two daily oral pills, which is much preferred from a quality of life standpoint.
Perfect. Okay. That program continues to move forward. Maybe we'll get additional updates in the phase I through the second half of the year.
Yeah
maybe first half 2027.
Right.
Would love to talk about palazestrant and obviously, persevERA, we saw that data at ASCO. Would love to hear your initial thoughts and why it matters for Olema in OPERA-02.
Right. I think persevERA was interesting for palazestrant. I think it's important to recognize that palazestrant's data to date based on phase II, both as monotherapy and in combination with CDK4/6, particularly KISQALI, ribociclib, which is what we're using in phase III, which is what the standard of care is today in the first-line setting, is superior to what has been seen with any other estrogen receptor agent. That's probably because palazestrant is a complete estrogen receptor antagonist. It has an eight-day half-life with daily dosing, leads to a higher exposure than any of the other agents. In addition, one important differentiator is that its combinability is superior. We do not have to dose-reduce either palazestrant or a combination agent, we have tried a lot. We've combined with palbociclib, ribociclib, alpelisib, everolimus. We're combining with atirmociclib, the Pfizer CDK4 selective now. Obviously, OP-3136 is ongoing.
I'm sure we'll do more things in the future. Our confidence in palazestrant, both in OPERA-01 and OPERA-02, is primarily based on data with palazestrant. That said, persevERA, which is a study with Roche's SERD, giredestrant, combined with palbociclib, IBRANCE, which is an older standard of care, I think the data is encouraging. They did not have a positive trial. They didn't meet statistical significance with a hazard ratio of 0.89. However, if you look at their median delta in PFS, it was about five months, 4.9. We think that that is very much indicative of a couple of things. One, as we had all suspected, as their lidERA trial in the adjuvant showed, aromatase inhibitors are inadequately suppressing the growth and proliferation signal from the estrogen receptor. We are leaving some efficacy on the table.
We think that giredestrant partly addresses that, because of its inferior exposure is limited in its ability to do so. I think that what they showed us is that they're getting close to what would be needed to have a positive trial and change the standard of care. I think with our superior data with the better CDK4/6 choice in KISQALI, I think it bodes very well for the OPERA-02 study. There are some implications beyond that probability of success boost from persevERA, that is there are aspects of persevERA that we're going to look at to see if we might want to make changes to the OPERA-02 trial. In particular, the control arm in persevERA modestly outperformed the historical control. The historical control, PALOMA-2, was 24.8 months.
They got a little over 28 months of median PFS. We may want to revise the design of the OPERA-02 trial, in particular, the number of patients enrolled. We'll look at that now. We also may wait for SERENA-4, which is the AstraZeneca phase III trial. Very similar design, but larger than persevERA and AstraZeneca has communicated that will be out in the second half of the year, and if they stay to that timeline, we could use that, too.
Yeah. Okay. The study was encouraging, even though it didn't hit statistical significance in that there was numerical benefit on PFS, that PFS was clinically meaningful.
Yes.
And you could-
That's a good point.
Like you argue that giredestrant may not get the proper exposure, palbociclib may not be the best CDK4/6, and those are areas where you feel like you have an edge on top of what Roche has done.
Yeah. I think that's exactly right. You make a good point, which is that five months is clinically meaningful if you get something statistically significant that you can file. Six months is kind of the slam dunk extension of PFS and obviously they weren't that far actually off of it. If you talk to breast cancer doctors, if you talk to patients, patient advocates, they say at six months you change the standard of care. At five months, they say definitely that's meaningful to us and we would use it. Four probably also. You get below that, it starts to get more complicated. The tolerability profile becomes a more important consideration. We think with superior activity in phase II, five months making it that modest increase to six is well within striking distance.
I think it's also important to remind people that breast cancer is the most common malignancy in women, second most common cause of cancer death. These are big market opportunities. The first-line setting is $10+ billion annually. The second, third line is $5 billion if you get both a mutant and wild type and that's also applicable to the KAT6 program in breast cancer, not really accounting for prostate cancer at all.
What do you make of the baseline characteristics in persevERA? In terms of there were a few things that looked interesting in terms of visceral disease.
Yeah.
It seemed a little bit higher. De novo diagnosis just seemed a little bit lower.
Yeah.
How does some of that data and some of that subgroup data inform your approach to OPERA-02?
Yeah. There are some properties that you look at that are a little different than historical trials. It is true visceral disease at 60% is a little higher. Why is that important? Visceral disease is a generally poor prognostic factor. Just to remind everybody, ER-positive HER2-negative breast cancer, also true of prostate cancer. These endocrine-driven tumors have a propensity to go to the bone when they metastasize and in some patients you get disease only in the bone in the metastatic setting. That tends to be the majority of patients that don't have visceral disease. They just have bone-only disease. Those patients do better pretty much with all therapies. They progress more slowly. When you have more visceral disease patients, you probably have a more difficult to treat patient population. The other thing that they had is 20% de novo patients.
This is usually more like 30%-40%. Why did they have so much less? Well, they capped it. That's why, and it's not clear to us why you would do that. To explain the difference between the de novo and the endocrine experienced, when patients are diagnosed with metastatic breast cancer, they really come to that through two pathways. One is their first diagnosis of breast cancer, they are found to have metastatic disease, and that's de novo. Obviously what that means is that they've never received any prior treatment. They never had a diagnosis of breast cancer. When you're giving them their initial CDK4/6 plus endocrine therapy, they're naïve to prior treatment.
The other way, the somewhat more common way to reach the diagnosis is you got diagnosed with early breast cancer, you got adjuvant therapy, you finished it, you had at least a year off, and then you were diagnosed with metastatic disease subsequently. You're endocrine sensitive by that treatment history, but you are not endocrine naïve because you've had prior therapy.
Okay. Okay. In terms of some of the data that they've shown in Western Europe, which seemed really strange, I believe the hazard ratio was like 1.29 or something like that. That was a quarter of the study, right?
Yeah.
It didn't seem like Roche had a great explanation for that. Just curious if you have any sort of hypotheses?
Yeah, I don't have an explanation for it. It is a subset. It's 25% of the study, you do have to be careful. You get large error bars around that. It does trend in a different direction than the other geographies. Interestingly, North America and Asia looked pretty positive, right there in the mid-0.7 range for hazard ratio. The thing that we look at when we see that is we sort of say, "Well, why is this?" There are two ways you can get a hazard ratio like that. You can see an underperformance of one of the arms so that patients did less well in one of the arms than elsewhere in the world. That isn't what happened here.
What happened here is it looks like the control arm did quite well, better than it did in the other populations. It is really unclear to us why palbociclib-AI would do better in Europe than it would in the rest of the world. I think one thing that would be useful to know, and I don't know if we'll ever get it, is are the demographics, these attributes we were talking about, are they distributed unequally geographically? That's hard to tease out.
Yeah. Okay. Going back to OPERA-02, you mentioned that persevERA will obviously inform how you enroll the trial in terms of the powering and things like that, right? SERENA-4 supposedly is supposed to come out in the second half, and that could be another data point. Maybe just talk about the differences in patient populations between persevERA and SERENA-4. Maybe SERENA-4 might be a little bit sicker, a little bit more endocrine sensitive. Do you share that view and-
Yeah. It's a much larger trial, is I think the biggest difference. persevERA was just below 1,000 patients. OPERA-02 was 1,000 patients, so very similar to that. SERENA-4 is just under 1,400, so it's quite a bit larger trial. The other thing that happened in persevERA, which is a bit strange, is that at the beginning of the trial, they allowed a group of patients where if they had progressed within one year of their adjuvant therapy on tamoxifen, they could go on the trial, and that was about 10% of patients. We don't allow that. Actually, none of the other trials in the first-line setting, PALOMA-2, MONALEESA-3, you can go through, also true of SERENA-4 and OPERA-02, allow progression within one year of completion of adjuvant therapy. They then, the discussant or the speaker reminded us they amended the trial to exclude that.
Afterwards, that was out. Those patients didn't look to do particularly well on the trial. Again, a small subset. SERENA-4 has none of those patients, and so it's all endocrine sensitive. The concern with SERENA-4 is camizestrant because of its inferior tolerability profile has the lowest exposure of all of the agents. Because of the time, the era when they were started, both persevERA and SERENA-4 are being conducted with an old standard of care CDK4/6. That is IBRANCE.
The standard of care has moved to KISQALI because of the survival benefit that that molecule confers. By virtue of the time that we started OPERA-02, we're able to adapt to that newer standard of care. The interesting part, however, is the PFS is the same amongst the different CDK4/6 agents. We think that this is interesting and informative information, and it would just be great to have two data sets rather than one to help us understand.
Yeah. You're going to make some, I guess, depending on some of the data, you will make some adjustments because, it's very important in that you don't want the drug to fail the trial. I think the drug works, but you don't want the trial to fail the drug, right?
Yeah, this is very important. People may be asking, "Hey, 25 months historically. Now it's 28. What happened there? What happened in persevERA?" The truth is we can't be 100% sure, but what we know is that in oncology and cancer treatment, it is very common over time for a given regimen to perform better. That's probably a combination of oncologists becoming more comfortable maintaining dose intensity, managing the AEs more effectively, and ancillary care improving over time. We have seen this in other types of cancer with other regimens that if you look at that same regimen over time, it actually does improve. I think that this was not unexpected.
Okay. Do you have an expectation in terms of what the control arm would show in SERENA-4?
My guess is it's probably pretty close to what you see in persevERA. You pointed out, I don't know how much 10% of the patients would affect, but it may be a little marginally better because they didn't have these patients that have progressed within a year of their adjuvant. That's not allowed in SERENA-4 or OPERA-02. To us, the bigger thing is just having two data sets just increases your confidence if you are going to go out and make changes to a trial.
Okay. In the last five minutes, maybe we can talk a little bit about OPERA-01. I think that's one of the more near-term catalysts in the fall. Talk a little bit about that, your prior phase II data, and what gives you so much confidence, going to that readout.
Right. OPERA-01 is a trial in the second, third line setting. It is a monotherapy trial with the control arm being fulvestrant or exemestane. It'll be 70%-80% fulvestrant actually. When you go into that setting, there's a prevalence of the ESR1 activating mutation as a resistance mechanism. The way that OPERA-01 is designed is it's almost like two trials in one. The analysis plan allows us to analyze the mutant and wild-type population separately. There's precedent, right? For having activity as monotherapy in the mutant population in this setting.
The first of these was elacestrant, ORSERDU and EMERALD, showed a modest benefit, a two-month increase in PFS, and it has led to its approval and success commercially. We saw seven months, over 7.3 is what we actually saw in a EMERALD-like population in phase II, as opposed to IV. We're hopeful that not only can we be active in that ESR1 mutant population, but we can give a greater benefit, and that will be tested in OPERA-01. Interesting thing is that in that same phase II population, if you were ESR1 wild type, we saw 5.5 months median PFS, which again, is better than ORSERDU saw in the mutant population. They had two months, actually, no effect at all in the wild type. We are hopeful that we can generate data that says we can treat this whole population.
In the ESR1 wild type population, no one has been successful to date, that remains a significant unmet need. It's 50%-60% of the patients. It is a large opportunity. As you said, enrollment is going very, very well, and that trial will have its primary readout in the fall of this year.
If you hit on wild type in OPERA-01, wouldn't that give you more confidence in OPERA-02?
They're different populations. I think first of all, having more activity always gives you more confidence in the subsequent trials. Simply put, yes. At the same time, remember, as I described, and we talked about this in terms of differences between persevERA and SERENA-4 and OPERA-02, the population in the first line is almost all wild type.
Yeah
It's endocrine-sensitive wild type.
The population in the second, third line is biologically different. It's endocrine resistant because they've all progressed. It is required to enter the trial that you have progressed on a CDK4/6 plus an AI. We even allow them to have a second endocrine therapy, and then they would've had to progress on that. It is a biologically different population. For instance, in the second-line setting, giredestrant had very little activity. As we discussed, it came close, and certainly showed some evidence of activity in the persevERA setting. I think it's important to recognize those are biologically different.
Yeah. Maybe in the last minute or two, just OPERA-02 is in the 1st line, OPERA-01 is in second and third line, but o bviously with lidERA, they're moving into adjuvant. Talk about how important is moving into adjuvant for you guys and talk about what are some of the gating factors?
Right
I think is one of them. Just talk about how much of a priority is that for Olema over the next few years?
Yeah, capital's the big one. The first thing is, remember, we're a company with a market cap of about $1 billion, enterprise value about $500 million. I would argue we're undervalued just for OP-3136. You get palazestrant, that's a cumulative $15 billion market opportunity as a bonus.
In that respect, adjuvant is a really large market opportunity. It's a large unmet need. It's a great option for us. At the same time, I'm not particularly worried about it in terms of delivering shareholder value and value for patients. On the other hand, I think in a partnering discussion as we seek a collaborator, it's a really important topic because it is an opportunity we would like to access. The current problem is really that you can't do a trial like lidERA, again, monotherapy head-to-head. You have to incorporate a CDK4/6 because that's the adjuvant standard of care now. When you do that with the size of the trial, the length of the treatment, it becomes in excess of $1 billion to do that trial.
We don't have that. We're in a great cash position with half a billion dollars on the balance sheet at the end of Q1, runway in the second half of 2028, that does not include putting in a billion-dollar adjuvant trial.
Yeah. For sure. All right. Well, thank you so much, Sean for hanging out with us and for this great discussion, and hope you have a great conference.
Great. Thank you, Dennis.
Thank you.