Olema Pharmaceuticals Guggenheim 3rd Annual Healthcare Innovation Conference

Let's get started with this next session. Thank you for joining us. My name is Paul Jeng. I am a biotech analyst with Guggenheim, and our next presenting company is Olema, and I am very pleased to be joined by Sean Bohen, President and CEO. Sean, welcome. Thank you, Paul.

Nice to be here. Maybe a good place to start for those who are newer to the story, could you provide a quick introduction to the company and your pipeline?

Sure. Olema Oncology is a company focused on breast cancer, primarily ER-positive, HER2-negative breast cancer is by far the largest, about 70% of breast cancer. Obviously, breast cancer, the most common malignancy in women, second most common cause of cancer death in women, and a huge unmet need in market. Our lead asset is palazestrant. It is a complete estrogen receptor antagonist and a selective estrogen receptor degrader, and that compound is in two phase III trials right now. One is the second, third line setting, so after patients have progressed on their CDK4/6 inhibitor plus an AI, and that trial is called OPERA-01. The other arm is fulvestrant or exemestane. It will be mostly fulvestrant. And that trial reads out in Q1 of next year. There are several opportunities within that population.

First of all, that's an aggregate is about a $5 billion a year market opportunity, and it's divided by a mutational status. The most common resistance mutation to CDK4/6 plus AI is to activate the estrogen receptor, so that's ESR1 mutant subset. That's about 40% of patients, a $2 billion market on its own, and there are other compounds that have had some success there, but all of them, the increase in PFS is about two months. We saw 7.3 months in our phase II, so if we can get in that range, always a question of is phase II replicated in phase III, then we would potentially be distinguishing ourselves by greater efficacy, greater prolongation of PFS in the mutant setting. The wild-type setting, the remaining 60%, $3 billion opportunity, is really unaddressed. No one's shown any treatment effect there.

We had 5.5 months in phase II, and again, if we are able to replicate something in that range, we may be the first compound to be able to address that ESR1 wild type post-CDK4/6. Other than the phase II data I cited, the reason really to believe here is we have very high exposure in addition to being a complete estrogen receptor antagonist. The other ongoing, and enrolling very robustly, phase III trial is called OPERA-02. That is a first-line setting, metastatic, in combination with KISQALI. So that's KISQALI plus palazestrant versus KISQALI plus letrozole, the standard of care AI. In its current design, that's a 1,000-patient trial. We may change the size of that trial. We're going to see the SERENA-4 data from AstraZeneca in December.

It looks like the control arm may be performing a little better than historical, so that would lead us to potentially add patients to the trial. The advantages we have here, we saw over a year median PFS post-CDK4/6 plus AI with our ribo-palazestrant combo. The advantage we have here is that we don't enhance toxicity. We don't have to dose modify either agent in combination, and obviously, we're the only company that's gone into this setting with a new endocrine agent in the context of combination with KISQALI, which is the standard of care because of its survival benefit. That's a $10 billion plus market opportunity in that first-line setting. Other than our data, the Roche PERSEVERA trial with palbociclib showed a clear signal that there's activity that you can do better than an AI. It had some design flaws.

They also have a much lower exposure of their agent, and so I think we, again, with the phase II data, feel confident that we have an opportunity to do better than the AI in the KISQALI combination. We have a phase I/II agent, which is a KAT6 inhibitor, OP-3136. We have presented monotherapy data. Interestingly, we think the lead molecule's Pfizer, which clearly has activity in breast cancer with fulvestrant. We saw monotherapy activity in breast cancer, interestingly, and different than Pfizer, we also saw monotherapy activity in prostate cancer, castration-resistant prostate cancer. So we are now expanding into prostate cancer in combination with NUBEQA. We don't have DLTs yet. We don't have an MTD, but we are combining with fulvestrant and with palazestrant, so the lead molecule. The palazestrant combo preclinically looks more active than anything we've seen, including the fulvestrant combo.

We're going to show the first fulvestrant combo data at San Antonio as a late-breaking abstract, and so that'll be some dose escalation data, but you will see early efficacy as well as combinability in that context. We do feel like there's a real opportunity to differentiate by efficacy, by tolerability, particularly cytopenias, rate of cell count decreases. Then obviously, the combination with NUBEQA in prostate cancer is something that will begin enrollment very soon.

Okay, great. Lots of topics to cover, obviously.

Yeah. Maybe starting with OPERA-01.

As you alluded to, there's been a history of this sort of class of agents in the setting.

Right Where ESR1 wild type has sort of been an unaddressed segment.

You alluded to the pharmacology and some of the clinical data, but what really gives you the most confidence that you could work potentially in this segment compared to others in the class?

Yeah, I mean, I do think the phase II data is probably the greatest factor that gives us confidence that there's an opportunity here. Just to remind everybody what happens in the context of fulvestrant or exemestane is really in this population, two, maybe three months is what you get as a median PFS with those agents. To be able to extend by a couple months or even close to that would be really differentiating and create a meaningful opportunity there. That's obviously what's being tested in OPERA-01, in addition to activity in the ESR1 mutant subset. Why would you have activity there when others haven't? Again, not all of the molecules, in particular the lead molecule there, ORSERDU, is not a complete estrogen receptor antagonist. It's a SERM. It's actually turning on the wild type receptor in some contexts, and you obviously don't want to do that in any context in ER-positive breast cancer.