Olema Pharmaceuticals, Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Great. Thank you, Emily. Good morning. Thanks for the chance to talk about Olema. We have been working on this problem for over a decade. The problem underlying is that the most common malignancy in women is breast cancer. The most common subtype, about 70%, is ER-positive, HER2-negative breast cancer. The disease has been known for decades to be primarily driven by the estrogen receptor growth and proliferation signal. Obviously, inhibiting that signal, turning off the estrogen receptor, is a key therapeutic modality in this cancer. We have also known for decades that we are not doing that optimally. Our lead asset, palazestrant, is a complete estrogen receptor antagonist with very high exposure, favorable tolerability, and a unique ability to combine with other targeted agents at full dose without pharmacological PK effects and without enhancement of toxicity.

We are testing that in two phase III trials right now. The first is OPERA-01. It is a second, third-line trial, so these are patients who have progressed on the first-line standard of care, which is a CDK4/6 inhibitor, now specifically KISQALI or ribociclib and an AI, and then are looking for alternative therapy after that. That trial will read out in Q1 of 2027. It is fully enrolled. At this point, what we are doing is we are really waiting for the assessment of progressions, the radiographic outcome, and sort of maturation of that data to be able to read out the trial. There are two relevant subsets in that patient population. About 40%-50% of the patients, their tumor will harbor an ESR1 activating mutation. That is the gene that encodes the estrogen receptor.

There is some demonstration that the next generation endocrine agents have better activity in that population. The remainder of the patients do not have a mutation, and they are a wild type genotype of their estrogen receptor. That is a place where no alternative therapy really has been successful, again, in decades. We, based on our phase II data, have some confidence that we should have an opportunity to address both populations, and that is being tested in the OPERA-01 trial. The second phase III trial is in the first-line setting. The first-line standard of care for metastatic ER-positive, HER2-negative breast cancer is pretty standardized. It is KISQALI or ribociclib plus an AI now based on the survival benefit shown by that regimen. We are testing the combination with KISQALI and palazestrant, which had, again, very promising phase II data.

We had over a year median progression-free survival in the post-CDK4/6 progression environment, including about 30% of patients who had actually had two prior CDK4/6 inhibitors and now going on to their third CDK4/6 inhibitor with KISQALI and combined with palazestrant. We think that's very promising. That's enrolling very well now. Again, a place where other agents in combination with IBRANCE, not KISQALI, have not succeeded. We have a second clinical asset, a KAT6 inhibitor called OP-3136. We presented that data at ASCO as monotherapy, but we have the combinations in breast cancer ongoing. Interestingly and uniquely, we also saw activity in castration-resistant prostate cancer. That combination with the androgen receptor inhibitor NUBEQA will start in Q4.

Right. Mechanistically, it's the complete antagonism. It's the ability to completely turn off the growth and proliferation transcriptional signal of the estrogen receptor. The first of the molecules to be positive was elacestrant or ORSERDU. That's a SERM. It's a partial antagonist, partial agonist, so it's turning the receptor on in some situations. You don't want to do that. Now, in the context of a ESR1 mutated receptor, that receptor's on all the time anyway. The normal biology of the estrogen receptor is it's a ligand-regulated transcription factor. It is inactive if estrogen isn't present. But these mutations, they're point mutations in the ligand binding domain. They actually turn it on without estrogen, and ORSERDU partially turns that off. That led to activity in the ESR1 mutated setting. But as you said, nothing has succeeded in wild type.

Our confidence comes from complete antagonism, very high exposure. This is a monotherapy trial, so the combinability isn't really as much of a factor. Then in our phase II data, in ESR1 wild-type setting, we saw 5.5 months median PFS in phase II, and that's more than anyone's seen, even with a mutant, in that second line setting. The question, of course, in OPERA-01 is can we reproduce it in the phase III?

Statistically, for sure. The important part in this line of therapy is clinically significant. Clinically significant is kind of generally agreed to be a 2-month prolongation of PFS. The control arm should be 2-3 months median PFS. That's been seen in multiple trials in this post-CDK4/6, progression setting. If you see 2-3 months, obviously if we reproduce something like 5.5, you're more than 2 months. imlunestrant was approved based on a 1.6 month prolongation of PFS. It's not hard and fast that it's 2 months, but that's really the range. Again, the question I think is not, was what we saw in phase II, if reproduced, clinically significant, but just can we reproduce it?

Yeah. There are a couple things to consider. One is that the overall second, third line market opportunity is about $5 billion a year, so it is very significant. If you divide that up, it is probably slightly more wild type than mutant, so it is kind of like $2 billion and change in the mutant, I am sorry, and about $3 billion in the wild type. If you get the mutant only, you are still in a significant market. The complexity there, as you mentioned before, is that it is competitive because there are other agents there. We think we have an opportunity not only to have an effective therapy there, but also to differentiate, and that differentiation would be a greater than 2 months prolongation of PFS. Every agent that has been successful there has been 2 months.

We saw 7.3 months in our phase II in the ESR1 mutated setting, and that again is unique. Then the question is, if we are able to reproduce that in the phase III, in OPERA-01, then that would be differentiated by efficacy, and that would be a significant opportunity.