Olema Pharmaceuticals, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

All right. Well, thank you all for coming today, and coming to the Morgan Stanley 24th Annual Global Healthcare Conference. My name is Ryuk Byun. I am head of West Coast Healthcare and Investment Banking for Morgan Stanley. I have the pleasure of hosting Sean P. Bohen, CEO of Olema. I think as we think about just to jump right in, the market keeps lumping every oral SERD together. You have to forecast a molecule by its own data, and from my standpoint, palazestrant does not look like everyone else's SERD. Why is treating this as one monolithic class the core mistake that investors are making?

Yeah. So, thank you, first of all, for the opportunity and the people here for listening to the Olema story. I think that there are a number of reasons why lumping these molecules together is a mistake, beyond an oversimplification. First of all, mechanistically, there are key differences. So palazestrant is a complete estrogen receptor antagonist. It binds and shuts off the estrogen receptor signal, growth and proliferation signal completely. That is true in the context of the wild type receptor, where it competes for estrogen, but also the ESR1 mutated receptor, which is turned on without estrogen needed. Some molecules are SERMs. They are agonists in some contexts, and you do not want to turn on the estrogen receptor in these cancers. In other cases, it is really got to do with exposure and pharmacology, right?

You need to have a high level of drug to force receptor binding and keep the receptor off all the time, because estrogen receptor is a transcription factor, so its signal is highly amplified, and we have by far the best exposure within the class. Then finally, combinability becomes very important. Our first phase III to read out in Q1, OPERA-01, is a monotherapy trial. The larger opportunity with this class of drugs is in combination with other targeted agents. We have found uniquely that we are able to combine with multiple different modalities without having to compromise our dose and without enhancement of toxicity. Why do investors do this, then? Why do they lump it all together? Well, I think the simple answer is it is complex.

Yeah. If you decide to do that, then you decide to ignore some very important data.

Yeah that can distinguish the molecules.

Got it. Thank you. Maybe just since it's topical on the SERENA-4.

Yeah. It seems like from my perspective, the first line misses are about exposure and dose, not necessarily mechanism. camizestrant carries, as you said, the lowest exposure of all the oral SERDs because of its tolerability ceiling.

Yes. Isn't that the very problem palazestrant designed out from the very beginning?

It is. It is one of the many. When the founders of palazestrant really took this on a little less than 10 years ago, other companies were working on this. By the way, they were addressing as well that they had also gotten to the concept that you want a complete antagonist. Camizestrant molecularly is a complete antagonist. Giredestrant, the Roche molecule, is a complete antagonist. They had made that observation as we did at Olema. But in looking at those molecules, it would seem that there were these liabilities, that they did not have high enough exposure. They had tolerability problems, and those tolerability problems are exacerbated in combination. The objective in designing palazestrant was let us address all these things. We have successfully achieved that. That is all demonstrated. But one of the obvious conclusions of wanting to address those things is also saying, "Hey, look, these liabilities are going to turn into limitations when you test these things for efficacy." We do not know what the data is from SERENA-4.

All we have is this cryptic, numerically different, for PFS. We do know what the data is from persevERA, from the Roche compound in its first-line phase III, and that data clearly indicates that there is better activity of an oral SERD than an aromatase inhibitor. They had a 5-month delta in PFS. They had a clear trend for hazard ratio, but did not quite make Yeah statistical significance, and that in spite of some design flaws.

I think those molecules demonstrate two things. One, we are leaving efficacy on the table with AIs, and we can improve upon it. Two, these liabilities, in terms of exposure and combinability, are turning into liabilities when you look at achieving a clinically meaningful outcome.

Got it. Thank you. Since you mentioned it, persevERA, what folks may flippantly call a negative trial, still delivered about a 5-month PFS delta.

Yeah while they were carrying about 10% endocrine-resistant patients, which diluted some of the treatment effect and efficacy signals.

In terms of your own trial, OPERA-02, can you tell us about how you've thought about patient selection exclusion, and also your decision to run a ribociclib backbone?