Perfect. So, let's go ahead and get started here. Thanks, everybody, for joining us, tuning in, second day of the Piper Sandler, or third day, of the Piper Sandler Annual Healthcare Conference. I want to thank, the ESSA team here for joining us. We have David, Peter, and David, to take us through the next 25 minutes. Maybe first, before we jump into Q&A, David, I could give you a couple minutes. You could introduce ESSA, what you guys have been up to, and what we have to look forward to. Thank you, Joe. Well, first of all, it's a pleasure to be here. Thank you for the invitation. I'm here with my colleagues, Peter Virsik, who's our Chief Operating Officer, and David Wood, our Chief Financial Officer. Just to give you a sense as to why we're doing what we're doing, prostate cancer, particularly in its early stages, is uniquely driven, as I think most people know, by male hormone biology, by androgens. That's been known for more than seven decades, and what we've seen over the last seven decades are progressively improved methods, often with better generation agents, but sometimes with a combination of those agents, directed at interfering with male hormone biology in early stages of disease. Every single time that's been accomplished, it's translated to clinical benefit for men with prostate cancer. We think we represent the next phase of that. Our molecules, which are uniquely directed towards the other end of the receptor, the so-called N-terminal domain, interfere with transcription in a way that is completely different from the current anti-androgens, which are good drugs on the market. We're not trying to compete with them, but rather, we have shown preclinically that by combining our drug with current anti-androgens, by shutting down transcription by two different complementary mechanisms of action, two different ends of the receptor, we get even more suppression of androgen biology. And as I said, historically, that translates to clinical benefit. That's what we're about. That's why we're doing this, is to bring good quality of life with an oral tablet given once or twice a day in combination with current therapies to really, we believe, potentially, extend the life of men with prostate cancer. So that's why we're here. Yeah, great. That's perfect and a great jumping point. I, of course, want to talk about masofaniten and sort of the data you guys have generated and future plans. But maybe you could just sort of start with a high-level question. I think something you guys have spent a lot of time digging into and thinking about, and that's, you know, what we now maybe know about the level of androgen receptor signaling dependency in a later line, castration-resistant prostate cancer population versus, you know, of course, an earlier line population. Maybe I'll start with that. And, you know, I'm a medical oncologist by background. When I saw the mechanism of action, I saw that preclinically, utilizing our Anitens, our N-terminal domain inhibitors, you could overcome essentially all the mechanisms of resistance to current anti-androgens, and resistance inevitably occurs in men receiving these anti-androgens. Our first thought was to use the drug to rescue men in advanced stages of the disease who had received these late-stage anti-androgens, but whose tumors were now progressing, presumably due to resistance. And so that's where, as in all oncology trials, we needed to start with masofaniten, what we now call masofaniten, previously EPI-7386. And, what we have found, as with other companies with androgen receptor-related mechanisms of action, is that after men have had the disease for a number of years, under therapeutic pressure, sometimes with chemotherapy, always with serial applications of different, anti-androgens, there's a lot more biology going on than just androgen receptor drive to the tumor. So while we did see significant evidence of anti-tumor activity, it wasn't meaningful enough for us to, to really think that that was the major future for the drug. We're still completing our single agent therapy in more advanced patients. We're learning a lot about the disease, a lot about the drug, from those patients. And if there is such a population that after progressing on current anti-androgens, they're still predominantly AR driven, that might be a direction to go in. On the other hand, we could be part of a solution with multi-approach because no single, I think, mechanism of action, biological mechanism of action, is going to address these late stage, complicated biology, heterogeneous biology patients. Our future, we believe, is in earlier lines of therapy where the disease is more homogeneously AR driven and where we believe we can achieve better suppression of androgen biology, together with the current drugs. So I think there's long been thinking around masofaniten, that the best use case for it is earlier line in combination. You guys have now started to generate some early data in combination, namely with enzalutamide, and provided some recent updates over the last couple of months. Maybe you could speak to the data set, but really sort of point out what you see as some of the key takeaways from the early data. Peter? Sure, sure. So we reported at the ESMO conference at the Prostate Cancer Foundation meeting, the first four cohorts from our phase I combination, dose escalation study with enzalutamide. And we saw very, interesting translational data that we look at as being reflective of what we were hoping to see based upon our preclinical. And you may recall, we've talked about this in the past. Preclinically, when you combine the two, you see this deeper, broader suppression. And so what we were looking for would be in patients, something similar. So that would translate to quick, rapid PSA decline that would occur in more patients, and the ultimate decline would be a deeper decline. And then ultimately, that should translate to a longer duration of PSA benefit in these patients. What we've reported on to date really are the first three, we couldn't really speak to. We saw very rapid, deep PSA declines in 13 of 16 patients achieve the PSA90. We also then had these duration so far has been also very encouraging. We really can't speak to that exactly yet, but at ASCO GU, we'll be updating our phase I data with longer-term data. When we talk to our investigators and people who are involved with the study, they look at our spider plot, which plots out all the PSAs, and it really looks like these are patients that when they respond, they respond pretty fully, and they seem to respond pretty quickly, and there seems to be a good duration so far. Yeah. So I think one thing you guys have emphasized is not just the rate of PSA 90 responses, but the kinetics of those- Yeah. - responses. Yeah. Maybe you could speak to that, how we should think about that in comparison to enzalutamide on its own, and ultimately, maybe what those kinetics imply about how masofaniten is contributing to the efficacy within the combination. Sure. So there's historical data here, where the investigators have looked retrospectively at two particular studies, the PREVAIL study and the PROSPER study. And those were both in the castration-resistant setting. One was metastatic versus non-metastatic. And what they showed was that the deeper you can suppress PSAs and more quickly, the better the overall survival in those patients. Right? So that's actually that concept of a rapid, deep decline is what we're using our phase II for our primary endpoint. And what we're seeing in our phase I data set so far is that 69% of patients achieve that PSA90 within 90 days, so very rapid. We would expect it, based upon the PREVAIL data, to have had roughly 37% of patients. And so a good delta. So it's encouraging so far. So, I just want to make sure I understand it. So it's not just about achieving PSA 90 at any time on study. There's evidence that if you achieve that earlier, that translates to better long-term responses than those who achieve PSA 90, say, at like six, seven, eight months. I think the data at that point start to be a little bit muddied. Yeah. But the rapid decline does seem to be a unique feature, and if you get a rapid decline, it means that the tumor is probably responding, and that's usually a good telltale sign. But you can have patients that have a slower decline, ultimately do reach a deep decline and still can do well. I think the other thing to point out is it doesn't appear that there's any penalty to pay for these patients in terms of decreased safety or tolerability. Basically, the profile, the safety profile and tolerability profile looks identical in the combination to that of enzalutamide. So that's really important because quality of life is really, really very important in early-stage prostate cancer. I want... I recognize sort of the data set is still on smaller, but I'm wondering- Yeah ... as we get sort of larger, if there actually should be some expectations that you should see some additive safety, but all along the sort of androgen-driven side- Right of things with deeper suppression comes with, you know, more hot flashes, things like that. We haven't seen more of that. We obviously do see that. We even saw that with single agent masofaniten, as you would expect. You know, these are the biological changes associated with inhibition of androgen biology, but it doesn't appear to be worse. So. Yeah. The one last point I think I want to make on the high-level data, then maybe we could dig into some more specifics, is the early signal that almost every, or I think every patient who achieves a PSA 50 will go on and achieve a PSA 90. And I think we saw that it going from ESMO to the Prostate Cancer Foundation- Yeah - in a couple of patients. I guess, what do you make of that? And again, what does that imply about sort of the mechanistic synergy between the two agents? Yeah. So this is where I- Yeah ... it's interesting when you think about what we were trying to achieve and hypothetically. So what we know about splice variants is that they're already there at this stage of the disease. So these are patients who have tumors that can be driven partially by full-length androgen receptor, where enza will work, but also by potentially splice variants, where there's no ligand binding domain and enza won't be active. And so if that's the case in a particular patient, we would expect that patient to have a partial response to enzalutamide. But with us, we should see a, a more complete response. And indeed, that, that does appear to be small data set, as you point out, Joe, but at least so far in the 16 patients that we've re-reported on, patients when they've had a response, have had a, a deep response. Whereas enzalutamide, only 60% of patients who were in the PREVAIL study, who achieved the PSA 50, went on to achieve a PSA 90, whereas we're much higher than that, right? I want to address maybe a couple of points of pushback I've heard on sort of the data set that I've heard from investors over the last couple of months. One is this idea that when you look at the PSA curves, during the masofaniten run-in, you know, for some patients, their PSAs are actually going up, and only when enza comes on board do you see that decline. I know we've spoken about that, but maybe you could just sort of speak to sort of the implications of that or the non-implications of that. I think, I think it's the non-implications of that. Peter, do you want to comment on, on- Sure, sure. There's so there's a lot of, there's a lot of factors here to consider. First off, I think it's important to acknowledge that the Prostate Cancer Working Group recommends not looking at PSAs until three months, and there's a reason for that. There's a history where they have looked at data, and PSAs fluctuate. What's also important for us, though, is that when you look at the actual half-life of PSA, for instance, it's, it's three days. So any changes are going to be slow to move. Plus our drug, when we start to give it, at the beginning, it's actually at a quite low concentration. It accumulates because it has a long half-life, so we don't actually get the full inhibition till a week. And so what we also know is that patients early on, when their tumors are starting to respond, they can lyse and release PSA and complicate things. And so it really is irrelevant. One month, I think, is probably the earliest- Yeah. that people have shown clinical validation to say, "Okay, that's a marker that one can look at." But when you look at studies that have tried to look earlier, they find that it's basically a normal distribution. Even drugs, even later, that would be very potent within the first two weeks, really can't see anything. Yeah. The other area that I've heard, and I know we've spoken about this, is like the low baseline PSAs—that many of these patients are coming on. Yeah, we've heard that. Whether that's, you know, playing a role. I know we've spoken about how there's actually data from PREVAIL and others that suggest that it shouldn't. But maybe you could just sort of touch on it. The other sort of area I heard is, you know, these low baseline PSAs maybe provide some confounding around when you actually measure PSA levels and sort of the height variability there. Yeah. So, let me speak to this. Yeah, sure. You can add to it. Sure. So, so Joe, actually, you were the first one in your team that brought to our attention this study that was done. It was PREVAIL, that looked at patients in that study that had a low PSA of less than 10 or higher than 10, if they fared any differently on PSA90. And as, as we've talked about in the past, that study showed, I think it was 47% versus 48% of patients overall achieved the PSA90, below 10 or above 10. So no real correlation there. But there's a couple of factors for why we have a low PSA coming into our study. One, one of them is actually, if you look at the field in general, patients are treated more close together. They don't have as many windows where they're not being treated, and therefore, patients don't have a chance for their PSAs to continue to rise. And so PREVAIL, it was 54, PSA of 54. When you did ACIS, it was 32 or something, and then you go to PROPEL, it was 18. So it just has been declining over time. But the other factor that's probably just as important, if not more important, is that in our study, we're allowing patients to enter who have had prior chemotherapy in the metastatic sensitive setting or the castration sensitive setting. And when you look at those patients, their PSA levels, they're coming in at much lower levels than our patients who haven't had that. And that's a very common theme. You can look at prior studies to see that trend, whether or not the prior chemo in that setting was different than the non-prior chemo, and they are indeed quite different. So because we have such a large proportion, 40%, that skews our numbers lower. But again, you have to ask yourself, were these easier to treat patients because they had chemo? Probably not. They probably had a tougher disease to treat, and so that low PSA really probably isn't relevant. Yeah. It might have been a discussion point with the first couple of cohorts, because most of them were fairly low starting off. It's not true of the second cohort. There's some pretty high PSAs in there. I think it's a canard. It's really nothing. My last question, I guess, as we look towards now the ongoing randomized study, is maybe first on your level of comfort of the exposures you're achieving. You've moved forward with the full dose of enza, and then I think the 600 mg BID for masofaniten. Just your overall level of comfort there and whether there's any additional kind of dosing work you're doing outside of the phase II. Well, first of all, we've shown we can give full dose enzalutamide because our drug does not affect the pharmacokinetics of enzalutamide. Secondly, we've confirmed our predictions, which were no surprises, that enzalutamide does accelerate the metabolism of our drug. Hence, we worked on giving higher and higher doses and gave 600 mg twice a day of our drug together with enzalutamide. We get excellent exposures, totally consistent with active levels of exposure from our preclinical data. On the other hand, we are not limited by safety and tolerability with our drug. And so, one of the things we all will almost certainly be doing going forward, we've gone into the phase II randomized study with full dose enzalutamide and with 600 mg twice a day of our drug, well-tolerated, safe. But we also did treat on the way up in the dose escalation. We treated 120 mg, so not full dose of enzalutamide, with 800 mg of our drug. And we got pretty good exposures in those relatively few patients. Now, we've made the decision to go into the phase II with the dose and schedule I described. Probably on the side, we'll take a look at additional patients because ultimately, Project Optimist from the FDA would want you to. We believe it's important. We believe you should try to get the exposures that are necessary for efficacy without any safety or tolerability price. We don't have that with our drug, so we will explore some additional doses and schedules of our drug with full dose enzalutamide, but we don't need that for the randomized phase II, which is proof of concept for the hypothesis with a higher level of evidence. Yeah. I actually want to go back to, Peter, you mentioned the next update we'll get from the phase I-B is at ASCO GU. It sounds like at that point, you know, the key focus will be sort of median time to PSA progression. Again, going back to the rates of PSA90, maybe you could just sort of speak to expectations and what would be indicative that, you know, the combination is also translating to benefit on time to PSA progression. Yes. So if you look at the historical data on time to PSA progression, across the different anti-androgens in the same patient population, it's actually remarkably consistent over time. So the PREVAIL study, it was, I think, 11.2 months. In the ACIS study, the abiraterone arm by itself was around 12 months. And then the PROPEL study recently, the abiraterone arm was around 12 months. So we have an expectation of around 12 months. You know, we also have some prior chemotherapy patients, which typically don't do as well, so it could be a little less than that. So we're looking at kind of a 11-12 months. Somewhere in that range is what we'd expect for single agent, conservatively. And then anything above that, you know, becomes something that we think we're, you know, helping to contribute to. Great. So maybe going back to the phase II. Yeah. I'm wondering if you could speak to early experience enrolling the trial? Mm-hmm. Sort of the site activation, how many additional sites you're bringing on board? Certainly. Then we could follow up with a couple more questions there. Well, you know, in the phase I, you're limited. You can only treat so many patients per cohort. You have to follow them for safety, tolerability, et cetera. When we finished the dose escalation, when the safety review board met and recommended going forward with the dose and schedule I've just talked about, we had spent the last nine, 10 months preparing for this phase II. So it was triggered immediately by the safety review board recommendation. That - what does that mean? Well, in addition to the five or so original sites who are going to contribute to the phase I- B of this, we actually are in the process of adding approximately another 20 sites in the United States and Canada. By the end of this calendar year, we'll have additional sites in Australia. While we were over at the ESMO meetings in October, we had an investigators meeting because we will be adding four countries: Belgium, Spain, France, and Italy, and investigators across those countries. We believe we have an adequately sized, basically, clinical trial consortium for the efficient accrual. We haven't given any guidance on how long. I can tell you there's great investigator enthusiasm. Patients are being screened as we've even as we speak, and we'll give a guidance, you know, as soon as we feel more comfortable that we understand the rate that this consortium is putting patients onto the trial. You know, probably first quarter, end of first quarter into the second quarter, next year. But we're doing everything possible. That includes social media activities and to really advertise the trial, because we think this is an important trial for men with prostate cancer. So, maybe looking beyond enrollment completion and time to sort of top-line data thereafter, how should we think about that relative to what the primary endpoint of the phase II is? I think originally it was PSA50 at 12 weeks. I think you have plans to maybe change that to PSA90. Correct. Correct. Yeah. So, that's exactly right. We plan to change that enrollment just because that criteria for the primary endpoint- Makes more sense. It's just that's really what we're trying to power for. It was always a secondary endpoint. Yeah. It's just which one do we pick? And so I think we'll pick the 90 because that's the most relevant at 90 days or 12 weeks. Our partners have looked at that, and it's really a key thing for them as well. So that really only takes about a little bit more than 12 weeks, but about 12 weeks to be able to see that in patients. And so our hope is once we can provide guidance, when we finish enrolling the study, that, you know, a few months after that, we should have our top-line data internally, and then we'll report it as soon as we can. And we'll also provide some guidance as to when we can report that, we have better assessment of the enrollment. Yeah, and then I guess in terms of absolute difference there, I'm guessing, you know, if you replicate what you've seen in phase I-B and enza behaves as we think it should, that's obviously a great outcome. I guess what's like the minimum magnitude of benefit that I think would still, you know, offer a path forward and translate to PFS ultimately? David, I'll let you answer this. We haven't given any guidance on that, and I think beauty is in the eye of the beholder, to be honest. But, from my perspective, speaking as a clinical oncologist, my background, it would be a, a compilation of not only a meaningful delta in the number of patients achieving a PSA 90, but a meaningful duration to that. Because ultimately, when all is said and done, we're not trying to reach a goal in 90 days. We're trying to preserve a good quality of life for a longer period of time in these men. We believe everything we've done pre-clinically, on top of the history of what you can achieve with better androgen suppression, is all consistent with that. So I, I, I don't want to give you a number, because I suspect it would be different in different hands. It'll have to be something that will be meaningful to the patients themselves. Yeah. Maybe in these last couple of minutes- Yeah ... we could talk about other efforts to combine, with other flutamides and where those efforts stand, and I guess what's like the next potential data point- Yeah - we could get from those trials? Good question. Sure. Peter, do you want to take that? Yeah. So we're just beginning studies now with other anti-androgens. The two that we're working on are with the J&J supplied drugs, so abiraterone and apalutamide. And with abiraterone, we're doing two groups of patients. One patient will be the same as we're doing with metastatic CRPC, those second-generation anti-androgen, but may have had prior chemotherapy. But the real more exciting one for us is the metastatic castration-sensitive population that we'll be getting into, because that's where we... Metastatic castration-resistant is important for us, but ultimately, we want to move to the metastatic castration-sensitive population. So that is going to be beginning here very soon. We also then have a non-metastatic CRPC study with apalutamide. That's beginning also very soon. And so we'll have data that we'll be able to report on those, because it's our study, next year. We haven't committed to exactly when, but we'll start reporting those data once they become available. And then we have two investigator-sponsored trials, one with darolutamide in the neoadjuvant setting that's beginning now, and then one that will begin probably early next year, with enzalutamide in the metastatic castrate-sensitive population, looking at the depth of PSA declines and what. So very relevant data for where we want to go. Yeah. I want to, I know we're out of time. I want to squeeze in one question. I know you're not giving guidance at this point on the phase II and timelines there, but of course, how should we think about potential timelines there, relative cash to cash and, and the runway you guys have? Yeah. So we reported $152 million cash at June 30th. So that's a runway through the end of 2025. So solid balance then. And that covers off the period when we'll be reporting out on the phase II data as well as the other studies. So, good cash through- Everything we need. Everything we need to do. Perfect. With that, we'll end there. Thank you, David, Peter, and David for your time. Thanks, everybody, for tuning in. Enjoy the rest of your day here. Take care. Thank you, Joe. Yep. Thank you.