We're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Fitzgerald Biotech Equity Research Team on this side of the table. On the other side of the table, we have the team from ESSA Pharma. We have David Parkinson, President and Chief Executive Officer, David Wood, Chief Financial Officer, and Peter Virsik, Chief Operating Officer. Gentlemen, welcome. Maybe we can start with a quick snapshot of ESSA, the company, and some of the key milestones we should be looking for in the 12-18 months ahead. Thank you for the invitation to be here, Josh. Just to give a context, we are focused on a unique way of shutting down androgen-driven transcription. You know, we have 70 years, that's seven decades, of experience in the oncology field with shutting down androgen biology, which is so important to early prostate cancer, with shutting it down through one end of the receptor, the so-called ligand binding domain. What we're focused on is small molecule inhibition of the other end of the receptor. The advantages to that, based on preclinical work, are that we can bypass the mechanisms of resistance to the C-terminal end, the ligand binding domain. But more importantly, in terms of our strategic focus, is the combination of our drug with anti-androgens, which gives you a more complete inhibition of male hormone biology. Historically, over decades of experience, the more completely you inhibit prostate cancer through androgen inhibition, the better the clinical results. That has been seen in all sorts of situations over many decades. That's what we're all about. We have shown that giving the single agent to late-stage patients with prostate cancer who have had the disease for many years, and including many years of androgen deprivation, doesn't lead to much activity, and the reason, as we and other investigational organizations in the field have shown, is that late-stage prostate cancer is very complicated biologically. It is not predominantly AR driven. AR is part of the drive, but there are many other genomic drivers, so no AR inhibition, or for that matter, from my perspective, any other physiological inhibition is going to completely solve the problem of late-stage prostate disease. And consistent with our preclinical studies, the opportunity to combine with an anti-androgen in earlier, more homogeneously AR, androgen receptor-driven populations, that forms the basis of our current activities. We have a randomized phase II clinical trial, which looks at enzalutamide versus our drug, masofaniten, with enzalutamide. That's currently in process. We're looking to put a hundred and twenty patients on that trial. We've said through guidance that we expect to get those patients accrued by first quarter of next year, with a readout of the first readout, the PSA90, the depth of PSA suppression some three months after that, plus, you know, analytical time, so mid-year, probably. In addition, we have a number of other trials. Peter, you may want to comment because it's related also to potential future strategies, with combinations with other anti-androgens. Yeah, so, thanks again, Josh. Thanks for the invite here. Because we wanted to ask the question clinically about the combinability with the other anti-androgens of masofaniten, and we designed and picked a drug, which we thought, preclinically at least, showed us that we could do that, so now we're in the clinical stage of trying to assess that and corroborate that. Obviously, the enzalutamide study, the phase II study, is our largest study and really is generating proof of concept for the combining effect, but we do have additional phase I studies that are smaller. Abiraterone study that we're doing with Johnson & Johnson, that's in metastatic CRPC patients and any other abiraterone-indicated patients. It's a phase I dose-escalation study. We also are working on a apalutamide study as well, so that is in the non-metastatic CRPC patient population. That's also in collaboration with Johnson & Johnson. We then have two investigator-sponsored studies, one in the neoadjuvant setting, with darolutamide, and these are patients who are high risk, and are undergoing prostatectomies, and they'll either get the combination of masofaniten and darolutamide or just darolutamide alone for three months, and we'll test the biology and measure different things, including PK, safety, and all those parameters. And then we have a final investigator-sponsored trial, which is a combination of masofaniten with enzalutamide in the metastatic castrate-sensitive patient population, and that's really ultimately where we think some of the best proof of concept could perhaps be generated because those are patients where AR is the fundamental driver of their biology, where hypothetically, an N-terminal and a ligand binding domain could perhaps show the biggest benefit. And so, you know, our strategy involves looking at these different early patient populations with different combinations with anti-androgens. The main phase II trial is together with Astellas and Pfizer, but we had to earn our way. You know, in cancer, with a new agent, new mechanism of action, you have to start late-stage, get in, and we've earned our way. The drug is safe, it's well-tolerated, it's oral, patients like being on it, investigators like using it, so we think we have a drug that's appropriate for early-stage prostate cancer, that's complementary to the current anti-androgen strategies, but we just have to prove it. Maybe we can talk a little bit about the androgen receptor structure. You talked about the C-terminal domain- Yes ... and you know how the N-terminal domain may differ. And as we're appreciating kind of that structure, what are the mechanisms of resistance to which masofaniten may be efficacious versus mechanisms of resistance where you'd not expect it to be as efficacious? Fascinating question. Peter, do you wanna- Sure. Comment on that? Yeah, so the androgen receptor is a steroid hormone receptor, similar in some ways to the glucocorticoid or the mineralocorticoid. Estrogen. Estrogen- Yeah probably the most well-known receptor. There's three domains. There's the ligand binding domain or the LBD on the C- terminus, there's the DNA binding domain, and then there's the N-terminal domain. What's unique about the androgen receptor is that all of the transcriptional activity from the androgen receptor from that molecule is driven through the N-terminal domain. Therefore, to be transcriptionally active, to promote growth, that N-terminal domain needs to be functional and present. So when you look at the resistance that occurs naturally or just biologically, what happens in tumors in response to anti-androgen therapy is the C-terminal domain or the LBD... The ligand binding domain itself or the C- terminus can be modified, and it can be modified through point mutations that occur in the ligand binding domain that make other anti-androgens agonists or just make them not active. You can entirely eliminate the C- terminus, and those are called splice variants. Those are done at the RNA level. There's also what's called genomic structural rearrangements, which are copies of the androgen receptor, where you're also missing the ligand binding domain, but that's at the DNA level. Then you have AR amplification, where you just make more copies of the androgen receptor. What's different is really the fact that you need this functional N-terminal domain to work. Okay, that's obvious then, once anybody understands, and the question is, why hasn't everybody and why isn't the world focused on the N-terminal domain for drug development? That's because it's intrinsically disordered. What that means is, it's kind of a funny name. I mean, intrinsically disordered, it's not really disordered, but it doesn't have a crystal structure, nice pocket binding area where you can design a drug to bind to. It's more floppy, but it obviously works with cofactors and transcriptional factors to very specifically regulate transcription. It's hard to get a molecule to bind to it. You need a screen that's done in cells. That's a very difficult procedure. A lot of pharma have tried and failed. The only reason we're here today is because of academic work that was done nearly twenty years ago, where they found an initial hit compound that ten years later, they figured out, "Oh, that, that's actually inhibiting it through the N-terminal domain." And it's from that work and then all the chemistry we did that we then developed the current drug. So masofaniten specifically binds to and inhibits the N-terminal domain from binding to DNA, or? It binds to an area called transcription activation unit 5. We've shown that, and, it does inhibit the formation of these, complexes of cofactors that represent the activated receptor that, translocates to the nucleus, binds to androgen response elements. And we've shown that, just as ligand binding domain inhibitors, interfere with activated receptor activation or the activated receptor binding to these elements, so do we, but through a completely different mechanism. But when you put those two mechanisms together, we completely inhibit, as neither one individually does, the, activated receptor binding. So it's a more complete inhibition, at least experimentally, in preclinical models of androgen biology. And as I say, historically, that is correlated with better clinical results. I should have this in my notes, but I don't. I, you had an earlier generation- Yes ... product? The company entered into the clinic with a first-generation molecule, late-stage disease. We saw enough from that experience to see that this mechanism was safe, it was well-tolerated. We saw hints of clinical activity, but the agent itself was not a good pharmaceutical agent. It was hard to formulate, not stable, et cetera, et cetera, et cetera. And so what we did was we took the learnings and the confidence that came from that phase I experience. We spent a year and a half, Peter led that activity, and synthesized more than five or six hundred molecules- Mm-hmm ... and came up with masofaniten, and since then, I think we've done another thousand molecules. Yeah. We have molecules with all sorts of, really interesting alternative characteristics, but nothing that we've seen that works better preclinically, at least, than masofaniten. So, you talked about the androgen receptor mutations to which masofaniten should have activity, but then you started out by also saying you'd moved into later lines of therapy and not seen clinical activity. So, what- Well- ... what do you feel were likely driving the resistance profile to masofaniten? And- Those patients have a lot more going on. Yeah. We would see WNT pathway changes, EGFR mutations, MEK changes beyond the AR mutations that Peter talked about. So there was a lot more biology, a lot of genomic drivers, and it's the same experience that's been shown over the last few years with people with other mechanisms of approaching AR. Just in late-stage disease, that's only one part of a complicated biological set of drivers. And so, it might be part of a therapeutic solution, but not a complete therapeutic solution. In theory, given the mechanism, masofaniten should have good monotherapy activity in earlier lines of- Yes ... of therapy. What, what is the rationale for kind of doubling up on AR inhibition by targeting both the N and C terminal? I would say that our preclinical suggestions are, yes, it should have a good monotherapy activity in newly diagnosed patients, for example, but probably not better activity than the current anti-androgens. Those are good drugs, and they're well-established. The community is comfortable with those, and we're looking not just to compete with those, we never, from day one, have ever tried to do that, but rather to get more clinical activity. The goal in oncology is always to improve efficacy and to try to do that without compromising toxicity, and that's what all the preclinical data suggests the combination should be. So right from the start, that's been our goal. But again, you know, you have to show safety and tolerability and enough efficacy to convince yourself, investors, regulators, investigators, and ultimately patients, that this is actually something worth trying, and we've done that. Now, I guess in theory, there should be patients who are just starting to break through of androgen receptor- Yes inhibition, who would be amenable to better control with masofaniten. Yeah. Are you exploring that? Yeah ... that setting at all, and in which of the trials? That's part of the reason we've taken the opportunity to explore our drug together with other anti-androgens, 'cause we've designed the drug to be able to do so, as Peter said. But we're also using it to explore earlier patient populations. For example, the neoadjuvant study that we're doing, in association with the Bayer molecule, darolutamide, and we're doing that in men who are newly diagnosed. They're due to have prostatectomy, and they are randomized. Their blood baseline studies are done, including pathology, of course, and molecular biology, and then they're randomized to receive darolutamide alone, which is approved in that indication, versus darolutamide plus our drug. And so three months later, then they have the prostatectomy, and so it's a fantastic opportunity for us to learn in a relatively small number of patients. And that study is very active at the moment, as we're running it in Australia as an investigator-sponsored study to give us a correlation between the doses we administer, the exposures that we achieve, the biology that we achieve, the changes in pathology and the clinical and radiological output. So that's actually a very important study for us. Maybe we can review some of the phase I and II findings thus far, and what is giving you that, the confidence that masofaniten is adding benefit to androgens- Do you want to comment on the combination phase I? Sure. So we're just coming back from ESMO, where we were presenting a phase I poster, updating the combination, enzalutamide combination, dose escalation portion of the study, and this was, again, 18 patients enrolled into the study across four different dose cohorts. These are patients who are first-line metastatic CRPC. What that means is they've not yet had a ARSI or a second-generation anti-androgen before, but they could have had chemotherapy in the metastatic castrate-sensitive setting. And so what we updated at the conference versus what we had at ASCO GU was we had a PSA90 rate of 88%, so that was up from 81%. And then we were looking at kind of the time-based measures, the durability measures, 'cause that's our real question we're trying to answer now, which is, okay, so these are... That's a very good PSA response. So we're quite pleased with that. But will it translate to a long-term benefit for these patients? And so we were looking at time to PSA progression, and that looked very good. We hadn't yet reached a median point. We had earlier in the year, at ASCO GU, we had 16.6 months, but we are no longer on the curve, so we don't yet have an estimate. And we also started to talk about radiographic progression-free survival, because that ultimately is the next measure to look at, and that's a clinical measure for approval purposes. And on that measure, we also were trending very well. So the real point was to say, "Okay, how did the PSAs end up?" They looked quite good. Was the safety maintained? Maintained. It was, in fact, maintained. And then the durability does fit what one would expect with a strong, deep PSA reduction, and that we don't yet have a good estimate for the durability, but it looks good so far. Maybe you can help contextualize that PSA90 and what one might have expected for enzalutamide alone. And, you know, I think what we tend to see is that there's always a range, you know- Yeah ... of outcomes and experiences. So if you can try to quantify that or capture that range for enzalutamide monotherapy. It's a small n, but- Yeah, it's a small end, so we have to always keep, you know- Yeah ... caveat that it's only 16 patients that are evaluable for the 88% PSA90 rate. But if you look at the historical studies done with enzalutamide, you'd look probably at the PREVAIL study. The PREVAIL study was done for registration in the same patient population, and there was a PSA90 rate there of 47%. I think there have been a few other studies, the Alliance study as well, that trended to something similar in that kind of 50% range. And I think the highest PSA90 rate that's been published, that I've found after doing an exhaustive literature search- Yeah ... through everything, is roughly around 60%-62% in patients who are a little bit milder, if you will, and in our poster, we provided background baseline information so people can understand the patients we've enrolled. There's nothing about them that stands out as being particularly less or harder to be able to treat than those patients we're talking about for PREVAIL, but that is a 10-year difference but since that study versus our study, but that is probably the best metric of that, is PREVAIL at 47%. So then, you described the phase II enzalutamide plus or minus masofaniten trial, 120 patients. What setting is that? It's this first-line metastatic CRPC. Same, same patient. It's exactly the same entry criteria to the study, so. Got it, and it's one-to-one randomization? Two to one. Two to one. 80/40. What's the dose that you're exploring, and how did you hone in on the optimal dose? What we saw is that with enzalutamide combination treatment, we have a reduction in our pharmacokinetics, our overall AUC, as it's called, or exposure. We anticipated that may occur, and which is why in our phase one monotherapy, we went to a 600 BID dose because we found, by going twice a day in our tox studies, we could actually get to higher exposures. That worked in the monotherapy, and we tested that in our combination study with Enza, and that worked very well. When you double the dose to 600 BID, you get back up to those kind of exposures, and so that's the one we picked. It's 600 BID masofaniten combined with the standard approved dose of 160 milligrams enzalutamide, and that was well-tolerated as well. Yes. Are you powered for statistical significance if you can kind of replicate that high 80% PSA90 versus a comparator in the 60% range? We are powered around the PSA90. You know, the registration endpoints in this setting are actually progression-free survival and overall survival. It's not a registration trial. This is a trial for decision-making, for confirming the hypothesis, and for, together with the other trials we're doing, to help us understand, when we do with a collaborator move to registration-directed trials, what patient population would make the most sense? The earlier you go, the more dependent on AR, and the more likely the benefit for all sorts of theoretical reasons that relate to not only depth of PSA suppression, but also the potential for preventing the development of resistance to the anti-androgens that's been observed. Yeah, we're powered to look at the difference in PSA90s, and that is a good correlate historically of eventual progression-free survival. Yeah. So it's for decision-making. Are there scenarios where you don't see a statistically significant difference on PSA90 or some of the other metrics, but there are favorable trends they would nonetheless advance into phase 3, or is stat sig really the bar you're looking for? Oh, no, I think there could very well be scenarios. One thing that's becoming very clear, you know, the last five years have just seen a revolution. We saw a lot more of it at ESMO meetings in Barcelona over the last few days is the beginning of the understanding of the different phenotypic types of patients that one sees in prostate cancer. They exist at the beginning, but they certainly emerge in later-stage disease under pressure. So the goal to get more complete inhibition earlier would, as I say, hopefully to prevent the emergence of those resistance mechanisms. But there clearly are different subpopulations of patients. So all these patients are having circulating tumor DNA studied, and we're looking at that. We will be looking at that very carefully. So you have a number of ongoing trials that you listed earlier. I mean, obviously, this is the main focal point, but as you're thinking about the next steps beyond the phase II how do you anticipate those other trials may inform your decision-making process, and when will they generate that data to help? Well- Yeah. Yeah, go ahead. I think the next year will tell the tale. We'll get better understanding of patient populations, better understanding of the characteristics of our drug together with the various anti-androgens. We'll get enough efficacy data to help us understand whether it would make more sense to go to an early patient population, which of course is going to take longer to read out, but where the potential benefit theoretically should be greater. Those would be my thoughts. There are a lot of practical issues related to all of those. From a business development perspective, would you comment? Yeah, I mean, I think, we have to understand where the market's going, where treatment's- Yeah ... going, and make sure that we're designing and thinking about the appropriate patient populations- Yeah, yeah ... to fit that. And so this first-line metastatic CRPC patient population we're talking about here, it still exists, but it is a shrinking population over time. Whereas the metastatic castrate-sensitive population is a much larger population and will remain much larger, they're on treatment for much longer, and is also much easier to enroll for studies because that's where standard of treatment is still kind of coming up to speed. And so, and we know pharma is interested in that population as well. That's where they're also conducting studies as well. So we'll look at all of those, and we've actually recently quantified the patient population sizes around there, and it's very supportive of kind of what we're talking about here. So we would look at multiple patient populations, look at the feasibility, but ultimately, we would need to do the phase 3s with a partner. These are large registrational studies. Yeah, yeah. Could we do them? Yes, as a company, we could. We'd need financing to do those, but it makes a lot more sense to leverage the benefits and the expertise of large global clinical infrastructures versus trying to build them out on our own. These changing patient populations are a function of really two major influences that are going on and really affecting the world of prostate cancer clinical investigation, and that was all over the Barcelona meeting. Mm-hmm. One is the advent of PSMA PET scan staging. So there's a big stage migration. All these patients who were non-metastatic become metastatic, but with lower tumor volume, you know? And then there's the influence from the ARCHES trial, which is that the upfront use of enzalutamide together with androgen deprivation therapy clearly has benefit, and so to the extent that different sides of the Atlantic, the different populations- Mm-hmm ... of physicians in the United States, the urology community treats a lot of these patients, versus the medical oncology community, who also treat a lot of these patients, adopt these new concepts and technologies differentially. We needed to understand that, hence the study we did, and we think we understand what the dynamics of those populations are. Is that shift to identifying more metastatic disease, when did that start, and has that finished? So I'd say it's roughly around 2018, I think- Yeah ... was around, you know, plus, minus, when PSMA PET began to be used. And reimbursed. reimbursed, I think it was actually... That might have been the... Yeah ... timer at the end. I think so, yeah. Australia was a little different. Australia's been using PSMA PET for longer. Yeah. And then it's interesting because we've done market research studies along the way, and it's now, its use is, I would say, it's pretty much ubiquitous in the U.S. It's used by oncologists, it's used by the urologists. It's pretty much used by everybody, and it's complicating even the larger clinical studies because physicians, as we're, as we learn, are seeing new lesions pop up under PSMA PET under clinical studies, and they are dropping their patients off- Yeah ... right? Even though they don't qualify under a CT or an MRI, now they are falling off. Yeah. So it's impacting all studies. All studies are having to adjust and add in PSMA PET, yet the medical community hasn't yet really put its arms around and figured out how to think about the prognosis of these patients that you only see under PSMA PET versus CT. So it's dynamic, and we're paying attention. As you think about your path towards phase III, and with a partner, do you have a hierarchy or a preference of which products, masofaniten may best combine with, or may serve as the best backbone? We designed the molecule to be able to be combined with any of the big four. And we expect that there would be less drug-drug interactions with abiraterone and darolutamide, just from theoretical basis, and we have some practical experience to suggest that's correct. Enzalutamide was the toughest one, and that's the one that we chose to do the initial phase II randomized study with, and we've shown that we can combine it with enzalutamide and get good exposures of both drugs. Apalutamide, similar drug in many respects to enzalutamide. Again, we've seen enough experience so far to believe that. So that means that we could combine with any or all four of those, which raises all sorts of interesting potential strategic questions that remain to be answered through experience and negotiation. Given that the phase III lift being what it is in prostate cancer, and, you know, you're kind of acknowledging that a strategic partner would probably be very important to facilitate with that- Yeah ... do you have a view in terms of what type of involvement you'd wanna have in development and/or commercialization? Those are all good questions, strategic questions- Yeah ... that every company goes through. I don't think we have a firm stance on that at this point. Yeah. I think we're trying to stay focused at this point on trying to generate as much quality data as we can across as many of these. We've obviously all been around and seen the different pluses and minuses of different company structures- Yeah ... and different- Collaboration structures. Yeah. Yeah. And we can work through that later. Right now- Yeah ... we're staying focused on execution. Yeah. Job one is getting this drug developed. If for some reason you don't necessarily see the signal you're hoping for for masofaniten, is there a plan B, are there other compounds that you may advance that you think have advantages? Do you wanna comment on the backup, program? Yeah, I mean, we have, we've established different backups, you know, a backup program to look at other molecules that are, potentially perhaps slightly different than masofaniten, and we have a whole suite of different compounds with different properties. I'd say there's not one that stands out that we'd say is better than masofaniten on every criteria, just 'cause masofaniten has been a pretty good molecule for us. Yeah. But we do have a whole suite of them that we could bring and look at and decide if that would address any question that we may find in any clinical study moving forward. Okay. I think we're out of time. David, David, and Peter, thank you so much for your time. Oh, it's been a pleasure. Thanks very much. Thank you. Thank you.