Hello everybody. All right, thank you all for coming into Auditorium CD. We're going to get started with our next presentation very shortly, so please take your seats. Next session of the afternoon is David Parkinson, President and CEO of ESSA Pharma. David, take it away. Thank you, Mina. Oh, thanks for coming this afternoon. Pleasure to be here. What I'd like to do is update you on what we're doing at ESSA. It's, this is an important year for us because we're in randomized phase II trials. So, it's been a long time coming. We had to earn our way into this space, but we're finally here, and, we've got some definitive trials underway. Forward-looking statements. You can look as forward as you want. And, which these days is like 24 hours, right? Yeah, I know. What I'll be talking about here is the fact that we continue to address an unmet medical need, that we are doing it with a, an agent that has a unique mechanism of action, and that we use together with antiandrogens. It follows some pretty interesting, intriguing data from a phase I study that we reported on last October and updated in February. We believe it fits into the rapidly evolving world of prostate cancer therapeutics. I'll go through all of these. So first of all, what I'll focus on in this talk is our combination therapy strategy. As many of you know, we have studied this agent as a single agent in late-stage prostate cancer. That's where you have to start in prostate cancer therapy. These were patients who had been through often many years of therapy, not just with antiandrogen-related therapies, but chemotherapy often, and very complicated patients, as we showed biologically. What we have now done is earned the right to use our agent together with antiandrogens in earlier line prostate cancer therapy. As I'll show you, that's where the androgen receptor biology is much more homogeneously a driver of the majority of patients with the disease. Our drug makes most sense in the early patients. But again, we had to earn our right to show a drug is safe, well-tolerated, and effective in these early populations. Just to give a context, prostate cancer remains a huge unmet medical need, large public health problem globally. Androgen receptors are known to be integral, or the androgen biology is known to be integral, has been since the 1950s, Nobel Prize for that, in the biology, particularly of early disease. Furthermore, any agent which can cause a deep PSA response, historically, has trend—or any—any therapeutic approach even, that historically has related to eventual clinical benefit. The deeper, the better. It's a huge market. Just these four of the latest generation antiandrogens represent a market globally of over $9 billion. What we'll be talking about here today is that we are not in competition with those agents. What we've shown preclinically and are in the process of studying clinically is the use of our agent together with those and one or another of those antiandrogens. So a little primer, very little, on prostate cancer. Often is diagnosed locally, eventually can become systemic. The patient populations in prostate cancer are actually evolving courtesy of new diagnostic technologies such as PSMA imaging. Nevertheless, those patient populations still remain defined largely by extent of disease, local versus systemic, extent of prior therapy, previous antiandrogens, or what we call ADT or androgen deprivation therapy, or not, and then amount of previous therapy with other agents, so first, second, third line, etc. Now, the interesting thing about the natural history of prostate cancer, which frankly we've learned an enormous amount about just in the last few years, courtesy of things like circulating tumor DNA, courtesy of the fact that there are now, for the first time in my, medical career, a whole host of new agents against prostate cancer, and these agents are defining the biology. So, as I mentioned in its earlier years, the, not 100%, but the majority of patients are very dependent on androgens for their biology. That changes over time. Part of it may just be time and genomic drift. A lot of it is due to the effect of therapeutic pressure from antiandrogens in particular. And so AR independence is a function of later-stage disease. AR independence is associated with all sorts of genomic change. Some of those are at the DNA level with respect to amplification or mutation of the androgen receptor itself. Some of them are at the RNA level with the loss of the C-terminal end of the receptor, one end of the receptor that happens to be the end associated with the blocking activity of the antiandrogens, which are blockers, the so-called lutamides. And then what we and others have shown with circulating tumor DNA studies in our phase I monotherapy studies are a whole host of other drivers. It's just unbelievable when you look at these patients circulating tumor DNA and see Wnt and Myc and p53 loss and etc. It's remarkable how complicated no single physiologically directed agent will ever solve the problem in late-stage prostate cancer. That's a place for anatomically directed therapies against the surface antigens, for example, radioligand therapy against PSMA. That's an example of that. So the strategy for therapeutic development is going to be different for late-stage disease versus earlier-stage disease. Okay, let's talk about what we used to call 7386, but now, as it rolls off the tongue, masofaniten. Acquired at great cost, I must say. I don't think it costs very much, actually. It's not worth very much. But what's interesting about it is that we've shown that this drug binds to a very specific area at the other end of the receptor from where antiandrogens work. This is the so-called N-terminal domain. It's Tau-5, Transcription Activation Unit 5. No one understands exactly how this works. This is the first small molecule in the clinic for any therapeutic indication, not just oncology, against an intrinsically disordered part of a protein. Without going into all the details, because it's extremely interesting, it appears that the mechanism of the drug relates to interfering with the formation of that activated cofactor and androgen receptor complex that binds ultimately to DNA. So we started, as I mentioned, with the single agent therapy in late-stage disease. And what we did in a phase I study, which goes back, gosh, 2.5, three years ago now when we started, was study the drug in escalating 200 mg increments from 200 to 1,000, anticipating that we would want to put the drug together with other drugs such as enzalutamide or Xtandi. We also studied twice a day dosing of 600 mg and 400 mg. We've gone on since. We've reported on all of this. We've gone on since to fill two additional expansion doses or cohorts of patients, again with single agent late-stage disease, trying to see whether we could identify biologically a group of patients who, even after all those years, many, often more than a decade of being on antiandrogens, were still sensitive to single agent antiandrogen therapy. We'll probably report on that late-stage disease. But I think you get a sense from the fact that we're focusing now on combination therapy in earlier-line patients as a sense of what we, together with others, with anti-AR directed mechanisms, have learned about the complicated biology of late-stage disease. What we did show from that phase I monotherapy study is that we had corrected a lot of the physiological pharmaceutical problems with the first generation agent that the company had developed several years ago. We wanted to develop a drug that was easy to synthesize, that would be stable, that could be formulated, that could be taken orally once or twice a day, that had, therefore, a good half-life, and that didn't cross the blood-brain barrier, because we did not want to take a chance on worsening the neurotoxicity that comes with enzalutamide or apalutamide, and also a drug that could survive the drug-drug interactions of being combined with drugs like enzalutamide, which is an extremely difficult drug to combine with. And I'm happy to report that that phase I did, in fact, show that the agent we had developed, masofaniten, meets all those criteria. While we were doing all of that, we were also doing preclinical work to explore the hypothesis that shutting down the receptor from both the N-terminal domain and, in combination with antiandrogens, the ligand binding domain actually gave a greater impairment or shutting down of androgen biology. And I'll summarize this just in the interest of time by showing that if you expose prostate cancer cell lines to an androgen, you see a lot of binding of the activated receptor to different places along this. Call it androgen response elements on genomic DNA. Either our drug, masofaniten, or enzalutamide really, really decreased that, probably 85%. You put the two together, shut down the receptor from both ends. Looks like 100%. So going back to my comment earlier that the deeper you can suppress androgen biology, the better the clinical result. This has been shown over 60, that is, 60 years of clinical investigation. This seemed to be a good direction to go in. To go in that direction, though, we needed to work with the companies which actually had the global, the global antiandrogens. We have set up those collaborations. They differ from one to another: Astellas and Pfizer, Janssen, Bayer. And one way or another, as I'll show you, we have a clinical trial program that has combinations with each of those antiandrogens. But the most important one in the near term is the one that's in combination with enzalutamide. First of all, all these antiandrogens, I think we, in the entire field, believe are equal in terms of efficacy. But they are very different in terms of their pharmaceutical characteristics, their drug-drug interactions. So each one of them has had to be studied with respect to drug-drug interactions with our drug. This is the study which is underway now. We'll give guidance in the next couple of months as to how long we think it'll take to put the 120 patients, 80 on the combination of enzalutamide with masofaniten, 40 with enzalutamide alone, in a group of patients who are identical to patients who have not yet received latest generation antiandrogens, and so identical to the patients we studied in the phase I, which I guess is the one described here on the left. We've studied the combination of our drug with enzalutamide first at on-label, but still lower than the usual dose used of enzalutamide, and then full dose enzalutamide. We've gone all the way up. The dose that we've chosen for the second part, which I'll discuss in a second, is 600 milligrams twice a day of our drug together with full dose enzalutamide. So it's in patients who have often a long history of prostate cancer treatment, but have not yet received latest generation antiandrogens. What we showed, and exactly what we had predicted, we did not affect the pharmacokinetics of enzalutamide. So we can give full dose enzalutamide. Second thing we showed, which is exactly what we had predicted, is that enzalutamide chews up. It's an incredible drug to try to combine with. It's a nasty drug from that perspective. But we can still get good exposures with the 600 mg twice a day. So we can give our drug together with enzalutamide and get good concentrations of both drugs. What we also showed is that patients seem to do pretty well, even in this phase I. Even patients who go into phase I studies are not the easiest patients, necessarily. And as of February, when we reported this at ASCO GU, 13 of the 18 patients were ongoing. A couple of them had progressed related to non, you know, one was a brain abscess, previous mantle cell lymphoma. One had a sudden death from cardiac disease, known cardiac history, but he died. It's what I used to call in medicine a Harvard death. His PSA was very low. But unfortunately, he died suddenly of a heart attack. Three of the patients did progress. Of the patients with measurable disease as of February, two of them had shown progression. Partial responses. So good sign of clinical activity. Here's the really interesting data. So the prediction from preclinical studies that we had done with the combination is that we should see more, deeper, and longer PSA declines. And that's kind of what we've seen in this population. So 18 patients, two of them just progressed immediately, clearly not sensitive. The rest showed a pretty dramatic deep PSA response. And 13 of 16, that is, 81% of the patients eventually got to a PSA 90, which has kind of been a historical roadmap for eventual clinical benefit when looked at in randomized phase III trials. 11 of the 16 actually got to PSA 90 in 90 days, which is the real thing that's been used, not for registration. PSA is not a registration endpoint, at least with the FDA in prostate cancer. That's progression-free survival and overall survival. But it is a terrific predictor in early-line patients of eventual clinical benefit. There was a hint that a couple of the patients began to lose their response after more than a year. This is another way of looking at the same data. As we've emphasized, you know, this is a single-arm study. It's a phase I study. The data wasn't fully mature. This is the data that you would expect to see when the combination might be better than single agent. The next step is to move to a higher level of evidence, which is the randomized trial. Now, how does that measure up against historical norms? This is what we found. This is what you see in different, very well-recognized, standardized clinical trials. Again, data is pretty interesting. The data validates going into the randomized setting. That's what's underway currently. Again, we'll give guidance on how long we think it'll take to get those 120 patients. Currently, we have 25 sites in the U.S., Canada, and Australia. We'll be opening another 15 ± sites, probably plus sites in France, Belgium, and Spain in the next few months. This just shows you what I've mentioned a couple of times before, which is that either in patients who have not yet received chemotherapy, the so-called PREVAIL study, or even earlier line of patients, these non-metastatic, but still castrate-resistant patients, the deeper you suppress PSA, the better the clinical result. So all of this is consistent with necessary for, but not sufficient for, or, you know, complete evidence for benefit of the combination over the single agent. So that's what's underway. That's job one for us as a company. The next six to 12 months will tell the tale. We expect to get the accrual. Again, we'll give guidance when we feel we can give beyond speculation. But in the meantime, we've shown that we can combine our drug with enzalutamide, that we have good pharmacology, that it's safe, and it's well tolerated. The safety profile is no different than enzalutamide alone. The only Grade 3 toxicity we had was a rash that came after the patient had been on our drug for a week with no rash. Enzalutamide was added. Rash the next day. That's on the label for enzalutamide. But I can't say that it's not due to some effect of the combination. But we haven't seen it in any patients since. We are also working with used to be Janssen. It's now J&J Innovation, I believe. I think it's still the same company, as far as I know. And so we're studying the combination of our drug with abiraterone, with Zytiga, and with apalutamide. We even have one cohort where patients who are really quite early will be treated with our drug for three months alone, and then the combination added. Hard to accrue because there are drugs already approved in the space. But we're trying. We're also combining our drug with darolutamide. We expect, by the way, no drug-drug interactions. It was complicated, but we were successful in combining our drug with enzalutamide. Apalutamide is going to be the same, very similar drug. Darolutamide and abiraterone, we would expect no drug-drug interactions at all. So full dose of both. And those studies are being done in a number of earlier prostate cancer populations. As I indicated, prostate cancer is increasingly being divided into populations that are distinctive by their previous history or their systemic distribution. They are now going to start to be divided by their biology. Hasn't happened yet. But they're coming back from the AACR meetings weekend before last. It's happening in real time. And that's pretty exciting for those of us who are interested in physiological or biologically directed approaches to the therapy of prostate cancer. So finally, that's us. I'm here with my colleagues, Peter Virsik, our Chief Operating Officer, David Wood, our Chief Financial Officer. Not here today, because she's running the shop in terms of patient accrual, is Alessandra Cesano, our Chief Medical Officer. And what will happen this year? Well, one thing has already happened. We reported on the increased duration associated with the phase I dose escalation of the combination. We're working job one to make that phase II trial successful and accrue as quickly as we can with good quality studies. We're doing the other combination studies that I talked about. I haven't had time, and I won't talk. We have additional studies, one in Australia with apalutamide, another up in northern New York State in the Cleveland area with enzalutamide, another study with enzalutamide, but in a very early patient population. The nice thing is we have enough money to do that. I know you don't hear that from everybody. Actually, at the moment, despite attempts to give us money, we've successfully fought them off for the time being. I also want to make it clear that could change at any moment, John. In the meantime, we have enough money to do everything I just talked about to take us through 2025. We haven't given guidance yet, but we believe that that'll be actually a good runway beyond the end of 2025. And so in the meantime, we will be able to, we believe, really test at a higher level of evidence the whole hypothesis, the value of a drug with such an innovative approach to AR inhibition, and set the stage, hopefully, for a strategy of working in collaboration with one or more of those pharma partners towards registration of a more effective treatment for men with early prostate cancer. And that's actually ultimately what we're all about. So thanks for the opportunity to talk. Thank you, David, for that great presentation. So we have time for one quick question, if there are any. I should have planted a question in the audience. Oh, this one I didn't plant. This is scary. Let me pass. So thank you for the presentation. And it's nice to see you guys coming along. So you have runway till end of next year. Do you foresee that you may have to take one of these to registration? And if so, can you do one registration? Have you talked to FDA about a special protocol assessment, like something creative that you could actually get an accelerated approval? What does that look like for investors? Because it looks like you may have to take it all the way through if your partners don't come through, right? Oh, I think we have interested partners, number one, interested from all sorts of perspectives, ranging from altruism to economics, not necessarily in that order. And this is not something we probably would want to do alone. The reason is we've moved to early prostate cancer. Those are larger trials. They're longer trials. And the real strategic questions which begin to emerge that follow from your question are, do we do that with one partner, or do we do that if we show, as we will, I'm pretty sure, that we can combine with any of the 4 antiandrogens and therefore potentially be an anchor for the use of these antiandrogens in earlier line therapy, which is where you know the whole field has moved, right? I mean, the literature strongly suggests that if you move those antiandrogens earlier, combine it with ADT, androgen deprivation therapy, the old LHRH analogs, the results are better clinically. And it all fits with that hypothesis I started with, which is the deeper you suppress androgen biology, the better the result. We think we're the next logical step with a drug that's safe, well tolerated, oral, etc. Do we do it with one potential partner or with all of them? Or do we do it with somebody else who then does it with them? Those are kind of the strategic options that I see emerging. We shouldn't try to do it ourselves.