Everyone, my name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. Thanks for joining us today. I'd like to welcome the team from ESSA Pharma. We've got the CEO, David Parkinson, Peter Virsik, Chief Operating Officer, and David Wood, CFO. Thanks so much for joining us today. We're going to do fireside chat format. Maybe to start off, David, if you want to tell everyone about the company, provide a one-minute intro. Sure. Okay. Well, first of all, thanks for the invitation to be here, Maury. At ESSA, we're focused on a novel way to shut down male hormone or androgen-driven transcription. Prostate cancer is unique in being driven, particularly in its earlier stages, by male hormone biology. There's a seven-decade history of incrementally better ways of shutting down androgen biology. Every one of those increments has resulted in improvement in clinical results. We represent, we believe, the next level of that, which is by shutting down transcription from the other end of the receptor by a mechanism completely different from the antiandrogens. We're not trying to compete with the antiandrogens, but by combining with the antiandrogens, by shutting down transcription from both ends of the receptor, we get, experimentally, a complete shutdown of androgen biology such as has translated to clinical benefit in the past. So that's what we're about. Makes sense. That's a great intro, basically hitting the androgen receptor from each side of the receptor so you get more complete knockdown. You recently reported some data at ESMO and then the PCF meeting. Maybe talk about those data and some of the key takeaways from that. Sure. Let me start, and then I'll ask my colleague Peter to comment as well. Based on the preclinical studies that we've done, when you do combine shutting down transcription from both ends of the receptor, we actually get a deeper inhibition of androgen-driven biology. And so from that, we would expect to see if the preclinical work translates to the clinical setting, we would expect to see a larger percentage of patients show a significant decline in PSA, which is a biomarker for prostate cancer, particularly early prostate cancer. So a more rapid, a deeper, and a longer, that is, a more durable, suppression of PSA markers. And I believe that's exactly what we've seen in the phase I study where we showed that we can safely combine our drug, which is called masofaniten, with the drug from Astellas and from Pfizer, enzalutamide, or Xtandi is the brand name. And I think that's exactly what we've seen at the clinical level. Why don't I ask Peter to just expand a little bit on what exactly we have found? Great. Thanks, David. Thanks, Maury, for having us here today. As David just mentioned, we did have an opportunity to report at both the ESMO meeting and at PCF. It was the phase I dose escalation portion of the study. There were 4 dose cohorts. First three had a dose of 120 mg of enzalutamide. That's a little bit less than the full dose. The final dose was with the full dose of enzalutamide. The first three cohorts of masofaniten had 600 qd, 800 qd, and then 600 bid, with the fourth cohort being then the combination of 160 mg of enza with 600 mg bid of masofaniten. As David indicated, the drugs together were safe and well tolerated. That was predicted from the preclinical studies, but always very good to see in the combination study, mostly grade 1, 2 adverse events. We did have one grade 3 rash that occurred once we gave enzalutamide. That is a known dose-limiting toxicity of enzalutamide, but overall very well tolerated. Then from a pharmacokinetic standpoint, that was our second real area of inquiry. And what we found is that masofaniten did not impact the absorption of enzalutamide or the metabolism, hence the fourth cohort being the full dose of enzalutamide. But what we did see, as expected, was that enzalutamide did impact the metabolism of masofaniten. However, the 600 bid dosing was able to overcome that clinically and get us into clinical ranges that we actually felt very good about. Then overall, from an efficacy standpoint, as David indicated, we did see deep responses in PSAs in the vast majority of patients. So far to date, the time to PSA progression is a measure we haven't yet had the chance to really look very closely at, but it looks like the durability perhaps will be there. We'll be reporting again in the future on some of those longer-term measures. What that did was immediately trigger going into a randomized phase II study to increase the levels of evidence around the test of the hypothesis. That is, the two drugs together will represent better clinical benefit. And so that's what, in the midst of doing, happy to discuss that in as much detail as you feel, Maury. Sure. Yeah. I had a couple of questions about the data. For the ESMO PCF data, you showed PSA90 responses at a pretty high rate. Seems like it's much better than what you would expect with enza monotherapy alone. And then you have the spider plot in your poster that shows that some of these patients are flatlining with durability on PSA. How convinced are you that this is different from enza monotherapy? Well, it's a first level of evidence. The numbers, the percentage of patients, that is 81% that we've seen so far and reported on, is much higher than one would expect from looking through the literature, everything we can find in the literature, patients who are comparable, times that are comparable, in which patients have been treated. So it's very encouraging, but it's not definitive. Thereby, you need to go into the randomized phase II setting. We spent the last nine months preparing to do so. It was triggered when we showed the drug was safe and well tolerated, that we were getting exposures that were relevant clinically based on our preclinical studies. So that's all underway. Many patients are being screened currently. We've added an additional 20 sites to the original 5 sites from the phase I dose escalation piece. Those 20 sites are in the U.S. and Canada. By the end of this year, we'll have additional sites in Australia. We are in the process of setting up to introduce sites also in Europe. It's a randomized phase II trial with 80 patients receiving the combination, 40 patients receiving enzalutamide alone. It's based on changes in PSA markers. Both we and our combination pharma drug partners agree that that's very strong evidence, assuming the hypothesis is confirmed, for going into later stage trials and exploring the potential clinical benefit of putting these two mechanisms of action together. Got it. Yeah. Makes sense. Also, for the PSA90 patients, there were a few patients that did not reach PSA90. Any insight into what happened with those patients? Was it an unusual tumor type, potentially neuroendocrine? Yeah. So of the 16 patients that were evaluable, I think at this point we have, what, 13 that achieved the PSA90 and one patient still who was on very short. So we haven't yet reported on that patient. But there were two patients, as you indicated, Maury, that their PSAs did not decline significantly. And that's not necessarily actually so strange at all within the prostate cancer realm. You'll see from the very beginning of the treatment of the disease that the patients who come in are very heterogeneous, and they don't all have a PSA response. And so these two particular patients, one had a very low PSA, one had a higher PSA. And there was nothing particular about their background profiles, their history, that would necessarily have indicated why they would or wouldn't respond. It's just part of the disease state. We don't expect everybody to respond. But what's really actually most interesting is to see that when patients do respond on the combination, they seem to respond quite deeply. That's what's unique. I think when you look at the historical data for enzalutamide or abiraterone or apalutamide or daralutamide in the same patient populations, you normally expect to see some patients that are kind of in between, if you will, partial response, but not a complete response. Whereas, at least in our patients to date and projected by the preclinical data, we're seeing a deep response in those who can have a PSA response. Yeah. I think I remember at ESMO you mentioning the patients who are getting to PSA 50. A lot of those patients are getting to PSA 90 as well. Yeah. So far to date, all of those who achieved the PSA50 went on to achieve a PSA90. Got it. And so that leads to the next question. For patient number 18, who is at PSA 70, I don't know if there's a status update on that patient or. We don't have an update on that, but at ASCO-GU. But thank you for asking. We will be reporting on that one additional patient who was at, after two months, a PSA70. And so we'll be able to say at that time if our prior data of anybody who achieved the PSA50 also achieved a PSA90 is still true or not. Got it. And for ASCO-GU, so anything additional you could say about what kind of data you could have at the conference there? It'll largely be around duration. As you indicated, we've got patients now from the first cohort who are out, must be 23 months at this point, which is pretty impressive. From the literature, you might expect somewhere between eight and 11 months median PSA progression-free survival based on the nature of the population and whether they previously received chemotherapy or not. So it's encouraging. But again, first level of evidence, it's time to get into the randomized higher levels of evidence clinical trial. And that's what we're doing. Got it. Makes sense. One of the other questions that came out of the ESMO data was for cohort 4. When patients were starting on maso alone, you see PSA go up a little bit for that first week, and then it starts to decline. We've talked a little bit about what could be happening there. Do you want to. I don't think anybody knows. In the field of prostate cancer, nobody really cares what's going on there because the design is that you get our drug for 7 days. It takes 7 days for our drug, which has a half-life of a little more than 24 hours, to build up to steady state, to actually a clinically relevant concentration. In clinical trials, Prostate Cancer Working Group guidelines are, don't even look at PSA for three months, 12 weeks. The reason is that PSA is not an acute phase reactant. It has a half-life of several days. It doesn't move quickly. I don't know how to interpret any of that. All patients enter with rising PSAs. That's part of the criteria for eligibility. I think we just ignore that. You don't see that in any of the literature because, and it's probably our fault for being too transparent and putting in all the data we actually have because it's confused people. But I just would ignore it. It doesn't mean anything. Yeah. Makes sense. It seems like a pretty variable move right at that. That is absolutely correct. A lot of kinetics going on. One of the other discussion points is baseline PSA, where some of the patients are starting a low baseline PSA. But I think in cohort 4, you've got a few examples in there where those patients are actually pretty high PSA. But maybe talk a little bit more about how those patients get to the low PSA to begin with with the prior treatment. Yeah. So we've talked a little bit about this, Maury. So if you look, there's a couple of factors at play here with respect to PSA levels. Historically, when you compare studies that are done year after year over the last 10 years, the average PSAs or the median PSAs in these studies have come down. And that's because PSAs, in general, our patients are managed more closely, more carefully by physicians. They don't wait as long in between studies to put them on. But what's an even greater factor for us is one of our criteria that we have in our study is that patients could have had prior chemotherapy in the hormone-sensitive setting. And what we see is that patients who are failing from that kind of a therapy are starting from a low PSA level. And they're failing from quite low. Their PSAs are rising, but they're rising at a level at that point which are lower than those patients who didn't have prior chemo. So we haven't actually broken that out, but we will in future looks at actually the patients. But our chemo patients, if you look at those who start with lower PSAs, it's generally those patients who had prior chemo. And we know those patients have a worse prognosis historically. There's a reason why they were chosen to give chemo at the beginning. And so those PSAs are low but rising, but they may not actually be the ideal patients. The patients who are higher PSAs may actually be easier to treat patients. We'll see. Yeah. In short, for previously treated patients, which all of these are, many roads lead to a particular PSA number, right? And the literature has no support for starting PSA as being an indicator of likelihood of response to an androgen-related mechanism. Makes sense. I think there's data that shows that regardless of what the starting baseline PSA is, if you get a PSA90, that's still meaningful. Oh, that's what's important. The depth of PSA decline, PSA90, beyond PSA90 to 0.2 ng/mL, or even further below limited quantitation, which is a really low number, the deeper, the better. Makes sense. And David, you talked a little bit about the phase II study. Is there anything else investors should know about the study design? And how do you think the patients are going to look like going into that study, especially with baseline PSA? I don't know if there's more you could say on that. Well, we have an expectation that they'll look very much like the patients in the phase I because the eligibility criteria are identical. Now, we are going to more clinical sites. But the main difference is we've simplified the trial. We had a lot of patients would turn us down in the phase I trial because there were so many visits for pharmacology, for measurements of drug levels. But that was the point of the trial. So we can't skip that. But in the randomized trial, it's more like clinical medicine. It's more like a phase III trial, regular clinical visits once a month. Patients are followed. It's not all these blood draws. But one additional thing, we will be studying these patients in great detail biologically with circulating tumor DNA, which we've used in the past to great insight. So getting back to your question about the two patients who showed no evidence of responsiveness, hopefully we'll begin from this kind of approach to get some insight into how those patients are different and either exclude them in the sense of enriching for patients who are more likely to benefit, or at least to understand the mechanism, and maybe we can do something about that therapeutically. So that's our approach to it. Got it. And for this study, you're anticipating having about 25 sites for the phase II? Or more. Yeah, I would say, yeah. It'll be 25 at the end of this year and potentially significantly number more. Our job right now is to execute and to put as many patients on good patients, highly good quality clinical trial. The sooner we do this, the sooner we'll get an answer to this question. So this is job one for us. Are you bookending what enrollment timelines could look like or when you can? Only in my dreams. We'll have a better sense after two or three months. I know a lot of patients are being screened. There's great investigator enthusiasm. Patients like being on this drug, we're told. But until we've actually experienced it, there's the usual hockey puck. But there are a lot of sites activated now because we've spent so much time over the last year anticipating this date. So when we got the final data from the combination, when the safety review committee met, when they recommended the particular dose and schedule to go forward with, that triggered a lot of sites to activate or for their IRBs to review the data and then activate. So it's full-court press at the moment. Got it. Any expectations for screen failure rate for this study and also dropout rate for patients? No, again, we'll know better after about three months. Because it's a similar patient population, at least in the first 5 centers, the staff understand who are appropriate for the study. We have another 20 centers right now, and they'll have to learn that. But that's the usual clinical trial practice. Got it. Okay. For the phase II, what delta in PSA90 versus enzalutamide monotherapy are you powered to detect in the study? Is there more that you can say about that? Well, the original design based on discussions with our collaboration partners was actually PSA 50. We're changing that to PSA 90. We haven't said publicly what our expectation for difference is because that's not going to be a hard number. It will be a number, necessarily a hard number because it's related also, is there any difference in toxicity in the arms and what is the nature of the benefit? So there's a lot of parameters involved in making a decision as to how important that difference is. But listen, based on the preclinical data and based on if the evidence is prescriptive from the phase I trial, it should be a significant and meaningful clinical difference. We're not here to do incremental stuff. Right. Makes sense. And what other key endpoints are you assessing in the phase II, and are you powered to detect a difference on radiographic DFS? The answer is no to the latter. This is not a registration trial. But the purpose of this phase II is really twofold. Beyond more safety and tolerability, but this is the safest drug I've ever worked with, is to show that the hypothesis is correct, that there is a delta between the 2 arms, get a sense of the magnitude of the arms and any clinical toxicity price one needs to pay, but we haven't seen any evidence of that so far. And that will help us, together with our collaboration partners, discuss what a registration strategy/trial would look like, how large it would need to be. Because registration endpoints in prostate cancer are not PSA-related. Despite the attempts of the community to do so over many years, they're PFS and OS-related. And so one would have to power a trial to that end. This will help a lot. That's what its purpose is, really, Maury. We'll measure everything. We'll measure responses. You saw in the poster, we had two responses out of the five eligible with two still underway because they were just recently treated. So where there is objective opportunity to measure responses, which is usually lymph nodes in prostate cancer, it's hard to do that with bone metastases. We'll measure it. We'll have PFS, ultimately, and OS. But neither we nor the partners we interact with believe that's necessary for the decision-making as to how important this phenomenon is and what a trial or trials in different patient populations. Because the earlier you go in prostate cancer, the greater the clinical benefit we would expect to see. Got it. Any more perspective on what your internal bar for the phase II is to move the program forward, potentially into a phase III registrational study? Probably not. Okay. I mean, I have my own numbers internally, but I don't share them. It's a private thing. Understood. Understood. Let's see. For the phase II, what's the expectation for baseline prior chemo? Will you stratify based on that? So we will stratify based upon prior chemotherapy. Coming into the phase I, we had 6 out of the 16 evaluable patients who had prior chemotherapy. And we would anticipate that that would end up being probably a similar number in the phase II as well. If you look at the studies that have been done more recently with a similar patient population, large registrational, they're kind of around 20%-30% of the population comes in with prior chemotherapy in the metastatic hormone-sensitive setting. Got it. In your phase I, I think you had about five patients with measurable disease. What is your experience so far with measurable disease and your expectations for this in the phase II? That's what David was just referring to. two out of the five had a partial response to date. two had a stable SD. And so those patients were earlier on, and we'll see whether or not those continue to convert. If you look at the historical data in this patient population, it's around this 50% plus-minus who have some kind of a response to enzalutamide. And so again, the PREVAIL studies, what we look at for is a good proxy. And those are kind of the measures and the patients that we look at for that. Got it. Okay. And then you've also planned a couple other combo studies as well, including with daralutamide, apalutamide, and abiraterone. Can you give us an update on the current status of those? Yeah. No, thanks, Maury. That's actually where we're going to spend a lot of time this coming year. We've spent the time talking about an ENZA combo, but we're about to start our abiraterone combo studies. And that's where we're going to be studying masofaniten with abiraterone in the same first-line metastatic CRPC population as we've done in the ENZA study. But then we're going to get into a much earlier patient population, metastatic castrate-sensitive population. And this is where AR therapy is known to be very relevant. The biology is much more AR-driven. And so we're very excited to get into that population. In addition, we'll be studying apalutamide in a combination with masofaniten in the non-metastatic CRPC population. So these are kind of earlier CRPC patient populations than we're treating currently. We'll have a three-month monotherapy window of masofaniten, and then we'll add apalutamide at that time. So that'll be an interesting study to look at the results as well. And then we have two investigator-sponsored studies that we're talking about now. One of them is the daralutamide combination study. That's actually screening patients as we speak. That is looking at daralutamide versus daralutamide and masofaniten in the neoadjuvant setting. So these are patients who are high-risk undergoing prostatectomies, and they're going to get three months' treatment of either daralutamide as monotherapy or the combination of the two together. And then the last study in combination that we have that should be beginning here fairly soon is actually a combination study with enzalutamide, but in the, once again, metastatic castrate-sensitive population. And we'll get additional experience in that population with enzalutamide as a combination partner in that case. Got it. That's helpful. And maybe a two-part question, just your thoughts on the evolving treatment landscape for prostate cancer and where you see masofaniten fitting in. And then what are your thoughts on BD strategy or potentially partnering? How are you thinking about that? Let me take the first part. We think we fit in perfectly with the history of the evolution of treatment of early prostate cancer. And that has been, as I mentioned, every time there's been an incremental improvement in antiandrogens that translated to clinical benefit, the last big step in that was moving these latest-generation antiandrogens earlier in lines of therapy in combination with androgen deprivation therapy. Massive move translated to survival benefits. We believe we represent the next increment to that. We're not competing with the antiandrogens. We're taking antiandrogen hormonal suppression to a whole new level. So we think we fit in beautifully with the evolution of early prostate cancer hormonally-based therapy. We do not add, as the phase I showed, to the toxicity of enzalutamide, which is pretty minimal in any case. So it's oral. It's a tablet. It's given once or possibly twice a day. It fits into the nature of the patient population involved. We've designed it to be able to be combined with the various drugs that Peter just went over. It makes sense in early prostate cancer, and it'll make most sense when we show the additional clinical benefit that can be achieved without any toxicity expense in that patient population. Got it. Now, with respect to BD strategy, why don't you give them everything? Yeah. Well, I can't really give you everything. But let's just say there's a lot of different companies that have a potential interest in this sort of a program. You could imagine the companies that we already work with. We have antiandrogen franchises, but those who also want to get into the prostate cancer realm or have just gotten in there, but without an antiandrogen, we also have a lot of geographic players as well. One thing is for certain, though, is while we do have the cash to undertake all of the work we've talked about here today, plus some, we would not undertake those phase III studies entirely on our own without first finding a partnership. Just because those are larger studies, you want to do them in parallel, and you really want to do them on a worldwide basis. So we'll work with a partner to really do the pivotal studies. Got it. And maybe two. Final cash? Close out. Yeah, if you want to mention cash runway and just key catalysts. Yeah. So the cash runway last reported June 30th was $152 million. So we have a solid runway well through the end of 2025. And that allows a number of data readouts, including the phase II study, as well as the other combination study. So solid cash. We've recently done some housekeeping and putting in place an S-3 and put in place an ATM, which had expired. We've never used the ATM before, but we just do that for housekeeping. So solid runway and looking good. Great. Thank you. You want to do catalysts? No, we don't need money. We don't need money, We don't need money, and we don't intend to raise money in the near future. So, just because there was some confusion around the ATM. But we had an ATM. We never used it. We've just brought in an ATM. It'll be there, but we have no expectations of using it currently. Got it. Well, thank you very much for joining us today.