Everyone, my name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the CEO of ESSA Pharma, David Parkinson, and the CFO, David Wood. Thanks so much for joining us today. We're gonna do fireside chat format. So maybe to start off, for those who are new to the story, if you can give a one-minute intro to ESSA. Yes, certainly. Thank you for the invitation to be here, Maury, and again, I'm happy to be here to represent the team at ESSA. What we're about is small molecule approach to the inhibition of male hormone androgen biology and prostate cancer. And, of course, there've been 70 years of development of anti-androgens for prostate cancer, but what's unique about what we're doing is that we inhibit androgen-driven biology at the other end of the receptor from where other approaches over those seven decades have utilized. The other approaches either inhibit synthesis of androgens or block androgens from binding and activating the receptor. We inhibit transcription through the N-terminal domain, the other end of the receptor. The strategy we're utilizing is to actually not try to compete with the current anti-androgens, but rather to partner with them, to combine with them, and to shut down the receptor from both ends. The result, at least experimentally, is a more complete inhibition of androgen biology. Historically, any time steps were made, either with a better drug or better pharmacology or better strategy to inhibit androgen biology, that translated into patient benefit. That's what we're about. We're currently in randomized phase 2 trials of our drug in combination with enzalutamide, Xtandi, or versus enzalutamide alone. We have a series of other trials combining our drug, masofaniten, with the other 3 anti-androgens, abiraterone, apalutamide, darolutamide, just to show that we can combine with them in feasibility. But the randomized trial is with enzalutamide, and that's what we're in the middle of doing currently. Got it. Yeah, it's a great intro and, maybe starting with the combo, we saw earlier this year the updated phase 1 data from your mazo plus enza combo study at the ASCO GU conference. Yeah. Can you recap key takeaways from that and talk about how these data stack up relative to historical benchmarks? Yeah. No, the purpose of the trial is a phase 1 trial, dose escalation of our drug, titrated against two different doses of enzalutamide, ending with full dose enzalutamide. The purpose is to show whether we could combine these with a favorable toxicity tolerability profile, and secondly, whether we could get adequate exposures of enzalutamide and our drug, masofaniten. I will summarize all of that by showing that, yes, we can give the two safely. The toxicity profile didn't look any different from that of enzalutamide alone, so extremely well-tolerated. We were able to use full dose enzalutamide, the approved dose, 160 milligrams a day, and we could get, despite enzalutamide's well-known predisposition to increasing the metabolism of drugs given together with it, excellent exposures to our drug. So, just from an operational point of view, that all worked well. Now, with respect to the results, these were patients with metastatic castration-resistant prostate cancer, who had had previous treatment. They with androgen deprivation therapy, they may or may not have had previous chemotherapy. What they had not received was latest generation anti-androgens. And so, we treated a group of patients. We showed what I talked about with respect to safety, tolerability, pharmacology. But we also interestingly found an 81% incidence of PSA90. Now, in the field, the depth of PSA decline correlates quite strongly in clinical trials with eventual clinical output, so it was very nice to see that. To your question, Maury, in this same patient population, and we have scoured the literature for, and there's a lot of literature and a lot of patients treated, it's in the 50%, plus or minus. If you've received previous chemotherapy, that falls considerably, maybe down to the 20s, 27, something like that%. So it seemed favorable in terms of the percentage of patients responding with deep PSA declines to this combination approach. So the next question: Is the depth and, you know, patients go beyond that to 0.2 nanogram per mL in absolute value or to BLQ, below the limit of quantitation. So we measured all of those, all quite impressive, related to historical norms, quite positive. We looked... People were asking us questions about PSA starting, as opposed to likelihood of falling, PSA 90. That's a non-question, we believe, after many discussions and scouring the literature and talking to experts. Your starting PSA doesn't correlate with the likelihood of your PSA 90 response. The other question we've been asked is, you know: Did you somehow select patients more likely? I wish I had that ability, to be honest. And what we did do was go back and look at the patients with the algorithm used for the risk of enzalutamide failure. It was used in the ENZAMET trial, and it's been used in other trials before that. 10 parameters defining risk of enzalutamide failure. 14 of the 16 patients were high risk. So, in short, we believe the data as we see it, but it is a small number of patients. It's a single arm, phase one trial. That's why we're going to a higher level of evidence with the randomized trial. Right. Yeah. Good, great summary of the phase one data and the updated ASCO GU. I guess one question is, a few months have passed since that update. Is there any status update on the phase one combo data you can share? Any even new anecdotal stories about individual patients? I love telling anecdotal stories, but usually requires alcohol. I will, we will be updating the data probably either at the ESMO meeting or at the Triple Meeting in September. That'll be a very meaningful—'cause that's seven months. Our expectation from the literature is that a time to PSA progression should be around the 11, 12-month kind of number. So, that should be very meaningful, and, we look forward to presenting the data at that time. Got it. And you mentioned the controlled phase 2 study is a higher level of evidence. In this study, you're comparing mazo plus enza versus enza alone, and this—which the study is focusing on PSA responses and PFS-2. But before we get into the phase 2, can you talk about the phase 2 trial design and what the PSA and PFS bars are based on your market research, and what you think KOLs will want to see, and what you want to see to justify advancement of the combo? Well, we want to see a higher group of patients achieve a lower depth of PSA decline. We think we saw that in the phase 1. We've built the trial to look at 80 patients versus of getting the combination versus 40 patients of getting enzalutamide alone. The trial was designed in combination with our partners, Astellas and Pfizer. And what we are looking at from the perspective of collaborating drug developers is a meaningful difference. Because PSA 90 does correlate so well with clinical outcome, this is not a trial for registration. Mm-hmm. The prostate cancer registration is related to PFS and overall survival. This is a trial for decision making, for planning, for proof of concept, that two is better than one, and if so, how much better is it than one? And because we are doing this in parallel with a series of other smaller trials to show that we can combine with abiraterone, with apalutamide, with darolutamide, we are doing this... This is the proof of concept for efficacy trial. The others are more a proof that we can actually combine with those drugs in a safe way. So overall, and the way we've designed those trials is to put them into slightly different patient, early prostate cancer, 'cause this is a drug for early prostate cancer, put them into different categories of patients. That, at the end of all of this, we'll have proof of concept. We'll have a sense of what the difference in the arms is. That'll help us plan for how large a registration trial should be, and also the experience across the different patient populations that are now defined operationally in prostate cancer, make some decisions as to which ones, together with a partner or, for that matter, partners, we would go forward into phase 3. Because we would need partners and some partnering strategy to get into the very large, long, expensive trials for the very, very large group of patients who would be affected if we can show that putting our drug, shutting the receptor from both ends, is better than just using an anti-androgen alone. Got it. And so just to clarify, for the phase one, you had 81%- Yes. of patients achieve that PSA90. That's what we reported. One patient had PSA 89, so we didn't count him, but, you know. And so if you can get somewhere close to that relative to- Yeah. You know, we're going against a benchmark of around an expectation of around 50%, ±. So you can sort of start to figure out with the kind of powers that one looks at in oncology trials, the kind of delta we would like to see, because we believe that's likely to correlate with clinical benefit. And our partners, and we, don't believe you need to follow patients for PFS. This is a good enough predictive marker in early prostate cancer to make those kinds of decisions, operational decisions and resource allocation decisions for clinical development. Got it. Will you still assess PFS? Oh, yeah in the study and follow? We're following these patients. We've already reported that there have been objective responses in the subset of patients, where you can actually measure disease by RECIST. We're following these patients with circulating tumor DNA because some very, very interesting information there about potentially, you know, patient segmentation into higher or lower responding patient subgroups. We're following patients with some new imaging software so that we follow not just as one does with RECIST, just, you know, you choose a few measurements, and you follow patients. In this case, you know, 70%-80% of the patients don't have measurable disease. We're following them with software that allows us to follow every single lesion over time in a patient. That'll give us insight into the heterogeneity that we saw in the late stage, single agent development of the drug. The late stage biological heterogeneity in prostate cancer is just remarkable. Earlier stage, much more homogeneous, much more AR-driven. That's the best site for this drug. ... Got it. And you said enrollment completion would be in first quarter 2025, and data would be reported mid-2025. Can you talk about enrollment rates so far and the feedback that you've heard from investigators? Well, we have 24 sites active in the U.S., Canada, and Australia. In the next couple of weeks, we're adding 14 additional sites in France, Belgium, Spain, some additional sites to come on in Europe. There's a new clinical trial system in Europe that even the regulators are getting used to, but we've managed to get past all of that, the new bureaucracy, and very interested investigators, good drugs, trials performing well. When we first started the trial, we didn't give guidance 'cause we just did not know how this new consortium would work. We recently did give that guidance that you just described because we feel more confident about the performance of the clinical trial sites that we're working with. They're great investigators. Got it. Is that the primary reason why you're adding the EU sites, is to loop in these investigators in the EU? Or what's the significance of having the additional sites, and could it potentially accelerate enrollment before the first quarter of 2025? Yeah, that's a very good question. Number one, there are great investigators in Europe. Number two, patterns of treatment in Europe haven't changed to the extent that they have in the United States with the advent of PSMA screening and the pretty widespread, although maybe 50% of patients in the United States, having these late-stage anti-androgens administered earlier in combination with ADT on the basis of really good trials like PREVAIL and AFFIRM. That's happened in about 50% of patients in the United States, 'cause that kind of shrinks the patient population that we're currently studying. It doesn't change the overall population of patients eligible for benefit from our drug, but that's what I meant about the segmentation of populations that's affected by PSMA screening, by this movement, left, if you will, earlier in time with the late-stage anti-androgen. Some of those steps have not occurred in Europe, so there are more patients available. But also, Europe has great investigator sites. They requested that we go there because there's a lot of interest in the drug and the mechanism, biology, et cetera. So, we're happy to go to Europe. I'm used to working in Europe, and we're looking forward to those sites joining us over the next few weeks. Got it. And so with the inclusion/exclusion criteria, that's staying the same, but is there- Exactly the same. ... any additional risk from adding patients from EU to the study based on the treatment? It's not a risk. You just pay attention to the mix of patient populations, how many of them... We accept patients who have had previous chemotherapy or not. We just need to keep track of that in the stratification. And so these are more technical issues, but they're totally appropriate patients to be approaching. Got it. And is there anything that you can say about what you're seeing so far in respective patient baseline characteristics for the patients that you're enrolling into the study? No. Okay. As expected. No. Yeah, as expected. I, that was just the feedback. And patient baseline status for the patients you're enrolling, I guess when thinking about the durability data you're seeing in the phase one, what's the treatment benefit you expect on PSA and also the durability or PFS you expect to see with the combo in the ongoing phase two with enza alone? Yeah, we haven't talked publicly about what the delta is that we're looking for in the arms. But, you know, a combination of the difference in the percentage of patients responding, plus the depth of their response, plus the durability of their response, plus the price you have to pay, which so far doesn't seem to be a price related to increased toxicity of a combination versus... I mean, it looks the same. Those are all the kinds of parameters that go into the decision, which you know, how much benefit do you get from this strategy, and what patient populations would make the most sense? In theory, the earlier one would go, the greater the potential benefit, because the earlier you go, the more homogeneously AR-driven the patient population is. On the other hand, the earlier you go, the longer the readout of the trial. So these are the kind of practical considerations that would affect clinical development decisions at some point. But, it's not one single number. It's kind of looking at it and saying: Is there net meaningful clinical benefit to the addition of this therapeutic strategy to the already, you know, really good, anti-androgen performance? But knowing that all those patients do become resistant to anti-androgens and that this strategy, in theory, could delay or prevent the emergence of resistance. But the only way to prove that is in the clinic. Got it. And the study's early, but it's open label. Can you say if you're seeing a difference on PSA between the two arms? That data is extremely restricted within the company. Not most of us don't even see that data, so I, I really can't comment on that. Got it. And you said patients will have initial PSA measurement three months on therapy. Is there a chance you could show some early PSA data or a ctDNA data cut prior to the first quarter of 2025 readout? Yeah, that's a good point. You know, so we actually measure PSA monthly. Right. But the convention is to look at PSA values at 90 days, 3 months, because that's the period of time that's been shown most to correlate with ultimate clinical benefit. You know, we'll be following the... Every 30 patients, there's a look by the Data Safety Monitoring Committee. And so, the trial is being monitored, and if things emerged earlier, we would certainly respond to that. ... Got it. And for any interim data that could come into the company, if you're doing an interim analysis every 90 days, I guess, could you potentially share some of that with collaborators? Probably not. I don't think we would want to get the clinical information from this trial that we share, even with collaborators, too separated from what we're talking about publicly. Mm-hmm. As a clinical investigator myself, I really think that we want to accrue all the patients, as quickly as we can. It's in the best interest of the integrity of the trial, which is, for us, the highest goal. Got it. Makes sense. Can you remind if there are any other exploratory biomarkers or measures you're collecting to better characterize the patients and their responses? Well, we will be doing circulating tumor DNA that proved very, very—as well as quantitative DNA in looking at the specific, you know, mutational profile of these patients. We'll certainly be doing that. Mm-hmm. I mentioned, Mm-hmm ... really innovative, imaging strategy we're using. We're trying to get as much insight as we can, as much learnings in this trial. What is the overall benefit to an unselected population? Mm-hmm Beyond the eligibility criteria? Are there subsets of patients we can identify who are benefiting more or less? That, again, would help define the design and execution of later registration-directed trials, hopefully make them more efficient. Got it. And, there were some patients in your phase I that had measurable disease. How many patients with measurable disease should we expect in the phase II? In general, in this population, in phase III trials, one sees about 30%, plus or minus. The measurable disease is generally in prostate cancer. It's metastatic disease to lymph nodes. The non-measurable disease is the very common metastases to bone. We'll be following all of those with respect to this software strategy that I talked about and imaging strategy. But in terms of measurements and classic RECIST-like registration endpoint measurements, it'll, it'll be a, a subset of patients, probably about a third, something like that. Got it. Makes sense. And if the Phase II data meets your internal bar, what are next steps? And given the evolution of the landscape, what are your latest thoughts on how to prioritize and pursue other settings besides mCRPC? Oh, well, the fact that we're putting, you know, these, these trials, combination trials with the various other, lutamides, including enzalutamide, in other clinical settings, and we have, I don't know, five, six, seven other trials, looking at that, tells you that, we're very interested in exploring the other, patient populations. As I mentioned earlier, the earlier you go, in theory, in the patient, natural history, the greater the benefit should be, shutting down the receptor from both ends, two different mechanisms, preventing the emergence of resistance to the anti-androgens, getting, you know, getting more mileage out of them from a clinical benefit point of view. So, that'll be the decision point. You know, if we have a positive Phase II proof of concept trial, the issue is partnering with one, partnering with them all. There's all sorts of interesting strategic options that, you know, we'll have to think about, that we do think about, have been thinking about. Got it. Makes sense. And then for the Phase II data in the middle of 2025, is it just going to be top line, or should we expect to see more detailed analyses? And when and where does it make sense to have this update? Yeah. So, you know, when you finish the trial, the first time we would even have PSA 90 on all the patients would be 90 days later, right? And then you need, like, four weeks or five weeks usually to bring in the data, clean the data, bring in the pharmacology, correlate that with the patient, et cetera. That said, if the trend, if there were trends earlier, then you know, we could come forth earlier, but I wouldn't want to predict that. Got it. That would mean mid-next year. Got it. Okay. And then for your monotherapy update and for some of the additional combo studies that you're running, what should we expect to see from those updates this year? Well, we'll give an update on the combination duration in the fall ESMO or triple meeting. As people know, we've done the single-agent dose escalation. We followed those patients for a long time. We've done two dose expansion cohorts with a lot of biological monitoring, again, to try to find whether if you've been on one or another of, usually more, of these late-stage anti-androgens, is there still a population that's still predominantly AR-driven? And if there is, it's not a very large population, would be a general statement. But what we're in the process of doing is following those patients, and we're beginning to bring in now circulating tumor DNA because we have that on all these patients. We'll be correlating the dose the patient received, the exposure the patient got, because we have pharmacology, the biology that we can understand of the patient, and then all the clinical. So when we present the phase I single-agent data, we'll present it as a sort of integrated set of data with the learnings that we've taken from that that are relevant for not only our development in earlier lines of patients, where we're now focused, because that's where the drug makes most sense, but also relevant to just the biology and the treatment of prostate cancer patients in general. This is a disease that goes on for a long time. There's therapeutic pressure for a long time. There's biological evolution towards much more genetic genomic heterogeneity over time. And, you know, targeted therapeutics need to respect that change. So it makes more sense for physiologically targeted, like AR in the early years, and more sense in the later years for anatomically targeted therapeutics, as we're seeing with all the new data with radioligand therapy and with ADCs, and with BiTEs. So, you know, the disease evolves under pressure, therapeutic application needs to respect that. Got it. Very good, and we're pretty much almost out of time, but I wanted to give David a opportunity to comment on cash- Yeah. -and how to think about OpEx. Yeah. So the cash reported March 31st, $136 million. So that's a runway through the end of 2025 with a substantial balance at that time. We haven't guided to that, but it's enough to get through these data points and do what we need to do. Got it. And maybe just to close out, David, if you want to just highlight key catalysts ahead, that investors should be focused on. Yeah. Well, yeah, by the fall, you'll see us present the durability data, which a lot of people are interested in, from the phase one combination, a dose escalation trial. You'll see probably the beginnings of us showing our ability to combine with apalutamide, with abiraterone, and with and with darolutamide. And then, of course, we will keep people apprised as to the progress. If we can do it more quickly, we will try to do that. It's job one for us with respect to the phase two randomized trial. So, it's going to be an interesting 9-12 months. We will may die a lot of things. We're not going to die of boredom, I'll tell you that. That's for sure. We're busy. Got it. Thanks so much for joining us today. Thank you for the opportunity. Appreciate it. Thank you, all.