All right, our next company for a fireside chat is ESSA Pharma. Today we have the CEO, David Parkinson, and Peter Virsik joining us today, Chief Operating Officer. David and Peter, very nice to have both of you joining us. Thanks for participating in our conference. If anyone in the audience has any questions, please feel free to email me at kpatel@brileyfin.com. David, maybe just to kick it off, give us a quick, you know, overview of ESSA Pharma as well as recent and upcoming development, and then we'll dive right into the Q&A. Well, thank you, Kalpit and Mandy. It's a pleasure to be here this morning. Thanks for the invitation. We at ESSA Pharma are focused on a novel way of shutting down androgen biology, that is male hormone-directed biology. This is particularly relevant to prostate cancer. That's our initial focus. We've been developing small molecules that inhibit androgen-driven biology in a completely unique way. There's a six or seven-decade history of incrementally better ways of shutting down androgen biology through with anti-androgens. People are generally familiar with that class of drugs. Our drug, on the other hand, which falls into a class called Anitens, works at the other end of the receptor, shuts down androgen-driven transcription in a novel way, bypasses the mechanisms of resistance associated inevitably with treatment with anti-androgens, and therefore offers interesting opportunities clinically, potentially in the rescue of men who are progressing on current anti-androgens. We believe, even more importantly, in the combination with those same anti-androgens in early patients to get deeper, longer, and associated with good quality of life treatment so that men can live with prostate cancer for much longer. To that end, we started with single agent therapy in late stage patients. We can talk about that. We're currently focused primarily now on combination therapy with anti-androgens in early patients. We've just shown that the drug is safe, it's well-tolerated. We now have about 2 and a half years of experience with the drug, comfortable taking the drug into early lines of therapy, where the biology of prostate cancer is more homogeneously driven by androgen biology. That's where we're at. Happy to go into more details, but we're pretty excited about where we are with the development of the drug. Okay. Maybe David, at a recent medical meeting, you showed that, you know, 5 out of 6 patients achieved a PSA90 with your drug plus enzalutamide, and then 4 out of 6 had the same, you know, PSA90 within 3 months. Maybe put some context behind these results. I want you to help us understand how relapsed or refractory these patients were, and then, you know, help us understand what the PSA90 would look like in these patients with salvage therapy. I'll ask Peter to go into more detail on this, but just to make a comment that we presented some of the early data in the combination, dose finding, because putting two drugs together, in combination therapy means that you have to work out any potential interactions between one drug and the other. We believe based on our preclinical studies, that we can combine 7386, our current drug, with any of the four major anti-androgens that are in clinical use. To do so, we have to work that out, and we have to actually demonstrate that. We showed some of the early data because of skepticism that we heard that we could do that we could do it safely, and in a way that would be appropriate for these early patients where androgen biology is so important. Peter, perhaps you could go over that data and put a context in it relative to historical experience in this area. Sure. Sure. Kalpit, you mentioned, we did present some data in the fall of 2022 at the Prostate Cancer Foundation meeting. It was from the first two cohorts of our combination study looking at EPI-7386 with enzalutamide. These two cohorts were with three-quarters of the regular dose of enzalutamide, which also resulted in three-quarters of the exposure of enzalutamide. Any comparisons we make actually are to historical data with enzalutamide at full dose and full exposure. Just keep that in mind. We did this for a potential drug-drug interaction that we could have. As it turns out, we don't have that, so we won't keep it at 120. We'll eventually move to 160. From these two cohorts, you're right, we did achieve a PSA90. 5 out of 6 patients eventually achieved a PSA90 in that study, with 4 of 6 achieving so at 90 days. Why is that important? Well, if you look at the historical development of enzalutamide in this same patient population, and this patient population really is defined by 2 groups. They're all first-line metastatic CRPC, but they may have had prior chemotherapy or not. Okay? We have a mixture of those 2 patient populations. What was done was, from those large pivotal studies, they looked at patients who achieved a significant PSA reduction at 90 days and then found that those were the patients that in the long term had good progression-free survival and good overall survival. This 90-day PSA reduction endpoint for us is actually an important one for giving us a better sense of where the study's going, the drug's effect, and potentially also then the powering assumptions for a larger pivotal study. We don't have comparisons yet in this study, but we can look at a historical comparison of how enzalutamide did at the full 160 milligram dose. Those are represented by two studies, the PREVAIL study, which was the pre-chemotherapy population, study, and then the AFFIRM, which was in the post chemotherapy. In the PREVAIL study, 37% of patients achieved a PSA90 in 90 days, with 47% achieving it eventually in that study. In the AFFIRM study, those numbers go down because they previously had chemotherapy, and only 13% of these patients achieved a PSA90 in 90 days and 25% achieving it eventually in that study. By either comparison, it's hard to compare because again, this is not the same study. Patient populations can drift over time, but surprisingly, in particular for the PREVAIL patients, subsequent studies that have been done since that time, these numbers seem to stick with respect to the PSA90s that are achieved in these pre-chemo population with a second-generation anti-androgen. We use those numbers in particular for comparison, but it'll be the phase 2, the randomized study, where we'll be pitting ourselves against single agent enzalutamide, where we'll really be able to show what kind of a difference we can achieve in this population. Got it. When the initial data came out, the, you know, the 5 out of 6 patients with PSA90, I guess there was some sort of debate about how to evaluate these data, right? Some investors may have been looking at the baseline, you know, PSA levels, and they were claiming that the baseline was low to start with and maybe a PSA90 is not a good representation of what could happen when the sample size gets bigger. Any thoughts on this view? I mean, should we be zooming in on at that detail? Lots of thoughts. We've had those questions. Peter, maybe you want to comment on that, please. Sure. We spent an exhaustive amount of time looking at all of this, just because it's something we're obviously very interested in as well. What's interesting is that Mary-Ellen Taplin did a study many years ago, looking at the PREVAIL study and looking at the question, exactly this question, patients who begin with a low PSA number. In this case, it was 10 nanograms per ml or less. Do those patients do any better or worse? I think what you generally find is that patients with lower PSA numbers overall generally have a better survival and do better, maybe perhaps long-term. It generally seems to be a trend. However, when you look at the PSA 90 in the near term and the effects of the drug, in that study, it was identical. It was 47% overall in the study achieved a PSA90 overall in the study if they were below 10 nanogram per ml. You may recall, I just said that for the study as a whole, 47% of all PSA varieties achieved the same PSA90. I think that's a pretty good, a pretty good measure, pretty good study, 'cause that was 122 patients out of the 872 that were treated. Not perfect, but a pretty good, pretty good analysis. In our view, gives us at least some level of comfort that the lower numbers should reflect generally how a patient behaves in general for PSA90. What I want to also highlight is we had a few that were low, but we did have some that were higher. While we haven't disclosed what our partner J&J had done in their study with 3 patients in the identical population, those numbers were also quite a bit higher, and they did very well for those higher numbers as well. We don't really think there's much to the PSA starting values. Okay, fair enough. That's super helpful. Maybe talk to us about, you know, potential toxicity from combining, you know, your agent with enzalutamide. We know that from historical combination-based studies of abiraterone plus enzalutamide, there was essentially no improvement in efficacy outcomes, but then there was some safety baggage or an increase in side effects in those combination studies. I guess, are there any pieces of evidence in your data set that suggest that, you know, the outcome might not be the same as what we have seen with Abi plus Enza? Maybe I'll take that. We've anticipated putting our drug together with anti-androgens, and in a selection of EPI-7386 as the drug candidate, we did everything we could to minimize any potential additional toxicity of combining our drug with enzalutamide. For example, our drug does not cross the blood-brain barrier, and as you well know, 1 of the dose-limiting toxicities of enzalutamide is related to neurological to seizure activity. That was 1 design issue. Secondly, we designed the drug to, as best we can, you can never totally eliminate this, be less likely to interfere with the metabolism of other drugs. This is not just an enzalutamide-specific issue. This is related to a population of older men in general who are on a lot of other medications. We think we've come up with a drug that's actually a pretty good partner. We have every reason to believe, as I mentioned earlier, that we should be able to combine EPI-7386 with any of the four anti-androgens, some more simply than others, but all could be done. We have seen no indication, as was predicted by our animal studies, of any increased toxicity in association with the combinations in our experience to date. Okay. That's helpful. Talk to us about the AUCs, the target AUCs, and the exposure levels. That you're achieving for both EPI-7386 and enzalutamide in the first few dosing cohorts. Are you already at the target exposure levels? You know, of those patients who achieved a PSA90, any color on their exposures, that would be good too. Peter, would you like to comment on that, please? Sure. So we think that the exposure levels of both drugs are clinically relevant that we began with. EPI-7386, we're getting exposures on average of 110,000 in the first cohort and then 150,000 in the second cohort. Of course, enzalutamide, as I mentioned before, is at about three-quarters of the typical exposure of the approved dose, which is still a very active clinical dose in our view. If you look back at our preclinical models and you ask, "Okay, so this 100,000 level or so, what does that look like?" Well, that was quite an active level in our AR-driven models. When we look at LNCaP, VCaP, the typical models that are used to evaluate AR-driven prostate cancer, those are very active doses. That 100,000 also translates to a overall exposure, if you will, from a preclinical standpoint of about 8 micromolars over 24 hours. If you go back and look at our data sets, at the RNA-seq, the ChIP-seq and all of our data, 8 micromolar is quite a potent concentration for us. We feel that the concentrations we're already achieving are clinically active and relevant. In particular, in combination, you may not need as much drug as well. That's certainly what we saw preclinically. Part of the reason for the dose escalation is to optimize all of this, but we think that we are in clinically relevant exposures already of both drugs. Okay. Got it. Where are you in terms of the dose escalation portion in this, in this combo trial, and when should we expect the next update here? We're currently at the third cohort, just finishing that off. That is a cohort that, as Peter indicated, is still with enzalutamide, at three-quarters of the dose, at 120. EPI-7386 is at 600 milligrams, twice a day. The next cohort will be 600 milligrams twice a day and enzalutamide at the full approved dose, which is 160. We expect to finish this work in the first half of this year, and we'll report it out as soon as we can at an appropriate time, soon thereafter. It's important to note that this is the dose-finding portion, if you will, the phase 1 portion of combining these two drugs. Our plans are to go immediately once we have demonstrated the safety and tolerability and good pharmacology to go right into a randomized phase 2. That'll be 40 patients randomized to enzalutamide and 80 patients randomized to the combination of 7386 plus enzalutamide. That, to that end, we have been adding up to 15 additional centers which will be ready to activate as soon as that protocol is ready. We'll go right into, from the phase 1 into the randomized phase 2. Again, that should start mid-year if not, if not earlier. Got it. Remind me, you know, based on your preclinical modeling, do you expect to go higher than I think, you mentioned cohort four, where you get the full dose of enzalutamide? I don't think, Kalpit, that we anticipate doing so. That'll be full dose of enzalutamide, we don't appear to be affecting the pharmacokinetics of enzalutamide. As Peter just indicated, that'll be good exposures of 7386, particularly in these early patient populations that we believe are more homogeneously AR-driven. There's not a lot of additional kinds of genomic change that we see in the really later-stage patients who've had the disease for years and, you know, been through many lines of treatment. That was our experience in the phase 1 clinical trial. No, I think we anticipate. Now, of course, you need to do it, but we anticipate that the fourth cohort will establish, and then we'll go directly and immediately, actually, into the randomized portion. Got it. Maybe Peter, talk to us about the strategy for your monotherapy, you know, monotherapy path for EPI-7386. I know you're heavily focused on the combination-based trials. Should we expect maybe a niche patient population that you go after in that setting? Yeah, sure. Sure, Kalpit. For monotherapy, I think what our goal and work for this year is to continue to narrow down that patient population that we were studying last year into what we believe could be clinically earlier-stage patients and to really spend a lot of time developing the biological characterization of these patients to then determine are there particular subsets that we think could be relevant and could be good active populations for us to go after with 7386 as a monotherapy. That, of course, is colored to some degree by, of course, the regulatory environment. We know the FDA is becoming more conservative, if you will, regarding accelerated approval pathways. We also know that the Inflation Reduction Act also provides for small molecule drugs as ours, who could have a very large, later opportunity, less incentive to moving quickly forward with an accelerated approval pathway. We have to look at all of that, when we think about the monotherapy decision and the direction that we end up going. That's a lot of what we'll do this year, is to develop more biological characterization, very deep biology of these patients, and really understand who are these patients and can we benefit some of them, and is that a large enough patient population? Okay. Okay, I've noted that your drug's enrolled in Project Optimus from the FDA. Was this something that was put forward by the FDA for EPI-7386, or did you actively, you know, go in and, you know, you wanted to dose optimize this agent? Well, we haven't formally enrolled in Project Optimus. We haven't talked with the FDA about this, but we followed, you know, the thinking and the reasons that Project Optimus has come to being, that's largely around getting drugs approved at doses that may be inappropriately toxic, relative to doses that could be efficacious. Safety is not an issue for us so far, thank goodness, as predicted by our toxicology. That being said, getting the dose and exposures correct for oncology drugs is a very challenging task, always has been. We've moved away from the days of a maximally tolerated dose as we've moved into biologically targeted therapies. What you're really trying to do is find the optimal relationship between the exposures you achieve and the biology you can effect. When you don't have a safety limitation, that actually becomes a little bit more challenging. We may very well explore a little bit as we're going along. It shouldn't hold up the program at all. Consistent with the philosophy of Project Optimus, you know, we're interested in trying to maximize, in the majority of patients, an exposure which will be active, but which will not expose them to more drug than we need to. Okay. Okay. Got it. I understand that the, you know, the investors' attention is on 7386, but you did have some preclinical work on your first generation, you know, molecule that's a degrader for the same N-terminal domain of the androgen receptor. Maybe highlight some of the important preclinical findings from that poster and when we should expect this to enter the clinic. Peter? Sure. there's two programs actually that we're focused on in the research pipeline, kind of a next generation Aniten approach, which takes over where EPI-7386 ended, if you will, continues to expand that. In that program, we're actually quite excited by some of the molecules we've been making, since EPI-7386. This is looking at potentially two different directions. One could be a molecule that would be used in an AR-driven sort of tumor, that's not prostate cancer. One direction could also be a follow-on in prostate cancer, if you will. We've made great progress in expanding our IP and actually developing additional molecules. That program is actually moving along quite well. The one you mentioned, our ANITAC program is also quite exciting for us because this is a N-terminal domain focused degrader. That is an area that we started about a year and a half ago, and we've made great progress, and we did present some data at the triple meeting last fall. Really where we're at at this point is that we've got molecules which can be quite potent, molecules which are stable, and that's not so easy to necessarily find with these PROTACs or these bifunctional degraders. The area we're still working on is selectivity and getting other characteristics that we wanna have for our drug candidate. While we're very excited by the progress we've made to date, we're not yet ready to declare an IND candidate in that program, but continue to really heavily push that program forward. We'll have further updates this year, but we really haven't committed yet when we'll be able to identify that IND candidate. It's looking very good, and we've made great progress so far. Got it. What I might add to that, Kalpit, is that, this will allow us to look at the pros and cons of inhibition versus degradation and, what the different characteristics of those mechanistic approaches are, whether they might serve different clinical applications, whether they might even in some situations become complementary, because I don't think the field really understands that yet. We'll have tool compounds that will allow us to sort that out. Would you not agree, Peter? Yeah, definitely. I think that's a real question the field is still trying to grasp, which is what is the real benefit of a PROTAC versus a great inhibitor. Got it. Maybe last couple minutes, any key milestones or updates that investors should be focused on for 2023 and maybe early 2024? Then what's your cash runway like? Well, we'll as I mentioned, finish the dose finding for the combination therapy with enzalutamide by mid-year. We'll be reporting that out clearly this year as soon as we can. We'll continue the monotherapy work and report out on the expansion of patients that we are treating currently with deep biological characterization. Not sure when that is. That's a function of accrual and whether we decide, consistent with our Project Optimus talk, just how much to explore further pharmacologically. Then we have the collaboration studies with combinations with other drugs than enzalutamide. As you know, we have agreed with Johnson & Johnson to switch roles in the collaboration with combining our drug with abiraterone and with their drug apalutamide. We're just finalizing the details of that collaboration. In addition, we've got a collaboration with Bayer, which is still in process of being developed, but separately, we are opening a study in Australia combining our drug with darolutamide in a neoadjuvant clinical trial. There's lots of clinical trial activities. Now that we've shown the drug is safe and well-tolerated, we can feel comfortable in moving it into clinical populations where we believe the androgen biology is most relevant. You will see over the next year and a half, unrolling of some of the clinical data from this in a fairly steady manner. The randomized phase two enzalutamide plus EPI-7386, that's gonna take more time, that's 120 patients. When we read that out, whether it be 2024, or longer, is completely going to be a function of accrual. Lots to say over the next year and a half, and we're now in the right patient population, we believe. It should be actually a pretty interesting time. Got it. Maybe, Peter, cash runway? Yes. I'll just say we've got plenty of cash to execute on all of those plans, plus more. We have $167 million at the end of September. September 30th, that was our cash balance. That gets us well through 2025 and allows us to fully invest in 7386 as we see fit. We feel like we're in very good shape. All right. Fantastic. We're right at time. Thank you very much, Peter and David for joining our conference today. I look forward to all the updates this year. Thanks for the audience for tuning in. Thank you. It was a pleasure. Thanks. Take care.