Our prostate cancer. Yes KOL panel just now. I'm Charles Zhu, one of the Senior Biotech Analyst at Guggenheim Securities. With us here today from ESSA Pharma are David as well as Peter. Thank you for joining us. Perhaps just to get us started off, could you give us, you know, some background into your company platform and pipeline, please? Certainly. Well, first of all, we're delighted to be here this morning, and we've just had a wonderful discussion, panel discussion that we listened to about current approaches in prostate cancer. At ESSA, we're involved in one of the main areas that was addressed in that panel discussion, which is the fact that prostate cancer is predominantly AR driven, androgen receptor driven, and that there is a huge unmet medical need because all men become resistant ultimately to the current anti-androgens that are being used. Those are good drugs, but men do become resistant. The approach that we're taking are small molecule inhibitors of the N-terminal domain of the androgen receptor, and that's important because our inhibition of transcription of male hormone biology is at the other end of the receptor from where 60 years of anti-androgen development have occurred. What that means is that in theory, we can bypass, in practice experimentally, we can bypass the resistance mechanisms associated with antiandrogens, and that allows potentially for the rescue or salvage of men whose tumors are progressing on those drugs. We believe, even more importantly, it allows us to develop a strategy of combining N-terminal domain inhibition with current antiandrogens, which work at the other end of the receptor, the ligand binding domain. What we've shown experimentally is that by doing so, you shut androgen biology down more deeply and potentially could prevent the emergence of resistance mechanisms through combination therapy. Historically, the deeper you can suppress androgen biology in early androgen-driven prostate cancer, the better the clinical result. That's what we're focused on. We've developed a class of molecules called anitens, and the current drug we have in clinical trial, 7386, is the drug we're exploring from the basis of that rationale. Great. Thanks for that. Can you maybe talk a little bit about why this 60 years of research in drug development has really targeted, you know, the other side of the... or one particular domain of the androgen receptor, and why haven't N-terminal domain inhibitors really emerged until more recently? Well, Peter, you might wanna comment on that. The N-terminal domain is a rather unique structure. Peter? Yeah. The N-terminal domain of the androgen receptor is what's called an intrinsically disordered protein. It doesn't have its own structure. That brings with it certain biology, but a challenge for drug discovery because you can't use traditional pharmaceutical screening methods to come up with hits. Because of that, it's been challenging for companies to come up with N-terminal domain inhibitors. That's an integral part of the biology and the androgen receptor. It is required to be functionally active. Without a functional N-terminal domain, it's transcriptionally inactive, so it's a very good target. It's just been very difficult for compounds and companies to be able to be found, you know, to that. We were lucky in the sense that we had an early screen with a hit compound, and that has led to our current chemistry program. Without that, it would be challenging to be able to come up with an initial hit. Got it. Great. I guess, you know, the AR pathway is obviously very important, but, you know, there is some historical data, I believe, with, you know, hitting different parts of that pathway with, let's say, abiraterone and enzalutamide. Yes. Not very much additional clinical benefit over either agent alone. No. I guess, you know, where would, you know, targeting the N-terminal domain be different? Anti-androgens are one of two kinds. You have the abiraterone-like drugs, which inhibit synthesis of the androgens, the lower levels of circulating androgens. You have the, quote-unquote, "lutamides," the enzalutamide, apalutamide, darolutamide sequence that inhibit blocking androgens to that ligand binding domain, the C-primed end, the one end of the receptor. All the mechanisms of resistance, which have been described over the years, involve the ligand binding domain because that's where the therapies have been. Along comes this class of anitens working at the other end of the receptor. They're not susceptible to the same mechanisms of resistance, whether at the DNA level or at the RNA level. You know, you hear about splice variants, truncated receptors, losing the ligand binding domain. Inherently, two different, two novel way, two different ways of shutting down transcription have the potential to both shut it down more deeply, but also to prevent, as historically combination therapy has done in the antibiotic world, the antiviral world, to prevent the emergence of resistance. Exactly how the combinations were working, how N-terminal domain transcription inhibition was working, you know, it's still very much a work in progress. You know, we have data from the original scientific founders of the company about the inhibition of complex formation. You yourself have addressed in a recent analysis of new therapeutic approaches in prostate cancer this whole area of condensates, of the formation of liquid-liquid phases and how N-terminal domain inhibition could actually interfere with transcription through that mechanism. We found that very interesting. We've been following the field, and while we don't have formal evidence yet for our drug being involved in that, everything we see about the work in that field suggests strongly that that's exactly what we do, is interfere with the liquid-liquid phase. A novel mechanism of inhibition of transcription, complementary to the current mechanisms, subverted by anti-androgens. Perfect. Great. Maybe now we can transition to some of the specific pipeline assets. Mm-hmm. Development programs you have. just to start us off there, could you give us an overview of how you're developing EPI? 7386. 86. Say it twice, and it's almost like singing, you know? Peter, do you want to comment on the development program? Sure. We've got two main areas how we're developing EPI-7386. First is in the monotherapy, and that's in kind of late-stage patients with metastatic CRPC. These are patients who have failed all the current therapies, and that's the first place we've started to do development with EPI-7386. The second area, which for us is even more interesting and compelling based upon a lot of preclinical work, and of really inhibiting both the ligand binding domain and N-terminal domain is combination work. Taking the current anti-androgens and combining it with our N-terminal domain in patients who are still AR driven to be able to suppress the AR biology more fully and completely. 'Cause what's really interesting from the preclinical standpoint is that when we do that in these AR-based preclinical models, so we inhibit the N-terminal domain and the ligand binding domain at the same time. We see a very significant deep inhibition of AR biology that's broader. Our question clinically now is, if that's true, clinically, we should be able to see patients have a deeper suppression of AR biology, more patients who have that, and a more rapid response, which ultimately could be a more durable response as well. Our second main area of development is in combination, and we have a series of combination studies underway or gonna be continue to be underway. Our first one is with enzalutamide, and then we have a series of other ones that will begin again with apalutamide, abiraterone, and then darolutamide as well. Happy to get into more of the specifics of the clinical program, but it's really those two main areas that we're focused on the development of EPI-7386. Got it. Great. Perhaps we'll just start off with some of your monotherapy studies. Mm-hmm. You know, I think if I recall correctly, you know, largely in a late line prostate cancer, you had some activity there. Especially when we're in such advanced disease, you know, what would one still expect, you know, this agent to still, you know, be very potent as a single agent? How dependent does prostate cancer remain on androgen receptor pathway in that sense? That's the key point that you just made, Charles. As, you know, we've developed experimentally, we can overcome all these mechanisms of resistance at the DNA level, the RNA level, protein level. Once you put it into late-stage patients, where, of course, you need to start with a new mechanism of agent in cancer patients, you need to start with patients who have run out of other therapeutic options. What's become clear, not just from our work, but from the work of other companies with various AR approaches, where they've had to start in late-stage disease, is that there's a lot more biology going on. Once you've had, as a prostate cancer patient, once you've had that disease for five or 10 years, once you've been on anti-androgens, usually, you know, either ADT therapy or next generation anti-androgens for several years, there's a lot of other biology going on. There's pathways, Wnt pathway changes, EGFR, P53, MYC, PTEN loss, a lot of drivers other than AR. While AR inhibition could potentially be part of a therapeutic solution for these late-stage patients, it's literally the worst biological situation to try to develop new AR agents. We spent two years showing that our drug is safe. It's well-tolerated. It's a tablet. It can be taken once or twice a day. We've earned the right through showing that safety and tolerability and hints of efficacy to go into the earlier line patients where we believe the biology is more homogeneously AR driven and where AR is the most relevant target. We're just now, as Peter indicated, moving into combination therapy studies in these early patients and, you know, so the next six months, 12 months are gonna be very, very interesting because we finally got our drug into the right patient biology positioning, we believe. Great. Maybe could you also remind us perhaps of, you know, some of the combination studies that you're doing in the earlier line patients, the results that you've generated so far, as well as how that informs your next steps? Peter, do you wanna comment on it? Sure. The study that we're conducting with help with a collaborator, Astellas on Pfizer, is our combination of EPI-7386 with enzalutamide, and that's in the first-line metastatic CRPC setting. We are in the process. I'll talk about those data in just a moment. We are in the process of changing a collaboration with J&J, where they were running a similar patient population with EPI-7386, and there are two drugs, apalutamide and abiraterone, and we will be taking that collaboration on to run those compounds in probably an earlier patient population. We also have a collaboration with Bayer for darolutamide, and that study has not yet started. The study that we're conducting is the one that we've actually presented some data on. We'll be presenting more data actually next week at ASCO GU. It's not gonna be entirely new data. It'll be similar to what we've presented in the past. What we're really trying to measure here and test is whether or not, as I said, preclinically, we can see these deeper, broader, faster inhibition of PSAs. Mm-hmm. The data are early. It's only the first two cohorts of patients who are started on therapy. They're not at full dose enzalutamide yet. They're not at full dose EPI-7386. We're seeing fast responses for PSA. We had four out of nine patients achieve a PSA90 in 90 days. We know that has a very good correlation in this patient population historically with anti-androgens and overall survival. We had five out of six patients ultimately achieve a PSA90. That's quite good. One of the other measures we'll be talking more about is actually an even more rigorous measure of PSA decline, and it's the achievement of a PSA down to what used to be considered undetectable, a 0.2 nanogram per ml. That has the best correlation across prostate cancer with being able to achieve that and having long-term outcomes. So we're looking at all of these measures as we continue through this dose escalation study. We think we'll finish the dose escalation portion the first half of this year, then we will pivot to our phase II study, which is an open label randomized study, 40 patients enzalutamide versus 80 patients of 7386 with enzalutamide. Great. maybe, two quick follow-ups on off of some of those comments. The first one being, and you touched upon this as well, but, you know, the correlation of, PSA responses, which is not an approvable endpoint but could be indicative of something more, you know. Yeah. How should we think about that relative to, let's say, another early, you know, marker of response, such as, you know, radiographic shrinkage for example? You use everything you've got, right? Not all patients with even with metastatic prostate cancer have measurable disease. A lot of them have bone metastases. You use biomarker like PSA. We definitely use scans. We've been using some new together with a company called AIQ out of the University of Wisconsin. We've been using imaging software that allows us to follow not just as one does with RECIST, four or five indicator lesions and following them from a measurable point of view, but following every single lesion that a patient has either by CT scan or MRI, a PET scan. At least in the late stage patients, what that has shown us is the remarkable heterogeneity biologically of prostate cancer that was referred to in your panel discussion. Because we would see when we use EPI-7386, we'd see lesions disappear, some not change, and other new lesions appear, reflecting late stage prostate cancer being so heterogeneous and therefore ultimately requiring really multi-therapeutic approaches, not single agents of any sort. That's different in the early patients. They're much more homogeneous. Where there's an opportunity to measure, we'll be measuring. Where there's an opportunity to watch PSA, it's much more relevant in those early patients. We're also using approaches like quantitative circulating tumor DNA, sequencing studies to characterize the patients biologically, to define that biological heterogeneity where it exists, and to identify the group of patients most likely to respond to a pure AR type approach. Got it. Great. You know, as to the second follow-up, you had mentioned a randomized phase II study, 80 versus 40 patients combo versus, you know, standard of care. Obviously not powered for re-registration, but, you know, I guess what sort of, I guess separation between the two arms would you need to see in order to justify, for further development? Comment on that, Peter? Yeah. The, the primary endpoints we're looking at here are endpoints that our partners as well came to the conclusion that these are the right markers for early assessments of activity. Again, it's the PSA50 or PSA90 at an early time point, because those endpoints have correlated historically with good overall survival and improvement in survival. You're exactly right. We're not powered for overall survival. We're really gonna be looking at these early markers of PSA decline at a rapid sort of way. In that sort of way, we've powered it so that we believe the kinds of numbers we need and would expect to see in this patient population we could achieve. We are enrolling patients into this study who are first-line metastatic CRPC, but they could have had prior chemotherapy in the hormone-sensitive setting. There's a good amount of literature out there pointing to what to expect out of enzalutamide as a single agent in this sort of a setting. Based upon that, we've powered it to be able to achieve what we think could be a good improvement from that, and that's kind of drives our powering assumption. It's around PSA90 at 90 versus overall survival. Got it. Great. You have a lot of ongoing partnerships and collaborations with manufacturers of traditional AR antagonists. Could you talk about those a little bit as well as, you know, how you're thinking about, you know, developing EPI-7386, you know, on your own versus leveraging your partners' expertise and bandwidth? Sure. When we originally selected EPI-7386, we anticipated that it could be used potentially in combination with all of the drugs. Our real question we want to answer is, can we be the backbone of AR therapy and be able to be used across the board with multiple agents? For that reason, we struck up different collaborations with partners that were really around clinical collaborations. There were three of these, one around Astellas with Pfizer on enzalutamide, one with J&J with their two drugs, and one with Bayer. In each of those collaborations, our partners or us are running the studies in these different patient populations to really get to these answers around population, PSA50, 90s in 90 days to see about powering. The studies for approval for us in this population we're talking about now, metastatic CRPC, it's something we potentially could do as a company on our own. It would probably be much better to do with a partner. The partner could be one of these companies that has current anti-androgen or could be one of the many companies that want to get into the prostate cancer space or are just trying to get into it right now. These studies are longer studies. If you do them correctly and you do them right, these are very large markets. Our goal is to not only work on the metastatic CRPC setting but also to move into the metastatic hormone-sensitive prostate cancer setting, something we just talked a little about at the panel. That's where those studies are longer. We'd really wanna make sure we do that with a partner. Great. Makes sense. Maybe one specific question. I believe you guys had a pre-press release saying that J&J had halted enrollment of one of their trials. Could you give us color as to why that happened and how you think about that partnership? Yeah. It was an operational decision by J&J. They're still very interested in how and what a combination would look like with either of their two agents, either abiraterone or apalutamide. They were having operational challenges related to their initial decision to do most of the work in Eastern Europe, which is not a great place currently to be doing clinical research. You know, we talked with them, and we've made the decision to reverse the roles. They'll now, and we're just finalizing all of these agreements, they'll supply us with drug. We'll operationalize the trial using the kind of places that we have used in the U.S., Canada and Australia. These will be short trials. We don't anticipate any complexity of combining our drug with abiraterone. We don't anticipate any drug-drug interaction, and the initial experience that Janssen had with the initiation of the trial would more or less confirm that. Similarly, apalutamide is very similar to enzalutamide in terms of what we anticipate a potential drug-drug interaction might look like. We've already been doing that with enzalutamide. We've shown to date no effect on enzalutamide, and the effect of enzalutamide on us is that we need to use good doses of 7386. So we've kind of worked that out already. We expect they'll be short trials, practice trials. The real proof of concept is coming from the enzalutamide combination, 40 versus 80 that you referred to earlier. Great. Great. You guys have some other assets in your early pipeline. I believe a next gen N-terminal inhibitor as well as a degrader. Could you perhaps also talk about, you know, some of the potential advantages of, let's say, your next gen N-inhibitor over your current N-inhibitor and how you're thinking about positioning the degrader? Peter, do you wanna comment on that please? Sure. Yeah. As you said, there's two active programs. Our next generation Aniten program, where we're taking EPI-7386 and trying to come up with either different or even better versions of that. The idea there is to. If you're successful, you always wanna follow on, right? That's one of the reasons we have that. We also are interested in other AR-driven tumors outside of prostate cancer. The profile for those compounds might be similar but could be a little bit different. Prostate cancer, I think you know, doesn't really have much metastases that occur in the brain. The best lutamide that's out there right now, anti-androgen is considered from a tolerability to be darolutamide because it doesn't cross the blood-brain barrier. 7386 doesn't cross the blood-brain barrier either, but there could be other AR-driven tumors where you'd want that to occur. That could be a potential reason for a different agent, a different Aniten, in addition to just securing and continuing to mine the IP space in this particular Aniten area. We have two very good programs there looking at a prostate cancer program as well as another AR-driven tumor. We've leveraged that into our N-terminal domain degrader program, and this is an earlier program. We've had some proof of concept molecules that are showing potency and stability. Those are two very difficult things to achieve. The idea there and the question we're still asking is we're showing biologically the benefits of inhibiting the N-terminal domain. If we degrade it, is there something more we gain? Is there some benefit to that? I think the field in general is still wondering, are degraders better than inhibitors in general? We have that continued question as well for us. In the interim, we're working hard to come up with a potential IND candidate that could be an N-terminal domain degrader. It is a little earlier than our Aniten program. Got it. Great. Perhaps just to close us out, could you remind us of your cash balance runway as well as, you know, upcoming near-term milestones? We've just reported $163 million. That's enough to support us all the way through 2025 with the current program. You know, we can do this right. We can do all the trials, all the preclinical studies that are necessary to support a registration-directed drug development program. It also allows us to support the Aniten program and the degrader program. Thanks God, we don't need to raise money right now. Perfect. All right. Well, thank you very much, and I hope you enjoy the rest of the conference. Charles, thank you very much for the opportunity. Thank you. Take care.