All right. Thanks for joining us on day three of Oppenheimer 31st Annual Healthcare Conference. My name is Mark Breidenbach. I'm part of the Biotech Equity Research team. Our next presenting company is ESSA Pharma, which is developing a novel drug for prostate cancer, and I'm delighted to introduce the company's CEO, David Parkinson, and COO, Peter Virsik, who are going to walk us through the story this morning. David, why don't you take it away? Mark, thank you very much for the kind introduction. Happy to be here this morning on behalf of my colleagues at ESSA, Peter and I will take you through the story of ESSA, why we're doing what we're doing, and why we think it's potentially quite important. Peter, can you please go on? Some forward-looking statements. Now, the origins of ESSA begin actually in the early 2000s with the work of two scientists, a biologist and a chemist at the University of British Columbia. What we'll be talking about here today is a new class of inhibitors of the androgen receptor. These drugs, which we term Anitens, are uniquely able to shut down androgen-driven transcription and do so in a way that's completely novel, that's different from the 60 years of drug development of the anti-androgens, which have focused on the other end of the receptor, the ligand binding domain or C-terminal receptor. We'll talk to you this morning about our current clinical candidate, 7386, where we are with clinical development, and why we think it can help make an important contribution in the treatment of men with prostate cancer. Next slide, please, Peter. I'm here on behalf of the team together with Peter. Both of us are experienced executives in the biotech, biopharma world. My own personal background is more on the development side and Peter very much on the operating side. Not here today is David Wood, our Chief Financial Officer, and Alessandra Cesano, our Chief Medical Officer. They, again, are very experienced individuals in both therapeutics and in the case of Alessandra, in diagnostics as well. Next slide, please, Peter. What we'll be talking about, again, is a novel approach to prostate cancer treatment. Very common tumor globally, and a tumor which has been known since the 1950s to be predominantly driven by androgens, by male hormones. Anti-androgens, of which there have been six decades of clinical development of incrementally better anti-androgens, that is, of ways of shutting down male hormone-driven biology, represent a very significant market because of the prevalence of this tumor. Important for today's discussion is the fact that the disease, prostate cancer, is predominantly driven by male hormones, and that remains true even in men who progress on the latest stage anti-androgens. There's a huge remaining unmet medical need because inevitably, all men on antiandrogens do become resistant to these drugs. Next slide, please. This cartoon shows how they become resistant. First of all, this is a cartoon of the androgen receptor itself. It normally sits in the cytoplasm of a prostate cancer cell and is, as represented by this cartoon, the right side of the molecule is the ligand- binding domain, that C-terminal end. In the upper left-hand corner are the drugs which interfere in one way or another of male hormones, of dihydrotestosterone binding to and activating this receptor. Some of those antiandrogens decrease the amount of circulating androgen. ZYTIGA is the latest drug in that list. The earlier drugs work centrally in the brain. ZYTIGA actually works by inhibiting the synthesis of androgens. The box below shows a whole series of drugs ending in the suffix lutamide, indicating they have generally similar mechanisms of action. They inhibit the binding of androgens to that end of the receptor. The central part of the receptor, as represented here, is the DNA binding domain. Once dihydrotestosterone binds to the ligand- binding domain, the receptor is activated, it translocates to the nucleus. There's a dimerization phenomenon, and through that DNA- binding domain, binding specifically to areas on genomic DNA called androgen response elements, is the drive to produce male hormone biology. This receptor drives the expression of a very large and very predictable group of genes. However, that specific binding does not occur without the influence of the left part of the cartoon, the N-terminal domain. That has been known for more than 20 years. It has been the target of drug development, but unsuccessful drug development until the ESSA drugs, the Anitens. The reason for that is that this is an intrinsically disordered part of the receptor. There's no crystal structure, although there are subunits of structure within it. But that specific binding to the DNA binding domain does not occur without the role of the N-terminal domain. The importance of developing a therapeutic against the N-terminal domain is that it would represent a novel way of shutting down transcription, because as I indicated and is shown on the far right of this slide, all men become resistant to anti-androgens, and the mechanisms of resistance are listed in the right part of the slide. Some of them are DNA-based, amplification of the receptor, some of them are RNA-based with the appearance of shortened RNA, truncated RNA that's constitutively activated without androgens. A novel way of shutting down androgen-driven transcription, thereby bypassing the resistance to current anti-androgens, would be a major therapeutic addition, and we believe that's what we have in the class of agents we call the anitens. Next slide, please. There was a first-generation agent, EPI-506, which was in the clinic, and it was actually a prodrug of a drug which was shown to bind specifically to the N-terminal domain by workers at the University of Barcelona. It was shown that the precursor to EPI-002 or EPI-506 binds specifically to an area called Transactivation Unit 5, probably changing conformation, definitely interfering with the complex formation necessary for that N-terminal domain-assisted DNA binding of the activated androgen receptor. Next slide. What we have in the ESSA drugs, the most recent drug we have, we will talk about soon, is EPI-7386, is a novel way of shutting down the most important and most validated pathway driving prostate cancer. On this slide is shown the approaches historically to the treatment of prostate cancer, diagnosed locally, often treated with what was called androgen deprivation therapy, those centrally acting LHRH agonists or antagonists that I referred to. When patients became resistant, their PSA, a very good marker that the pathway was on and that tumor was progressing. That is the setting in which the lutamides were introduced, initially following androgen deprivation therapy. After work over the last four or five years, we now know that if you move those lutamides up, if you combine them with androgen deprivation therapy, the two different approaches shutting down androgen biology more completely, that translated to greater clinical benefit. That's the general approach to prostate cancer therapy, but as I indicated, all men become resistant to these drugs. Down in the lower right-hand corner of this slide is where we need to start with the phase I clinical trial in men with progressive prostate cancer. Next slide, please. Indeed, ESSA was formed following the work of those Vancouver scientists several years ago and introduced about five years ago into the clinic, a first-generation agent, EPI-506. That drug was a prodrug. It broke down quickly into the active drug, EPI-002. Peter and I arrived at ESSA soon after the phase I clinical trial of that particular molecule had started. Together with David Webb, we managed the clinical trial through that phase I. It was a challenging phase I clinical trial related to not the binding specificity, the drug was extremely specific in its binding, not to any toxicity-related issues, because the drug was generally very well-tolerated, but rather because of the poor pharmaceutical characteristics of that first-generation drug. On the next slide is a summary of the characteristics which we were able to determine during the conduct of the phase I clinical trial. We made a decision that EPI-506 would never be a pharmaceutical agent, but that phase I clinical trial was extremely useful in defining what the target product profile needed to be, what the improvement of characteristics needed to be to make a more legitimate N-terminal domain inhibitor, which could be used generally in the pharmaceutical industry. At this point, I'm going to turn it over to my colleague, Peter Virsik, who will describe to you the characteristics which we recognized and then briefly describe to you how we believe that the current generation molecule, EPI-7386, overcomes those limitations. Peter? Thank you, David. As David indicated, we spent some time after that initial clinical program, EPI-506, working on a better next generation program. There were a number of characteristics we were trying to improve in a next generation candidate. EPI-7386 is the culmination of over a year and a half of work on that. The reason we selected it as our clinical candidate is listed here on slide 10. From an in vitro potency standpoint, EPI-7386 is 20 x more potent than that first generation clinical candidate, EPI-506, and now has similar potencies as the leading anti-androgens. From a xenograft mouse tumor model activity perspective, EPI-7386 works in both models where enzalutamide is active, so the anti-androgen sensitive models, as well as those models where enzalutamide loses activity. These are the spliced variant, the AR-V7, as it's called, models. Activity in both resistant as well as sensitive xenograft models. From an ADME perspective, meaning overall pharmaceutical properties with respect to half-life and exposures, EPI-7386 is a very stable molecule and is predicted to have a half-life in patients of over 30 hours, and we've seen very good half-life already in patients in our initial clinical study we'll talk about. A very stable molecule. From a selectivity standpoint, it's very important to maintain the on-target specificity and minimize off-target binding. We've gone through extensive on- and off-target modeling as well as various assays and believe the compound is very specific to the N-terminal domain of the androgen receptor, and our tox studies corroborated that, where we were able to achieve very high exposures with very minimal toxic effects to animals. The compound is very selective. From a drug-drug interaction standpoint, while we're initially going to be developing this as monotherapy in late-stage patients, our long-term goal is to be able to antiandrogens. For that reason, we need to make sure that we don't, first off, exacerbate their toxicities. We paid particular attention to the combined ability with respect to toxicity profile. Secondly, we also need to make sure that we do not cause any problematic drug-drug interactions so that the two drugs could be used together. We believe we have a good, favorable profile to be able to be combined with the current antiandrogens. Last, the drug needs to look like a drug and act like a drug and be able to be manufactured like a drug. This is a high-melting point, crystalline solid. We've already developed a formulation of it that is now in a tablet form. It's a drug that is scalable and works very well from a CMC standpoint. Based upon a lot of preclinical work, our IND-enabling toxicity studies, as I mentioned before, we were able to achieve very high exposures in animals. At the very highest exposures in those studies, we had just a little bit of anti-androgen effects on tissue weights, androgen tissue weights, red blood cells, cholesterol, and then just had a reduction in weight gain and in eating. It's a very favorable profile for us, very high exposures. That allowed us to propose to the FDA a starting dose of 200 mg once daily in patients. We have projected that that would get us an exposure in patients of roughly 130,000- 140,000. Based upon our modeling, which on this slide here on the left from some xenograft studies, we estimated that that kind of an exposure may be in a range where we could start to see some biological activity in patients if they had similar biology to this VCaP xenograft model. Our ultimate goal, though, is to get to exposures in patients of roughly 300,000 AUC, that's area under the curve. That's nanogram hour per ml. That's a total daily exposure of drug. The reason we're targeting that is because that's the exposure in animal studies where we saw very good anti-tumor effect across all the models. Our current projections estimate that that exposure would be achieved roughly at the 600 mg or 800 mg level. David, I'll turn it back over to you to talk a little bit about the clinical study. Yeah. Thanks, Peter. As I mentioned earlier, when one starts with a novel drug mechanism like this, it's appropriate to start in patients who have received all approved therapies that are appropriate for them. The trial consists of men who have had at least two lines of therapy, one of those lines being a latest generation antiandrogen. In reality, of course, in these late-stage prostate cancer patients, many of these men have had 7- 10 or more courses of different therapies over often five or 10 years of period. It's a standard 3+3 design. As Peter indicated, we start at the 200 mg once-a-day dosing, which is projected to be at the low end of the biologically active dose. We were very happy with that initial starting dose. The goals of the phase I trial are pretty conventional. What I've indicated is that we're selecting patients based on clinical characterization and their history of previous treatment. Really important in these late-stage patients who have often quite heterogeneous biology because other genomic changes do arise, whose influence is really unknown on this kind of response, we're characterizing these patients to our best ability with biological characterizations, with biomarker studies. We're looking at circulating tumor DNA for a group of more than 70 prostate cancer-relevant genes. We're examining, enumerating the number of circulating tumor cells and examining those circulating tumor cells for the presence of AR-V7. It's representative of that shortened RNA constitutively activated receptor situation I talked about earlier. The IND was filed first quarter last year, the trial began in the middle of the COVID activities last summer, but the trial's been moving along very nicely, and we reported on that trial at the ASCO GU meeting several weeks ago. The first experience, that is the earliest cohort of these patients, and I'll talk about that in a second. Before I go on to the single agent trial study, I'd like to speak also to combination studies, because I referred earlier to the fact that the history of prostate cancer therapeutics development, antihormone development in prostate cancer, is a series of incrementally better drugs that were better at shutting down androgen biology. Most recently, that was accomplished by using these latest generation antiandrogens in combination with that classic androgen deprivation therapy. Pre-clinically, we have shown, through a number of studies, that the combination of an N-terminal domain inhibition with ligand- binding domain inhibition by the antiandrogens quantitatively shuts down androgen biology much more extensively than either approach alone. Beyond the quantitative aspect, there's a qualitative aspect. A broader group of genes are captured by inhibition of both ends of the receptor. In addition, there's the theoretical potential benefit of shutting down the receptor and therefore transcription by two independent mechanisms and hopefully therefore delaying, if not preventing, the emergence of resistance that has been classic for the antiandrogens. In the third quarter of this year, we together with collaborators, and one set of trials is with Janssen, the other trial is with Astellas/Pfizer. We'll be studying our drug EPI-7386 in combination, in the case of Janssen, with abiraterone, and then separately, in other trial with their drug apalutamide. In the case of Astellas/Pfizer, we'll be studying EPI-7386 in combination with enzalutamide. Next slide, please, Peter. We presented the clinical data at the ASCO GU meeting, and that's summarized here. I won't go over the study design again, but at the time of the ASCO GU meeting, we reported on the 200 mg cohort. That is the first cohort. The purpose of the poster was basically to show the pharmacokinetics of the drug, the performance characteristics of the drug. There were so many limitations we described, and Peter described what we set out to achieve in a next generation drug as represented by EPI-7386. The purpose of this poster at ASCO GU was to basically show people that we believe we have achieved that target product profile. We also indicated that at the time of the ASCO GU meeting, so that's several weeks ago, we were enrolling patients at the 600 mg level, so had cleared the 400 mg level for safety as well. The trial has been moving along very nicely, the single agent therapy. Next slide, please, Peter. Peter, maybe you want to comment on some of the pharmacokinetics that we observed in these patients related to what you had shown were our goals with EPI-7386 based on preclinical data. Thanks, David. On this slide is just a summary of the various preclinical data that were pulled together that then provided the projections for us for what we would see in the clinic. The bottom line is on the bottom left, you can see the half-life projections. We're showing two different methods of over 30 hours, half-life projections in patients. On the right-hand side, you can see an exposure projection for the different doses given in the clinic. Again, the 200 mg was projected to yield an AUC of 137,000. How did we do compared to all of the projections? This slide here on slide 15 is the actual clinical data from the first cohort of patients at 200 mg once daily. What you can see from the top left box, if you look at the AUC 0 to 24 hours, you can see that at 28 days, the AUC in patients was roughly 147,000 ng*hr/ mL. Very close to our 140,000 ng*hr/mL projection, so we're very pleased with that. Our half-life projection here is a little bit lower than what we believe is likely the reality in these patients. The challenge in this study with developing a half-life in patients and measuring it and calculating it and estimating it, is that for patients who have a very long half-life, it's very difficult to do in the confines of a daily dose study. The patients with the longest half-lives are actually not included in the data here. These data for half-life under-report the patient half-life. We assume it'll probably be similar to our projections of over 30 hours per day. Then the bottom right is looking at a measure of CYP induction. As one develops a drug, one looks at possible drug-drug interactions with other drugs you may combine with, but also one's own metabolism as one goes up in dose escalation. This particular measure here for 4β-hydroxycholesterol is a leading indicator, a measure of whether or not we would expect to induce one of these particular pathways that's called CYP3A. We do not see from these data that we're inducing metabolism of our own drug or this marker. That gives us a favorable direction as we continue to move further in the clinic. David, I'll turn it back over to you to go through the actual clinical results. Certainly. We entered four patients into this initial cohort. All of these men were very, very heavily pre-treated patients. You can see that one of the men did not make it through the four weeks. He progressed rapidly. We had a lot of discussions about whether to enter this man into the trial because he had extensive liver and lung metastases before starting. In any case, we entered him, but he, after three weeks of tolerating the drug extremely well, came into the emergency room with a brain metastasis and so did not finish the cohort. In retrospect, with markers coming back in later, he had evidence of neuroendocrine de-differentiation, as did the lowest patient on that plot. That's something that occurs in very late-stage prostate cancer. Men have tumors that differentiate down a neuroendocrine line. They look more like small cell lung cancer. They are not responsive to hormone-based therapies. In general, the three men tolerated the drug well. You've seen the pharmacology. They had good exposures. You see the toxicities in the lower right-hand corner. The only one that, to my mind, is really related to the drug itself or the hot flashes, which are consistent with anti-androgen therapy. The neutropenia was preexisting from a previous taxane therapy in another man, and the others were just short-lived and Grade 1 or Grade 2 toxicities. The very interesting patient is shown on the next slide. The three patients are shown at the top, and two of them progressed with respect to PSA. The third patient is a very, very interesting patient, which we believe is proof of success of the mechanism of action of this drug and validates the drug being active. This is a man who had a classic history of prostate cancer therapy. Local therapy initially, treated sequentially with bicalutamide or CASODEX. When he progressed on enzalutamide or XTANDI. When he progressed, went on to PROVENGE. He progressed, he went on to ZYTIGA or abiraterone. Slowly progressed over approximately a year and then went on to EPI-7386 and by the 12-week mark, began showing declines in PSA, which continued to the point of the ASCO GU presentation. We indicated have continued post ASCO GU poster cutoff. This was at the 200 mg level. This man was actually at the lower end of the exposures among the patients at this level. The kinetics were interesting that it took 12 weeks to show the PSA decline, and interestingly enough, it had taken four weeks previously for him to respond to enzalutamide. Tumor kinetics in this particular man were fairly characteristic for the pattern of response seen with antiandrogens in late-stage prostate cancer. Next slide, please, Peter. By the way, the man tolerated the drug extremely well, and we indicated at the ASCO GU presentation that we were about to and have subsequently doubled his dose and so he is now at the 400 mg level, has been on drug now going through the eighth month. On this slide shows the size of the market on the left for these late-stage patients with single agent therapy. As you can appreciate, potential combination of EPI-7386 with one or more of the lutamides in earlier line patients represents a much, much larger market. Although the single agent market is large in and of itself. Next slide, please. Just to finish up, we recently completed a financing, raised $150 million. We are now funded to support all the work we need to do to take this drug through single agent registration and to contribute to the collaboration studies which we have announced with various partners. This financing was done just in the last several weeks. With that, I'd like to finish and thank you for your attention. You'll see the milestones here on the final slide, and you can expect to hear more detail and great detail about the phase I trial in the fall of this year at the ESMO meetings or at the Triple meeting. In the meantime, we will be presenting additional biophysical data, preclinical data at the AACR meetings in mid-April. With that, thank you very much. Appreciate the opportunity to talk about what we're doing here at ESSA. Thanks. Mark? All right. Thank you, David and Peter. We're just about out of time. Very quickly, questions from the audience include, is the PSA 50 responder still on drug? Yes. Okay. That's excellent. In terms of the next clinical update from phase I dose escalation, how many cohorts should we expect? Yeah Any timing on that? Yes. We've announced that we'll certainly achieve a recommended phase II dose in the second quarter of this year. That allows us to then expand and treat many more patients at that dose. We'll be reporting on that in the fall. Our projections, as Peter talked about earlier, were that 600 mg or 800 mg would be the appropriate dose, and we have no reason to change that statement. Okay. Very quickly, do we know if the PSA 50 responder wasn't carrying the AR-V7 splice variant? We don't know because the assay that we've been using depends on the presence of circulating tumor cells, and this man had no circulating tumor cells. By the literature, he would certainly be positive, but we don't know that for a fact. We are looking at additional technologies that will allow us to look at the presence of splice variants, even in the absence of circulating tumor cells. In the future, we will have that information, hopefully, on all patients. Okay. Thank you very much. We're over time. Thanks to everyone for listening in, and feel free to disconnect. Thank you, Mark. Appreciate it. Of course. Thanks, Mark.