ESSA Pharma Inc. (EPIX) Earnings Call Transcript & Summary

The next presentation is for ESSA Pharma. Please begin.

Great. And thank you again for attending the Solebury Trout Virtual Global Healthcare Conference. My name is Alan Lada, the Vice President in Solebury Trout's Boston office. And before I introduce the next speaker, as a reminder, feel free to submit your questions throughout the presentation. While there won't be an answer session, we will follow-up with answers individually. With that, it's my pleasure to introduce the next speaker, David Parkinson, CEO of ESSA Pharma. David, please go ahead.

Well, thank you, Alan. First of all, let me give my thanks to Alan and his colleagues for permitting us to present today for this opportunity. And it's a pleasure to be able to describe to you, albeit briefly, what ESSA is all about and where we are in our development activities. So after this forward-looking statement, just a general context to set. ESSA was founded based on science that came out of the University of British Columbia, a biologist, Marianne Sadar; and a natural products chemist, Raymond Andersen. And what you're going to hear in the next few minutes is a story about a unique way to shut down male hormone signaling affecting prostate cancer, and really the first novel way to do this in 60 years of anti-androgen therapy development for prostate cancer. What you're going to hear is that we have just filed our IND that we're preparing to go in clinic in men whose tumors are progressing after failure with the current blockbuster anti-androgens. We have enough money, courtesy of fundraisers that we did last year, to allow us to do all of this over the next couple of years. Now I won't spend a lot of time, except to say -- on personnel, except to say that all of us are experienced, all of us have complementary skill sets. And I'm the CEO; Peter Virsik, the Chief Operating Officer; David Wood, Chief Financial Officer; and our Chief Medical Officer, Alessandra Cesano, are supported by a really excellent team of internal specialists and supported by, as you can imagine, a broad network of external consultants, many of whom we've worked with in our previous biopharma lives. Now just a general context for the prostate cancer, I think many of you are familiar with this area, but nevertheless, just a few comments to tell you why we're doing, what we're doing, and why we believe this therapeutic is potentially so important. Prostate cancer remains a very large public health problem. As I'm sure you're aware, that's a global problem, that is reflected in the size of the pharmaceutical market for new -- for therapies for prostate cancer, which we estimate is more than $6.5 billion annually currently. Now what we'll be talking about is a novelty of treating prostate cancer through the androgen receptor, that is interfering with male hormone biology influence on prostate cancer. Prostate cancer is unique in the sense that most patients have tumors, which remain dependent on the influence of male hormones throughout the natural history of their disease. And it is amongst the most validated, if not, together with estrogen receptor, the most validated target in all of cancer. And this is true, as I indicated, right through to the later stages of the disease. And what's really important to note is that even in men whose tumors are progressing on the current anti-androgens, the various lutamides that you're all familiar with. That pathway is still on and is still an important driver in the tumor in the majority of patients. What I'm saying is that resistance develops inevitably in men with receiving these anti-androgens. And that even when the tumors progress, they still remain dependent on androgen-associated pathways. Now on the next slide, Slide 6, let me just give you a little bit of biology so that you'll appreciate why we're doing, what we're doing and how what we're doing differentiates us from the current anti-androgens, the product of 6 decades, 60 years of therapy towards the androgen receptor. I'll focus first on the biological differentiation of the current drugs in order to show you how ESSA's new class of drugs, the Anitens, extends and really is complementary to. We are not trying to compete with the current anti-androgens, rather we complement them, the potential of the drug that we are developing, EPI-7386 is to both rescue men from progressing on current anti-androgens. But also and probably in the longer term, even more important, is in combination with those anti-androgens, the various lutamides that you're familiar with, to be used earlier in the natural history of the disease to get deeper and longer clinical responses. Now Slide 6 is a busy cartoon of the androgen receptor, which normally sits in the cytoplasm of the cell. The right side of the receptor has been the target of all of these years of anti-androgen development. And in the upper left-hand corner, you will see that the 2 classes of anti-androgens, which have been developed over all these years. One class and the most recent example of that is Zytiga, or abiraterone, interferes with synthesis or production of androgens. The second class, as indicated here, with the big drugs enzalutamide, apalutamide, the more recent drug, darolutamide, these are all inhibitors of binding. But they all work through, and this is very important to understand through that right or C-primed end of the receptor as depicted in the charts here. Now not surprisingly, all the mechanisms of resistance, which have been defined over the last few years, therefore, involve that right side of the molecule. Some of them are at the DNA level with androgen receptor amplification, or gain of function mutations. Some are at the RNA level when ends up with a truncated constitutively activated receptor, and that's due to the formation of what are called splice variants. AR-V7 is a term you'll see, but there are actually a whole family of splice variants, which are capable of doing this. Now the middle part of the molecule is the part through which the receptor when activated binds to genomic DNA. So androgen comes into a cell in normal biology, binds to that right side of the receptor, activates the receptor, the receptor then moved into the nucleus, and through this central DNA binding domain drives all the things that drive male hormone biology. Now the left side of the molecule is what we're going to talk about here today because that has been the target of ESSA's drugs, our affinitives. It's called the N-terminal domain. The way we portrayed it on the slide is not an accident. We've tried to make it look like what it is, it is flexible. It is constitutively unstructured. It floats. And only when the receptor is activated, does it become involved, but it is absolutely necessary for that specific DNA binding and driving of transcription by androgens that I just described. Now through the work of the East Vancouver scientists that I -- who I referred to earlier, came a lead compound and a subsequent early generation of compounds, which have been shown by a number of labs around the world to bind to that N-terminal domain. Work out of Barcelona showed specific binding of one of the initial compounds in the series. Two, an area called transcription activating Unit 5. And for the purposes of today, I'll just say that what that appears to do is impose a structure on that N-terminal domain and interfere with the assembly of these complexes of co-factors necessary for driving transcription. By interfering at this other end of the receptor in ways that are physically and chemically quite distant from the right side of the molecule from a C-primed or ligand-binding domain, we have found a series of drugs, which are capable of shutting down androgen-driven transcription in a mechanism that is completely known and that bypasses all those mechanisms of resistance. So it was based on this kind of observation that ESSA was formed because these kinds of drugs should be able to help rescue men who are progressing on current anti-androgens, and I'll talk more about that in a few minutes. So just to step back for a second and talk about the approach to prostate cancer and focus you in on where we're initially focusing the use of this drug. On this slide, what we're showing is the natural history of the treatment of prostate cancer, it starts off, it's localized, the treatment in many people. And then when the disease progresses and becomes more systemic as it does in quite a number of people, it goes through a series of stages. Those stages are associated with incremental -- historically with incremental changes in the approach to hormonal therapy. The most recent application of these latest generation anti-androgens was, first, in the treatment of metastatic castrate-resistant prostate cancer. But then subsequently, with the movement of those drugs earlier in the natural history, that is to men before they have progressed significantly and used in combination with the classic first approach to prostate cancer therapy, so-called androgen deprivation therapy, the LHRH agonist and antagonist. Now our drug initially will be developed at the far right in men who are progressing after the use of those anti-androgens. Just to set that tone, but just to future attractions, the data that we and others have been generating, showing that combination of N-terminal domain inhibitors with the ligand-binding domain of the anti-androgens seems to be very powerful, seems to suppress transcription even more deeply and in theory should prevent the emergence of resistance. So one would foresee in the future, the combination of EPI-7386, the drug I'm going to tell you more about, with anti-androgens, we can anticipate that will be explored significantly in the future. Now here's the history of the development of the agent we'll talk about here today. As I mentioned, the work started in Vancouver in the early 2000s. By approximately 10 years ago, the first iteration of ESSA Pharma was created. A first-generation drug was taken into the clinic from late 2015 into third quarter of 2017. That drug was a prodrug. It had 3 acetates on it to increase some of its bioavailability. The drug had very, very significant physical chemical challenges, very lipophilic drug, hard to manufacture, not particularly stable. And as we were able to show in the conduct of the Phase I clinical trial, was rapidly metabolized at a relatively short half-life, but what the clinical trial did do was confirm the relative specificity of the drug. The drug was generally well tolerated. And it also showed in the patients receiving some of the highest doses, a decline in PSA in these men who otherwise were entered into the trial with rising PSAs indicating their resistance to anti-androgens. So we presented that data approximately a little over 2 years ago. We believed and our investors believed that we have proof-of-concept, but that we needed a better generation drug. We reconfigured the company as a preclinical company and spent almost 2 years synthesizing a whole new series of drugs based on some clues we had as to how to increase potency. And what I'm going to talk about now is the drug candidate that we've selected. Now on this slide, Slide 10, what you see are the characteristics that were in that first generation drug. So we had specificity. We had a drug that seemed to be well tolerated, but what we needed was a drug with better pharmacological properties. We needed to increase potency. We needed to maintain the activity that was associated with the treatment of cell lines that were resistant to anti-androgens, but responsive to this generation of drugs. We needed to have a drug with good physical chemical properties. And while we're able to maintain that explicit selectivity that was a remarkable finding from the work in Vancouver. We needed to create a drug that would be easy to manufacture, that would be stable, ideally, that could be in a tablet and given orally, ideally once-a-day. And drug that could be given with other drugs because these are older men and many of them have -- are on pharmaceutical medications for other conditions. What I'm going to do in the next few slides is just relatively, briefly -- we've presented a lot of this work in the last few months at various scientific conferences. And if we ever have scientific conferences again, we have a lot more work to present and so we look forward to doing that. But on this first slide, I will summarize by basically indicating that what we have done is create a drug that is approximately 20x more potent than the first generation compound, EPI-506. And in the same ballpark in terms of cellular potency as the current anti-androgens. With respect to that potency, on this slide, I will not dwell on it given the time available, but I'd like to just make these important points. On the left side is a cell line that's driven by wild-type prostate cancer. And what you see that the very tall columns are the effect of androgens in driving the expression of these various genes outlined along the x-axis. What you see is that both enzalutamide in the red and EPI-7386 in the blue, they both shut down these genes. However, on the right, you have a cell line that is driven largely by a truncated AR-V7 splice variant-driven, so it's resistant to enzalutamide. You don't need to add androgen here. The receptor is constitutively activated. And what you see are 2 kinds of genes. There are genes that are repressed by androgens and there are genes that are actually activated by androgens. And what you see is that enzalutamide has no effect in the system. But what EPI-7386 does is repress the -- derepresses the repressed genes and it represses the activated genes. It does exactly what we would have predicted from our chemistry and from the in vitro studies. And on this slide is just a summary of the various cell lines, each with different characteristics related to the type of androgen receptor driving them and each affected appropriately per what I just described by EPI-7386 in a way that's quite differentiated from that of enzalutamide as representative of the class of anti-androgens. Now this is an important slide. This is a VCaP model, and we like this model because we think it emulates basically the situation in men with prostate cancer. The line starts off with a wild-type receptor. It is, therefore, for the first 3 weeks of culture, basically sensitive to enzalutamide, as you can see, enzalutamide is the line in the red. But after about 3 weeks, individual tumors start to break out and the tumor starts to progress, very much like the natural history of tumors in the patient setting. 7386 is controlled throughout the experiment, which went to the day 51 or day 52. What I'd also like to point out on this slide, we don't have a lot of time to talk about that here today, is the purple below. The purple is the combination of enzalutamide and 7386. A combination of 2 different ways, 2 different shutdowns of the receptor from different ends of the receptor. The upper right corner -- upper right-hand corner, shows the individual mice, just to show you that data. This is day 41. You will also see that the -- again, the combination is more homogeneous, more routinely date. And by day 51, they were complete responses also in the combination. That is confirmed by the serum PSA changes in the lower right-hand corner. Now we also indicated that first drug was rapidly metabolized. In fact, it had a half-life of about 3 hours, rapidly metabolized by the liver, largely oxidation, some glucuronidation. And what this slide shows is that the team at ESSA has been able to create a drug that is stable, that is resistant to metabolism, that has a predicted half-life of some 30 hours. And that starts to put it in the same ballpark as the most optimal lutamides, including enzalutamide. So predicted once-a-day dosing, predicted that we can keep the therapeutic levels of these drug over thresholds of activity for 24 hours a day, which is what you need to do with transcription inhibition. Now this slide just confirms our other goal, which was to maintain that exquisite selectivity we found in the first drug. And in fact, if anything, we've been able to improve that. And I will not dwell on the data, except to say that we've characterized this extensively and importantly, we made sure that the molecule had no interference with the GABA chloride channel. That's the channel that leads seizures to the various lutamides when they're given in doses above the clinically safe doses. I also should have mentioned that we've designed the drug to minimize the drug-drug interaction effects. Again, this drug will have to be given with other drugs that men are receiving. In addition, I've talked about the desirability. We believe in the future of combining this with drugs like the lutamides, and we've done our best to minimize drug-drug interactions so that this drug will behave well pharmaceutically. It does behave well pharmaceutically in the context that we've done an excellent formulation. We've had the ability to get huge exposures in the toxicology studies, as I'll mention in a second. We've been able to formulate it in a solid tablet form as you can see on this slide. We have completed the toxicology studies. We have filed the IND. The toxicology studies confirmed that we're able to get extremely large doses of drug that in general, the animals, which are rats and dogs, tolerated the drug quite well. And we believe that, that is a point of discussion in the future with the FDA. We'll be able to give a starting dose, which approaches the doses where we'll find biologically and hopefully, product activity. The Phase I trial has been designed. It's obviously been submitted as part of the IND. We're moving to set up and activate the clinical trial sites. It's a classic design that will be in men who are entered on clinical findings, that is they're -- they've been treated with one or another of the -- latest anti-androgens, their tumor is progressing. It is still dependent on the androgen receptor as evidenced by rising PSAs, and we will enter them on the basis of those clinical considerations. However, we will characterize them with all of the various new technologies, which allow us to look at DNA and RNA and protein associated with various mechanisms of resistance. We would hope to begin this study in the next quarter. There are certain uncertainties associated with the current pandemic we're dealing with, but hopefully, we'll be able to start the study on time. And on this slide, as we approach the end of this discussion, just to confirm that even just the market for these men who are progressing on current anti-androgens is a very large market. This is a large unmet medical need, and this indication alone is an important indication. However, when we start to talk about the potential for combining this with the various lutamides and using this in earlier lines of therapy in the hopes of getting deeper responses that are more prolonged and therefore, allowing them to live out a natural life with their prostate cancer, then the market becomes extremely large. The company is in good shape financially. We have no debt. We raised enough cash last year to allow us to do both the Phase I study, an expansion cohort of that Phase I study and to initiate combination therapy study or studies as we go through over the next couple of years. And then finally, just to remind you where we're at. We've spent the last 2 years. We've -- this is risk-managed in the sense that we're building on the experience with first generation agent. We determined the limitations in various characteristics of that first generation agent. We have fixed those characteristics, we believe. And we have just submitted in the last few days, our IND for review by the regulatory authorities. We intend to conduct the Phase I study at 5 -- 4 or 5 institutions in United States and Canada. And so we will be working on getting this drug into the clinic over the next several months. You can see some of the additional upcoming milestones that we anticipate over the next year or so. And we're very excited about taking this molecule in to the long road. And we believe that we have a potential, very important, very innovative next treatment for prostate cancer, which is complementary to the current anti-androgens, which are in broad clinical use. Thank you all very much for the opportunity to speak to you today about something we believe so strongly in, and we are proud of the accomplishments over the last couple of years. So with that, I will close, and thank you all for listening.