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

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. And our conference, if anyone in the audience has any questions, please feel free to e-mail me at [email protected]. So with that, David, maybe just to kick it off, give us a quick 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. So thanks for the invitation. We at ESSA are focused on a novel way of shutting down androgen biology. That is male hormone-directed biology. This is particularly relevant for prostate cancer, and that's our initial focus. We've been developing small molecules that inhibit androgen-driven biology in a completely unique way. There's a 6- or 7-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, but we believe even more importantly, in the combination with those same anti-androgens in early patients to get deeper, longer and associated with a good quality of life treatment so that men can live with prostate cancer for much longer. So 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 2.5 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. So that's where we're at. We're happy to go into more details, but we're pretty excited about where we are with the development of the drug.

Okay. And maybe, David, at the recent medical meeting, you showed that 5 out of 6 patients achieved a PSA 90 with your drug plus enzalutamide and then 4 out of 6 had the same PSA 90 within 3 months. So maybe put some context behind these results, and I want you to help us understand how relapsed or refractory these patients were. And then help us understand what the PSA 90 would look like in these patients with salvage therapy?

Well, 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 2 drugs together in combination of therapy means that you have to work out any potential interactions between one drug in the other. We believe based on our preclinical studies that we can combine 7386, our current drug with any of the 4 major anti-androgens that are in clinical use. But 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, 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. So Kalpit, you mentioned we did present some data in the fall of 2022 at the Prostate Cancer Foundation meeting. It was from the first 2 cohorts of our combination study looking at 7386 with enzalutamide. These 2 cohorts were with 3/4 of the regular dose of enzalutamide which also resulted in 3/4 of the exposure of enzalutamide. So any comparisons we make actually are 2 historical data with enzalutamide at full dose and full exposure. So 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. But from these 2 cohorts, you're right, we did achieve a PSA 90, 5 out of 6 patients eventually achieved a PSA 90 in that study with 4 of 6 achieving so at 90 days. And 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? And we have a mixture of those 2 patient populations. But 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 have good progression-free survival and good overall survival. So this 90-day PSA reduction endpoint for us is actually an important one for giving us a better sense of where the study is going, the drug's effect and potentially also then the powering assumptions for a larger pivotal study. So 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. And those are represented by 2 studies, the PREVAIL study, which was the pre-chemotherapy population study and in the AFFIRM, which was an post-chemotherapy. In the PREVAIL study, 37% of patients achieved a PSA 90 in 90 days, with 47% achieving it eventually in that study. And in the AFFIRM study, those numbers go down because they previously had chemotherapy and only 13% of these patients achieved a PSA 90 in 90 days and 25%, achieving it eventually in that study. So 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 PSA 90s that are achieved in these pre-chemo population with a second-generation anti-androgen. So we use that -- those numbers in particular for comparison, but it will be the Phase II, 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. And when the initial data came out, the 5 out of 6 patients with PSA 90, I guess there was some sort of debate about how do we evaluate these data, right? Some investors may have been looking at the baseline PSA levels and they were claiming that the baseline was low to start with and maybe PSA 90 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 it, please?

Sure. We spend an exhaustive amount of time with you at all of this just because it's something we're obviously very interested in as well. And so 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. So in this case, it was 10 nanograms per ml or less and do those patients do any better or worse. And 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 PSA 90 and not overall in the study if they were below 10 nanograms per ml. And you may recall, I just said, that for the study as a whole, 47% of all PSA varieties achieved the same PSA 90 so I think that's a pretty good measure, a pretty good study because that was 122 patients out of 872 that were treated. So not perfect, but a pretty good analysis. And 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 PSA 90. And what I want to also highlight is we had a few that were low, but we did have some that were higher and again, while we haven't disclosed what our partner J&J have done in their study with 3 patients in the identical population, those numbers were also quite a bit higher, and they did very well from those higher numbers as well. So 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 potential toxicity from combining 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. So I guess are there any pieces of evidence in your data set that suggest that 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 selection of 7386, this is the drug candidate. We did everything we could to minimize any potential additional toxicity of combining our drug with enzalutamide. So for example, our drug does not cross the blood brain barrier and as you well know, one of the dose-limiting toxicities of enzalutamide is related to neurological to seizure activity. So that was one 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. These are -- 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. And 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 7386 with any of the 4 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 AUC, the target AUC and the exposure levels that you're achieving for both 7386 and enzalutamide in the first few dosing cohorts. Are you already at the target exposure levels? And of those patients who achieved the PSA 90, 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. So 7386, we're getting exposures on average of 110,000 in the first cohort and then 150,000 in the second cohort. And of course, enzalutamide, as I mentioned before is at about 3/4 of the typical exposure of the approved dose, which is still a very active clinical dose in our view. So if you look back at our preclinical models and you asked, okay, so this 100,000 level or so, what is that -- what does that look like? Well, that was quite an active level in our AR-driven models. So 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 an overall exposure, if you will, from a preclinical standpoint of about 8 micromolars over 24 hours. And 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. So we feel that the concentrations we're already achieving are clinically active and relevant. And in particular, in combination, you may not need as much drug as well. That's certainly what we saw preclinically. And so 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 for both drugs.

Okay. Got it. And where are you in terms of the dose escalation portion in this combo trial? And when should we expect the next update here?

Well, we're currently at the third cohort, just finishing that off. That is a cohort that as Peter indicated, is still with enzalutamide at 3/4 of the dose at 120 and 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 I portion of combining these 2 drugs and our plans are to go immediately once we have shown -- demonstrated the safety and tolerability and good pharmacology, to go right into a randomized Phase II. And that will 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. And so we'll go right into from the Phase I into the randomized Phase II. Again, that should start midyear, if not earlier.

Got it. And remind me, based on your preclinical modeling, do you expect to go higher than I think you mentioned, cohort 4, where you get a full dose of enzalutamide.

I don't think, Kalpit that we anticipate doing so. That will be full dose of enzalutamide and we don't appear to be affecting the pharmacokinetic of enzalutamide and as Peter just indicated, that will 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 been through many lines of treatment that was our experience in the Phase I clinical trial. So no, I think we anticipate, 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. Got it. Maybe Peter, talk to us about the strategy for your monotherapy path for the 7386. I know you're heavily focused on the combination-based trial, but should we expect maybe a niche patient population that you go after in that setting?

Yes, sure. Sure, Kalpit. So for monotherapy, I think what our goal and work for this year is, 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, and we know the FDA is becoming more conservative, if you will, regarding accelerated approval pathways. And 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. So we have to look at all of that when we think about the monotherapy decision and the direction that we end up going. But 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 there a large enough patient population?

Okay. Okay. And I've noted that your drug is enrolled in Project Optimus from the FDA. Was this something that was put forward by the FDA for 7386 or did you actively go in and you want 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 the thinking and the reasons that Project Optimus has come to being. That's largely around getting drugs approved at doses that may be an appropriately 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 moved into biologically targeted therapies. And what you're really trying to do is find the optimal relationship between the exposures you achieve and the biology you can affect. And when you don't have a safety limitation, that actually becomes a little bit more challenging. So we may very well explore a little bit as we're going along. It shouldn't hold up the program at all. But consistent with the philosophy of Project Optimus, we're interested in trying to maximize in the majority of patients and exposure, which will be active, but which will not expose them to more drug than we need to.

Okay. Got it. And I understand that the investor attention is on 7386, but you did have some preclinical work on your first-generation molecule that would be greater for the same end 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. So there's 2 programs actually that we're focused on in the research pipeline, kind of the next-generation ANITen approach, which takes over where 7386 ended, if you will, continues to expand that. And in that program, we're actually quite excited by some of the molecules we've been making since 7386. This is looking at potentially 2 different directions. One could be a molecule that would be used in an AR-driven sort of tumor, and that's not prostate cancer. And then one direction could also be a follow-on in prostate cancer, if you will. And we've made great progress in expanding our IP and actually developing additional molecules and so that program is actually moving along quite well. And then the one you mentioned, our [ Antech ] program is also quite exciting for us because this is an end terminal domain, focus to greater and that is an area that we started about 1.5 years ago, and we've made great progress, and we did present some data at the [ triple ] meeting last fall and 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 PROTAC, with these bifunctional degraders. But the area we're still working on is selectivity and getting other characteristics that we want to have for our drug candidate. And so 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. And we'll have further updates this year, but we really haven't committed yet when we'll be able to identify that IND candidate. But it's looking very good, and we've made great progress so far.

And 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 have served different clinical applications, whether they might even in some situations, become complementary because I don't think the field really understands that yet, and we'll have tool compounds that will allow us to sort that out. Would you not agree, Peter?

Yes, 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 grade inhibitor.

Got it. And maybe last couple of minutes, any key milestones or updates that investors should be focused on for 2023 and maybe early 2024? And then what's your cash run may like?

Well, as I mentioned, finished the dose finding for the combination therapy with enzalutamide by midyear. 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. And so 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 and we are 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. So 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. So you will see over the next year, 1.5 years, enrolling of some of the clinical data from this in a fairly steady manner. The randomized Phase II enzalutamide plus 7386, that's going to take more time. And that's 120 patients. When we read that out, whether it be 2024 or longer, is completely going to be a function of accruals. So lots to say over the next year, 1.5 years, and we're now in the right patient population, we believe. So it should be actually a pretty interesting time.

Got it. And then maybe, Peter, cash runway?

Yes. So I'm just saying we've got plenty of cash to execute on all of those plans plus more. We have $167 million at the end of September, so September 30. That was our cash balance. That gets us well through 2025 and allows us to fully invest in 7386 as we see fit. So we feel like we're in very good shape.

All right. Fantastic. We're right out of time. Thank you very much, Peter and David for joining our conference today. And I look forward to all the updates this year. Thanks for the audience for tuning in.

Thank you. It was a pleasure. Take care.