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

Good afternoon, ladies and gentlemen, and welcome to ESSA Pharma's conference call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to hand the call over to Dr. David Parkinson, Chief Executive Officer at ESSA. Please go ahead.

Good afternoon. Thank you for joining us here today. I'm David Parkinson, President and CEO of ESSA Pharma, and I'm joined here today by our Chief Medical Officer, Dr. Alessandra Cesano; and our Chief Operating Officer, Peter Virsik. In this presentation, we will outline the biological rationale for targeting the N-terminal domain of the androgen receptor and how this therapeutic strategy compares, contrasts and potentially complements EPI-7386 as used in combination with the current latest generation of antiandrogens. We will present the complete clinical experience to date with the Phase Ia dose escalation trial of EPI-7386, including the safety, tolerability, pharmacology and clinical effects of the drug administered as a single agent in 36 patients with advanced metastatic castrate-resistant prostate cancer resistant to latest generation antiandrogens. Today, we will also present the preliminary clinical data on the combination of 7386 with enzalutamide in 3 metastatic CRPC patients naive to second-generation antiandrogens. This slide illustrates what we believe are the takeaways from today's presentation. First of all, the drug exhibits favorable ADME properties with target drug plasma exposures achieved and with higher exposures seen with BID dosing. We show also that the drug is safe and well tolerated at all doses, schedules and combinations tested, and that the Phase I monotherapy study reveals the biological complexity and heterogeneity of this late-stage population of mCRPC patients. Despite this biological complexity, the drug shows clear clinical signals of AR-biology inhibition as well as meaningful clinical effects. The upcoming Phase Ib study is expected to further narrow enrollment criteria and deeply characterize patient biology with the goal of identifying the most appropriate patients for single-agent therapy. The first combination cohort of 7386 plus enzalutamide, Xtandi, is safe and well tolerated with drug exposures in the biologically active range. On this next slide, for those of you who are not familiar with the relevant underlying biology of prostate cancer, this is a tumor known for many years to be predominantly driven, particularly in its early stages by male hormones or androgens. The standard approach to the systemic therapy of prostate cancer improved incrementally over the latest -- over the last several decades involves therapy with antiandrogens Currently, there are 4 major latest-generation antiandrogens: Abiraterone, which decreases the level of circulating antiandrogens; and 3 so-called lutamides, all of which block the binding of androgens to the ligand-binding domain of the androgen receptor. All antiandrogens, therefore, work through the ligand-binding domain and inevitably all men become resistant to antiandrogens through molecular mechanisms involving that end of the receptor. Unlike the antiandrogens, EPI-7386 is a small molecule of a novel class developed to interrupt androgen-driven transcription and therefore, biology through a mechanism involving the other end of the receptor, the N-terminal domain. This slide describes the unique binding of 7386, the latest generation of a new class of N-terminal domain AR-binding drugs termed anitens. As a result of its unique transcription inhibiting mechanism, 7386 can be active against multiple AR forms, including those resistant to current antiandrogens. This characteristic raises the possibility of a therapeutic benefit from treating patients who have become resistant to current antiandrogens. We have demonstrated in preclinical studies the potential for deeper suppression of androgen biology and the subsequent potential benefit to prostate cancer patients through treatment of a combination of 7386 with current antiandrogens. This information is available through a series of published posters accessible through the ESSA website. On the next slide, the general pharmaceutical characteristics of 7386 are listed. This second-generation N-terminal domain inhibitor, or aniten, has been shown to be potent, well absorbed and active against a range of androgen-resistant as well as sensitive preclinical models. The drug exhibits good pharmaceutical characteristics, including a long half-life, minimal predicted drug-drug interactions and the ability to be formulated as an oral tablet. 7386 exhibits great specificity of binding to the N-terminal domain, as we have shown, with a favorable safety profile in toxicology studies. The next slide demonstrates the clinical stages of prostate cancer, ranging from initially diagnosed local disease to the stages associated with incrementally more aggressive therapeutic approaches. This slide also emphasizes the changes in androgen pathway dependency often observed with advancing stage of disease. As you can see, with time and multiple lines of antiandrogen as well as other therapies, many different genomic alterations occur either to the AR region directly itself or to other non-AR oncogenic driver pathways. These changes can result in the tumor becoming less dependent for growth on the AR pathway and therefore, less likely to benefit from AR-based therapeutic mechanisms of action. This slide indicates also in the lower right-hand corner, the patient population in which a potential new therapeutic for prostate cancer needs to be initially studied. When the drug has been shown to be safe and well tolerated, it can be moved into patient populations less heavily pretreated, less biologically advanced and complex and potentially more likely to benefit, and all of this is exactly consistent with ESSA's long-term development plan for 7386. Now at this point, I'd like to introduce Dr. Alessandra Cesano, ESSA's Chief Medical Officer, to describe the clinical findings from the Phase I dose escalation clinical trial. Alessandra?

Thank you, David. I will start with providing an update on the EPI-7386 monotherapy study. The dose escalation phase of the EPI-7386 first-in-human clinical trial was designed to answer 4 questions. This question is related first to the safety and tolerability of the drug. And second, to the kind of exposure that could be achieved with EPI-7386 when administered orally established once or twice a day. The third question relating to developing evidence for target engagement by the drug. This target engagement evidence included any biological changes associated with therapy. In addition, despite the advanced stage of patients enter into the trial, it was important to document the clinical effect associated with treatment with EPI-7386 monotherapy as a mechanism of inhibition of androgen biology. And the final question, very much relating to the third, involves developing any information which could be useful to identify the most biological relevant patient population for this very targeted anti-hormonal therapy. The Phase I first-in-human study is a multicenter, open-label, 2-part study. The Phase I dose escalation part is a standard 3 plus 3 design, and this is followed by a Phase Ib expansion part. Under the original study protocol, patient with metastatic castration-resistant prostate cancer with failed standard of care therapy received EPI-7386 as oral tablet once a day in cohort with 200 milligram increments from 200 milligrams up to 1,000 milligram QD. For these patients, there were no limitations on the number of prior lines of therapy in patients with visceral disease as well as patients who had received prior chemotherapy were permitted. 31 patients were enrolled under this original protocol. And because of the eligibility criteria, they were, in general, very heavily pretreated patients. Following an amendment instituted later last year, we also studied a twice-a-day dose regimen, meaning BID. Today, we will describe our experience to date with the 400 milligram BID dose schedule. We are currently completing the 600 milligram BID cohort. Also, part of the same protocol amendment was a refinement of the patient population, limiting to 3 the number of previous lines of therapy for metastatic castration-resistant prostate cancer and excluding patients with visceral metastases. One line of prior chemotherapy was still permitted. The results for these patients are all under the QD pre and BID post amendment will be shown separately, except for the safety and the PK analysis for which the results from the 2 groups will be consolidated. On the next slide is a description of the patient population treated under the QD arrangement. You can see that these patients were very heavily pretreated with a median of 7 lines of prior therapies for prostate cancer and 4 lines of therapy for metastatic castration-resistant prostate cancer. 83% of patients had been treated with both abiraterone and one of the lutamides and almost 60% of patients have been treated with prior chemotherapy. Historically, this is a group of patients in which existing AR-directed therapy would be expected to be ineffective. On the next slide is demonstrated that this patient entered the trial also with very rapid progressive disease as evidenced by a median PSA doubling time of only 2.1 months and the median circulating tumor DNA percentage of 29%. Almost 1/3 of the patients had lung, liver or brain metastases and an overlapping 1/3 of patients had observed neuroendocrine differentiation as determined by the use of serum biomarker like neuron-specific enolase, NSE, from the slide. The next slide portrays the molecular characterization of the group of patients treated under the QD dose regimen by ctDNA analyses utilizing a panel of 73 prostate cancer relevant genes developed by the British Columbia Cancer Agency by Dr. Alexander Wyatt and colleagues. It is evident that this group of patients expressed a very high percentage of both AR-related and non-AR-related genomic changes. This molecular profile is characteristic of very advanced patients with the history of chronic antiandrogen and other therapeutic treatments. Particularly important to note here are the extensive non-AR-associated genomic changes. This denotes the presence of multiple other oncogenic drivers associated with late-stage prostate cancer, including, among others, activation of the PI3-kinase pathway, loss of TP53 and loss of Rb1. On the next slide, we demonstrate the baseline disease characteristics of the patients treated under the BID dose schedule post amendment. Despite the fact that there are relatively few patients enrolled to date, these patients had a history of fewer lines of prior therapy, have a longer PSA doubling time and a significant lower median baseline of percent of circulating tumor DNA and do not add obvious neuroendocrine differentiation as judged by biomarkers. On this slide, we demonstrate that EPI-7386 has a favorable safety profile as a single agent at all dose levels and schedules tested. All treatment related adverse events are grade 1 or 2 with one exception. There was one occurrence of grade 3 anemia initially reported to be possibly related to treatment. But with further observation, the patient was demonstrating to have a very extensive bone marrow involvement and that attribution of the adverse event was changed by the investigator to unlikely related. There was no apparent dose dependency in any of the side effects. There were 3 episodes of grade 2 treatment-related adverse events of diarrhea occurring in the QD group at doses greater than 60 milligram QD. Beside the fact this appeared with dose reductions and we have not subsequently observed diarrhea in the trial, the 8.1% dose reduction rate that is seen in the table is entirely relating to diarrhea adverse events. On the next slide is demonstrating the serious adverse event experience in the trial. None of the serious adverse events were considered to be treatment-related, all were considered to be relating to disease progression and on underlying comorbidity. I have already described the particular situation relating to anemia, which was a one-off and ultimately deemed to be likely due to disease progression. So the answer to the first question the study was designed to address is that the drug has been safe and well tolerated to date at all dose and scheduled studies. With respect to the second question regarding exposure, the next slide demonstrated that as predicted by the preclinical profiling, EPI-7386 has a long half life in patients greater than 24 hours, supporting once-a-day administration. The steady state exposure of EPI-7386 increased with higher doses. Doses greater than 400 milligram per day exhibit area under the curve concentration generally above the upper target threshold of 300,000 nanogram per hours per milliliter developed from extensive preclinical experience. The 600 milligram QD cohort exhibited the highest area under the curve of exposure. And the exposures achieved at 800 and 1,000 milligram levels administered QD were not linearly increased, suggesting a possible limitation in drug absorption. Our experience in the toxicology study has shown that dose splitting could achieve higher exposure. Hence, our decision to study BID dosing and potentially explore higher exposure in the post amendment study. I indicated we are still awaiting the pharmacology from the 600 milligram BID dosing. All patients have been enrolled in this cohort, but this data is not available to us yet. A number of observations relating to the duration of time on study emerged from the data portrayed on this slide. The QD patient group is portrayed on the top on the left, with the BID patient portrayed in orange in the lower left part of the slide. Several of the latter are still on therapy, as indicated by the forward arrows. The middle part of this graphic portray show the number of previous line of therapy. You can see that patients who are on study longer are those patients with fewer previous line of therapy. Despite the late stage of their disease, 1/3 of these patients across all dose levels remain on therapy for longer than 3 months. Those patients who progress at or before 12 weeks in general are either biomarker consistent with neuroendocrine differentiation, had exposure to prior chemotherapy, had visceral metastases or were patients who had received more than 3 previous lines of therapy for metastatic castration-resistant prostate cancer. One patient, the least heavily pretreated in the first group of this trial, was treated for a total of 18 months with EPI-7386 before progressing radiographically. Additionally, one patient is currently on study in cycle 13 at 1,000 milligram QD dose level. And we should point out that at least in this early experience, no obvious dose response was noted. The third question to be answered by the trial relates to sign of target engagement by EPI-7386. The obvious biological complexity of the patient in this first stage of EPI-7386 clinical development confounds a clear interpretation of clinical effects in this patient. We have, therefore, examined a series of parameters which can relate to interruption of male hormone biology in patients. This includes the documentation of the well-known metabolic effects, such as change in cholesterol as well as describing the changes in tumor biomarkers such as PSA and quantitative circulating tumor DNA. We are examining, in addition, the effect of therapy on PSA doubling time in individual patients. Together, we documented, with new technology, the more traditional tumor measurement -- imaging measurement of the change in size of tumor masses. We note here that we have also tended to numerous circulating tumor cells and to characterize the splice variants, AR-V7 in CTC. But those -- but found those assays not to be robust and reproducible. As evidence for the target engagement on the next slide, it's demonstrating the effect of EPI-7386 on circulating cholesterol levels. It has long been demonstrated that patients initiating androgen deprivation therapy experience increases in the plasmatic lipids. In this trial, a correlation between the plasma's concentration of EPI-7386 at study state and the plasmatic LDL level measured throughout the dosing cycle was observed. This next slide summarizing the observations we made with respect to achievement of PSA reduction in the Phase Ia of the study. As reported by the Prostate Cancer Working Group 3 guidelines, PSA is an unreliable marker of tumor responsiveness in the late-stage patients. In the upper left-hand corner is the waterfall plot of the best PSA changes during therapy from baseline for the patient enrolled in the QD dose regimen. Below the waterfall plot, the AR and non-AR genomic changes in this patient tumor are portrayed. The middle part shows the same information for the patient enrolled in the BID dose regimen. PSA decreases or PSA stabilization were more likely to be observed in patients with no visceral disease, less DNA genomic aberration in the non-AR oncogenic pathway as well as in those patients with fewer than 3 lines of previous therapy for metastatic castration-resistant prostate cancer. We should note that those patients treated with the BID schedule are still on therapy. Unfortunately, the patient with the deepest PSA decline had non-detectable circulating tumor DNA at baseline consistent with a relatively low tumor burden. Consequently, we do not add the molecular information for that particular patient before he started his therapy nor when he became resistant to EPI-7386. The next slide makes an important point about the relationship of tumor burden with both percent circulating tumor DNA and PSA level. An important observation is that for the patients all under the QD dose regimen had good correlation of circulating tumor DNA with overall tumor burden as measured by imaging was observed, while a similar relationship was not observed with PSA level, demonstrating the complexity of interpreting PSA changes in this very late-stage patient population. As a result of the observed correlation of circulating tumor DNA with patient tumor burden, we were particularly interested in analyzing the changes in percent circulating tumor DNA associated with administration of EPI-7386 therapy. We noted that circulating tumor DNA declines were observed in a subset of patients, including patients whose PSA levels were stable or increasing. And these declines were observed even in patients with both wild-type AR and AR point mutation as well as some non-AR mutation. We should also note that no clear dose response was observed for the percent circulating tumor DNA decreases. In this slide, the best changes in measurable lesion is presented for this group of patients who remain on study for more than 12 weeks, those are 10 patients, and had both measurable disease and scan measurable available, 5 patients of this 10 patients. Decreases in measurable disease were observed in all of these 5 patients even in the absence of parallel PSA decrease. Of note, decreases in measurable target lesion was observed in patients whose tumor had AR amplification or mutation, although the small number prevent any overreaching conclusions. Of the remaining 5 patients of this group, 4 had bone disease only and 1 patient had no scan measurements available. This slide represents the first of 2 particularly attractive patient profiles we believe demonstrate the kind of clinical effect that can be observed with EPI-7386 even in this very late patient population. This is a 79-year-old man who had previously progressed on 2 second generation antiandrogens administered for metastatic castration-resistant prostate cancer. He began treatment at the 200 milligram QD level. Under treatment with EPI-7386, his PSA level declined progressively reaching a nadir PSA 18 between week 32 and 36. Radiographically, there was a reduction of 20% in target lesions with the nadir at week 36. Beyond that point, PSA level continually increased despite intra-patient dose escalation as permitted by the protocol. During this time, he reported a good quality of life until finally progressing radiographically and discontinuing therapy around 18 months. As part of our attempt to understand further the complicated biology of this patient, clinical end response to EPI-7386 therapy in this late-stage disease, we have used several volumetric analysis of CT and bone scan in patients during EPI-7386 treatment. This study has been done in collaboration with AIQ solutions. The advantage of this approach is that it allows characterization of changes over time in each of the main lesions often present in these patients, allowing a much more complete analysis of treatment-associated changes than traditionally obtained with the RECIST methodology. Of note, in this slide, the different lesion responses to treatment at 36 weeks is highlighted with lesion clearly decreasing in size in green color, while other remaining stable in gray and other increasing in size, red, compared to baseline expansion. The next slide is the patient profile of a second instructive patient. This one is receiving EPI-7386 at 400 milligram BID dose regimen. This patient presented with metastatic disease after previous treatment with docetaxel and abiraterone. He had a PSA doubling time of 3 months indicating aggressive disease, but a low baseline PSA level, had no circulating tumor cells and had a relatively low circulating DNA percentage -- tumor DNA percentage of 7%. He received a good exposure with EPI-7386. And over the course of 24 weeks, the PSA level has slowly decreasing, reaching PSA 30 decrease. And radiographically, he had a decrease in target lesion measurement of 23%. This slide summarizes the next step on the EPI-7386 monotherapy study. Specifically, once the last cohort of the Phase I part of the study, the cohort evaluating the 600 milligram BID dose schedule, we'll complete the DLT period, a decision about dose schedules likely more than one in agreement with the recommendation of the FDA Project Optimus will be moved on to the Phase Ib part of the study. And this will trigger the parallel opening of 2 study arms evaluating dose schedule in 2 different patient populations, one will enroll a patient population of metastatic castration-resistant prostate cancer similar to the one treated under the BID dose regimen in the escalating phase, but with the additional exclusion of prior chemotherapy. Up to 12 patients for each dose schedule will be evaluated to gain additional information about the safety, tolerability, exposure and antitumor activity of EPI-7386 single agent in a less pretreated patient population. In parallel, a window of opportunity with clinical endpoint, meaning PSA decrease cohort will be open, enrolling patients with non-metastatic castration-resistant prostate cancer to be treated with EPI-7386 single agent up to 12 weeks before initiating standard of care treatment. The main object of this cohort is to assess the antitumor activity of EPI-7386 single agent in a patient population in which the disease is mainly AR-driven and the tumor biology not previously perturbed by second-generation antiandrogen therapy. As mentioned before, the extensive preclinical study has been conducted demonstrating that EPI-7386 and second generation antiandrogen combination therapy by shutting down the androgen receptor from both ends leads to a more complete suppression of androgen biology. Historically in prostate cancer, such improved androgen suppression has translated to increased clinical benefits. And our preclinical study strongly suggests the same will be true with EPI-7386 combined with currently approved second-generation antiandrogen. A favorable safety profile and tolerability of EPI-7386 at all dose and levels tested has enabled the study to this trend into early stage of patients, patients who have not yet received and became resistant to second-generation antiandrogen. The following slide demonstrates the initial -- that the initial combination trial will be conducted in patients who have not yet received and have become resistant to the latest generation antiandrogen. Our clinical development program for EPI-7386 with approved second-generation antiandrogens is summarized in this slide. ESSA is conducting a Phase I/II study to evaluate EPI-7386 in combination with enzalutamide in metastatic castration-resistant prostate cancer patients naive to second-generation antiandrogen. This study began in the first quarter of 2022. This study is conducted in collaboration with Pfizer/Astellas, which are providing enzalutamide for this study. The study is ongoing, and we'll provide more information in the next slide. In parallel, Janssen is conducting a 2-arm Phase I/II study to evaluate EPI-7386 in combination with apalutamide and abiraterone acetate in metastatic castration-resistant patient naive to second-generation antiandrogen. This study is also ongoing. And in addition, Bayer has a collaboration with ESSA to evaluate 7386 in combination with darolutamide in a Phase I/II clinical study in metastatic castration-resistant patients. Finally, a 12-week 2-arm randomized study of darolutamide versus EPI-7386 plus darolutamide in newly diagnosed prostate cancer patients undergoing prostatectomy with high-risk localized prostate cancer, which is the last phase of -- finally will also occur. In this slide, the design of the ESSA sponsor combination study of EPI-7386 in combination with enzalutamide is depicted. The study is designed as a Phase I/II multicenter, open-label study enrolling patients naive to second-generation antiandrogen. The Phase I part of the study is testing escalating dose of EPI-7386 in combination with a fixed dose of enzalutamide with the main objective being evaluation of the PK and safety of EPI-7386 and enzalutamide when administered in combination along with establishing the recommended Phase II for both drugs to address any possible drug-drug interaction. Once the recommended Phase II doses for both, EPI-7386 and enzalutamide when administered in combination are established, the Phase II component of the study will start. This part of the study is designed as a 2-arm, randomized 2 to 1 study and will evaluate head-to-head the antitumor activity of EPI-7386 in combination with enzalutamide versus enzalutamide single agent as the standard of care dose in this patient population. This slide provides an update of the current status of this study. The Phase I part of the study is currently ongoing with 5 enrolling sites in U.S. and Canada. The first cohort of 3 patients, which evaluate the EPI-7386, 600 milligram QD dose in combination with enzalutamide at the dose of 120 milligram QD, has been enrolled and cleared the DLT period with no safety issue. The safety profile was consistent with second-generation antiandrogens, meaning grade 1 or 2 adverse event of fatigue and hot flashes. From a PK point of view, enzalutamide exposure was only minimally impacted by EPI-7386 administration, while as expected, EPI-7386 exposure was impacted by enzalutamide with decreased exposure level of EPI-7386 observed. As planned, 3 to 4 cohorts will be needed to determine the optimal dose of each drug when given in combination. From an antitumor activity point of view, 2 of the 3 patients achieved a rapid decline of PSA level by week 4 and PSA-90 within 3 months from starting combination treatment. One patient achieved a PSA below 0.2 nanograms per milliliter within 3 months and this patient had received no prior chemotherapy. The third patient was discontinued from the study at the end of cycle 2 when it became clear from the PK data that there was a drug-drug interaction between a concomitant medication he was taking with both enzalutamide and EPI-7386 resulting in a significant decrease in the exposure of both of these drugs. I will now ask Dr. Parkinson to make the concluding remarks.

Thank you, Dr. Cesano. By way of summary, this dose escalation phase of 7386 development has shown the drug to be safe and well tolerated at all doses and schedules tested. The drug has been administered either once or twice daily as oral tablets and experience has confirmed the favorable pharmaceutical properties associated with the drug. The exposures achieved in patients are consistent with those active in preclinical models. These exposures have resulted in metabolic changes associated with antiandrogen therapy. In addition, despite the very advanced stages of their malignancy in the patients described today, we have demonstrated clear antitumor effects as evidenced by achievement of significant deep PSA response sustained for a year in 1 patient, less dramatic PSA responses in other patients and objective tumor shrinkage in individual lesions as measured radiographically in additional patients. While modest, the best results are clearly seen in those less heavily pretreated. And the first observations from follow-up of those patients accrued since the protocol amendment suggest that while still having advanced metastatic castrate-resistant prostate carcinoma, this newer group of patients are less biologically complex patient population. Clearly, efficient single-agent clinical development going forward will require a focus on those patients whose tumors are more likely to be predominantly AR-driven and therefore, who are most likely to benefit. To that end, the expansion phase that we are now beginning will include patient entry criteria designed to enrich for that group of patients. The accompanying circulating tumor DNA and RNA characterization will, we believe, greatly assist in identification of these still AR driven, although antiandrogen resistant patients and will inform the single-agent development strategy going forward. As you've also seen, the favorable safety and tolerability profile of the drug has enabled the initiation of the combination therapy series of trials. We believe that combination N-terminal domain inhibition in anti-androgen therapy is the much greater potential opportunity for EPI-7386 to contribute to improvement of prostate cancer therapy. While we are encouraged by the initial experience emerging from the first cohort of EPI-7386 plus enzalutamide in combination, we look forward to reporting the full combination Phase I data results when the data are mature. In closing, we'd like to thank all of the patients, investigators and clinical research staff participating in this trial. These are challenging times for clinical investigation in general, and their contributions towards development of a potential new therapy for prostate cancer are recognized and much appreciated. Thank you all for your attention.

[Operator Instructions] And our first question comes from Maury Raycroft with Jefferies.

Congrats on the update. I guess first question is for the Phase Ib dose expansion and window of opportunity studies. Can you talk more about what efficacy bars you're looking to achieve in those studies, including on ctDNA and PSA responses?

Maury, as we move into the expansion phase, I think what you're going to see is a population of patients treated who, while still having advanced disease, as I just mentioned, are less advanced than the original population of patients entering the trial. So we would expect to see more clinical activity if, in fact, these men still have their tumors largely driven by AR. But to that end, we will be confirming that with the Wyatt and the Caris assays that we just described at the end. It's quite clear that the biology of late-stage patients who have progressed on these latest generation antiandrogens is more than just AR. And so as a first step in trying to find a population that's more homogeneous, that's more AR driven and to get a true sense of the activity of the drug, we need to look at patients who are ultimately selected by biology as well as clinical correlates. But two, I think that's where you see the work that we're doing in the window of opportunity study should give us real insight into what you're really asking about, which percentage -- the classic things that one did with enzalutamide 10 or 12 years ago, which has asked, what's the percentage response in a marker like PSA or perhaps even a better marker like ctDNA in a more homogeneous patient population more suited to the mechanism of this drug. I don't have numbers for you in terms of expectations, but we would expect to see a very significant amount of activity.

Got it. That's helpful. And for the window of opportunity study, are you saying how many patients you would include in that study? And is that something you plan on -- could you potentially have an update on that by the end of this year?

I'll ask Alessandra to comment on that.

Yes. So the answer to the first question about the number of patients right now is relatively limited because of the early stage of the patient population. And -- but it's like up to 10, 12 patients, really to get a signal. We know that this is a patient population that should be as was said, that's why we chose it, driven -- in which the tumor is driven by AR, and we know the response rate, for instance, to darolutamide or apalutamide. In term of -- its relatively also a short trial or I should say cohort because it's up to 12 weeks before the patients are really switching, if appropriate, to the label of -- so if they have a double time of PSA below the month, they are candidates for darolutamide, for instance. And so we will have the results. It depends how quickly we can enroll this patient population, but we are expecting because we have sites in not only in the United States, which this therapy are standard and actually reimbursed, but also in Canada and in Australia. And so that's -- we are hoping that we can get this quarter pretty quickly and should be...

It's so hard to predict exactly when, Maury, but we're not treating the patients for a long period of time, as Alessandra just said, and we've opened up additional sites to try and get that answer as quickly as we can.

Got it. That's really helpful. And maybe a last quick question for me. Just for the combo study for the third patient in there with the drug-drug interaction, can you say what the concomitant drug is that caused the exposure decrease?

Yes, it was primidone. It's a drug that was given to the patient for essential tremor. It's actually a very strong inducer of the CYP3A4. And so as you can see probably from -- in the slides, that what's affecting on just EPI-7386 that we had some suspicion that it was a substrate, metabolic substrate for that, but also enzalutamide since the level of exposure to enzalutamide were definitely below what we would expect.

And our next question comes from Joe Catanzaro with Piper Sandler.

Thanks for the update. Maybe first one, just following up on a couple of points here on this sort of patient selection process. I'm wondering, and I know you're doing the work on genomic and transcript, they'll make biomarkers, whether potentially not even necessary as you look at just enrolling earlier line, no prior chemo, no visceral disease and whether that is sufficient to still enroll patients with AR-dependent disease and maybe it was touched on in an earlier slide. But for those 5 patients that were enrolled, on the protocol amendment, did you see distinct differences there in terms of the AR pathway and non-AR pathway oncogenic profiles? And I have a couple of follow-ups.

Interesting question. Alessandra, do you want to comment? I have some thoughts as well.

Yes, definitely. What we are trying to see if essentially we can -- so the clinical, if you want selection, as you point it out, that is what we are looking right now. How we essentially correlate it with the molecular and seeing if, in fact, additional particularly from a transcriptional point of view, we might -- when that is possible, for instance, with the Caris assay that allows for looking at the transcription part could provide additional information. But clearly, even just selecting the patients, the reason why we selected was based on a retrospective analysis of the clinical characteristic of the patients enrolled in the first part of the study as it was -- we tried to document it. So you could see in the slide that we're showing the swimmer plot, that the patient that stay in the trial longer had -- rarely had prior chemotherapy, they definitely had no visceral metastases and we saw a very good overlap between visceral metastases and neuron-specific enolase, for instance, as a biomarker.

Yes. I would add to that, Joe, that clinical research is an iterative process, right? We treat and we characterize and we learn from outcome. We've watched while other companies with AR-related mechanisms have also struggled in the really late-stage patients to find those patients most suitable biologically for their particular mechanisms of action. And that's exactly what we've done. And we think that first amendment was a giant leap forward. I would not be surprised if your characterization of an even earlier clinical phenotype, less heavily pretreated, et cetera, ultimately turns out the way to pick particularly a rich group of patients. But we think that the biological characterization will help us along the way determine that. Whether you need that kind of technology ultimately to select patients, I don't know. And -- but we should know an awful lot more after the expansion phase as we start to treat more patients.

As it was mentioned, one of the limitation is the circulating tumor DNA in early line of therapy is actually less prevalent. And for instance, in our patients, as we mentioned, the most -- the one that has the deepest PSA response in those patients circulating tumor DNA was not detectable, in particular, not detectable at the level that allow for characterization of, for instance, amplifications or additional -- one is amplification and deletion.

Great. If I could ask one on safety here. I'm wondering if it was surprising to you at all that there was no correlation between tolerability and overall exposure levels. Was that based -- was that expected based on GLP tox experience? Has that been seen with other antigen pathway inhibitors? Would just love to hear your thoughts there.

Yes. Sure, Joe. Let me ask Peter Virsik to comment on that. Peter?

Yes, Joe. So you may recall in our tox studies, we were able to achieve pretty high exposures in both the rat and dog species. And there weren't really any major findings aside from some antiandrogen findings with dose and then a little bit of tolerability around perhaps GI. But that was -- these were really, really much higher exposures. And so our preclinical assumptions coming into the study were that the drug, if it behaved as it did in animals at these kinds of exposures, should be pretty well tolerated. And so from the early clinical read, I think the kind of tox-related toxicities that we might expect, perhaps GI or whatnot, would be expected at higher doses and we would expect that these kinds of ranges maybe starting to see antiandrogen effects, if you will, if you want to call those safety or adverse events. But I don't think it was a surprise. I think the drug has been well tolerated in all the preclinical work, and that was our hope and expectation going into the clinical study.

Yes. And I would just add that the exposure, in fact, correlates for it as we show with increasing cholesterol level. So that is actually -- you could consider a safety because it's one of the things that we measure for safety. And that there was a correlation, so essentially, between exposure and increase in lipid metabolism. So we are thinking that the recent dose response when there is something to measure that's essentially related.

Correct, and something is actually happening.

Okay. Maybe if I could just squeeze in one last quick one. I know it's just NF2, but can you maybe put into context the kinetics of those PSA declines you've observed early on with the combo relative to what maybe you would expect with enzalutamide?

Yes, sure. Let me ask Peter to handle that one.

Sure. So Joe, so first, let's caveat it again by saying this isn't NF2. And while we're pleased, we want to keep that in mind. As we've mentioned before, I think, in our discussions, there were several studies previously conducted with enzalutamide looking at similar patient populations. And so the pre-chemo population study, the PREVAIL study, in that population, 47% of patients achieved the PSA-90 over the course of that study. If you look more closely at it, 37% actually achieved the PSA-90 within the 12 weeks or within the 90 days. And even more detailed in that study within the 90 days, 5% of those patients achieved the level of PSA less than 0.2 nanograms per mL. So that's the one type of patient population. If you look at the other patient population, the post-chemo, that's represented by the AFFIRM study, we know that in that study, 25% of patients achieved a PSA-90 during the course of the disease and that 13% of them achieved that PSA-90 within the first 90-day period. So those are our comparisons and benchmarks that we're looking at.

Next question comes from Mark Breidenbach with Oppenheimer.

Just a couple for me. I guess, I'm curious, once you introduced the protocol amendments for the BID dosing cohorts, sort of qualitatively, what was the impact on your patient screening success rate? Did you see a big decline in enrollment rate after introducing those changes? And I guess, what I'm ultimately getting at is with all the protocol amendments you're planning for the Phase Ib expansion, what slice, what fraction of the overall metastatic castrate-resistant prostate cancer population do you think that applies to or encompasses?

It's a great question, hard to answer it too precisely. The timing of the protocol amendment was late -- in practice, was instituted really in November. And we managed to just hit the Christmas holidays and the little thing called Omicron which basically shut down a lot of accrual from a number of our sites. So I don't know that we have a good feel of that. We know there are lots of patients with -- who would fit into this category, Mark. And so I don't think it will be difficult to find patients like this. But to that end, it may be more difficult in the United States than it might be in Canada or in Europe or Australia. And to that end, we are opening sites in additional geographies just to ensure that we don't have to slow an accrual because we think that this is potentially an important therapy, and we'd rather move it along. We're now finally no longer constrained by the Phase I limitations of 3 patients per cohort, follow for a month, et cetera. Now we can move into the expansion phase. We can expand that additionally. We can move into Phase II. We are only encumbered by a number of sites and the number of patients per site. So I can't answer your question precisely, but I don't really think and we've been assured by our investigators that there are lots of these patients around. The practice in the United States is more complicated, but there are lots of these patients around.

Okay. That's helpful. And maybe a quick follow-up. I guess, I'm just wondering mechanistically what makes patients with prior chemo experience less sensitive to AR-directed therapies? I mean this seems to be the case of 7386 as well as some of the lutamides. What's going on there? And maybe I should ask the same question about visceral metastases. Is there something about those that make them less sensitive to treatment?

Well, visceral, I would say, is easier to answer because that really correlated, at least with our early experience, with the development of neuroendocrine differentiation. The issue about chemotherapy is a major question overhanging the entire antiandrogen field because it's -- well, we found that, I think that's been found since the earliest days of the lutamides. Peter, do you want to comment on that?

Yes. So one thing -- I think there's two aspects to think about. So there is some preclinical data to support that there can be some level of resistance from some of the chemos like docetaxel in particular with respect to AR-V7 and how that can work and how that can impact those in response to docetaxel treatment. But I'm not sure those are really what's happening here. I think there's been a general change in the overall treatment of patients and that patients who are now presenting perhaps are -- having that actually perhaps a different disease biologically than maybe what they would have 10 years ago. And so it's a good question, I think there's a lot of good answers. We don't know the specific data to it. We will learn more as we look at the molecular characterization, but these patients could just be different patients starting off versus anything specific to AR.

That's caused by the chemotherapy.

Yes. The chemotherapy impacted AR.

Absolutely correct. It could be an ascertainment bias issue that the kind of patients who received chemotherapy previously are different from the kind of patients who didn't receive chemotherapy and therefore, respond differently to anti-hormonal therapy.

Yes, that seems to be the case at least for some of the patients in which essentially you will -- they will receive chemotherapy just based on the risk that is calculated based on the nomogram that today physicians use to actually evaluate the patient at the beginning. So that means it's actually a clinical evaluation of, if you want, underlying biology that manifest with high risk.

That's true. There is some new data, though, on docetaxel cause transcriptional pattern changes. So to be continued, I guess, is a discussion.

Our next question comes from David Martin with Bloom Burton.

I had to switch lines halfway through, so I'm hoping these haven't been answered. But -- so for the 4 patients that have got 400 mg BID, 2 of them are still on trial. Could we see the PSAs go down further for the 1 patient and possibly start to trend down for the other patients on trial? Certainly, your first patient that you reported on last February, it took a while to get the most PSA decline out of that patient.

Yes. So the answer is, yes. We have started this cohort, the 400-milligram and even the 600-milligram and enrolled the last patient as late as March. So essentially, the follow-up of this patient is going. We can definitely -- I think we present the second patient data showing not only that there is a decrease in the PSA, but also a shrinkage that is progressive in the radiographic lesion. So with the follow-up of this patient -- for the patients that are still on the study, we are definitely following up and thinking that they -- this drug, as you pointed out, is we didn't see effect in the monotherapy very quickly. And so like at least you have to wait for 1 month.

12 weeks.

12 weeks, I'm sorry, start to see the decline. So yes, this growth is very immature. That's the way I would describe it.

Okay. Second question. Why do you think you're seeing a lot of circulating tumor DNA decreases, but relatively fewer PSA decreases? You think if the tumor is no longer driven by AR, wouldn't you expect to see few decreases both of the ctDNA and the PSA?

Yes, Dave, I think the interpretation of these biomarkers is really complicated in these patients with really advanced heavily pretreated disease, a lot of exposure to chemotherapy, exposure to multiple antiandrogens. And clearly, we've only just shown the tip of the AIQ software analysis of longitudinal images in these patients. The amount of tumor heterogeneity is remarkable. We can see lesions, which disappear. We can see at the same time, new lesions appearing. Some of these are clearly PSA driven. Therefore, it would be my interpretation. And some of these are clearly not. So the ctDNA, as I understand it, is -- one can think of it as an integral of tumor burden overall. PSA on the other hand would really represent only a subfraction of the tumor. And frankly, in these late-stage patients is well known from 30 years of clinical investigation to be an imperfect unreliable indicator of what's going on with that tumor burden. That's why it's not a regulatory endpoint. So I don't have a simple answer for you. But I think what it means is that we need to use all the tools we have available in these late-stage patients to try to understand the effect of one particular targeted approach amongst all of this complicated biology. And then as soon as we can, move towards a group of patients, and that's what we're doing as you've heard today, who we believe are more biologically homogeneous doesn't eliminate in the future, the opportunity to use our approach in combination with other mechanisms of action drugs. But for us to sort all these things out and to find an efficient place, for further development in 7386 as a single agent in antiandrogen-resistant patients, we need to find the patients who are more homogeneously driven by AR.

Okay. My last question. The 2 BID cohorts, you've gone to patients with 3 or fewer lines of therapy. However, the press release said the PSA decreases or stabilizations were in patients with fewer than 3 lines of therapy. So 1 or 2, not 1, 2 or 3. So will you amend the dose expansion protocol to include only patients with 1 or 2 prior lines of therapy?

Actually, I think that the press release should have said 3 or fewer because that's what we have amended. So what we have done is to exclude chemotherapy from the -- in the amended one. So that's another -- it's a difference between the population in the BID. We actually definitely concluded that excluding chemotherapy moving forward was another step.

The next step, right.

Yes.

Okay. So it is 3 or fewer, not fewer than 3. And by excluding chemotherapy, I know you had a related question, but could that limit the patient enrollment because patients of standard of care will be to move on to chemo for a lot of patients or do relatively few patients move on to chemo?

Well, these are older men. I would say at least 50% of them are probably not chemotherapy candidates right from the start, just from general chemotherapy principles. Would it limit? Yes, it will limit somewhat patients. But on the other hand, we're thinking that it will give us more information around the effects of our drug. And we can always go back and add on patients later once we sort all this out. But as I think the very, very first question from Maurice asked what kind of steps can you take to try to move in on the population that's most appropriate? Based on our experience to date, removing chemotherapy at the moment seems to make sense, but we'll find out.

Thank you. There are no further questions at this time. I'll turn the floor back to management for closing remarks.

Well, first of all, I'd like to thank you all for attending today. We are pleased to present basically 2 years of hard work, and I say hard work because it's been conducted under challenging circumstances, anyone running clinical research trials during COVID knows that. And I know you all have other companies that you follow. So we -- I really want to just add to the final remarks I made in the presentation, which is that we believe we have a drug with a novel mechanism of action that's really, really relevant to the treatment of patients with prostate cancer, which is the next logical step in what has been a 60-year path of increasingly suppressing androgen biology and doing that early and earlier in the natural history of the disease. We believe that adding 7386 to the combination, in combination with current antiandrogens, based on everything we've learned from the biology and the preclinical experience is a next major step. We have, I think, shown you today the first steps we've taken to earn the right to study earlier patients with our drug in combination with antiandrogens. And along the way, we'll try to determine whether there is a niche and how large that niche is for single-agent therapy in late-stage patients or as part of combination strategies for the very complex biology of late-stage patients. So thanks for listening today, and we look forward to further discussions as we move forward in our program. Thank you very much.

Thank you. This concludes today's webcast. Participants may disconnect. Have a good evening.