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Business Update
Encouraging Data from Phase 1 Trial of EPI-7386
On June 27, 2022, ESSA Pharma, Inc. (NASDAQ:EPIX) provided an update on the company's Phase 1 clinical trial of EPI-7386 in patients with mCRPC who had progressed on two or more systemic therapies, including at least one second generation anti-androgen therapy (NCT04421222). A copy of the company's presentation can be found here. It is a multi-center, open label, ascending multiple dose trial with the primary objective being to evaluate the safety and tolerability of EPI-7386. Secondary objectives include determining the maximum tolerated dose of EPI-7386, defining the recommended Phase 2 dose of EPI-7386, evaluating the pharmacokinetics (PK) of EPI-7386, and assessing any potential drug-drug interactions.
The purpose of the Phase 1 trial is to answer the following questions regarding EPI-7386, which we will discuss in greater detail.
1) Is EPI-7386 safe and well-tolerated?
2) Do drug exposures exceed previously predicted efficacious thresholds observed in preclinical studies?
3) In which patient populations will EPI-7386 be most effective?
4) Is there evidence of androgen-pathway inhibition and clinically important efficacy signals?
Is EPI-7386 safe and well-tolerated?
Yes, EPI-7386 appears to be well-tolerated with all treatment-related adverse events (TRAEs) being reported as Grade 1 or Grade 2. There was one report of Grade 3 anemia, however the treating physician changed the attribution to "unlikely related" to EPI-7386 treatment. The following table gives an overview of reported TRAEs. All Grade 2 diarrhea occurred at doses ≥ 600 mg QD.
In addition, serious adverse events (SAEs) were uncommon and were attributed to either disease progression or underlying comorbidities with no treatment related SAEs. Thus, we find the safety and tolerability of EPI-7386 to be acceptable to continue advancing the drug in development.
Do drug exposures exceed previously predicted efficacious thresholds observed in preclinical studies?
ESSA did extensive preclinical work characterizing the pharmacokinetics (PK) of EPI-7386 that was used to develop a targeted efficacious range. The following figure shows that all doses tested in the Phase 1 trial reached exposure levels above the minimum predicted target drug threshold and doses of EPI-7386 > 400 mg QD had AUC concentrations above the highest target drug threshold. The company also reported that 400 mg given twice a day (BID dosing) allowed for a higher minimum drug concentration (Cmin). The data for the 600 mg BID cohort is still being collected and analyzed.
In which patient populations will EPI-7386 be most effective?
The patients enrolled in the QD dosing regimen in the Phase 1 trial were heavily pretreated, with a median seven lines of prior therapy, with most having abiraterone and/or enzalutamide. In addition, these patients had rapidly progressive disease (as shown by a PSA doubling time of approximately two months) and a high tumor burden (median baseline PSA of 94.5 ng/mL and median baseline circulating tumor DNA [ctDNA] of 29%). Approximately one-third of the patients had evidence of visceral disease and markers of neuroendocrine differentiation. All of this points to a very difficult to treat patient cohort. This is exemplified by the following figure, which generally shows that the patients that had fewer lines of prior therapy tended to stay on treatment with EPI-7386 longer. These data support the idea that treating patients with EPI-7386 earlier in the course of the disease is likely to increase the chance of clinical success.
A detailed molecular profile of the patients in the QD dosing regimen showed that there was a high percentage of non-androgen receptor (AR) alterations at baseline. The following table shows that while 86% of samples examined showed alterations in AR-associated genes, 93% of samples showed alterations in non-AR associated genes, including those involved in the PI3K pathway, DNA repair, and P53 pathway. These non-AR associated genetic alterations mean those patients are less likely to respond to AR-targeted therapies, they are unlikely to have a clinically meaningful outcome following EPI-7386 treatment, and enrollment for future trials should focus on those patients with fewer non-AR oncogenic drivers.
Is there evidence of androgen-pathway inhibition and clinically important efficacy signals?
The anti-androgen effects of EPI-7386 were evaluated through a metabolic biomarker and anti-tumor biomarkers. The metabolic effect was examined through changes in serum cholesterol levels and the anti-tumor effect was examined through changes in circulating PSA levels, changes in ctDNA levels, and radiographic changes in disease burden as measured by RECIST criteria.
The use of anti-androgens is known to cause increases in lipid. The following graph shows that there was a significant correlation between the plasma concentration of EPI-7386 at steady state and LDL cholesterol, thereby suggesting that EPI-7386 is exerting anti-androgen effects.
In regards to anti-tumor efficacy, PSA reductions were observed in a clinically defined subset of patients who had no visceral disease, fewer DNA alterations in non-AR oncogenic pathways, and had received fewer than three lines of prior therapy. Of the 17 patients with measurable ctDNA levels, 11 patients had ctDNA levels decrease, however there was no dose response observed. Lastly, for the 10 patients who remained on the study for >12 weeks, five of those patients had measurable disease at baseline and all five patients had a decrease in tumor volume, as shown in the following image.
ESSA reported on two case studies; one from the QD dosing cohort and one from the BID dosing cohort. The QD dosing case involved a 79-year-old man who received 18 cycles of EPI-7386 that ranged from 200 mg QD to 1000 mg QD. He showed a robust decrease in PSA levels through week 36 of dosing, as shown in the following graph. In addition, he had a 20% decrease in target lesions at week 36.
In the second case study, a 71-year-old man has been on 400 mg EPI-7386 BID and has experienced a slow but steady decline in PSA levels along with progressive tumor shrinkage, as shown in the following table. The patient's baseline tumor burden has gone from 4.0 cm to 3.1 cm (-23%), with no new lesions reported.
Next Steps
Overall, the results presented by ESSA are encouraging, particularly given the very difficult patient cohort that was enrolled into the study. It is clear the company will need to move EPI-7386 to earlier line patients in order to ensure that they are targeting those with few to no non-AR genomic alterations. In support of this, following the finalization of the recommended Phase 2 dose, ESSA will be initiating the Phase 1b dose expansion study with two dosing cohorts (600 mg QD and 400 or 600 mg BID), with eligible patients having ≤ 3 prior lines of therapy, no visceral disease, and no prior chemotherapy. A third cohort (the "Window of Opportunity") will consist of non-metastatic CRPC patients with the same two dosing schedules that will receive 12 weeks of EPI-7386 therapy before initiating standard of care therapy. This will help gather important information on the activity of EPI-7386 in less heavily pretreated patients.
Combination Studies
While still very early, ESSA did provide an update on the combination trial of EPI-7386 and enzalutamide. Thus far there have been no DLTs, no Grade 3 or higher drug-related AEs, and the safety profile is consistent with second generation antiandrogens. While enzalutamide exposure is minimally impacted by EPI-7386 administration, EPI-7386 exposure is impacted by enzalutamide and it will require 3-4 dose cohorts to determine the optimal dose of each drug in combination.
Of the three patients who have been treated thus far, two of the patients achieved PSA90 within three months, as shown in the following figure. The third patient was discontinued from the study due to a concomitant medication that resulted in significantly lower exposure to both enzalutamide and EPI-7386.
In addition to the combination trial of EPI-7386 and enzalutamide, three additional combination trials will be taking place:
• Janssen will be conducting a two-arm Phase 1/2 clinical trial in mCRPC patients naïve to second generation antiandrogens to evaluate EPI-7386 in combination with Erleada® (apalutamide) and Zytiga® (abiraterone acetate).
• Bayer will be conducting a Phase 1/2 clinical trial in mCRPC patients that will evaluate EPI-7386 in combination with Nubeqa® (daralutamide).
• An investigator-sponsored neoadjuvant study will be conducted in prostate cancer patients undergoing prostatectomy for high-risk localized prostate cancer in which the combination of EPI-7386 and Nubeqa will be evaluated against Nubeqa® alone.
Conclusion
The encouraging early results presented by ESSA support its continued development in mCRPC patients as there are no signs of safety or tolerability issues and the drug is essentially performing as predicted by preclinical PK and ADME studies. There is clear evidence of target engagement and some modest anti-tumor activity seen, which is noteworthy given the molecular profile of the patients showing a very high percentage of them harbor non-AR-associated oncogenic drivers. The company now has a plan in place to select for earlier line patients that are more likely to respond to EPI-7386 therapy and we look forward to results from the dose expansion portion of the trial along with the combination trials, which at this point are most likely to deliver clinically meaningful results. Based on these results we have made a couple of changes to our model, including decreasing the probability of approval for EPI-7386 to 33% and due to the overall negative sentiment in the biotech sector we have raised the discount rate to 13%. This has resulted in a decrease in our valuation to $25 per share.
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