EPIX: Additional Preclinical Data Shows EPI-7386 Inhibits AR-Driven Transcription…

By David Bautz, PhD

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Additional Preclinical Data Presented at AACR 2021

On April 10, 2021, ESSA Pharma, Inc. EPIX announced the presentation of encouraging preclinical data at the 2021 American Association of Cancer Research (AACR) annual meeting. A copy of the presentation can be found here. The data presented by ESSA builds on previous preclinical research presented by the company showing that EPI-7386, the company's lead small molecule inhibitor of the N-terminal domain, binds to the full-length androgen receptor (AR), inhibits the transcription of AR-driven genes, and interacts with the AR splice variant AR-V7 (which lacks the ligand binding domain and thus leads to resistance to the current anti-AR therapies).

The following graphs show the results of reporter gene expression assays and a cell viability assay in CWR-R1 cells that express either full-length AR (CWR-R1-AD1) or the ARv567es splice variant (CWR-R1-D567), in which exons 5, 6, and 7 of the AR gene are deleted. Arv567es is one of two splice variants frequently found in human metastatic castration-resistant prostate cancer (mCRPC) samples and it typically portends rapid tumor progression (Hörnberg et al., 2011). The graph on the left shows that increasing concentrations of both EPI-7386 and enzalutamide results in decreased AR-driven gene expression. The middle graph shows that EPI-7386 is able to inhibit AR-driven gene expression in cells that express the ARv567es splice variant while enzalutamide does not. The graph on the right shows that EPI-7386 decreases cell viability in the CWR-R1-D567 cell line both in the presence and absence of R1881, a synthetic androgen.

Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed that EPI-7386 inhibits AR binding to genomic DNA. ChIP-seq is a method to analyze protein interactions with DNA and can identify global binding sites for a protein such as the AR. ChIP-seq starts with DNA-protein complexes being crosslinked together, antibodies specific for the protein of interest are used to immunoprecipitate the DNA-protein complexes, and the DNA is then extracted and sequenced. The following graph shows the number of binding events detected for the AR per 1000 LNCaP cells for various genes after six and 24 hours of treatment. The large number of binding events in the presence of R1881 is indicative of the AR's ability to induce gene expression, while the decreased number of binding events in the presence of R1881 + EPI-7386 shows that the drug is able to inhibit the binding of the AR to DNA and thus decrease expression of AR-driven genes.

When examining transcriptional activity, EPI-7386 inhibits AR-driven gene expression in a similar manner to enzalutamide, however combination treatment with both drugs results in a broader and deeper inhibition. The following heat map shows the top 50 R1881-responsive genes in LNCaP cells that are up-regulated (red) or down-regulated (blue) more than three-fold by single agent and combination treatment. Treatment with EPI-7386 or enzalutamide decreases the expression of a number of the R1881-responsive genes (denoted by the light red/white/blue colors compared to the dark red in the R1881 only column) while combination therapy further decreases the expression of those R1881-responsive genes so their expression more resembles the genes that are R1881-repressed.

Similar results are seen in the VCaP model, which is initially driven by full-length AR but is then followed by AR-V7-driven growth. The following heatmap again shows decreased gene expression for R1881-activated genes following treatment with EPI-7386 or various ‘lutamide drugs (enzalutamide, ENZ; daralutamide, DAR; apalutamide, APA). However, the greatest change in gene expression is seen with combination therapy of EPI-7386 and a ‘lutamide, which is very encouraging since VCaP cell growth is driven in part by AR-V7, which confers resistance to treatment with ‘lutamide monotherapy.

To summarize, the data presented by ESSA at the 2021 AACR meeting show that EPI-7386 prevents AR-driven gene expression for both full-length AR and AR splice variants (AR-V7 and ARv567es). In addition, combination therapy with EPI-7386 and a ‘lutamide results in broader and deeper inhibition of the AR pathway than monotherapy treatment with either compound.

ESSA has previously presented initial Phase 1 data from a monotherapy study of EPI-7386 in patients with mCRPC (see here for our analysis of that data), and the trial is currently dosing the 800 mg cohort. In addition, the company has recently entered clinical trial partnerships with Janssen and Astellas to examine combination therapy of EPI-7386 with apalutamide or abiraterone acetate + prednisone and enzalutamide, respectively. The combination treatment data shown above increases our confidence that combination therapy will lead to positive clinical outcomes and we eagerly await initial results from those trials.

Conclusion

The preclinical data presented at AACR 2021 adds to a growing body of evidence suggesting that treatment of mCRPC patients with EPI-7386 is likely to result in a clinical benefit and we look forward to additional data from the ongoing Phase 1 clinical trial of EPI-7386 and the planned combination therapy trials later in 2021. With no changes to our model our valuation currently stands at $40 per share and ESSA remains one of our top picks among our small-cap biotech coverage universe.

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