masofaniten (EPI-7386)

P2, N=35, Not yet recruiting, Pedro Barata, MD, MSc

P1/2, N=150, Recruiting, ESSA Pharmaceuticals

Conclusions With no safety concerns from cohorts 1-3, cohort 4 is currently enrolling at EPI-7386 BID + 160 mg QD Enz to evaluate optimal RP2Ds before the P2 component of the trial. Updated results, including cohort 4, will be presented.

P1b, N=3, Terminated, Janssen Research & Development, LLC | N=82 --> 3 | Trial completion date: Jun 2025 --> Sep 2022 | Suspended --> Terminated | Trial primary completion date: Jan 2024 --> Sep 2022; Administrative Decision

However, we recently demonstrated that EPI-7386, an AR NTD small molecule inhibitor, inhibits AR activity by binding to Tau5 region of the NTD. In summary, we report preclinical data on the first generation of ANITAC molecules, that can be orally bioavailable and show activity against forms of AR expressed in late stage CRPC patients.

In AR-V7 driven cell lines, LNCaP95 and 22Rv1, EPI-7386 showed superior activity to enzalutamide in inhibiting AR-regulated genes expression. The agent has the potential for providing clinical benefit as a single agent in patients whose tumors are progressing on anti-androgens or in combination with current anti-androgens in earlier line patients. The Phase I dose escalation first in human clinical trial of EPI-7386 single agent (NCT04421222) is currently enrolling.

Results EPI-7386 has an IC50 of 421 nM in LNCaP reporter assays, it inhibited both AR full-length and AR-V7 dependent gene expression and maintained antitumor activity in AR-V7-expressing tumor models, including in in vivo models resistant to enzalutamide (ENZ). Legal entity responsible for the study: ESSA Pharma Inc. Funding: ESSA Pharma Inc.

Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its transcriptional activity even in the presence of LBD-driven resistance.  EPI-7386 is a second-generation AR NTD inhibitor with excellent potency, metabolic stability and preclinical efficacy compared to first generation AR NTD inhibitor (“aniten”) EPI-506...EPI-7386 was able to induce tumor regression in CRPC xenografts and show single-agent superiority to enzalutamide (ENZ) in ENZ resistant models with a wide therapeutic range... EPI-7386 is a second-generation AR NTD inhibitor with excellent potency and metabolic stability.  Based on the results of preclinical efficacy models, this agent demonstrates the potential to be developed clinically both as a single agent in the setting of anti-androgen clinical resistance as well as in combination therapy with anti-androgens in earlier stages of the disease. Source of Funding: ESSA Pharmaceuticals Corp