ESSA Pharma (EPIX) 2024 Cantor Fitzgerald Global Healthcare Conference summary

Strategic focus and clinical development

• Targeting androgen-driven transcription in prostate cancer by inhibiting the N-terminal domain of the androgen receptor, aiming for more complete androgen inhibition when combined with anti-androgens.

• Current main effort is a randomized phase II trial comparing enzalutamide alone versus enzalutamide plus masofaniten in first-line metastatic CRPC, with 120 patients targeted for enrollment and primary readout expected mid-next year.

• Additional phase I studies are ongoing with abiraterone and apalutamide, and investigator-sponsored trials are exploring combinations in neoadjuvant and metastatic castrate-sensitive settings.

• The drug is oral, well-tolerated, and designed to be combinable with all major anti-androgens, with a focus on early-stage, AR-driven patient populations.

• Strategic goal is to demonstrate improved efficacy without added toxicity, with future phase III studies likely requiring a partner.

Mechanism of action and resistance

• Masofaniten inhibits the N-terminal domain, which is essential for androgen receptor transcriptional activity, overcoming resistance mechanisms affecting the C-terminal domain.

• The N-terminal domain is intrinsically disordered, making drug development challenging, but masofaniten was developed through extensive academic and chemical research.

• Preclinical data show that combining N- and C-terminal inhibition leads to more complete androgen receptor blockade.

• Resistance in late-stage disease is driven by multiple genomic alterations beyond AR, limiting monotherapy efficacy in these settings.

Clinical results and trial design

• Phase I combination with enzalutamide in first-line metastatic CRPC showed an 88% PSA90 rate, notably higher than historical rates for enzalutamide monotherapy (47% in PREVAIL, up to 62% in other studies).

• Durability of response and radiographic progression-free survival are trending positively, with safety maintained at the selected 600 mg BID dose.

• The phase II trial is powered to detect differences in PSA90, a strong correlate of progression-free survival, and uses a 2:1 randomization (masofaniten+enzalutamide vs. enzalutamide alone).

• Ongoing studies in earlier patient populations and with other anti-androgens will inform future phase III trial design and patient selection.