EPIX: Initial Data from Combination Trial of Masofaniten and Enzalutamide Expected in 2024…
NASDAQ:EPIX
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Business Update
Update on Masofaniten Clinical Programs
ESSA Pharma Inc. (NASDAQ:EPIX) is developing masofaniten (EPI-7386), its next-generation antigen molecule that is designed to target the N-terminal domain (NTD) of the androgen receptor (AR) as a treatment for prostate cancer. Masofaniten is currently being evaluated in two clinical trials: EPI-7386-CS-001 and EPI-7386-CS-010.
EPI-7386-CS-001 has a monotherapy and combination arm in patients with metastatic castration resistant prostate cancer (mCRPC). The company completed the Phase 1a dose escalation portion of the monotherapy arm in which 600 mg QD and 600 mg BID were the two doses selected to advance into the dose expansion portion of the trial. For the dose expansion portion of the study, the 600 mg BID cohort of 12 patients has been fully enrolled and the 600 mg QD cohort is currently enrolling. Trial EPI-7386-CS-001 also has a combination component: Cohort 1 is evaluating masofaniten with abiraterone acetate/prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) or mCRPC; Cohort 2 is evaluating masofaniten 600 mg BID for a limited window of time (up to 12 weeks before patients start standard of care) in non-metastatic CRPC (nmCRPC) patients. Following the 12-week dosage of masofaniten, the company will evaluate masofaniten in combination with apalutamide.
EPI-7386-CS-010 is a combination trial of masofaniten and enzalutamide (Enz). The company has completed the dose escalation portion of the trial (see below for results recently presented) and the recommended Phase 2 combination doses are masofaniten 600 mg BID and Enz 160 mg. The trial is currently enrolling and we anticipate an update from the company on timing of the first data release after the trial has been ongoing for a few months.
Dose Escalation Data Presented at ESMO 2023
In October 2023, ESSA announced that updated data from the dose escalation portion of the Phase 1/2 trial of masofaniten and Enz was presented at the 30th Annual Prostate Cancer Foundation Scientific Retreat. A copy of the poster can be found here.
The Phase 1 portion of the study enrolled 18 patients in four dose cohorts, with 16 patients evaluable for efficacy as per protocol. The following table gives an overview of the patients baseline characteristics for each dosing cohort.
The combination of masofaniten and Enz is safe and well tolerated, with an adverse event profile that is consistent with single-agent Enz. The following table shows that the most frequent adverse events (AEs) were either related to androgen receptor inhibition or gastrointestinal tract irritation and were Grade 1 or 2 in severity. In Cohort 4, there was a report of a Grade 3 rash that was deemed to be possibly related to study drug. It was observed after administration of masofaniten and Enz in combination during the dose-limiting toxicity period. The patient has since discontinued the study due to disease progression. It should be noted that the monotherapy study of masofaniten did not report a similar rash, while Enz’s Phase 1 dose escalation study had a rash as a dose limiting toxicity at higher Enz exposures.
To investigate drug-drug interactions (DDIs), a 7-day run-in period with masofaniten was initiated at the beginning of Cycle 1 for each dose before introducing Enz. Serum levels of masofaniten, Enz, and N-desmethyl Enz were measured. The results show that masofaniten does not affect the metabolism of Enz with similar PK parameters regardless of the dose of masofaniten or Enz. However, Enz does affect the metabolism of masofaniten, resulting in a decrease in PK parameters such as AUC and Cmax. After switching the masofaniten dosing from 600 mg QD to 600 mg BID, the drop in exposure caused by Enz was partially mitigated and masofaniten stayed at clinically relevant levels.
The following chart shows the current patient disposition. Of the 18 patients enrolled in the trial, 13 are still on treatment and five have discontinued (disease progression = 3; brain abscess = 1 (non-related event); non-cancer related death = 1). Of the 18 enrolled patients, 13 have non-measurable disease while five have measurable disease. Of the five with measurable disease, two had a partial response, two had stable disease, and one had progressive disease.
Across all dosing cohorts, patients showed a rapid, deep, and durable decrease in prostate-specific antigen (PSA). The following chart shows the PSA outcomes for all enrolled patients, including for patients from Cohort 4. The current response rates in evaluable patients show that 88% (14/16) have achieved PSA50 (a 50% decrease in PSA levels from baseline), 81% (13/16) have achieved PSA90 (a 90% decrease in PSA levels from baseline), and 56% (9/16) have achieved PSA <0.2 ng/mL. In addition, the graph in the upper right shows the time to PSA progression and how that compares to the Phase 3 PREVAIL trial and the P3 AFFIRM trial, which examined Enz in the pre-chemotherapy and post-chemotherapy setting, respectively.
While difficult to do cross-trial comparisons, the Phase 3 clinical trials of Enz show what is to be expected when treating patients either pre-chemotherapy (PREVAIL trial; Beer et al., 2014) or post-chemotherapy (AFFIRM trial; Scher et al., 2012) with single agent Enz. The following table summarizes the data from those trials in regards to PSA response.
PSA response is an important prognosticator, as it was shown to be correlated with a number of positive outcomes from the PREVAIL study (Armstrong et al., 2019). This agrees with multiple other studies of hormone-sensitive prostate cancer (HSPC) patients that show greater PSA responses are associated with better long-term prognoses. In addition, PSA response was shown to correlated with five-year survival in the PREVAIL study:
• Armstrong et al., 2020: This was a long-term safety and efficacy analysis of the PREVAIL trial that evaluated 5-year survival and its correlation with various pretreatment prognostic factors and post-treatment PSA declines. The results showed that the 5-year survival rate for those with a best overall PSA decline of < 0.2 ng/mL was 71% compared to just 11% for those with no PSA decline or < 30% confirmed decline. Even for those who achieved PSA90, the 5-year survival rate was only 42%. This exemplifies the importance of achieving PSA < 0.2 ng/mL and how that can have a positive impact on long-term survival. Approximately 11% (100/872) of patients treated with Enz in PREVAIL achieved PSA < 0.2 ng/mL.
PSA responses of < 0.2 ng/mL do not appear to be commonly reported in studies of mCRPC patients, however the Phase 3 ACIS study showed that 25% of mCRPC patients treated with apalutamide plus abiraterone acetate and prednisone achieved a PSA level < 0.2 ng/mL at any time during treatment compared to 19% treated with just abiraterone acetate and prednisone (Saad et al., 2021).
Financial Update
On December 12, 2023, ESSA announced financial results for the fourth quarter and full year for fiscal year 2023 that ended September 30, 2023. For fiscal year 2023, the company reported a net loss of $26.6 million, compared to a net loss of $35.1 million for fiscal year 2022. R&D expenses for fiscal year 2023 were $21.3 million compared to $24.4 million for fiscal year 2022. The decrease was primarily attributable to decreases in preclinical and data analysis, share-based compensation, and manufacturing costs. G&A expenses for fiscal year 2023 were $10.8 million compared to $12.5 million for fiscal year 2022. The decrease was primarily due to lower insurance renewal premiums and lower non-cash share-based payments.
As of September 30, 2023, ESSA had approximately $148.1 million in cash, cash equivalents, and short-term investments. We estimate this is sufficient to fund operations at least through 2025. As of December 11, 2023, the company had approximately 44.1 million shares outstanding and, when factoring in stock options and warrants, a fully diluted share count of approximately 55.2 million.
Conclusion
We look forward to initial data from the dose expansion portion of the Phase 2 trial of masofanitan and Enz in 2024, and we anticipate the company sharing when that initial data will be available once that portion of the trial has been going on for a few months. We have advanced our DCF model ahead one year, which has increased our valuation to $29 per share.
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