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EPIX: Promising Early Data for EPI-7386 in Combination with Enzalutamide…

By David Bautz, PhD

NASDAQ:EPIX

READ THE FULL EPIX RESEARCH REPORT

Business Update

Positive Preliminary Results from Combination Therapy of EPI-7386 and Enzalutamide

On October 28, 2022, ESSA Pharma Inc (NASDAQ:EPIX) announced multiple poster presentations at the 29th Annual Prostate Cancer Foundation Scientific Retreat, including an update on the Phase 1/2 Study of EPI-7386 in combination with enzalutamide, an update on the Phase 1a dose escalation study of EPI-7386 as a monotherapy in mCRPC patients, and preclinical data on the company’s first-in-class N-terminal domain androgen receptor protein degrader (ANITAC™) program. Each of the posters can be found on ESSA’s website here.

Phase 1/2 Study of EPI-7386 in Combination with Enzalutamide (Enz) Compared with Enz Alone in Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC): Preliminary Results from the Phase 1 (P1) Dose-optimization Component of the Study

This is a Phase 1/2 multicenter, open label clinical trial of EPI-7386 in combination with a fixed dose of enzalutamide (NCT05075577). Seven patients have enrolled in the first two cohorts: three patients in cohort 1 (600 mg QD EPI-7386 + 120 mg QD Enz) and four in cohort 2 (800 mg QD EPI-7386 + 120 mg QD Enz). The following chart shows that the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 adverse events of fatigue and hot flash) with no dose-limiting toxicities (DLTs).

Pharmacokinetic (PK) results showed that Enz exposure was minimally impacted by EPI-7386 (below top figures), however EPI-7386 exposure was reduced by approximately 60-80% by Enz (below bottom figures). This was anticipated as Enz is a known CYP3A4 inducer. However, even with the reduction, observed EPI-7386 exposures remained in the clinically relevant range as suggested by preclinical xenograft studies.

Of the seven patients enrolled into the trial in the first two cohorts, one patient discontinued because after one cycle there was a drug-drug interaction with a concomitant medication (primidone, CYP3A4 inducer) that resulted in negligible exposure to EPI-7386. The following chart shows each of the seven patients' treatment duration and the fact that five of seven patients received prior chemotherapy.

The following chart shows the prostate specific antigen (PSA) responses for each of the patients, with the patient that discontinued denoted by the asterisk. Five of the six evaluable patients achieved PSA90 (a 90% decrease in PSA level from baseline) regardless of prior chemotherapy status.

These results compare favorably to historical controls, which are provided in the following table. The studies listed include those with Enz, abiraterone acetate, and one with abiraterone acetate + apalutamide. The PSA90 rates at 3 months range from 13% to 37%, with the overall PSA90 rates ranging from 14% to 53%. While the results presented by ESSA are very early, with only seven patients enrolled thus far, the fact that five out of six evaluable patients have achieved PSA90 is very encouraging. In addition, the PSA90 levels for ESSA are confirmed, meaning that there are more than one at that level, and they are sustained. In the AFFIRM trial of Enz in mCRPC patients previously treated with chemotherapy, a confirmed PSA90 by 3 months was associated with greater median OS, 12- and 16-month OS, median PSA PFS, median rPFS, and pain response (Armstrong et al., 2017). Thus, any treatment that can increase the percentage of patients that achieve PSA90 by three months could have a very positive impact in this population. Lastly, it should be noted that the results reported by ESSA were achieved with a 120 mg Enz dose. Based on the PK and safety data obtained thus far, the company is planning to increase the Enz dose to the standard 160 mg in cohort four.

Oral EPI-7386 in Patients with Metastatic Castration-Resistant Prostate Cancer: Results From the First-in-Human Dose Escalation Phase 1a Study

This is a Phase 1, multicenter, open label, dose escalation (Phase 1a) and expansion (Phase 1b) study to test the safety, PK, pharmacodynamics (PD), and antitumor activity of EPI-7386 in mCRPC patients progressing on standard of care treatment, including next-generation antiandrogens and chemotherapy. A total of 31 patients were enrolled in the QD cohorts and 8 in the BID cohorts. The following charts show that the 39 patients enrolled in the study had rapidly progressing disease as judged by the median baseline PSA doubling time of 2.5 months for the patients in the QD cohorts and 2.8 months for the patients in the BID cohorts.

EPI-7386 was well tolerated at all dose levels and schedules. All of the treatment related adverse events were Grade 1 or 2 (one occurrence of Grade 3 anemia was originally called treatment-related but later considered non-related). In addition, serious adverse events were uncommon and all were attributed to disease progression.

PSA decreases/stabilizations along with increases in PSA doubling time were seen in less pre-treated patients with no visceral disease and less DNA genomic aberrations in non-androgen receptor (AR) oncogenic pathways. The following figure shows the PSA changes for each patient along with both AR and non-AR mutations. Additional results showed a number of patients had decreases in circulating tumor DNA (ctDNA) and decreases in measurable target lesions even in those whose PSA levels were increasing.

To follow up on the data collected thus far in the Phase 1a portion of the trial, ESSA has selected two dose-schedules to be evaluated in two sequential cohorts in the Phase 1b portion of the trial: 600 mg BID and 600 mg QD. In addition, enrollment will be restricted to patients having ≤ 3 prior lines of therapy, no visceral disease, and no prior chemotherapy. The company will also be evaluating 600 mg BID in non-metastatic CRPC patients for 12 weeks prior to starting standard of care therapy.

Advances in the Development of a Targeted N-Terminal Domain Androgen Receptor Degrader (ANITAC) for the Treatment of Prostate Cancer

The company previously reported preclinical data on the first-generation androgen receptor (AR) ANITen bAsed Chimera (ANITAC™) N-terminal domain (NTD) degraders. Please see our previous report that provides background on targeted protein degradation (here). Below we provide an update on additional data recently presented by the company on its ANITAC development product EPI-8207.

The following graph shows AR degradation induced by EPI-8207 along with other development candidates. The important point from this data is that the company has produced a molecule (EPI-8684) with picomolar activity. The data are presented in relation to ARV-110, a protein degrader molecule being developed by Arvinas Therapeutics.

The following figure shows degradation of the AR with and without various mutations initiated by EPI-8207. The location of each of the mutations in the ligand binding domain (LBD) of the AR is also shown. This data shows that EPI-8207 is capable of degrading clinically relevant forms of AR.

AR degradation by EPI-8207 leads to a suppression of AR-regulated genes. The following figure shows the expression level of various genes under control of the AR. R1881 is the positive control, with EPI-8207-inactive being a negative control. The results for EPI-8207 are shown in relation to ARV-110, a PROTAC® protein degrader being developed by Arvinas Therapeutics (ARVN, which shows similar efficacy in suppressing AR-regulated gene expression.

Janssen Suspends Phase 1 Collaboration Trial

On October 31, 2022, ESSA announced that Janssen is suspending enrollment of the Phase 1 clinical trial of EPI-7386 with apalutamide or EPI-7386 with abiraterone acetate plus prednisone in mCRPC patients as a result of operational recruitment challenges. Thus far, Janssen has treated three mCRPC patients (all pre-chemotherapy) with the combination of EPI-7386 and apalutamide or abiraterone acetate plus prednisone for up to four months of therapy. Initial clinical activity showed that two of the three patients achieved PSA90 within 12 weeks. ESSA is now in discussions with Janssen to supply abiraterone acetate and apalutamide for a combination study that ESSA will sponsor.

Conclusion

The data provided on the combination trial of EPI-7386 and Enz are very encouraging, as the two drugs are well tolerated when dosed together and the fact that five out of six patients have achieved PSA90 compares very favorably to historical data. We look forward to additional updates on the combination trial along with the Phase 1b portion of the monotherapy trial. The ANITAC program is an exciting addition to the company’s pipeline and we look forward to additional updates as the company progresses that program to the clinic. With no changes to our model our valuation remains at $25 per share.

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