ralaniten acetate (EPI-506) / ESSA Pharma - LARVOL DELTA

EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 update on safety, tolerability, pharmacokinetics and efficacy (ESMO 2017) - P1/2; "...Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally...Inclusion criteria include: mCRPC with progression after > =1 line of hormonal therapy or chemotherapy, failure to treatment with enzalutamide and/or abiraterone...EPI-506 is well-tolerated with an acceptable safety profile. PK indicates dose-proportionality. PSA declines and stable disease have been observed at higher dose cohorts in this ongoing study."

Clinical • P1 data • Prostate Cancer

Modeling mechanisms of acquired ralaniten resistance to promote drug discovery and optimize clinical responses (EORTC-NCI-AACR 2018) - P1/2; "We have generated a model of acquired ralaniten resistance, and demonstrated that selective modification of ralaniten can improve drug stability by reducing its metabolism by glucuronidation. LNCaP-RALR cells remain dependent upon AR signalling, and are sensitive to both EPI-045 and antiandrogens used clinically. This work highlights the potential for combination or sequential therapy following ralaniten resistance, and will hopefully drive the discovery of additional AR-NTD inhibitors."

Clinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Combination of an antagonist to the androgen receptor N-terminal domain with enzalutamide for the treatment of castration resistant prostate cancer (AUA 2019) - "...Recently the PLATO trial showed that the addition of abiraterone to ongoing ENZ did not improve progression-free survival in patients with castration resistant prostate cancer (CRPC)...Both AR and truncated AR-Vs require a functional N-terminal domain (NTD) for activity and hence first-in-class antagonists of the AR NTD have been developed such as EPI-002 (ralaniten)... The role of AR-Vs in the mechanism of ENZ resistance was provided by knockdown experiments and response to EPI-7170. Synergic inhibition was achieved with a combination of EPI-7170 with ENZ. These results suggest that targeting AR-NTD in addition to AR-LBD to block both FL-AR and AR-Vs could be a potential treatment option for CRPC."

Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. (ASCO-GU 2019) - P1/2; "EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites."

Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. (ASCO-GU 2019) - P1/2; "EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites."

P1 data

Molecular characterization of next generation AR-NTD inhibitors (AACR-NCI-EORTC 2022) - P1, P1/2 | "Ralaniten acetate (EPI-506, NCT02606123) and next generation EPI-7386 (NCT04421222) remain the only AR-NTD inhibitors to have progressed to clinical trials. Here we characterize the molecular profile of several next generation AR-NTD inhibitors compared against traditional AR-LBD antagonist enzalutamide (ENZA). LNCaP and LN95 cells treated with EPI-002, EPI-7170 or ENZA were subjected to RNA-seq to identify differences in mechanisms of action for each class of inhibitor... We identified clear differences in the mechanisms of action between traditional AR-LBD inhibitor enzalutamide and AR-NTD inhibitors; in terms of AR-regulated gene expression, disruptions to the cell cycle and DNA damage response. This work highlights the potential for combination therapies which utilize both classes of inhibitors. An ongoing clinical trial is currently investigating EPI-7386 in combination with enzalutamide (NCT05075577)."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • NCOR1 • TBL1XR1

Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies. (PubMed, Pharmacol Res) - "Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors."

Journal • Review • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CTNNB1

Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone. (ASCO 2017) - P1/2; "EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies."

Biosimilar • Prostate Cancer

Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors. (PubMed, Adv Exp Med Biol) - "This chapter will provide an introduction of the structure and function of the domains of nuclear hormone receptors, followed by a discussion of the rationale supporting the development of N-terminal domain inhibitors. Chemistry and mechanisms of action of small molecule inhibitors will be described with emphasis on N-terminal domain inhibitors developed to the androgen receptor including those in clinical trials."

Journal • AR

Differential Gene Expression Profiles between N-Terminal Domain and Ligand-Binding Domain Inhibitors of Androgen Receptor Reveal Ralaniten Induction of Metallothionein by a Mechanism Dependent on MTF1. (PubMed, Cancers (Basel)) - "In addition, these studies revealed a unique and strong induction of expression of the metallothionein family of genes by ralaniten by a mechanism independent of AR and dependent on MTF1, thereby suggesting this may be an off-target. Due to the relatively high doses that may be encountered clinically with AR-NTD inhibitors, identification of off-targets may provide insight into potential adverse events, contraindications, or poor efficacy."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • MFI2

A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer. (PubMed, Invest New Drugs) - "This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development."

Clinical • Journal • P1 data • PK/PD data • Fatigue • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor

Cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ralaniten analogues for the treatment of androgen receptor-positive prostate and breast cancers. (PubMed, Mol Cancer Ther) - "Androgen receptor (AR) has essential roles in the growth of prostate cancer and some breast cancers. Importantly, sequential combination treatments with palbociclib administered first then followed by EPI-7170, resulted in more cells accumulating in G1 and less cells in S phase than concomitant combination which was presumably because each inhibitor has a unique mechanism in modulating the cell cycle in cancer cells. Together these data support that the combination therapy was more effective than individual monotherapies to reduce tumor growth by targeting different phases of the cell cycle."

Combination therapy • Journal • Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

[VIRTUAL] Preclinical and clinical pharmacology of EPI-7386, an androgen receptor N-terminal domain inhibitor for castration-resistant prostate cancer. (ASCO-GU 2021) - P1 | "Compared to the first generation aniten, EPI-506, which showed poor pharmacokinetic properties in patients, EPI-7386 is metabolically stable in vitro and in vivo. Pre-clinical characterization predicts that EPI-7386 has the appropriate PK and metabolic properties to afford exposure in patients at potentially efficacious levels following once-daily oral administration. PK measurements in the initial cohort of patients treated in the Phase 1 study will be presented."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CYP1A2 • CYP3A4

Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor. (PubMed, Commun Biol) - "Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC."

Clinical • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Isolation and characterization of castration-resistant prostate cancer LNCaP95 clones. (PubMed, Hum Cell) - "Seven clones from the LNCaP95 cell line were isolated and characterized using morphology, in vitro growth rate, and response to ralaniten (AR N-terminal domain inhibitor) and enzalutamide (antiandrogen). In castrated immunodeficient animals, the growth of subcutaneous xenografts of the D3 clone was the most reproducible compared to the parental cell line and other clones. These data support that the enzalutamide-resistant LNCaP95-D3 subline may be suitable as a xenograft tumor model for preclinical drug development with improved reproducibility."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants. (PubMed, Cancers (Basel)) - "Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer. (PubMed, Mol Oncol) - "Resistance of castration-recurrent prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD...In addition, this drug enhanced the anti-tumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC."

Combination therapy • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

[VIRTUAL] Pre-clinical development of the second-generation N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer (AACR-II 2020) - "Additionally, EPI-7386 also demonstrated remarkable activity in several models in vivo, including a CRPC patient derived xenograft (PDX) resistant to enzalutamide (ENZ). The second generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It has a favorable safety and ADME profile, with predicted long half-life in human, supporting once daily dose. In vivo, EPI-7386 demonstrated potential as a single agent in overcoming anti-androgen clinical resistance as well as in combination therapy."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • FKBP5 • KLK3 • STEAP4 • UBE2C

[VIRTUAL] The preclinical characterization and development of EPI-7386, an N-terminal domain androgen receptor inhibitor, for the treatment of prostate cancer (AUA 2020) - "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"

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies. (PubMed, ACS Pharmacol Transl Sci) - P1/2 | "Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors."

Journal • AR

Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor. (PubMed, Expert Opin Drug Discov) - "The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.Expert opinion: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins."

Journal • AR

Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor (AACR-NCI-EORTC 2019) - "Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model...Conclusion The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506...As a single agent, EPI-7386 may overcome anti-androgen clinical resistance in advanced mCRPC as well as potentially in combination therapy with anti-androgens in earlier stages of the disease. The clinical strategy supporting the development of this Aniten N-terminal domain inhibitor of AR will be discussed."

Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P1/2; N=28; Terminated; Sponsor: ESSA Pharmaceuticals; N=166 ➔ 28; Active, not recruiting ➔ Terminated; Trial primary completion date: Mar 2018 ➔ Dec 2017; Trial completion date: Dec 2018 ➔ Dec 2017; At end of Phase 1 excessive high pill burden (18 capsules/day)

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P1/2; N=166; Recruiting; Sponsor: ESSA Pharmaceuticals; Trial primary completion date: Mar 2017 ➔ Mar 2018

Clinical • Trial primary completion date

Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P1/2; N=166; Recruiting; Sponsor: ESSA Pharmaceuticals

Clinical • New P1/2 trial