RedHill Biopharma Ltd. (NASDAQ: RDHL) has announced the initiation of patient recruitment for a Phase 2 clinical trial evaluating the combination of opaganib and darolutamide in men with metastatic castrate-resistant prostate cancer (mCRPC). The study, sponsored by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd. (ANZUP) and supported by Bayer and Ramsay Hospital Research Foundation, represents a significant advancement in precision medicine approaches for advanced prostate cancer treatment.
Precision Medicine Strategy with Biomarker Selection
The innovative 60-participant, double-blind, placebo-controlled randomized study employs a companion lipid biomarker test called PCPro to select mCRPC patients with poor prognosis who are most likely to benefit from the opaganib and darolutamide combination. Led by Professor Lisa Horvath from Sydney's Chris O'Brien Lifehouse, the trial will recruit patients across at least 10 sites in Australia and New Zealand.
The study design involves screening 200 patients with prostate cancer for eligibility, with 5-ml plasma samples taken for PCPro testing. Those who test PCPro-positive (estimated 40% of patients) will be randomized on a 1:1 ratio to receive either darolutamide 600mg twice daily plus placebo (n=30) or darolutamide 600mg twice daily plus opaganib 500mg twice daily (n=30). The study is registered on clinicaltrials.gov (NCT04207255).
Mechanism of Action and Treatment Rationale
The combination therapy targets a critical challenge in prostate cancer treatment: resistance to androgen receptor pathway inhibition (ARPI). Cancer cells can block apoptosis (programmed cell death), a crucial process for eliminating abnormal cells and fighting cancer spread. Prior research demonstrates that opaganib enhances androgen receptor signaling inhibitor efficacy in vitro through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS).
The study's primary endpoint is improved 12-month radiographic progression-free survival (rPFS), with several secondary and exploratory endpoints also being evaluated. The target population includes mCRPC patients who have not received treatment with newer, potent AR signaling inhibitors including darolutamide, enzalutamide, apalutamide, or abiraterone.
Addressing Significant Disease Burden
Prostate cancer represents the second most diagnosed cancer globally, with approximately 1.5 million new cases annually and nearly 400,000 deaths each year. The global prostate cancer market was valued at approximately $12 billion in 2023. The disease burden has increased substantially, with cases rising by almost 120% from 1990 to 2019.
The prognosis for advanced prostate cancer remains challenging. While five-year survival rates for Stage 1 prostate cancer reach 100%, this drops dramatically to just 28% for patients with Stage 4 (advanced) disease. When prostate cancer spreads beyond the prostate to other parts of the body, such as lymph nodes or bones, it is classified as advanced or metastatic prostate cancer.
Opaganib's Broad Therapeutic Potential
Opaganib (ABC294640) is a first-of-its-kind proprietary investigational host-directed drug with anticancer, anti-inflammatory and antiviral activity. The compound works through inhibition of multiple pathways, induction of autophagy and apoptosis, and disruption of viral replication via simultaneous inhibition of three sphingolipid-metabolizing enzymes.
The drug has demonstrated safety and tolerability in more than 470 people across multiple clinical studies and expanded access use. Opaganib has received several orphan-drug designations from the FDA in oncology and other diseases, and has undergone studies in advanced cholangiocarcinoma (Phase 2a) and prostate cancer.
Strategic Significance for RedHill
This study marks a key step in RedHill's development of opaganib in oncology, complementing its U.S. Government-supported medical countermeasures and infectious diseases programs. The company is a specialty biopharmaceutical company primarily focused on U.S. development and commercialization of drugs for gastrointestinal diseases, infectious diseases and oncology.
RedHill's clinical pipeline includes multiple late-stage development programs beyond opaganib, including RHB-204 for Crohn's disease and pulmonary nontuberculous mycobacteria disease, RHB-107 for COVID-19 and other indications, and RHB-102 for various gastrointestinal conditions.
Collaborative Research Framework
The study benefits from strong institutional partnerships, with ANZUP serving as the leading cancer-cooperative clinical trials group that brings together professional disciplines involved in researching and treating urogenital cancers. ANZUP's mission focuses on improving lives of people affected by bladder, kidney, testicular, penile and prostate cancers.
Chris O'Brien Lifehouse, a comprehensive cancer hospital based in Sydney, Australia, specializes in complex and rare cancers, offering patients comprehensive services under one roof. The Ramsay Hospital Research Foundation, established in 2017, supports healthcare delivery improvements and patient outcome enhancement in Australia.
