Stenoparib is an investigational, orally-available small molecule targeted inhibitor of Poly ADP ribose polymerase (PARP), a key enzyme involved in DNA damage repair in cancer cells. Stenoparib was until August 2020 known as "2X-121".
How it Works
The drug candidate has a novel dual-inhibitory action against both PARP 1/2 and Tankyrase 1/2 (important regulators of canonical Wnt/β-catenin, a critical checkpoint in metastases, particularly in triple-negative breast cancer).
The molecule is also active in P-glycoprotein expressing cells, suggesting it may overcome PARP inhibitor resistance.
Based on its ability to pass through the blood-brain barrier, Stenoparib has potential to treat brain metastases and primary brain tumors.
Another PARP inhibitor Mefuparib has been shown to have promising antiviral activity against the virus that causes COVID-19, Oncology Venture is testing if Stenoparib possess comparable properties.
PARP inhibitor Stenoparib (formerly known as 2X-121) has shown in vitro anti-viral activity against Coronavirus in pre-clinical studies conducted at the Pathogen and Microbiome Institute at Northern Arizona University (NAU), a leading U.S. infectious disease test center.
Oncology Venture intends to work closely with the U.S. FDA and National
Institutes of Health (NIH) to advance Stenoparib as quickly as possible for the benefit of patients suffering from COVID-19 infection.
Background for Coronavirus studies
The PARP inhibitor, Mefuparib (CVL218), has been shown to have promising antiviral activity against the virus that causes COVID-19. See the pre-publication Y. Ge et. al, “A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19”. CVL218 was more potent than Remdesivir (an antiviral therapy) in blocking Coronavirus infection of cells and equally as potent as Remdesivir in blocking replication of virus once it has entered the cells.
Based on the promising results seen with CVL218, Oncology Venture will test the similar ability of its PARP inhibitor, Stenoparib, to block the infection of cells and replication of coronavirus in pre-clinical experiments, at the Pathogen and Microbiome Institute at Northern Arizona University, a leading U.S. infectious disease test center.
Several patients have been dosed at Dana-Farber Cancer Institute Boston with Stenoparib, a PARP inhibitor in development for advanced ovarian cancer. Stenoparib has previously shown promising results in ovarian cancer patients in a phase 1 study performed by EISAI. The DRP® selection, aimed to find the best responding patients, is under development in order to achieve an increased response rate in order to outperform currently marketed drugs for the same indication.
Additionally, OV-U.S. is collaborating with the NCI Pediatric Preclinical Testing Consortium (PPTC), funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to evaluate Stenoparib in pediatric cancers, including rare cancer types seen by the NCI, assuming Stenoparib demonstrates activity in the PPTC models. Positive response prediction signals have been identified, and preclinical studies are underway to evaluate Stenoparib against in vivo panels of certain pediatric tumors including neuroblastoma, sarcoma and renal tumors using different mouse models like SCID or other immunodeficient mice strains.
Stenoparib was previously evaluated in an open label, multi-center Phase 1/2 dose-ranging study in 41 patients with advanced solid tumors. Two patients had partial response and 13 patients had stable disease, with eight of these >24 weeks. No significant hematological toxicity and no Grade 4 or 5 adverse events were seen. The study abstract was presented at the 2018 the American Society for Clinical Oncology Clinical Meeting.
The ongoing and planned studies using the Stenoparib DRP are expected to significantly improve response rates seen in this first-in-human study.
A molecular model of Stenoparib
The mRNA-driven multiple biomarker DRP for this product candidate was validated in 2017 in a 13-patient blinded study. The DRP correctly predicted response to treatment with Stenoparib and overall survival with a p-value of 0.07 and a hazard ratio on overall survival of 0.26 in this study. Notably, this study also established the ability of the Stenoparib DRP to predict responders irrespective of BRCA mutation status (Plummer ER et al 2018; Access abstract).
Foegh M, Knudsen S. A multigene mRNA biomarker for the PARP/Tankyrase inhibitor 2X-121. Poster presented at: The PARP & DDR Inhibitors Summit 2020; 2020 Jan 28-30; Boston, MA.
Plummer ER et al. First-in-human phase 1 study of the PARP/tankyrase inhibitor 2X-121 (E7449) as monotherapy in patients with advanced solid tumors and validation of a novel drug response predictor (DRP) mRNA biomarker. J Clin Oncol 36, 2018 (suppl; abstr 2505).