On October 18, 2021 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that a research team led by Prof. Shaomeng Wang, Ph.D., Co-Founder and Chief Scientific Advisor of Ascentage Pharma, and Warner-Lambert/Parke-Davis Professor in Medicine, Professor of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, has recently published a paper in the renowned Journal of Medicinal Chemistry demonstrating the highly promising therapeutic potential of the embryonic ectoderm development (EED) inhibitor, EEDi-5273 (APG-5918), and the compound’s ability to achieve complete and persistent tumor regression by modulating the epigenetics and microenvironment of tumors and overcoming drug resistance (Press release, Ascentage Pharma, OCT 18, 2021, View Source [SID1234591479]). Ascentage Pharma has obtained the exclusive global development rights to EEDi-5273 and is currently actively preparing to submit an Investigational New Drug (IND) application for this drug candidate.
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This paper published by Dr. Shaomeng Wang’s research team was titled Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression. The study found that the oral administration of EEDi-5273 is capable of achieving complete and persistent tumor regression in the KARPAS422 xenograft model in mice. As an exceptionally potent novel EED inhibitor that is capable of epigenetic modulations, EEDi-5273 has broad therapeutic potential in the treatment of multiple hematologic malignancies, solid tumors, and non-oncologic indications.
According to the paper, the polycomb repressive complex 2 (PRC2) is a protein complex that consists core subunits including the enhancer of zeste homolog 2 (EZH2), EED, and suppressor of zeste 12 (SUZ12). Of these components, EED allosterically stimulates the methyltransferase activity of EZH2 through its binding to H3K27me3. Therefore, EED inhibitors can theoretically produce antitumor effects similar to that of EZH2 inhibitors, and deliver even more potent antitumor activity by overcoming resistance to EZH2 inhibitors while simultaneously inhibiting EZH2 and EZH1. In 2017, scientists from Novartis and AbbVie reported their discovery of A-395 and EED226, respectively, as allosteric inhibitors of EED. To date, only two EED inhibitors, MAK683 from Novartis and FTX-6058 from Fulcrum Therapeutics, have progressed into clinical development.
Previous preclinical and clinical studies have shown the broad therapeutic potential of EZH2/EED inhibitors in the treatment of multiple tumor types and non-oncologic indications. EZH2/EED inhibitors also have immunomodulatory functions that can render "cold" tumor "hot" through mechanisms such as antigen presentation, thus enhance tumor response to immune-checkpoint inhibitors, leading to improved antitumor efficacy. Clinical studies investigating the immunomodulatory functions of EZH2/EED inhibitors are currently ongoing. By bolstering the expression of fetal hemoglobin (HbF), EEH inhibitors may also achieve therapeutic effects in the treatment of multiple subtypes of anemia associated with low levels of hemoglobin.
Compared to A-395 and EED226, EEDi-5273 has higher binding affinity to EED and more potent cell growth inhibitory activity in the KARPAS422 cell line carrying a Y641N EZH2 mutation. In the KARPAS422 xenograft model, EEDi-5273 at 50mg/kg achieved complete tumor regression after 5 weeks of treatment and maintained the complete regression until at least day 114, thus demonstrated persistent antitumor activity. Meanwhile, ADME and PK studies of EEDi-5273 have demonstrated excellent drugability. In these studies, EEDi-5273 did not display obvious inhibitory and inducive activity in cytochrome P450 (CYP) enzymes, signaling a low risk of drug-drug interactions. In the plasma of all tested preclinical species and human, EEDi-5273 has demonstrated a half-life of over 2 hours, showing an excellent plasma stability. Collectively, data from this study showed that EEDi-5273 represents a highly promising EED inhibitor.
Dr. Shaomeng Wang said: "ED inhibitors have the promising therapeutic potential for the treatment of human cancers carrying EZH2 mutations and other types of human cancers, as well as other human diseases such as sickle cell anemia. Our data suggest that EEDi-5273 (APG-5918) possess an excellent profile as a development candidate and has the potential to become the best-in-class EED inhibitor."
Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma, commented: "These findings by Dr. Wang’s team are indeed very exciting, as they further validated APG-5918 as a highly promising EED inhibitor with the most potent vitro activity and impressive in vivo efficacy, thus provide solid preclinical data supporting our future clinical development of the compound. EED inhibitors have broad clinical applications and enormous therapeutic potential especially in the treatment of non-oncologic indications. We will press forward with the development of APG-5918 and advance the compound to the clinical-stage as soon as possible in effort to bring a novel therapeutic to patients in need."