The Journal of Medicinal Chemistry Publishes Study Showing Potential of the Potent EED Inhibitor EEDi-5273 (APG-5918) to Achieve Complete Tumor Regression by Modulating the Epigenetics

Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced 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. 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.

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."

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong, S.A.R., China Limited with the stock code: 6855.HK.

Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of eight clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. HQP1351, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML), has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA. A New Drug Application (NDA) for HQP1351 has been submitted and subsequently granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China. To date, Ascentage Pharma has obtained a total of 12 ODDs from the US FDA for 4 of the company's investigational drug candidates.

Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights, and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs, and is setting up its world-class commercial manufacturing and Sales & Marketing teams. Ascentage Pharma aims to continuously strengthen its R&D capabilities and accelerate its clinical development programs to fulfil its mission of 'addressing unmet clinical needs in China and around the world' for the benefit of more patients.

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Source: Ascentage Pharma