SUZHOU, China and ROCKVILLE, Md., Nov. 10, 2022 /PRNewswire/ — 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 its novel inhibitor of the embryonic ectoderm development (EED) protein, APG-5918, has been approved by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) to enter a Phase I study in patients with advanced solid tumors or hematologic malignancies. Following the recent clearance for the study in the US, this approval in China marks another milestone for the company’s strategy of simultaneous clinical development in the two countries. APG-5918 is the first domestically developed novel EED inhibitor entering clinical development in China.
This multicenter, open-label Phase I dose-escalation and dose-expansion study is designed to assess the safety, pharmacokinetics, and efficacy of orally administered APG-5918 in patients with advanced solid tumors or hematologic malignancies. Prof. Ruihua Xu, President and Director of Sun Yat-Sen University Cancer Center, and President of the Chinese Society of Clinical Oncology, will be the principal investigator of this study.
EZH2, which is highly expressed in multiple tumors in humans, was found to promote the development and progression of tumors, and targeted inhibition of EZH2’s methyltransferase activity has already proved to be an effective mechanistic approach for cancer treatment. However, the secondary mutation of EZH2 may lead to acquired drug resistances, while the homologous EZH1 also has methyltransferase (MTase) activity that could limit the effects of EZH2 inhibitors. Studies have shown that the PRC2 complex’s component proteins and EZH2’s histone (MTase; HMTase) activities are highly dependent on the scaffold and modulating effects of EED. Compounds with inhibitory effects on EED, a subunit of PRC2, can disrupt the protein-to-protein interaction between EED and EZH2, culminating in damaged PRC2 functions, H3K27me3-induced silencing of PRC2 expressions, and blockade of the triple-methylation of H3K27.1 Therefore, allosteric targeting of EED has in recent years gained a great deal of traction as a promising approach for inhibiting the replacement of inactivated PRC2.
Discovered and developed by Ascentage Pharma, APG-5918 is an orally active, potent, selective, small-molecule EED inhibitor with high binding affinity. APG-5918 can regulate the epigenetics of tumors and the tumor microenvironment, and therefore has broad therapeutic potential for the treatment of hematologic malignancies, solid tumors, and nononcologic conditions. APG-5918 can selectively bind to the H3K27me3 domain of the EED protein, leading to the conformational changes to H3K27me3’s binding pockets in the EED protein, which can then block EED from interacting with the histone methyltransferase EZH2. Preliminary data showed that APG-5918 has in vitro antiproliferative activity in various tumor cell lines and antitumor activity in patient-derived xenograft (PDX)/cell line-derived xenograft (CDX) models of EZH1-mutant B-cell non-Hodgkin lymphoma, IN1-negative malignant rhabdoid tumor, BAP1-mutant mesothelioma and prostate cancer.
Prof. Ruihua Xu commented, “Targeting PRC2 complex proteins, especially the EED, may be an effective mechanistic approach for treating cancer patients with certain genetic profiles. In both in vitro studies and in vivo studies in animal models, the EED inhibitor APG-5918 has shown clear targeted binding and target-based antitumor activity, thus warranting further clinical evaluations.”
Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, “This approval of the clinical study of APG-5918 in China came shortly after the clearance for the study in the US, hence signals major progress in Ascentage Pharma’s efforts to simultaneously advance clinical programs in China and the US, and is also a strong testament to our global innovation capabilities. We look forward to closely collaborating with Prof. Xu to advance the clinical development of APG-5918, which we hope will offer a novel therapeutic to patients in need.”
1. Erokhin M, Chetverina O, Győrffy B, Tatarskiy V V, Mogila V, Shtil AA, et al. Clinical correlations of polycomb repressive complex 2 in different tumor types. Cancers 2021;13:3155.
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 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 9 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 1/2 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.
Olverembatinib, 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 four 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. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients.
The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.