SUZHOU, China and ROCKVILLE, Md., Aug. 27, 2020 /PRNewswire/ — Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that preclinical study results of the company’s novel inhibitor of apoptosis proteins (IAP) antagonist APG-1387 in the treatment of CHB infection have been presented in an oral presentation at the Digital International Liver Congress™ 2020 (Digital ILC 2020) held by the European Association for the Study of the Liver (EASL). Prof. Xiaoyong Zhang from the Department of Infectious Diseases at Southern Medical University (Guangzhou, China) was the presenter.
EASL is a leading authoritative association for the study of liver diseases in the world. The International Liver Congress (ILC) is EASL’s annual flagship congress which often has significant influence in shaping and informing hepatology research globally by providing clinician expertise in best practices and disseminating the latest scientific breakthroughs in hepatology. Given the continuing impact of the COVID-19 pandemic and ongoing restrictions, EASL decided to hold a Digital ILC 2020 on 27–29 August 2020 (Central European Summer Time).
APG-1387 is a novel small molecule IAP antagonist, that was discovered and is being developed by Ascentage Pharma. APG-1387 degrades IAPs by mimicking endogenous second mitochondrial-derived of caspases (SMAC) to induce programmed cell death or apoptosis. As the first IAP antagonist entering clinical stages in China, APG-1387 is being investigated in several clinical trials for the treatment of CHB and solid tumors. Findings from the preclinical study spearheaded by Prof. Xiaoyong Zhang, which were presented orally, show that APG-1387 is able to clear chronic HBV infection in various mouse models with a unique induction of apoptosis and immunoregulation mechanism. Application of IAP antagonist might represent a novel immunotherapeutic strategy for HBV functional cure.
«Interestingly, IAP inhibitors have the potential to regulate the host immune system, in addition to inducing cell apoptosis. The results from our study show that APG-1387 treatment is able to enhance HBV-specific T cell responses and break up the immune tolerance microenvironment in the liver of HBV mouse models. This effect induces the transformation of ‘chronic’ infection to ‘acute’ infection immune status, and results in HBV clearance,» said Prof. Zhang. «This novel mechanism of action sheds light on hepatitis B cure research, and further in-depth investigation of its mechanism will also help to develop new therapeutics.»
«At present, CHB still presents considerable unmet medical needs. APG-1387 is the first IAP antagonist entering clinical stage in China and a Phase II study in CHB is ongoing. This presentation at ILC shows the potential of APG-1387 in clearing chronic HBV infection, providing scientific rationale for clinical development in the treatment of CHB,» said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. «We hope to bring new approach to patients with CHB worldwide who are in urgent need for more effective therapies.»
Results: Compared to vehicle injection, APG-1387 treatment for 4-20 weeks in different models led to completely clearance of HBsAg, HBeAg and HBV DNA in serum, as well as HBcAg and HBV replicative intermediates in infected livers, and no relapse after stop therapy. After APG-1387 injection, cleaved-caspase-3 expression in HBcAg-positive hepatocytes was detected, and serum transaminase levels were transiently elevated and its peak levels were associated with the baseline HBsAg levels. However, pan-caspase inhibitor Emricasan or Z-VAD-FMK treatment could not block the antiviral effect of APG-1387. Furthermore, clearance of HBV by APG-1387 was found to be associated with upregulation of intrahepatic HBV-specific CD4+ and CD8+ T cells frequency and function. As expected, APG-1387 was unable to clear HBV in TNFα, CD4 or CD8 deficiency mice. Finally, Gene Set Enrichment Analysis of RNA-seq data showed that multiple immune-related genes were upregulated by APG-1387, similar to the genes induced in the liver during HBV clearance in chimpanzees.
Conclusion: These findings indicated that APG-1387 was able to clear chronic HBV infection in various mouse models with a unique induction of apoptosis and immunoregulation mechanism. Application of IAP antagonist might represent a novel immunotherapeutic strategy for HBV functional cure.
APG-1387 is a novel small molecule IAP (Inhibitor of Apoptosis Protein) antagonist, that was discovered and is being developed by Ascentage Pharma. APG-1387 degrades IAPs by mimicking endogenous SMAC molecule to induce programmed cell death or apoptosis. Ascentage Pharma is developing APG-1387 globally and has completed Phase I dose-escalation trials in patients with solid tumors in China and Australia, and a Phase Ib/II clinical trial of APG-1387 and pembrolizumab combination is currently ongoing in the US. In February 2020, Ascentage Pharma was cleared to initiate a Phase Ib/II study of APG-1387 in combination with nab-paclitaxel plus gemcitabine for the treatment of advanced pancreatic cancer. In addition, APG-1387 is being investigated in the clinical trial for the treatment of patients with Chronic Hepatitis B (CHB) in China. A Phase II study of APG-1387 in combination with nucleos(t)ide analog entecavir for the treatment of CHB dosed its first patient in June 2020.
About Ascentage Pharma
Ascentage Pharma (6855.HK) is a globally, clinical-stage biotechnology company engaged in developing novel therapies for cancers, CHB, and senesce 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 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. 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, and China. The company has submitted a New Drug Application for its core drug candidate HQP1351 in China. HQP1351 was recently granted orphan drug and fast-track designations by the US Food and Drug Administration (FDA), APG-2575, another key drug candidate of the company, was recently granted orphan drug designation by the FDA.
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