Ascentage Pharma Released Preclinical Results of MDM2-p53 Inhibitor APG-115 in an Oral Presentation at WCLC 2020, Demonstrating Therapeutic Potential in STK11-Mutant Non-Small Cell Lung Cancer
SUZHOU, China and ROCKVILLE, Md., Feb. 2, 2021 /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, announced that the company recently released the results from a preclinical study of APG-115, a novel MDM2-p53 inhibitor being developed by Ascentage Pharma, in the treatment of non-small cell lung cancer (NSCLC) harboring STK11 mutations through an oral presentation on January 29, 2021, at the 2020 World Conference on Lung Cancer (WCLC 2020). The presentation was delivered by Dr. Hao Sun, from Guangdong Provincial People's Hospital and Dr. Yilong Wu's research team at Guangdong Lung Cancer Research Institute.
The World Conference on Lung Cancer, organized by the International Association for the Study of Lung Cancer (IASLC), is the world's largest multidisciplinary scientific conference that focuses on the cutting-edge research and clinical advancements in the field of lung cancer and other thoracic malignancies.
APG-115 is an orally administered, selective, small-molecule inhibitor of the MDM2 protein. APG-115 has strong binding affinity to MDM2 and is designed to activate tumor suppression activity of p53 by blocking the MDM2-p53 protein-protein interaction. APG-115 is the first MDM2-p53 inhibitor entering clinical development in China, and is currently being investigated in multiple Phase Ib/II clinical studies in solid tumors and hematologic malignancies in China and the US.
The report presented by Dr. Sun was titled "MDM2 Inhibitor APG-115 Suppresses Cell Proliferation and Tumor Growth in Preclinical Models of NSCLC Harboring STK11 Mutations". Results from this study showed that APG-115 has therapeutic potential in NSCLC harboring STK11 mutations, and shows the potential of a new treatment option for the subgroup of patients with drug resistance to approved PD-1 inhibitors.
STK11/LKB1 and KRAS co-mutations represent one of the three common oncogenic subtypes of KRAS-mutant lung adenocarcinoma. STK11/LKB1 mutations affect the tumor immune microenvironment, and are associated with the reduction of invasive cytotoxic CD8+T-cells in both patient-derived xenograft (PDX) models and mouse models. STK11/LKB1 mutations are a main driver of drug resistance to PD-1 inhibitors in patients with KRAS-mutant lung adenocarcinoma, therefore could predict the poor prognosis of immunotherapy in these patients. In addition, STK11/LKB1 mutations also have implications on cysteine metabolism.
This study showed, compared to the wild-type cell line, the NSCLC cell line harboring STK11/LKB1 mutations was highly sensitive to APG-115. APG-115 achieved its antitumor effects by inducing ferroptosis in the cancer cells harboring STK11/LKB1 mutations. In the PDX models of STK1/LKB1-mutant NSCLC, APG-115 as a single agent displayed potent antitumor activities, achieving a response rate of 66% in PDX models harboring mutant STK11. These results suggest that STK11/LKB1 mutations may be used as a biomarker for potential treatment by MDM2 inhibitors, and APG-115 as a potential therapy for STK11/LKB1-mutant NSCLC and possibly a new treatment option for those patients with primary drug resistance to PD-1 inhibitors.
"There remains to be enormous unmet medical needs in the treatment of NSCLC, particularly with those patients harboring STK11 mutations who are resistant to immunotherapies and therefore lack effective treatment options," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "As the first MDM2-p53 inhibitor entering clinical development in China, APG-115 is currently being investigated in multiple Phase Ib/II clinical studies. Those results reported at WCLC 2020 have demonstrated APG-115's therapeutic potential in STK11-mutant NSCLC, and provided additional scientific basis warranting the future clinical investigation of the drug candidate in patients with NSCLC, in particular, those with primary drug resistance to PD-1 inhibitors. We will accelerate the clinical development of APG-115 and strive to bring a novel therapeutic to patients in need."
About Ascentage Pharma
Ascentage Pharma (6855.HK) is a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, CHB, 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 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, and China. 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, and a New Drug Application (NDA) for the drug candidate has been submitted in China. To date, Ascentage Pharma has obtained a total of ten ODDs from the US FDA for four of the company's investigational drug candidates.
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Company Codes: HongKong:6855