AACR 2023 | Ascentage Pharma Presents Results from Three Studies Underscoring Exploratory Efforts in Potential New Indications

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Apr 17, 2023, 21:08 ET

SUZHOU, China and ROCKVILLE, Md., April 17, 2023 /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 it had released results from three preclinical studies of the company's China-approved novel third-generation BCR-ABL inhibitor olverembatinib (HQP1351), and two key investigational apoptosis-targeted drug candidates of Ascentage Pharma, the Bcl-2 inhibitor lisaftoclax (APG-2575) and the MDM2-p53 inhibitor alrizomadlin (APG-115), in Poster Presentations at the 2023 American Association of Cancer Research Annual Meeting (AACR 2023; Orlando, FL).

"The data we presented at this year's AACR Annual Meeting highlight the three drug candidates' potential for clinical development and promising synergistic utilities in new indications," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "We will investigate these assets in the clinical setting and hope that these efforts will result in new therapeutic options for patients in need."

The details of these posters presented at AACR 2023 are as follows:

Combination of olverembatinib (HQP1351) with Bcl-2 inhibitor lisaftoclax (APG-2575) overcomes resistance in gastrointestinal stromal tumors (GISTs)

Abstract#: 1631
Time: Monday, April 17, 2023, 9:00 AM-12:30 PM, EDT
GISTs are common malignant mesenchymal tumors that occur in the GI tract, with an estimated incidence rate of 1% to 2%. About 75% to 80% of patients with GIST have mutations in the KIT gene, while 5% to 10% have mutations in the platelet-derived growth factor receptor α (PDGFRA) gene. Tyrosine kinase inhibitors (TKIs) offer patients an improved quality of life, but increased pharmacological resistance to TKIs is often observed. Bcl-2 is expressed in >80% of GISTs, and amplification of Bcl-2 and Bcl-xL is a common feature associated with disease progression. One approach to GIST is to concurrently inhibit oncogenic KIT signaling while actively engaging apoptotic pathways. Olverembatinib (HQP1351) is a third-generation TKI that targets BCR-ABL1, KIT and PDGFRA and is currently in development for relapsed or refractory chronic myeloid leukemia and GIST. Lisaftoclax (APG-2575) is a selective Bcl-2 inhibitor under development for hematologic malignancies. The purpose of this study was to evaluate whether combining a Bcl-2 inhibitor, lisaftoclax, with olverembatinib enhances treatment effect on imatinib-resistant GISTs.
The results demonstrate that olverembatinib and Bcl-2 inhibitor lisaftoclax have synergistic antitumor effects in imatinib-resistant GIST. Considering that the resistance mechanisms are similar for most TKIs, this novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with imatinib or other TKIs.

Olverembatinib (HQP1351) enhances antitumor effects of immunotherapy in renal cell carcinoma (RCC)

Abstract#：5071
Time: Tuesday, April 18, 2023, 1:30 PM-5:00 PM, EDT
In solid tumors, resistance to checkpoint inhibitors (CPIs) is frequently observed, partially due to upregulation of vascular endothelial growth factor A (VEGFA) and programmed death-ligand 1 (PD-L1) leading to an immunosuppressive tumor microenvironment and immune escape. Inhibitors against VEGF and the VEGF receptor (VEGFR) foster tumor vessel normalization and immunostimulatory reprogramming, in turn promoting treatment effects of immunotherapies. In recent years, tyrosine kinase inhibitors (TKIs) plus immunotherapy have been approved to treat advanced RCC. Olverembatinib is a third-generation multikinase inhibitor with targets including VEGFR, fibroblast growth factor receptor (FGFR), SRC, BCR-ABL1, c-KIT, and platelet-derived growth factor receptor (PDGFR). The drug is approved in China for the treatment of adult patients with TKI-resistant chronic phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation, and is currently under clinical development for relapsed or refractory CML and gastrointestinal stromal tumor. The aim of this study was to assess whether olverembatinib combined with immunotherapy can promote inhibitory effects on RCC.
The results demonstrate that combining olverembatinib with a CPI confers synergistic antitumor effects in an RCC mouse model by targeting tumor growth, angiogenesis, and immune regulation. This novel combination may provide an alternative approach to enhance treatment effects with CPIs in renal cancers.

MDM2 inhibitor alrizomadlin (APG-115) promotes antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma

Abstract#：1632
Time: Monday, April 17, 2023, 9:00 AM-12:30 PM, EDT
Uveal melanoma (UM) is the most common primary intraocular malignancy, yet its molecular pathogenesis is poorly understood. Most UM cases have activating mutations in genes encoding G protein subunits alpha Q or 11, leading to activation of downstream effectors. These include protein kinase C, mitogen-activated protein kinases (MAPK1/3; also termed extracellular signal-regulated kinase 2/1 [ERK2⁄ERK1], respectively), and yes-associated protein, suggesting a rationale for therapeutically targeting these related pathways. Genetic analyses show that TP53 is infrequently mutated in UM, but associated pathways may be functionally inactivated. Ubiquitination-mediated degradation of p53 activates MAPK signaling such that active p53 may promote suppression of MAPK signaling. Alrizomadlin (APG-115) is a small molecule targeting p53/MDM2 that is in clinical development for solid and hematologic cancers. This study evaluated the antitumor effect of alrizomadlin, alone or combined with other targeted therapies, in preclinical models of UM.
The results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.

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 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.

Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product, has been granted Priority Review designations and a Breakthrough Therapy designation by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). Furthermore, it has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU 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. 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.

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SOURCE Ascentage Pharma