Ascentage Pharma (6855.HK) announced today that the company announced three latest preclinical research results in the form of posters at the 2023 American Association for Cancer Research Annual Meeting (AACR 2023), including the original Class 1 new drug of the marketed variety-the third The new generation of BCR-ABL inhibitor Orebatinib (Nilic, HQP1351), important pipeline of apoptosis pipeline Bcl-2 inhibitor APG-2575 and MDM2-p53 inhibitor APG-115.

Dr. Zhai Yifan, Chief Medical Officer of Ascentage Pharma, said: 'At this AACR annual meeting, we demonstrated the clinical development potential and significant combination therapy potential of Ascentage Pharma's three important drug candidates, providing important support for further related research. .We will continue to advance more in-depth clinical exploration to provide patients with new treatment options.'

Ascentage Pharma's poster information on AACR 2023 is as follows

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

Orebatinib (HQP1351) combined with Bcl-2 inhibitor APG-2575 can overcome drug resistance in gastrointestinal stromal tumors (GISTs)

Abstract number: 1631

Time: April 17, 2023 (Monday) 09:00-12:30 (US Eastern Time) / April 17, 2023 (Monday) 21:00-00:30 (Beijing Time)

GIST is a common malignant stromal tumor of the digestive tract, and its incidence is about 1%-2%. About 75%-80% of GIST patients have KIT gene mutations, and about 5-10% have platelet-derived growth factor receptor alpha (PDGFRA) gene mutations. Although tyrosine kinase inhibitors (TKIs) can improve the quality of life of patients, TKI resistance also commonly occurs. More than 80% of GIST patients express Bcl-2, and the amplification of Bcl-2 and Bcl-xL may be a common feature associated with disease progression. Inhibiting oncogenic KIT signaling while acting on the apoptotic pathway is one of the therapeutic strategies for GIST. Orebatinib (HQP1351) is a new third-generation TKI that can target BCR-ABL1, KIT and PDGFRA, and is undergoing clinical trials for the treatment of relapsed/refractory chronic myeloid leukemia and GIST. APG-2575 is a selective Bcl-2 inhibitor in clinical trials for the treatment of hematological malignancies. This study aimed to evaluate whether the Bcl-2 inhibitor APG-2575 combined with orebatinib can improve the efficacy of imatinib-resistant GIST.

The results of this preclinical study showed that orebatinib and the Bcl-2 inhibitor APG-2575 have synergistic antitumor effects in imatinib-resistant GIST. Considering that most TKIs have similar resistance mechanisms, this new dual-drug combination therapy is expected to bring a new treatment strategy for GIST patients who develop resistance after receiving imatinib or other TKIs.

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

Orebatinib (HQP1351) enhances the antitumor effect of immunotherapy in renal cell carcinoma (RCC)

Abstract number: 5071

Time: April 18, 2023 (Tuesday) 13:30-17:00 (US Eastern Time) / April 19, 2023 (Wednesday) 01:30-05:00 (Beijing Time)

Checkpoint inhibitor (CPI) resistance is common in many solid tumors. Reasons for this include upregulation of vascular endothelial growth factor A (VEGFA) and programmed death-ligand 1 (PD-L1), resulting in an immunosuppressive tumor microenvironment and immune escape. VEGF and VEGF receptor (VEGFR) inhibitors can promote the normalization of tumor blood vessels and the reprogramming of immunostimulatory cells, thereby enhancing the efficacy of immunotherapy. In recent years, several combinations of tyrosine kinase inhibitors (TKIs) and immunotherapy have been approved for the treatment of advanced RCC. Orebatinib is a new generation multi-kinase inhibitor that acts on VEGFR, fibroblast growth factor receptor (FGFR), SRC, BCR-ABL1, c-KIT and platelet-derived growth factor receptor multiple targets. The drug has been approved in China for the treatment of adult patients with any TKI-resistant chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase (AP) with T315I mutation, and is being developed for the treatment of relapsed/ Clinical trials for refractory CML and gastrointestinal stromal tumors. The aim of this study was to evaluate whether orebatinib combined with immunotherapy can promote the suppression of RCC.

The results of this preclinical study showed that Orebatinib combined with CPI achieved a synergistic anti-tumor effect in a mouse model of renal cell carcinoma by targeting tumor growth, angiogenesis and immune regulation. This novel combination therapy is expected to provide a new strategy to enhance the efficacy of CPI for patients with RCC.

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

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

Abstract number: 1632

Time: April 17, 2023 (Monday) 09:00-12:30 (US Eastern Time) / April 17, 2023 (Monday) 21:00-00:30 (Beijing Time)

Uveal melanoma (UM) is the most common primary intraocular malignancy, yet knowledge of the molecular pathogenesis of the disease remains very limited. Most patients with UM have mutations in the genes encoding the G-protein subunits Q or 11, which lead to protein kinase C, mitogen-activated protein kinase (also known as MAPK1/3 or extracellular signal-regulated kinase 2/1 [ERK2/ ERK1]) and activation of downstream effectors such as YES-related proteins. This provides a rationale for targeting these pathways in therapy. Genetic analysis revealed that TP53 mutations are rare in UM patients, but the pathways associated with it may be functionally inactive. Ubiquitination-mediated degradation of p53 activates MAPK signaling, so active p53 may enhance inhibition of MAPK signaling. APG-115 is a small molecule drug targeting p53/MDM2, which is undergoing clinical trials for the treatment of various solid tumors and blood tumors. The study aims to evaluate the anti-tumor activity of APG-115 alone and in combination with other targeted drugs in preclinical UM models.

The results of this preclinical study showed that APG-115 combined with MAPK pathway inhibitors has therapeutic potential for UM.

Contact:

Email: IR@ascentage.com

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