Ascentage Pharma Announces IND Clearance by the US FDA for Lisaftoclax (APG-2575) as Single Agent or in Combinations for the Treatment of ER+ Breast Cancer and Other Solid Tumors

SUZHOU,China,and ROCKVILLE,Md.,June 15,2021 --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 the Investigational New Drug (IND) application for the company's novel Bcl-2 inhibitor,lisaftoclax (APG-2575),has been cleared by the US Food and Drug Administration (FDA) and the company is poised to initiate a clinical study of lisaftoclax as a single agent or in combination with other antitumor therapies for the treatment of patients with advanced estrogen receptor-positive (ER+) breast cancer or other solid tumors.

This global multicenter,open-label Phase Ib/II clinical study is designed to evaluate the safety,tolerability,pharmacokinetics (PK),and preliminary efficacy of lisaftoclax as a single agent in patients with advanced solid tumors,or in combination with palbociclib in patients with metastatic ER+ and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer relapsed or refractory to prior treatment with cyclin–dependent kinase 4/6 (CDK4/6) inhibitors.

Breast cancer is one of the most common malignancies in women. About 75% of all breast cancer cases are hormone receptor positive (HR+)1,mainly estrogen receptor positive (ER+),and the antiapoptotic protein Bcl-2 is overexpressed in around 85% of this subset2. Endocrine therapy is the standard of care treatment for patients with early-stage or metastatic HR+/HER2- breast cancer. In the first-line treatment of metastatic ER+ breast cancer,an CDK4/6 inhibitor (palbociclib,ibociclib,or abemaciclib) in combination with endocrine therapy can offer longer progression-free survival (PFS) and overall survival (OS),as compared to endocrine therapy alone3,4. In the second-line setting,phosphoinositide 3-kinase (PI3K) inhibitor plus fulvestrant,and everolimus plus endocrine therapy can effectively target the PI3K-AKT-mTOR pathway,thus offering additional treatment options for patients who failed first-line treatments3. However,patients treated with endocrine therapies and targeted therapies commonly develop drug resistances,eventually necessitating chemotherapies. Therefore,there is an urgent clinical need for novel targeted therapies that can effectively blockade mutational pathways and delay chemotherapies.

Lisaftoclax is a novel,orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma. Lisaftoclax is designed to treat hematologic malignancies and solid tumors by selectively blocking antiapoptotic protein Bcl-2 to restore the normal apoptosis process in cancer cells. Lisaftoclax is the first China-developed Bcl-2 inhibitor entering clinical development in China. Previously,lisaftoclax had received clearances and approvals for multiple Phase Ib/II clinical studies in China,Australia,the US,and Europe,and is currently being developed in a range of hematologic malignancies globally. As a single agent,lisaftoclax has potent antitumor activity in Bcl-2-dependent tumor cell lines,and has shown broad antitumor effects when combined with other antitumor therapies.

Preclinical data of lisaftoclax in combination with palbociclib showed that palbociclib can induce cell cycle arrest and apoptosis,while lisaftoclax can bolster the expression of proapoptotic proteins such as BIM and downregulate ER levels,while lowering the levels of phosphorylated Rb protein,and the cyclin D1 and E. Therefore,Bcl-2 inhibitors combined with CDK4/6 inhibitors can synergistically enhance cell cycle arrest while inducing the cell death of ER+ tumors.

"Lisaftoclax is a core drug candidate in our apoptosis-targeted pipeline. This IND clearance by the US FDA for lisaftoclax in patients with solid tumors marks another major milestone for this drug candidate," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "As the first China-developed Bcl-2 inhibitor entering clinical development in China,lisaftoclax has enormous therapeutic potential,both as a single agent and in combinations. Lisaftoclax has shown promising clinical activity and favorable tolerability in hematologic malignancies,and we look forward to expanding and deepening our investigation of lisaftoclax in solid tumors. We are now advancing the clinical development of this drug candidate globally in the hope of soon benefiting patients in China and around the world."

References

McDonald,E.S.,et al.,Clinical Diagnosis and Management of Breast Cancer. J Nucl Med,2016. 57 Suppl 1: p. 9s-16s.

Razavi,P.,The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell,2018. 34(3): p. 427-438.e6.

Rozeboom,B.,N. Dey,and P. De,ER+ metastatic breast cancer: past,present,and a prescription for an apoptosis-targeted future. Am J Cancer Res,2019. 9(12): p. 2821-2831.

Lynce,F.,A.N. Shajahan-Haq,and S.M. Swain,CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. Pharmacol Ther,2018. 191: p. 65-73.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused,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 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,Europe,and China. Olverembatinib (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. A New Drug Application (NDA) for olverembatinib 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 11 ODDs from the US FDA for 4 of the company's investigational drug candidates.

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