Ascentage Pharma Announces Approval for the Phase Ib/II Clinical Study of MDM2-p53 Inhibitor APG-115 in Combination with Immunotherapy for the Treatment of Patients with Advanced Liposarcoma or other Advanced Solid Tumors in China

SUZHOU,China and ROCKVILLE,Md.,Oct. 27,2020 -- 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 Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) has approved a Phase Ib/II study of Ascentage Pharma's novel MDM2-p53 inhibitor APG-115 in combination with PD-1/PD-L1 inhibitors for the treatment of patients with advanced liposarcoma (LPS) or other advanced solid tumors.

This multicenter,open-label Phase Ib/II study of the combination therapy in patients with advanced LPS or other advanced solid tumors in China comprises two stages - a Phase Ib dose-escalation study designed to evaluate the safety and tolerability of APG-115 in combination with a PD-1 inhibitor (toripalimab); and a Phase II dose-expansion study which will also assess the efficacy in the treatment of patients with TP53 wild-type MDM2-amplified LPS.

LPS is a common histologic subtype of soft issue sarcomas,accounting for around 20% of all soft tissue sarcoma incidences. MDM2 amplification is common in LPS,while TP53 wild-type LPS accounts for approximately half of all LPS cases[1].Surgical resection is the current primary standard of care treatment for LPS,and pre/post-surgical chemotherapy,with or without radiation,are also recommended. Patients with advanced relapsed or metastatic LPS also receive systemic chemotherapy. However,according to the existing data,chemotherapy only offers limited benefits to patients with advanced LPS,with 80% LPS cases eventually relapsing[2]. Furthermore,current targeted therapies and immunotherapies for the treatment of LPS remain very limited in options and efficacy[3]. Therefore,a comprehensive understanding of the pathological characteristics of LPS and the development of novel and effective combination therapies for LPS are urgently needed.

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,with multiple ongoing clinical studies in solid tumors and hematologic malignancies in China and the US.

Thus far,APG-115 as a single agent in advanced LPS has already shown promising antitumor activities. The Phase I study of APG-115 single agent demonstrated clinical activities in LPS and other tumors of the TP53 wild-type,implicating that TP53 wild-type is a potential biomarker for predicting the efficacy of APG-115 in the treatment of LPS and other tumor types. The study has observed over 10 months of sustained post-treatment response in a patient who had achieved partial response (PR),indicating the potential host immune-modulating effect of APG-115. These results paved the way for the further investigation of APG-115 as a single agent or in combinations with immunotherapies[4]. Preclinical studies have shown that APG-115 could stimulate the release of proinflammatory cytokines in T-cells,enhance the activation of CD4+ T-cells,and elevate the PD-L1 expression in various tumor cells. Also observed was that the APG-115 plus PD-1 inhibitor combination significantly bolstered the antitumor activities in multiple tumor models.

"At present,there is urgent unmet medical need in the treatment of LPS and other solid tumors globally," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "As the first MDM2-p53 inhibitor entering clinical development in China,APG-115 single agent has demonstrated promising clinical utility in the treatment of advanced LPS. Meanwhile,preclinical studies of the APG-115 plus PD-1 inhibitor combination has also shown encouraging results. We will press ahead with this Phase Ib/II study of APG-115 plus immunotherapy combination in China,which hopefully will offer a new option to the treatment of LPS and other solid tumors."

References

1.Rayburn E,Zhang R,He J,Wang R. MDM2 and human malignancies: expression,clinical pathology,prognostic markers,and implications for chemotherapy. Curr Cancer Drug Targets. 2005 Feb;5(1):27-41.

2.Mankin H J,Mankin K P,Harmon D C. Liposarcoma: a soft tissue tumor with many presentations. Musculoskelet Surg. 2014 Dec;98(3):171-7.

3.Soft Tissue Sarcoma,Version 2.2018,US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16(5):536–563.

4.Zhang,X. Phase I study results of APG-115,a MDM2-p53 antagonist in Chinese patients with advanced liposarcoma and other solid tumors. ASCO 2020 Annual meeting,Poster #430.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally,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. 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 has been granted an Orphan Drug Designation (ODD) and a Fast Track designation by the US Food and Drug Administration (FDA),and a New Drug Application for the drug candidate has been submitted in China. To date,Ascentage Pharma has obtained a total of six ODDs from the FDA for four of the company's investigational drug candidates.

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