Ascentage Pharma Announces Clearances in China and the US for the Phase IIa Study of APG-115 Single Agent or in Combination with APG-2575 for the Treatment of Relapsed or Refractory T-cell Prolymphocytic Leukemia

SUZHOU,China and ROCKVILLE,Md.,Dec. 2,2020 -- 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 IIa clinical study of the company's novel MDM2-p53 inhibitor APG-115,as a single agent or in combination with the company's novel Bcl-2 inhibitor APG-2575,for the treatment of patients with relapsed/refractory T-cell prolymphocytic leukemia (r/r T-PLL). Prior to this approval in China,the study had already received clearance from the US Food and Drug Administration (FDA).

This global multicenter,open-label Phase IIa clinical study was designed to evaluate the safety,pharmacokinetics,and preliminary efficacy of APG-115 as a single agent or in combination with APG-2575 for the treatment of patients with r/r T-PLL.

T-PLL is an aggressive T-cell leukemia1 and an ultra-rare disease with an incidence rate of just 0.6 cases per million,and a median age of onset of 61 years2,3. The treatment options for T-PLL remain very limited. T-PLL is not very responsive to conventional chemotherapies,and there have been very few clinical studies targeting this disease4. To date,no therapy has been approved by the US FDA,European Medicines Agency (EMA),or China National Medical Products Administration (NMPA) for the treatment of T-PLL. Relapsed T-PLL often has a very poor prognosis,with an overall survival rate of just six to nine months5-8. There is an urgent need for identifying effective novel therapies for T-PLL.

Ataxic telangiectasia mutation (ATM) caused by the deletion or missense mutation of 11q23 occurs in up to 80-90% of patients with T-PLL9. In patient-derived xenograft (PDX) models harboring the ATM mutation，APG-115 demonstrated impressive antitumor activity. In a panel of cancer cell line or patient-derived xenograft models (CDX or PDX) representing human hematologic or solid malignancies,APG-115 plus APG-2575 has demonstrated potent synergistic effect and significantly enhanced antitumor activities. It is worth noting that the combination produced a response rate of 100% in xenograft models of MV-4-11 acute myeloid leukemia (AML) and Z138 mantle cell lymphoma (MCL) cell lines.

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.

APG-2575 is a novel,orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma. APG-2575 is designed to treat hematologic and solidmalignancies by selectively blocking antiapoptotic protein Bcl-2 to restore the normal apoptosis process in cancer cells. As a bona fide Bcl-2 inhibitor,APG-2575 demonstrated desired target engagement. APG-2575 selectively binds to Bcl-2,disrupts Bcl-2:BIM complexes,and releases proapoptotic protein BIM. Freed BIM subsequently activates BAX/BAK for pore formation on the mitochondria membrane,leading to mitochondrial outer-membrane permeabilization (MOMP),cytochrome c release,caspase activation,and apoptosis of cancer cells. APG-2575 is the first China-developed Bcl-2 inhibitor having entered clinical development in China. As a single agent,APG-2575 has potent antitumor activity in Bcl-2-dependent tumor cells,and has shown a broad range of antitumor activities when combined with other oncologic drugs. Previously,APG-2575 had received clearances and approvals for multiple Phase Ib/II clinical studies in China,Australia,and the US,and is currently being developed in a range of hematologic malignancies globally.

Based on T-PLL's pathogenesis and the molecular therapy's potential in bringing about a clinical breakthrough to the treatment of T-PLL,supported by the positive preclinical results and early clinical data of APG-115 and APG-2575,the Investigational New Drug Application (IND) for this Phase IIa study of APG-115 as a single agent or in combination with APG-2575 for the treatment of r/r T-PLLhas already received clearance from the US FDA.

"Both APG-2575 and APG-115 are key drug candidates in our apoptosis-targeted pipeline. We look forward to commencing this study evaluating the combination of our two novel compounds in T-PPL in China and the US,which hopefully will lead to a safe and effective novel therapy for T-PPL that currently has no approved treatment," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "Combination therapy is playing an increasingly important role in cancer treatment. Concurrent inhibition of both MDM2-TP53 and BCL-2 apoptosis pathways by the combination of APG-115 and APG-2575 has great therapeutic potential in triggering 'synthetic lethality' and effectively induce cell death by simultaneously blocking two important nodes of both apoptosis pathways10. Second，both APG-115 and APG-2575 are orally bioavailable,targeted agents. The combination may provide a chemo-free treatment option for patients with T-PLL. Further,the combination treatment in T-PLL is an innovative experimental therapy worldwide. We will strive to deliver a clinical breakthrough for patients with T-PPL."

References

1. Swerdlow SH,Campo E,Pileri SA,et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.

2. Matutes E,Brito-Babapulle V,Swansbury J,et al. Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood. 1991;78(12):3269-3274.

3. Herling M,Khoury JD,Washington LT,Duvic M,Keating MJ,Jones D. A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories. Blood. 2004;104(2):328-335.

4. Mercieca J,Matutes E,Dearden C,MacLennan K,Catovsky D. The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype. J Clin Oncol. 1994;12(12): 2588-2593.

5. Herbaux C,Genet P,Bouabdallah K,et al. Bendamustine is effective in T-cell prolymphocytic leukaemia. Br J Haematol. 2015; 168(6):916-919.

6. Jain P,Aoki E,Keating M,et al. Characteristics,outcomes,prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL). Ann Oncol. 2017;28(7):1554-1559.

7. Dearden CE,Khot A,Else M,et al. Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route. Blood. 2011;118(22):5799-5802.

8. Keating MJ,Cazin B,Coutré S,et al. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol. 2002;20(1): 205-213.

9. Schrader A,Crispatzu G,Oberbeck S,et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun. 2018;9(1):697.

10.Pan R,Ruvolo V,Mu H,et al. Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy. Cancer Cell. 2017 Dec 11; 32(6): 748–760.e6.

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,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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