Ascentage Pharma Announces Clearances for Three Phase Ib/II Clinical Studies of APG-2575 in China and the U.S., Beginning Simultaneous Clinical Development in Three Hematologic Malignancy Indications

SUZHOU,China and ROCKVILLE,MD.,March 9,2020 -- 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 two clinical studies of APG-2575,a novel Bcl-2 selective inhibitor being developed by Ascentage Pharma,have recently received clearances from the U.S. Food and Drug Administration (FDA). These studies include one Phase Ib/II trial of APG-2575 as a single agent or in combination for the treatment of relapsed/refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (r/r SLL); and another Phase Ib/II trial of APG-2575 as a single agent or in combination for the treatment of Waldenstrom macroglobulinemia (WM) (MAPLE-1). Furthermore,following recent approval from the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA),the company will initiate a Phase Ib study of APG-2575 as a single agent or in combination for the treatment of relapsed/refractory acute myeloid leukemia (r/r AML) in China.

APG-2575 is a novel,orally administered Bcl-2 selective inhibitor being developed by Ascentage Pharma. APG-2575 is designed to treat a variety of hematologic malignancies by selectively blocking Bcl-2 to restore the normal apoptosis process in cancer cells. It has proved to be difficult to develop drugs targeting the Bcl-2 family of proteins. However,the marketed Bcl-2 inhibitor Venclexta® (venetoclax),approved by the U.S. FDA in April 2016,has validated the clinical basis for further development of new agents in this class. Globally,Ascentage Pharma's APG-2575 is one of the few Bcl-2 selective inhibitors in active clinical development. With the Phase I study of APG-2575 in hematologic malignancies initiated in China last year,APG-2575 represents the first China-made Bcl-2 selective inhibitor to enter clinical trials.

A Phase I study of APG-2575 in hematologic malignancies was previously commenced in the U.S. and Australia. No dose-limiting toxicity or tumor lysis syndrome (commonly associated with other Bcl-2 inhibitors) has been observed,suggesting that APG-2575 may have a favorable safety profile. Based on preclinical and early-stage clinical data,Ascentage Pharma has been granted a number of clearances in China and the U.S. for the Phase Ib/II studies of APG-2575 in combination with anti-CD20 monoclonal antibodies,Bruton's tyrosine kinase (BTK) inhibitors,and other therapeutic agents in CLL/SLL,WM,and AML.

A Phase Ib/II study of APG-2575 as a single agent or in combination with rituximab or acalabrutinib for the treatment of patients with r/r CLL/SLL.

This global multicenter,open-label Phase Ib/II dose-escalation and dose-expansion study is designed to evaluate the safety,tolerability,and anticancer activity of APG-2575 as a single agent or in combination with rituximab or acalabrutinib in patients with r/r CLL/SLL.

CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms and is the most common form of adult leukemia in North America and Europe,accounting for about 30% of all new leukemia cases,with an annual incidence of 2 to 6 cases/100,000,and 12.8 cases/100,000 in the population aged 65 or older[1]. The incidence rate of CLL in Asia is lower than in North America and Europe but has been increasing in recent years,with more patients developing the condition at younger ages and displaying greater disease invasiveness. Despite significant initial responses to current first-line treatments,many patients with CLL need ongoing treatment to maintain these responses,and relapse often portends a poor prognosis. Recent studies in CLL showed that combining BTK inhibitor ibrutinib with another Bcl-2 inhibitor can deepen responses and even shorten cyclic treatment,making it possible for patients to achieve complete remission and therefore discontinue treatment. These findings have provided a compelling rationale for exploring APG-2575 in combination with other therapeutic agents.

A Phase Ib/II clinical study of APG-2575 as a single agent or in combination with ibrutinib or rituximab for the treatment of patients with WM.

This is a global multicenter,open-label Phase Ib/II dose-escalation and dose-expansion study designed to evaluate the safety,pharmacokinetics (PK),and efficacy of APG-2575 as a single agent or in combination with ibrutinib or rituximab in patients with WM.

WM is a rare indolent B-cell lymphoma. Treatment recommendations for WM from current guidelines[2] suggest an objective response rate (ORR) of about 80% with contemporary therapies,but they deliver a very low rate of very good partial response or deeper responses (20% or lower),with most patients eventually relapsing or experiencing further disease progression. Furthermore,patients are diagnosed with WM at a median age of 70,when many individuals are intolerant of aggressive therapies because of poor health conditions,hence presenting an urgent clinical need for more effective therapies[2].

Preclinical study data of APG-2575 have shown responses generated in WM models resistant or insensitive to ibrutinib,as well as the synergistic effect with ibrutinib in various models of non-Hodgkin's lymphoma,including follicular lymphoma,diffuse large B-cell lymphoma,and WM.

A Phase Ib study of APG-2575 as a single agent or in combination with chemotherapy for the treatment of patients with r/r AML in China

This multicenter,open-label Phase Ib dose-escalation and dose-expansion study is designed to evaluate the safety and PK of APG-2575 as a single agent or in combination with chemotherapy for the treatment of AML.

AML is the most common form of leukemia in China,with an incidence rate of about 1.62 to 2.32 cases/100,000. AML mainly affects the elderly population,and the median age at diagnosis is 67. The incidence rate of AML increases with age,reaching a peak of 22.5 cases/100,000 in the population aged 80 or older.

Despite recent therapeutic advances in AML,the standard treatment strategy for this condition has remained unchanged,with intense chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary treatment modalities. Because of rapid progression,a high incidence rate,and the complex genetic mutations associated with AML,the rate of long-term survival in patients with AML is still very low,with more than 40% of newly diagnosed patients becoming relapsed or refractory after failing to achieve complete response (CR) during remission induction therapies,or relapse within 6 months after achieving CR. Moreover,an aging population also contributes to the low remission rate,because many elderly patients are intolerant of intensive chemotherapy[3].

Preclinical studies of APG-2575 have shown promising anticancer activity and strong synergistic effects with a range of chemotherapies. In addition,Bcl-2 inhibitors in combination with chemotherapies have demonstrated favorable safety and tolerability profiles,suggesting their potential clinical benefits for elderly patients with AML and those who are intolerant of chemotherapies.

"APG-2575 is a key drug candidate in our development pipeline targeting apoptosis,and it is the first China-made Bcl-2 selective inhibitor to enter clinical studies. As a testament to the encouraging preclinical and early-stage clinical data,and Ascentage Pharma's commitment to its global clinical development strategy,APG-2575 has recently been granted clearances for several Phase Ib/II clinical studies,by the China CDE and U.S. FDA," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "Combination therapy is playing an increasingly important role in cancer treatment. We hope that these studies will show clinical benefits for patients with relapsed or refractory hematologic malignancies."

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally-focused,and age-related diseases. The company focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis,or programmed cell death. On October 28,2019,Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited.

Ascentage Pharma has built a pipeline of eight clinical drug candidates,including a novel,highly potent Bcl-2/Bcl-xL inhibitor,as well as candidates aimed at IAP and MDM2-p53 pathways,and next-generation tyrosine kinase inhibitors. The company is conducting 28 Phase I/II clinical trials to evaluate the eight drug candidates in the United States,Australia,and China.

References:

1. Slager SL,Benavente Y,Blair A,et al. Medical history,lifestyle,family history,and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014;48:41-51.

2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN guidelines®). Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma. Version 1.2020 December 6,2019. Available from: https://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf.

Last accessed March 8,2019.

3. Thol F,Schlenk RF,Heuser M,Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood 2015;126:319-27.

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