Ascentage Pharma's Bcl-2 Inhibitor APG-2575 Receives Three Ib/II Clinical Trial Approvals in the US and China, Advancing Development Across Three Hematologic Malignancies

Suzhou, China and Rockville, Maryland, USA – March 9, 2020 – Ascentage Pharma (6855.HK), a clinical-stage biopharmaceutical company dedicated to developing innovative drugs in the fields of oncology, hepatitis B, and age-related diseases, announced today that its novel Class 1 investigational drug in clinical development, the Bcl-2 inhibitor APG-2575, has recently received two Investigational New Drug (IND) approvals from the U.S. Food and Drug Administration (FDA). These approvals will enable Phase Ib/II studies of APG-2575 as monotherapy or combination therapy for relapsed/refractory Chronic Lymphocytic Leukemia (r/r CLL) and Small Lymphocytic Lymphoma (r/r SLL), as well as Phase Ib/II studies for Waldenström Macroglobulinemia (WM). Additionally, APG-2575 has recently obtained clinical trial approval from the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) to conduct a Phase Ib study as monotherapy or combination therapy for relapsed/refractory Acute Myeloid Leukemia (r/r AML).

APG-2575 is a novel oral, Bcl-2-selective small-molecule inhibitor in clinical development by Ascentage Pharma. It restores the programmed cell death mechanism (apoptosis) in tumor cells by selectively inhibiting the Bcl-2 protein, thereby killing tumors, and is intended for the treatment of various hematologic malignancies. Drug development targeting Bcl-2 family proteins has long been proven extremely challenging; however, Venclexta, a Bcl-2-selective inhibitor successfully launched in the United States in April 2016, provided strong clinical validation for this class of therapeutics. APG-2575 is one of the few Bcl-2-selective inhibitors worldwide to enter clinical development following Venclexta. Last year, APG-2575 initiated Phase I clinical studies in China for hematologic malignancies, becoming the first domestically developed Bcl-2-selective inhibitor to reach the clinical stage.

Previously, the Phase I clinical trial of APG-2575 for the treatment of hematologic malignancies was initiated in the United States and Australia. To date, no dose-limiting toxicities (DLTs) or tumor lysis syndrome (TLS), which is commonly associated with Bcl-2 inhibitors, have been observed, demonstrating the favorable safety profile of APG-2575 in clinical trials. Based on the robust preclinical and early clinical data of APG-2575, Ascentage Pharma has sequentially obtained clinical trial approvals from the regulatory authorities in both China and the United States for its Phase Ib/II studies evaluating APG-2575 in combination with CD20 monoclonal antibodies, BTK inhibitors, and other agents for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström’s macroglobulinemia (WM), and acute myeloid leukemia (AML).

This is a global, multicenter, open-label Phase Ib/II dose- and efficacy-exploration study designed to evaluate the safety and tolerability of APG-2575 as monotherapy or in combination with rituximab/acalabrutinib, and to preliminarily assess its efficacy in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a clonal proliferative neoplasm of mature B lymphocytes. It is the most prevalent adult leukemia in developed countries in Europe and America, accounting for approximately 30% of all leukemia cases. The annual incidence rate ranges from 2 to 6 per 100,000 individuals, rising to as high as 12.8 per 100,000 among those aged 65 and older. Although the incidence of CLL in Asian countries is lower than that in Europe and America, it has shown an upward trend in recent years, characterized by an earlier age of onset and higher aggressiveness. Despite first-line regimens significantly improving initial remission rates in treatment-naïve CLL patients, long-term medication is required to control the disease, and prognosis is often poor upon relapse. Recent studies have found that combining the BTK inhibitor ibrutinib with a Bcl-2 inhibitor for the treatment of CLL offers the advantage of high deep response rates, potentially transforming long-term therapy into fixed-duration treatment, thereby providing the possibility of clinical cure and treatment discontinuation for CLL patients. This undoubtedly lays the foundation for exploring combination therapies involving APG-2575.

This study is a global, multicenter, open-label Phase Ib/II dose- and efficacy-exploration study designed to evaluate the safety, tolerability, pharmacokinetic (PK) profile, and preliminary efficacy of APG-2575 as monotherapy or in combination with ibrutinib or rituximab in patients with Waldenström macroglobulinemia (WM).

Waldenström macroglobulinemia (WM) is a rare indolent mature B-cell lymphoma. Current guideline-recommended treatment regimens for WM achieve an objective response rate (ORR) of up to 80%; however, the rate of deeper responses, such as very good partial response (VGPR) or better, remains low (approximately 20% or lower), and many patients ultimately experience relapse or disease progression. Furthermore, the median age at onset of WM is around 70 years, and patients’ physical condition often precludes tolerance of intensive therapies. Therefore, improving therapeutic outcomes in WM is an urgent unmet clinical need².

Preclinical data confirm that APG-2575 can overcome ibrutinib-insensitive resistant WM models, while demonstrating significant synergistic effects with ibrutinib in non-Hodgkin lymphoma (NHL), including follicular lymphoma, diffuse large B-cell lymphoma, and WM models.

This study is a multicenter, open-label Phase Ib dose-finding study designed to evaluate the safety and pharmacokinetics of APG-2575 as monotherapy or in combination with chemotherapy in patients with acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is the most common leukemia in China, with an incidence rate of approximately 1.62 to 2.32 per 100,000 people. It primarily affects older adults, with a median age of 67 years at diagnosis. The incidence of AML increases with age, peaking in individuals aged ≥80 years, with an incidence rate of 22.5 per 100,000 people.

Although treatment options for acute myeloid leukemia (AML) continue to advance, the fundamental treatment paradigm has remained unchanged in recent years, with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation serving as the primary therapeutic approaches. Despite this, long-term survival rates for AML remain low. Up to 40% of newly diagnosed AML patients either fail to achieve complete remission (CR) during initial induction therapy, thereby becoming refractory cases, or relapse within six months after achieving CR. This is closely associated with the rapid onset, high relapse rate, and complex genetic mutations characteristic of AML. Additionally, the aging patient population is another factor affecting cure rates, as many elderly patients cannot tolerate intensive chemotherapy³.

Preclinical evidence demonstrates that APG-2575 monotherapy exhibits certain anti-AML effects; meanwhile, the combination of APG-2575 with various chemotherapy regimens shows strong synergistic activity in the treatment of AML. Notably, Bcl-2 inhibitor-based combination chemotherapy also demonstrates favorable safety and tolerability profiles, holding promise as a new therapeutic option for elderly patients with AML and those intolerant to intensive chemotherapy.

Yifan Zhai, Chief Medical Officer of Ascentage Pharma, stated, “APG-2575 is a key clinical development asset in the Company’s apoptosis product pipeline and the first domestically developed Bcl-2 selective inhibitor to enter clinical trials. Based on favorable preclinical and early clinical data, APG-2575 has received multiple approvals from China’s Center for Drug Evaluation (CDE) and the U.S. Food and Drug Administration (FDA) to conduct Phase Ib/II clinical trials, reflecting the comprehensive advancement of our global clinical development strategy. Combination therapy represents the future trend in oncology treatment, and we hope that our clinical trials will enable patients with relapsed or refractory hematologic malignancies to benefit sooner and more rapidly.”

Ascentage Pharma (6855.HK) is a China-based, globally oriented clinical-stage biopharmaceutical company dedicated to developing innovative drugs in the therapeutic areas of oncology, hepatitis B, and age-related diseases. The Company possesses a proprietary protein-protein interaction (PPI) targeted drug design platform. On October 28, 2019, Ascentage Pharma was successfully listed on the Main Board of The Stock Exchange of Hong Kong Limited.

Ascentage Pharma’s R&D pipeline primarily focuses on inhibitors of key proteins in the apoptosis pathway, such as BCL-2, IAP, and MDM2-p53, to reactivate apoptotic programs in tumor cells; it also includes second- and third-generation inhibitors targeting kinase mutants that emerge during cancer treatment. The company currently has eight Class 1 novel drugs in clinical development, with 28 Phase I/II clinical trials underway in China, the United States, and Australia.

References:

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.