Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies,  announced that a New Drug Application (NDA) for its inhouse developed investigational novel Bcl-2 selective inhibitor, lisaftoclax (APG-2575), for the treatment of patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been accepted and recommended the Priority Review designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA). This NDA, the first for a domestically developed Bcl-2 inhibitor in China, could potentially lead lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world.

This NDA is based on results from a pivotal registrational Phase II study in China (APG2575CC201) that evaluated the efficacy and safety of lisaftoclax in patients with r/r CLL/SLL. The primary endpoint of the study is the overall response rate (ORR).

CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms. It primarily affects older populations and is among the most common leukemia subtypes in the Western World, with over 100,000 new diagnoses reported globally each year¹. In China, where the incidence rate of CLL/SLL is lower than that of the western countries, the disease is occurring at a rapidly rising rate, with a younger age of onset and higher aggressiveness². SLL and CLL are two different manifestations of the same disease and approximately 20% of all SLL cases would progress to CLL³. Treatments such as immunotherapies and Bruton's tyrosine kinase inhibitors (BTKis) have significantly improved patients' responses to initial treatment. However, due to the limitations of existing treatment options, the poor prognosis of patients, severe impact on patients' quality of life and high complexity of the disease, patients with r/r CLL/SLL are in desperate need for new treatment options that are safe and effective.

The introduction of Bcl-2 inhibitors has further revolutionized the treatment of CLL/SLL. Bcl-2 is an apoptosis suppressor factor that regulates cell survival by controlling mitochondrial membrane permeability. It suppresses apoptosis by inhibiting the release of cytochrome C from mitochondria or by binding to apoptotic activators to inhibit the activity of caspase. The overexpression of Bcl-2, found in a variety of hematologic malignancies, particularly CLL/SLL, is a key mechanism by which tumor cells evade apoptosis.

However, the development of Bcl-2 as a therapeutic target is challenging mainly because its mechanism of action is based on the protein-protein interaction (PPI). The binding interface of Bcl-2 is relatively large, making it difficult for small-molecule inhibitors to exert blocking effects. Additionally, the Bcl-2 protein is located on the mitochondrial membrane, and mitochondria, with its double-membrane structure, is among the most complex and challenging cellular components. Drugs must first penetrate the cell membrane before they can further act on the mitochondrial membrane. In nearly 40 years since the discovery of this target, only one Bcl-2 inhibitor has been approved globally, a reality highlighting the immense difficulty and challenges in this field of research and development. In western countries, the treatment of CLL/SLL has entered a new era of chemotherapy-free and fixed-duration regimens, while no Bcl-2 inhibitor has been approved in China in this therapeutic area. Therefore, patients in China have an urgent unmet need for such novel therapies that can offer both efficacy and safety.

Lisaftoclax is a novel, investigational orally administered small-molecule Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat patients with malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor in China and the second anywhere globally that has demonstrated compelling clinical benefit and entered a pivotal registrational study. Lisaftoclax has broad therapeutic potential for a variety of hematologic malignancies and solid tumors, particularly as a single agent and in combinations in CLL/SLL. Lisaftoclax is a potential drug that may offer patients a safe, effective, and easy to use treatment option.

Lisaftoclax is being evaluated in multiple registrational Phase III studies, including a global registrational Phase III study of lisaftoclax in combination with a BTKi in previously treated patients with CLL/SLL (cleared by the US FDA); a global registrational Phase III study of lisaftoclax in combination with acalabrutinib for the first-line treatment of treatment-naïve patients with CLL/SLL; a global registrational Phase III study of lisaftoclax in combination with azacitidine (AZA) for the first-line treatment of elderly/unfit treatment-naïve patients with acute myeloid leukemia (AML) who were intolerant of standard induction chemotherapies; and a global registrational Phase III study of lisaftoclax in combination with AZA for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS).

"Ascentage Pharma's founding team has over 20 years of deep experience in developing apoptosis-targeted therapies and has made significant strides with the Bcl-2 target," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "To date, only one Bcl-2 inhibitor has been approved globally, which is a reality underscoring the immense difficulty and challenges in this field of research and development. This NDA submission for lisaftoclax could potentially pave the way for lisaftoclax to become the first approved China-developed Bcl-2 inhibitor, thus marking another major milestone that is a culmination of the Ascentage Pharma's deep commitment and perseverant work in the past 15 years."

Dr. Yang continued, "Globally, r/r CLL/SLL represents an area of urgent unmet clinical needs. To have successfully advanced lisaftoclax to this point, it is a true testament to Ascentage Pharma's robust capabilities in global pharmaceutical innovation. Moving forward, we will accelerate the global development of lisaftoclax in other indications to bring benefit to patients as quickly as possible. Remaining steadfastly committed to our mission of addressing unmet clinical needs in China and around the world, we will strive to develop more novel therapeutics for patients in need."