Ascentage Pharma has announced that the New Drug Application (NDA) for lisaftoclax (APG-2575), a novel Bcl-2 selective inhibitor, has been accepted and granted Priority Review designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA). The application seeks approval for the treatment of patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This marks a significant step as it is the first NDA for a domestically developed Bcl-2 inhibitor in China and could potentially make lisaftoclax the second Bcl-2 inhibitor approved globally.
The NDA is based on data from a pivotal registrational Phase II study conducted in China (APG2575CC201), which assessed the efficacy and safety of lisaftoclax in patients with r/r CLL/SLL. The study's primary endpoint was the overall response rate (ORR).
Addressing Unmet Needs in CLL/SLL Treatment
CLL/SLL, a hematologic malignancy arising from mature B-cell neoplasms, predominantly affects older individuals. While less prevalent in China compared to Western countries, its incidence is increasing with a trend towards younger onset and greater aggressiveness. Current treatments, including immunotherapies and Bruton's tyrosine kinase inhibitors (BTKis), have improved initial responses, but limitations persist, leading to poor prognosis, reduced quality of life, and disease complexity. Consequently, there is a critical need for new, effective, and safe treatment options for patients with r/r CLL/SLL.
The Role of Bcl-2 Inhibition
The introduction of Bcl-2 inhibitors has transformed CLL/SLL treatment. Bcl-2, an apoptosis suppressor, regulates cell survival by controlling mitochondrial membrane permeability. Overexpression of Bcl-2, a common feature in hematologic malignancies like CLL/SLL, allows tumor cells to evade apoptosis. Lisaftoclax selectively blocks the antiapoptotic protein Bcl-2, restoring normal apoptosis in cancer cells.
Challenges in Targeting Bcl-2
Developing Bcl-2 inhibitors is challenging due to the protein-protein interaction (PPI) mechanism, where the binding interface is large, making it difficult for small-molecule inhibitors to exert blocking effects. Additionally, the mitochondrial membrane location adds complexity. Despite these challenges, lisaftoclax has demonstrated compelling clinical benefit and entered a pivotal registrational study.
Lisaftoclax: A Potential New Treatment Option
Lisaftoclax is an investigational, orally administered small-molecule Bcl-2 selective inhibitor. It is currently being evaluated in multiple registrational Phase III studies, including:
- A global Phase III study of lisaftoclax in combination with a BTKi in previously treated patients with CLL/SLL.
- A global Phase III study of lisaftoclax in combination with acalabrutinib for the first-line treatment of treatment-naïve patients with CLL/SLL.
- A global 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.
- A global Phase III study of lisaftoclax in combination with AZA for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS).
"This NDA submission for lisaftoclax could potentially pave the way for lisaftoclax to become the first approved China-developed Bcl-2 inhibitor," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma.
