Ascentage Pharma, an international biopharmaceutical company dedicated to discovering, developing, and commercializing innovative treatments addressing worldwide unmet medical needs, particularly in cancer, has announced that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has accepted its New Drug Application (NDA) for lisaftoclax (APG-2575). This investigational Bcl-2 selective inhibitor is designed for treating patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has been recommended for Priority Review. This submission marks the first domestically innovated Bcl-2 inhibitor NDA in China and positions lisaftoclax to potentially become the second Bcl-2 inhibitor approved globally.
This NDA submission is supported by data from a pivotal Phase II clinical trial in China (APG2575CC201), which assessed the safety and effectiveness of lisaftoclax in r/r CLL/SLL patients. The primary focus of this trial was the overall response rate (ORR).
CLL/SLL represents a blood cancer deriving from mature B-cell neoplasms, predominantly affecting older individuals and ranking among the most prevalent forms of leukemia in Western nations, with over 100,000 new cases reported worldwide each year. Despite having a lower prevalence in China compared to Western countries, the incidence of CLL/SLL is rapidly increasing, with patients presenting at younger ages and with more aggressive disease. CLL and SLL, though distinct, are two facets of the same illness, with around 20% of SLL cases advancing to CLL. Despite advances in treatment with immunotherapies and Bruton’s tyrosine kinase inhibitors (BTKis), limitations remain in current treatments, leaving patients, particularly those with r/r CLL/SLL, in dire need of safer and more effective therapeutic options.
The advent of Bcl-2 inhibitors has brought a transformative approach to managing CLL/SLL. Bcl-2 acts as an apoptosis inhibitor, regulating cellular survival by modulating mitochondrial membrane permeability. It prevents apoptosis by blocking cytochrome C release from mitochondria or binding to apoptotic inducers to inhibit caspase activation. Bcl-2 overexpression is a known strategy used by tumor cells, including those in CLL/SLL, to circumvent cell death.
Targeting Bcl-2 for treatment remains challenging due to its reliance on protein-protein interaction (PPI), where Bcl-2’s extended binding domain complicates the efficacy of small-molecule inhibitors. Furthermore, Bcl-2’s mitochondrial membrane localization, coupled with the mitochondria’s complex double-membrane structure, complicates drug delivery. In the nearly 40 years since identifying this target, just one Bcl-2 inhibitor has achieved global approval, underscoring the substantive obstacles and challenges encountered in this research domain. While Western nations have moved into a new era of chemotherapy-free and finite-duration treatments for CLL/SLL, China has yet to approve a Bcl-2 inhibitor for this therapeutic purpose, highlighting the urgent need for effective novel treatments.
Lisaftoclax stands as a novel, investigational oral small-molecule Bcl-2 selective inhibitor under development by Ascentage Pharma. It’s crafted to manage cancer by specifically obstructing the antiapoptotic protein Bcl-2, thus reinstating normal cell death processes in cancerous cells. Régarded as the first Bcl-2 inhibitor in China and the second worldwide with significant clinical benefits, lisaftoclax has initiated a pivotal registrational study. The drug’s therapeutic range extends across various hematologic malignancies and solid tumors, especially as a monotherapy and in combination regimens for CLL/SLL. Lisaftoclax holds the potential to offer a secure, effective, and user-friendly treatment solution.
The development of lisaftoclax is currently being evaluated across several Phase III global registrational trials. These encompass combinations with BTKi in previously treated CLL/SLL patients (with FDA clearance), with acalabrutinib for initial treatment in newly diagnosed CLL/SLL patients, with azacitidine (AZA) for first-line therapy in elderly/unfit AML patients intolerant to standard induction chemotherapy, and for newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS).
“Ascentage Pharma’s founding experts possess over two decades of intensive experience in apoptosis-focused therapies and have achieved significant progress targeting Bcl-2,” shared Dr. Dajun Yang, chairman & CEO of Ascentage Pharma. “Globally, only one Bcl-2 inhibitor has achieved approval, accentuating the complexity and challenges present within this research area. The NDA for lisaftoclax might position it as the first domestically developed Bcl-2 inhibitor approved in China, signifying a significant milestone from our unwavering dedication and perseverance over the last 15 years.”
Dr. Yang added, “On a global scale, the treatment of r/r CLL/SLL remains an area of critical unmet medical need. Successfully bringing lisaftoclax to this juncture validates Ascentage Pharma’s strong capability in worldwide drug innovation. Looking ahead, we intend to accelerate lisaftoclax’s global development across additional indications, benefiting patients swiftly. Firmly committed to addressing clinical gaps both in China and internationally, we aim to create cutting-edge therapeutics for those who need them.”