Ascentage Pharma has received clearance from the US Food and Drug Administration to proceed with a global registrational Phase III clinical trial for lisaftoclax (APG-2575), marking a significant milestone in the development of what could become the second Bcl-2 inhibitor approved worldwide. The study will evaluate the novel oral Bcl-2 inhibitor in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were previously treated with Bruton's tyrosine kinase inhibitors (BTKi).
Regulatory Milestone and Clinical Significance
The FDA clearance represents a major advancement following China's Center for Drug Evaluation approval for a registrational Phase II study in relapsed/refractory CLL/SLL patients in December 2021. The global, multi-center, randomized-controlled Phase III study (APG2575CG301) is designed to assess the efficacy and safety of lisaftoclax plus a BTKi in previously BTKi-treated CLL/SLL patients, with initiation planned for the second half of 2023.
CLL/SLL represents the most common form of adult leukemia, accounting for one-quarter of all leukemia cases in the Western world with over 100,000 new diagnoses globally each year. Despite significant initial responses to current first-line treatments including immunotherapies, chemotherapies, and BTKis, relapse and drug resistance remain major clinical challenges.
Promising Clinical Data Across Multiple Indications
Ascentage Pharma has initiated 19 clinical studies of lisaftoclax globally, treating more than 600 patients, including over 300 with CLL/SLL. Initial results from a global Phase II study demonstrated encouraging objective response rates when lisaftoclax was combined with next-generation BTKi acalabrutinib, achieving an ORR of 100% (16/16) in treatment-naïve patients and 98% (56/57) in relapsed/refractory patients.
At the 65th American Society of Hematology Annual Meeting, Ascentage Pharma presented results from three clinical studies of lisaftoclax, expanding evidence of its therapeutic potential across multiple hematologic malignancies.
CLL Clinical Results
Updated data from two Phase 1b/2 studies (APG-2575-CN001 and APG-2575-CC101) in 47 CLL patients showed an overall response rate of 73.3% (33/45) and a complete response/incomplete hematological recovery rate of 24.4% (11/45). The median follow-up duration was 14.06 months, with patients having received a median of multiple prior treatment lines. Notably, 23.4% of patients had prior BTKi exposure and 66.0% had received two or more lines of treatment.
Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, stated: "Lisaftoclax is the first Bcl-2 inhibitor in China and the second globally that has demonstrated promising efficacy. Clinical results to be presented at the ASH Annual Meeting this year further validate the drug's potential as an alternative treatment option for a number of hematologic malignancies, including R/R CLL."
Expansion into AML and MDS
A multicenter Phase 1 study evaluated lisaftoclax as monotherapy and in combination with azacitidine or homoharringtonine in 115 patients with treatment-naïve or relapsed/refractory acute myeloid leukemia, myelodysplastic syndrome, or other myeloid neoplasms. Among 21 treatment-naïve AML patients, the ORR and composite remission rate were 71.4% and 47.6%, respectively. In 36 relapsed/refractory AML patients, these rates were 75.0% and 44.4%, with a progression-free survival of 10.22 months.
Multiple Myeloma Activity
The first data in relapsed/refractory multiple myeloma showed lisaftoclax combination regimens achieved an ORR of 66.7% in 21 evaluable patients when combined with pomalidomide and dexamethasone. The study enrolled 30 patients across three treatment arms, with a median of 4 prior therapy lines and 18 patients being triple-class-exposed.
Safety Profile and Mechanism of Action
Lisaftoclax demonstrated favorable tolerability across studies with manageable adverse events. In CLL patients, 76.6% experienced grade ≥3 treatment-emergent adverse events, with only one incident of tumor lysis syndrome reported. The drug utilizes a daily dose ramp-up schedule to prevent tumor lysis syndrome while allowing patients to quickly reach target doses.
As a selective Bcl-2 inhibitor, lisaftoclax works by blocking the antiapoptotic protein Bcl-2, thereby restoring normal apoptosis processes in cancer cells. This mechanism represents a targeted approach to treating malignancies that rely on Bcl-2 for survival.
Global Development Strategy
Ascentage Pharma has positioned lisaftoclax as a key asset with global best-in-class potential. The company is conducting more than 40 Phase I/II clinical trials across the US, Australia, Europe, and China, focusing on therapeutics that inhibit protein-protein interactions to restore programmed cell death.
The upcoming Phase III trial represents a critical step toward potential regulatory approval and could address significant unmet medical needs in CLL/SLL treatment, particularly for patients who have developed resistance to current therapies or experienced relapse after initial treatment success.
