The National Medical Products Administration’s Center for Drug Evaluation in China has accepted and recommended priority review designation for the new drug application (NDA) seeking approval of lisaftoclax (APG-2575) for use in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This regulatory milestone could pave the way for a new treatment option for patients in China battling these hematologic malignancies.
The application is supported by findings from a registrational phase 2 trial (APG2575CC201) conducted in China. This trial specifically examined the safety and efficacy of lisaftoclax, a BCL-2 inhibitor, in the target population of patients with relapsed or refractory CLL/SLL. The primary endpoint of the study is overall response rate (ORR).
Ascentage Pharma's Perspective
Dajun Yang, MD, PhD, chairman & chief executive officer of Ascentage Pharma, emphasized the company's extensive experience in developing apoptosis-targeted therapies, particularly those targeting BCL-2. He noted that only one BCL-2 inhibitor has been approved globally to date, highlighting the challenges in this field. Yang stated that this NDA submission for lisaftoclax could potentially lead to its approval as the first China-developed BCL-2 inhibitor, marking a major achievement for Ascentage Pharma.
Ongoing and Prior Clinical Trials
In August 2023, the FDA cleared a global, registrational, phase 3 study (APG2575CG301) evaluating lisaftoclax in combination with BTK inhibition for patients with relapsed or refractory CLL/SLL who had previously received a BTK inhibitor. Lisaftoclax was also previously investigated in a phase 1/2 trial (NCT04215809) in combination with acalabrutinib (Calquence) or rituximab (Rituxan) in patients with treatment-naive or relapsed/refractory CLL/SLL. In treatment-naive patients (n = 16), the combination of lisaftoclax and acalabrutinib resulted in an ORR of 100%. In relapsed/refractory patients (n = 57), the ORR was 98%.
Phase 1/2 Trial Details
The early-phase trial enrolled patients with confirmed CLL/SLL requiring therapy based on the 2018 International Workshop on CLL (iwCLL) criteria. Key inclusion criteria included an ECOG performance status of 0 to 2 and adequate bone marrow, renal, and hepatic function. Exclusion criteria involved significant cardiovascular disease, a QTc interval exceeding 480 ms, or the use of warfarin or equivalent vitamin K antagonists. Notably, patients with disease relapsed or refractory to a BCL-2 inhibitor were eligible for enrollment in the acalabrutinib cohorts.
In the dose-escalation phase, single-agent lisaftoclax was administered at doses of 400 mg (n = 18), 600 mg (n = 16), and 800 mg (n = 12). Subsequently, lisaftoclax was combined with rituximab (n = 9) or acalabrutinib (n = 9) at the same dose levels (400 mg, 600 mg, and 800 mg, n = 3 per cohort). Rituximab was given at 375 mg/m2 on day 8 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6. Acalabrutinib was administered continuously at 100 mg twice daily.
During the dose-expansion phase, lisaftoclax/rituximab cohort (n = 30) received lisaftoclax at doses of 400 mg (n = 10), 600 mg (n = 12), and 800 mg (n = 8). In the lisaftoclax/acalabrutinib cohort (n = 70), the agent was explored at the same dose levels of 400 mg (n = 13), 600 mg (n = 42), and 800 mg (n = 15).
Safety Profile
In the monotherapy cohort, the most common grade 3 or 4 toxicities associated with lisaftoclax included neutropenia (30.3%), COVID-19 (28%), pneumonia (6.5%), febrile neutropenia (4%), multiorgan failure (2%), and clinical tumor lysis syndrome (TLS; 2%). The most common grade 3/4 toxicities in the rituximab cohort were neutropenia (21%) and clinical TLS (2.7%). In the acalabrutinib cohort, these included neutropenia (23%), COVID-19 (11.5%), atrial fibrillation (3.8%), and abscesses (3%).
