Lisaftoclax NDA Accepted for Review in China for Relapsed/Refractory CLL/SLL

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The National Medical Products Administration’s Center for Drug Evaluation in China has accepted and recommended priority review designation the new drug application (NDA) seeking the approval of lisaftoclax (APG-2575) for use in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

The application is supported by findings from a registrational phase 2 trial (APG2575CC201) has been completed in China, which examined the safety and efficacy of the BCL-2 inhibitor in this population. The primary end point of the study is overall response rate (ORR).

“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,” Dajun Yang, MD, PhD, chairman & chief executive officer of Ascentage Pharma stated in a news release. “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.”

Last year, in August 2023, the FDA cleared a global, registrational, phase 3 study (APG2575CG301) that is evaluating lisaftoclax paired with BTK inhibition in patients with relapsed or refractory CLL/SLL who previously received a BTK inhibitor.^2,3 The agent was previously examined in a phase 1/2 trial (NCT04215809), which examined the agent with acalabrutinib (Calquence) or rituximab (Rituxan) in patients with treatment naive or relapsed/refractory CLL/SLL.4 In evaluable patients with treatment naive disease (n = 16), lisaftoclax paired with acalabrutinib led to an ORR of 100%; in evaluable patients with relapsed/refractory disease (n = 57), the ORR was 98%.^4,5

The early-phase trial enrolled patients with confirmed CLL/SLL requiring therapy per the 2018 International Workshop on CLL (iwCLL) criteria. Participants had an ECOG performance status of 0 to 2 and acceptable bone marrow, renal, and hepatic function. Exclusion criteria included significant cardiovascular disease, a QTc interval over 480 ms, or receipt of warfarin or an equivalent vitamin K antagonist; other anticoagulants were permitted. Notably, those whose disease was relapsed or refractory to a BCL-2 inhibitor were allowed to enroll in the acalabrutinib cohorts.

In the first part of the dose-escalation phase, patients were given single-agent lisaftoclax at the following doses: 400 mg (n = 18), 600 mg (n = 16), and 800 mg (n = 12). In the second part, patients received lisaftoclax plus rituximab (n = 9) or acalabrutinib (n = 9) at the following doses 400 mg, 600 mg, and 800 mg (n = 3/cohort). Rituximab was given at a dose of 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 a twice-daily dose of 100 mg.

In the dose-expansion phase, patients in the 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).

In the monotherapy cohort, the most common grade 3 or 4 toxicities experienced 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%).

References

1. Ascentage Pharma announces a new drug application for its novel Bcl-2 inhibitor lisaftoclax accepted and recommended priority review designation by CDE of China NMPA. News release. Ascentage Pharma. November 17, 2024. Accessed November 20, 2024. https://www.ascentage.com/ascentage-pharma-announces-a-new-drug-application-for-its-novel-bcl-2-inhibitor-lisaftoclax-accepted-and-recommended-priority-review-designation-by-cde-of-china-nmpa/
2. Pipeline. Ascentage Pharma. Accessed November 20, 2024. https://www.ascentage.com/science/pipeline/
3. Ascentage Pharma received clearance from US FDA to proceed with global registrational phase III clinical trial for lisaftoclax (APG-2575) in previously treated patients with CLL/SLL. News release. Ascentage Pharma. August 6, 2023. Accessed November 20, 2024. https://ascentage.com/ascentage-pharma-received-clearance-from-u-s-fda-to-proceed-with-global-registrational-phase-iii-clinical-trial-for-lisaftoclax-apg-2575-in-previously-treated-patients-with-cll-sll/
4. Davids MS, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL): initial data from a phase 2 global study. Blood. 2022;140(suppl 1):2326-2328. doi:10.1182/blood-2022-160386
5. Live from ASH 2022 | Ascentage Pharma presents latest data of APG-2575, including encouraging results of the combination with BTKi in patients with R/R CLL/SLL. News release. Ascentage Pharma. December 14, 2022. Accessed November 20, 2024. https://ascentage.com/live-from-ash-2022-ascentage-pharma-presents-latest-data-of-apg-2575-including-encouraging-results-of-the-combination-with-btki-in-patients-with-r-r-cll-sll/