Live from ASH 2024 | Ascentage Pharma Releases Updated Data of Bcl-2 Inhibitor Lisaftoclax in MDS that Demonstrates Potential Clinical Benefits and Favorable Safety

At the 66th American Society of Hematology (ASH) Annual Meeting, Ascentage Pharma has unveiled promising updates on its Bcl-2 inhibitor, lisaftoclax, in the treatment of myelodysplastic syndromes (MDS). The company's latest data from a Phase 1b/2 study showcases the potential clinical benefits and favorable safety profile of lisaftoclax in combination with azacitidine, a hypomethylating agent.

MDS is a group of blood cancers that affect the bone marrow, leading to abnormal blood cell production. The standard of care for MDS typically involves hypomethylating agents like azacitidine, but new therapeutic options are needed, especially in cases of resistance or failure. Enter lisaftoclax, a novel, investigational BCL-2 inhibitor that has shown synergistic effects when combined with an HMA in preclinical studies.

The Phase 1b/2 study enrolled 49 patients with higher-risk MDS, including those with treatment-naïve (TN) or relapsed or refractory (R/R) disease. Patients received lisaftoclax alone at an assigned dose (400, 600, or 800 mg) orally once daily from Days 1 to 14, combined with azacitidine (75 mg/m2/day) on Days 1 to 7 in repeated 28-day cycles. A daily ramp-up was used before the first cycle to prevent tumor lysis syndrome (TLS).

The primary objectives of the study were to assess the efficacy and safety of this combination in patients with MDS and establish the recommended phase 3 dose for lisaftoclax. Complete response (CR) and marrow CR rates were evaluated in accordance with 2006 International Working Group (IWG) criteria.

As of July 1, 2024, the overall response rate (ORR) in the combination therapy was 75.0% (95% CI, 34.9-96.8) in patients with R/R MDS and 77.5% (95% CI, 61.5-89.2) in patients with TN MDS. Notably, the CR rate in TN MDS patients was 25.0% per IWG 2006 criteria. Furthermore, the composite CR rate (CR2023 = CR + CRL) in 23 patients with TN MDS receiving lisaftoclax 600 mg combined with azacitidine was 69.6%, with a median time to CR of 2.84 months.

The combination therapy demonstrated manageable safety, with no 60-day mortality and few dose modifications. Common grade ≥ 3 nonhematologic TEAEs included pneumonia (24.4%) and hypokalemia (10.2%), while common grade ≥ 3 hematologic TEAEs included leukocyte count decreased (75.5%), neutropenia (69.4%), and thrombocytopenia (65.3%). Neither 60-day mortality nor TLS was reported, and lisaftoclax dose reduction occurred in only 4 (8.2%) patients.

These encouraging results support the emerging role of lisaftoclax in combination with azacitidine for the treatment of patients with higher-risk TN or R/R MDS. The combination therapy was efficacious and well-tolerated, resulting in no 60-day mortality, few dose modifications, and low infection rates. Ascentage Pharma's findings at ASH 2024 underscore the potential of lisaftoclax in addressing the unmet medical needs of MDS patients and highlight the importance of continued clinical development in this area.