On June 12, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released results from a Phase I study of the company’s novel Bcl-2-selective inhibitor lisaftoclax (APG-2575) in Chinese patients with relapsed/refractory non-Hodgkin lymphoma (r/r NHL) at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (EHA 2022) (Press release, Ascentage Pharma, JUN 12, 2022, View Source;ascentage-pharma-releases-encouraging-results-of-bcl-2-inhibitor-lisaftoclax-apg-2575-in-chinese-patients-with-relapsedrefractory-non-hodgkin-lymphoma-301566251.html [SID1234615913]).
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The EHA (Free EHA Whitepaper) Congress is the largest gathering of the hematology field in Europe. It showcases the most cutting-edge research and state-of-the-art innovative therapies, attracting over 10,000 clinical experts and researchers from more than 100 countries every year.
The data presented at this year’s EHA (Free EHA Whitepaper) Congress show that lisaftoclax was well tolerated at doses of up to 800 mg/day, without evidence of tumor lysis syndrome (TLS). In addition, lisaftoclax demonstrated preliminary efficacy in a range of relapsed/refractory hematologic malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and T-cell NHL, having achieved 4 complete responses (CRs) and 8 partial responses (PRs) in 32 efficacy evaluable patients.
In the 11 efficacy evaluable patients with CLL (all of whom were heavily pretreated and had failed prior therapies such as chemoimmunotherapies and Bruton’s tyrosine kinase [BTK] inhibitors, and the majority had at least 1 type of adverse prognostic factors such as 17p deletion/TP53 mutation), there were 8 efficacy evaluable patients in cohorts received 200 mg or higher doses, including 3 CRs and 4 PRs, thus demonstrating an ORR of 87.5%. In the 6 efficacy evaluable patients with MCL, the ORR was 33.3% (1 CR). In the 4 efficacy evaluable patients with MZL, the ORR was 50%. In the 3 efficacy evaluable patients with T-cell NHL, the ORR was 33.3%.
Lisaftoclax is a novel, orally administered small-molecule Bcl-2-selective inhibitor being developed by Ascentage Pharma to treat hematologic malignancies and solid tumors by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor developed and entering clinical development in China, and is also the second such agent entering pivotal trials globally. Lisaftoclax is being studied in multiple clinical studies encompassing a range of solid tumors and hematologic malignancies, and has shown high clinical potential.
Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented, "Lisaftoclax is a key drug candidate in Ascentage Pharma’s apoptosis-targeted pipeline. It has shown favorable tolerability and efficacy in multiple clinical studies in patients with solid tumors and hematologic malignancies. The drug candidate’s therapeutic potential was further validated by the data released at EHA (Free EHA Whitepaper) 2022. We will press ahead with the clinical development of lisaftoclax in efforts to bring a much-needed new treatment option to patients."
Highlights of this abstract on lisaftoclax are as follows:
Preliminary Results of a Phase 1 Study of Novel Bcl-2 Inhibitor Lisaftoclax (APG-2575) in Chinese Patients (pts) with Relapsed or Refractory (r/r) Non-Hodgkin Lymphomas (NHLs)
Abstract: #P1106
Highlights:
This multicenter, single-agent, Phase I trial consists of a dose escalation and a dose expansion and is the first-in-human study of lisaftoclax in adults with R/R NHL in China. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of lisaftoclax in Chinese patients with R/R NHL.
Patients were dosed with lisaftoclax orally once daily in 28-day cycles. A daily ramp-up schedule was used in patients with CLL or NHL with medium/high-risk TLS.
As of January 1, 2022, 40 patients had been treated with lisaftoclax (dose range 20-800 mg), including 20 who remain in the trial. NHL subtypes included: 12 CLL, 9 follicular lymphoma (FL), 7 MCL, 4 MZL, 4 T-cell lymphoma, 2 diffuse large B-cell lymphoma, and 2 Waldenström macroglobulinemia.
With a median treatment duration of 4 cycles, 4 of 32 evaluable patients achieved CR and 8 achieved PR, resulting in an ORR of 37.5%. In the 11 evaluable patients with CLL, the ORR was 63.6%, the CR rate was 27.3%, and the PR rate was 36.4%. In patients with CLL treated at doses ≥ 200 mg, the ORR was 87.5%. In the 6 evaluable patients with MCL, 1 patient achieved CR and 1 achieved PR. In the 4 evaluable patients with MZL, 2 achieved PR. In the 3 evaluable patients with T-cell NHL, 1 achieved PR.
Lisaftoclax was generally well tolerated. Most treatment-emergent adverse events (TEAEs) were grade 1-2 (67.5%). Dose-limiting toxicity (DLT) and laboratory/clinical TLS were not observed in any of the dose cohorts, and there were no dose-reduction or discontinuation due to intolerance.
Conclusions:
Lisaftoclax showed promising antitumor activity and favorable responses in subtypes of NHL including CLL/SLL, MZL, MCL, T-cell NHL. In addition, lisaftoclax demonstrated a favorable safety profile, with no TLS or DLT observed during the dose ramp-up from 20 mg – 800 mg/day.