On August 12, 2024 Ascentage Pharma (6855.HK), a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing both first- and best-in-class therapies for malignancies, reported that it has been cleared by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) to initiate a registrational Phase III study of lisaftoclax (APG-2575), one of the company’s key drug candidates, in combination with azacitidine (AZA) for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS) (Press release, Ascentage Pharma, AUG 12, 2024, View Source [SID1234645753]). This clears the fourth registrational Phase III study of lisaftoclax, marking another major milestone in the clinical development of the drug.

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This study (GLORA-4) is a multi-center, randomized, double-blind, pivotal registrational Phase III trial to evaluate the efficacy of lisaftoclax in combination with AZA in newly-diagnosed adult patients with higher-risk MDS.

As a heterogeneous myeloid clonal disease originating from hematopoietic stem cells, MDS commonly occurs in older population with a median age of onset of 70 years and an incidence rate that increases with age.1 MDS is characterized by the abnormal growth of myeloid cells. Its clinical manifestations include hematopoietic failure, refractory cytopenia, and the propensity for high-risk patients to progress to acute myeloid leukemia (AML). Data show that approximately 10% of low-risk patients and 50% of high-risk patients with MDS would progress to AML and thereafter face a dismal prognosis.2

At present, there are limited treatment options for patients with MDS and the treatment outcome for most patients remains relatively poor. Demethylation agents (AZA or decitabine) are the current standard first-line treatment for patients with higher-risk MDS. Studies showed that compared to conventional care regimens, monotherapy with AZA can improve the overall survival of patients with MDS.3 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only available curative treatment for MDS. However, the complex characteristics of MDS and the old ages of patients have resulted in the intolerability of chemotherapies that limited the rate of transplantation, and the high rate of transplantation-associated mortality among patients with MDS. The low survival rate of patients with higher-risk MDS underscores an urgent unmet medical need for novel therapies and medicines that can offer higher efficacies.

Lisaftoclax is a novel, orally administered Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat the patients with malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is expected to be the first Bcl-2 inhibitor for which an NDA will be filed for chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) in China and the second anywhere globally that has demonstrated clinical activity for the treatment of patients with CLL and entered pivotal registrational studies. In published clinical results released at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, the drug candidate lisaftoclax has demonstrated clinical benefit and tolerability in patients with higher-risk MDS.4

"There is considerable unmet clinical need for patients with MDS. Lisaftoclax, a Bcl-2 inhibitor, has already shown promising clinical benefit and tolerability in early studies in patients with MDS," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "We are very encouraged by this approval for initiation of the registrational Phase III study in the first-line treatment of patients with higher-risk MDS, as it clears the way for the fourth registrational Phase III study of lisaftoclax. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will actively press ahead with the clinical trials of lisaftoclax for the benefit of more patients."

*Lisaftoclax is an investigational drug that has not been approved in any country or region.