Lisaftoclax (APG-2575; BCL-2-selective inhibitor)
A Highly selective and potent BCL-2 Inhibitor for the Treatment of
Multiple Solid and Hematologic Malignancies
Lisaftoclax was developed to target the BCL-2-regulated apoptosis pathway, which is the most important intrinsic apoptotic pathway for cancer. As a prime example of rational drug design, Ascentage has engineered a state-of-the-art, highly selective, oral BCL-2 inhibitor with a unique pharmacokinetic (PK) profile. This PK profile, which features a short elimination half-life and a high maximum concentration (Cmax), is based on the principles of the “hit and run” hypothesis critical for BCL-2 inhibition. The “hit” signifies potent target inhibition at Cmax, while the “run” relates to limited plasma residence because of the short half-life, which may circumvent potentially later-emerging systemic toxicities. Our preclinical and preliminary clinical data suggest significant efficacy for lisaftoclax while potentially limiting toxicities such as neutropenia, thrombocytopenia, and tumor lysis syndrome. Another potentially beneficial property of lisaftoclax is a short ramp-up period (1 week), which quickly allows patients to receive the full therapeutic dose of drug while potentially reducing burden on the healthcare system.
Lisaftoclax is currently in clinical development as a single agent or in combination for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, acute myeloid leukemia, multiple myeloma (MM), and Waldenström macroglobulinemia (WM), with potential for treatment of additional types of solid tumors and hematologic malignancies.
Lisaftoclax has been granted Orphan Drug Designations by the US Food and Drug Administration (FDA) for the treatment of CLL, WM, MM and AML.
Ascentage retains global rights to lisaftoclax and is conducting global studies in multiple cancer types, as both a single agent and in combination with other standard-of-care drugs.
Pelcitoclax (APG-1252; dual BCL-2/BCL-xL inhibitor)
A Potent, Dual BCL-2/BCL-xL Inhibitor for Treatment of Lung Cancer and Myeloproliferative Neoplasms
Pelcitoclax is a novel, highly potent, small-molecule candidate designed to restore apoptosis through selective inhibition of BCL-2 and BCL-xL proteins. This agent has demonstrated an overall favorable safety and tolerability profile, including limited platelet toxicity. Its safety profile as a single agent suggests broad potential as one component of a combination approach. Pelcitoclax combination treatments are being evaluated for the treatment of small-cell and non-small-cell lung cancer and has potential in the treatment of specific lymphomas, gastrointestinal tumors, and myelofibrosis.
APG-1252 has been granted Orphan Drug Designations by the US Food and Drug Administration (FDA) for the treatment of small cell lung cancer.
Ascentage retains global rights to APG-1252 and is conducting global studies.
Alrizomadlin (APG-115; MDM2 inhibitor)
An MDM2-p53 Inhibitor for Solid Tumors and Hematologic Malignancies
Targeting the MDM2-p53 pathway, alrizomadlin is an orally administered, selective, small-molecule inhibitor of the MDM2-p53 protein-protein interaction that is designed to overcome the tumor suppression activity of p53 and induce apoptosis in cancer cells. The mechanism of action and favorable safety profile of alrizomadlin enable it to be evaluated either as a single agent or in combinations, because nonclinical data suggest that alrizomadlin demonstrates resensitization to immune therapies.
In addition, alrizomadlin-mediated p53 activation promotes antitumor immunity in the tumor microenvironment. As a single agent, alrizomadlin increases T-cell proliferation, enhances CD4⁺ T-cell activation, promotes a shift of immunosuppressive M2, to proinflammatory M1, macrophages, and upregulates programmed death ligand-1
(PD-L1) expression on tumor cells in vitro and in vivo. In immunocompetent syngeneic tumor models, alrizomadlin synergizes with programmed death-1 (PD-1) blockade to enhance antitumor immunity.
In 2020, FDA granted alrizomadlin Orphan Drug Designations (ODD) for the treatment of gastric cancer, soft-tissue sarcoma, and AML. In 2022, FDA granted Rare Pediatric Disease Designation of APG-115 in neuroblastoma. In addition, the FDA granted Orphan-Drug Designation for APG-115 for the treatment of neuroblastoma.
Alrizomadlin is currently being evaluated in global trials for the treatment of various solid tumors and hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome, T-cell prolymphocytic leukemia, malignant peripheral-nerve sheath tumor, melanoma, salivary gland carcinoma, and other potential indications. Combination therapy of alrizomadlin with immuno-oncologic medications have entered clinical development for patients with various solid tumors in US, Australia and China.
The preliminary clinical data from an ongoing Phase II study has shown that alrizomadlin in combination with pembrolizumab is efficacious in patients with IO relapsed/refractory metastatic melanoma, including uveal, mucosal and cutaneous melanoma.
APG-1387 (IAP inhibitor)
A Second Mitochondria-Derived Activator of Caspase (SMAC) Mimetic Dimer Inhibitor of Apoptotic Proteins (IAP) Antagonist for Treatment of Solid Tumors and Chronic Hepatitis B (CHB) Infection
APG-1387 is a novel and highly specific, small molecule antagonist of IAP designed to restore caspase activity and induce apoptosis. IAPs are a family of proteins that act to promote cell survival. APG-1387 was designed to block the activity of IAP family proteins (i.e. XIAP, cIAP-1, cIAP-2, ML-IAP), key regulators of apoptosis frequently found to be overexpressed in various cancers and virally infected cells. APG-1387 has potential in the treatment of heavily pretreated advanced solid tumors, when combined with immuno-oncologic medications or chemotherapies. APG-1387 is also being evaluated in the combination setting for the treatment of CHB infection.
APG-1387 is being evaluated in combination with the nucleos(t)ide analog entecavir for management of CHB infection. Upregulated IAP expression in liver tissue of HBC patients may promote HBV-infected hepatocytes survival during immune clearance of HBV, resulting in persistent infection. Targeting IAPs in both liver cells and lymphocytes may promote HBV-specific T cell – mediated clearance of viral DNA and antigens to potentially cure HBV infection. As an IAP inhibitor, APG-1387 plays an important role in immune modulation, which partially contributes to its mechanisms of action in cancer and CHB treatment.
APG-1387 is also has potential in the treatment of solid tumors and is being evaluated in a combination approach for the management of advanced pancreatic cancer. Upregulation of IAPs is associated with many cancer types as a mechanism of resistance to cell death. As an IAP inhibitor, APG-1387 plays an important role in induction of immune modulation, which also contributes to its mechanisms of action in cancer. APG-1387 is currently used in combination with chemotherapeutic agents for treatment of patients with metastatic pancreatic cancers; also used in combination with immuno-oncology therapy for treatment of patients with advanced head & neck cancers including NPC or other solid tumors in China and in US.