Our Pipeline

Summary

Lisaftoclax (APG-2575): BCL-2 Selective Inhibitor for Solid and Hematologic Malignancies

APG-2575 is an orally active, highly selective small molecule antagonist of BCL-2. Mechanistically, APG-2575 induces cellular apoptosis through selective disruption of interaction of anti-apoptotic protein BCL-2 with pro-apoptotic proteins such as BIM. APG-2575 effectively competes with BIM for the binding to the BCL-2:BIM complex. Consequently, pro-apoptotic protein BIM is released from the complex to trigger the downstream apoptotic signaling cascade, leading to apoptotic cell death of cancer cells. In addition, APG-2575 upregulates another pro-apoptotic BH3-only protein NOXA. Thus, APG-2575 induces cellular apoptosis by disrupting BCL-2/BH3 interactions, and indirectly neutralizing MCL-1 functions, leading to downstream caspase activation.
Through potently inducing apoptosis of cancer cells, APG-2575 demonstrates single-agent activity in the preclinical models of hematologic malignancies, such as CLL, ALL, AML, DLBCL, FL, MM and WM. Such activity is further enhanced in combination treatment. Synergistic activity of APG-2575 combination treatment is well established in solid tumors.

Through the use of a classic rational design approach to the discovery of this candidate, lisaftoclax demonstrates unique pharmacokinetic properties in the inhibition of its target. These properties include potent inhibition at the time of maximum concentration with limited persistence in plasma. Data support clinical efficacy with a promising safety profile. In addition, the short ramp-up period for lisaftoclax dosing provides potential advantages both for patients and the health care system.

Currently, APG-2575 is under clinical development in patients with hematologic malignancies and breast cancer globally.
Lisaftoclax is in development as a single agent or as a component of combination therapy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), acute myeloid leukemia (AML) and Waldenström macroglobulinemia (WM), and has potential for development in additional indications. Lisaftoclax has been granted Orphan Drug Designations by the U.S. FDA for the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, AML and FL . Proof-of-concept has been achieved in the patients with CLL.

Commercial Rights

Ascentage retains global rights for lisaftoclax and is pursuing initial registration in major markets both as a single agent and in combination with other standard of care therapeutics.

Partnerships

Clinical Trials

Summary

Alrizomadlin (APG-115): MDM2-p53 Inhibitor for Solid and Hematologic Malignancies

APG-115 is a potent, orally bioavailable MDM2 inhibitor that binds to human recombinant MDM2 protein with high affinity. Mechanistically, APG-115 interferes the binding of MDM2 oncoprotein with the tumor suppressor P53 protein, leads to increased P53 and P21 protein expression and trigger P53-mediated apoptosis. In addition to its direct tumor-targeting activity, APG-115 plays an important role in immune modulation through its effects on immune cells, tumor cells and multiple cytokines.
Alrizomadlin single agent or in combination with other agents demonstrates potent antitumor activity in a xenograft tumor models of various TP53 wild-type cancer types, including solid tumors and hematologic malignancies. In syngeneic mouse tumor models, alrizomadlin promotes antitumor immunity in the tumor microenvironment (TME) and enhances the antitumor response of PD-1 blockade. Such an immune enhancing effect of APG-115 is independent of P53 status of tumors due to its T cell-dependent antitumor activity induced through the TME.

In clinic,, Alrizomadlin monotherapy and combination (i.e., PD-1 blockade) therapy are being developed for the treatment of various solid tumors and hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), T-cell prolymphocytic leukemia (T-PLL), and malignant peripheral-nerve sheath tumor (MPNST), advanced solid tumors, as well as other indications. Alrizomadlin has been granted Orphan Drug Designations by the U.S. FDA for the treatment of gastric cancer, soft-tissue sarcoma, AML, Retinoblastoma, IIB-IV melanoma and Neuroblastoma.

Impressively, synthetic lethality is achieved by simultaneously triggering both BCL-2-mediated mitochondrial apoptosis by APG-2575 and MDM2-P53 apoptosis by APG-115 in preclinical models of solid and hematologic malignancies. Thus, the combination treatment is able to overcome multiple drug resistance to current therapeutics.

Commercial Rights

Ascentage has global rights, US Clinical Collaboration for Phase II combination trial with pembrolizumab for advance solid tumors.

Summary

APG-1387: SMAC Mimetic Dimer IAP Antagonist for Solid Tumors and Chronic Hepatitis B Infection

APG-1387 is a novel and highly specific small molecule IAP antagonist designed to restore caspase activity and induce apoptosis. APG-1387 as a component of combination therapy with immuno-oncology or chemotherapy treatment has notable potential to improve treatment for solid tumors that have been refractory to multiple prior lines of therapy. This candidate is being evaluated in a combination approach for the treatment of advanced pancreatic cancer. In addition, APG-1387 combination therapy is being evaluated for the treatment of chronic hepatitis B infection.

Commercial Rights

Ascentage has global rights.

Clinical Trials

Summary

Pelcitoclax (APG-1252): Dual BCL-2/BCL-xL Inhibitor for Lung Cancer and Other Solid Tumors

Pelcitoclax is a novel, highly potent, small molecule designed to restore apoptosis through selective disruption of interaction of antiapoptotic proteins BCL-2 and BCL-xL with proapoptotic proteins such as BIM, etc. This agent has demonstrated reduced platelet toxicity and improved tolerability relative to others of the dual BCL-2 and BCL-xL inhibitor class. Its safety profile as a single agent suggests broad potential as a component of a combination approach to treatment. Pelcitoclax combination treatments are being evaluated for the treatment of lung cancers (small cell lung cancer and non-small cell lung cancer) and has potential in the treatment of specific lymphomas, gastrointestinal tumors, and myelofibrosis.

Commercial Rights

Ascentage retains global rights for commercial development of pelcitoclax.

Partnerships

Clinical Trials