Research & Development

Ascentage is driven by science, combining knowledge of small molecule discovery and the ability to conduct clinical studies worldwide. Using state-of-the-art technologies, including chemical synthesis and targeted protein degradation (PROTAC knockdown), the company develops innovative therapeutic agents to treat cancers and improve options for patients.

The company’s distinctive expertise in understanding protein-protein interactions (PPI) enables the development of small molecule inhibitors aimed at critical molecular targets in multiple cell death pathways, including the BCL-2, MDM2-TP53, and IAP pathways. The company also develops next-generation cell signaling inhibitors (i.e., BCR-ABL1, ALK, FAK inhibitors) and epigenome-modifying agents (i.e., EED inhibitor) to address unmet medical needs. Our goal is to use emerging scientific discoveries to create breakthrough medicines in order to treat a wide range of cancers and other diseases.

 

Unlocking the
Potential of
Apoptosis

Each day, billions of cells in the body experience a natural process called programmed cell death, or apoptosis. In certain cancers, cells can evade this process, leading to excessive cell production and disease burden for patients. At Ascentage, novel investigational therapies are being engineered to renew intrinsic apoptogenic forces that facilitate killing of “rogue” cancer cells. Ascentage is at the forefront of the discovery and development of small molecule therapeutics targeting key protein-protein interactions (PPI) regulating apoptosis pathways.

 
Cell Death (or Apoptosis)
Promoting Compounds
Cell-Signaling Inhibitors

Cell Death (or Apoptosis) Promoting Compounds

Ascentage has built a pipeline of four clinical drug candidates designed to regulate apoptosis, including novel, potent highly selective Bcl-2 inhibitor and a dual Bcl-2/Bcl-xL inhibitor, and two additional anti-apoptosis drugs which target IAP and MDM2-p53 pathways.

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.

APG-2575

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.

Pelcitoclax (APG-1252; dual BCL-2/BCL-xL inhibitor)

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.

APG-115 diagram

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

Ascentage retains global rights to APG-1387.

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.

Cell-Signaling Inhibitors

The advent of targeted therapies has ushered in a new era of enhanced patient care. These therapies include tyrosine kinase inhibitors (TKIs) that modulate cancer cell signaling. Through state-of-the-art small molecule synthesis, discovery, and development, Ascentage endeavors to engineer innovative targeted therapies that advance the standard of care for patients with cancer.

Olverembatinib (HQP1351)

A Novel, Potent, Orally Active BCR-ABL1/KIT Tyrosine Kinase Inhibitor (TKI) for Treatment-Resistant Cancers, Including Chronic Myeloid Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Gastrointestinal Stromal Tumor (GIST)

Olverembatinib is the first third generation BCR-ABL1 TKI developed in China to treat drug-resistant CML. It is also the second such TKI developed around the world. Through state-of-the-art drug synthesis, discovery, and development, olverembatinib was engineered to address treatment acquired resistance, which is a major, widespread challenge in the treatment of CML. Nonclinical and clinical data suggest that olverembatinib retains efficacy in the presence of the pivotal “gatekeeper” T315I mutation, which confers resistance against most marketed TKIs. Further, olverembatinib retains clinical efficacy in the presence of other multiple mutations, which can complicate CML management with currently available TKIs. A potential added clinical advantage of olverembatinib is its favorable safety and tolerability profile.

In addition to CML, as a multikinase inhibitor, olverembatinib is in development for the treatment of GIST and has potential for development in multiple other malignancies, including acute myeloid leukemia and ALL, through inhibition of FLT3 and other drug targets.

Olverembatinib has been granted Fast Track and Orphan Drug Designations by FDA in 2020 for the treatment of patients with relapsed or refractory CML who failed to respond to existing TKIs. The New Drug Application of olverembatinib for treatment of relapsed or refractory CML -CP and CML-AP with T315I mutation has been approval by China’s National Medical Products Administration in November 2022.

Ascentage retains global commercial rights to olverembatinib.

APG-2449

A FAK/ALK/ROS1 Tyrosine Kinase Inhibitor (TKI) for Treatment of Non-Small-Cell Lung Cancer (NSCLC)

APG-2449 is a potent, orally bioavailable inhibitor of FAK, ROS1, and ALK kinase. In preclinical models, APG-2449 has demonstrated antitumor activity and overcomes drug resistance to first- and second-generation ALK inhibitors, particularly in the presence of G1202R and L1196 mutations. In addition, APG-2449 exhibits synergistic effects with approved EGFR inhibitors. As a new generation of ALK inhibitor, APG-2449 is currently in clinical development for treatment of patients with solid tumors including NSCLC that failed to respond to earlier-generation ALK inhibitors.

As a novel FAK and third generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), APG-2449 has a favorable safety and PK profile and was well tolerated in a Phase I study. Preliminary efficacy was observed in the patients with NSCLC whose disease was resistant to second-generation ALK TKIs, especially among those with brain metastases, and in TKI- naïve pts. Biomarker data indicated potential target engagement on FAK, ALK and immunomodulatory effects of APG-2449.

Ascentage retains global rights to APG-2449.

HQP8361

A Selective c-Met Tyrosine Kinase Inhibitor (TKI) for Treatment of c-Met-Positive Cancers

HQP8361 is a second-generation c-Met TKI in development for the treatment of
c-Met⁺ cancers, including gastric cancer, non-small-cell lung cancer (NSCLC), and liver cancer. HQP8361 is also being evaluated in clinical trials of combination treatment with an EGFR inhibitor for patients with EGFR TKI-resistant NSCLC. In early clinical studies, HQP8361 has been well tolerated and efficacious, conferring clinical benefits in patients with advanced cancers.

Ascentage retains Asia Pacific market rights to HQP8361 and is developing the compound in China.

Learn more about our apoptosis targeting therapies