Our Pipeline

The ability to create compounds that affect apoptosis allows new approaches to treat diseases where cell death has an important role, including cancers, hepatitis B and age-related disease.

Ascentage has a four small molecule candidates that act via the several major molecular pathways linked to apoptosis. Each candidate is designed with attributes providing the potential to lead to a best in class or first in class therapy and are being developed to address specific needs in markets around the world.

Next-Generation Kinase Inhibitors

Candidate
Candidate
Molecule
Molecule
Condition
Condition
Preclinical
Pre
Phase I
Ph I
Phase II
Ph II
Filed
Filed
Marketed
Mkd
BCR-ABL/KIT
Resistant CML
Resistant CMLCOUNT: 2
GIST
GISTCOUNT: 1
Ph + ALL
Ph + ALLCOUNT: 1

Summary

Olverembatinib (HQP1351): BCR-ABL/KIT Kinase Inhibitor for Treatment Resistant Cancers including Chronic Myeloid Leukemia (CML), Acute Lymphoblastic Leukemia (ALL) and Gastrointestinal Stromal Tumors (GIST)

Acquired resistance to treatment is a significant and widely recognized challenge in the treatment of CML. Olverembatinib was engineered to address this challenge, demonstrating clinical efficacy in the presence of the key T315I mutation that confers resistance to most of the current tyrosine kinase inhibitor therapeutics. In addition to T315I mutation, olverembatinib has also shown clinical activity in disease characterized by multiple additional mutations and compound mutations. Beyond its efficacy in the treatment of resistant disease, olverembatinib has shown high potency in the management of treatment-naive CML expressing BCR-ABL, implicating for its potential for the first line therapy. Another advantage of olberembatinib demonstrated in clinic is its favorable safety profile in comparison with the counterparts.

Olverembatinib is also under the clinical development for the treatment of gastrointestinal stromal tumors (GISTs) owing to its potent activity in inhibiting c-KIT oncogene. The latter is the crucial driver in GISTs. Further, by targeting FLT3, olverembatinib has demonstrated potent antitumor activity in preclinical models of FLT3 mutant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Olverembatinib has been granted Fast Track and Orphan Drug Designations by the U.S. FDA for the treatment of patients with CML and has received the priority review for its New Drug Application from the China regulatory authorities.

Commercial Rights

Ascentage retains global commercial rights for olverembatinib and is pursuing regulatory approval in U.S. and China markets.

Partnerships

Clinical Trials

c-Met Selective
Cancer (c-Met+)
Cancer (c-Met+)COUNT: 1

Summary

HQP8361: Selective c-Met Kinase Inhibitor for c-Met Positive Cancers

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

Commercial Rights

In-licensed China Rights from MSD.

FAK/ALK/ROS1
NSCLC
NSCLCCOUNT: 1

Summary

APG-2449: FAK/ALK/ROS1 Tyrosine Kinase Inhibitor (TKI) for Non-Small Cell Lung Cancer (NSCLC) and other solid tumors

APG-2449 is a potent, orally bioavailable inhibitor of FAK, ROS1 and ALK tyrosine kinases. In preclinical models of ALK-positive NSCLC, APG-2449 has demonstrated antitumor activity and the ability to overcome resistant mutations the first generation and second generation ALK inhibitors, including G1202R mutations. In addition, APG-2449 single agent and combination therapy effectively inhibits tumor growth of ALK-positive neuroblastoma in preclinical setting.

Through targeting FAK signaling pathway, APG-2449 demonstrates synergistic or enhanced antitumor activity in combination therapy in the preclinical tumor models of mesothelioma, EGFR mutant NSCLC, and ovarian cancer.

APG-2449 is currently in clinical development for treatment of patients with NSCLC failed to respond to treatment with earlier-generation ALK inhibitors.

Commercial Rights

Ascentage has global rights.

Clinical Trials

Apoptosis Targets (Protein-Protein Interactions)

Candidate
Candidate
Molecule
Molecule
Condition
Condition
Preclinical
Pre
Phase I
Ph I
Phase II
Ph II
Filed
Filed
Marketed
Mkd
Bcl-2 Selective
CLL/SLL(China)
CLL/SLL(China)COUNT: 1
CLL/SLL(Global)
CLL/SLL(Global)COUNT: 1
WM
WMCOUNT: 1
T-PLL
T-PLLCOUNT: 1
AML
AMLCOUNT: 1
MM
MMCOUNT: 1
Solid Tumors
Solid TumorsCOUNT: 1
ER+/HER2- Breast Cancer
ER+/HER2- Breast CancerCOUNT: 1
MDS
MDSCOUNT: 1

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

Bcl-2/Bcl-xL
NSCLC + TKI
NSCLC + TKICOUNT: 1
MF
MFCOUNT: 1
NET
NETCOUNT: 1

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

MDM2-p53
Solid Tumors (IO combo)
Solid Tumors (IO combo)COUNT: 1
AML,MDS
AML,MDSCOUNT: 1

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.

IAP/XIAP
Solid tumors + IO
Solid tumors + IOCOUNT: 1
PDAC + Chemo
PDAC + ChemoCOUNT: 1
HBV
HBVCOUNT: 1

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

Discovery

Candidate
Candidate
Molecule
Molecule
Condition
Condition
Preclinical
Pre
Phase I
Ph I
Phase II
Ph II
Filed
Filed
Marketed
Mkd
EED Selective
Oncology / Hemoglobinopathy
Oncology / HemoglobinopathyCOUNT: 1

Summary

APG-5918, EED inhibitor for solid and hematologic malignancies

APG-5918 is a potent, selective and orally bioavailable EED inhibitor. As an epigenetic modifier, APG-5918 exerts its antitumor activity through allosterically inhibiting H3K27me3 recognition by EED, subsequently inhibiting the methyltransferase activity of polycomb repressive complex 2 (PRC2) and finally derepressing the transcription of tumor suppressor genes. APG-5918 demonstrates excellent antitumor activity in preclinical xenograft models of multiple blood cancers and solid tumors including EZH2 mutant diffuse large B cell lymphoma (DLBCL) and SMARCB1-deficient malignant rhabdoid tumor. APG-5918 is currently under preclinical development for IND filing.

Commercial Rights

Ascentage has global rights

PROTACs MDM2
PROTACs MDM2
PROTACs MDM2COUNT: 1

Commercial Rights

Agreement with the University of Michigan for Global rights.

Allosteric BCR-ABL
CML
CMLCOUNT: 1

Summary

AS1266, BCR-ABL1 allosteric inhibitor for CML

AS1266 is an allosteric inhibitor targeting BCR-ABL1, it specifically binds to the myristoyl pocket of BCR-ABL1 protein and inhibits the kinase activity. In ABL1 protein, the pocket is occupied by myristoylated N-terminus resulting in autoinhibition, however, the myristoylated N-terminus is lost in the BCR-ABL1 fusion protein in CML, leading to the constitutive activation of ABL1 kinase. Binding of AS1266 to the myristoyl pocket restores autoinhibition and this novel mechanism is proposed to increase AS1266’s specificity and safety in comparison to current tyrosine kinase inhibitors.

In preclinical settings, AS1266 demonstrated significant antiproliferative and antitumor activity in both BCR-ABL1 wild-type and T315I mutant cells and tumor models.

Bcl family
DME
DMECOUNT: 1

Commercial Rights

Ascentage has licensed a library of BCL2 family molecules to Unity for Non-Oncology rights in the US.