Research & Development

Backed by our strong scientific foundation, knowledge of small molecule discovery and capabilities to conduct clinical trials worldwide, we use state-of-the-art technologies to develop innovative therapeutic agents to treat cancers and address unmet medical needs within this patient population. Our initial focus has been to leverage our expertise in chemistry to synthesize what we believe are best-in-class inhibitors targeting proteins and pathways that drive the key hallmarks of cancer. Earlier in our pipeline, we are harnessing our understanding of protein degraders to develop therapies, such as PROTACs, that target traditionally undruggable proteins that are implicated in oncogenesis.

We are empowered by our technical expertise in structure-based drug design and our innovative drug discovery engine, which allows us to address unmet medical need by targeting key apoptotic pathways and validated tyrosine kinases. These core competencies have allowed us to develop small molecule and degrader therapies targeted at Bcl-2, Bcl-2/Bcl-xL, IAP and MDM2, in addition to building next-generation cell signaling inhibitors (i.e., BCR-ABL1, ALK, FAK inhibitors) and epigenome-modifying agents (i.e., EED inhibitor). Beyond our two lead assets, we have several other potentially first- and/or best-in-class assets in U.S. or international clinical trials.

 

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 (APG-2575) is a novel, oral Bcl-2 inhibitor developed to treat a variety of hematologic malignancies and solid tumors by selectively blocking Bcl-2 to restore the normal apoptosis process in cancer cells.

We plan to submit an NDA for lisaftoclax for the treatment of r/r CLL/SLL to the Center of Drug Evaluation, or CDE, of China’s National Medical Products Administration, or NMPA, in 2024 and expect it will be the second Bcl-2 inhibitor for which an NDA application is filed in the world and the first in China for the CLL/SLL indication.

Currently, lisaftoclax has received clearances and approvals for 21 Phase Ib/II clinical studies in China, the United States, Australia, and Europe, with indications including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), non-Hodgkin’s lymphoma (NHL), AML, MDS, multiple myeloma (MM), Waldenström’s macroglobulinemia (WM), with potential for treatment of additional types of solid tumors and hematologic malignancies. Among those trials, we received clearances and approvals for registrational clinical trials for CLL/SLL, AML and MDS in multiple countries.

APG-2575

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.

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

Alrizomadlin (APG-115) is a novel, orally bioavailable, highly selective, small molecule inhibitor of mouse double minute 2 homolog, MDM2. Alrizomadlin is a MDM2 inhibitor that has a stable chemical structure, high cell permeability, high binding affinity and favorable PK profile. The MDM2 protein is an antagonist of the p53 transcription factor, a well-known tumor suppressor. Overexpression and amplification of MDM2 has been associated with various cancers, such as liposarcomas, soft tissue tumors, osteosarcomas, and esophageal carcinomas, and implicated in disease progression, treatment resistance and poor patient outcomes for other immunotherapies, such as PD-1/PD-L1 checkpoint inhibitors. Various approaches to inhibit MDM2 have been attempted for more than three decades, with hundreds of small molecule inhibitors evaluated in preclinical studies and clinical trials, but no MDM2 inhibitors havebeen approved to date. Using a structure-based approach, we designed a new class of potent, selective, cell permeable, non-peptidic, small molecule inhibitors of the MDM2, and selected alrizomadlin as our lead MDM2 inhibitor.

APG-115 diagram

Alrizomadlin is undergoing multiple clinical trials as a monotherapy or in combination with immunotherapy or chemotherapy in treating solid tumors and hematologic malignancies in sites around the world, including United States, China and Australia. We believe alrizomadlin has potential to treat a number of serious rare and orphan diseases and address unmet medical need in both adult and pediatric indications. Compared with adult tumors, pediatric solid tumors are characterized by low TP53 mutation frequency and high MDM2 amplification frequency. To date, the FDA has granted us six ODDs, including for soft-tissue sarcoma, gastric cancer and neuroblastoma, and two RPDD, including for neuroblastoma and retinoblastoma. In addition, we plan to pursue FTD, ODD and RPDD for our late-stage programs for alrizomadlin in malignant peripheral nerve sheath tumors, or MPNST, and adenoid cystic carcinoma, or ACC, for which we recently reported preliminary Phase 2 results in 2022 and 2023, respectively. The preliminary clinical data from an ongoing Phase II study has also shown that alrizomadlin in combination with pembrolizumab is efficacious in patients with IO relapsed/refractory metastatic melanoma, including uveal, mucosal and cutaneous melanoma. We are also developing alrizomadlin for the treatment of other solid tumors and hematological malignancies, including AML, MDS, and T-PLL.

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)

Our first lead asset, olverembatinib, is a novel, next-generation TKI. Olverembatinib is the first and only third generation BCR-ABL1 TKI approved in China for treatment of patients with CML-CP with T315I mutations, CML- AP with T315I mutations and CML-CP that is resistant and/or intolerant to first and second-generation TKIs. 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. Currently, olverembatinib has received clearances and approvals for registrational phase 3 clinical trials for CML, Ph+ALL and GIST in multiple countries.

The Food and Drug Administration (FDA) has granted four ODDs to olverembatinib, including for CML, ALL, AML and gastrointestinal stromal tumor (GIST), and Fast-Track Designation for treatment of CML in patients with certain genetic markers who have failed to respond to prior 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.

Furthermore, in January 2023, olverembatinib was successfully included in the 2022 NRDL for the indication of T315I- mutant CML-CP and CML-AP. The new version of the NRDL took effect on March 1, 2023, in China. The inclusion will bolster the accessibility of olverembatinib, allowing more CML patients to easily and affordably access the medication.

In November 2023, the China National Medical Products Administration (NMPA) has approved olverembatinib for the treatment of adult patients with CML-CP resistant and/or intolerant of first-and second-generation tyrosine kinase inhibitors (TKIs).

On June 14, 2024, Ascentage Pharma and Takeda entered into an exclusive option agreement, pursuant to which we granted Takeda an exclusive option to enter into an exclusive license agreement for olverembatinib. If exercised, the Option would allow Takeda to license global rights to develop and commercialize olverembatinib in all territories outside of, among others, People’s Republic of China, Hong Kong, Macau and Taiwan.

The Exclusive Option Agreement calls for Ascentage to receive an option payment of US$100 million related to intellectual property income and option payment under the Exclusive Option Agreement. Additionally, Ascentage is eligible for an option exercise fee and additional potential milestone payments of up to approximately US$1.2 billion and double-digit royalties on annual net sales.

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.

Learn more about our apoptosis targeting therapies