Apoptosis Targeting Compounds

Targeting the Bcl-2 Pathway

 

APG-2575

Bcl-2 selective inhibitor
(Granted ODD)

Indications: chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and breast cancer

APG-2575 is a novel, orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma. APG-2575 is designed to treat hematologic malignancies and solid tumors by selectively blocking antiapoptotic protein Bcl-2 to restore the normal apoptosis process in cancer cells. APG-2575 is the first China-developed Bcl-2 inhibitor entering clinical development in China.

At present, APG-2575 has been cleared and approved to enter multiple Phase Ib/II studies in the US, China, Europe, and Australia, and is being developed globally for the treatment of multiple hematologic malignancies including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and breast cancer. To date, APG-2575 has been granted five ODDs by the US FDA for the treatment of Waldenström macroglobulinemia (WM), CLL, multiple myeloma (MM), AML, and follicular lymphoma (FL).

 

 

 

APG-2575
 

APG-1252

Bcl-2/xL inhibitor

Indications: small cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), lymphoma, and other solid tumors

APG-1252 is a novel, highly potent, small-molecule drug that was discovered and is being developed by Ascentage Pharma. APG-1252 is designed to treat SCLC, NSCLC, lymphoma, and other solid tumors by selectively blocking Bcl-2 and Bcl-xL to restore the apoptosis process.

Two Phase I dose-escalation trials in patients with advanced cancers are currently ongoing in the U.S. and Australia, and a Phase I dose-escalation/expansion trial as monotherapy in patients with SCLC is ongoing in China.

 

 

 

APG-1252
 

AT-101

Bcl-2/Bcl-xL/Mcl-1 inhibitor

Indications: chronic lymphocytic leukemia

AT-101 is a pan-Bcl-2 inhibitor we are developing for CLL and MM that blocks Bcl-2, Bcl-xL, Bcl-w and Mcl-1 proteins. Since 2005, 14 Phase I and II clinical trials for AT-101 have been conducted among more than 700 patients with solid tumors or blood cancers. Chinese patients were also enrolled in a multinational, multicenter, randomized, double-blinded Phase II trial in non-small cell lung cancer. Results from these trials show that AT-101 is well tolerated. AT-101, either as a single agent or in combinations, has shown anti-tumor activity in CLL or hormone refractory prostate cancer. We are currently conducting a Phase II trials for AT-101 in combination with lenalidomide or rituximab in patients with relapsed/refractory CLL, or r/r CLL, in China. Additionally, we are coordinating an investigator-initiated Phase I/II trial in the United States to investigate the efficacy and safety of AT-101 in patients with r/r CLL or relapsed/refractory multiple myeloma, or r/r MM.

 

 

 

 

Targeting the IAP Pathway

 

APG-1387

IAP antagonist

Indications: Hepatitis B, advanced pancreatic cancer and other solid tumors

APG-1387 is a novel small molecule IAP (Inhibitor of Apoptosis Protein) antagonist, that was discovered and is being developed by Ascentage Pharma. APG-1387 degrades IAPs by mimicking endogenous SMAC molecule to induce programmed cell death or apoptosis.

Ascentage Pharma is developing APG-1387 globally, and has completed Phase I dose-escalation trials in patients with solid tumors in China and Australia, and a Phase Ib/II clinical trial of APG-1387 and pembrolizumab combination is currently ongoing in the US. In addition, APG-1387 is also being investigated in a Phase Ib trial for the treatment of patients with Chronic Hepatitis B (CHB) in China. Ascentage Pharma was cleared to initiate a Phase Ib/II study of APG-1387 in combination with nab-paclitaxel plus gemcitabine for the treatment of advanced pancreatic cancer. The company received clearance for a Phase II study of APG-1387 in combination with entecavir for the treatment of CHB.

 

 

 

APG-1387
 

Targeting the MDM2-p53 Pathway

 

APG-115

MDM2-p53 inhibitor

Indications: acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), salivary gland cancer and other solid tumors

APG-115 is an orally administered, selective, small-molecule inhibitor of the MDM2-p53 PPI. APG-115 has strong binding affinity to MDM2 and is designed to activate p53 tumor suppression activity by blocking the MDM2-p53 PPI.

Ascentage Pharma has previously commenced three clinical trials of APG-115 in the US, including a Phase I study as single agent, a Phase Ib/II study in combination with pembrolizumab for treatment of metastatic melanoma and other advanced solid tumors, and a Phase I/II study as a single agent or in combination with chemotherapy for treatment of salivary gland cancer. APG-115 is the first MDM2-p53 inhibitor to enter clinical studies in China. A Phase I study as a single agent, and a Phase Ib study as a single agent or in combination with chemotherapy for treatment of AML or MDS are ongoing in China.

This marks the fifth ODD granted to alrizomadlin, after those for the treatment of gastric cancer, acute myeloid leukemia, soft tissue sarcoma, and retinoblastoma.

 

 

APG-115