DNA Damage Response Program

Sapacitabine (CYC682)

Sapacitabine, a DNA damage response inhibitor (DDRi), is an oral prodrug of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine). During cell division CNDAC gets incorporated into the DNA leading to double strand break. Normal cells can repair this DNA damage through homologous recombination repair, or HRR. If unrepaired, especially in repair-deficient cells, this damage leads to cell death. As a result, repair-deficient or fast-growing cancer cells are more sensitive to sapacitabine (CNDAC).

Sapacitabine has progressed through various stages of clinical development to establish a safety-tolerability profile and a clinically relevant dose. The compound has been evaluated in both hematological cancers and solid tumors. Over 1,000 patients have received sapacitabine in Phase 1, 2 and 3 studies including the phase 3 SEAMLESS trial where elderly patients with acute myeloid leukemia (AML) were treated with Sapacitabine and decitabine.

Currently a phase 1/2 study is investigating safety/tolerability and efficacy of sapacitabine in combination with venetoclax, a BCL2 inhibitor, in relapsed and/or refractory AML/MDS patients (NCT01211457). This oral-oral regimen is being evaluated at the MD Anderson Cancer Center. In advanced solid tumors, sapacitabine is being studied in a Phase 1b/2 investigator-sponsored trial (IST) in combination with olaparib, an approved PARP inhibitor, in PARP inhibitor-naive, metastatic HER2-negative breast cancer with germline BRCA1/2 mutation (NCT03641755). Dana-Farber Cancer Institute is conducting the trial supported by the company and AstraZeneca. Preclinical data support the hypothesis that dual targeting of the DNA damage response pathway by combining olaparib with sapacitabine may enhance the efficacy of standard of care treatment for BRCA positive patients with breast cancer.

Learn more about sapacitabine (PDF)

ASH 2019 Poster #3926 (PDF)

Research & Development