DNA Damage Response Program

CYC682 (Sapacitabine)

Sapacitabine is an oral drug that 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 and over 1,000 patients have received sapacitabine in Phase 1, 2 and 3 studies.

Sapacitabine acts through a novel mechanism whereby its metabolite CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine) is incorporated into DNA ultimately leading to a DNA 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 ultimately leads to cell death. As a result, repair-deficient or fast-growing cancer cells are more sensitive to sapacitabine and CNDAC.

Sapacitabine is the prodrug of CNDAC as the metabolite is an active compound and exerts a cytotoxic effect against cancer cells. CNDAC has a significantly longer resident time in the blood when produced through natural metabolism than when administered directly, and contributes to the efficacy and influence the overall therapeutic index of sapacitabine.

In the Phase 3 SEAMLESS study in acute myeloid leukemia, or AML, in the elderly, sapacitabine has been evaluated in an alternating schedule with decitabine. The study did not reach statistically significant superiority in overall survival (OS), although an improvement in complete remission rate was observed. In the stratified subgroup of patients with low baseline peripheral white blood cell count, comprising approximately two-thirds of the study's population, an improvement in OS was observed for the experimental arm.

Additional studies are ongoing in solid tumors where sapacitabine is assessed in combination with the company's other CDK inhibitors, either concomitant or sequential administration, in patients with advanced solid tumors. Sapacitabine is also being studied in a Phase 1b/2 investigator-sponsored trial (IST) of sapacitabine with olaparib, an approved PARP inhibitor, in BRCA positive patients with breast cancer. 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