Median survival for patients with intermediate-2 or high-risk disease, as defined by the International Prognostic Scoring System (IPSS), is 4.3 to 5.6 months. 1, 2 Patients with high IPSS scores also have a high probability of experiencing transformation of their MDS into AML, an aggressive form of blood cancer with typically poor survival.
Prebet T, Gore S, et al, Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure, Journal of Clinical Oncology 2011, 10.1200/JCO.2011.35.8135.
Jabbour E, Garcia-Manero G, et al, Outcome of Patients With Myelodysplastic Syndrome After Failure of Decitabine Therapy, Cancer 2010, 10.1002/cncr.25247.
Sapacitabine (CYC682), an orally-available nucleoside analogue, is in the SEAMLESS, registration-directed, Phase 3 trial in elderly patients with newly diagnosed acute myeloid leukemia (AML), and in the investigator-led, Phase 2/3 LI-1 Trial in patients aged 60 years or older with previously untreated AML or high risk MDS who are unfit for intensive chemotherapy. Sapacitabine is in Phase 2 trials in patients with hematological malignancies, including myelodysplastic syndromes (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and non-small cell lung cancer (NSCLC), a Phase 1 trial in combination with seliciclib in patients with advanced solid tumors and an investigator-led, Phase 2/3 study comparing sapacitabine to low dose cytarabine as front-line treatment of elderly patients with AML or high risk MDS unfit for intensive chemotherapy. Sapacitabine acts through a novel DNA single-strand breaking mechanism, leading to production of DNA double strand breaks (DSBs) and/or checkpoint activation. Unrepaired DSBs cause cell death. Repair of sapacitabine-induced DSBs is dependent on the homologous recombination DNA repair (HRR) pathway. Both sapacitabine and CNDAC, its major metabolite, have demonstrated potent anti-tumor activity in preclinical studies.
Over 500 patients have received sapacitabine in Phase 2 studies in AML, MDS, CTCL and NSCLC and Phase 1 studies in both hematological malignancies and solid tumors. At the 2009 Annual Meeting of the American Society of Hematology (ASH), Cyclacel reported data from a randomized Phase 2, single-agent study of sapacitabine including promising 1-year survival in elderly patients with AML aged 70 years or older. At the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), Cyclacel reported data from a pilot Phase 1/2 study including promising response rate, low 4-week and 8-week mortality in elderly patients with AML aged 70 years or older receiving sapacitabine alternating with decitabine. Cyclacel is currently enrolling patients in the SEAMLESS, Phase 3, randomized, registration-directed study of sapacitabine in elderly patients with acute myeloid leukemia (AML). The FDA and the European Medicines Agency have designated sapacitabine as an orphan drug for the treatment of both AML and MDS. Sapacitabine is part of Cyclacel's pipeline of small molecule drugs designed to target and stop uncontrolled cell division.