The US Food and Drug Administration (FDA) has issued a complete response letter to Eisai Inc., a US subsidiary of Eisai Co., Ltd., stating that the FDA cannot approve the company’s supplemental New Drug Application (sNDA) for Dacogen (decitabine), the DNA methylation inhibitor proposed for the treatment of acute myeloid leukaemia (AML) in adults 65 years of age or older who are not considered candidates for induction therapy.

FDA declined to approve the application because it said that the primary study (DACO-016) did not provide convincing evidence of the safety  and effectiveness of Dacogen for the proposed AML indication. Eisai will give careful consideration to the issues raised in the complete response letter before determining next steps.

Dacogen was approved by the FDA in 2006 as a treatment for myelodysplastic syndromes (MDS) and has been marketed in the United States by Eisai Inc. since 2008. In 2010, a new five-day dosing regimen with a shorter administration time was approved as an alternative to the existing three-day dosing regimen in which Dacogen is administered by continuous intravenous infusion over three hours repeated every eight hours for three consecutive days. The approval of the five-day regimen provides MDS patients with a new dosing option that takes into consideration their quality of life.

Dacogen is used for injection, its generic name decitabine is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anaemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anaemia with excess blasts in transformation, chronic myelomonocytic leukaemia) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups.

Dacogen is administered at a dose of 15mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks. Dacogen is administered at a dose of 20mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. This cycle should be repeated every 4 weeks.

In phase III clinical trials in MDS patients, the highest incidence of Grade 3 or Grade 4 adverse events was neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). In the single-arm study in MDS patients (N=99), the highest incidence of Grade 3 or Grade 4 adverse events when Dacogen was administered at a dose at 20mg/m2 by intravenous infusion over 1 hour daily for 5 consecutive days was neutropenia (37%), thrombocytopenia (24%) and anaemia (22%).

DACO-016 was a phase III randomized open-label, multi-centre trial comparing Dacogen versus patient's choice with physician's advice of either supportive care or low-dose cytarabine in patients 65 years and older with
newly diagnosed de novo or secondary AML and with poor- or intermediate-risk cytogenetics.

Of the 485 patients, 242 were randomized to Dacogen and 243 to patient's choice of supportive care or low-dose cytarabine. Dacogen was administered at 20 mg/m2 for one hour by intravenous infusion once daily for five consecutive days repeated every four weeks, continued as long as the patient derived benefit. Patients treated with cytarabine received 20 mg/m2 subcutaneously once daily for 10 consecutive days every four weeks.

The median duration of treatment for patients on Dacogen was 4.4 months, compared with 2.4 months in the cytarabine group.