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FDA Approved Drugs » 2006
Medical Areas: Hematology
View By:Year | Company | Conditions | Therapeutic Areas | Drug Names
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: MGI Pharma
Approval Status: Approved May 2006
Treatment Area: Myelodysplastic Syndromes
Dacogen is a nucleoside analog, designed to disrupt DNA
synthesis. This disruptive activity promotes cytotoxic DNA
hypomethylation and apoptotic cell death in rapidly dividing
Dacogen is specifically indicated for the treatment of multiple
types of myelodysplastic syndromes, including previously treated
and untreated, de novo and secondary myelodysplastic
syndromes (MDS) of all French-American-British (FAB) subtypes
(refractory anemia, refractory anemia with ringed sideroblasts,
refractory anemia with excess blasts, refractory anemia with excess
blasts in transformation, and chronic myelomonocytic leukemia) and
intermediate-1, intermediate-2, and high-risk International
Prognostic Scoring System (IPSS) groups.
Dacogen is supplied as a a sterile lyophilized white to almost
white powder, for reconstitution in sterile water and dilution for
intravenous injection. Recommended initial dosing is 15 mg/m2 via
continuous 3-hour intravenous infusion, once every 8 hours for 3
days. Treatment cycles should be repeated every 6 weeks, for a
minimum of 4 cycles, barring serious adverse reaction. If adverse
reaction (including insufficient hematologic recovery occurs 6
weeks after a dosing cycle) occurs, subsequent cycles can be
delayed until recovery is achieved. Treatment should be
discontinued if evidence of disease progression is observed.
Approval of Dacogen was based on 3 clinical trials: one pivotal
phase III trial and a pair of phase II trials.
Phase III Trial
This randomized open-label, multicenter, controlled study enrolled
170 patients with MDS meeting FAB classification criteria and
International IPSS High-Risk, Intermediate-2 and Intermediate-1
prognostic scores. 89 subjects were randomized to receive Dacogen
plus best-supportive-care, and 81 received best-supportive-care
alone. 12 patients (9 Dacogen, 3 supportive care) were excluded
from the study after randomization due to revised diagnosis of
acute myeloid leukemia. Dacogen was administered at a dose of 15
mg/m2 via 3-hour infusion every 8 hours for 3 consecutive days
every 6 weeks. Supportive care included blood and blood product
transfusions, prophylactic antibiotics, and hematopoietic growth
factors. Trial data met one of the study's co-primary endpoints
subjects receiving Dacogen achieved an overall response rate
(complete response rate + partial response rate) of 17% (9%
complete response, 8% partial response) in the intent to treat
population, compared to 0% for supportive care; median duration of
response for Dacogen was 288 days. Dacogen did not significantly
improve median time to progression to acute myeloid leukemia or
Phase II Trials
These open-label, single-arm, multi-center studies were designed to
investigate the safety and efficacy of Dacogen in MDS patients.
Subjects received 15 mg/m2 of the drug via 4 hour infusion on the
usual 8 hours/3 day/6 weeks dose cycle schedule. Results from the
studies were consistent with those observed in the phase III trial,
with overall response rates of 26% (n=66) and 24% (n=98).
Adverse events associated with the use of Dacogen may include,
but are not limited to, the following:
As anticipated, use of Dacogen is associated with incidence of
bone marrow suppression, including neutropenia and
thrombocytopenia. The most frequently observed serious (Grade 3) or
severe (Grade 4) adverse events observed in pivotal trials were
neutropenia (87%), thrombocytopenia (85%), febrile neutropenia
(23%) and leukopenia (22%). Bone marrow suppression was the most
frequent cause of dose reduction, delay or discontinuation. 6
subjects experienced fatal events associated with myelosuppression.
Careful monitoring of complete blood and platelet counts should be
maintained throughout treatment cycles, with dose adjustment,
delay, or discontinuation as appropriate.
Dacogen is an analogue of the nucleoside 2’-deoxycytidine. It is
believed to exert its antineoplastic effects after phosphorylation
and direct incorporation into DNA and inhibition of DNA
methyltransferase, causing hypomethylation of DNA and cellular
differentiation or apoptosis. DNA hypomethylation is achieved at
concentrations below those required to significantly inhibit DNA
synthesis, which may promote restoration of function to genes
associated with control of cellular differentiation and
proliferation. Cytotoxicity in rapidly dividing cells may also
result from covalent adducts between DNA methyltransferase and
decitabine incorporated into DNA.
Wijermans P, Lbbert M. Epigenetic therapy with
decitabine for myelodysplasia and leukemia. Future
Oncology 2005 Oct;1(5):585-91
Ruter B, Wijermans PW, Lubbert M. Superiority
of prolonged low-dose azanucleoside administration? Results of
5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia
patients. Cancer 2006 Apr 15;106(8):1744-50
Schaefer HE, Lubbert M. The hematopathological
basis for studying effects of the demethylating agent
5-aza-2'-deoxycytidine (decitabine) in myelodysplasia.
Annals of Hematology 2005 Dec;84 Suppl 13:67-79
Chuang JC, Yoo CB, Kwan JM, Li TW, Liang G, Yang AS,
Jones PA. Comparison of biological effects of
non-nucleoside DNA methylation inhibitors versus
5-aza-2'-deoxycytidine. Molecular Cancer Therapeutics
For additional information regarding Dacogen or Myelodysplastic
Syndromes, please visit the Dacogen web page.
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