Decitabine is a hypomethylating agent (HMA) and was approved by FDA for treatment of intermediate/high-risk MDS for IV infusion in 2006. Oral administration of decitabine, or other HMAs as single agent, has proven challenging as high first-pass due to metabolic degradation by cytidine deaminase (CDA) results in low bioavailability. Cedazuridine, a synthetic analog of tetradrouridine, is a potent inhibitor of CDA and oral combination with decitabine enhances its bioavailability. Astex developed INQOVI, oral decitabine+cedazuridine, and achieved approval of the label with the same indication as IV decitabine, using clinical pharmacology data as primary endpoint in the registrational phase-3, targeting pharmacokinetic (AUC) equivalence against reference IV decitabine to demonstrate biological comparability. Additional supportive pharmacodynamic data (LINE-1 demethylation) were also submitted. Clinical efficacy and safety were secondary endpoints in phase-3. Details of clinical development (including nonclinical background); regulatory considerations; clinical pharmacology endpoints comparing oral vs IV; CMC challenges and evolution and development of formulation for the combination, including the final fixed-dose combination single tablets will be presented.
General presentation (~45 min):
CMC presentation (~45 min)
Additional Clinical Pharmacology considerations (~20 min)
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