FDA Approves Inqovi (decitabine/cedazuridine) for Myelodysplastic Syndromes

Decitabine is a nucleoside metabolic inhibitor that is incorporated into DNA, inhibiting DNA methyltransferase, resulting in hypomethylation of DNA and cellular differentiation or apoptosis. Cedazuridine is a cytidine deaminase inhibitor that prevents the degradation of decitabine, thereby increasing its systemic exposure.

Inqovi is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

The recommended dosage of Inqovi is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity. Take on an empty stomach (no food 2 hours before and 2 hours after each dose). Swallow tablets whole; do not cut, crush, or chew. If a dose is missed within 12 hours, take as soon as possible and extend the dosing period by one day to complete 5 daily doses. If vomiting occurs, do not take an additional dose. Consider antiemetics prior to each dose. Do not substitute Inqovi for IV decitabine within a cycle. Obtain complete blood cell counts prior to initiation and before each cycle. Delay next cycle if ANC <1000/μL and platelets <50,000/μL in absence of active disease. For hematologic recovery within 2 weeks of remission, continue same dose; if not, delay up to 2 additional weeks and resume at reduced dose (Days 1-4). Further dose reductions: Days 1-3, then Days 1,3,5. Delay cycle for non-hematologic toxicities: serum creatinine ≥2 mg/dL, bilirubin ≥2x ULN, AST/ALT ≥2x ULN, or active/uncontrolled infection.

Inqovi was evaluated in Study ASTX727-01-B, an open-label, randomized, 2-cycle, 2-sequence crossover study (NCT02103478) that included 80 adult patients with MDS (IPSS Intermediate-1, Intermediate-2, or high-risk) or CMML. Patients were randomized 1:1 to receive Inqovi orally in Cycle 1 and decitabine 20 mg/m2 IV in Cycle 2 or the reverse sequence. Starting with Cycle 3, all patients received Inqovi orally once daily on Days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. Twelve (15%) of the 80 patients went on to stem cell transplantation following Inqovi treatment. Baseline demographics: median age 71 years (range 32-90), 76% male, 93% White, 44% ECOG 0, 48% ECOG 1, 9% ECOG 2. Disease categories: MDS INT-1 (44%), MDS INT-2 (24%), MDS High-Risk (11%), CMML (21%). Prior HMA therapy: azacitidine 4%, decitabine 4%.

Not reported in label.

Inqovi provides an oral alternative to intravenous decitabine for the treatment of MDS, potentially reducing the burden of IV administration. The approval is based on a pharmacokinetic exposure-matching study rather than a comparative efficacy trial.