FDA Approves Oral INQOVI® for Myelodysplastic Syndromes

SUMMARY: The FDA on July 7, 2020, approved INQOVI®, an oral combination of Decitabine and Cedazuridine, for adult patients with MyeloDysplastic Syndromes (MDS), including previously treated and untreated de novo and secondary MDS with the following FAB subtypes – Refractory Anemia, Refractory Anemia with Ringed Sideroblasts, Refractory Anemia with Excess Blasts, Chronic MyeloMonocytic Leukemia (CMML), and Intermediate-1, Intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). CMML (Chronic MyeloMonocytic Leukemia) is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the US is approximately 1,100 new cases per year. About 15-30% of patients with CMML develop AML. Patients with higher risk MDS and CMML are often treated with hypomethylating agents such as Decitabine (DACOGEN&reg) and Azacitidine (VIDAZA®). These agents are administered by IV infusion, or by large-volume subcutaneous injections.

INQOVI® is an orally-administered, unique fixed-dose combination of the DNA hypomethylating agent and DNA MethylTransferase (DNMT) inhibitor Decitabine, the active ingredient in Dacogen®, and the novel Cytidine deaminase inhibitor, Cedazuridine (35 mg Decitabine and 100 mg Cedazuridine). INQOVI® was designed to deliver Decitabine by oral administration. Cedazuridine prevents the degradation of Decitabine in the gut and liver by inhibiting Cytidine deaminase and the combination thereby permits the efficient delivery of Decitabine orally, at exposures that are equivalent to the approved intravenous form of Decitabine administered over 5 days.

The present FDA approval was based on data from two open-label, randomized, crossover clinical trials, ASTX727-01-B, which included 80 adult patients with MDS (IPSS Intermediate-1, Intermediate-2, or high-risk groups) or CMML, and ASTX727-02, which included 133 adult patients with MDS or CMML, including all FAB subtypes and IPSS Intermediate-1, Intermediate-2, or high-risk groups. In these two trials, patients were randomized 1:1 to receive INQOVI® orally in cycle 1 and Decitabine 20 mg/m2 intravenously in cycle 2 or the reverse order. Both oral INQOVI® and intravenous Decitabine were administered once daily on days 1 through 5 of a 28-day cycle. 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. Both trials provided comparison of exposure and safety in the first two cycles between oral INQOVI® and IV Decitabine and description of disease response with INQOVI®. Comparison of disease response between the INQOVI® and IV Decitabine was not possible because all patients received INQOVI® starting from Cycle 3. The Primary endpoint was total 5-day AUC exposures of Decitabine following INQOVI® therapy compared with IV Decitabine, as measured across the first 2 cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, clinical responses, RBC transfusion independence, Leukemia-free survival, and Overall Survival.

ASTX727-01-B trial which included 80 patients demonstrated a Complete Response (CR) rate of 18% and median duration of CR of 8.7 months. Among the 41 patients who were dependent on RBC and/or platelet transfusions at baseline, 49% became transfusion independent during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 64% remained transfusion independent during any consecutive 56-day post-baseline period.

ASTX727-02 trial, which included 133 patients, demonstrated a 99% geometric mean ratio of the 5-day cumulative Decitabine AUC following 5 consecutive once daily doses of the oral combination therapy, versus that of IV Decitabine, with a 90% Confidence interval between 93% and 106%. This confirmed equivalence of oral INQOVI® and IV Decitabine. Efficacy results demonstrated that 21% of patients achieved CR, and median duration of CR was 7.5 months. Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 53% became transfusion independent during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion independent during any 56-day post-baseline period. The most common Adverse Events related to INQOVI® included fatigue, rash, dizziness, headaches, anorexia, nausea, diarrhea, constipation, mucositis, hemorrhage, myalgia, arthralgia, febrile neutropenia, and transaminase elevation.

It was concluded that INQOVI® which is a fixed-dose combination of Cedazuridine and Decitabine is a new treatment option for patients with MDS and CMML, and is an oral hypomethylating agent alternative to IV Decitabine.