On June 6, 2019 Astex Pharmaceuticals, Inc. a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., reported top-line results from the ASCERTAIN phase 3 study evaluating cedazuridine and decitabine fixed-dose combination (ASTX727) vs decitabine IV in adults with intermediate and high-risk MDS or CMML (Press release, Astex Pharmaceuticals, JUN 6, 2019, View Source [SID1234536948]).

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The study met its primary endpoint of decitabine exposure equivalence of 5-day dosing between orally administered ASTX727 and IV decitabine as per the protocol analysis plan. Safety and clinical activity were similar to that observed in a previous phase 1/2 study. The full data will be presented at an upcoming scientific meeting.

Astex plans to file an NDA with the US FDA by the end of 2019.

"We are delighted with the outcome of the ASCERTAIN trial, and the demonstration that the fixed dose combination of cedazuridine with decitabine enables successful oral delivery of decitabine, alleviating the significant burden of five days of monthly IV infusions for patients who may continue to benefit from the drug for several months or even years," said Mohammad Azab, Astex Pharmaceuticals’ president and chief medical officer. "Subject to regulatory review and approvals, ASTX727 could bring a new treatment option to patients with these deadly diseases. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to this effort."

About Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727)

ASTX727 is a novel, orally administered fixed dose combination of cedazuridine, an inhibitor of cytidine deaminase, with the anti-cancer DNA hypomethylating agent, decitabine.1 By inhibiting cytidine deaminase in the gut and the liver, ASTX727 allows for oral delivery of the approved DNA hypomethylating agent, decitabine at exposures which are equivalent to the approved intravenous form of decitabine administered over 5 days.

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study in patients with MDS and CMML to define appropriate doses of the individual components of ASTX727 (cedazuridine and decitabine) so that decitabine exposure after oral administration of ASTX727 is similar to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 20 mg/m2 (see View Source NCT02103478). This study demonstrated that ASTX727 allowed decitabine to be delivered orally at a dose that emulates parenteral pharmacokinetics, as measured by 5-day area-under-the-curve (AUC).3 The drug’s safety profile was similar to that of IV decitabine. Of particular note was the low level of gastrointestinal adverse events.3

The concept of using cedazuridine to block the action of cytidine deaminase is also being evaluated in a low dose formulation of cedazuridine and decitabine for the treatment of lower risk MDS (see View Source NCT03502668). ASTX727 may also have potential in all-oral combination regimes for the treatment of a range of different tumor types.

Astex is also expanding the evaluation of cedazuridine – decitabine combinations through a program of investigator-sponsored trials.

ASTX727 is an investigational compound and is not currently approved in any country.

About the ASCERTAIN Study

The ASCERTAIN study was designed to demonstrate that the cedazuridine and decitabine fixed-dose combination (ASTX727) could deliver orally a pharmacokinetically equivalent exposure of decitabine compared to IV decitabine in adults with previously untreated or treated MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, int-2, or high-risk MDS. (see View Source NCT03306264). The study was designed as a randomized, open-label cross-over study in which patients were randomized in a 1:1 ratio to receive ASTX727 daily x 5 in the first 28-day cycle followed by IV decitabine daily x 5 in the second 28-day cycle, or the converse order. Following completion of the first two cycles, patients continued to receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or the subject decided to discontinue treatment or withdrew from the study. The primary endpoint of the study was total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine as measured across the first two cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, secondary PK parameters, clinical responses, red blood cell transfusion independence, leukemia-free survival, and overall survival. The study was conducted in 138 patients at 46 sites in the US and Canada.

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. US incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.4,5 The prevalence has been estimated to be from 60,000 to 170,000 in the US.6 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.7 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML. CMML 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,8 and CMML may transform into AML in 15% to 30% of patients.9 The hypomethylating agents decitabine and azacitidine are effective treatment modalities for hematologic cancers and are FDA-approved for the treatment of higher risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.