EMA Accepts Marketing Authorization Application for Fixed-Dose Decitabine/Cedazuridine Combo in AML

The European Medicines Agency (EMA) has accepted the marketing authorization application (MAA) for the oral fixed-dose combination of decitabine and cedazuridine (ASTX727) for the frontline treatment of adults with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy.¹

The MAA is based on findings from the phase 3 ASCERTAIN trial (NCT03306264) in which the novel oral fixed-dose combination demonstrated pharmacokinetic (PK) exposure equivalence to a standard 5-day regimen of intravenous (IV) decitabine, with an oral/IV 5-day decitabine area under the curve (AUC) of approximately 99% (90% CI, approximately 93%-106%),² meeting the primary end point of the study. Additionally, the fixed-dose combination of decitabine and cedazuridine demonstrated similar safety findings as IV decitabine.

The current standard treatment for patients with AML is IV chemotherapy or parenterally administered hypomethylating agents (HMAs) for patients who are unfit for chemotherapy. However, fatigue can limit daily function and reduce health-related quality of life.

ASTX727 is an orally administered, fixed-dose combination of decitabine and the cytidine deaminase inhibitor cedazuridine. By inhibiting cytidine deaminase in the gut and the liver, the fixed-dose combination allows for oral delivery of decitabine over 5 days in each cycle to achieve similar systemic exposure to IV decitabine administered over the same period.

If approved, oral decitabine and cedazuridine would be the first and only oral HMA licensed in the European Economic Area for the frontline treatment of adults with AML who are ineligible for intensive chemotherapy, offering a potentially more convenient method of administration.

In January 2022, the fixed-dose combination received an orphan drug designation from the European Commission,³ and in April 2022, the EMA agreed to a Pediatric Investigation Plan in the European Union for the fixed-dose combination.¹

ASCERTAIN employed a two-cycle cross-over study design in which patients with intermediate- or high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or AML with 20% to 30% bone marrow blasts were randomly assigned 1:1 to 1 of 2 sequences.⁴

Sequence A comprised 35 mg of oral, fixed-dose decitabine plus 100 mg of cedazuridine given as 1 daily tablet for 5 days in cycle 1 and 20 mg/m2 of IV decitabine for 5 days in cycle 2 or IV decitabine in cycle 1 and the fixed-dose regimen in cycle 2. All patients received the fixed-duration regimen from cycle 3 onward until progression, toxicity, or withdrawal.

The primary end point of the study was the total 5-day decitabine AUC equivalence (oral/IV 90% CI between 80% and 125%). Key secondary end points included efficacy measured by objective response, transfusion independence, duration of response, leukemia-free survival, and overall survival, safety, and maximum LINE-1 demethylation.

Further PK data demonstrated a 13.7% LINE-1 methylation decrease in cycle 1 of the fixed-dose combination compared with baseline. The change was less than 1% in cycles 1 and 2 with overlapping confidence intervals, illustrating similar biologic effects between oral vs IV treatment.

References

1. European Medicines Agency commences review of oral fixed-dose combination of decitabine and cedazuridine for the treatment of adults with acute myeloid leukemia. News release. Astex Pharmaceuticals, Inc; August 22, 2022. Accessed August 22, 2022. https://bit.ly/3QLXU5c
2. Savona MR, McCloskey JK, Griffiths EA, et al. Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Presented at: 16th International Congress on Myelodysplastic Syndromes; September 23-26; virtual poster. Abstract P48. https://bit.ly/3ENe1cV
3. Oral decitabine and cedazuridine (ASTX727) granted orphan drug designation (ODD) by the European Commission for the treatment of acute myeloid leukemia (AML). News release. Astex Pharmaceuticals, Inc. January 6, 2022. Accessed August 22, 2022. https://bit.ly/3TlKGxN
4. Study of ASTX727 vs IV decitabine in MDS, CMML, and AML. ClinicalTrials.gov. Updated August 1, 2022. Accessed August 22, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03306264