2018 EBF: Development and validation of an LC-MS/MS method for the simultaneous quantitation of cedazuridine (E7727), epimer of cedazuridine and decitabine in THU-stabilized K2EDTA human Plasma

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Summary

Abstract:

Cedazuridine is a novel cytidine deaminase inhibitor that inhibits the in vivo metabolic degradation of decitabine when administered orally in combination with decitabine (known as ASTX727) in clinical trials. Cedazuridine inhibits degradation of decitabine by inhibiting cytidine deaminase in the gut and liver thereby increasing oral bioavailability of decitabine. To support clinical trial pharmacokinetic studies for ASTX727, a sensitive LC-MS/MS method for the simultaneous quantitation of decitabine and cedazuridine, as well as the epimer of cedazuridine, in human plasma was developed and validated. Decitabine is known for its instability in human plasma over time as well as a previously observed chromatographic interference in certain subjects that was inseparable using reverse-phase chromatography. To stabilize decitabine, tetrahydrouridine (THU) was mixed with the human plasma samples. Chromatographic interference was resolved using normal phase chromatography. In-house synthesized stable-label internal standards for all three analytes were employed to ensure assay robustness. Stability of cedazuridine and cedazuridine-epimer were carefully evaluated and extensive experiments were conducted to ensure no inter-conversion occurs. As a result, a 3-in-1 method (single sample extraction) for the quantitation of cedazuridine, cedazuridine epimer and decitabine has been developed and fully validated. Protein precipitation (PPT) was used to extract all analytes from THU-stabilized human plasma samples. The analytes were separated on two different HPLC columns (reverse phase for cedazuridine and cedazuridine epimer and normal phase for decitabine). The method has been applied for clinical studies to evaluate the pharmacokinetics of cedazuridine, cedazuridine-epimer and decitabine in human.

 

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2018 ASTX727 Poster presented at EBF

2019 MDSF: Development of an oral hypomethylating agent (HMA) as a fixed dose combination (FDC) of decitabine and CDA inhibitor cedazuridine

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Summary:

Background: Hypomethylating agents azacitidine and decitabine are not readily bioavailable orally due to their degradation in the gut and liver by CDA. We developed a selective, potent, and safe CDA inhibitor cedazuridine. The combination of cedazuridine with decitabine delivered orally as an FDC tablet is developed to achieve an equivalent AUC exposure to IV decitabine.

Methods: A phase 1-2 study was conducted in 124 patients eligible to receive IV decitabine. The phase 1 dose escalation (n=44 patients) established a recommended dose for both oral decitabine (35 mg), and cedazuridine (100 mg) likely to achieve a decitabine AUC exposure equivalent to decitabine IV at 20 mg/m2. The phase 2 (n=80 patients) was conducted using a randomized cross-over design comparing IV decitabine to oral ASTX727 to confirm intra-patient decitabine AUC exposure equivalence between standard IV decitabine and the selected ASTX727 FDC doses (35/100 mg decitabine/cedazuridine).

Results: In the phase 2 patients were randomized to either decitabine IV 20 mg/m2/d x5 or oral ASTX727 (decitabine/cedazuridine 35/100 mg/d) x5 Q 28 days in Cycle 1 and crossed over to the other arm in Cycle 2. All patients continued to receive oral ASTX727 from Cycle 3 onwards until progression or treatment discontinuation for other reasons. The median age was 69.7 years, median weight was 82.7 Kg (range 40-122), and median BSA was 1.99 m2 (range 1.3-2.4). The MDS-IPSS status of the patients was Int-1 in 44%, Int-2 in 24%, and HR in 11%, with 21% having CMML. No differences were observed between the 2 randomized arms. The decitabine AUC0-t (h*ng/mL) 5-Day geometric mean estimate was 745 from decitabine IV and 727 from the oral FDC tablet resulting in an oral/IV AUC ratio of 97.6% (80% CI of 80, 118%). Hypomethylating activity as measured by LINE-1 demethylation, and safety were comparable between decitabine IV and oral ASTX727 in the first 2 randomized cycles. Of note is the absence of grade 3 or higher GI AEs related to ASTX727. Overall response rate in the phase 2 population was 65% including 18% CR by the IWG 2006 MDS response criteria

Conclusions: ASTX727 FDC oral tablet at the selected doses (35/100 mg decitabine/cedazuridine) with no body weight or BSA adjustment achieved an equivalent decitabine AUC exposure to IV decitabine 20 mg/m2 over the 5-day cycle. LINE-1 demethylation and safety in the 2 randomized cycles were comparable and overall response rate was consistent with expected decitabine IV clinical response

 

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2019_ASTX727_Poster_MDSF_abst_MDSF19-0166_Garcia-Manero-Final

Ferraris et al., “Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase.” Journal of Medicinal Chemistry, 2014

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Abstract:

Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.

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Ferraris et al., “Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase.” J.MedChem. ,2014, 57 (6), pp 2582–2588 DOI: 10.1021/jm401856k

 

 

2017 ASH: A Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS)

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Summary

An oral hypomethylating agent which could be administered at a dose which would emulate parenteral pharmacokinetics would be more convenient and potentially enhance adherence to treatment. Heretofore, rapid clearance by cytidine deaminase (CDA) during first pass has prevented good oral bioavailability for decitabine (DAC). Cedazuridine (E7727), a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models. A phase I dose finding study found that a fixed oral combination of 35 mg of decitabine and 100 mg of E7727 (ASTX727 with 35 mg decitabine/100 mg cedazuridine (ASTX727 35/100 mg) should produce similar PK to decitabine administered intravenously at 20 mg/m2 as a 1-hour infusion.3 We tested this hypothesis in a phase 2 cross-over study, and report the preliminary results here.

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A Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS)

2017 ACOP8: Evaluation of Potential Doses and Regimens of an Oral Fixed Dose Combination of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) to Minimize Decitabine-Mediated Neutropenia in Low-Risk MDS Subjects Using Systems Pharmacology Modeling

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Evaluation  of Potential Doses and Regimens of an Oral Fixed Dose Combination of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) to Minimize Decitabine-Mediated Neutropenia in Low-Risk MDS Subjects Using Systems Pharmacology Modeling

Objectives: To simulate the effect of decitabine on neutrophils for optimization of dose and regimen(s) of an Oral Fixed-Dose Combination (ASTX727 Low Dose) of Cytidine Deaminase Inhibitor E7727 with Decitabine for treatment of subjects with Low-Risk myelodisplastic syndromes.

Methods: A quantitative systems pharmacology (QSP) model was previously developed describing myeloblasts cell cycle; leukemic blasts, neutrophils and platelets in physiological compartments (bone marrow and blood); PK of decitabine after IV infusion, after dosing with SQ guadecitabine (SGI-110) (dinucleotide of decitabine linked to deoxyguanosine) and oral ASTX727; LINE-1 demethylation; effect of decitabine on leukemic cells, neutrophils and platelets. Model parameters were identified against in vitro and clinical data. The effect of decitabine on neutrophils was calibrated against clinical data on neutrophil counts during treatment of AML patients with guadecitabine. The model was validated against clinical data on blast dynamics in blood and bone marrow of AML patients during treatment with guadecitabine.

Results: The model was succesfully calibrated and validated against various types of data. It succesfully reproduces clinical data on neutrophil count changes during treatment with guadecitabine. Simulations with different doses and regimens of low-dose ASTX727 administration were performed and the model predicts that neutrophil levels depend on dose and frequency of ASTX727.

2017 EHA: DOSE-CONFIRMATION STUDY OF ORAL ASTX727, A COMBINATION OF ORAL DECITABINE WITH A CYTIDINE DEAMINASE INHIBITOR (CDAI) E7727, IN SUBJECTS WITH MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS

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Summary
An oral hypomethylatingagent which could be administered in a dose which would emulate parenteral pharmacokinetics would be more convenient and potentially enhance adherence to treatment. Heretofore, rapid clearance by cytidine deaminase (CDA) during first pass has prevented oral administration.1E7727, a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models.2A phase I dose finding study found that a fixed oral combination of 35 mg of decitabine and 100 mg of E7727 (ASTX727) should produce similar pharmacokinetics (PK) to decitabineadministered intravenously at 20 mg/m2 as a 1-hour infusion (DAC IV).3We tested this hypothesis in a randomized cross-over study of DAC IV vs ASTX727 and report the preliminary results here.

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ASTX727_Poster_EHA_abst-E1192_Garcia-Manero_final.pdf

2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes.

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Summary

ASTX727 is an oral Fixed Dose Combination of a novel and potent oral CDA inhibitor, E7727 with decitabine for the treatment of patients with MDS. Decitabine is an approved IV treatment of MDS that is rapidly degraded by cytidine deaminase resulting in poor and variable oral bioavailability. Low doses of oral decitabine co-administered with E7727 were shown to produce exposures similar to IV decitabine with acceptable inter-patient variability.

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2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

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Summary

Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MOS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727).

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2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

2016 EHA: Phase 1 dose-escalation study of ASTX727: comparable variability in pharmacokinetics

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Summary

Hypomethylating agents (HMA) are typically administered parenterally and adjusted to body surface area (BSA) in order to achieve target pharmacokinetic (PK) parameters associated with response. Much of the variation associated with administration of HMAs is related to the intrinsic activity of cytidine deaminase (CDA) an enzyme which rapidly metabolizes HMAs and is highest in the gut and liver. We report here intra-and inter-patient pharmacokinetic variation in patients from a study aiming to match PK parameters of BSA adjusted dosing with IV decitabine (DAC) with a novel fixed-dose oral combination (ASTX727), of DAC and E7727, a CDA inhibitor. Preliminary safety and clinical activity were previously reported and are updated here.

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EHA: Phase 1 dose-escalation study of ASTX727: comparable variability in pharmacokinetics

2015 ASH: Results of FIH P1 PK Guided Dose-Escalation Study of ASTX727 in Subjects with MDS

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Summary

Treatment of MDS patients with parenteral hypomethylating agents (HMA) such as decitabine (DAC) requires frequent visits to the physician. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and permit the exploration of extended treatment schedules with lower doses of DAC. Neither DAC nor azacitidine is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models. We report here the first in human Phase 1 results of a PK-guided dose escalation trial of ASTX727 (the orally administered combination of DAC
and E7727).

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2015 ASH: Results of FIH P1 PK Guided Dose-Escalation Study of ASTX727 in Subjects with MDS