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

2013 ASH: Preclin Data in Cynomologus Monkeys of ASTX727, an oral HMA composed of decitabine & E7727

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2013 ASH: Preclin Data in Cynomologus Monkeys of ASTX727, an oral HMA composed of decitabine & E7727