Garcia-Manero et al., Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML

View further details:

Garcia-Manero et al, “Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML”. Blood. 2020 Apr 13. pii: blood.2019004143. doi: 10.1182/blood.2019004143. [Epub ahead of print]


This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with
cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-
1/2- or high-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral
cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral
cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage
and then as a single fixed-dose combination (FDC) tablet. Primary endpoints: mean decitabine systemic exposure (geometric least-squares
mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), % long interspersed nuclear element 1
(LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and
treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1%, 106.5%) and 97.6% (80.5%, 118.3%)
for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical
responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events
regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35
mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar
efficacy. NCT02103478.

2019 ASH – Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine

View Presentation
Abstract # 846 – Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine

Authors: Guillermo Garcia-Manero, MD1, James McCloskey, MD2, Elizabeth A. Griffiths, MD3, Karen W.L. Yee, MD4, Amer M. Zeidan, MBBS, MHS5, Aref Al-Kali, MD6, Kim-Hien Dao, DO, PhD7, H. Joachim Deeg, MD8, Prapti A. Patel, MD9, Mitchell Sabloff, MSc, MD, FRCPC10, Mary-Margaret Keating, MD11, Nancy Zhu, MD12*, Nashat Y. Gabrail, MD13*, Salman Fazal, MD14, Joseph Maly, MD15, Olatoyosi Odenike, MD16, Aditi Shastri, MD17, Amy E. DeZern, MD18, Casey L. O’Connell, MD19, Gail J. Roboz, MD20, Aram Oganesian, PhD21*, Yong Hao, MD, PhD21*, Harold N. Keer, MD, PhD21, Mohammad Azab, MD21 and Michael R. Savona, MD22

1The University of Texas MD Anderson Cancer Center, Houston, TX; 2John Thuerer Cancer Center, Hackensack Medical Center, NJ; 3Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4Princess Margaret Cancer Centre, Toronto, ON, CAN; 5Yale University and Yale Cancer Center, New Haven, CT; 6Mayo Clinic, Rochester, MN; 7Oregon Health & Science University, Portland, OR; 8Fred Hutchinson Cancer Research Center, Seattle, WA; 9University of Texas Southwestern Medical Center, Dallas, TX; 10Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; 11Hematology/Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; 12University of Alberta, Edmonton, AB, Canada; 13Gabrail Cancer Center, Canton, OH; 14West Penn Hospital, Allegheny Health Network, Pittsburgh, PA; 15Norton Cancer Institute, Louisville, KY; 16University of Chicago, Chicago, IL; 17Department of Hematology and Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 18Johns Hopkins University Hospital, Baltimore, MD; 19USC Keck School of Medicine, University of Southern California, Los Angeles, CA; 20Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY; 21Astex Pharmaceuticals, Inc., Pleasanton, CA; 22Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN

 Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int’l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study).

 Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

 Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of <1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting.

Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned.

2019 ACOP: A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

View Poster
A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes


Cytidine deaminase (CDA) rapidly degrades decitabine (DAC), an approved treatment for myelodysplastic syndromes, resulting in poor and variable bioavailability. Low doses of oral DAC co-administered with a novel and potent CDA inhibitor, cedazuridine (E7727), have been shown in clinic to produce exposures similar to IV DAC with acceptable inter-patient variability. The objective of this work was to further develop a semi-physiological population PK model ([1]) to characterize the PK enhancement of oral DAC when co-administered with cedazuridine and to identify potential covariates that impact the PK of DAC and/or cedazuridine.

Model development utilized serial cedazuridine and DAC plasma concentration observations of IV DAC, oral DAC, and cedazuridine monotherapies and DAC+cedazuridine combinations. Observations from Phase 1/2 Study ASTX727-01 included dose escalation data (n=43; cohorts of 40:20, 60:20, 100:20, 100:40, and 100:30 mg cedazuridine:DAC with n=6 per cohort), dose confirmation data (n=42; 35:100 mg cedazuridine:DAC), and an FDC formulation extension (n=26). R was used for data processing, exploratory analysis, and visual predictive checks, while model development and parameter estimation utilized NONMEM. Covariate effects were explored using a full model approach.

Mono- and combination therapy data were sequentially integrated into a semi-physiological population PK model. Semi-physiological structural modeling elements included an IV DAC depot, oral DAC and cedazuridine transit compartment absorption, and portal vein, liver, central, and peripheral compartments. CDA metabolism of DAC primarily occurs in the liver compartment, with additional extra-hepatic metabolism. A maximum effect (Emax) inhibition model, dependent on local cedazuridine concentrations, described the drug effect of the oral ASTX727 combination therapy on CDA metabolism of DAC. IV DAC data were used to parameterize distribution and metabolism of DAC, while oral DAC monotherapy data was used to parameterize oral absorption. cedazuridine mono- and combination therapy data were used to parameterize cedazuridine PK parameters. Stratified individual-level random effects did not demonstrate systematic biases for any covariates, including weight-based effects.

A semi-physiological population PK model was sequentially developed from mono- and combination therapy observations of plasma concentrations from the ASTX727-01 dose escalation and confirmation study. The analysis characterized the PK enhancement of oral DAC when co-administered with cedazuridine across a range of dose regimens and found no significant covariate effects, including weight-based effects. The resulting model will be used to interpret outcomes from an ongoing Phase 3 study (FDC ASTX727 of 35 mg DAC / 100 mg cedazuridine), while simulations will quantitatively inform future clinical development of ASTX727.

Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study

View further details

Savona et al, “Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study”, The Lancet Haematology, Volume 6, Issue 4, e194 – e203  DOI:10.1016/S2352-3026(19)30030-4



Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.METHODS:

In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of decitabine and cedazuridine. The starting dose was decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral decitabine on day -3, a 1-h intravenous infusion of decitabine 20 mg/m2 on day 1, and cohort-defined doses of oral decitabine plus cedazuridine on days 2-5. In cycles 2 and beyond, the oral decitabine and cedazuridine were given on days 1-5. The dose of cedazuridine was escalated first and decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with, number NCT02103478.


Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng × h/mL for decitabine 30 mg, and 221 ng × h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]).


Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted.


de Witte, Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?

Click for link to article:

“Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?” The Lancet Haematology, Volume 6, Issue 4, PE170-E171, DOI 10.1016/S2352-3026(19)30025-0•


Curative treatment options for patients with intermediate-risk or high-risk myelodysplasia are intensive chemotherapy and allogeneic stem cell transplantation, but most patients with myelodysplasia are too frail to be treated with these demanding interventions because of advanced age and comorbidities. Alternative treatment approaches are either ineffective or result in short response durations with little survival benefit.



2019 ICTXV: Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)

Click here to view presentation:

Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)


Cedazuridine (E7727) is a synthetic nucleoside analog derived from tetrahydrouridine (THU) and designed as a potent inhibitor of cytidine deaminase (CDA) with improved stability over THU. It is currently being developed in combination with hypomethylating agent decitabine (ASTX727) as an oral option for treatment of MDS and CMML. Concomitant administration of cedazuridine enhances oral bioavailability of decitabine and achieves therapeutic AUC exposures in the clinic at low doses of decitabine (similar to IV dose, in mg) that are well tolerated.

Nonclinical development of cedazuridine included full toxicological and DMPK evaluation. Cedazuridine is well tolerated in mice and monkeys (tox species) over 1-cycle of 7 days dosing, (followed by recovery), with NOAEL at 1000 mg/kg and 200 mg/kg, respectively. Subchronic studies of 13-weeks duration with multi-cycles (28 days/cycle with dosing on days 1-7) resulted in NOAEL of 100/300 mg/kg in mice (females/males) and 60 mg/kg in cynomolgus monkeys. The highest non-severely toxic dose (HNSTD) in multi-cycle study was 200 mg/kg/dose in monkeys. Target organs at the NOAEL were lymph nodes in mice and GI mucosa and bone marrow (RBC parameters) in monkeys. These dose levels offer a large safety margin over the clinical dose (and systemic exposures) used for cedazuridine (100 mg fixed dose, in combination with 35 mg decitabine). Cedazuridine in mouse in vivo micronucleus study was negative at up to 2000 mg/kg and was negative in in vitro Ames and chromosome aberration tests at concentrations that were not cytotoxic.

Co-administration with decitabine in mice and monkeys resulted in significant increase in systemic exposures compared with decitabine administered alone. Cedazuridine is metabolically stable in liver microsomes and hepatocytes, does not inhibit major human CYP enzymes, and is not a substrate and/or inhibitor of major human drug transporters. It does not accumulate in tissues and is excreted mainly renally. The main metabolite was its epimer, to which it partially converts in acidic environment in the stomach prior to absorption.

In summary, cedazuridine has been well characterized in nonclinical toxicology and DMPK studies and its nonclinical data profile supports late-stage clinical development.

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



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.


View further details below

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


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


View further details below


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


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.

View further details:

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)


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.

View further details below
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)