-
Cedazuridine and decitabine, administered orally as a fixed-dose
combination (ASTX727), met the primary endpoint of decitabine exposure
equivalence of total 5-day dosing between oral ASTX727 and IV
decitabine in the phase 3 ASCERTAIN study in MDS and CMML patients -
The study confirmed that the safety profile and clinical activity of
the cedazuridine and decitabine fixed-dose combination was similar to
that observed in the phase 1/2 study and similar to the expected
clinical profile of decitabine IV -
Astex plans to file a New Drug Application (NDA) with the US FDA by
the end of 2019 -
Astex is continuing to develop cedazuridine and decitabine fixed-dose
combination in additional patient populations including those with
acute myeloid leukemia (AML) and low-risk MDS
PLEASANTON, Calif. & TOKYO–(BUSINESS WIRE)–Astex Pharmaceuticals, Inc. a member of the Otsuka group of companies,
and Otsuka Pharmaceutical Co. Ltd., announce 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.
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 https://www.clinicaltrials.gov
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 https://www.clinicaltrials.gov
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 https://www.clinicaltrials.gov
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.
About Astex Pharmaceuticals, and Otsuka Pharmaceutical
Astex is a leader in innovative drug discovery and development,
committed to the fight against cancer and diseases of the central
nervous system. Astex is developing a proprietary pipeline of novel
therapies and has multiple partnered products in development under
collaborations with leading pharmaceutical companies. In October 2013
Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co.
Ltd., based in Tokyo, Japan.
Otsuka Pharmaceutical is a global healthcare company with the corporate
philosophy: “Otsuka–people creating new products for better health
worldwide.” Otsuka researches, develops, manufactures and markets
innovative and original products, with a focus on pharmaceutical
products for the treatment of diseases and nutraceutical products for
the maintenance of everyday health.
For more information about Astex Pharmaceuticals, please visit: http://www.astx.com
For more information about Otsuka Pharmaceutical, please visit: http://www.otsuka.com/en/
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Contacts
Martin Buckland
Chief Corporate Officer
Astex Pharmaceuticals,
Inc.
4420 Rosewood Drive, Suite 200
Pleasanton 94588, CA, USA
Tel:
+1-925-560-2857
Email: info@astx.com