BOSTON and EDISON, New Jersey, July 15 --
-- Pharmacokinetic Analysis of Atrial Fibrillation Study May Explain Bleeding
Rate Difference between Once-Daily and Twice-Daily Dosing Regimens with Same
Total Exposure of Factor Xa Inhibitor --
A sub-analysis of a Phase IIb multinational study(1) with edoxaban(2) -- an
investigational oral Factor Xa inhibitor - provides insights into why patients
with non-valvular atrial fibrillation (AF) receiving edoxaban once daily (OD)
experienced fewer bleeding events than patients given edoxaban twice a day
(BID). The analysis finds that bleeding associated with edoxaban is most closely
correlated with minimum concentration levels of the drug in the blood, and that
these trough levels may best predict bleeding events, rather than total exposure
or maximum concentration levels.
These findings were presented today at the XXII International Society on
Thrombosis and Haemostasis Congress in Boston. Edoxaban is being developed
solely by Daiichi Sankyo Company, Limited (TSE: 4568) as a potential treatment
for the prevention of both arterial and venous thromboembolism; a Phase III
trial is underway among patients with AF.
This pharmacokinetic (PK) analysis of the Phase IIb study examined the
relationship between bleeding events reported in patients taking 30 or 60 mg
edoxaban given either OD or BID and the concentration of edoxaban in their
blood. The analysis examined overall bleeding rates when drug concentration
levels reached the highest points (known as Cmax), lowest points (known as Cmin)
as well as overall edoxaban exposure (measured by area under the curve or AUC).
Delivering a compound twice per day generally allows for more consistent
concentration levels in the blood. With twice-daily dosing, the Cmin levels
(troughs) do not dip as low, and the Cmax levels (peaks) do not reach as high as
when the compound is delivered once per day.
When we assessed the pharmacokinetics in patients taking edoxaban once a day,
lower minimum concentrations and fewer bleeding events were observed, compared
to the same total daily dosage given twice a day, said Robert P. Giugliano,
M.D., S.M., Associate Physician, Cardiovascular Division, Brigham and
Women’s Hospital. These results countered our expectations that patients
with higher maximum concentrations of edoxaban, in this case, those that
received their total dose once daily, would have the most bleeding events. It
may be that reaching lower Cmin levels with edoxaban once-a-day permits some
degree of normal hemostasis to be temporarily reestablished, and that may be the
reason why bleeding rates are lower with once-daily dosing.
This Phase II study was a decisive study for Daiichi Sankyo in that it directed
us to the optimal dosing regimen to study in our Phase III clinical trial ENGAGE
AF-TIMI 48 - the more convenient 60 and 30 mg once-daily doses, said Francis
Plat, M.D., vice president, clinical development at Daiichi Sankyo Pharma
About the Phase IIb Safety Study
A total of 1,146 patients with AF with a CHADS2 index greater than or equal to
2 were enrolled in the initial Phase II study for three months. Patients were
randomly assigned to receive either one of the four fixed dose regimens of
edoxaban (30mg/N=235 or 60mg/N=234 administered once daily; 30mg/N=244 or
60mg/N=180 administered twice daily), or warfarin (N=250) dose-adjusted locally
to a target International Normalized Ratio (INR) of 2.0-3.0 for 12 weeks. The
INR was determined weekly for four weeks and every two weeks thereafter.
Investigators, sponsors and study subjects were blinded to the edoxaban dose;
however, those taking warfarin were aware they were randomized to the warfarin
Bleeding events were evaluated using guidelines established by the
International Society on Thrombosis and Haemostasis(3), the most sensitive scale
of those currently used in clinical studies in cardiovascular disease. In the
treatment groups receiving a once-daily dose of edoxaban, the lowest bleeding
rates were observed in 17 patients (7.3 percent) in the 60 mg OD (N=234) and 13
patients (5.5 percent) in the 30 mg OD (N=235). In the treatment groups
receiving a twice-daily dose of edoxaban, the highest bleeding rates were
observed in 33 patients (18.3 percent) in the 60 mg BID (N=180) and 31 patients
(12.7 percent) in the 30 mg BID (N=244). This sub-analysis examined only the
population receiving edoxaban from the initial study. PK samples were taken
before dosing and one to three hours post-dosing on day 28. The relationship
between PK and all bleeding events was examined using logistical regression.
Edoxaban, the molecule originally referred to as DU-176b, is an oral
anticoagulant that directly inhibits Factor Xa, a clotting factor in the blood.
Daiichi Sankyo is developing edoxaban as a potential new treatment for the
prevention of both arterial and venous thromboembolism. Notably, Daiichi Sankyo
has more than 25 years experience conducting research in the area of Factor Xa
inhibition, and was the first company to test these compounds in humans.
Daiichi Sankyo is actively enrolling 16,500 patients in its pivotal Phase III
trial for edoxaban in patients with atrial fibrillation. The Phase III study,
Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation
(ENGAGE-AF), is comparing edoxaban with warfarin (INR2-3) for the prevention of
stroke and systemic embolic events (SEE) in patients with atrial fibrillation.
Edoxaban is also being studied for treatment of VTE, and for the prevention of
DVT after major orthopaedic surgery.
About Daiichi Sankyo
A global pharmaceutical innovator, Daiichi Sankyo Co., Ltd., was established in
2005 through the merger of two leading Japanese pharmaceutical companies. This
integration created a more robust organization that allows for continuous
development of novel drugs that enrich the quality of life for patients around
the world. A central focus of Daiichi Sankyo research and development are
thrombotic disorders, malignant neoplasm, diabetes mellitus, and autoimmune
disorders. Equally important to the company are hypertension, hyperlipidemia or
atherosclerosis and bacterial infections.
This news release may contain forward-looking statements based on current
assumptions and forecasts made by Daiichi Sankyo group. Various known and
unknown risks, uncertainties and other factors could lead to material
differences between the actual future results, financial situation, development
or performance of the company and the estimates given here. These factors
include those discussed in our public reports, which are available on the
website at www.daiichisankyo-us.com. The company assumes no liability whatsoever
to update these forward-looking statements or to conform them to future events
(1) Randomized, Parallel Group, Multicenter, Multinational Study Evaluating
Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial
Fibrillation, presented at American Society of Hematology annual meeting in
(2) Edoxaban tosylate is also known as DU-176b.
(3) Schulman S., et al. Definition of major bleeding in clinical investigations
of antihemostatic medicinal products in non-surgical patients. Journal of
Thrombosis and Haemostasis 2005;3: 692-694.
SOURCE: Daiichi Sankyo, Inc.
Toshiaki Sai, Daiichi Sankyo Co., Ltd (Tokyo), +81-3-6225-1126; or Kimberly Wix,
Daiichi Sankyo, Inc. (US), +1-973-944-2338, Mobile: +1-908-656-5447; or Dr.
Michaela Paudler-Debus, Daiichi Sankyo Europe, +49-(0)89-7808-685, Mobile: +