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News Release

FOR IMMEDIATE RELEASE
February 25, 2005

Eisai Announces the Intermediate Analysis of Anti-osteoporosis Treatment Post-marketing Research to Investigate the Benefits of Menatetrenone As Part of the Ministry of Health, Labour and Welfare's Pharmacoepidemiological Drug Review Program

Eisai Co., Ltd. (Headquarters: Tokyo, President: Haruo Naito) announced today the intermediate analysis of clinical trial for the "Anti-osteoporosis Treatment Post-marketing Research Project" that in 1995 the Ministry of Health, Labour and Welfare (then the Ministry of Health and Welfare) designed to investigate the benefits of menatetrenone (Glakay(R) capsules 15mg) as part of pharmacoepidemiological drug review program and asked Eisai to cooperate the study. Eisai took over the project from the ministry in 1997 and has since been conducting clinical trial at the hand of the original study group led by Dr. Tetsuro Inoue.

This is the first, large-scale, pharmacoepidemiological clinical trial to investigate the benefits of anti-osteoporosis treatment such as prevention of osteoporosis-related fracture and improvement of patients' quality of life involving 4,000 participants in Japan. The primary objective of the study called "OF Study (short for Osteoporosis Fracture Study)" was to examine the new incidence of vertebral fractures in patients with osteoporosis who were randomized to be treated with either daily dose of calcium supplement as a monotherapy (the calcium monotherapy group) or menatetrenone plus calcium supplement as a combination therapy (the menatetrenone combo therapy group) over 36 months, followed by an observational research over 12 months. We have obtained and summarized the first clinical data analysis of the 36-month trial on some endpoints including the primary endpoint, new incidence of vertebral fracture.

The approved indication and effects of Glakay(R) capsules 15mg is improvement of bone mass decrease and relief of back pain in patients with osteoporosis.

Background of Anti-osteoporosis Treatment Post-marketing Research Project
1.
The Health and Welfare Ministry planned a large-scale epidemiological study to help create the nation's post-marketing research guideline in the aim of Post-marketing evidence-based medicine.
2.
In 1995, the ministry determined to launch the Anti-osteoporosis Treatment Post-marketing Research Project as part of pharmacoepidemiological drug review program.
3.
The ministry asked Eisai to cooperate OF Study and Eisai accepted the offer.

Summary of Study Results
1.
In the primary statistical analysis, no specific difference was observed on the effectiveness in preventing new incidence of vertebral fracture between patients treated with the calcium monotherapy and those treated with the menatetrenone combo therapy.
2.
Other statistical analyses demonstrate the following properties of the menatetrenone combo therapy in comparison with the calcium monotherapy.
  1)
In a stratified analysis on new incidence of vertebral fracture, more reduced fracture incidences were seen in patients with at least five vertebral fractures at baseline who received the menatetrenone combo therapy.
  2)
In a stratified analysis on loss of height frequently seen in osteoporosis patients, patients aged 75 years and older, women more than 30 years past menopause and patients with at least five vertebral fractures who received menatetrenone combo therapy lost less height respectively.
  3)
In a statistical analysis on activities of daily living, walking and the degree and duration of back pain at rest were more improved in the menatetrenone combo therapy group.
3.
The overall incidence of adverse effects (per 100 person-year)* was 2.9 in the calcium monotherapy group vs. 3.6 in the menatetrenone combo therapy group.
*  the incidence of adverse effects (per 100 person-year): The number of adverse effects incidence per 100 person per year of observation.


We are currently under way of the 12-month observational follow-up study and will also analyze the data about new incidence of femur and other bone fractures after the completion of the research.

[For more information, see reference data including clinical study design and summary of the findings attached below.]

Contacts:

Corporate Communications Department
Eisai Co., Ltd.
03-3817-5120 (Tokyo)


Reference Data
1.
Clinical Study Design
1)
Objective
A randomized controlled clinical trial was conducted in adult patients with primary osteoporosis over three years. Participants were randomly allocated to be treated with either daily dose of calcium supplement as a monotherapy (the calcium monotherapy group) or menatetrenone plus calcium supplement as a combination therapy (the menatetrenone combo therapy group) to compare the new incidence of vertebral fractures between the two groups. Participants who completed the study have been being monitored in a one-year observational follow-up study to investigate the effectiveness of both therapies in preventing the risk of clinical fractures.

2)
Period
i)
Treatment period: 36 months after the initiation of treatment
ii)
Follow-up period: 12 months following the treatment period (No limitation on the use of any treatments including investigational agents)
3)
Endpoints
i)
Primary endpoint: New incidence of vertebral fracture during the treatment period.
ii)
Secondary endpoint: New incidence of clinical fracture throughout the treatment and follow-up phases - which includes the upper forelimb bone fracture, femur, radius and vertebral fracture associated with such severe trauma that can cause fracture in normal bones of young adults, which is due to be analyzed after the completion of a 48-month study period.
iii)
Other endpoints: Activities of daily living (ADL), height
4)
Time Frame
From April 1996 to March 2005
5)
Planned enrollment number of participants
Patients with pre-existing vertebral fractures: 1,200
Patients with no vertebral fracture: 2,800
Total number of participants: 4,000


2.
Summary of Findings
Total number of enrolled participants: 4,378

i)
Patients with pre-existing vertebral fractures: the calcium monotherapy group - 697;
the menatetrenone combo therapy group - 695

ii)
Patients with no vertebral fracture: the calcium monotherapy group - 1,496;
the menatetrenone combo therapy group - 1,490

1)
Primary statistical analysis (new incidence of vertebral fracture)
Among patients with no vertebral fracture, the incidence of vertebral fractures (per 100 person-year)* was 2.6 in the calcium monotherapy group and 2.7 in the menatetrenone combo therapy group (p=0.666). As for patients with vertebral fractures, the incidence of fractures was 13.8 in the calcium monotherapy group and 13.8 in the menatetrenone combo therapy group (p=0.929). No specific difference was observed between the two groups of each cohort. (For details, see the following table.)
*  the incidence of fractures (per 100 person-year): The number of fracture incidence per 100 person per year of observation.

Patients with no fracturePatients with fractures
Calcium mono. group Menatrenone combo. groupCalcium mono. group Menatrenone combo. group
Subjects1,1221,117516502
Cases of fracture incidence7176152151
Fracture rate (per 100 person-year)2.62.713.813.8
P-value0.6660.929

2)
Other statistical analyses
*As to other analyses, though no adjustment procedure to avoid possible multiplicity in the process of statistical inference was designated in a protocol, data tested at a two-sided 10% level of statistical significance show the following differences between the two treatment groups.


i)
Clinical data were analyzed on primary endpoint - new incidence of vertebral fracture - for subgroups divided depending on the age, postmenopausal years, body mass index (BMI) and the number of pre-existing vertebral fractures at baseline. Data show that the incidence of fractures in cases with at least five vertebral fractures at baseline in the menatetrenone combo therapy group vs. the calcium monotherapy group was 20.3 to 33.2, indicating that the fracture incidence reduced more in the menatetrenone combo therapy group than the calcium monotherapy (p=0.029). (See the following table.)


Patients with fractures
at least five vertebral fractures
Calcium mono. group Menatrenone combo. group
Subjects7989
Cases of fracture incidence4634
Fracture rate (per 100 person-year)33.220.3
P-value0.029

ii)
Data were statistically analyzed on loss of height for the subgroups up to the age, postmenopausal years, BMI, the vertebral fracture number at baseline and a few other conditions. The results demonstrate that patients aged 75 years and older, women more than 30 years past menopause and cases with at least five vertebral fractures who received menatetrenone combo therapy lost less height compared with the respective counterparts treated with calcium monotherapy. (p=0.100 to p<0.001)


iii)
The improvement of patients' ADL performance was statistically evaluated in terms of capacity of walking and participating in various events, the degree and duration of back pain at rest, and the degree of pain on motion. The analysis show that the quality of ADL associated with walking and the degree and duration of back pain at rest were more improved in the menatetrenone combo therapy group in comparison with the calcium monotherapy group up to the initial 12 months (p=0.092 to p=0.001).


No specific difference on other endpoints was seen between the two groups.


3)
Safety (Adverse Drug Reaction)
The overall incidence of adverse events (per 100 person-year) in the study was 9.2 in the calcium monotherapy group and 10.1 in the menatetrenone combo therapy group (p=0.181). The incidence of ADR was 2.9 in the calcium monotherapy group and 3.6 in the menatetrenone combo therapy group (p=0.041).
The reported ADR with p-value below 10% were as follows:


i)
Among patients with no vertebral fracture, adverse events were reported in 7.9 of the calcium monotherapy group and 9.3 of the menatetrenone combo therapy group (p=0.062).


ii)
The incidence of ADR among patients with no vertebral fracture was 2.6 in the calcium monotherapy group and 3.6 in the menatetrenone combo therapy group reported adverse effects (p=0.031).


iii)
The following tables represent the incidence of ADR (per 100 person-year) reported in the two treatment groups that were classified according to the suffered organs.


[Adverse events]

Calcium mono. groupMenatrenone combo. groupP-value
Skin and skin appendage lesions0.20.6<0.001
Collagen diseases0.10.00.026
GI disorders2.02.50.062
General systemic disorders0.20.60.003

[Adverse effects]

Calcium mono. group Menatrenone combo. groupP-value
Skin and skin appendage lesions0.10.5<0.001
Hearing and vestibule disorders0.00.10.081
General systemic disorders0.00.20.018