News Release

Yamanouchi Pharmaceutical Co., Ltd.

Micardis(telmisartan) exerts hypotensive effect over a 24-hour period after administration
- The results showed that the hypotensive effect of telmisartan was higher compared to valsartan in the 6-hour period before administration when the drug efficacy tends to diminish -

November 6, 2003

At the 26th Annual Scientific Meeting of the Japanese Society of Hypertension held at Miyazaki city from 30 October to 1 November, Prof. William B. White (University of Connecticut School of Medicine) presented a study entitled "Effects of long half-life versus intermediate half-life angiotensin II blockade on the circadian variation of blood pressure" This study measured 24-hour blood pressure in a telmisartan-administered (long half-life) group versus a valsartan-administered (intermediate half-life) group using ABPM (ambulatory blood pressure monitoring), and analysed the mean blood pressure for 4 periods: 6 hours mean prior to the next administration, 24 hours mean, as well as during daytime and nighttime. The implication of the study results is that telmisartan may provide a sustainable hypotensive effect compared to valsartan.

Clinical trials have shown that cerebral and cardiovascular events such as stroke and myocardial infarction are reported to frequently occur in the early morning when an elevation of blood pressure is often observed. From these facts, the importance of pressure control in the early morning to suppress the occurrence of such events is increasingly emphasised in recent years. The early-morning blood pressure elevation has been associated with the RA (renin-angiotensin) system and the sympathetic nerves. In the RA system, blood pressure elevates with the enhancement of activity in the night and upon awakening.

Early morning blood pressure are strongly linked to cardiovascular events such as stroke. Therefore, blood pressure monitoring around the clock is more accurate than in-clinic blood pressure in predicting CV events in patients with hypertension. In the reported study, the duration of hypotensive effect of a long half-life telmisartan versus a intermediate half-life valsartan was compared using ambulatory blood pressure monitoring (ABPM).

In this study 80 mg of telmisartan or 160 mg of valsartan was administered once daily in the morning as a maintenance dose over an 4-6 week period, after 40 mg telmisartan or 80mg valsartan once daily for 2 weeks run-in period, to 490 patients of mild-to-moderate hypertension (244 patients in the telmisartan group and 246 patients in the valsartan group) and the hypotensive effect of these drugs was compared over 24 hours. In addition to mean 6 hours prior to the next administration, mean 24 hours, daytime and night time DBP and SBP were observed and analysed. The primary endpoint is the change in DBP from baseline during the last 6 hours of the 24-hour dosing interval. The results showed that the hypotensive effect of telmisartan was higher compared to valsartan in the 6-hour period before administration.

Prof. White said in the session, "Telmisartan lowered both systolic and diastolic pressure to a greater extent than valsartan for the last 6-hour of the dosing interval. The implication of the results obtained in this trial is that telmisartan with a longer half-life may provide better control of ambulatory systolic and diastolic blood pressure, leading to improved cardiovascular outcomes."


INFORMATION TO THE EDITOR
MICARDIS is a once daily oral administration anti-hypertension treatment of ARB (Angiotensin II Receptor Blocker) class. 24 hours action of MICARDIS, unique amongst the ARB class, ensures blood pressure controlling in the early morning when patients have an elevated risk for CV events. It is also favourably administrated to patients with renal dysfunction, which in many cases complicates with hypertension, because of its unique hepatic/bilary metabolism with least involvement of the kidneys.

MICARDIS is on the market in over 65 countries, including the U.S.A. and European countries. Large-scale long-term clinical trials, ONTARGET, TRANSCEND and PROTECTION, are conducted globally to see effects of MICARDIS in protecting patients from cardiovascular disease and death, progression of renal dysfunction amongst other endpoints.


About ONTARGETTM
ONTARGET is a multi-centre, double-blind, randomised global outcome trial that involves patients from Asia, Australia, Europe, the Americas, the Middle East and South Africa. Patients are divided into three treatment groups. One group receives Micardis (telmisartan) once daily, another group receives ramipril once daily, and the third group receives the combination of Micardis plus ramipril once daily. Ramipril is globally supplied for the study by Aventis.

The composite cardiovascular endpoint will be the reduction of risk of cardiovascular mortality, stroke, myocardial infarction and hospitalisation for congestive heart failure.

Patient enrolment started in November/December 2001, and the study is expected to be completed in 2007. Patients in the study are at least 55 years of age with a history of coronary artery disease, stroke, transient ischaemic attack, peripheral vascular disease or high-risk diabetics with evidence of end-organ damage, (e.g. microalbuminuria - an imbalance of serum proteins in the urine).


About TRANSCENDTM
TRANSCEND is a double-blind, parallel-group study that began in November 2001 and will be completed by 2007. It runs simultaneously with ONTARGET and assesses the ONTARGET study objectives for treatment with 80 mg Micardis (telmisartan) versus placebo in patients who are intolerant to ACE inhibitors.

The primary objective for the study is the effect of Micardis on the composite endpoint of cardiovascular mortality, stroke, acute myocardial infarction and hospitalisation for congestive heart failure. The secondary objective for TRANSCEND is its impact on the incidence of newly diagnosed congestive heart failure, acute ischaemic syndromes, revascularisation procedures, newly diagnosed diabetes, transient ischaemic attack, dementia, new onset of atrial fibrillation, and development of overt nephropathy or dialysis among diabetics.

Patients 55 years of age or older with a history of coronary artery disease, stroke, peripheral vascular disease or type I or II diabetes with end-organ damage may be eligible for enrolment. Symptomatic heart failure patients are excluded from the study.

About The PROTECTION Programme
PROTECTION (Program of Research tO show Telmisartan End-organ proteCTIOn poteNtial) is aimed at showing the potential of Micardis(telmisartan) to protect against end-organ damage caused by hypertension and examines the efficacy of telmisartan in many stages of the cardiovascular continuum.

The trials aim to provide further evidence on the role of ARBs in cardiovascular protection, with endpoints in renal and cardiac target-organ damage and in vascular and early morning blood pressure surge protection in high-risk populations.

This programme includes INNOVATION study for type II diabetic nephropathies in Japan.

Company Profiles

Nippon Boehringer Ingelheim Co.,Ltd.(www.boehringer-ingelheim.co.jp)
Establishment: June 1961
Head Office: 3-10-1, Kawanishi-shi, Hyogo, Japan
President: Akio Ohsawa
Net Sales: 88.6 billion yen (as of March 2003)
Number of
Employees:
1,699(as of 1st April 2003)
Major Business: Research & development, import, manufacturing, and marketing of pharmaceuticals
Import/export and marketing of pharmaceutical active ingredients and intermediates


Boehringer Ingelheim GmbH (www.boehringer-ingelheim.com)
Establishment: 1885
Head Office: Ingelheim, Germany
Representative: Prof. Rolf Krebs (Chairman of the Board)
Consolidated Net Sales: EUR 7.6 billion (as of December 2002) / about 9600 billion yen
Consolidated Number of Employees: about 32,000
Major Business: Research & Development, manufacturing, and marketing of prescription medicine, consumer healthcare products, animal health product, bio-pharmaceuticals, and chemicals
Operation Sites: 156 sites around the world