March 10, 2004

Takeda Chemical Industries, Ltd.

New data on the effect of candesartan cilexetil

on NYHA functional class in a broad spectrum of heart failure patients

Osaka, Japan, 10 March 2004 - Data presented today at the American College of Cardiology (ACC) annual meeting add weight to the evidence shown in the original publications from the CHARM* Programme of the effects of candesartan cilexetil in chronic heart failure (CHF) patients. The results from further analysis of the data add further support for the CHARM study as a landmark clinical research programme.

Importantly, one analysis1 found that New York Heart Association (NYHA) functional class improved in a broad spectrum of CHF patients treated with candesartan cilexetil. Of all CHARM patients, 35.4% taking candesartan cilexetil improved in NYHA functional class, 55.6% remained unchanged and 9% worsened. This compared with 32.5%, 57.5% and 10.3% respectively in the placebo group (p=0.004).

Commenting on this additional analysis, Professor John McMurray, principal investigator in the CHARM-Added study, Glasgow University and Western Infirmary, Glasgow, Scotland, said "Improving symptomatic well-being is a key objective of heart failure treatment. NYHA functional classification is the most widely used and validated measure of symptomatic limitation in CHF. That candesartan has been shown to improve NYHA functional class across the broad spectrum of CHF investigated in the CHARM Programme will have significant implications for clinical practice. These findings are consistent with a reduction in CHF hospitalisations".

A further analysis2 suggests that the development of atrial fibrillation (AF) in some patients with symptomatic chronic heart failure may also be reduced. Of the 7,601 heart failure patients in CHARM, 72.6% did not have atrial fibrillation (AF) at baseline. This new analysis found that, in the patients randomised to candesartan cilexetil, new incidence of AF during the trial was 6.5%, compared to 7.9% in the placebo group (p=0.048), indicating that candesartan cilexetil may prevent the development of AF in some patients with symptomatic chronic heart failure.

A similar analysis3 showed that, during the CHARM Programme, the number of patients who were newly diagnosed as having Type II diabetes mellitus (6.0% on candesartan cilexetil compared to 7.4% on placebo; p=0.020) was significantly lower in the group treated with candesartan cilexetil.
Commenting on the presentations, CHARM co-chairman, Professor Karl Swedberg, Göteborg University and Sahlgrenska University ospital/östra, Göteborg, Sweden, said: "CHARM was a unique programme which found that candesartan reduced both cardiovascular death and hospital admission in a broad spectrum of heart failure patients.These additional findings add further evidence to the clinical effectiveness of candesartan in heart failure."

CHARM study was sponsored and conducted by AstraZeneca.

Candesartan cilexetil was discovered and originally synthesized by Takeda Chemical Industries, Ltd, and it was jointly developed with AstraZeneca. Candesartan cilexetil is marketed worldwide under the brand name of Blopress® by Takeda and Atacand® by AstraZeneca in around 70 countries.

*Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity

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References

• 1.John J. McMurray, Jan Ostergren, Bertil Olofsson, et al. Candesartan improves functional class across a broad spectrum of patients with chronic heart failure: Results of the Candesartan in Heart Failure- Assessment of Reduction in Mortality and Morbidity Programme (CHARM). Presented at the American College of Cardiology annual conference on Tuesday, 9 March 2004; 9:30 AM - 9:45 AM
• 2.Karl Swedberg, Marc Pfeffer, Alain Cohen-Solal, et al. Prevention of AF in Symptomatic Chronic Heart Failure by Candesartan - Results From CHARM. Presented at the American College of Cardiology annual conference on Tuesday, 9 March 2004;1.00 PM - 2PM.
• 3.Salim Yusuf, Jan B. Ostergren, Hertzel Gerstein, et al. Impact of the Angiotensin-Receptor Blocker Candesartan in Preventing Diabetes in Patients With Heart Failure. Presented at the American College of Cardiology annual conference on Monday, 8 March 2004; 11:00 AM -11:15 AM

otes to editors

• ♦The CHARM Programme recruited 7,601 patients (long term follow up data from 7,599 patients).
• ♦In the CHARM programme, patients were randomised to either candesartan cilexetil or placebo in a 1:1 ratio in each of the three component studies. The CHARM results showed that candesartan cilexetil is the first Angiotensin Receptor Blocker (ARB) to increase survival in chronic heart failure patients with left ventricular dysfunction, whether or not they are taking an ACE-inhibitor. In patients who were not taking ACE-inhibitors due to previous intolerance, candesartan cilexetil significantly reduced the risk of cardiovascular death or hospitalisation for chronic heart failure, with an overall risk reduction of 23% (p<0.0004). In patients that were prescribed conventional therapy for chronic heart failure including an ACE inhibitor, candesartan cilexetil demonstrated additional mortality and morbidity benefits. Candesartan cilexetil produced an additional reduction in the risk of cardiovascular death or hospitalisation for chronic heart failure of 15% (p=0.011) when compared to conventional treatment alone.

The CHARM Programme also included the largest completed trial in chronic heart failure patients with preserved LV function, patients for whom little evidence based treatment guidance presently exist. In CHARM-Preserved the primary endpoint of cardiovascular death or hospitalisations for chronic heart failure showed a trend, 11% risk reduction in favour of candesartan cilexetil (p=0.118), consistent with the significant findings seen in the other two studies. Pooled analysis of the three studies showed that candesartan cilexetil provided a significant reduction in cardiovascular death and also demonstrated a positive trend in the overall reduction in all cause mortality approaching statistical significance (p=0.055).

♦New York Heart Association (NYHA) Classification is a widely used and validated measure of symptomatic limitation in CHF.

	Class I	:	No limitation. Ordinary physical exercise does not cause fatigue, dyspnoea (breathlessness) or palpitations
	Class II	:	Slight limitation of physical activity. Comfortable at rest but ordinary physical activity results in symptoms
	Class III	:	Marked limitation of physical activity. Comfortable at rest but less than ordinary activity results in symptoms
	Class IV	:	Unable to carry out any physical activity without discomfort. Symptoms present even at rest with increased discomfort with any physical activity

• ♦Takeda is a global research-based pharmaceutical company, largest in Japan and one of the leaders in the world. Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products.
• ♦From Takeda's own R&D activities, products such as candesartan cilexetil (marketed as Blopress®, Kenzen® and Amias®), pioglitazone hydrochloride, leuprolide acetate and lansoprazole, have been successfully developed and are now available over 100 countries worldwide.

Publication of CHARM Programme on ACC

• ♦Monday 8 March, Morning Session, Poster Session, MCC Convention Center: Scott Solomon et al., Cause of Death Across Full Spectrum of Ventricular Function in Patients with Heart Failure: The CHARM Study: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
• ♦Monday 8 March, 11.00 - 12.15, Oral Presentation, Session Number 810, MCC Convention Center: Salim Yusuf et al., Impact of the Angiotensin-Receptor Blocker Candesartan in Preventing Diabetes in Patients With Heart Failure: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
• ♦Monday 8 March, 15.00 - 17.00, Poster Session, Session Number 1108, MCC Convention Center: John McMurray et al., Low Hemoglobin is an Independent Predictor of Adverse Fatal and Non Fatal outcomes in Both Reduced and Preserved Systolic Function Chronic Heart Failure: findings from the Candesartanin Heart failure: Assessment of Reduction in Mortality and morbidity Programme (CHARM): 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
• ♦Tuesday 9 March, 08.30 - 10.00, Oral Presentation, Session Number 835, MCC Convention Center: John McMurray et al., Candesartan Improves Functional Class Across a Broad Spectrum of Patients With Chronic Heart Failure: Results of the Candesartan in Heart Failure- Assessment of Reduction in Mortality and Morbidity Programme (CHARM): 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
• ♦Tuesday 9 March, 12.00 - 14.00, Poster Session, Session Number 1145, MCC Convention Center: Karl Swedberg et al., Prevention of AF in Symptomatic Chronic Heart Failure by Candesartan - Results From CHARM: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.

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