May 30, 2005

Takeda Pharmaceutical Company Limited

DIRECT − the first large-scale international clinical programme for the treatment of diabetic retinopathy
Baseline data published from landmark DIRECT^*1 trial Programme which evaluates the role of candesartan cilexetilin reducing the onset and progression of diabetic retinopathy,the most feared complication of diabetes*²

OSAKA, JAPAN --- Takeda Pharmaceutical Company Limited ("Takeda") announced  today that The Journal of the Renin-Angiotensin-Aldosterone System (JRAAS) has today published baseline data relating to the 5231 patients randomized into the major clinical trial programme, DIabetic REtinopathy Candesartan Trials (DIRECT). DIRECT is the first clinical trial programme designed to establish whether treatment with an angiotensin receptor blocker (ARB), candesartan cilexetil, targeting the renin-angiotensin system (RAS), can provide effective treatment against the onset and progression of diabetic retinopathy. Diabetic retinopathy is a microvascular complication to diabetes with impairment of the retina, the nerve-rich, light-sensing membrane at the back of the eye.

In the developed world, diabetic retinopathy is a leading cause of blindness in the working population*³ and the most commonly feared complication of diabetes.*²  It is estimated that in 2003, approximately 194 million people worldwide had diabetes, and that this figure will rise to approximately 333 million people by 2025.*⁴
In patients with a 20 year history of diabetes, nearly all type 1 patients, and over 60 percent of type 2 patients will have developed some degree of diabetic retinopathy,*⁵which can ultimately lead to blindness in both type 1 and type 2 diabetic patients.

Current treatment approaches of diabetes-related microvascular complications in the eye and kidney have reduced the frequency of incapacity from blindness and renal failure, however loss of vision still results in many patients. Major factors associated with the development and progressions of retinopathy are duration of diabetes, HbA1c level (an indicator of metabolic "sugar" or glucose control) and blood pressure. At baseline in the DIRECT Programme, the level of retinopathy in both Type 1 and Type 2 diabetic patients showed significant correlation with those factors.

"DIRECT represents an important step forward in the fight against the visual deterioration caused by diabetic retinopathy", said Professor Anne Katrin Sjølie, Chair of the DIRECT Steering Committee, University of Southern Denmark, Odense.
"We look forward to the results from the DIRECT Programme in 2007, which will tell us more about the potential for using a drug such as candesartan cilexetil to halt progression of, and possibly prevent, diabetic retinopathy, a common and frightening condition among people with diabetes. Our aim is to bring hope to the large and ever increasing number of patients with diabetes, by helping to limit retinal damage and, in some patients, preserve vision."

Trial design and patient baseline demographics
A total of 5,231 patients in 309 investigational sites in 30 countries have been randomized into the 3 studies that comprise the DIRECT Programme. In this double-blind programme, patients are assigned to receive 32 mg of candesartan cilexetil or placebo.
The three separate clinical studies will investigate the effects of candesartan cilexetil, in addition to other necessary treatments, in:
1.Type 1 diabetic patients without retinopathy for primary prevention (n=1421)
2.Type 1 diabetic patients with retinopathy for secondary prevention (n=1905)
3.Type 2 diabetic patients with retinopathy for secondary prevention (n=1905)

HbA1c showed mean values of 8.1% in Type 1 primary prevention, 8.5% in Type 1 secondary prevention, and 8.2% for the Type 2 secondary prevention studies. 49% of patients in the Type 1 secondary prevention study had mild non-proliferative retinopathy in at least one eye, and 9% had moderate-moderately severe non-proliferative retinopathy. In Type 2 diabetes patients 17% had moderate-moderately severe non-proliferative retinopathy, and the remainder less severe retinopathy.

The DIRECT Programme is being conducted and jointly sponsored by AstraZeneca and Takeda  Pharmaceutical Company Limited.

References

• *1.Sjølie A-K. The DIRECT Programme Study Group. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics. JRAAS 2005; 6:25?32.
• *2.Dunning PL. Diabetes Education 1995; 21 (N1): 58-65.
• *3.Hutchinson A, McIntosh A, Peters J, et al. Effectiveness of screening and monitoring tests for diabetic retinopathy ? a systematic review. Diabetic Med 2000; 17: 495-506.
• *4.IDF Diabetes Atlas, 2005 .
• *5.American Diabetes Association. Diabetic Retinopathy. Diabetes Care 2000; 23: S73-76.

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