Public Release: 

Phosphate reduction starts within one week of treatment with Fosrenol(r) (lanthanum carbonate)

Phase III data published in American Journal of Kidney Diseases confirm efficacy and tolerability of lanthanum carbonate in end-stage renal disease (ESRD)

Resolute Communications

Basingstoke, UK - 30 June 2003 - Treatment with Fosrenol® (lanthanum carbonate) initiates rapid, statistically significant reductions in serum phosphate within one week of starting therapy (p < 0.0001), according to a study published for the first time today in the American Journal of Kidney Diseases1. Results from this peer-reviewed publication of pivotal Phase III data for lanthanum carbonate, Shire Pharmaceuticals' candidate phosphate binder agent for use in end-stage renal disease (ESRD) showed that lanthanum carbonate (750 - 3000 mg/day) effectively controlled serum phosphate to target levels of < 5.9mg/dL (1.90 mmol/L) and was well tolerated.

Hyperphosphataemia (excessive levels of phosphate in the blood) affects as many as 80% of patients undergoing dialysis for ESRD2. Without effective treatment, hyperphosphataemia can lead to bone pain, skeletal deformities and fractures, and is associated with the development of cardiovascular disease, which accounts for nearly 50% of all deaths in dialysis patients3.

"As clinicians, we need phosphate binders that can quickly and effectively reduce serum phosphate levels without causing an increase in serum calcium levels, a common side-effect of existing therapies. The results of this study suggest that lanthanum carbonate could represent a significant advantage over calcium-based phosphate binder treatment, as it enables effective independent control of serum calcium", said William F. Finn, M. D., principal study investigator and Professor of Medicine at the University of North Carolina School of Medicine, USA.

The study assessed haemodialysis patients from 14 US centres using a three-stage protocol:

  • 163 patients entered a screening and wash-out phase (1 - 3 weeks)
  • 126 individuals then entered a 6-week open-label dose titration phase where all patients received treatment with lanthanum carbonate.
  • 94 patients then entered into the 4-week double-blind maintenance phase and were randomly assigned either to continue on lanthanum carbonate or switch to placebo.

During the open label dose titration phase, treatment with lanthanum carbonate resulted in significantly reduced serum phosphate levels. This reduction commenced within one week of starting therapy (p < 0.0001). Following randomization, mean phosphate levels remained <6.0mg/dL (1.94mmol/L) in the lanthanum carbonate group but were substantially increased in those patients receiving placebo. By the end of the double-blind phase, the mean difference in serum phosphate levels between the lanthanum carbonate and placebo groups was 1.91 mg/dL (0.62 mmol/L) (p<0.0001). In addition, compared to placebo, lanthanum carbonate achieved significantly lower calcium x phosphate product (p<0.0001). High calcium x phosphate product has been shown to be an important predictor of mortality, and morbidity due to cardiovascular disease in dialysis patients4. Overall, this research suggests that lanthanum carbonate is an effective and well-tolerated phosphate binding agent in patients with ESRD.

"Our study clearly illustrates the role that lanthanum carbonate could play in managing hyperphosphataemia, a serious complication of end-stage renal disease", concluded Dr. Finn.

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Shire received an approvable letter for Fosrenol on 28 February 2003 from the U.S. Food and Drug Administration (FDA). The company has also submitted the drug for regulatory review in the European Union and Canada. Shire has an exclusive worldwide licence to develop, manufacture, use and sell Fosrenol under patents owned by AnorMED Inc. ends

For further information please contact:
Global (outside US & Canada)
Gordon Ngan - Shire Investor Relations
Jessica Mann - Shire Media Relations
Anna Korving - Resolute Communications
Paul Blackburn - Resolute Communications 44-1256-894-160, 44-1256-894-280, 44-20-7357-8149, 44-20-7357-8146
US & Canada
Gordon Ngan - Shire Investor Relations
Michèle Roy - Shire Media Relations
Christine Gerstle - Porter Novelli 44-1256-894-160, 1-450-978-7876, 1-212-601-8144

Notes to editors
Hyperphosphatemia and its consequences
Chronic kidney failure is complicated by hyperphosphataemia - high phosphate levels in the blood - caused by the inability of the kidneys (and dialysis) to filter out excess phosphate from food. Even with a low-phosphate diet as many as 80% of Europe's 225,000 and the United States' 269,000 dialysis patients develop hyperphosphataemia2,5 and need treatment with a phosphate-binder. The most well-known consequences of hyperphosphataemia are a range of bone diseases which can cause bone pain, skeletal deformities and fractures. Hyperphosphataemia is also associated with the development of cardiovascular disease, which accounts for nearly 50% of all deaths in dialysis patients3. Ironically, currently available phosphate binders - although they help control phosphate levels - can worsen these complications. Aluminium-based phosphate binders are associated with severe bone toxicity while calcium-based binders contribute to cardiovascular disease by promoting the deposition of hard calcium deposits (calcification) in the heart and blood vessels.

References:
1. Joy MS, Finn WF. Randomized, double-blind, placebo-controlled, dose-titration, Phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphataemia. Am J Kidney Dis 2003; 46:92-107
2. Numbers of patients on dialysis broadly equates to patients with end stage kidney disease. Source: Market Research, Insight International, Dec 01/Jan 02.
3. Davies MR, Hruska K. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001 Aug;60(2):472-9
4. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kid Dis 1998;31:607-17
5. USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2002, page 44.

Lanthanum carbonate (Fosrenol®)
FL works by binding to dietary phosphate in the GI tract; once bound, the FOSRENOL/phosphate complex cannot pass through the intestinal lining into the blood stream and is eliminated from the body. As a consequence, overall phosphate absorption from the diet is decreased significantly. Shire has conducted an extensive clinical research programme for FOSRENOL involving almost 1700 patients, some of whom have been treated for 36 months or more. This programme has demonstrated that FOSRENOL is an effective phosphate binder with a proven safety profile for long-term use.

Study history
Preliminary results from this study were first announced at the American Society of Nephrology in 2002. The AJKD publication is the first time the data have been seen in their entirety.

Shire Pharmaceuticals Group plc
Shire Pharmaceuticals Group plc (Shire) is a rapidly growing international emerging pharmaceutical company with a strategic focus on four therapeutic areas - central nervous system disorders (CNS), gastrointestinal (GI), oncology, and anti-infectives. Shire also has three platform technologies: advanced drug delivery, lead optimisation for small molecules and Biologics. Shire's core strategy is based on research and development combined with in-licensing and a focus on key pharmaceutical markets. For further information on Shire, please visit the company's website: http://www.shire.com

THE "SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995. Statements included herein that are not historical facts, are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialise, Shire's results could be materially affected. The risks and uncertainties include, but are not limited to, risks associated with the inherent uncertainty of pharmaceutical research, product development, manufacturing and commercialisation, the impact of competitive products, including, but not limited to, the impact on Shire's Attention Deficit Hyperactivity Disorder (ADHD) franchise, patents, including but not limited to, legal challenges relating to Shire's ADHD franchise, government regulation and approval, including but not limited to the expected product approval date of lanthanum carbonate (Fosrenol®) and Methypatch ® , and other risks and uncertainties detailed from time to time in our filings, including the Annual Report filed on Form 10-K by Shire with the Securities and Exchange Commission.

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