Led by Prof. Dr. Marc E. De Broe of the Department of Nephrology-Hypertension at the University of Antwerp in Belgium, the phase III study compared the effects of FOSRENOL with those of calcium carbonate in 98 renal dialysis patients from 18 centres in 12 countries (mainly in Europe) - a study cohort that reliably reflected a typical population starting dialysis. The principal aim was to establish the effects of both treatments on bone, given the high prevalence of renal osteodystrophy among this patient population.
Histological examination of tetracycline-labelled bone biopsies is regarded as the gold standard approach to studying bone biology. In this study - which showed that the majority of enrolled patients had some form of pre-existing bone disease - biopsies taken at baseline and after 12 months of FOSRENOL treatment revealed that a proportion of patients with pre-existing adynamic bone disease, osteomalacia or hyperparathyroidism had evolved towards a more normal state. Overall, the number of patients with these forms of renal osteodystrophy had halved from 36 to 18 percent (12 to 6 patients) after a year's treatment with FOSRENOL.
This contrasted with the group treated with calcium carbonate, in whom the number of patients with these forms of renal osteodystophy had increased by nearly a quarter from 43 to 53 percent (13 to 16 patients):
No. of patients with osteomalacia, adynamic bone disease or hyperparathyroidism
FOSRENOL group (n=49)
After 12 months: 6 (18%)
Calcium carbonate group (n=49)
Pre-treatment: 13 (43%)
After 12 months:16 (53%)
The authors state that, overall, treatment with FOSRENOL led to a "considerably better outcome" on bone histology than treatment with calcium carbonate.
Both treatments showed well controlled phosphate levels (with doses up to 3,750 mg/day for lanthanum and up to 9,000mg/day for calcium carbonate) and the incidence and types of adverse effects observed in the study were similar in the two treatment groups. A notable exception to this was hypercalcaemia which was appreciably lower in the FOSRENOL group compared to the calcium carbonate group (6% and 49% respectively). This is important as excess calcium load can lead to the deposition of hard calcium deposits (calcification) in the heart and blood vessels, promoting potentially fatal cardiovascular disease.
"These results demonstrate the potential advantages of FOSRENOL in the dialysis population" comments Dr. Wilson Totten, Group R&D Director of Shire. "Currently available phosphate binders can have shortcomings - amplifying the serious risks of bone disorders and cardiovascular disease. The evidence we now have leads us to believe that FOSRENOL is not associated with adverse effects on bone and does not promote hypercalcaemia or excess calcium load. Further, the findings help substantiate the status of FOSRENOL as a candidate phosphate binder of great clinical promise".
FOSRENOL received an approvable letter in March 2003 from the U.S. Food and Drug Administration. Submissions also have been made by Shire to gain marketing approval in Europe and Canada, whilst development continues in Japan. Shire has an exclusive worldwide license to develop, manufacture, use and sell FOSRENOL under patents owned by AnorMED Inc.
For further information please contact:
Global (outside US & Canada)
Gordon Ngan - Shire Investor Relations +44 1256 894 160
Jessica Mann - Shire Media Relations
+44 1256 894 280
Anna Korving - Resolute Communications
+44 20 7357 8149
Paul Blackburn - Resolute Communications
+44 20 7357 8146
US & Canada
Gordon Ngan - Shire Investor Relations
+44 1256 894 160
Michèle Roy - Shire Media Relations
+1 450 978 7876
Christine Gerstle - Porter Novelli
+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' 269,0001 dialysis patients develop hyperphosphataemia2 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.
1. U.S. Renal Data System. 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.
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
Renal bone disease (renal osteodystrophy)
Dialysis patients are prone to a range of metabolic bone diseases collectively termed renal osteodystrophy1,2,3 :
High turnover bone disease
Osteitis fibrosa cystica (due to secondary hyperpara-thyroidism)
Mixed abnormalities (both high & low turnover)
Mixed uraemic osteodystrophy
Low turnover bone disease
-Osteomalacia (aluminium exposure or non-aluminium cause)
-Adynamic bone disease
Bone tissue is in a continual state of flux (known as bone turnover) with new bone constantly being formed while older bone is remodelled and minerals such as calcium and phosphorus are released back into the blood. Bone turnover is tightly regulated by numerous hormones, of which parathyroid hormone is the most important. Osteitis fibrosa cystica develops as a result of enhanced synthesis of parathyroid hormone by the parathyroid gland (secondary hyperparathyroidism) which is a direct consequence of hyperphosphataemia4. In this condition, bone re-models with excessive rapidity, replacing strong lamellar bone with structurally inferior woven bone. Both bone formation and bone resorption ("dissolving" of bone to release its minerals back into the bloodstream) are accelerated 1. The causes of low bone turnover disease are less clearcut. Osteomalacia - characterised by an accumulation of soft, unmineralised bone - has been principally associated with the use of aluminium-containing phosphate binders while adynamic bone disease is associated with over-suppression of parathyroid hormone, concomitant diabetes and calcium overload.1
1. Malluche HH & Monier-Faugere MC. Understanding and managing hyperphosphataemia in patients with chronic renal disease. Clin Nephrol 1999; 52 (5): 267 - 277.
2. Martin KJ, Gonzalez EA. Strategies to minimise bone disease in renal failure. Am J Kidney Dis. 2001; 38 (6): 1430 - 1436.
3. Malluche HH & Monier-Faugere MC. Hyperphosphataemia: pharmacology intervention yesterday, today an tomorrow. Clinical Nephrology 2000; 54 (4): 309 - 317.
4. Norris KC. Toward a new treatment paradigm for hypephosphataemia in chronic renal disease. Dialysis & Transplantation 1998; 27 (12): 767 - 773.
Lanthanum carbonate (FOSRENOLTM)
FOSRENOL works by binding to dietary phosphate in the stomach; once bound, the FOSRENOL/phosphate complex cannot pass through the stomach 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.
Shire Pharmaceuticals Group plc
Shire Pharmaceuticals Group plc (Shire) is a rapidly growing international specialty pharmaceutical company with a strategic focus on three therapeutic areas - central nervous system disorders (CNS), oncology and anti-infectives. Shire also has two platform technologies: advanced drug delivery and Biologics. Shire's core strategy is based on research and development combined with in-licensing and a focus on eight key pharmaceutical markets. For further information on Shire, please visit the company's website: 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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