Fosrenol shows significant reduction in serum phosphate in Chinese end-stage kidney disease patients

November 17, 2003

Shire Pharmaceuticals Group plc (NASDAQ: SHPGY, LSE: SHP.L, TSE: SHQ CN) announced that treatment with FOSRENOL (lanthanum carbonate) significantly reduced and maintained phosphate levels in a study of Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia, according to data presented at the American Society of Nephrology (ASN) 36th Annual Meeting.

The 11-week study, presented by Professor Wu-Chang Yang, Taipei Veterans General Hospital, Taiwan R.O.C. and his co-authors Dr. S.S. Chiang and Dr. J.B. Chen, in 61 hemodialysis patients showed that patients' serum phosphorus levels in the lanthanum carbonate group decreased to an average of 5.13 mg/dL, significantly lower than those receiving placebo (7.24 mg/dL, p < 0.001). This reduced phosphate level was well within the phosphorus range of 3.5 to 5.5 mg/dL recommended in the new Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines on Bone Metabolism and Disease in Chronic Kidney Disease.

"Data from our study demonstrates that lanthanum carbonate has the potential to reduce high phosphate levels quickly, safely and effectively to levels that comply with the new K/DOQI guidelines. These data suggest that lanthanum carbonate, when approved and available, may provide substantial clinical benefits to people on dialysis," said Prof. Wu-Chang Yang.

Sixty percent (n=18) of lanthanum carbonate-treated patients in the study had serum phosphorus levels of less than 5.6 mg/dL (the study target level), compared with only 10 percent (n=3) of patients receiving placebo. This was considered highly statistically significant, p<0.001.

At the end of the study, patients in the lanthanum carbonate group also showed significantly lower calcium x phosphate product. A high calcium x phosphate product is a measurement that has been linked to illness and death within this patient population. Specifically, at the start of the study, the lanthanum carbonate and placebo groups had average calcium x phosphate product levels of 62.33 and 58.04, respectively. At week eight, the lanthanum carbonate group's average level dropped to 48.56, well below the new K/DOQI guidelines of less than 55 mg2/dL2, the placebo group increased to 66.06, p<0.001.

During the trial, adverse events were comparable between the lanthanum carbonate and placebo groups and were typical of populations with ESRD undergoing dialysis. Further, the adverse events noted during this study were consistent with adverse event findings from previous studies with lanthanum carbonate.

Pre-clinical Data Supports Safety of Lanthanum Carbonate
In addition to the significant phosphate reduction seen in Yang's study, pre-clinical data also presented at ASN continued to support the overall safety profile of lanthanum carbonate. According to data from ASN posters FPO651 and FPO654, lanthanum carbonate was safe and very well tolerated by a variety of animal species, including mice, rats and dogs, at plasma exposure levels substantially higher than those used in dialysis.

Additional studies examined the effects of multiple doses of lanthanum carbonate on rats, mice and dogs. In these studies, lanthanum carbonate was administered to rats (n=120) and mice (n=100) by oral gavage throughout their lifespans and to dogs (n=8) by capsule (52 weeks). No histopathological changes were seen in the brains or livers of lanthanum carbonate-treated animals, and there was no significant penetration of lanthanum carbonate into the brain. Similarly, neurobehavioral screens in mice or dogs receiving lanthanum carbonate for up to 62 weeks were normal.

Managing Hyperphosphatemia
Phosphorus, an element found in nearly all foods, is absorbed from the gastrointestinal tract into the blood stream. When the kidneys fail, they no longer effectively filter out phosphates, even with the help of blood-cleansing dialysis machines. While the normal adult range for phosphorus is 2.5 to 4.5 mg/dL, the blood phosphorus levels of many patients on dialysis exceed 6.5 mg/dL. Such levels have been linked to a significantly higher illness and death risk for patients who have undergone at least one year of dialysis. Most dialysis patients, including some 243,000 Americans, develop hyperphosphatemia.

Hyperphosphatemia disrupts the delicate interplay between the body's levels of calcium, parathyroid hormone (PTH) and vitamin D. Over time, hyperphosphatemia can ultimately lead to calcification of the heart, lung and some arteries. Accumulating evidence shows that hyperphosphatemia contributes to cardiovascular disease, which accounts for almost half of all deaths among dialysis patients. In fact, studies have shown that cardiovascular mortality in dialysis patients aged 25-34 years is more than 5 times greater than that in people aged 65-74 in the general population.

Since diet restrictions alone generally cannot control phosphate levels, patients traditionally manage hyperphosphatemia with phosphate binding agents, typically calcium or sevelamer, or occasionally aluminum salts, at every meal and snack. Such binders "soak up" phosphate in the gastrointestinal tract, before it can be absorbed into the blood. Although these agents can be effective, they can cause potentially serious side effects including hypercalcemia, bone toxicity and tolerability problems.

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

Lanthanum carbonate works by binding to dietary phosphate in the stomach. Once bound, the lanthanum carbonate/phosphate complex cannot pass through the stomach lining into the blood stream and is eliminated from the body. Consequently, a patient's overall absorption of phosphate from the diet significantly decreases. Shire has conducted an extensive clinical research program for lanthanum carbonate involving more than 1,700 patients, some of whom have been treated for 36 months or more. These clinical trials demonstrate that lanthanum carbonate is an effective phosphate binder and is well tolerated in long-term use.

Shire Pharmaceuticals Group plc
Shire Pharmaceuticals Group plc (Shire) is a global specialty pharmaceutical company with a strategic focus on meeting the needs of the specialist physician and currently has a range of projects and products in the areas of central nervous system (CNS), gastrointestinal (GI), and renal. Shire has operations in the world's key pharmaceutical markets (US, Canada, UK, France, Italy, Spain and Germany) as well as a specialist drug delivery unit in the US. For further information on Shire, please visit the Company's website: www.shire.com http://www.shire.com/
-end-
Poster PO652 "Efficacy and Safety of Lanthanum Carbonate in the Treatment of Hyperphosphatemia in Chinese Chronic Renal Failure Patients" Wu-Chang Yang, Nephrology Department, Taipei Veterans Hospital, Taipei, Taiwan, et al.

Porter Novelli

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