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Fosrenol Has Long-Term Safety and Efficacy in End-Stage Renal Disease Patients Treated for up to 6 Years

Additional data reveal that the Fosrenol®-phosphate complex, in vitro, may be more stable than that of sevelamer hydrochloride in the presence of bile acid

PHILADELPHIA, PA -- November 14, 2005 -- According to data presented this weekend at the annual meeting of the American Society of Nephrology (ASN), non-calcium Fosrenol® (lanthanum carbonate) effectively maintains reductions in mean serum phosphorus levels while demonstrating safety and tolerability in end-stage renal disease (ESRD) patients for up to 6 years.

"These study results provide strong evidence of the safety and efficacy of Fosrenol®," said Dr. Alastair Hutchison, one of the trial's lead investigators from the Manchester Institute of Nephrology & Transplantation, Manchester, United Kingdom. "With a robust long-term safety profile, ESRD patients and physicians can rely on Fosrenol® to help manage hyperphosphatemia and meet K/DOQI (Kidney Disease Outcomes Quality Initiative) guidelines."

The open-label extension study enrolled 93 patients, of which 32 were treated with Fosrenol® for up to 6 years. The study revealed that as patients continued on Fosrenol® therapy, the number of drug-related adverse events did not increase in frequency as drug exposure increased.

The most common treatment-related adverse events were gastrointestinal (GI) in nature and no new or unexpected adverse events occurred during long-term treatment with Fosrenol®.

Importantly, Fosrenol®-treated patients in the study also maintained reduced serum phosphorus and calcium-phosphorus product (Ca x P) levels, demonstrating the long-term effectiveness of Fosrenol®. The patients successfully controlled their serum phosphorus and Ca x P levels to within the K/DOQI guidelines effective at the time the study was conducted.

Phosphate-Binding Affinity of Fosrenol in Vitro
Data presented at the ASN meeting showed that the phosphate-binding affinity of Fosrenol® was more than 200 times higher compared to sevelamer hydrochloride (HCl) at pH 3. When assessed at pH 5 to 7, the affinity of Fosrenol® was four-fold higher compared to sevelamer HCl, demonstrating the pH binding affinity and independence of Fosrenol® in vitro. In addition, the presence of bile acids did not affect the stability of the Fosrenol®-phosphate complex, whereas bile acids led to a more than 13-fold reduction in phosphate-binding affinity of sevelamer HCl with the consequent release of its phosphate. The clinical relevance of the effect of pH on in vivo phosphate binding of Fosrenol® has not been established.

"These data illustrate the pH independence, affinity and selectivity of Fosrenol® for phosphorus, in vitro, compared to other traditional and non-selective binders," study author Dr. Stephen Damment, Senior Vice President of Biosciences R&D, Shire, UK explained.

Managing Hyperphosphatemia
Even with a low-phosphorus diet, most ESRD patients in the United States will develop hyperphosphatemia (high phosphorus levels in the blood). Without effective treatment, hyperphosphatemia may lead to renal osteodystrophy, a collection of bone diseases characterized by bone pain, brittle bones, skeletal deformities and fractures. Evidence also shows that hyperphosphatemia may contribute to cardiovascular disease, which accounts for almost half of all deaths among dialysis patients.

Phosphorus, an element found in nearly all foods, is absorbed from the gastrointestinal tract into the bloodstream. When the kidneys fail, they no longer effectively remove phosphorus, 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 often 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 1 year of dialysis.

Of the approximately 20 million Americans who have some form of kidney disease, more than 512,000 have developed ESRD, a figure that has grown 400 percent over the last 20 years.

Hyperphosphatemia is managed with a combination of diet restriction and phosphorus-binding agents, since diet alone generally cannot adequately control phosphorus levels. Such binders "soak up" phosphorus in the gastrointestinal tract, before it can be absorbed into the blood. Because dietary phosphorus absorption begins as soon as phosphorus enters the stomach, it is important for phosphate binders to work at the variety of pH levels found throughout the gastrointestinal tract.

Despite the availability of phosphorus-binding agents, it remains a challenge for some ESRD patients to maintain target ranges. According to the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease, Guideline 3, Evaluation of Serum Phosphorus Levels, fewer than 30 percent of dialysis patients are able to maintain serum phosphorus levels in the target range.

The K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease also note in Guideline 5, Use of Phosphate Binders in Chronic Kidney Disease (CKD), that non-calcium and non-aluminum phosphate binders are a first-line treatment option in lowering serum phosphorus levels.

Fosrenol®
Fosrenol®, a non-calcium phosphate binder, which received FDA approval in October 2004 to reduce serum phosphorus in patients with end-stage renal disease, is formulated as an easy-to-use, chewable only tablet that can be taken without water, an important consideration for ESRD patients who must restrict their fluid intake. Fosrenol is available in 250 mg and 500 mg strengths and the recommended initial daily dose is 750 mg to 1.5 grams for adults; physicians should adjust the dose to reach target serum phosphorus levels. Most patients require a total daily dose between 1.5 and 3.0 grams to achieve serum phosphorus control, which equates to one to two Fosrenol tablets per meal. The daily dose should be divided and taken with, or immediately after, meals. Tablets should be chewed completely before swallowing intact tablets should not be swallowed.

The most common adverse events were gastrointestinal, such as nausea and vomiting, and generally abated over time with continued dosing. The most common side effects leading to discontinuation in clinical trials were gastrointestinal events (nausea, vomiting, and diarrhea). Other side effects reported in trials included dialysis graft complications, headache, abdominal pain and hypotension. Although studies were not designed to detect differences in risk of fracture and mortality, there were no differences demonstrated in patients treated with Fosrenol® compared to alternative therapy for up to 3 years.

The duration of treatment exposure and time of observation in the clinical program are too short to conclude that Fosrenol® does not affect the risk of fracture or mortality beyond three years. While lanthanum has been shown to accumulate in the GI tract, liver and bone in animals, the clinical significance in humans is unknown.

Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in Fosrenol® clinical studies. Caution should be used in patients with these conditions. Fosrenol® should not be taken by patients who are nursing or pregnant. Fosrenol® should not be taken by patients who are under 18 years of age.


SOURCE: Shire Pharmaceuticals Group plc

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