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Phase III Trial Results Show Lanthanum Carbonate Controls Hyperphosphatemia

DALLAS, April 4 /PRNewswire-FirstCall/ -- Shire Pharmaceuticals Group plc (NASDAQ:SHPGY) (NASDAQ:LSE:) (NASDAQ:SHP.L) (NASDAQ:TSE:) (NASDAQ:SHQ) (NASDAQ:CN) announced that continued, long-term treatment (one-year) with FOSRENOL(TM) (lanthanum carbonate) maintains decreased levels of phosphate, which frequently escalate in end-stage renal disease (ESRD) patients, according to data from an extension trial presented on April 3, 2003 at the National Kidney Foundation Annual Meeting.

This extension trial data supports positive efficacy and safety findings from two previous, short-term studies, which documented that lanthanum carbonate treatment effectively reduced phosphorus with a low incidence of elevated calcium levels. Hypercalcemia is a side effect of some current therapies and has been linked to increased calcification of the body's major arteries, including the heart's coronary arteries, which may increase the incidence of cardiovascular disease.

"In this study, long-term lanthanum carbonate treatment successfully maintained lowered phosphate levels, which frequently increase to harmful levels in end-stage kidney patients," said principal investigator William F. Finn, M.D., professor of medicine at the University of North Carolina School of Medicine at Chapel Hill. "Paired with earlier data from a phase three long-term safety trial, our findings suggest that lanthanum carbonate has a good safety and tolerability profile and can be used long-term to provide a real clinical advantage to dialysis patients."

Shire received an approvable letter for lanthanum carbonate from the U.S. Food and Drug Administration on Feb. 28, 2003. The company also submitted the drug, under the trade name of FOSRENOL, for regulatory review in the European Union and Canada. The product is under development in Japan.

Lanthanum Carbonate Reduces Phosphorus in Majority of Patients The 52-week, open-label extension study assessed the persistence of patients' improvement with chronic administration of lanthanum carbonate. Finn found that extension treatment with lanthanum carbonate yielded reduced serum phosphorus levels that averaged less than the target amount of 5.9 milligrams per deciliter (mg/dL) in 53 percent of participants, all of whom had participated in one of two previous shorter-term studies. Most physicians consider an ESRD patient's phosphate levels controlled with the achievement of concentrations of 5.9 mg/dL or less, Finn noted.

At the study end, participants averaged phosphorus levels of 5.7 +/- 1.4 mg/dL. When the study began, patients averaged levels of 6.6 +/- 2.0 mg/dL, likely due to the inclusion of patients in the extension study who had received placebo in one of the short-term studies, Finn explains. By week four, the average levels dropped to 5.7 +/- 2.0 mg/dL, a significant change from the patients' levels at the start of the extension trial, p = 0.002. For the duration of the study, patients averaged levels below the target.

"Although the participants' average phosphorous levels had minor fluctuations after the second week, the majority of patients maintained controlled levels at or below the therapeutic target throughout the study, demonstrating the efficacy of lanthanum carbonate," Finn said.

The participants' serum calcium levels remained within the normal range specified by the study design, 8.4 to 10.4 mg/dL, throughout the extension trial.

Lanthanum carbonate exhibited a good safety profile during the extension trial. No treatment-related serious adverse events occurred. The most frequently reported adverse events by participants were nausea (26.0 percent), peripheral edema (23.4 percent) and myalgia (20.8 percent). However, investigators related study treatment to only two events that each occurred in more than one person, but neither event occurred at significant rates: dyspepsia in three participants and constipation in two participants.

Study Design
For this pooled extension study, investigators enrolled 77 patients who all received lanthanum carbonate for 52 weeks at doses established during earlier studies. All extension study patients had previously participated in one of two shorter-term trials as described below. These studies were reviewed by institutional ethical review boards to ensure that they met appropriate ethical standards.

In the first short-term trial, investigators gave participants placebo for up to three weeks, then randomized them to receive either drug or placebo for six weeks (double-blind). Participants then underwent a two-week placebo run out, followed by possible extension treatment for up to 48 weeks. During the double-blind phase, patients received placebo or lanthanum carbonate at fixed doses containing 225, 675, 1,350 or 2,250 mg/day of elemental lanthanum. During the extension period, patients received doses ranging from 300 to 2,250 mg/day. Eleven of these patients subsequently enrolled in the pooled extension trial.

In the second short-term trial, investigators titrated participants' doses of lanthanum carbonate for six weeks and then randomized them to receive either the drug or a placebo for four weeks (double-blind). During titration, patients received doses ranging from 750 to 3,000 mg/day. Sixty-six of these patients enrolled in the pooled extension trial.

Managing Hyperphosphatemia
Controlling normal phosphorus levels is a challenge for ESRD patients, since phosphorus is a common element found in nearly all foods and is absorbed from the gastrointestinal tract into the bloodstream. Most dialysis patients will develop hyperphosphatemia (high serum phosphate levels), a condition associated with significant illness, vascular calcification, bone disease and death. When the kidneys fail, they no longer effectively filter out phosphates, even with the help of blood-cleansing dialysis machines, causing phosphorus levels in the blood to rise. When serum phosphorus levels reach higher than normal levels, hyperphosphatemia occurs and is considered significant when levels are greater than 5 mg/dL.

Hyperphosphatemia disrupts the delicate interplay between the body's levels of calcium, parathyroid hormone (PTH) and vitamin D. Over time, hyperphosphatemia can lead to calcification of the heart, lungs and some arteries. This calcification may increase the incidence of cardiovascular disease. Heart disease accounts for nearly 50 percent of all deaths in dialysis patients.

Hyperphosphatemia also can lead to renal osteodystrophy, the painful thinning and malformation of bone that increases the likelihood of fractures. Some 90 percent of ESRD patients develop this bone disease.

Control of hyperphosphatemia requires strict adherence to a low-phosphorus diet; however, diet restrictions alone generally cannot adequately control phosphate levels. Patients traditionally manage hyperphosphatemia with phosphate binder agents, typically calcium or sevelamer, or occasionally aluminum salts, at every meal. 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. Of note, calcium-containing phosphate binders may worsen hypercalcemia.

Lanthanum carbonate (FOSRENOL(TM))
Lanthanum carbonate (FOSRENOL(TM)) is a candidate non-calcium, non-aluminum, phosphate binder, which is formulated as a chewable tablet. FOSRENOL 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.

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