Washington Editor

A panel of kidney and cardiovascular experts Tuesday told the FDA that phosphate binders used to control serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis should be approved for use in predialysis patients with hyperphosphatemia, an abnormally high level of phosphate in the blood.

While members of FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that more studies are needed to determine whether the drugs' benefits of reducing phosphate levels outweigh any risks associated with their use in predialysis patients, panelists were split on whether study results were needed before the FDA should approve the predialysis indication.

About 10 percent of the U.S. population is affected by CKD, a condition in which the filtering capacity of the kidney continually diminishes until renal replacement therapy is required.

Patients with CKD are at an increased risk of death, said Keith Hruska, director of the Division of Pediatric Nephrology at Washington University School of Medicine in St. Louis.

A 30-year-old dialysis patient has the same risk of death as that of a 90-year-old person with normal kidney function, Hruska told the panel.

"These patients [who] progress to dialysis represent the survivors. That's why it's important to help kidney patients stay as healthy as possible from the early stages of their disease," he declared.

CKD is classified in five stages on the basis of the presence of kidney damage and the glomerular filtration rate. Stage 5 is the point at which patients generally are treated with dialysis.

Because hyperphosphatemia typically manifests before stage 5, the three drug companies contended that therapeutic intervention with phosphate binders should begin at stage 4.

Hyperphosphatemia, which affects up to 120,000 patients with CKD, has been recognized as an independent risk factor for cardiovascular disease and has been implicated as a central component of a metabolic and bone abnormality syndrome known as chronic kidney disease-mineral and bone disorder (CKD-MBD).

Kathe LeBeau of the Renal Support Network noted that patients can control phosphorus levels somewhat by avoiding certain dietary products, including colas, chocolate, cheese and dried beans.

But, she said, because many food labels do not identify phosphorus-containing products used in processing foods, such as phosphoric acid, polyphosphates, pyrophosphates and sodium dicalcium phosphate, it is nearly impossible for patients with CKD at stage 4 to control phosphorus levels and avoid hyperphosphatemia without the help of phosphate binders.

The three firms that market phosphate binders in the U.S. - Genzyme Corp., which markets Renagel (sevelamer hydrochloride), Fresenius Medical Care, which sells Phoslo (calcium acetate) and Shire Pharmaceuticals Inc., which makes Fosrenol (lanthanum carbonate) - argued that, because CKD is a disease that progresses as a continuum, no distinction should be made about the use of the drugs based on a patient's dialysis status.

The National Kidney Foundation (NKF) recommends that monitoring for disordered mineral metabolism begin in patients with CKD stage 3, and that serum phosphorus be maintained within the target range of 2.7 to 4.6 mg/dL in patients with CKD stages 3 and 4 or 3.5 to 5.5 mg/dL for CKD stage 5.

The normal adult range for serum phosphorus is 2.5 to 4.5 mg/dL. Serum phosphorus levels of many patients on dialysis often exceed 6.5 mg/dL.

"It is imperative to prevent hyperphosphatemia and maintain phosphorus levels within normal range," Kerry Willis, NKF's senior vice president of scientific activities, told the committee.

Pamela M. Williamson, senior vice president of regulatory affairs and collaboration corporate quality at Genzyme Corp., noted that phosphate binders are widely used "off-label" by nephrologists in treating stages 4 and 5 predialysis patients.

She argued that because there is a "well-established" safety profile for the drugs in patients on dialysis, that the expected risks in the predialysis population would be small.

Delaying treatment with phosphate binders in patients with hyperphosphatemia, she asserted, "provides a greater risk" that those patients will develop cardiovascular disease and CKD-MBD.

While the three drug companies were able to provide ample data showing that uncontrolled phosphorus levels lead to hyperphosphatemia, the firms had little data available at the meeting to support the approval of phosphate binders in the predialysis population.

However, noted Genzyme's Williamson, all three companies are conducting ongoing studies of phosphate binders in dialysis and predialysis patients.

Shire's Raymond Pratt, vice president of research and development, told the panel that results of a recently completed Phase II double-blind, placebo-controlled study of 119 patients showed that serum phosphate in patients who received Fosrenol was reduced to 4.7 mg/dL after eight weeks.

Given the mixed outcome of the committee's votes, Pratt told BioWorld Today, the companies will need to discuss with the FDA "how we can work out a way forward" for approval of the predialysis indication.

"We will need to consider what additional studies may get us there," he said.