Pam Harrison

June 02, 2014

AMSTERDAM — A new oral phosphate binder that replenishes iron stores in patients with chronic kidney disease (CKD) and anemia who are not yet on dialysis is effective and well tolerated, according to results from a phase 2 trial.

Levels of transferrin saturation increased significantly after 12 weeks of treatment with ferric citrate coordination complex (from 22% to 32%), and levels of serum phosphate decreased significantly (from 4.5 to 3.9 mg/dL), report Geoffrey Block, MD, from Denver Nephrologists PC, and colleagues.

The novel oral compound also produced "remarkable reductions" in key secondary end points, including intact and C-terminal FGF23, said Dr. Block.

"Having studied [phosphates] for almost 20 years, this is so exciting to us, and to me personally, because we've never had anything that does what this medication does," Dr. Block told Medscape Medical News.

"The kind of reductions we saw in FGF23 have not been demonstrated with any intervention other than cinacalcet in dialysis patients, in whom FGF23 is reduced by about 50%. We believe that the combination of an FGF-lowering, phosphate-lowering, iron-repletion medication all together in a single intervention is quite important," he explained.

Dr. Block presented the study results here at the European Renal Association-European Dialysis and Transplant Association 51st Congress.

Non-Dialysis Dependent CKD

The double-blind, placebo-controlled trial involved 149 patients with non-dialysis-dependent CKD. They were randomized to ferric citrate coordination complex for 12 weeks or to placebo. No intravenous iron or erythropoiesis-stimulating agents were allowed.

The dose of ferric citrate, taken orally with each meal, was titrated up to achieve a serum phosphate level from 3.0 to 3.5 mg/dL.

At baseline, estimated glomerular filtration rate (eGFR) in the study cohort was below 60 mL/min per 1.73 m², transferrin saturation was below 30%, serum ferritin level was below 300 ng/nL, and serum phosphate level was from 4.0 to 6.0 mg/dL.

The primary end points were changes in transferrin saturation and serum phosphate from baseline, and secondary end points included changes in levels of hemoglobin, urinary phosphate, and intact and C-terminal FGF23.

After 12 weeks, the increase in transferrin saturation from baseline was significantly better in the ferric citrate group than in the placebo group (10% vs 0%; P < .001). The decrease in serum phosphate was also significantly better in the ferric citrate group (0.6 vs 0.3 mg/dL; P < .001).

In addition, changes from baseline for the secondary end points were significantly better in the ferric citrate group than in the placebo group. Specifically, hemoglobin increased by 0.5 g/L (P < .001), urinary phosphate decreased by 39% (P < .001), and intact FGF23 deceased by 119 RU/mL (P < .017).

Fewer patients failed to achieve target serum phosphate levels in the ferric citrate group than in the placebo group (1 vs 11).

Safety Perspective

The medication was very well tolerated. Despite being an oral iron preparation, which is notoriously difficult to administer successfully, "we had an excellent safety profile and our overall adverse event rates were quite similar in both arms," Dr. Block reported.

In fact, serious adverse event rates were lower in the ferric citrate group than in the placebo group.

In addition, "the majority of the gastrointestinal events were discolored feces, which is essentially unavoidable with iron repletion," he explained.

Phosphate binders are not very effective in bringing serum phosphate levels down in CKD patients. Dr. Block cited a study in which there was virtually no change in serum phosphate (0.2 mg/dL) after 9 months of high-dose phosphate binder therapy, despite 35% to 40% reductions in levels of urinary phosphate.

There is also "highly consistent" evidence that the risk for CKD progression is strongly related to serum phosphate levels above 4 mg/dL.

"When your serum phosphate is above 4 mg/dL, there is a striking increase in the incidence of progression of CKD, even after adjustment for eGFR," said Dr. Block.

Even in a healthy population, a serum phosphate level above 4 mg/dL is associated with a doubling of risk for dialysis over an extended period of time.

"From our study, we can say that ferric citrate reduces serum phosphate below what I believe is an important threshold of 4 mg/dL, it repletes iron stores to recommended levels, and it lowers FGF23, which we believe will ultimately be important in reducing cardiovascular risk," he explained. "So it addresses multiple potential aspects of cardiovascular and renal risk in patients with CKD "

The investigators are planning to conduct a phase 3 study of the effect of ferric citrate on CKD patients with anemia.

The new binder offers dual therapeutic actions in a single intervention, said Denis Fouque, MD, PhD, professor of nephrology at University Claude Bernard Lyon in France.

"Usually, phosphate binders just bind phosphate as a single activity," he told Medscape Medical News. "This one has 2 properties. First, it improves iron status and anemia without requiring erythropoiesis-stimulating agents. Second, it binds phosphate so it helps to control these 2 independent metabolic abnormalities."

The fact that it is available as an oral agent could prove to be an advantage as well, he said, although some patients do not tolerate the kind of doses that are high enough to affect iron stores. These patients might require intravenous formulations of iron to overcome poor tolerance to oral iron.

This study was funded by Keryx Pharmaceuticals. Dr. Block reports financial relationships with Amgen, Keryx, and Shield Therapeutics. Dr. Fouque has disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress: Abstract 4025. Presented June 2, 2014.

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