Phase 3 data comparing ferric citrate with active controls show the new compound is effective for reducing hyperphosphatemia and improving iron levels in patients receiving dialysis, researchers report in an article published online July 24 in the Journal of the American Society of Nephrology.
In addition, an associated reduction in need for erythropoietin-stimulating agents (ESAs) is expected to have both clinical and economic implications for patients with end-stage renal disease who are being treated with dialysis.
"[F]erric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and [ESA] use while maintaining hemoglobin," write Julia B. Lewis, MD, from the Division of Nephrology and Hypertension at Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues.
The researchers conducted a sequential, randomized trial during which 441 adults with end-stage renal disease who were receiving hemodialysis or peritoneal dialysis 3 times per week for at least 3 months were treated either with ferric citrate or with active control (calcium acetate or sevelamer carbonate) for 52 weeks. This was followed by a 4-week placebo control period during which patients initially assigned to receive ferric citrate and who completed the active control period were re-randomized to receive either ferric citrate or placebo. Patients with an absolute requirement for oral iron or vitamin C therapy or with intolerance to calcium acetate and sevelamer were excluded, as were those with parathyroidectomy within 6 months before the screening visit.
The primary endpoint was mean change in phosphorus between ferric citrate and placebo during the 4-week placebo control period.
Prespecified secondary endpoints were serum ferritin, transferrin saturation, and intravenous iron and ESA usage in the 52-week active control period.
The investigators report that during the 4-week placebo control period, ferric citrate was associated with a 2.2 mg/dL greater lowering of phosphorus levels compared with placebo (P < .001). During this period, treatment failure (serum phosphorus level ≥9 mg/dL) occurred in 1 patient receiving ferric citrate and 21 control patients receiving placebo.
During the preceding 52-week active-control period, phosphorus levels were similar in the ferric citrate and active control groups, as were adverse events, which occurred in 39.1% of patients receiving ferric citrate and 49.0% of patients receiving active control.
In addition, patients receiving ferric citrate, compared with patients receiving active controls, had:
mean ferritin: 899 ng/mL vs 628 ng/ml with active control (P < .001);
transferrin saturation: 39% vs 30% with active control (P < .001);
less need for intravenous elemental iron: median, 12.95 mg/week vs 26.88 mg/week active control (P < .001);
less need for ESAs: median epoetin-equivalent, 5306 units/week vs 6951 units/week with active control (P = .04); and
higher mean hemoglobin levels: 11.42 g/dL vs 11.14 g/dL (P = .02).
"The data clearly show ferric citrate is comparable to standard therapies for phosphate control," Daniel W. Coyne, MD, told Medscape Medical News. "It also shows ferric citrate rapidly increases iron stores, and can greatly diminish or preclude the need for [intravenous] iron. The ESA-sparing effect appears real and is financially relevant and possibly clinically important." Dr. Coyne is professor of medicine, renal diseases, Washington University School of Medicine, St. Louis, Missouri, and was not involved in the study.
Dr. Coyne added, "This is a well-done trial that anticipated many of the potential problems from using a large dose of an absorbable form of oral iron as a phosphate binder. Iron poisoning is a real problem in children. Just a few pills could cause severe, life-threatening iron poisoning in children, so patients need to be warned to secure [oral iron] at all times."
According to Dr. Coyne, economic factors might also be important. The authors estimate a savings of $2101 per patient per year from the decrease in ESAs and intravenous iron usage associated with ferric citrate. "Intravenous iron and ESAs are bundled items paid for by the dialysis units. Phosphate binders are paid for by insurers and patients and [are] usually adjusted by the unit dietician. We might expect to see units and chains push the adoption of this agent. It will save them [intravenous] iron costs and ESA costs," Dr. Coyne said.
However, he would like to see a longer study of the risks and benefits associated with the higher iron status associated with ferric citrate. This is particularly important because the current trial excluded patients with ferritin levels higher than 1000 ng/mL (about 15% of US patients receiving dialysis).
"In practice, I expect such patients to get this drug," Dr. Coyne predicted. "The lack of differences in [adverse events and serious adverse events] is reassuring, but iron overload causes damage to organs over many years. One year is just too short to determine if these high iron stores can cause organ damage. Patient preference for binders varies greatly, so another binder is a welcome addition. As the discussion in the paper alludes to, clinicians will have to consider stopping this phosphate binder if iron stores get too high."
The trial was funded by Keryx Biopharmaceuticals, Inc. All of the authors have received research grants from, acted as consultants for, and received travel support from Keryx Biopharmaceuticals, Inc. Dr. Coyne has received consulting fees from Keryx Biopharmaceuticals and from Fresenius Medical Care. He has also consulted for companies manufacturing intravenous iron products.
J Am Soc Nephrol. Published online July 24, 2014. Abstract
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Cite this: Dialysis: Ferric Citrate Reduces Phosphate, Iron Problems - Medscape - Jul 30, 2014.