Renal anemia and hyperphosphatemia are both common complications associated with chronic kidney disease (CKD). Phosphate binders are frequently prescribed to prevent intestinal absorption of dietary phosphate and reduce serum phosphorous levels. However, iron-based phosphate binders represent a new class that could provide a dual benefit through reducing serum phosphorous levels while releasing iron to improve anemia. Several iron-based phosphate binders have undergone testing in clinical trials.

Ferric citrate (Keryx’s Auryxia) is one such iron-based phosphate binder that is available for use being found safe and effective in decreasing serum phosphorus levels.

Notably, ferric citrate binds with dietary phosphate in the gastro intestinal (GI) tract and precipitates as ferric phosphate with some iron being partially absorbed. Theoretically, this could lead to an increase in hemoglobin (Hb) levels and a reduction in the need for erythropoietin stimulating agent (ESA) and intravenous (IV) iron, and consequently cost savings.

In a Phase III trial comprising 441 patients on dialysis, treatment with ferric citrate significantly reduced the use of IV iron by 51.6% and ESAs by 27.1% versus comparator [p = 0.0322]) compared with the non-iron-based phosphate binder (Keryx press release, January 28, 2013). Based on an analysis of safety data, the side-effect profile of ferric citrate and the active control group appeared similar. The overall rate of GI-related adverse events, were 39% ferric citrate versus 44% active control. The most common GI adverse events were: diarrhea, including soft stools (27% ferric citrate versus 14% active control), nausea (14% ferric citrate versus 14% active control), vomiting (9% ferric citrate versus 13% active control) and constipation (8% ferric citrate versus 5% active control). In another pivotal Phase III trial in nondialysis patients who previously had not adequately responded to or tolerated oral iron therapies, 52% of patients who received ferric citrate achieved a 1g/dL or greater rise in Hb during the 16-week efficacy period, compared to 19% who received placebo (p<0.001). Statistically, significant mean changes in ferritin and transferrin saturation (TSAT) from baseline to the end of 16-week treatment period were also observed (Keryx press release, January 12, 2017).

Ferric citrate launched for hyperphosphatemia in CKD patients on dialysis in Japan and the United States in 2014. A year later, Keryx received EU approval for the product to treat hyperphosphatemia in both CKD-nondialysis (CKD-ND) and dialysis patients. Given the positive impact of ferric citrate on renal anemia parameters, Keryx is now seeking to expand the indication for ferric citrate to include the treatment of iron deficiency anemia (IDA) in CKD-ND patients. The Food and Drug Administration (FDA) is reviewing the supplemental New Drug Application (sNDA) for ferric citrate’s expanded role with a Prescription Drug User Fee Act (PDUFA) target action date for completion of November 6, 2017.

Interviewed experts view ferric citrate as a treatment option for increasing Hb levels from baseline, but some express concern that only half of the patients in the pivotal Phase III clinical trial increased their Hb levels by 1g/dL. These physicians would like to see head-to-head studies of ferric citrate versus iron supplements. However, the majority of interviewed physicians believe that ferric citrate is an attractive alternative to oral iron supplements, such as ferrous sulfate, particularly for patients who suffer from GI distress secondary to oral iron supplements. In these patients, the better tolerated ferric citrate could potentially encourage patient compliance. Some experts point out that ferric citrate could also compete with IV iron supplements, such as ferumoxytol (AMAG’s Feraheme) and ferric carboxymaltose (American Regent’s Injectafer). Ferumoxytol and ferric carboxymaltose are more frequently prescribed in the CKD-ND population than in dialysis and CKD-ND patients would opt for therapies that are administered orally. On the other hand, physicians are concerned over ferric citrate’s high price tag and believe that will be the biggest challenge to its uptake in the treatment of renal anemia. Thus, demonstration of cost-effectiveness is going to be crucial to ensure adoption and uptake of ferric citrate for the treatment of renal anemia.

If ferric citrate is approved for treating renal anemia, it would be the first iron-based phosphate binder to do so. Ferric citrate is likely to be used ahead of IV iron supplementation, due to its more convenient administration, and its improved safety profile, compared with other oral iron supplements, which could improve compliance amongst CKD-ND patients. However, ferric citrate’s limited efficacy for increasing Hb levels in the broader population, in addition to the high price tag of this agent, will hinder its use; we anticipate that this will be compounded by access restrictions imposed by payers. Overall, we expect modest uptake of ferric citrate for treating renal anemia in the CKD-ND population.

To learn more about DRG’s pipeline assessment, latest pharmaceutical forecast, and, analysis of the renal anemia market, please click here.

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