Ferric Citrate [Zerenex] For The Treatment Of Hyperphosphatemia: A New Use For An Old Compound

Ferric citrate is being developed as a phosphate binder by Keryx Biopharmaceuticals (NASDAQ:KERX) for the treatment of hyperphosphatemia in patients with chronic kidney disease [CDK] on dialysis, with a PDUFA date of June 7, 2014. Ferric citrate is also being investigated by Keryx for the treatment of iron deficiency anemia and elevated phosphorus in non-dialysis dependent CDK.

Hyperphosphatemia is defined as abnormally high serum phosphate levels and can be associated with hypocalcemia [low calcium levels]. Thus, although most patients with hyperphosphatemia are asymptomatic, they may occasionally report hypocalcemic symptoms, such as muscle cramps, tetany [involuntary muscle contraction], and perioral numbness or tingling. Other symptoms may include bone and joint pain, itching, and rash. It is currently not known whether treatment to lower phosphate levels in patients with chronic or end-stage kidney disease results in long-term patient benefit, i.e., lower morbidity and mortality. Phosphate binders bind to dietary phosphate in the gastrointestinal tract, and the bound phosphate is then eliminated in the feces. A study published in 2009 showed that patients treated with phosphate binders had a decrease in one-year mortality, but the effect did not correlate with the degree of hyperphosphatemia. A more recent study demonstrated that when compared with placebo, patients with moderate chronic kidney disease treated with one of three phosphate binders had lower serum phosphate but greater acceleration of vascular calcification of coronary arteries and the abdominal aorta, placing the patients at higher risk of mortality.

Whether these findings have directly affected physician practice is unknown. However, the BioTrends Research Group has issued a report that the use of phosphate binders in the United States has declined for hemodialysis and peritoneal dialysis patients over the past two years. The "ChartTrends: Bone and Mineral Metabolism in Dialysis (U.S.) 2013" report found that physicians were initiating phosphate binders at higher serum phosphorus levels compared to 2012. A significantly higher percentage of patient charts identified two reasons for non-use of phosphate binders: cost and the belief that hyperphosphatemia is a low priority for treatment. The global market for phosphate binders has been estimated at $1.5 billion per annum.

The most common cause of hyperphosphatemia is renal failure. In patients with advanced CDK, the rate of hyperphosphatemia is at least 70%, and almost all patients with dialysis-dependent kidney failure experience hyperphosphatemia at some time during the course of their disease. Patients with CDK are advised to avoid foods that are especially high in phosphate and may receive phosphate binders. These agents include aluminum hydroxide, a variety of calcium derivatives, such as calcium carbonate or acetate, magnesium hydroxide, sevelamer carbonate, lanthanum carbonate and, most recently approved, sucroferric oxyhydroxide. Sevelamer carbonate, which was used in the active control arm of Keryx's Phase 3 of ferric citrate, is a polymeric phosphate binder for oral administration. It lowers serum phosphate to near normal levels in hemodialysis patients without the risk of inducing hypercalcemia or increasing aluminum levels. Sucroferric oxyhydroxide (Velphoro®, Vifor Fresenius Medical Care Renal Pharma) is a phosphate binder for patients receiving dialysis for CDK, with a lower daily pill burden than sevelamer carbonate.

Ferric citrate is widely available for purchase, and one of its uses is to provide a source of iron in cell culture applications. In its incarnation as a phosphate binder, it was licensed in 2007 by Keryx to Japan Tobacco [JT] and Torii, JT's pharmaceutical business subsidiary, for commercialization in Japan. In January, 2014, JT received marketing and manufacturing approval of ferric citrate from the Japanese Ministry of Health, Labour and Welfare. In the United States, Keryx submitted an NDA for ferric citrate in August, 2013. This NDA submission was based primarily on the datasets derived from the Phase 3 registration program, which was conducted pursuant to a Special Protocol Assessment [SPA] agreement with the FDA, and was also supported by safety and efficacy data from several additional studies, including four Phase 3 studies conducted in Japan in CKD patients on dialysis.

Keryx's Phase 3 was presented at the 2013 World Congress of Nephrology. This study was a multicenter, randomized, open-label safety and efficacy clinical trial in 441 patients on hemodialysis or peritoneal dialysis. The study consisted of a 2-week washout period, followed by a 52-week Safety Assessment Period [SAP] in which subjects were randomized 2:1 to receive either ferric citrate or an active control [sevelamer carbonate and/or calcium acetate]. The 52-week SAP was followed by a 4-week Efficacy Assessment Period [EAP]. During the EAP, only those patients randomized to treatment with ferric citrate during the SAP, and having completed the 52-week SAP, were randomized in a 1:1 ratio to either continue treatment with ferric citrate or switched to placebo for a 4-week treatment period. Subjects were titrated during the study to achieve normal serum phosphorus levels of 3.5 to 5.5 mg/dL. The primary outcome measure was serum phosphorus levels over the course of the study.

There was no statistical difference between serum phosphorus levels of patients treated with ferric citrate or active control over the 52 weeks of the study. At the end of the study, during the EAP, ferric citrate was shown to control serum phosphorus significantly better than placebo.

Serum Phosphorus (mg/dL)

Ferric citrate
N=92

Placebo
N=91

Week 52 Baseline, Mean (SD)

5.1 (1.2)

5.4 (1.5)

Week 56, Mean

4.9 (1.3)

7.2 (1.8)

Change from Baseline

-0.2

+1.8

LS Mean (SE) Treatment Difference

-2.27 (0.21)

Click to enlarge

Treatment difference P < 0.0001 [The Least Squares (LS) Mean treatment difference and P-value were created via an ANCOVA model with treatment as the fixed effect and baseline as the covariate].

A summary of safety data was made available, and did not identify any significant differences between ferric citrate and active control.

Deaths, SAEs and notable SAEs by
System Order Class

Ferric citrate

Active Control

Subjects exposed to Study drug (N)

289

149

Deaths, n (%)

13 (4.5%)

8 (5.4%)

Subjects with an SAE, n (%)

114 (39.4%)

73 (49.0%)

Infections and Infestations, n (%)

36 (12.5%)

27 (18.1%)

Vascular Disorders, n (%)

22 (7.6%)

14 (9.4%)

Gastrointestinal Disorders, n (%)

20 (6.9%)

18 (12.1%)

Cardiac Disorders, n (%)

20 (6.9%)

17 (11.4%)

Click to enlarge

Ferric citrate was also reported to have beneficial effects on two indices of iron deficiency anemia, ferritin and transferring. Hemoglobin was reported to be well-maintained with ferric citrate during the SAP as compared to Active Control despite significantly lower IV iron and ESA (erythropoiesis stimulating agent) use.

Hemoglobin (g/dL) Mean

Zerenex
N=245

Active Control
N=132

Day 0 (Study Baseline)

11.6 (1.2)

11.7 (1.2)

Week 12

11.8 (1.4)

11.5 (1.3)

Week 24

11.6 (1.4)

11.4 (1.2)

Week 36

11.5 (1.4)

11.3 (1.2)

Week 52

11.4 (1.5)

11.1 (1.4)

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Treatment difference P < 0.05, using the same model described above.

From these data, it would appear that ferric citrate has met its primary efficacy endpoint. The safety profile appears to be similar, or perhaps slightly better than the active control arm, though not significantly so.

It should be noted that there are many phosphate binders in clinical use. What appears to differentiate ferric citrate from the other phosphate binders is its effect on hematologic parameters. While sucroferric oxyhydroxyde is also an iron-based therapy, it is minimally absorbed and does not have an effect on circulating iron levels. The dialysis patient is in a state of continuous iron loss from gastrointestinal bleeding, blood drawing, and the dialysis treatment itself, losing an average of 2 g of iron per year. While treatment of less-than-severe anemia by an ESA in patients with CDK is controversial, iron deficiency will develop in virtually all dialysis patients receiving an ESA unless supplemental iron therapy is given orally or intravenously. This need to treat iron deficiency anemia in some CDK patients may be a competitive advantage for ferric citrate. However, it should be noted that a recent meta-analysis of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia concluded that "Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The long-term safety and efficacy of this treatment strategy requires further study." Oxidative stress can result in cellular damage. Whether such findings are unique to intravenous iron therapy, as opposed to all iron therapy in this setting, is unknown.

Based on the publicly available data, ferric citrate would appear to be approvable. Manufacturing issues appear unlikely given the provenance of ferric citrate. Possible regulatory issues could include the fact that only one Phase 3 trial was conducted by Keryx, as opposed to the two typically required by the FDA. The patient database appears to be substantially smaller than that submitted for approval of sucroferric oxyhydroxide. Presumably, Keryx is relying on the data generated by its partner, JT, as confirmatory of the US data. While the effect of ferric citrate on hematologic parameters appears to be favorable, it is also possible that it may raise some long-term safety concerns. Keryx's near-term future appears to be entirely dependent on the success of ferric citrate, as there are no follow-on compounds in development listed on the company's website.

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