According to the WCN program (see here), a poster (#SU401) entitled ” Ferric citrate is a novel efficacious phosphate binder” will be presented on June 2nd by Dr. Julia Lewis from Vanderbilt University Medical Center (view abstract) during the Annual Meeting in Hong Kong. Top-line results of the phase 3 study were announced by Keryx Biopharmaceuticals on January 28, 2013 (see News release). The study was a multi-center, randomized, open label trial of ferric citrate, a novel non-calcium containing phosphate binder, in 441 dialysis patients (HD and PD). The study included a 52 week safety assessment whereby the subjects were randomized 2:1 to receive ferric citrate or an active control (either calcium acetate or sevelamer carbonate). The safety assessment was followed by a one-month efficacy assessment period during which 192 subjects who remained on ferric citrate were randomized 1:1 to either continue on ferric citrate or switch to placebo. The ferric citrate doses, given as 1 g capsules with meals were titrated during the study to achieve a serum phosphorus concentration between 3.5 and 5.5 mg/dL. Oral iron was not permitted and intravenous iron was only permitted if serum ferritin was >1000 ng/ml or TSAT was >30%. Fairly detailed results are available within the Press Release by Keryx Biopharmaceuticals (see News release) .
The primary efficacy endpoint was the change in mean serum phosphorus from week 52 to week 56. Mean phosphorus levels were 4.9 ± 1.4 and 7.2 ± 1.5 mg/dL for Zerenex and placebo, respectively (p<0.01). All the secondary endpoints were also met. Of interest were the effects of ferric citrate on iron metabolism and on hemoglobin levels. The mean change in ferritin from baseline to week 52 was 302 ng/mL for Zerenex, compared to 9 ng/mL for placebo (p<0.0001). There was also a higher mean Hb concentration in the Zerenex group compared to placebo (11.4 ± 1.5 vs 11.1 ± 1.4 g/dL) at week 52. Most importantly, Zerenex appeared to be safe and well tolerated. Excluding stool discoloration, which is a known effect of iron salts, the gastrointestinal side effects were similar between Zerenex and active control. Full analysis of these data will be presented at the WCN and we expect that they will be also published at about the same time (see News release).
According to Keryx, the NDA (New Drug Application) and European MAA (Marketing Authorization Application) is anticipated in the second quarter of 2013. Generally it takes about one year from the NDA submission until approval.
Commentary: Phosphate retention and hyperphosphatemia are common consequences of ESRD and lead to multiple complications, which include not only secondary hyperparathyroidism and renal osteodystrophy, but also vascular calcifications and increased mortality, primarily from coronary artery disease complications (see here). The use of calcium-free phosphate binders such as sevelamer can result in stabilization and even regression of vascular calcifications (see here). However, to be effective, all currently available phosphate binders require multiple pills that need to be taken with meals. The large pill burden often results in gastrointestinal side effects and low patient adherence. Ferric citrate is no exception. Zerenex doses are not given in the available Press Release. In the phase 2 study, patients received three 1 g capsules, which were titrated to obtain the desirable serum phosphorus levels (see Yang et al). Being an iron compound, it is not entirely surprising to see a beneficial effect of Zerenex on iron metabolism and on Hb concentrations. The overall effect was a reduction in cumulative intravenous iron doses and a reduction in cumulative ESA doses. A recently published pharmacoeconomic evaluation assessed the potential cost savings from the use of ferric citrate compared to other phosphate binders (see Mutell et al.). The authors concluded that the use of ferric citrate to treat hyperphosphatemia in ESRD patients may help reduce treatment costs. The study was sponsored by Keryx Biopharmaceuticals.
Based on what is known in the public domain, the overall data package that will be submitted in support of an NDA appears to be very favorable and could lead to the approval of Zerenex for treatment of hyperphosphatemia in ESRD patients on dialysis. Additional studies are underway to assess its effectiveness in the management of hyperphosphatemia and anemia in CKD patients not on dialysis (see here).