Mechanism of Action and Clinical Attributes of Auryxia® (Ferric Citrate)
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Chronic kidney disease (CKD) is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are the many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Hyperphosphatemia and elevated levels of fibroblast growth factor 23 (FGF23) have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Auryxia® (ferric citrate; Keryx Biopharmaceuticals, Inc., Boston, MA, USA) is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult CKD patients not treated with dialysis. This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD. Consistent with the chemistry and mechanism of action of Auryxia, multiple clinical studies have demonstrated its efficacy in both lowering serum phosphate levels and improving iron parameters in patients with CKD. Levels of FGF23 decrease significantly with Auryxia treatment, but the effects associated with the cardiovascular system remain to be evaluated in longer-term studies.
Patients with chronic kidney disease (CKD) frequently have high levels of phosphate and low levels of iron in the blood, both of which are associated with elevated risks of cardiovascular disease and death.
The drug Auryxia (ferric citrate) has a special formulation that enables it to both increase iron levels in patients with CKD who are not receiving dialysis and decrease phosphate levels in patients with CKD who are receiving dialysis.
Chronic kidney disease (CKD) represents a major global public health concern . The United States Renal Data System estimated that in 2017, 30 million American adults had CKD . CKD is associated with serious comorbidities, most importantly cardiovascular disease [1, 2]. Furthermore, the financial burden of CKD is high; in the USA, with total Medicare expenditures exceeding $64 billion in 2015 . Magnifying this burden is the undertreatment of CKD , especially in the earlier stages of the disease, highlighting the need for better awareness of all therapeutic options with regard to their efficacy, safety, tolerability, and cost effectiveness.
1.1 Perturbations of Bone and Mineral Metabolism and Iron Parameters in Chronic Kidney Disease
Alterations of bone and mineral metabolism and anemia are common and occur early in the course of CKD and when left untreated carry an increased risk for adverse outcomes [4, 5]. Approximately 36% of hemodialysis patients in the USA have hyperphosphatemia (when defined as a phosphate concentration > 5.5 mg/dL) , although older surveys cite higher percentages [7, 8, 9]. Hyperphosphatemia is an independent risk factor for cardiovascular events, and has been shown to be associated with a higher mortality rate [10, 11]; however, it is important to note that the evidence supporting the association between phosphorus levels and mortality is derived from observational studies, which are potentially subject to confounding. A National Health and Nutrition Examination Survey estimated that 15.4% of patients with CKD in the USA are anemic, defined as having blood hemoglobin levels ≤ 12 g/dL in women and ≤ 13 g/dL in men, representing 4.8 million affected individuals . As with hyperphosphatemia, patients with CKD who also have anemia are at increased risk of cardiovascular disease and death, among other comorbidities . It is expected that, in theory, successful treatment of hyperphosphatemia and anemia in patients with CKD could help avoid adverse clinical outcomes; however, with the exception of renal replacement, no interventions have yet been proven to improve outcomes.
The pathophysiologic networks that regulate bone and mineral metabolism and iron distribution are complex. An increasing number of studies support the idea that fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone, is associated with adverse outcomes in CKD . Along with parathyroid hormone (PTH), FGF23 is an important factor involved in the disordered bone and mineral metabolism that contributes to CKD morbidity and mortality [5, 12]. Normally, FGF23 regulates phosphate and vitamin D metabolism through a negative endocrine feedback loop it shares with PTH; however, production of 1,25-dihydroxyvitamin D3 is inhibited by FGF23 but stimulated by PTH, whereas both FGF23 and PTH share the phosphaturic effect [12, 13, 14]. In patients with early CKD, as renal function begins to decrease, compensatory increases in FGF23 and PTH may help maintain normal phosphate balance, mainly by stimulating greater urinary phosphate excretion [13, 15]. These increases in FGF23 and PTH in early CKD precede frank hyperphosphatemia, which is observed only with advanced renal disease after the compensatory mechanisms have been overwhelmed [13, 15]. In a cross-sectional study of patients representing a spectrum of CKD severity, increased FGF23 levels were significantly associated with deteriorating renal function . For reasons that are not yet clear, FGF23 also may be related to the development of iron deficiency anemia; in a recent cohort study, elevated concentrations of FGF23 were associated with a higher incidence of anemia, particularly in patients with iron deficiency . Importantly, increased serum FGF23 concentrations are associated with increased risk of cardiovascular events and death in CKD . Several studies have highlighted the relationships of inflammation and iron deficiency anemia, both commonly present in CKD, with FGF23 levels that rise early in the course of the disease [17, 18, 19]. Thus, interventions that decrease levels of FGF23 may favorably affect several important outcomes in patients in CKD, although this has yet to be established in long-term clinical studies.
1.2 Treatment of Hyperphosphatemia and Iron Deficiency Anemia in Chronic Kidney Disease
With the high prevalence of hyperphosphatemia among hemodialysis patients in the USA, restoration of phosphate balance using phosphate binders has long been a therapeutic goal in CKD management [7, 8, 9]. In the 1970s to 1990s, aluminum-based and then calcium-based phosphate binders were often used for the control of hyperphosphatemia in patients with end-stage renal disease [7, 20]. However, associations with aluminum toxicity for aluminum-based binders and hypercalcemia and metastatic calcification for calcium-based binders motivated the development of calcium-free, aluminum-free phosphate binders [7, 20, 21, 22]. In fact, the Kidney Disease: Improving Global Outcomes (KDIGO) 2017 guidelines for CKD-mineral bone disorder recommend restricting the dose of calcium-based phosphate binders in adult patients with stage 3–5 CKD receiving phosphate-lowering treatment . However, the Dialysis Clinical Outcomes Revisited trial, which compared mortality among hemodialysis patients treated with calcium-based phosphate binders and sevelamer hydrochloride, failed to demonstrate the superiority of the non-calcium-containing sevelamer hydrochloride with respect to death and hospitalization rates . Ultimately, improvements in clinical outcomes in patients with hyperphosphatemia may not be achieved by improving phosphate balance alone.
Iron deficiency anemia in CKD has long been treated with iron supplementation using either oral or intravenous (IV) therapy . The decision between oral and IV iron should involve an assessment of benefit and risk. Most oral iron formulations may be less expensive but are often associated with adverse gastrointestinal (GI) effects, whereas IV iron may be more effective than oral iron but carries the risks of adverse reactions during IV administration and potential for long-term iron overload [25, 26, 27, 28]. IV administration may be the preferred route of administration of iron for hemodialysis patients partly because it is easily administered during hemodialysis; however, this is not necessarily true for patients that are not on dialysis (or are on peritoneal dialysis) .
1.3 Auryxia: an Iron-Based Treatment for Hyperphosphatemia and Iron Deficiency Anemia in Chronic Kidney Disease
Iron-based compounds, such as ferric citrate (Auryxia®; Keryx Biopharmaceuticals, Inc., Boston, MA, USA), represent a new category of phosphate binders . Auryxia has the advantage of dual functionality (i.e. controlling serum phosphate levels and treating iron deficiency anemia) . In the USA, Auryxia is indicated as a phosphate binder for the control of serum phosphate levels in adult patients with CKD treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult patients with CKD not on dialysis . Similar ferric citrate products are approved for use in other countries under different brand names. In the European Union, ferric citrate coordination complex (Fexeric® Keryx Biopharma UK Ltd, London, UK) is indicated for the control of hyperphosphatemia in adult patients with CKD . In Japan, ferric citrate hydrate (Riona® Torii Pharmaceutical Co., Ltd., Tokyo, Japan) is indicated to treat hyperphosphatemia in patients with CKD [33, 34]. In Taiwan, ferric citrate (Nephoxil®, Panion & BF Biotech Inc., Taipei, Taiwan) is indicated for controlling hyperphosphatemia in adult patients with CKD undergoing hemodialysis . This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD.
2 Chemical Composition of the Active Pharmaceutical Ingredient (API) in Auryxia
The API of Auryxia is not a single compound but rather a solid mixture of ferric citrate coordination complexes (FCCCs) with the following chemical formula: iron (+ 3), x (anion of 1,2,3-propanetricarboxylic acid, 2-hydroxy-), y (H2O), where x ranges from 0.70 to 0.87 and y ranges from 1.9 to 3.3 [31, 36]. As opposed to iron salts, which readily dissociate into their component ions in water, the bonds that coordinate the central metal atom with the surrounding ligands allow the complex to retain its identity as a unit with properties different from those of its components. Furthermore, Auryxia has different properties from those of commercial-grade ferric citrate , which was the material investigated in early studies. Most important among these differences among ferric citrate preparations is that the API of Auryxia has a defined molar ratio of ferric iron (Fe3+) to citrate anions , whereas ferric citrate from commercial sources may have variable molar ratios of ferric iron, citric acid, and associated hydrates . It is important to first establish what is known about ferric citrate in general before understanding more about the specific physicochemical profile of the pharmaceutical-grade ferric citrate that constitutes the API of Auryxia.
2.1 Structural Chemistry of Ferric Citrate
2.2 Ferric Citrate as API of Auryxia
The API of Auryxia has a defined molar ratio of ferric iron to citrate anions, predominantly in the molar ratio of 2:2, whereas ferric citrate from commercial sources may have variable molar ratios of ferric iron and citric acid . The API in Auryxia is described in US patents 7,767,851; 8,338,642; 8,609,896 and 8,901,349 [51, 52, 53, 54]; chemical analysis shows that this material contains a positively charged Fe(III) complex, presumably [Fe(H2O)6]3+, and a negatively charged complex, [Fe2Citrate2(H2O)2]2− . The major component in the API corresponds to the dinuclear complex 2 (Fig. 2).
Unlike simple iron salts, the FCCCs in Auryxia help maintain ferric iron in solution at the varying conditions in different portions of the GI tract (i.e. at various pH levels) . The relatively high solubility of the pharmaceutical-grade ferric citrate in Auryxia contrasts with some commercial iron salts, particularly at high pH; for example ferrous (Fe2+) sulfate, an iron supplement commonly used to treat iron deficiency anemia, is practically insoluble at high pH [36, 43, 44]. An additional distinguishing characteristic of the FCCCs in Auryxia is their large surface area, which is at least 16 times that of commercial-grade ferric citrate . High surface area generally favors rapid disintegration and therefore dissolution . In the case of Auryxia, the rate of dissolution of its API at pH 8 is 3.08 times the rate of commercial-grade ferric citrate; the solubility of the Auryxia FCCCs is vital to the absorption of their iron [36, 51].
3 Absorption of Iron from Auryxia
4 Phosphate Binding Capacity of Auryxia
A non-calcium, iron-based phosphate binder, sucroferric oxyhydroxide (Velphoro®; Fresenius Medical Care North America, Waltham, MA, USA), was shown to effectively lower and maintain serum phosphate levels for over 1 year in patients receiving dialysis . Treatment with sucroferric oxyhydroxide did not significantly affect iron-related parameters such as TSAT, serum iron, and blood hemoglobin concentrations, which remained unchanged over the long-term .
5 Iron Supplementation with Auryxia
6 Iron Overload
As mentioned previously, long-term administration of medicinal iron raises a concern about eventual iron overload, and the risk is higher with IV iron products than with oral products, because IV administration bypasses the physiologic regulation of iron absorption [25, 26, 27, 28]. Indeed, with the exception of one patient who also received IV iron, iron overload has not been observed in patients after treatment with Auryxia in clinical studies . Furthermore, in patients with CKD treated with dialysis, treatment with Auryxia led to few serious adverse events in organ systems usually affected by iron overload . Ferric iron, such as in Auryxia, is delivered relatively slowly and consistently, likely allowing the iron-regulatory peptide hormone, hepcidin, to slowly upregulate, as reflected in maintenance of clinically appropriate levels of iron markers [44, 84].
The iron-storage protein, ferritin, and the iron-carrier protein, transferrin, are both critical for iron homeostasis and have traditionally served as markers of iron status; however, there are caveats for their use as indicators of iron overload [57, 85, 86, 87, 88]. Neither serum ferritin nor TSAT alone is accurate as a standalone measure of iron overload; serum ferritin is severely affected by inflammation, and TSAT, which is proportional to serum iron, is affected by the timing of the sample relative to IV or oral iron administration [86, 87, 88]. However, waiting at least 48 hours to draw blood after iron administration  allows a more accurate picture of iron overload using TSAT; TSAT tends to stabilize within 2 weeks after beginning IV iron administration, so that high TSAT values at this point or later suggest iron overload or the inability to regulate iron; this timeline has not been studied extensively with oral iron [90, 91, 92]. In patients with iron deficiency anemia and NDD-CKD who were treated with Auryxia, 17.9% had transient elevations of TSAT ≥ 70%, yet none had iron overload . Persistent increases in serum ferritin in the absence of clinically identifiable episodes of inflammation, but accompanied by increased TSAT, together may suggest iron overload. The only definitive outcome that indicates clinically significant iron overload is dysfunction of the end organs.
Auryxia and Riona share the same API, although the dosage forms and strengths differ (210 mg ferric iron per pill of Auryxia; approximately 62 mg ferric iron per pill of Riona) [31, 93]. The United States Food and Drug Administration (FDA) label for Auryxia carries a warning for iron overload recommending that iron parameters (e.g. serum ferritin and TSAT) should be assessed prior to initiating Auryxia and should be monitored while on therapy . In a 56-week, Phase 3, randomized, controlled trial in patients with CKD treated with dialysis in which concomitant use of IV iron was permitted, 19% of patients treated with Auryxia had at least one measurement of serum ferritin > 1500 ng/mL, as compared with 10% of patients treated with the active controls (sevelamer carbonate and/or calcium acetate) . Therefore, the FDA label includes a recommendation that patients receiving IV iron may require a reduction in dose or discontinuation of the IV iron therapy . Because elevations in serum ferritin have been observed in previous studies of Auryxia and Riona [72, 94], a recent retrospective analysis of a Japanese Phase 3 trial in hemodialysis patients with hyperphosphatemia investigated the factors that may be associated with these elevations; the factor most strongly associated with elevations in serum ferritin, second only to the dose of Riona, was reduction in the dose of erythropoiesis-stimulating agent (ESA), presumably causing decreased utilization of iron for erythropoiesis [82, 84]. Importantly, no studies of Auryxia and Riona supported an association with clinically significant iron overload despite the observed elevations in serum ferritin levels [72, 82, 84, 94, 95].
7 Clinical Characteristics of Auryxia
7.1 Effects on Iron Levels When Used to Treat Hyperphosphatemia
The chemical attributes of Auryxia and its biological interactions are reflected in its clinical characteristics. For example, when used to treat hyperphosphatemia, it may also have beneficial effects on measures of iron status in disease settings where functional or true iron deficiency and hyperphosphatemia coexist. In patients with CKD treated with dialysis, studies have shown that treatment with Auryxia reduces serum phosphate and improves iron parameters [72, 95]. In a Phase 3, 56-week, placebo- and active-controlled trial in patients with dialysis-dependent CKD, Auryxia (dosed and titrated to maintain serum phosphate control) significantly improved iron parameters compared with active controls (sevelamer carbonate and/or calcium acetate) as early as Week 12 (ferritin: mean difference of 281.8 ± 42.9 ng/mL at week 52, p < 0.001; TSAT: mean difference of 9.55% ± 1.58%, p < 0.001) . Additionally, two studies have suggested that Auryxia may reduce the need for IV iron when used as a phosphate binder in patients with CKD treated with dialysis [72, 96, 97]. Lower percentages of patients required IV iron in the Auryxia group compared with an active control group at all time points over the 52-week active control period; at the end of this period, 85.4% and 69.0% of patients did not receive IV iron at week 52 in the Auryxia and active control groups, respectively (p < 0.001) . The cumulative dose of IV iron was less in the Auryxia group as compared with the active control group over the entire 52-week active control period (median [interquartile range] dose of 12.9 [1.0–28.9] mg/week with Auryxia vs 26.8 [13.4–47.6] mg/wk with active control; p < 0.001). Similarly, in the same study and over the same period, the cumulative dose of ESAs was lower in the Auryxia group compared with the active control group (median [interquartile range] dose of 5303 [2023–9695] units/week with Auryxia vs 6954 [2664–12,375] units/week with active control; p = 0.04) .
The effects of treatment with Auryxia could lead to clinical outcomes that are different from those with other therapies. Of note, treatment to a higher hemoglobin target has been associated with increased risk of vascular thrombosis, and higher ESA doses have been explored as a plausible mechanism for this increased risk ; therefore, a reduction of ESA dose may lower risk of cardiovascular events, thereby decreasing hospitalization. Infections are also an important driver of readmission after hospitalization in patients with CKD who are receiving hemodialysis . In the aforementioned 56-week, Phase 3 trial in patients with end-stage renal disease on dialysis, treatment with Auryxia was associated with reductions in overall hospitalizations, cardiac-related hospitalizations, and infection-related hospitalizations as compared with active control . Treatment with Auryxia also reduced health-care costs; the cost savings were attributed to a decrease in use of IV iron and ESA and to a reduction in the number of hemodialysis sessions that were missed as a result of hospitalizations [101, 102].
Thus, the ability of Auryxia to deliver iron, because of its chemical composition, is an added benefit when it is already being used to control phosphate levels and may improve clinical outcomes that are unrelated to hyperphosphatemia. The benefit of Auryxia as a therapy for the treatment of iron deficiency may be particularly important in light of recent research that has implicated IV iron therapy in non-alcoholic fatty liver disease (NAFLD) [103, 104]. In a longitudinal study of 7 patients undergoing IV iron therapy, hepatic proton density fat fraction and liver iron concentration levels increased significantly, suggesting that iron overload in these dialysis patients may have led to or exacerbated NAFLD .
7.2 Effects on Serum Phosphate Levels When Used to Treat Iron Deficiency Anemia
7.3 Effects on FGF23 Levels
Consistent with its chemistry and mechanism of action, Auryxia is effective both in reducing serum phosphate levels in patients treated with dialysis and in improving iron parameters in CKD patients not on dialysis. Overall, across both CKD patient populations, treatment with Auryxia was considered to have good safety and was similarly well tolerated compared with other study treatments. In dialysis patients, 21% discontinued Auryxia due to an adverse reaction versus 14% who discontinued active control (which patients had tolerated before enrollment); in patients with NDD-CKD, 10% discontinued Auryxia due to an adverse reaction versus 9% who discontinued placebo . The balance of these characteristics distinguishes Auryxia from commercial-grade ferric citrate and differentiates it from other common therapies used to treat hyperphosphatemia and iron deficiency anemia in patients with CKD.
The authors acknowledge Keryx Biopharmaceuticals, Inc. (Boston, MA, USA; now a wholly owned subsidiary of Akebia Therapeutics, Inc., Cambridge, MA, USA) for supporting the preparation of this manuscript. Under the authors’ direction, Madhura Mehta, Ph.D., and Michael J. Theisen, Ph.D. (CHC Group, LLC, North Wales, PA, USA) provided writing and formatting assistance. Editorial assistance in the form of proofreading, copyediting, and fact checking was also provided by CHC Group. The authors exercised full editorial control and provided input on and approval of the content of the manuscript at each stage of development. All authors have been involved in research relating to Auryxia: TG conducts research studying the mechanism of iron absorption from Auryxia, AB is involved in research studying the chemical structure of Auryxia, and IBS studies the use of Auryxia in children.
Compliance with Ethical Standards
Conflict of interest
TG is a scientific cofounder and shareholder of Intrinsic LifeSciences and Silarus Pharma. He is a consultant for Ablynx, Ambys, Akebia Therapeutics, Gilead, Global Blood Therapeutics, Keryx Biopharmaceuticals, La Jolla Pharmaceutical Company, Sierra Oncology and Vifor. He has received Grant support from Akebia Therapeutics and Keryx Biopharmaceuticals. AB was a consultant to Keryx and received support for characterizing the structural composition of Auryxia. IBS is a consultant for Akebia Therapeutics, Keryx Biopharmaceuticals, Amgen, and Ultragenyx. He has received Grant support from Amgen and AbbVie.
Support was provided by Keryx Biopharmaceuticals, Inc., which is now a wholly owned subsidiary of Akebia Therapeutics, Inc.
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