Ferumoxytol: a new era of iron deficiency anemia treatment for

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to Iron Sucrose Trial (FIRST) has started. This is a mul- ... iron sucrose for the treatment of iron deficiency anemia in adult subjects ... of ferumoxytol is above the permeability cutoff of standard hemodialysis ... of 9.3 hours with a dose of iron of 1 mg/kg body weight, to ... safer for the patient, and do not have a requirement for a.
JNEPHROL 2011; 24 ( 06 ) : 717-722

REVIEW

DOI:10.5301/jn.5000025

Ferumoxytol: a new era of iron deficiency anemia treatment for patients with chronic kidney disease Mariusz Kowalczyk 1, Maciej Banach 2, Jacek Rysz 1

Abstract Ferumoxytol is a new product approved for intravenous use by the US Food and Drug Administration (FDA) in the treatment of iron deficiency anemia in adults with chronic kidney disease. This approval was based on data from 3 open-label, randomized, controlled clinical trials. In all of these trials, ferumoxytol was well tolerated, and hemoglobin levels were significantly increased compared with those achieved by orally administered iron. Ferumoxytol, a superparamagnetic iron oxide coated with a carbohydrate shell, is also used as a magnetic resonance imaging (MRI) agent due to its magnetic properties. In addition, it has demonstrated a greater T1 relaxation time than MRI gadoliniumcontrast agents. Currently, the Ferumoxytol Compared to Iron Sucrose Trial (FIRST) has started. This is a multicenter randomized trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in adult subjects with chronic kidney disease, where intravenous ferumoxytol is being compared with other intravenous agents to evaluate the safety of ferumoxytol and assess changes in hemoglobin level. Key words: Chronic kidney disease, Ferumoxytol, Iron

deficiency anemia

Introduction Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD). Although multiple factors contribute to the anemia of CKD, the primary cause remains

Department of Nephrology, Hypertension and Family Medicine, Division of Nephrology and Hypertension, Medical University of Lodz, Lodz - Poland 2 Department of Hypertension, Division of Nephrology and Hypertension, Medical University of Lodz, Lodz - Poland 1

an insufficient production of endogenous erythropoietin (EPO), and very often the most appropriate management of anemia in CKD requires supplying both iron and erythropoiesis-stimulating agents (ESAs). In the past, recombinant human erythropoietin (rHuEPO), blood transfusion and anabolic steroids were commonly used. The introduction of rHuEPO changed the way anemia was managed, and with time and experience, it became clear that new approaches to anemia therapy, including new ESAs and new iron preparations were needed (1). Darbepoetin alfa, the second generation of ESA, was another step forward in the treatment. Most recently, several innovative agents (continuous erythropoiesis receptor activator, hematopoietic cell phosphatase inhibitors, hypoxia-inducible factor prolyl hydroxylase inhibitors, synthetic erythropoiesis protein, EPO gene therapy and EPO mimetics) have been under investigation (1). According to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines for treatment of anemia (2, 3), patients should have a sufficient iron level to achieve and maintain a hemoglobin of 11-12 g/dL and a hematocrit of 33%-36%. The guidelines suggest administering sufficient iron to maintain a transferrin saturation (TSAT) of ≥20% and a serum ferritin ≥100 ng/mL (2, 3). Oral iron administration is generally ineffective in maintaining iron stores in most patients on dialysis (4-6), thus intravenous iron has become pivotal in the management of anemia in patients with CKD. Initially, the introduction of parenteral iron in humans, which was administered as an iron oxyhydroxide complex, appeared to be very toxic. This problem was solved by incorporating the toxic iron into a carbohydrate shell consisting of molecules such as dextran, sucrose or gluconate. The first

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dextran-containing iron compounds carried a risk of anaphylaxis and anaphylactoid reaction, which was reduced later by using a low-molecular-weight dextran shell. Despite the fact that successful administration of supplemental iron has greatly progressed since its beginning in the 1930s, available iron preparations are not ideal, either because of safety concerns or dose limitations. Recently, newer intravenous iron preparations have appeared on the market, including ferumoxytol (Feraheme) and ferric carboxymaltose (Ferinject). These preparations are effective, are considered safer for the patient, and do not have a requirement for a test dose; also, a much higher dose of iron can be delivered in a single administration (7-9). In this review, we present ferumoxytol’s main properties, safety and efficacy compared with other enteral and parenteral iron preparations.

Ferumoxytol Mechanism of action, physicochemical properties and pharmacological effects Ferumoxytol consists of a superparamagnetic iron oxide core stabilized by a shell of low-molecular-weight semisynthetic carbohydrate and polyglucose sorbitol ether (Fe5874O8752-C11719H18682O9933Na414). The shell is designed to minimize immunologic sensitivity and protect the bioactive iron from plasma components until the complex enters the reticuloendothelial system of the liver, spleen and bone marrow. The iron is released from the complex within macrophage vesicles and then either enters the intracellular iron storage pool or is transferred via iron-binding protein to erythroid precursor cells for incorporation into hemoglobin (7, 8, 10-12). The drug is available for sterile intravenous injection in single-use vials. Each vial contains 510 mg of elemental iron in 17 mL (30 mg/mL of elemental iron and 44 mg/mL of mannitol) and has an average colloidal particle size of 30 nm by light scattering and a molecular weight of 750 kDa. Originally developed as a magnetic resonance imaging (MRI) contrast agent, ferumoxytol is an isotonic and neutral pH chemical product and is administered as a rapid intravenous bolus (10, 11). An analysis of the physicochemical properties of ferumoxytol may explain an advantage of this novel drug over the currently available intravenous iron formulations. All current intravenous agents have a colloidal structure consisting of an iron oxide core and a carbohydrate shell that stabilizes the iron oxide and slows the release of bioactive iron from the core. Ferumoxytol particles have a diameter of 6.4 ± 0.4 nm; however, analysis of iron dextran, iron su718

crose and ferric gluconate has resulted in definitions that are not as clear as that for ferumoxytol. Although it is difficult to accurately measure particle dimensions, the following trend has been observed: ferumoxytol > iron dextran > iron sucrose > ferric gluconate (13). The same sequence regarding molecular weight has been proved by other investigators (13, 14), as has the relative ordering of iron oxide core size (15). Furthermore, because the molecular weight and size of ferumoxytol is above the permeability cutoff of standard hemodialysis (HD) membranes, it can be administered any time during the HD procedure (12, 16). Molecular weight may also affect other biological characteristics of intravenous agents, such as the rate of release of bioactive iron from the ferric hydroxide core and the rate of plasma clearance of the agent after administration. The release of bioactive iron from intravenous agents results mainly from intracellular release after clearance of the agent from plasma by macrophage cells (13, 17). Some in vitro studies, however, suggest that the release of bioactive or catalytic iron may occur before cellular uptake of the intact intravenous agents (18, 19). Iron release in vitro appears to occur in an inverse sequence: the smaller the particle size and molecular weight, the more rapid the release of bioactive iron (13, 20). Thus, in contrast to intravenous iron sucrose and sodium ferric gluconate administration, intravenous ferumoxytol has shown minimal detectable freeiron release. Bioactive iron or free iron may have a role in infection, oxidative stress and inflammation in most patients with advanced CKD. Although there is no strong clinical evidence for an association of intravenous iron with infections, there is some evidence for its critical role in microbial growth and leukocyte function. In vitro, bioactive iron enhances growth of selected bacteria (21); in vivo, transfusional iron overload is associated with microbial infection (22). Both in vivo and in vitro intravenous iron is associated with defects in neutrophil function (13, 23, 24). In light of these observations, because ferumoxytol releases minimal detectable free iron compared with other iron agents, it may hypothetically decrease the risk of infections in dialysis and in patients with CKD dependent on intravenous iron supplementation. Further investigation is required.

Pharmacokinetic properties The pharmacokinetics of ferumoxytol have been examined in healthy subjects and in patients with CKD on HD, and the observed plasma pharmacokinetics characteristics were similar in both groups (12). Ferumoxytol exhibited dose-dependent and capacity-limited elimination, with an elimination half-life of 9.3 hours with a dose of iron of 1 mg/kg body weight, to

© 2011 Società Italiana di Nefrologia - ISSN 1121-8428

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14.5 hours with a dose of iron of 4 mg/kg. The clearance (CL) was decreased by increasing the dose of ferumoxytol. The volume of distribution (Vd) was consistent with plasma volume and was not significantly different per kilogram. After the administration of two 510-mg doses within 24 hours, the CL was 69.1 ml/hour, with an estimated Vd of 3.16 L (data obtained from the US Food and Drug Administration [FDA]). The mean maximum plasma concentration (Cmax) values increased with dose, and the Cmax and time of maximum concentration (tmax) were 206 µg/mL and 0.32 hours, respectively (per the FDA). The pharmacokinetic behavior of ferumoxytol does not depend on the rate of infusion or the patient’s sex, and the drug is not removed by HD (12).

Clinical trials with ferumoxytol Ferumoxytol was approved by the FDA after analysis of all of the studies and data from 3 phase III, open-label, randomized, controlled clinical trials. Patients with CKD and iron deficiency anemia in all 3 trials (2 trials enrolled patients with non-dialysis-dependent CKD, and 1 trial enrolled patients who were undergoing HD) were randomized to treatment with ferumoxytol or oral iron. Ferumoxytol injection was administered as 2 single intravenous doses, 510 mg, within 5 days ± 3 days, and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg of elemental iron daily for 21 days. The primary efficacy end point was the change in hemoglobin from baseline to day 35. Using another method of online searching, ferumoxytol was found to be the main subject of 21 studies. Nine trials have a completed status, whereas 1 was terminated (at the request of the sponsor), and the majority of these (including those evaluating ferumoxytol as an MRI agent) are in the recruiting or active phase. In all of these studies, ferumoxytol was compared only with an orally administered iron. However, a new study (ClinicalTrials.gov identifier: NCT01052779) is set to yield data on the safety and efficacy of intravenous ferumoxytol compared with intravenous iron sucrose for the treatment of iron deficiency anemia in patients with CKD.

Main advantages of ferumoxytol Drug safety The safety of ferumoxytol was evaluated and confirmed in every clinical trial. In 1 study (a multicenter phase III, doubleblind, crossover, randomized, placebo-controlled study), a single 510-mg dose of ferumoxytol (17 mL) versus saline

(17 mL) as placebo was administered during 17 seconds on day 0, and the alternate agent was given on day 7 (25). A total of 750 randomly assigned patients with CKD stages 1 to 5 (60% were not on dialysis therapy) were included. In total, 420 adverse events were reported; 242 occurred in 152 patients (21.3%) receiving ferumoxytol, and 178 in 119 patients (16.7%) receiving placebo. The most common adverse events after each treatment included symptoms related to the injection and infusion site, such as dizziness, pruritus, headache, fatigue and nausea. More serious adverse events were reported in 21 patients (2.9%) after ferumoxytol and in 13 patients (1.8%) after placebo. There were no episodes of hypotension in either the ferumoxytol or the placebo group (25). This study concluded that ferumoxytol in anemic patients with CKD stages 1 to 5 is well tolerated, with a safety profile similar to placebo (25). In other studies to evaluate the drug’s safety, intravenous ferumoxytol was compared with oral iron. In a study by Provenzano et al (8), it emerged that when ferumoxytol was used as an intravenous iron replacement therapy in patients undergoing HD, adverse event rates were comparable in 2 groups of patients with CKD on HD and on a stable ESA regimen – 1 group having received 2 injections of 510 mg of ferumoxytol within 7 days (n=114) and another group having received 200 mg elemental oral iron daily for 21 days (n=116). In the randomized phase, adverse events related to treatment were less frequent in the ferumoxytol group (8.2%) compared with the oral iron group (15.9%). Serious adverse events ware similar in the ferumoxytol (12.7%) and oral iron groups (12.3%). Hypotension as the most serious adverse event was reported in only 2 patients in the ferumoxytol group. There was 1 death in the ferumoxytol group (0.9%) and 3 deaths in the oral iron group (2.7%), none of which was considered related to the treatment (8). In the readmission phase of the same study, adverse events in each group ware comparable. Spinowitz et al (7) reported an even better safety profile of ferumoxytol compared with oral iron. Most adverse events, as in the study by Provenzano et al, were mild to moderate in intensity, and they occurred in 35.5% of patients receiving intravenous ferumoxytol compared with 52.0% of patients receiving iron orally (7). In conclusion, ferumoxytol is generally well tolerated and safe for intravenous administration. The safety profile of this novel drug favors several properties such as low immunogenicity and stable binding of the iron to its carrier molecule in serum, with minimal direct release of iron in the serum, which thereby avoids the generation of a free or labile iron pool until it is taken up into the reticuloendothelial system (13, 20). The extremely low immunogenicity of ferumoxytol was exhibited in the rat paw edema test (13, 26, 27). A com-

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parison of bleomycin-detectable iron and TSAT in the serum of patients receiving ferumoxytol, iron gluconate or iron sucrose proved that ferumoxytol generated the least catalytic free iron for comparable levels of TSAT (7, 8, 13, 26, 27).

Drug efficacy In all of the studies reviewed, ferumoxytol was administered as two 510-mg single intravenous doses within 5 ± 3 days, and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg of elemental iron daily for 21 days. Ferumoxytol treatment resulted in a statistically greater mean change in hemoglobin (≥1 g/dL), TSAT and ferritin from baseline to day 35, compared with oral iron (Tab. I). This is consistent with the conclusion of a recent metaanalysis comparing traditional intravenous iron preparations with oral iron therapy in the treatment of the anemia of CKD (28). Both patients receiving ESA therapy and those without ESA therapy had increased hemoglobin levels after treatment with ferumoxytol or oral iron. However, in the study by Spinowitz et al (7), patients not receiving ESA had a greater

increase in hemoglobin at day 35 (0.62 g/dL) after ferumoxytol treatment than did patients who were on ESA and oral iron treatment (0.19 g/dL). The same study showed that patients who were initially on oral iron had a mean increase in hemoglobin of 0.69 g/dL after subsequent treatment with ferumoxytol during the readmission phase (7).

Conclusions The standard dosage regimen of intravenous ferumoxytol is 510 mg in a single dose, and the second dose should be delivered 3 to 8 days after the first dose. Ferumoxytol does not require a test dose and is administered intravenously at the rapid rate of 30 mg/s. Ferumoxytol is more effective in increasing hemoglobin levels in patients with all stages of CKD than is oral treatment, and it can possibly decrease the societal and economic impact of renal anemia on patients with CKD. The total cost of treatment could be lower than that of oral iron supplementation because hospital admission rates, drug administration costs and cost of unnecessary blood transfusions would be re-

TABLE I BASELINE AND MEAN CHANGES TO DAY 35 IN HEMOGLOBIN, TSAT AND FERRITIN IN EACH TREATMENT GROUP FOR TRIALS 1, 2 AND 3 Trial 1: Nondialysis CKD End point

Trial 2: Nondialysis CKD

Trial 3: CKD on dialysis

Ferumoxytol (n=226)

Oral iron (n=77)

Ferumoxytol (n=228)

Oral iron (n=76)

Ferumoxytol (n=114)

Oral iron (n=116)

Baseline Hgb, g/dL

9.9 ± 0.8

9.9 ± 0.7

10.0 ± 0.7

10.0 ± 0.8

10.6 ± 0.7

10.7 ± 0.6

Hgb change at day 35, from baseline, g/dL

1.2* ± 1.3

0.5 ± 1.0

0.8* ± 1.2

0.2 ± 1.0

1.0* ± 1.1

0.5 ± 1.1

Baseline TSAT, %

9.8 ± 5.4

10.4 ± 5.2

11.3 ± 6.1

10.1 ± 5.5

15.7 ± 7.2

15.9 ± 6.3

TSAT change at day 35, from baseline, %

9.2 ± 9.4

0.3 ± 4.7

9.8 ± 9.2

1.3 ± 6.4

6.4 ± 12.6

0.6 ± 8.3

Baseline ferritin, ng/mL

123.7 ± 125.4

146.2 ± 136.3

146.1 ± 173.6

143.5 ± 144.9

340.5 ± 159.1

357.6 ± 171.7

Ferritin change at day 35, from baseline, ng/mL

300.7 ± 214.9

0.3 ± 82.0

381.7 ± 278.6

6.9 ± 60.1

233.9 ± 207.0

−59.2 ± 106.2

Values are means ± SD. CKD = chronic kidney disease; Hgb = hemoglobin; SD = standard deviation; TSAT = transferrin saturation. *p≤0.001 for main efficacy end point. 720

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duced. Furthermore, with intravenous treatment, the poor absorption, gastrointestinal intolerance and noncompliance associated with the orally administered drug is avoided. The available data suggest that ferumoxytol has a good safety profile when compared with placebo, and it is even better when compared with oral iron. However, in all studies, patients with a history of iron allergies and multiple drug allergies have been excluded, and the true rate of adverse events for ferumoxytol in the general population will emerge only after the administration of millions of doses. Moreover, there has been no direct comparison of ferumoxytol with other parenteral iron preparations. Finally, the duration of the follow-up of the available studies was short. Therefore, there is a need for the data from the new clinical trials with larger numbers of patients and longer follow-up where ferumoxytol will be compared with other traditional

intravenous iron preparations. Only then will we be able to finally answer all of the questions concerning the efficacy and the clinical and economic benefits and limitations of ferumoxytol (29, 30). Financial support: None. Conflict of interest statement: None.

Address for correspondence: Maciej Banach, MD, PhD, FESC, FASA, FRSPH Head, Department of Hypertension WAM University Hospital in Lodz Medical University of Lodz, Poland Zeromskiego 113 PL-90549 Lodz, Poland [email protected]

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Accepted: August 08, 2011

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