Safety and efficacy of ferumoxytol for the episodic treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy: Results of a phase III, open-label, 6-month extension study.

To the Editor: Although oral iron supplementation is recommended as first-line treatment for iron deficiency anemia (IDA), many patients are intolerant of oral iron due to gastrointestinal side effects or do not achieve adequate replenishment of iron stores 1,2. For such patients, administration of iron intravenously (IV) may be the preferred alternative 1,3,4; however, there are limited data evaluating repeat IV iron dosing over an extended period of time in patients intolerant to oral iron and without concurrent advanced renal dysfunction.

Ferumoxytol is a colloidal iron oxide product approved in the United States for the treatment of IDA in adults with chronic kidney disease. The results of a phase III, 5-week, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT01114139) showed that ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used 5. Patients who completed the primary phase III study were eligible to enroll in an open-label extension study (see Supporting Information Fig. 1 study design). The objective of this extension study was to assess the safety and efficacy of ferumoxytol for the episodic treatment of IDA over a 6-month period (NCT01114217). The extension study included a 14-day screening period followed by 6 months of observation during which patients were evaluated for IDA monthly. Those with persistent or recurrent IDA (hemoglobin [Hgb] <11.0 g/dL and transferrin saturation [TSAT] <20%) at any evaluation visit began a 5-week treatment period (TP), in which patients received two 510-mg doses of ferumoxytol administered 2–8 days apart, then resumed monthly monitoring for IDA; patients were retreated if criteria for IDA were met again. The first ferumoxytol treatment (2 × 510 mg) for patients who previously received placebo in the primary study was Treatment Course 1; subsequent treatment courses were serially numbered. For patients who previously received ferumoxytol in the primary study, their first ferumoxytol treatment in the extension study was Treatment Course 2; subsequent courses were serially numbered.

The primary efficacy endpoint was mean change in Hgb from TP baseline (defined as level immediately prior to ferumoxytol treatment course) to week 5 following the first ferumoxytol treatment course. Other efficacy and safety endpoints and statistical methods are shown in Supporting Information Table I.

Of the 808 patients from the original study, 634 enrolled in the present study. A total of 151 placebo- and 186 ferumoxytol-treated patients met the criteria for treatment during the 6-month extension and received ≥1 course of ferumoxytol (intent-to-treat population) (Supporting Information Fig. 2). Among the remaining 297 patients, mean monthly Hgb remained ≥12 g/dL without further treatment. For the 151 patients who received placebo during the primary study, their first course of ferumoxytol during the extension study was categorized as Treatment Course 1. Treatment Course 2 (n = 244) included 58 patients who received Treatment Course 1 in the extension study and 186 patients who previously received Treatment Course 1 of ferumoxytol in the primary study. Treatment Course 3 (n = 69) included 15 patients who received both Treatment Courses 1 and 2 of ferumoxytol in the extension study and 54 patients who received Treatment Course 1 in the primary study and Treatment Course 2 in the extension study. Baseline patient characteristics and demographics are summarized in Supporting Information Table II.

Baseline Hgb and TSAT values were lower for Treatment Course 1 (8.7 g/dL and 5.1%, respectively) than for Treatment Courses 2 (10.2 g/dL and 8.8%) and 3 (10.2 g/dL and 10.1%). For the primary efficacy analysis, there was a statistically significant increase in Hgb of 2.6 g/dL from TP baseline to week 5 (P < 0.0001) among the 151 patients who received their first course of ferumoxytol treatment during the extension study (Table1; Supporting Information Fig. 3). Patients also achieved statistically significant increases in Hgb from TP baseline to week 5 following the second and third ferumoxytol treatment courses (Table1; Supporting Information Fig. 3); however, since the TP baselines were higher, the mean Hgb increases were lower (1.5 g/dL and 1.1 g/dL for Treatment Courses 2 and 3, respectively; P < 0.0001 vs. TP baseline for each), as expected, than those after the first treatment course. Mean monthly Hgb values from baseline to the end of the study among patients who did and did not receive ferumoxytol are shown in Supporting Information Fig. 4. Among the 337 patients who received ferumoxytol, mean Hgb increased from 10.1 g/dL at baseline to 11.6–11.8 g/dL by months 2–5 and remained relatively stable for the duration of the extension study. Significantly more patients with baseline Hgb ≤8.5 g/dL required more than one course of treatment compared with patients who had baseline Hgb >8.5 g/dL (i.e., 50% vs. 33%, respectively; P < 0.0001). More specifically, patients with baseline Hgb ≤8.5 g/dL were twice as likely to require >1 dose of treatment compared with patients with baseline Hgb >8.5 g/dL (odds ratio, 2.0; 95% confidence interval, 1.4–2.9). Other efficacy endpoints are summarized in Supporting Information Table III.

Table 1

Efficacy Results (Intent-to-Treat Population)

	Ferumoxytol treatment course
	Course 1 (n = 151)		Course 2 (n = 244)		Course 3 (n = 69)
Outcome	Value	95% CI; P-value	Value	95% CI; P-value	Value	95% CI; P-value
Baseline Hgb, g/dL, mean (SD)	8.7 (1.02)		10.2 (0.89)		10.2 (0.93)
Change in Hgb between TP baseline and week 5, g/dL, mean (SD)	2.6 (1.55)	2.4–2.8; <0.0001	1.5 (1.28)	1.3–1.7; <0.0001	1.1 (1.30)	0.8–1.4; <0.0001
Achieved ≥2.0-g/dL increase in Hgb between TP baseline and week 5, n (%)	119 (78.8)	72.3–85.3	107 (43.9)	37.6–50.1	26 (37.7)	26.2–49.1
Achieved Hgb ≥12.0 g/dL between TP baseline and week 5, n (%)	58 (38.4)	30.7–46.2	139 (57.0)	50.8–63.2	28 (40.6)	29.0–52.2
Baseline TSAT, %, mean (SD)	5.1 (4.63)		8.8 (8.16)		10.1 (6.59)
Change in TSAT between TP baseline and week 5, %, mean (SD)	12.8 (10.19)	11.2–14.5; <0.0001	11.7 (12.47)	10.6–13.2; <0.0001	7.5 (9.13)	5.3–9.7; <0.0001

CI: confidence interval; Hgb: hemoglobin; SD: standard deviation; TP: treatment period; TSAT: transferrin saturation.

Supporting Information Table IV summarizes treatment-emergent adverse events (TEAEs) occurring in ≥2% of patients in the treated safety population. The most common TEAEs were headache, urinary tract infection, and nausea. The overall incidence of TEAEs decreased with repeated treatment courses (Supporting Information Table V). Overall, 30 ferumoxytol-treated patients (8.9%) experienced an event that was considered by investigators to be related to study medication. Treatment-related adverse events that occurred in ≥1% were nausea (1.2%) and headache (1.2%). TEAEs by category are summarized in Supporting Information Table V. No serious TEAEs were considered by investigators to be drug related.

In summary, this extension study demonstrated ferumoxytol to be an effective treatment option for patients with persistent or recurrent IDA and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used, producing durable responses in the majority of patients. Mean Hgb increased significantly following Treatment Course 1 with smaller increases after Treatment Courses 2 and 3 (P < 0.0001 for all). Overall, 61% of ferumoxytol-treated patients never required a second course of treatment. Ferumoxytol was well tolerated with no new safety signals identified among patients who received repeat dosing.

Authorship Contributions

S.V.-R. contributed patients; performed the clinical trial; wrote, edited, and proofread the manuscript; provided input on the study; and agreed upon the data presented; D.C.F. contributed patients; performed the clinical trial; wrote, edited, and proofread the manuscript; and agreed upon the data presented; N.V.D. analyzed the data; wrote, edited, and proofread the manuscript; and agreed upon the data presented; K.B. designed and oversaw the execution of the trial; analyzed the data; wrote, edited, and proofread the manuscript; and agreed upon the data presented; Z.L. designed and oversaw the execution of the trial; analyzed the data; performed statistical analysis; wrote, edited, and proofread the manuscript; and agreed upon the data presented; L.F.A. designed and oversaw the execution of the trial; analyzed the data; wrote, edited, and proofread the manuscript; and agreed upon the data presented; W.E.S. designed and oversaw the execution of the trial; analyzed the data; wrote, edited, and proofread the manuscript; and agreed upon the data presented.