Hemoglobin Response Following Ferumoxytol Administration in CKD Patients:
Impact of Baseline Hemoglobin and Iron Parameters
B Spinowitz,1 M Stevenson,2 B Pereira2
New York Hospital Medical Center Queens, Flushing, NY; 2AMAG Pharmaceuticals, Inc., Lexington, MA
1
These observations provided a basis for investigating whether baseline Hgb and
iron parameters have an effect on response to IV iron therapy with ferumoxytol,
a novel IV iron replacement therapy for the treatment of iron deficiency
anemia (IDA) in patients with CKD. Ferumoxytol is a superparamagnetic iron
oxide nanoparticle coated with a semi-synthetic carbohydrate (polyglucose
sorbitol carboxymethylether) and formulated as a suspension with 30 mg/mL
of elemental iron. Ferumoxytol is isotonic and has a distinct physicochemical
profile relative to other IV iron therapies, with evidence of a lower free iron
content (Table 1).4 Pivotal clinical studies in patients with CKD have shown that
ferumoxytol, given by rapid IV injection in doses of up to 510 mg, is well
tolerated and more effective than oral iron at increasing Hgb.5,6
Table 1: Physicochemical Properties of Ferumoxytol Compared With Other
IV Iron Therapies
Bleomycin Detectable
% Free Iron by Osmolality
Free Iron (μM; mean ± SD) Ultrafiltration (mOsm/kg)
Ferrlecit Venofer®
INFeD®
Ferumoxytol
®
7.26 ± 2.62
6.70 ± 1.78
3.03 ± 0.90
1.15 ± 0.46
2.360
0.038
0.298
0.001
990
1316
500
297
Results
p=0.0002
1.0
Demographics and baseline characteristics for these HD patients are shown
in Table 2. No statistically significant differences between the ferumoxytol and
oral iron arms were apparent, with the exception of sex and ethnicity. More men
(62.9%) than women were randomized into the oral iron group. The majority of
patients in both groups were black, African American (60.5% ferumoxytol;
57.8% oral iron).
7.7-9.7
10.5-11.1
5.2-6.5
6.0-8.0
We examined the effects of ferumoxytol on Hgb response relative to baseline
levels and iron indices, compared with oral iron, in anemic patients with CKD
stage 5D on HD (ClinicalTrials.gov identifier NCT00233597).
Methods
This post hoc analysis was performed on data from a Phase III, open-label,
multicenter study that examined the safety and efficacy of ferumoxytol in
patients with CKD stage 5D on HD. Patients were randomly assigned in a
1:1 ratio to receive either 2 doses of 510 mg of ferumoxytol with HD (no more
than 5 ± 3 days apart) or 200 mg of elemental oral iron daily for 21 days.
2 x 510 mg ferumoxytol
p=0.0067
0.8
Oral iron
0.6
Figure 3: Change in Hemoglobin at Day 35 by Baseline TSAT
Demographic
2 x 510 mg Ferumoxytol
(n=114)
0.4
1.0
0.5
Sex, n (%)
0.0395*
Female
Male
Missing
57 (50.0)
57 (50.0)
0
42 (36.2)
73 (62.9)
1 (0.9)
Black, African American
White
Asian
American Indian,
Alaskan Native
Native Hawaiian,
Other Pacific Islander
Other
Missing
69 (60.5)
37 (32.5)
6 (5.3)
67 (57.8)
40 (34.5)
2 (1.7)
0
0
2 (1.8)
0
1 (0.9)
1 (0.9)
4 (3.4)
1 (0.9)
9 (7.9)
105 (92.1)
0
19 (16.4)
96 (82.8)
1 (0.9)
Height (cm)
Mean ± SD
168.6 ± 9.9
87.1 ± 24.9
*Statistically significant at a p-value <0.05.
0.0463*
Day 21
n=35
0.0
Changes in Hgb at Day 35 stratified by baseline Hgb are depicted in Figure 2.
At every quartile of baseline Hgb, ferumoxytol produced greater increases
in Hgb than did oral iron, with approximately 1-g/dL increases regardless of
baseline Hgb subgroup. In the ferumoxytol arm, patients with more severe
anemia had slightly greater Hgb increases than those with less severe anemia.
Overshoot (>13 g/dL) in mean Hgb levels was not observed, even at the highest
baseline Hgb quartile.
Figure 2: Change in Hemoglobin at Day 35 by Baseline Hemoglobin
n=30
86.3 ± 28.5
Conclusion
–0.5
2 x 510 mg ferumoxytol
Oral iron
>10 to 14
>14 to 21
>21 to 30
Changes in Hgb at Day 35 stratified by baseline ferritin are shown in Figure 4.
At every quartile of baseline ferritin, except the highest (>466.25 to
599.00 ng/mL), ferumoxytol produced greater increases in Hgb than did
oral iron. There were approximately 1-g/dL increases in Hgb regardless of
baseline ferritin subgroup. Even at the highest quartile of baseline ferritin, a
clinically meaningful Hgb response to ferumoxytol was observed (approximately
0.7 g/dL).
n=21
n=36
0.5
n=33
n=26
0.0
n=30
n=20
n=32
–0.5
n=25
>10.3 to 10.7
2.Coyne D, Kapoian T, Suki W, et al, for the DRIVE Study Group. Ferric gluconate is highly
efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin
saturation: results of the dialysis patients’ response to IV iron with elevated ferritin (DRIVE)
study. J Am Soc Nephrol. 2007;18:975-984.
3.Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant
human erythropoietin. Kidney Int. 2005;68:1337-1343.
4.Data on file. AMAG Pharmaceuticals, Inc.
6.Spinowitz BS, Kausz AT, Baptista J, et al. Ferumoxytol for treating iron deficiency anemia
in CKD. J Am Soc Nephrol. 2008;19:1599-1605.
1.5
1.0
n=27
n=31
0.5
n=30
n=34 n=22
0.0
n=28
n=26
n=25
–0.5
2 x 510 mg ferumoxytol
Oral iron
2 x 510 mg ferumoxytol
Oral iron
8.2 to 10.3
1.Fishbane S, Kowalski E, Imbriano L, Maesaka J. The evaluation of iron status in hemodialysis
patients. J Am Soc Nephrol. 1996;7:2654-2657.
5.Singh A, Patel T, Hertel J, Bernardo M, Kausz A, Brenner L. Safety of ferumoxytol in patients
with anemia and CKD. Am J Kidney Dis. 2008 Sep 27. [Epub ahead of print]
2.0
1.0
•Regardless of baseline hemoglobin, TSAT, or ferritin levels, IV ferumoxytol can
consistently produce clinically meaningful increases in hemoglobin relative to
oral iron.
References
Figure 4: Change in Hemoglobin at Day 35 by Baseline Ferritin
1.5
•A Hgb increase of approximately 1 g/dL was seen in the TSAT quartile of 22%
to 30% and was superior to oral iron. This warrants a re-evaluation of the
guidelines with respect to TSAT markers in treating with IV iron.
•Even at the ferritin quartile of >466.25 to 599.00 ng/mL, an approximate
0.7-g/dL increase in Hgb was observed following 1 g of ferumoxytol.
n=22
n=26
Day 35
–1.0
–1.0
0.8326
n=26
Squares represent mean values; bars represent 95% confidence intervals.
0.5734
169.3 ± 9.3
Weight (kg)
Mean ± SD
0.4511
n=25
n=25
Baseline TSAT (%)
2.0
Ethnicity, n (%)
Hispanic, Latino
Not Hispanic, Latino
Missing
n=32
0 to 10
Oral Iron 200 mg/day
(n=116)
p-value
0.4817
•Even at the highest baseline Hgb quartile, ferumoxytol treatment did not
produce an overshoot (>13 g/dL) in Hgb levels.
–1.0
0.0
Age (y)
60.8 ± 13.0
Mean ± SD
59.5 ± 14.3
Median (range)
60.0 (27.0-87.0)
61.0 (24.0-87.0)
Summary
1.5
0.2
Table 2: Patient Demographics at Baseline (Intent-to-Treat Population)
In a multivariate analysis, the statistically significant increase in Hgb following
ferumoxytol compared with oral iron at Day 35 persisted even after adjustment
for baseline Hgb level (p=0.0003), TSAT level (p=0.0001), and serum ferritin
level (p=0.0001), and there were no significant interactions.
2.0
Hgb Change at Day 35 (g/dL)
1.2
Race, n (%)
pH
Figure 1: Overall Change in Hemoglobin at Days 21 and 35
Changes in Hgb at Day 35 stratified by baseline TSAT are shown in Figure 3.
At every quartile of baseline TSAT, ferumoxytol produced greater increases
in Hgb than oral iron. There were approximately 1-g/dL increases in Hgb
regardless of baseline TSAT subgroup.
Hgb Change at Day 35 (g/dL)
Response to iron administration in erythropoiesis-stimulating agent (ESA)–
treated patients on HD has drawn attention in relation to the phenomenon
of Hgb cycling.3 It has been suggested that Hgb cycling and variability are
associated with increased adverse events in HD. During ESA therapy in patients
on HD, Hgb levels rise and fall in a cyclic, patient-specific pattern.3 The Hgb
cycling poses a dosing challenge, as ESA and iron dosing may need to be
adjusted or temporarily interrupted accordingly to prevent Hgb levels from
exceeding the target range.3
The primary endpoint was the mean change from baseline in Hgb at Day 35.
Other endpoints included the mean change in Hgb at Day 21, and the mean
changes in ferritin and TSAT from baseline to Day 35. Hgb response at Day
35 was stratified by baseline Hgb, TSAT, and ferritin levels. An analysis of
covariance model was used to compare Day 35 treatment differences in Hgb
change from baseline when adjusted for baseline Hgb, TSAT, and ferritin.
The mean baseline Hgb values were similar in both treatment arms. Relative to
oral iron treatment, ferumoxytol treatment resulted in significantly larger mean
increases in Hgb at Days 21 and 35 (Figure 1). At Day 21, the mean change
from baseline Hgb in patients in the ferumoxytol treatment arm (0.71 g/dL) was
significantly greater (p=0.0067) to that of patients in the oral iron treatment
arm (0.35 g/dL). At Day 35, the mean change was 2.2-fold, statistically
significantly greater (p=0.0002) in patients treated with ferumoxytol (1.02 g/dL)
compared with oral iron (0.46 g/dL).
Change in Hgb (g/dL)
The effect of baseline anemia and iron indices on hemoglobin (Hgb) response
in patients with chronic kidney disease (CKD) on dialysis has been a subject
of debate. Some studies have suggested that serum ferritin and transferrin
saturation (TSAT) have predictive ability to identify the functional iron deficiency
that is most common in patients on hemodialysis (HD).1 However, the recent
DRIVE study suggests that the response to intravenous (IV) iron was similar in
different strata of ferritin and TSAT.2
Inclusion criteria were: patients ≥18 years of age who had been on HD for at
least 90 days; Hgb ≤11.5 g/dL, TSAT ≤30%, and serum ferritin ≤600 ng/mL;
and stable (±25%) dose of ESA therapy for at least 10 days prior to dosing.
Patients were expected to remain on a constant ESA dose during the study.
Hgb Change at Day 35 (g/dL)
Background
>10.7 to 11.2
Baseline Hgb (g/dL)
Squares represent mean values; bars represent 95% confidence intervals.
>11.2 to 11.5
8.00 to 207.75
>207.75 to 360.50
>360.50 to 466.25
>466.25 to 599.00
Baseline Ferritin (ng/mL)
Squares represent mean values; bars represent 95% confidence intervals.
Presented November 2008 at the American Society of Nephrology Annual Meeting.