Daniel M. Keller, PhD

July 12, 2010

July 12, 2010 (Munich, Germany) — A preparation of iron isomaltoside 1000 (MonoFer, Pharmacosmos A/S) administered intravenously in high doses was effective, safe, and well tolerated when used to replenish iron stores in patients with anemia of chronic kidney disease (CKD). It might allow iron repletion with a single dose, based on a low risk for toxicity related to free iron.

According to Philip Kalra, MD, professor and consultant nephrologist at the University of Manchester and at Salford Royal Hospital in the United Kingdom, who presented a poster here at the XLVII European Renal Association-European Dialysis and Transplant Association Congress, iron isomaltoside 1000 is a preparation of isomaltoside that strongly binds iron, resulting in low levels of free iron. As the sugar moiety degrades, iron is released.

The primary aim of the study was to obtain safety data on the use of a single high dose of iron isomaltoside in patients with CKD (n = 40) or congestive heart failure (CHF; n = 20) and iron deficiency anemia. Hematologic parameters were secondary end points. The study analyzed outcomes from the 30% of patients in previous safety studies for whom clinicians opted for high single-dose infusions.

Those studies were open label, ran for 8 weeks, and used iron total dose infusions below 10 mg iron/kg over 30 minutes, 10 to 20 mg iron/kg over 60 minutes, or more than 20 mg iron/kg split into 2 infusions. Because the drug is supposedly nonanaphylactic, no initial test doses were given. Patients were seen at weeks 1, 2, 3, 4, and 8 for assessments of safety and hematologic parameters.

CKD patients in the studies not receiving parenteral iron could be predialysis or on dialysis with hemoglobin below 11 g/dL at screening. If CKD patients were already receiving parenteral iron, they had to be willing to switch to iron isomaltoside and have hemoglobin below 13 g/dL at screening. For CHF patients, hemoglobin had to be below 11.5 g/dL in women and below 12 g/dL in men. All patients were at least 18 years old and had serum ferritin below 800 μg/L at screening.

The mean age of the 60 patients in the study was 67 years (range, 29 to 88 years; 47% female). Of the 40 CKD patients, 19 were on dialysis and 21 were predialysis. The mean dose of iron isomaltoside 1000 was 975.3 mg (range, 462 to 1800 mg). The mean dose for the CHF patients was 868.3 mg (range, 650 to 1000 mg). Of the 60 patients, 58 had their iron need covered by a single dose; only 2 CKD patients required 2 divided doses.

Safety and Efficacy Demonstrated

The researchers observed only 1 possibly treatment-related adverse reaction (classified as serious), related to a single-dose administration. It was an episode of angina pectoris occurring 10 or 11 days after a 1400 mg dose in an 80-year-old CKD patient who had a history of angina.

No anaphylactic, anaphylactoid, or delayed allergic reactions were noted, and there were no clinically significant changes in routine laboratory tests, vital signs, or electrocardiograms.

For all 60 patients, blood hemoglobin, serum ferritin, and transferrin saturation significantly increased by week 8, compared with baseline (P < .05 for all). For serum iron, serum transferrin, and transferrin saturation, there was an initial spike in each level when measured 1 week after iron isomaltoside 1000 administration, which then fell over time. The increases for hemoglobin and serum ferritin levels are shown in Table 1.

Table 1. Change at Week 8 From Baseline

Patient Cohort Hemoglobin (g/dL) Serum Ferritin (μg/L)
CKD 0.98 191.7
CHF 0.44 216.8

Based on the low frequency of adverse events and the significant improvement in laboratory markers of anemia, the researchers concluded that intravenous administration of iron isomaltoside 1000 in high doses was safe, effective, and well tolerated. Therefore, full iron repletion can be achieved by most CKD or CHF patients in a single visit.

Dr. Kalra explained to Medscape Medical News that the importance of very short, nonbranched sugar chains in the iron isomaltoside 1000 preparation means that "the likelihood of an anaphylactic reaction is really, really reduced to negligible levels. . . . Because of the low anaphylactogenesis, there is no requirement for a test dose at all, and that was shown in this study."

He said up to 1800 mg could be given in 60 minutes without the need for a test dose. In addition, he said the iron is released very slowly, preventing free-iron toxicity, which is manifested as hypotension.

The sort of adverse reactions that can be expected with iron isomaltoside 1000 are typical gastrointestinal effects, such as diarrhea, constipation, or abdominal pain, and these were very uncommon, according to Dr. Kalra.

He said he understands that the drug is approved for sale in several European countries, and that the manufacturer is applying for registration in the United Kingdom and might apply to the US Food and Drug Administration (FDA) next year. "In terms of the United States and the FDA, we now need to see some comparative data [from other iron preparations] in hemodialysis patients," he said.

Lucia Del Vecchio, MD, from the nephrology department at Alessandro Manzoni Hospital in Lecco, Italy, who was not involved with the study, told Medscape Medical News that she thinks new iron preparations are likely to be "very safe in that they will not [increase] free iron molecules, so they will not increase oxidative stress." She said the efficacy studies are very preliminary and nothing has been published yet.

Dr. Del Vecchio noted that there is renewed interest in iron replacement therapy for anemia since the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study showed that darbepoetin could be harmful and did not prevent cardiovascular events or death in patients with diabetes and CKD. Patients need to be iron replete if erythropoiesis-stimulating agents are to work optimally.

Francesco Locatelli, MD, head of the Department of Nephrology, Dialysis, and Transplantation at Alessandro Manzoni Hospital, said he sees a problem in that designers of studies of the new iron drugs choose to compare them only to older drugs and not to the other newer ones. The new drugs "for sure are more interesting because of no experience or reported side effects," he said.

George Bailie, PharmD, PhD, professor of nephrology pharmacy at Albany College of Pharmacy and Health Sciences in New York, said that, from what he has seen in presentations on iron isomaltoside 1000, "it became clear to me that there is no [peer-reviewed] published information for that drug yet. . . . They have a total of 200 patients. That particular agent has been approved for use in 20 European countries on the basis of that, something I find really quite surprising." To be fair, he said, the manufacturer has 4 or 5 more studies planned.

The study was funded by manufacturer Pharmacosmos A/S. Dr. Kalra reports lecturing for Pharmacosmos A/S and has been involved in study design; he has also lectured for Vifor Pharma, Amgen, Daiichi Sankyo, Bristol-Myers Squibb, Genzyme, and Shire. Dr. Del Vecchio reports that she participates in a study on ferric carboxymaltose, and has spoken on erythropoiesis-stimulating agents for Amgen and Roche. Dr. Locatelli has disclosed no relevant financial relationships. Dr. Bailie reports receiving grants, honoraria, or speaking fees from American Regent, Vifor Pharma, Fresenius, and Genzyme.

XLVII European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress: Abstract Su571. Presented June 27, 2010.


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