Highlights of the Annual Dialysis Conference: Chronic Kidney Disease Related-Anemia

February 18-20, 2007; Denver, Colorado

Anne G. Le, PharmD, RPh

Disclosures

April 02, 2007

In This Article

Efficacy and Safety of Methoxy Polyethylene Glycol-Epoetin Beta

Receptor Affinity and Cellular Consumption of Methoxy Polyethylene Glycol-Epoetin Beta vs Epoetin Beta

In vitro studies presented by Michael Jarsch, MD, from Roche Diagnostics GmbH, in Penzberg, Bavaria, Germany, compared the binding and consumption of methoxy polyethylene glycol-epoetin beta and epoetin beta with the extracellular domain of the soluble human erythropoietin receptor using a surface plasma resonance assay.[2] The surface plasma resonance binding assay format was used to measure the change in the refractive index, which allowed for the calculation of the association rate, dissociation rate, and equilibrium constant. Using the equilibrium constant analysis, Jarsch and colleagues were able to calculate the binding affinity of epoetin beta and methoxy polyethylene glycol-epoetin beta, which showed that methoxy polyethylene glycol-epoetin beta had a lower binding affinity (Kd) than epoetin beta (approximately 140 nM vs approximately 2.9 nM, respectively). Furthermore, the surface plasma resonance binding kinetics showed that the dissociation rate from the receptor was approximately 1.5 times faster for methoxy polyethylene glycol-epoetin beta than epoetin beta, and the association rate of methoxy polyethylene glycol-epoetin beta from the soluble human erythropoietin receptor was slower. Therefore, the increase in Kd seen with methoxy polyethylene glycol-epoetin beta can be attributed to methoxy polyethylene glycol-epoetin beta's lower association rate. In addition, based on a competitive binding assay against 125I-epoetin in UT-7 cells, methoxy polyethylene glycol-epoetin beta was also found to have a different (lower) affinity at the soluble recombinant human erythropoietin receptor than epoetin beta (half-maximal inhibitory concentrations of 200 nM vs 1.5 nM, respectively), which means that approximately 100 times more methoxy polyethylene glycol-epoetin beta is needed to compete with epoetin beta for binding at the receptor. Finally, using UT-7 cell consumption assays during a 120-hour incubation with 1000 pM methoxy polyethylene glycol-epoetin beta or 100 pM epoetin beta, methoxy polyethylene glycol-epoetin beta concentrations remained sufficient to stimulate cell proliferation after 120 hours vs epoetin beta, and epoetin beta concentration in supernatant declined significant vs methoxy polyethylene glycol-epoetin beta concentration in supernatant (did not change significantly at time points). In conclusion, methoxy polyethylene glycol-epoetin beta was found to be less rapidly consumed by target cells and thus remained at stimulating concentrations for longer periods. These findings support a different activity of methoxy polyethylene glycol-epoetin beta at the receptor level. Moreover, this mechanistic difference further supports extended administration intervals between methoxy polyethylene glycol-epoetin beta and traditional ESAs for anemia treatment.

Hemoglobin Stability and Dose Change of Intravenous Methoxy Polyethylene Glycol-Epoetin Beta vs Intravenous Epoetin Therapy

Allen Nissenson, MD, Professor of Medicine, Associate Dean and Director of the Dialysis Program at the David Geffen School of Medicine at University of California, Los Angeles, California, presented the results from a randomized, open-label trial to assess hemoglobin stability and dose changes in adult anemic patients on dialysis (hemodialysis or peritoneal dialysis ≥ 12 weeks) with intravenous (IV) methoxy polyethylene glycol-epoetin beta or IV epoetin alfa or beta.[3] Baseline hemoglobin levels were between 10.5 and 13.0 g/dL and patients had to have adequate iron status and been on IV maintenance epoetin at the same dosing interval for ≥ 8 weeks before screening and during the baseline period. After a 4-week screening and baseline treatment period, patients were randomized to 1 of 3 groups: IV methoxy polyethylene glycol-epoetin beta every 2 weeks (n = 223); IV methoxy polyethylene glycol-epoetin beta every 4 weeks (n = 224); or IV epoetin 1-3 times weekly (n = 226) for a 28-week dose titration period, followed by an 8-week evaluation period. The starting dose of methoxy polyethylene glycol-epoetin beta was based on the epoetin dose administered during the week preceding the switch. Doses of methoxy polyethylene glycol-epoetin beta and epoetin beta were adjusted every 4 weeks to maintain hemoglobin within ± 1.0 g/dL of baseline levels and between 10 and 13.5 g/dL. The primary endpoint was the change in hemoglobin levels between baseline and the evaluation period. Secondary endpoints included the number of patients who maintained hemoglobin within ± 1 g/dL of baseline, incidence of transfusions, and number of dose changes per patient during the titration period. The results included the intent-to-treat (ITT), safety, and per protocol populations. Results showed that baseline demographics were similar in all 3 groups. Average hemoglobin levels were analyzed in the ITT population and at baseline, titration, and the evaluation period -- there was no significant difference in the 3 groups. There was also no significant difference between the primary end point between methoxy polyethylene glycol-epoetin beta and epoetin. In the ITT and per-protocol populations, all patients maintained hemoglobin within ± 1 g/dL (70% of patients in the methoxy polyethylene glycol-epoetin beta every 2- and 4-week groups vs 72% in the epoetin group). In the safety population, there was no significant difference between the 3 groups in red blood cell transfusions.

Subcutaneous Methoxy Polyethylene Glycol-Epoetin Beta vs Subcutaneous Epoetin Therapy for Maintenance of Hemoglobin Levels in Dialysis Patients

Rebecca Schmidt, DO, Professor of Medicine and Chief, Section of Nephrology, at West Virginia School of Medicine, in Morgantown, West Virginia, presented the results of a randomized, controlled, open-label, multi-center, parallel group trial comparing the safety and efficacy of methoxy polyethylene glycol-epoetin beta administered subcutaneously or subcutaneous (SC) epoetin alfa or beta for the maintenance treatment of anemia in adult dialysis (patients undergoing hemodialysis or peritoneal dialysis for12 weeks or longer).[4] Patients had to have baseline hemoglobin levels between 10.5 and 13.0 g/dL, adequate iron status, and been on subcutaneous maintenance epoetin (1-3 times weekly) at the same dosing interval for 8 weeks or longer before screening and during the baseline period. After a 4-week screening period, 572 patients (48 on peritoneal dialysis and 524 on hemodialysis) were randomized to 1 of 3 groups: SC methoxy polyethylene glycol-epoetin beta every 2 weeks (n = 190); SC methoxy polyethylene glycol-epoetin beta every 4 weeks (n = 191); or subcutaneous epoetin 1-3 times/week (n = 191) for a 28-week dose titration period followed by an 8-week evaluation period and a 16-week safety period. Doses of methoxy polyethylene glycol-epoetin beta could be adjusted every 4 weeks to maintain hemoglobin within ± 1.0 g/dL of baseline and within a range of 10-13.5 g/dL during the evaluation period. The primary endpoint was change in hemoglobin levels between baseline and the evaluation period. Secondary endpoints included number of patients who maintained hemoglobin within ± 1.0 g/dL of baseline and number of red blood cell transfusions. Results showed that baseline demographic data was similar in the 3 groups. Average hemoglobin levels were analyzed in the ITT population and showed no significant difference in change in hemoglobin in all 3 groups from baseline, titration, and evaluation periods. Patients maintained hemoglobin within ± 1.0 g/dL of baseline in all 3 groups and adverse events in all 3 groups were similar and relatively low. In conclusion, these results demonstrate that treatment with subcutaneous methoxy polyethylene glycol-epoetin beta administered every 2 weeks or every 4 weeks was as effective as SC epoetin treatment. In addition, the incidence of treatment-related adverse events was low and similar between the 3 treatment groups.

Efficacy of Intravenous Methoxy Polyethylene Glycol-Epoetin Beta in Correcting Anemia of Chronic Kidney Disease in Adults Undergoing Dialysis

Michael Germain, MD, from the Western New England Renal and Transplant Associates in Springfield, Massachusetts, presented the results of the methoxy polyethylene glycol-epoetin beta AdMinistered Intraveneously for Anemia Correction and SUStained Maintenance in Dialysis (AMICUS) study, which sought to determine the efficacy and safety of IV methoxy polyethylene glycol-epoetin beta once every 2 weeks in ESA-naive CKD patients to epoetin alfa or epoetin beta 1-3 times/week, in 181 patients undergoing dialysis.[5] This was an open-label, randomized, multicenter, parallel group, phase III study that included patients undergoing hemodialysis or peritoneal dialysis for 2 weeks or longer previously and with a hemoglobin level between 8 and 11 g/dL and adequate iron stores. Patients had to be ESA-naive, in other words, no ESA treatment in the previous 12 weeks. After a 2-week screening period, patients were randomized to receive either IV methoxy polyethylene glycol-epoetin beta every 2 weeks (n = 135) or IV epoetin alfa or beta 3 times weekly (n = 46) according to the label for 24 weeks. Iron was supplemented as needed to maintain serum ferritin ≥ 100 mg/dL or transferring saturation ≥ 20%. The primary endpoint was the hemoglobin response rate, or the proportion of patients achieving an increase in hemoglobin of ≥ 1 g/dL from baseline and a single hemoglobin measurement of ≥ 11 g/dL without red blood cell transfusion. Secondary endpoints included hemoglobin values over time, change in hemoglobin from baseline over time, red blood cell transfusion rate, and safety and tolerability. Results were based on the ITT, per-protocol, and safety groups and showed that the baseline characteristics of the ITT population were very similar between the 2 groups. The results using data from the ITT and per-protocol groups showed equal, non-inferiority between the 2 groups in their hemoglobin response rates. Moreover, the red blood cell transfusion rates were similar in both treatment groups (5.2% methoxy polyethylene glycol-epoetin beta vs 4.3% with epoetin). Safety and tolerability data between the 2 groups showed no difference. Hypertension was the most common adverse event in both groups, followed by procedural hypotension and arteriovenous fistula thrombosis; event rates did not differ. In conclusion, IV methoxy polyethylene glycol-epoetin beta administered every 2 weeks in ESA-naive patients with CKD who are undergoing dialysis effectively corrects anemia with a higher response rate. In addition, methoxy polyethylene glycol-epoetin beta provides a steady and controlled increase in hemoglobin levels and a safety profile consistent with existing ESAs.

Retrospective Claims Database Analysis of Erythropoiesis-Stimulating Agents Use Before Onset of Dialysis on Cardiovascular Outcomes

Jay Wish, MD, Professor of Medicine at Case Western Reserve University in Cleveland, Ohio, and colleagues performed a retrospective claims database analysis using health insurance claims data from 2001 to 2005 and presented his data, which compared how ESA use in predialysis patients with CKD and anemia would affect cardiovascular outcomes after initiation of dialysis.[6] Patients had to be 18 years or older and were required to have at least 24 months of continuous enrollment before onset of dialysis and at least 1 month of continuous enrollment at or after onset of dialysis. Coding data were used to classify patients as anemic. Patients using ESAs at baseline were classified using a modified ESA consistency algorithm that resulted in 4 ESA groups: least consistent, inconsistent, more consistent, and most consistent. The primary outcome was cardiovascular outcomes. Of 5848 eligible patients, 3028 (52%) were identified as being anemic at baseline. Of this group, 1888 patients were on ESA treatment at baseline. Using these 1888 patients, 30% were classified as being least consistent; 26% as inconsistent; 21% as more consistent; and 23% as most consistent. Results showed that baseline demographics and clinical characteristics of the predialysis anemic patients by ESA treatment and consistency status were similar between the groups. Postdialysis cardiovascular outcomes (including acute myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular accident/transient ischemic event, and inpatient mortality) in dialysis and predialysis ESA treatment status showed that there was a highly statistically significant difference in time to event (233 for ESA treatment vs 128 for no ESA treatment; relative risk: 0.70; P < .0001). In addition, there was a statistically significant reduction in mortality in all ESA treatment groups. In conclusion, patients with predialysis ESA use had a decrease in incidence of cardiovascular outcomes and mortality postdialysis. These findings add to the current evidence that optimizing anemia treatment could lead to better clinical outcomes for patients with CKD and ESA-use in predialysis patients with anemia and CKD could significantly improve clinical outcomes when treating end-stage renal disease.

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