Original Article
A Peptide-Based Erythropoietin-Receptor Agonist for Pure Red-Cell Aplasia
N Engl J Med 2009; 361:1848-1855November 5, 2009
- Abstract
Background
We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies.
Methods
In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions.
Results
We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10×109 per liter before treatment to peak counts of greater than 100×109 per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period.
Conclusions
This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.)
Media in This Article
Figure 1
Changes in Median Reticulocyte Counts during the First 6 Months of Treatment with a Novel, Synthetic, Peptide-Based Erythropoietin-Receptor Agonist.Figure 2
Median Hemoglobin Concentrations and Number of Patients Receiving Red-Cell Transfusions over Time, after Subcutaneous Administration of a Novel, Synthetic, Peptide-Based Erythropoietin-Receptor Agonist Every 4 Weeks.Article Activity
- Article
The induction of neutralizing antierythropoietin antibodies is a rare complication of the use of recombinant human erythropoietin to increase red-cell production in patients with the anemia of chronic renal failure. Such antibodies can cause pure red-cell aplasia.1-3 They neutralize not only epoetin and darbepoetin alfa but also the patient's own erythropoietin. In severe cases of antibody-mediated pure red-cell aplasia there are virtually no erythroblasts in the bone marrow, the reticulocyte count is less than 10×109 per liter, and the patient is reliant on transfusions.4
The neutralizing antierythropoietin antibodies, which are largely of the IgG1 or IgG4 subtype, are directed against the protein portion of the molecule, since deglycosylation of erythropoietin does not abolish antibody binding.5 The incidence of antibody-mediated pure red-cell aplasia was most common in association with the subcutaneous administration of a formulation of epoetin alfa that was marketed outside the United States (Eprex or Erypo [Janssen-Cilag]),6 and this complication led to the temporary withdrawal of the license for subcutaneous administration of these products in Europe and elsewhere. The decrease in the use of the subcutaneous route of administration and a modification in this formulation of epoetin alfa were associated with a rapid decline in the incidence of antibody-mediated pure red-cell aplasia, but this complication persists at a low rate and has been reported with most currently available erythropoiesis-stimulating agents.6,7 To decrease the risk of antibody formation, in November 2005 the manufacturers of erythropoiesis-stimulating agents recommended the intravenous administration of all such products licensed in the United States among patients undergoing hemodialysis, even though subcutaneous injection, as compared with intravenous administration, requires lower doses of epoetin to achieve the same hemoglobin level.8
Pure red-cell aplasia that is due to the presence of antierythropoietin antibodies is only rarely self-limiting, and management of this condition has been problematic.9 Treatment with immunosuppressive agents has cured some cases,9 but reexposure to epoetins or darbepoetin alfa can re-induce the formation of antibodies.10 Anaphylactoid reactions after repeated injections of epoetin or darbepoetin alfa have been reported in a patient with pure red-cell aplasia.11
The observation that a peptide can act as an erythropoietin-receptor agonist, and thereby stimulate erythropoiesis, was reported in 1996, but the original peptide (EMP-1) was not developed as a therapeutic agent.12 Subsequently, a synthetic peptide-based erythropoietin-receptor agonist with an amino acid sequence that is unrelated to native or recombinant erythropoietin (Hematide, Affymax) was developed and was shown to stimulate erythropoiesis in vitro and in a variety of animal species.13 Results of phase 1 and phase 2 trials have shown that erythropoiesis can be stimulated in healthy volunteers and in patients with chronic kidney disease or cancer.14-17 (Editor's note: Readers can find detailed information on the structure and pharmacology of the agonist in Current Opinion in Investigational Drugs 2008;9:1034-47.)
Antierythropoietin antibodies do not inhibit the stimulation of erythroid-cell proliferation by the agonist in an erythroleukemia cell line or primary bone marrow culture.18 In a rat model of antibody-mediated pure red-cell aplasia, this erythropoietin-receptor agonist corrected the anemia that had been induced by antierythropoietin antibodies.18 In this article, we report the results of the use of this peptide-based erythropoietin-receptor agonist for the treatment of patients who have pure red-cell aplasia due to antierythropoietin antibodies.
Methods
Study Design
The primary objective of this open-label, single-group study was to determine whether the synthetic peptide-based erythropoietin-receptor agonist could increase and maintain hemoglobin levels above 11 g per deciliter without the need for red-cell transfusions in patients with antierythropoietin antibodies and pure red-cell aplasia. The effect of this agonist on the necessity for red-cell transfusions, the time required to correct anemia in the absence of transfusions, dose requirements, and safety were also assessed. We report here the results of the first 14 patients who were enrolled between March 23, 2006, and September 8, 2008, and were followed through March 31, 2009.
The trial was designed, implemented, and overseen by a steering committee that was composed of three nephrologists, a hematologist, a pharmacist, and two representatives of the sponsor (Affymax). The steering committee reviewed and confirmed the patients' eligibility for enrollment and reviewed emerging safety and efficacy data on a regular basis. Data were acquired and verified by each investigator, and Parexel International was contracted to check the accuracy and validity of the data according to International Conference on Harmonisation–Good Clinical Practice guidelines. One of the academic investigators wrote the first draft of the manuscript, and the steering committee made the decision to submit the manuscript for publication. All the authors contributed to the manuscript, approved the final version, and vouch for the completeness and accuracy of the data.
The study protocol was approved by the national health authorities in the United Kingdom, France, and Germany and by the local ethics committee at each site. All patients gave written informed consent, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
Eligibility
Patients were eligible for inclusion in the study if they were older than 18 years of age and if they had chronic kidney disease (with or without the need for dialysis) and pure red-cell aplasia or red-cell hypoplasia due to the presence of antierythropoietin antibodies. The steering committee verified that each patient had a documented history of severe erythroid hypoplasia or aplasia and had received a diagnosis of pure red-cell aplasia or hypoplasia on the basis of the results of bone marrow histopathological findings; were positive for antierythropoietin antibodies, as assessed with the use of a radioimmunoprecipitation assay5; had reticulocyte counts of less than 30×109 per liter; and had a decrease in hemoglobin concentration, or a need for red-cell transfusions, or both, while receiving a stable or increased dose of epoetin alfa, epoetin beta, or darbepoetin alfa. Some patients were receiving immunosuppressive therapy, which was to be discontinued at least 3 months before enrollment. Seven patients who received the diagnosis of pure red-cell aplasia shortly before entering the study had not been treated with immunosuppressive therapy. At the time of enrollment, patients had to be transfusion-dependent or have a hemoglobin concentration consistently below 11 g per deciliter. The major exclusion criteria were the presence of another hematologic disorder or other cause of pure red-cell aplasia or current treatment with an erythropoiesis-stimulating agent or immunosuppressive agent.
Treatment and Outcome Measures
Blood samples were obtained at baseline for a complete blood count and assessments of reticulocyte count, urea levels, electrolyte levels, liver-function values, iron status, and levels of antierythropoietin antibodies and antiagonist antibodies. Treatment with the synthetic peptide–based erythropoietin-receptor agonist was initiated at a dose of 0.05 mg per kilogram of body weight in 12 patients and 0.075 mg per kilogram in 2 patients (the protocol allowed for an initial dose up to 0.10 mg per kilogram). The agonist was administered by subcutaneous injection every 4 weeks, and the dose was adjusted on the basis of the specified target hemoglobin level. Initially, the target level was 11 to 13 g per deciliter, but it was changed to 11 to 12 g per deciliter in early 2007 after publication of the results of the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta trial (CREATE; ClinicalTrials.gov number, NCT00321919)19 and the Correction of Hemoglobin and Outcomes in Renal Insufficiency trial (CHOIR; NCT00211120),20 both of which were designed to study the correction of anemia in patients with chronic kidney disease, and the updated recommendations of Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation.21
Patients were required to travel to the study center in their country of residence for regular monitoring and to receive the agonist. Hemoglobin and reticulocyte counts were performed weekly, and samples were obtained monthly for liver-function tests and for measurement of urea and electrolyte levels and levels of antierythropoietin and antiagonist antibodies.
The antiagonist antibody assay was performed in the laboratories of Affymax (Palo Alto, CA) and Pharmaceutical Product Development (Richmond, VA) with the use of an enzyme-linked immunosorbent assay, with a sensitivity of 225 to 300 ng per milliliter.13,18 Agonist-neutralizing antibodies were detected with the use of a cell-proliferation assay. To determine whether antierythropoietin antibodies cross-reacted with the erythropoietin-receptor agonist, serum from three patients was tested in bone marrow cultures established from healthy human donors.22 Culture conditions included a final concentration of 20% fetal-calf serum or the patient's serum, and included 1 IU per milliliter of recombinant human erythropoietin or 0.55 μg per milliliter of the agonist (a concentration that was previously shown to be equivalent to 1 IU per milliliter of erythropoietin for erythroid growth). Erythroid colonies were counted on day 7.
Adverse events were assessed by the investigators, who recorded the intensity of the event (according to the World Health Organization [WHO] toxicity criteria23), the relation of the event to the study drug, the action taken, and the outcome of the event. The definition of a serious adverse event according to the criteria of the International Conference on Harmonisation (ICH) can be found in the legend to Table 2 in the Supplementary Appendix, available with the full text of this article at NEJM.org.23,24
Statistical Analysis
On the basis of the investigators' estimate of the maximum number of potentially eligible patients with access to the study centers, the study was designed to enroll 5 to 20 patients with pure red-cell aplasia due to antierythropoietin antibodies. Patients were to be treated for an initial 6-month period; if their response was considered to be satisfactory (see below), administration of the agonist could be extended for up to an additional 54 months. All patients were included in the safety and efficacy analyses through 1 month after discontinuation of the study drug or through March 31, 2009. Results were summarized with the use of descriptive statistics, and data are presented as medians, interquartile ranges, and ranges.
Results
Patients and Baseline Characteristics
A total of 14 eligible patients were enrolled consecutively between March 23, 2006, and September 8, 2008: 6 in Germany, 4 in the United Kingdom, and 4 in France. Results are reported through March 31, 2009, at which time the median duration of treatment was 28 months (range, 3 to 36). Of the 14 patients, 9 were undergoing dialysis (7 were undergoing hemodialysis, and 2 peritoneal dialysis), and 5 did not require renal-replacement therapy at the time of enrollment. The median age at enrollment was 72 years (range, 38 to 91), and 9 of the 14 patients were men. Twelve patients had received transfusions of a median of 8 units of red cells during the 3 months before entry (Table 1 in the Supplementary Appendix), and 12 patients had a serum ferritin level higher than 1000 ng per milliliter. Before treatment, the median hemoglobin concentration was 9.0 g per deciliter (range, 7.5 to 10.8), and reticulocyte counts were 10×109 per liter (range, 0 to 70×109). Antierythropoietin antibodies were detected in all the patients. The bone marrow findings in 11 patients were consistent with pure red-cell aplasia. In three patients (Patients 3, 4 and 7; see Table 1 in the Supplementary Appendix), erythropoiesis was present in the marrow, but red-cell hypoplasia was evident. Of these three patients, the diagnosis of pure red-cell aplasia in one (Patient 3) was based on a low reticulocyte count and the presence of antierythropoietin antibodies; Patient 4 had previously received a diagnosis of pure red-cell aplasia and had a relapse after reexposure to epoetin, as evidenced by an increase in antierythropoietin-antibody levels and a fall in hemoglobin concentration; Patient 7 had received a diagnosis of pure red-cell aplasia 6 months before enrollment and was transfusion-dependent; his reticulocyte count was 31×109 to 70×109 per liter before his entry into the study.
Bone Marrow Cultures
In the presence of 1 IU per milliliter of erythropoietin, serum from three patients completely inhibited erythroid growth (Fig. 1 in the Supplementary Appendix). In contrast, erythroid differentiation was observed under the same conditions when the agonist (0.55 μg per milliliter) was added to the cultures.
Results of Treatment
Of the 14 patients, 13 reached the primary end point of a hemoglobin concentration above 11 g per deciliter without regular transfusions. The median duration of treatment was 28 months. The reticulocyte count increased in all 14 patients within 2 weeks after each injection of the agonist, with the median peak counts increasing to greater than 100×109 per liter (the median baseline value was 10×109 per liter) (Figure 1Figure 1
Changes in Median Reticulocyte Counts during the First 6 Months of Treatment with a Novel, Synthetic, Peptide-Based Erythropoietin-Receptor Agonist.). The median hemoglobin concentration increased from 9.0 g per deciliter (often with support from red-cell transfusions) before treatment with the agonist to 11.4 g per deciliter at the time of the last administration of the agonist (Figure 2Figure 2Median Hemoglobin Concentrations and Number of Patients Receiving Red-Cell Transfusions over Time, after Subcutaneous Administration of a Novel, Synthetic, Peptide-Based Erythropoietin-Receptor Agonist Every 4 Weeks.); the median time to achievement of the primary end point was 11 weeks (range, 4 to 24). Over the course of the study, the dose of the agonist was increased from a median starting dose of 0.05 mg per kilogram per month (range, 0.05 to 0.075) to 0.10 mg per kilogram per month (range, 0.025 to 0.21) at the time the hemoglobin level reached the target range. The dose of the agonist was adjusted according to each patient's response (as determined by hemoglobin level); three patients who required more frequent dosing than usual to achieve the targeted hemoglobin levels received the agonist every 2 weeks on a temporary basis (two patients received one extra dose in 4 weeks and one patient had four extra doses in 16 weeks).After treatment with the erythropoietin-receptor agonist, transfusion requirements diminished, and most patients did not require transfusions after the first month of treatment (Figure 2). Two patients required regular transfusions through 4 and 6 months. After that time, four patients received transfusions transiently either during hospitalization for an intercurrent infection (which was due to renal transplantation complicated by cytomegalovirus infection in one patient and to tuberculous peritonitis in another) or during an interruption of agonist treatment in two patients who were unable to travel to the study site.
One patient (Patient 10) had an initial response to the synthetic peptide-based erythropoietin-receptor agonist, but within 3 months after the initiation of therapy, and despite increasing doses, the hemoglobin level and reticulocyte count steadily declined. Antiagonist binding and neutralizing antibodies were detected after approximately 4 months of therapy. After 6 months, the agonist was discontinued and treatment with red-cell transfusions was resumed. Antibodies against the agonist have not developed in the other 13 patients. Antierythropoietin antibodies persisted in 8 of the 14 patients, and the titers fell below the detection limit of the assay in 6 patients (data not shown).
At the time of data cutoff, the median ferritin levels had decreased from 1713 μg per liter (range, 229 to 6510) to 613 μg per liter (range, 168 to 3162), and the median transferrin saturation had decreased from 86% (range, 23 to 94) to 52% (range, 31 to 98).
Safety
Most adverse events were considered to be mild or moderate (i.e., grade 1 or 2, respectively), but eight patients had an event that was graded as severe (grade 3) or life-threatening (grade 4) during the study period; of these eight, seven had one or more serious adverse events, as defined according to ICH guidelines. One patient (Patient 8) had a fatal recurrent vascular event 4 months after stopping treatment, and one (Patient 10) had two serious events that required an intervention (a blood transfusion to treat severe anemia owing to a lack of response to the agonist). The other five patients had serious events that required or prolonged a hospitalization or required intervention, or both: Patient 2 had lower-extremity gangrene due to peripheral-artery disease; Patient 5 had optic ischemic neuropathy and endocarditis and underwent surgery for placement of an arteriovenous shunt; Patient 7 had atrial flutter requiring high-frequency ablation and a femoral artery aneurysm; Patient 11 had tuberculosis, peritoneal tuberculosis, a pseudoaneurysm, and pulmonary edema; and Patient 12 had cytomegalovirus infection, nephropathy, leukopenia, pneumonia, and bacteremia. Table 2 in the Supplementary Appendix lists all reported adverse events and identifies those that were serious or grade 3 or greater in severity.
Two patients were withdrawn from the study after undergoing kidney transplantation, and their data were censored at 3 months and 6 months, respectively.
Discussion
This study shows that a synthetic peptide-based erythropoietin-receptor agonist can stimulate erythropoiesis in patients with pure red-cell aplasia that is caused by the presence of antierythropoietin antibodies. Of the 14 patients, 13 reached the primary end point of an increase in hemoglobin to a level higher than 11 g per deciliter without regular blood transfusions. Although the number of patients we treated is small, the beneficial effect was durable in 13 of the 14 patients.
All the patients in this study had antierythropoietin antibodies that had developed during previous treatment with epoetin alfa, epoetin beta, or darbepoetin alfa (Table 1 in the Supplementary Appendix). Four patients with pure red-cell aplasia due to antierythropoietin antibodies had been transfusion-dependent for up to 6 years before enrollment. In three patients, pure red-cell aplasia had recurred when they were reexposed to epoetin after a fall in antibody titers. Other patients had received a diagnosis of pure red-cell aplasia shortly before entering the study, and several had not been treated with immunosuppressive therapy because previous experience has shown that the response of the disease to immunosuppressive agents is limited.4 In all the patients, the presence of antierythropoietin antibodies precluded further treatment with a conventional erythropoiesis-stimulating agent. In some patients, the early interruption of exposure to epoetin led to a reduction in antierythropoietin-antibody levels, with the result that they had red-cell hypoplasia in the bone marrow (rather than complete suppression of erythropoiesis) and required few or no red-cell transfusions before enrollment. Similar features have also been reported in other patients with antierythropoietin antibodies.25
In one patient who responded to the agonist initially, hemoglobin and reticulocyte concentrations diminished despite increasing doses of the agonist. Antibodies against the agonist were detected and red-cell transfusions were resumed. Pure red-cell aplasia originally developed in the patient after he had had only a relatively brief exposure to epoetin beta and darbepoetin alfa administered together. At study entry, the patient's antierythropoietin-antibody titer was the highest observed to date — approximately 30 times as high as the mean titer in 208 patients with pure red-cell aplasia whose samples have been evaluated in this laboratory (unpublished data). The patient had IgA nephropathy, but apart from antibody-mediated pure red-cell aplasia, he had no other evidence of an immune-mediated disease. Although the diminished hemoglobin response was associated with the presence of neutralizing antibodies, other contributory factors cannot be ruled out, and the reason for the patient's unusual immune response to different erythropoiesis-stimulating agents is unknown.
In the peptide-based erythropoietin-receptor agonist that we studied, the peptide portion is synthesized by traditional solid-phase technology, followed by conjugation to a novel linker–spacer attached to a high-molecular-weight polyethylene glycol moiety to increase in vivo persistence of the peptide. The peptide portion was generated by engineering chemical analogues from a family of peptide sequences that bind to the erythropoietin receptor. The synthetic peptide–based erythropoietin-receptor agonist acts in a manner similar to that of erythropoietin: it causes dimerization of the erythropoietin receptor and stimulation of Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-5 pathways of intracellular signaling.13 However, antierythropoietin antibodies do not neutralize the action of this agonist as they do the action of epoetins or darbepoetin alfa.18,25
Our findings suggest that this peptide-based erythropoietin-receptor agonist could be an alternative therapy for the management of anemia in patients who require an erythropoiesis-stimulating agent. The synthetic peptide-based erythropoietin-receptor agonist that we used appears to have a safety profile that is similar to that of other erythropoiesis-stimulating agents,14-17 but its long-term safety and adverse-event profile can be established only with the completion of ongoing phase 3 trials.
The concept that a synthetic peptide–based compound can mimic the biologic activity of a recombinant protein has implications for other biologic systems involving protein-receptor interactions. The development of a recombinant human thrombopoietin, for example, was discontinued because recipients formed neutralizing antibodies. Another approach to stimulating platelet production makes use of a mimetic molecule that, despite being structurally unrelated to thrombopoietin, activates the thrombopoietin receptor.26-28
The results of this study support the principle that a structurally unrelated peptide can mimic the biologic effects of a therapeutic protein and can stimulate a potent biologic response even in the presence of neutralizing antibodies to the therapeutic and endogenous proteins.
Dr. Macdougall reports receiving consulting fees, lecture fees, and grant support from Amgen, Ortho Biotech, Roche, Shire, and Affymax; Dr. Rossert, receiving consulting or lecture fees, or both, from Affymax, Amgen, Ortho Biotech, and Shire and grant support from Roche and being currently employed by Amgen; Dr. Casadevall, receiving consulting fees from Shire and consulting and lecture fees from Amgen, Ortho Biotech, and Roche; Dr. Stead, receiving consulting fees from Affymax and owning equity in Affymax and Amgen; Dr. Froissart, receiving consulting fees from Roche, Genzyme, and Hospira, consulting and lecture fees from Shire, and grant support from Affymax and Roche; and Dr. Eckardt, receiving consulting fees from Amgen, Ortho Biotech, Roche, Affymax, Stada, and Sandoz (Hexal) and lecture fees from Amgen, Ortho Biotech, and Roche. No other potential conflict of interest relevant to this article was reported.
We thank Dr. Curtis Johnson (Madison, WI) for his participation in the steering committee and his review of the manuscript; Dr. Beatriz Tucker (London), Dr. Christine Koch, Dr. Michaela Streubert, and Mrs. Ulrike Alberth-Schmidt (Erlangen) for their support at the three study centers; Dr. Peter Schatz (Affymax) for the assay for anti–Hematide antibodies and for the in vitro data; Dr. Kathryn Woodburn (Affymax) for the animal data; Martin Horowitz, Cristina Pulido, and Min-Jia Chen (Affymax) for compiling the data and preparing the figures; Anouk van Harten (Parexel International) for coordinating the implementation and monitoring of the study; the regulatory groups at Affymax and Parexel International for initiating and maintaining the necessary clinical trial applications; Deborah M. Lidgate (under contract to Affymax) for her technical assistance with the manuscript; and the nephrologists at the patients' own renal units for their support in the conduct of the trial.
Source Information
From the Department of Renal Medicine, King's College Hospital, London (I.C.M.); the Departments of Nephrology (J.R.) and Physiology (M.F.), Georges Pompidou European Hospital, Assistance Publique–Hôpitaux de Paris; Paris-Descartes University (J.R., M.F.); and the Department of Hematology, Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris and Pierre et Marie Curie University (N.C.) — all in Paris; INSERM Unité 790, Villejuif, France (N.C.); BioPharma Consulting Services, Bellevue, WA (R.B.S.); Affymax, Palo Alto, CA (A.-M.D.); and the Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany (K.-U.E.).
Address reprint requests to Dr. Macdougall at the Renal Unit, King's College Hospital, London SE5 9RS, United Kingdom, or at iain.macdougall@kch.nhs.uk.
- References
References
1
Bergrem H, Danielson BG, Eckardt KU, Kurtz A, Stridsberg M. A case of antierythropoietin antibodies following recombinant human erythropoietin treatment. In: Bauer C, Koch KM, Scigalia P, eds. Erythropoietin: molecular physiology and clinical application. New York: Marcel Dekker, 1993:266-75.
2
Peces R ,de la Torre M ,Alcazar R ,Urra JM . Antibodies against recombinant human erythropoietin in a patient with erythropoietin-resistant anemia. N Engl J Med 1996;335:523-524
Full Text | Web of Science | Medline3
Gershon SK ,Luksenburg H ,Cote TR ,Braun MM . Pure red-cell aplasia and recombinant erythropoietin. N Engl J Med 2002;346:1584-1585[Erratum, N Engl J Med 2002;347:458.]
Full Text | Web of Science | Medline4
Rossert J ,Casadevall N ,Eckardt KU . Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004;15:398-406
CrossRef | Web of Science | Medline5
Casadevall N ,Nataf J ,Viron B , et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469-475
Full Text | Web of Science | Medline6
Bennett CL ,Luminari S ,Nissenson AR , et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351:1403-1408
Full Text | Web of Science | Medline7
Howman R ,Kulkarni H . Antibody-mediated acquired pure red cell aplasia (PRCA) after treatment with darbepoetin. Nephrol Dial Transplant 2007;22:1462-1464
CrossRef | Web of Science | Medline8
Kaufman JS ,Reda DJ ,Fye CL , et al. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. N Engl J Med 1998;339:578-583
Full Text | Web of Science | Medline9
Verhelst D ,Rossert J ,Casadevall N ,Kruger A ,Eckardt KU ,Macdougall IC . Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004;363:1768-1771
CrossRef | Web of Science | Medline10
Andrade J ,Taylor PA ,Love JM ,Levin A . Successful reintroduction of a different erythropoiesis-stimulating agent after pure red cell aplasia: relapse after successful therapy with prednisone. Nephrol Dial Transplant 2005;20:2548-2551
CrossRef | Web of Science | Medline11
Weber G ,Gross J ,Kromminga A ,Loew HH ,Eckardt KU . Allergic skin and systemic reactions in a patient with pure red cell aplasia and anti-erythropoietin antibodies challenged with different epoetins. J Am Soc Nephrol 2002;13:2381-2383
CrossRef | Web of Science | Medline12
Wrighton NC ,Farrell FX ,Chang R , et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996;273:458-464
CrossRef | Web of Science | Medline13
Fan Q ,Leuther KK ,Holmes CP , et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006;34:1303-1311
CrossRef | Web of Science | Medline14
Stead RB ,Lambert J ,Wessels D , et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood 2006;108:1830-1834
CrossRef | Web of Science | Medline15
Macdougall IC, Tucker B, Yaqoob M, et al. Hematide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), achieves correction of anemia and maintains hemoglobin (Hb) in patients with chronic kidney disease (chronic renal failure) not on dialysis. Presented at the American Society of Nephrology 11th Annual Renal Week, San Diego, CA, November 14–19 2006.
16
Besarab A, Zeig S, Geronemus R, et al. Hematide, a synthetic peptide-based erythropoiesis stimulating agent, maintains hemoglobin in hemodialysis patients previously treated epoetin alfa (erythropoietin). Presented at the National Kidney Foundation Spring Clinical Meeting, Orlando, FL, April 10–14 2007.
17
Pickering LM ,Cwiertka K ,Jassem J , et al. Hematide, a synthetic peptide-based erythropoiesis stimulating agent (ESA), assessed for correction of anemia in oncology patients receiving chemotherapy. Blood 2006;108:378a-378a
Web of Science18
Woodburn KW ,Fan Q ,Winslow S , et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol 2007;35:1201-1208
CrossRef | Web of Science | Medline19
Drueke TB ,Locatelli F ,Clyne N , et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-2084
Full Text | Web of Science | Medline20
Singh AK ,Szczech L ,Tang KL , et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098
Full Text | Web of Science | Medline21
KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis 2007;50:471-530
CrossRef | Web of Science | Medline22
Casadevall N ,Dupuy E ,Molho-Sabatier P ,Tobelem G ,Varet B ,Mayeux P . Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 1996;334:630-633
Full Text | Web of Science | Medline23
World Health Organization Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, WHO Offset Publication No. 48, 1979.
24
Guideline for industry: clinical safety data management: definitions and standards for expedited reporting. No. ICH-E2A. Silver Spring, MD: Food and Drug Administration, March 1995. (Accessed October 9, 2009, at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf.)
25
Casadevall N ,Rossert J ,Swanson S , et al. Anti-erythropoietin antibodies (Abs) not associated with pure red cell aplasia (PRCA), in patients treated with erythropoiesis-stimulating agents (ESAs). J Am Soc Nephrol 2004;15:545A-545A26
Bussel JB ,Kuter DJ ,George JN , et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006;355:1672-1681[Erratum, N Engl J Med 2006;355:2054.]
Full Text | Web of Science | Medline27
Bromberg ME . Immune thrombocytopenic purpura -- the changing therapeutic landscape. N Engl J Med 2006;355:1643-1645
Full Text | Web of Science | Medline28
Cwirla SE ,Balasubramanian P ,Duffin DJ , et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 1997;276:1696-1699
CrossRef | Web of Science | Medline
- Citing Articles (26)
Citing Articles
1
Paul McGonigle. (2012) Peptide therapeutics for CNS indications. Biochemical Pharmacology 83:5, 559-566
CrossRef2
J. Huang, B. Ru, P. Zhu, F. Nie, J. Yang, X. Wang, P. Dai, H. Lin, F.-B. Guo, N. Rao. (2012) MimoDB 2.0: a mimotope database and beyond. Nucleic Acids Research 40:D1, D271-D277
CrossRef3
Li Ding, Allen Mo, Kamonwan Jutivorakool, Minjal Pancholi, Steven M. Holland, Sarah K. Browne. (2011) Determination of Human Anticytokine Autoantibody Profiles Using a Particle-Based Approach. Journal of Clinical Immunology
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Iain C. Macdougall. (2011) New Anemia Therapies: Translating Novel Strategies From Bench to Bedside. American Journal of Kidney Diseases
CrossRef5
S. Chateauvieux, C. Grigorakaki, F. Morceau, M. Dicato, M. Diederich. (2011) Erythropoietin, erythropoiesis and beyond. Biochemical Pharmacology 82:10, 1291-1303
CrossRef6
Manfred Nairz, Thomas Sonnweber, Andrea Schroll, Igor Theurl, Günter Weiss. (2011) The pleiotropic effects of erythropoietin in infection and inflammation. Microbes and Infection
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Stephan Haehling, Markus S. Anker, Ewa A. Jankowska, Piotr Ponikowski, Stefan D. Anker. (2011) Anemia in chronic heart failure: Can we treat? What to treat?. Heart Failure Reviews
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Anatole Besarab. (2011) Anemia and Iron Management. Seminars in Dialysis 24:5, 498-503
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W. Jelkmann, C. Lundby. (2011) Blood doping and its detection. Blood 118:9, 2395-2404
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Ines Möller, Andreas Thomas, Hans Geyer, Wilhelm Schänzer, Mario Thevis. (2011) Synthesis, characterisation, and mass spectrometric detection of a pegylated EPO-mimetic peptide for sports drug testing purposes. Rapid Communications in Mass Spectrometry 25:15, 2115-2123
CrossRef11
Christian Reichel. (2011) Recent developments in doping testing for erythropoietin. Analytical and Bioanalytical Chemistry 401:2, 463-481
CrossRef12
Jay B Wish. (2011) Erythropoiesis-stimulating agents and pure red-cell aplasia: you can’t fool Mother Nature. Kidney International 80:1, 11-13
CrossRef13
Iain C. Macdougall. (2011) Anaemia and chronic renal failure. Medicine 39:7, 425-428
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Y. Ciccarella, C. Balestra, J. Valsamis, P. Van der Linden. (2011) Increase in endogenous erythropoietin synthesis through the normobaric oxygen paradox in cardiac surgery patients. British Journal of Anaesthesia 106:5, 752-753
CrossRef15
C. G. Ullman, L. Frigotto, R. N. Cooley. (2011) In vitro methods for peptide display and their applications. Briefings in Functional Genomics 10:3, 125-134
CrossRef16
Nadine Conzelmann, Armin Schneider. (2011) A screen for peptide agonists of the G-CSF receptor. BMC Research Notes 4:1, 194
CrossRef17
Semira Sheikh, Tim J Littlewood. (2010) Erythropoiesis-stimulating agents for anemic patients with cancer. Expert Review of Hematology 3:6, 697-704
CrossRef18
Sarah K Browne, Steven M Holland. (2010) Immunodeficiency secondary to anticytokine autoantibodies. Current Opinion in Allergy and Clinical Immunology 10:6, 534-541
CrossRef19
Sarah K Browne, Steven M Holland. (2010) Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms. The Lancet Infectious Diseases 10:12, 875-885
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Wolfgang Jelkmann. (2010) Biosimilar epoetins and other “follow-on” biologics: Update on the European experiences. American Journal of Hematology 85:10, 771-780
CrossRef21
Daisuke Katagiri, Maki Shibata, Takashi Katsuki, Shoichi Masumoto, Ai Katsuma, Eri Minami, Taro Hoshino, Tsuyoshi Inoue, Manami Tada, Fumihiko Hinoshita. (2010) Antiepoetin antibody-related pure red cell aplasia: successful remission with cessation of recombinant erythropoietin alone. Clinical and Experimental Nephrology 14:5, 501-505
CrossRef22
Robert N. Foley. (2010) Emerging erythropoiesis-stimulating agents. Nature Reviews Nephrology 6:4, 218-223
CrossRef23
(2010) A Peptide-Based Erythropoietin-Receptor Agonist for Pure Red-Cell Aplasia. New England Journal of Medicine 362:7, 656-657
Full Text24
Baldo Lucchese. (2010) Chronic kidney disease: New hope for patients with pure red-cell aplasia or hypoplasia. Nature Reviews Nephrology 6:2, 65-65
CrossRef25
(2010) Journal Club. Kidney International 77:2, 81-82
CrossRef26
Bunn, H. Franklin, . (2009) End Run around Epo. New England Journal of Medicine 361:19, 1901-1903
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