Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model

Woodburn, Kathryn W.; Fan, Qing; Winslow, Susan; Chen, Minjia; Mortensen, Richard B.; Casadevall, Nicole; Stead, Richard B.; Schatz, Peter J.

doi:10.1016/j.exphem.2007.05.007

Cited by 53 publications

(40 citation statements)

References 15 publications

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“…Second, patients with antibody-mediated pure red cell aplasia should be able to respond to Hematide therapy by an increase in their hemoglobin concentration, because Hematide is not neutralized by anti-EPO antibodies. This latter hypothesis has already been confirmed in animals (46). Rats that received regular injections of recombinant human EPO were shown to develop anti-EPO antibodies.…”

Section: Peptide-based Esassupporting

confidence: 61%

Novel Erythropoiesis-Stimulating Agents

Macdougall

2008

Clinical Journal of the American Society of Nephrology

102

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Nearly two decades ago, recombinant human erythropoietin transformed the management of chronic kidney disease anemia by allowing a more sustained increase in hemoglobin than was possible by intermittent blood transfusion. The treatment was highly effective, but because of the fairly short half-life of the molecule at approximately 6 to 8 h, injections usually had to be administered two to three times weekly. A second-generation erythropoietin analogue, darbepoetin alfa, was then created, with a longer elimination half-life in vivo that translated into less frequent dosing, usually once weekly or once every 2 wk. More recently, another erythropoietin-related molecule has been produced called Continuous Erythropoietin Receptor Activator with an even greater half-life, and other molecules are in development or are being licensed, including biosimilar epoetin products and Hematide. The latter is a synthetic peptide-based erythropoietin receptor agonist that, interestingly, has no structural homology with erythropoietin, and yet is still able to activate the erythropoietin receptor and stimulate erythropoiesis. The search goes on for orally active antianemic therapies, and several strategies are being investigated, although none is imminently available. This article reviews the latest progress with these novel erythropoietic agents in this new era in anemia management.

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Section: Peptide-based Esassupporting

confidence: 61%

Novel Erythropoiesis-Stimulating Agents

Macdougall

2008

Clinical Journal of the American Society of Nephrology

102

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“…The antibody titers were low and did not appear to affect the patients' Hb concentrations or safety profiles; however, this study did not have long-term follow-up of these patients. Importantly, given the lack of immunological cross-reactivity of peginesatide with erythropoietin (20), the potential risk of inducing antibodymediated PRCA with peginesatide is extremely low. No patients with peginesatide-induced PRCA have been reported during clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Dose-finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients

Macdougall

Wiȩcek

Tucker

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesisstimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients.Design, setting, participants, & measurements Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks).Results Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions Ͼ13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population.Conclusions This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.

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“…In the clinical setting, recombinant EPO ESAs have been associated with the development of anti-EPO antibody-mediated pure red cell aplasia (PRCA). 5 By virtue of this lack of immunological cross-reactivity, hematide corrects anemia in rats with PRCA, 5 and restores Hgb to the target range in PRCA patients while eliminating the need for red blood cell transfusions. 6 This is the first study in which an exogenous ESA has been evaluated following long-term administration to normocythemic adult animals without data being confounded by extramedullary hematopoiesis, as occurs in rodents, 4,7,8 and immunogenic interference, as is the case for human EPO variants.…”

Section: Introductionmentioning

confidence: 99%

Chronic preclinical safety evaluation of HematideTM, a pegylated peptidic erythropoiesis stimulating agent in monkeys

Woodburn¹,

Wilson²,

Fong³

et al. 2008

Haematologica

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Hematide is a synthetic peptide-based, pegylated erythropoiesis stimulating agent in clinical development for treatment of anemia. To support chronic clinical dosing requirements, a 9-month repeat dose IV monkey safety study was undertaken. Animals received 0, 0.2, 2 or 20 mg/kg hematide IV every three weeks for nine months followed by a 14-week recovery. Hematide administration was associated with time and dose-dependent polycythemia. Histological findings were related to exaggerated pharmacology that was secondary to the administration of an erythropoiesis stimulating agent to a normocythemic animal. In conclusion, these results support the use of repeated administration of hematide for the correction of anemia.

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Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model

Cited by 53 publications

References 15 publications

Novel Erythropoiesis-Stimulating Agents

Novel Erythropoiesis-Stimulating Agents

Dose-finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients

Chronic preclinical safety evaluation of HematideTM, a pegylated peptidic erythropoiesis stimulating agent in monkeys

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