Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia

Fan, Qing; Leuther, Kerstin K.; Holmes, Christopher P.; Fong, Kei-Lai; Zhang, Junfeng Jim; Velkovska, Svetlana; Chen, Minjia; Mortensen, Richard B.; Leu, Karen; Green, Jennifer M.; Schatz, Peter J.; Woodburn, Kathryn W.

doi:10.1016/j.exphem.2006.05.012

Cited by 109 publications

(100 citation statements)

References 18 publications

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“…Peginesatide is a synthetic, PEGylated, investigational, peptide-based ESA that acts via stimulation of the erythropoietin receptor (8). In a study of healthy volunteers, peginesatide was well tolerated and associated with a clinically and statistically significant increase in hemoglobin (Hb) that was sustained for Ͼ1 month (9).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Mircera ® is approved to treat anemia associated with CKD in Europe. Hematide is a synthetic ESA comprised of nonnaturally occurring amino acids in a dipeptide that binds to the EPO receptor, thereby activating it [63,64]. The peptide was pegylated to increase serum half-life and is currently in clinical development.…”

Section: Other Esasmentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

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Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesisstimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivospecific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

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“…2 Hematide is a synthetic peptide-based, PEGylated ESA that was designed to specifically bind and activate the erythropoietin (EPO) receptor resulting in production of red blood cells. 3,4 Hematide's amino acid sequence is unrelated to EPO and, as a result is not likely to induce a cross-reactive immune response against either recombinant or endogenous EPO. In the clinical setting, recombinant EPO ESAs have been associated with the development of anti-EPO antibody-mediated pure red cell aplasia (PRCA).…”

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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Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia

Cited by 109 publications

References 18 publications

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

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

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

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

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