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

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Dose-Finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients Article Article Dose-finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients Iain C. Macdougall,* Andrzej Wiecek,† Beatriz Tucker,‡ Magdi Yaqoob,§ Ashraf Mikhail, Michal Nowicki,¶ Iain MacPhee,** Michal Mysliwiec,†† Olgierd Smolenski,‡‡ Władysław Sułowicz,§§ Martha Mayo, Carol Francisco, *Renal Unit, King’s Krishna R. Polu, Peter J. Schatz, and Anne-Marie Duliege College Hospital, London, United Kingdom; †Department Summary of Nephrology, Background and objectives Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis- Endocrinology and stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a popu- Metabolic Diseases, Medical University of lation of 139 nondialysis chronic kidney disease patients. Silesia, Katowice, Poland; ‡Mayday Design, setting, participants, & measurements Chronic kidney disease patients who were not on dialysis and University Hospital, not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug adminis- Croydon, United Kingdom; §Department tration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (dif- of Nephrology, ferent body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and Hypertension and frequency of administration (every 4 or 2 weeks). Kidney Transplant, Royal London Hospital, London, United Results Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship Kingdom; ʈRenal was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses pro- Medicine, Morriston duced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions Ͼ13 g/dl Hospital, Swansea, tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The United Kingdom; ¶Department of range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all co- Nephrology, horts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious Hypertension and event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were Kidney Transplant, consistent with those routinely observed in this patient population. Medical University of Lodz, Poland; **Renal Medicine, St. George’s Conclusions This study suggests that peginesatide administered every 4 weeks can increase and maintain Hospital, London, hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of United Kingdom; †† patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimu- Department of lating agent. Nephrology and Transplantation, Clin J Am Soc Nephrol 6: 2579–2586, 2011. doi: 10.2215/CJN.10831210 Wojewo´dzki Szpital Specjalistyczny, Bialystok, Poland; ‡‡Department of Introduction Peginesatide is a synthetic, PEGylated, investiga- Nephrology, Anemia in patients with chronic kidney disease tional, peptide-based ESA that acts via stimulation of Wojewo´dzki Szpital (CKD) is often accompanied by a decreased quality of the erythropoietin receptor (8). In a study of healthy Specjalistyczny, life and an increased risk of red blood cell (RBC) volunteers, peginesatide was well tolerated and associ- Krakow, Poland; §§Department of transfusions (1,2). The mainstay of treatment for this ated with a clinically and statistically significant increase Nephrology, Oddział condition is erythropoietin-replacement therapy with in hemoglobin (Hb) that was sustained for Ͼ1 month Kliniczny Kliniki an erythropoiesis-stimulating agent (ESA), which has (9). Because the amino acid sequence of peginesatide is Nefrologii Szpitala Uniwersyteckiego, been associated with an improved quality of life (3) unrelated to that of erythropoietin, peginesatide is un- Krakow, Poland; and and fewer RBC transfusions (4). Several ESAs are likely to induce a cross-reactive immune response ʈʈAffymax, Inc., Palo currently available in the United States and Europe against either endogenous or recombinant erythropoie- Alto, California for the correction of anemia in CKD, but these agents tin. Indeed, a clinical study of peginesatide showed that are approved for dosing three times per week (such as it increased the Hb in most patients with antierythro- Correspondence: Prof. Iain C. Macdougall, epoetin alfa) or dosing every 2 weeks (such as darbe- poietin antibody-mediated pure red cell aplasia (PRCA) Renal Unit, King’s poetin alfa) (5–7). Another ESA (methoxy polyethyl- from protein-based ESAs (10). College Hospital, ene glycol-epoetin beta) is approved and marketed These preliminary findings supported further London SE5 9RS, UK. for dosing every 2 weeks to once monthly in Europe. study in a broader population of nondialysis CKD Phone: 44-203-299- 6233; Fax: 44-203-299- These large protein-based molecules require complex patients who were anemic. Most patients in this study 6472; E-mail: manufacturing processes using recombinant DNA received every-4-weeks dosing with peginesatide iain.macdougall technology and mammalian cell lines. from the outset. The primary objective of the study @nhs.net www.cjasn.org Vol 6 November, 2011 Copyright © 2011 by the American Society of Nephrology 2579 2580 Clinical Journal of the American Society of Nephrology was to determine the range of peginesatide doses that in a long-term extension study were followed for 28 days increase and maintain Hb between 11 and 13 g/dl, an after their last peginesatide dose, until the stabilization of acceptable Hb range when the study was conducted. The AEs, or until Hb concentration was Ͻ13.0 g/dl, whichever safety and tolerability of peginesatide were also evaluated. occurred later. Materials and Methods Study Drug TM Study Population Peginesatide (Hematide ; Affymax, Inc., Palo Alto, The study included adult patients with CKD stage 3 or 4 CA) was supplied as a preservative-free, aseptically man- (estimated GFR of Յ60 ml/min per 1.73 m2). Before study ufactured, sterile parenteral isotonic phosphate-buffered drug administration, patients were required to have two solution in a single-use vial. Hb values from 9.0 to Ͻ11.0 g/dl and adequate iron stores (serum ferritin concentration Ն100 ng/ml and transferrin Assessments saturation [TSAT] Ն20%). The main exclusion criteria in- Pharmacodynamic response was assessed by the per- cluded ESA treatment in the 12 weeks before study drug centage of patients in each cohort who achieved a Hb administration and previous hemodialysis or peritoneal response, defined as a Hb increase of Ն1.0 g/dl from dialysis. A complete list of eligibility criteria is provided in baseline (mean of the three Hb values [two screening and Supplementary Table 1. one predose] collected most recently before the first pegi- nesatide dose) and a Hb value of Ն11.0 g/dl at any time Study Design during the study. Other pharmacodynamic parameters This was a phase 2, multicenter, open-label, sequential, were the mean changes from baseline in Hb and reticulo- dose-finding study conducted at six sites in the United cyte counts, and the percentages of patients during the first Kingdom and seven sites in Poland. All of the sites re- 8 weeks of the study who experienced rapid rates of Hb Ͼ Ͼ ceived approval from their ethics committee/institutional increase ( 1 g/dl increase in any 2-week period or 2 review board, all of the patients provided written informed g/dl increase in any 4-week period) and elevated Hb ex- Ͼ consent, and the study was performed in accordance with cursions (Hb 13 g/dl). Hemoglobin data collected sub- the Declaration of Helsinki and the International Confer- sequent to a phlebotomy, or within 4 weeks after a RBC ence on Harmonisation Guidelines for Good Clinical Prac- transfusion, were excluded. tice. The study was registered with ClinicalTrials.gov Safety was assessed from AE reports. AE severity was (NCT00228436). graded according to the World Health Organization Tox- The study design allowed for multiple cohorts of pa- icity Criteria (grades 1 to 4; grades 1 and 2 were considered tients, with Յ15 patients sequentially enrolled in each. mild and moderate, respectively). The main serious AEs Patients received peginesatide treatment for Յ24 weeks. (SAEs) were fatal, life-threatening, or required hospitaliza- Ͼ Cohorts differed in starting peginesatide dose (body tion ( 24 hours). Each AE and SAE was assessed by the weight–based or absolute doses), route of administration investigators as being either related or unrelated to the (intravenous [IV] or subcutaneous [SC]), and frequency of study drug. Other safety end points included reasons for administration (every 4 weeks [Q4W] or every 2 weeks study withdrawal, number of phlebotomies and RBC [Q2W]). In the first cohort, SC peginesatide was adminis- transfusions, changes in clinical laboratory results and vital tered Q4W (0.05 mg/kg starting dose). The decision to add signs, and antibody evaluations. the next cohort in the sequence was made on the basis of predetermined criteria including the observed safety Statistical Analyses and pharmacologic response for this cohort. After week 5, This was an exploratory study intended to characterize each patient’s peginesatide dose was adjusted on the basis the preliminary efficacy and safety of peginesatide and of prespecified dosing guidelines (Supplementary Table 2). inform dose selection
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