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Article Peginesatide for Maintenance Treatment of Anemia In Article Peginesatide for Maintenance Treatment of Anemia in Hemodialysis and Nondialysis Patients Previously Treated with Darbepoetin Alfa | Steven Fishbane,* Simon D. Roger,† Edouard Martin,‡ Grant Runyan,§ Janet O’Neil,§ Ping Qiu,§ and Francesco Locatelli Summary Background and objectives Peginesatide (Omontys) is a novel, synthetic, PEGylated, peptide-based erythropoiesis- *Hofstra North Shore– fi Long Island Jewish stimulating agent (ESA) that is designed to speci cally stimulate the erythropoietin receptor. This study eval- School of Medicine, uated maintenance of hemoglobin levels in patients after conversion from darbepoetin alfa to once-monthly Great Neck, New peginesatide. York; †Gosford Hospital, Gosford, New South Wales, Design, setting, participants, & measurements This open-label, multicenter study included 101 CKD patients, 52 Australia; ‡South of whom were receiving dialysis. The duration of the study was 24 weeks. The primary endpoint was the mean Florida Nephrology change in hemoglobin from baseline to the evaluation period (weeks 19–24). The study was conducted during the Associates, period from September 22, 2008 to December 24, 2009. Lauderdale Lakes, Florida; §Takeda – fi – – Global Research & Results The mean change among hemodialysis patients was 0.42 g/dl (95% con dence interval, 0.65 to 0.19) Development Center and the mean change among CKD nondialysis patients was 0.49 g/dl (95% confidence interval, 0.26–0.71). The Inc, Deerfield, Illinois; | percentages of patients who maintained hemoglobin levels within 61.0 g/dl of baseline values were as follows: and Department of 80.0% for hemodialysis and 68.1% for nondialysis, and73.3% for hemodialysis and 68.1% for nondialysis within Nephrology, Manzoni Hospital, Lecco, Italy the target range of 10.0–12.0 g/dl. Few patients received red blood cell transfusions (hemodialysis, 5.8%; non- dialysis, 2.0%). Seventy-nine patients experienced adverse events, the majority of which were mild or moderate in Correspondence: severity. There were 40 serious adverse events and 2 deaths reported. Dr. Steven Fishbane, Hofstra North Shore– Conclusions In this study, once-monthly peginesatide resulted in a slight decrease in mean hemoglobin levels in Long Island Jewish individuals on hemodialysis and a small increase in individuals with CKD who were not on dialysis. School of Medicine, – 100 Community Clin J Am Soc Nephrol 8: 538 545, 2013. doi: 10.2215/CJN.03440412 Drive, Second Floor, Great Neck, NY 11021. Email: Introduction recombinant erythropoietin proteins, and therefore sfi[email protected] CKD is a worldwide health problem with increasing have the potential to induce anti-erythropoietin anti- incidence and prevalence (1). Anemia associated with bodies and pure red cell aplasia (16). The first ap- CKD is primarily caused by the inability of the diseased proved ESA, epoetin alfa, is administered up to three kidneys to produce adequate amounts of endogenous times per week (17). The frequent dosing requirement erythropoietin (2). The prevalence of anemia increases is often burdensome to patients and health care provid- with progressive deterioration of renal function, and ers, and new agents allowing for less frequent dosing anemia affects .90% of patients with ESRD (3). are desired. Less frequent dosing of ESAs could poten- Anemia is associated with increased mortality (4), tially allow more time for physicians and nurses to increased likelihood of hospitalization (5), increased address other issues in patients (18); although this is left ventricular hypertrophy and heart failure (6), and de- particularly true in nondialysis patients, less frequent creased quality of life (7,8). Erythropoiesis-stimulating dosing could also decrease the time nurses spend pre- agents (ESAs) are an effective treatment for CKD- paring and injecting ESAs in dialysis patients. Darbe- associated anemia and have improved the manage- poetin alfa, although administered less frequently than ment of anemia over alternatives such as transfusion. epoetin alfa, is dosed up to once per week in dialysis The use of ESAs has been associated with transfu- patients (19). Although methoxy polyethylene glycol- sion avoidance, decreased hospitalization, and—in epoetin b, a once-monthly ESA, is available in Europe some reports—an improved quality of life (9–12). In (20) and in other parts of the world, it is currently not contrast, the use of ESAs to target near normal hemo- available in the United States; it is also a recombinant globin (Hb) levels for extended periods of time has erythropoietin protein. been associated with adverse cardiovascular outcomes, Peginesatide (Omontys) is a synthetic, PEGylated, an increased risk of death, and increase in thrombotic peptide-based ESA that is designed to specifically events (13–15). To date, all available ESAs have been stimulate the erythropoietin receptor. The amino acid 538 Copyright © 2013 by the American Society of Nephrology www.cjasn.org Vol 8 April, 2013 Clin J Am Soc Nephrol 8: 538–545, April, 2013 Peginesatide Maintenance Treatment, Fishbane et al. 539 sequence of peginesatide is unrelated to that of erythropoi- etin. The PEGylation of the peptide and its extended Table 1. Peginesatide starting doses erythropoietic activity (21) allows for a once-monthly dosing Darbepoetin Alfa interval. Results from the phase 3 peginesatide program Starting Peginesatide Dose during Screening Dose (mg/kg once-monthly) have shown that peginesatide effectively maintained Hb lev- (mg/kg per week) els after conversion from epoetin in CKD dialysis patients with once-monthly administration (22,23). ,0.5 0.04 The purpose of this study was to demonstrate whether 0.5 to ,1.0 0.08 once-monthly peginesatide treatment could maintain Hb 1.0 to ,1.5 0.12 $ levels in CKD hemodialysis patients (HD) and CKD 1.5 0.16 nondialysis patients (CKD-ND) after conversion from dar- bepoetin alfa treatment. The safety of peginesatide was also assessed. maintain Hb levels in the range of 10.0–12.0 g/dl and within 61.5 g/dl of baseline (i.e., the mean of the four most recent Hb values taken before enrollment and the value on the day Materials and Methods of enrollment). Iron levels were recommended to be main- Study Population tained according to the Kidney Disease Outcomes Quality The study included adult HD and CKD-ND patients who Initiative treatment guidelines. Patient visits occurred every were receiving stable doses of darbepoetin alfa for at least 8 otherweekduringthetitrationperiodandeveryweekdur- weeks before enrollment. Patients were also required to ing the evaluation period. have stable Hb levels and adequate iron stores (see Sup- plemental Table 1 for a list of key eligibility criteria). Key Study Drug Hb and iron entry criteria included the following: four Peginesatide (Affymax Inc, Palo Alto, CA) was supplied consecutive Hb values with a mean $10.0 and #12.0 g/ as an aqueous, phosphate-buffered, isotonic, sorbitol so- dl during the screening period, with the difference be- lution (pH approximately 6.0). Each single-use glass vial tween the mean of the first two consecutive Hb values contained 1 ml of solution at a peginesatide concentration and the mean of the last two consecutive values being of 10 mg/ml. The formulation included polysorbate 20 as a #1.0 g/dl, and ferritin .100 ng/ml. The following comor- surfactant. Vials were stored at 2°C–8°C. bidities were excluded: known bleeding or coagulation disorder, poorly controlled hypertension within 4 weeks before enrollment, advanced chronic congestive heart fail- Assessments ure (CHF) defined by New York Heart Association class III At each study visit, Hb, concomitant medications, in- or IV, uncontrolled or symptomatic inflammatory disease, formation about transfusions and therapeutic phleboto- seizure disorder, or active malignancy. Patients provided mies, and adverse events (AEs) were assessed. All reported written informed consent before participating in any AEs were graded by severity with the use of the National study-specific procedures. The protocol was approved by Cancer Institute Common Terminology Criteria for Ad- – the independent ethics committees of the participating verse Events (version 3.0) (i.e., grades 1 5) (24). Events centers (see protocol at ClinicalTrials.gov; identifier graded as 1 or 2 were considered mild and moderate, re- NCT00752609). The study was conducted in accordance spectively. Each AE and serious adverse event (SAE) was with the Declaration of Helsinki (2002 version), the Inter- assessed by the investigators as related or unrelated to the national Conference on Harmonization Good Clinical study drug. Each month, blood chemistry and hematology Practice Guidelines, and all applicable regulatory require- panel, serum pregnancy test, vital signs, and samples for fi ments. assessment of peginesatide-speci c antibodies were col- lected. Iron status evaluation and physical examination Study Design This was an open-label, multicenter, single-arm study to evaluate the conversion from darbepoetin alfa to peginesa- Table 2. Regimen for dose adjustments tide in HD and CKD-ND patients. The study consisted of a screening period (week 26 to week 21), enrollment (day Hemoglobin Level Action – 1/week 0), a titration period (weeks 0 18), and an evalu- , – fi 9.5 g/dl or decrease of 25% dose increase ation period (weeks 19 24). Patients received their rst 1.0–1.5 g/dl from dose of peginesatide during enrollment, which occurred baseline on the day that the patient was to receive his or her next Decrease of .1.5 g/dl 50% dose increase scheduled dose of darbepoetin alfa. Peginesatide starting from baseline doses were determined with the use of a tiered weight- $12.0 g/dl 25% dose decrease based dose conversion table (Table 1). Peginesatide was $12.5 g/dl Dose delay until administered via thesameroute(i.e., subcutaneous or intra- hemoglobin was ,12.5 venous) as each patient’s previous dose of darbepoetin alfa. g/dl; 25% dose decrease Thereafter, peginesatide was administered at 4-week inter- on recommencement Increase of .1.0 g/dl 25% dose decrease vals throughout the study duration.
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