Article

Peginesatide for Maintenance Treatment of in Hemodialysis and Nondialysis Patients Previously Treated with

| Steven Fishbane,* Simon D. Roger,† Edouard Martin,‡ Grant Runyan,§ Janet O’Neil,§ Ping Qiu,§ and Francesco Locatelli

Summary Background and objectives (Omontys) is a novel, synthetic, PEGylated, peptide-based - *Hofstra North Shore– fi Long Island Jewish stimulating agent (ESA) that is designed to speci cally stimulate the 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 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, , 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 (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 - 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 . The

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 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- 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. During the titration over the level recorded and evaluation periods, peginesatide doses were adjusted 2 weeks prior according to the predetermined guidelines (Table 2) to 540 Clinical Journal of the American Society of Nephrology

were performed every 12 weeks. Hb and all clinical labo- antibodies. All safety results were summarized descriptively ratory tests were performed by a central laboratory. by group.

Statistical Analyses Results Patients who received at least one dose of the study drug Patient Disposition and Baseline and Demographic were included in all analyses. For all results, HD and CKD- Characteristics ND groups were listed separately. Baseline and demo- Patient disposition is provided in Figure 1. Of the 182 graphic characteristics were summarized descriptively. fi patients who were screened, a total of 102 patients were The primary ef cacy endpoint was the mean change in enrolled from 18 sites (10 in the United States, 3 in Italy, 3 Hb from baseline to the evaluation period (i.e., the mean of in Australia, and 2 in the United Kingdom). One patient theHbvaluesfromweeks19to24).Atwo-sided95% fi withdrew consent before receiving study treatment, leav- con dence interval (CI) of the estimated mean change ing 101 patients for analysis (HD, n=52; CKD-ND, n=49). from baseline in Hb was derived assuming that the vari- Ten patients discontinued from the study (HD, n=8; CKD- able follows a t-distribution. Secondary endpoints in- ND, n=2), four of them due to AEs. cluded the percentage of patients who had mean Hb – Baseline and demographic characteristics are detailed in values within the range of 10.0 12.0 g/dl during the eval- Table 3. Mean baseline Hb values were similar for HD and uation period, the percentage of patients who had a CKD-ND patients, and diabetes was the most common change in Hb from baseline to the evaluation period 6 primary cause of CKD in both groups. The majority of within 1.0 g/dl, and the percentage of patients who re- HD patients were on dialysis for .1 year at baseline. ceived red blood cell (RBC) transfusions during the titra- More HD patients had CHF than did CKD-ND patients. tion and evaluation periods. For all secondary endpoints, a Median baseline ferritin levels in HD patients were more two-sided 95% CI of the percentage was calculated using than twice that of patients not on dialysis; median trans- the normal approximation with continuity correction. Pri- ferrin saturation (TSAT) levels were similar in both groups. mary and secondary endpoints were summarized descrip- tively. Median first and last doses of peginesatide were also summarized descriptively; doses of intravenous and Efficacy Endpoints subcutaneous peginesatide were listed separately for each The mean change in Hb from baseline to the evaluation group. period was 0.04 g/dl with a 95% CI of 20.14 to 0.23 g/dl. The safety evaluation included the incidence of AEs, AEs In the HD group, the mean (SD) change in Hb from base- leading to withdrawal, the incidence of SAEs and deaths, the line to the evaluation period was –0.42 (0.76) g/dl with a proportion of patients who received phlebotomies, the pro- 95% CI of –0.65 to –0.19 (Table 4). In the CKD-ND group, portion of patients who had Hb excursions (i.e., two consec- the mean (SD) change in Hb from baseline to the evalua- utive Hb values .12, .13, or .14 g/dl), clinical laboratory tion period was 0.49 (0.77) g/dl with a 95% CI of 0.26–0.71 results, iron levels, vital signs, and peginesatide-specific (Table 4). Over the course of the study, mean Hb values

Figure 1. | Patient disposition. aOne patient was enrolled but withdrew consent before receiving treatment with study drug. bOne patient enrolled but discontinued from the study before receiving treatment with study drug. HD, CKD hemodialysis patients; CKD-ND, CKD non- dialysis patients. Clin J Am Soc Nephrol 8: 538–545, April, 2013 Peginesatide Maintenance Treatment, Fishbane et al. 541

cardiovascular complications) and one patient in the CKD- Table 3. Baseline and demographic characteristics ND group (one patient due to ARF) (Table 4). HD CKD-ND Characteristic (n=52) (n=49) Peginesatide Dosing Because the HD group was receiving a higher mean Men, n (%) 35(67.3) 16(32.7) baseline dose of darbepoetin alfa than the CKD-ND group Age (yr), mean (SD) 66.4 (12.6) 68.6 (12.1) (Table 3), the median starting dose of peginesatide was Race, n (%) White 42 (80.8) 27 (55.1) higher in the HD group than it was in the CKD-ND group Black 8 (15.4) 20 (40.8) (Table 5). This difference was maintained throughout the Asian 2 (3.8) 1 (2.0) study, with the HD group having a higher median final Native Hawaiian or 0(0) 1(2.0) dose of peginesatide than the CKD-ND group (Table 5). Pacific Islander Hemoglobin (g/dl), 11.2 (0.5) 11.1 (0.5) mean (SD) Safety Darbepoetin alfa dose 0.53 (0.44) 0.24 (0.18) A total of 78.2% of patients reported at least one AE, most (mg/kg per week), of which were assessed as either mild (50.3%) or moderate mean (SD) (39.6%) in severity. The most common AEs were diarrhea Route of administration, 90.4/9.6 0.0/98.0a (15.4%), decreased appetite (13.5%), and nausea (11.5%) in intravenous/ the HD group and diarrhea (12.2%), upper respiratory tract subcutaneous, % infection (12.2%), and peripheral edema (12.2%) in the CKD- History of CHF, n (%) 15(28.8) 11(22.4) ND group. Other common AEs are presented in Table 6. On dialysis .1yr,n (%) 46 (88.5) NA AEs that led to study discontinuation occurred in two HD hsCRP (mg/L), 4.8 (8.4) 2.7 (5.6) median (IQR) patients (vomiting related to nausea and decreased appetite; TSAT (%), median (IQR) 28.5 (18.5) 29.0 (12.0) fatal ischemic cerebral infarction [detailed below]) and two Ferritin (ng/ml), 366 (391) 174 (131) CKD-ND patients (noncardiac chest pain; ARF). Four pa- median (IQR) tients experienced AEs considered related to the study drug, CKD (yr), mean (SD) 8.2 (6.3) 6.4 (6.3) including three HD patients (anemia; nausea, vomiting, and Primary cause of CKD, decreased appetite; cough) and one CKD-ND patient (hypo- b n (%) tension). All of these AEs were mild or moderate in severity. Diabetes 16 (30.8) 25 (51.0) A total of 22 patients (HD, n=16; CKD-ND, n=6) reported Hypertension 8 (15.4) 12 (24.5) 40 SAEs during the study. The most common SAEs (i.e., Other 9 (17.3) 9 (18.4) reported by .1 patient) were CHF (HD, n=1; CKD-ND, Autoimmune disease 6 (11.5) 1 (2.0) fi Unknown 6 (11.5) 1 (2.0) n=2), chest pain (HD, n=2), arteriovenous stula thrombo- CKD stage, n (%) sis (HD, n=2), and hyperkalemia (HD, n=2). Two patients, 3 0 (0) 22 (44.9) both in the HD group, died during the study. One patient 4 0 (0) 23 (46.9) was a 69-year-old man who had an extensive history of 5 52 (100.0) 4 (8.2) smoking. This patient was hospitalized 5 weeks after his first dose of peginesatide because of a diagnosis of lung HD, hemodialysis patients; CKD-ND, patients with CKD not cancer. The patient received one additional dose of pegi- receiving dialysis; CHF, congestive heart failure; hsCRP, high nesatide, but died due to lung cancer. Baseline Hb was sensitivity C-reactive protein; NA, not applicable; IQR, inter- 10.6 g/dl and final Hb was 10.8 g/dl. The investigator quartile range; TSAT, transferrin saturation. a considered the event unrelated to the study drug. The Information on the baseline darbepoetin route of administra- other death was in a 69-year-old woman with a history tion was missing from one patient; this patient was treated with of peripheral vascular disease, pulmonary edema, cardio- subcutaneous peginesatide . b . myopathy, hypertension, and hyperlipidemia. Twelve Values present the primary causes of CKD reported by 5% of ’ fi patients overall. days after the patient s rst dose of study drug she was hospitalized because of worsening vasculopathy in her right lower extremity. A computed cranial tomographic encephalography revealed a subacute ischemic lesion. Af- were in the range of 10.0–12.0 g/dl and they were main- ter discharge, the patient experienced a severe cerebral tained within 61.0 g/dl from baseline in the majority of ischemic attack and was re-hospitalized. The patient did patients in both groups (Figure 2). not attend her week 4 visit and was withdrawn from the Analysis of the secondary efficacy endpoints revealed that study. The patient died due to cerebral ischemic attack 38 the majority of patients in both the HD and CKD-ND groups days after receiving her first and only dose of study drug. maintained Hb values within the range of 10.0–12.0 g/dl Hemoglobin level at enrollment was 12.3 g/dl and the during the evaluation period (Table 4). The majority of pa- final Hb level was 11.6 g/dl. The investigator considered tients in both groups maintained Hb values within 61.0 g/ the event and the outcome unrelated to the study drug dl of baseline during the evaluation period (Table 4). Few because of the patient’s history of extensive peripheral patients in either group received RBC transfusions during and cardiovascular disease and other risk factors for the study, including three patients in the HD group (one . patient due to worsening anemia, one patient due to aortic No therapeutic phlebotomies were required during the valve replacement, and one patient due to multiple study. 542 Clinical Journal of the American Society of Nephrology

Table 4. Primary and secondary endpoints

Outcome HD(n=52) CKD-ND (n=49)

Primary endpoint Mean (95% confidence interval) change in Hb from 20.42 (20.65, 20.19) 0.49 (0.26, 0.71) baselinea to evaluation, g/dl Secondary endpoints Patients with Hb within 10.0–12.0 g/dl 73.3 (59.3, 87.4) 68.1 (53.7, 82.5) during evaluation Patients with Hb change within 61.0 g/dl of baseline 80.0 (67.2, 92.8) 68.1 (53.7, 82.5) during evaluation Red blood cell transfusions 5.8 (0.0, 13.1) 2.0 (0.0, 7.0)

Data are percentages (95% confidence intervals) unless otherwise indicated. HD, patients on hemodialysis; CKD-ND, patients with CKD not on dialysis; Hb, hemoglobin. aThe mean of the four most recent Hb values before enrollment and the Hb value on the day of enrollment.

Figure 2. | Mean (SD) hemoglobin change from baseline, by group. *Indicates a significant (P,0.05) change from baseline. HD, CKD he- modialysis patients; CKD-ND, CKD nondialysis patients.

Table 5. Peginesatide doses, by group and route of administration

HD CKD-ND Dose (mg/kg) Intravenous (n=47) Subcutaneous (n=5) Subcutaneous (n=49)

First, median (Q1, Q3) 0.05 (0.04, 0.08) 0.04 (0.04, 0.08) 0.04 (0.04, 0.04) Last, mean (Q1, Q3) 0.06 (0.04, 0.11) 0.05 (0.04, 0.05) 0.03 (0.02, 0.03)

HD, patients on hemodialysis; CKD-ND, patients with CKD not on dialysis; Q1, first quartile; Q3, third quartile.

During both the titration and evaluation periods, CKD-ND were not associated with bilirubin elevations or clinical symp- patients were more likely to experience a Hb excursion .12.0 toms, and resolved without a change to the dose of study drug. g/dl than were HD patients (Table 7); excursions .13.0 g/dl In the HD group, median (interquartile range [IQR]) or 14.0 g/dl were relatively infrequent (Table 7). serum ferritin was 366 (IQR, 391) ng/ml at baseline, which Two patients in the HD group had liver enzymes .3times increased to 390 (IQR, 290) ng/ml at week 24; median the upper limit of normal. These elevations were temporary, TSAT was 29% (IQR, 19) at baseline, which increased to Clin J Am Soc Nephrol 8: 538–545, April, 2013 Peginesatide Maintenance Treatment, Fishbane et al. 543

period, mean Hb levels were within 60.5 g/dl of baseline Table 6. Most common (occurring in >5% of patients overall) values and the majority of patients maintained Hb levels adverse events, by group within 61.0 g/dl of baseline and within the study target range of 10.0–12.0 g/dl. Overall, few patients received HD CKD-ND Adverse Event (n=52) (n=49) RBC transfusions. These data indicate that, after conver- sion from darbepoetin alfa, treatment response to pegine- Diarrhea 8 (15.4) 6 (12.2) satide is within the range of what has been reported with Decreased appetite 7 (13.5) 2 (4.1) other ESAs in current clinical use (25,26). Results of this Nausea 6 (11.5) 3 (6.1) study are also consistent with those of the phase 3 studies Upper respiratory 3(5.8) 6(12.2) of peginesatide, which demonstrated that once-monthly tract infection peginesatide treatment maintained Hb levels in CKD pa- Cough 4 (7.7) 4 (8.2) tients on HD after conversion from epoetin treatment Peripheral edema 2 (3.8) 6 (12.2) fi Dizziness 2 (3.8) 5 (10.2) (22,23). The unique pharmacokinetic pro le of peginesa- Hypertension 4 (7.7) 3 (6.1) tide and its extended erythropoietic activity may explain Constipation 4 (7.7) 2 (4.1) the mechanism for the extended dosing interval. Headache 4 (7.7) 2 (4.1) There were some differences in Hb responses to pegine- Vomiting 6 (11.5) 0 (0.0) satide between the HD patients and CKD-ND patients, in that the mean Hb level decreased slightly in the HD group Data are shown as n (%). HD, patients on hemodialysis; CKD- but increased slightly in the CKD-ND group from baseline ND, patients with CKD not on dialysis. to the evaluation period, despite a higher median starting dose of peginesatide in the HD group (0.05 mg/kg) than in the CKD-ND group (0.04 mg/kg). The differences in starting dose were reflective of higher doses of darbepoetin alfa in the HD group before conversion to peginesatide, Table 7. Hemoglobin excursions during the titration and evaluation periods, by group consistent with greater anemia severity in these patients, and lower doses of darbepoetin alfa in the CKD-ND group. HD CKD-ND During the study, median peginesatide doses were higher Hemoglobin Excursions (n=52) (n=49) for the HD group and lower for the CKD-ND group. These results suggest that the peginesatide starting dose may . a 12 g/dl have been lower than required for HD patients and higher Titration period 12 (23.1) 34 (69.4) than required for CKD-ND patients. These differences in Evaluation period 4 (8.9) 17 (36.2) .13 g/dla treatment response may be explained by differences in Titration period 1 (1.9) 11 (22.4) baseline characteristics, anemia severity, and comorbidities Evaluation period 0 (0.0) 1 (2.1) between HD and CKD-ND patients. For example, the HD .14 g/dla patients had a lower percentage of Black patients and a Titration period 0 (0.0) 3 (6.1) higher percentage of men, higher baseline serum ferritin Evaluation period 0 (0.0) 0 (0.0) and hsCRP levels, and a higher rate of CHF than did the CKD-ND group. Despite these differences, the results of Data are shown as n (%). HD, patients on hemodialysis; CKD- this study show that peginesatide at 4-week intervals ND, patients with CKD not on dialysis. maintained Hb levels in the study target range of 10.0– a Two consecutive hemoglobin values. 12.0 g/dl in most HD and CKD-ND patients during the evaluation period. Hemoglobin excursions greater than 12.0 g/dl were more common in CKD-ND patients than they were in HD patients 39% (IQR, 19) at week 24. In the CKD-ND group, median during the titration and evaluation periods, likely a reflection serum ferritin was 174 (IQR, 131) ng/ml at baseline, which of the higher-than-required starting doses that were used in decreased to 110 (IQR, 90) ng/ml at week 24; median TSAT the CKD-ND group. Excursions were more common during was 29% (IQR, 12) at baseline, which increased to 34% the titration period, as would be expected during a dose- (IQR, 13) at week 24. None of these changes were adjustment interval (the titration period was also substantially fi statistically signi cant. Thirty-eight HD patients (73.1%) longer than the evaluation period). Per the dose-adjustment received iron supplementation during the study (intrave- guidelines, a dose decrease did not occur until a patient’s nous, n=36 [69.2%]; oral, n=1 [1.9%]; route of administra- Hb level was $12.0 g/dl. Importantly, the incidence of tion missing, n=4 [7.7%]) and 23 CKD-ND patients (46.9%) sustained excursions greater than 13.0 or 14.0 g/dl was received iron supplementation (intravenous, n=2 [4.1%]; low. oral, n=21 [42.9%]). Patients may have had more than Most AEs reported in this study were mild or moderate one route of administration. in severity and were generally typical of those experienced fi No patients developed peginesatide-speci cantibodies by patients with advanced CKD. No SAEs or deaths re- during the study. ported during the study were considered by the study investigators to be related to peginesatide, but the lack of Discussion randomization does not permit us to determine what Overall, the mean change in Hb from baseline to the proportion of the SAEs and deaths were due to the study evaluation period was 0.04 g/dl. During the evaluation drug. Because of safety concerns with the ESA class of 544 Clinical Journal of the American Society of Nephrology

drugs, deaths and cardiovascular events from this study Rai Mehta, Arlington Nephrology, Arlington, Texas; Sandip Mitra, were reviewed and no obvious safety signals in this regard Department of Renal Medicine, Manchester Royal Infirmary, Man- were noted. No patients developed peginesatide-specific chester, United Kingdom; Nicholas R. Pritchard, Addenbrooke’s antibodies. Two patients developed fistula thromboses Hospital, Cambridge, United Kingdom; Bruce A. Pussell, GCHSM, during the course of the study. Although the investigators Prince of Wales Hospital, Randwick, New South Wales, Australia; assessed these AEs as unrelated to the study drug, it should David A. Roer, Nephrology & Hypertension Associates, Middlebury, be noted that fistula thromboses have been associated with Connecticut; Simon D. Roger, Renal Research, Gosford, New South the use of ESAs (13). Wales, Australia; Michael Suranyi, Liverpool Hospital, Liverpool, This study has several limitations. The study was a New South Wales, Australia; Mark Thomas, Birmingham Heartlands single-arm study, the sample size was relatively small, and Hospital, Birmingham, United Kingdom; Giuseppe Villa, U.O. di the 24-week duration of the study did not allow for long- Nefrologia ed Emodialisi, dell’Istituto Scientifico di Pavia, Fondazione term evaluation of peginesatide. These limitations have S. Maugeri-Clinica del Lavoro e della Riabilitazione (IRCCS), Pavia, been addressed in the phase 3 peginesatide development Italy; Raja I. Zabaneh, Northwest Louisiana Nephrology, Shreveport, program (22,23). This was an open-label study and the Louisiana. primary endpoint was an objective measure (i.e., Hb levels, This study was sponsored by Takeda Global Research & De- all of which were assayed at a central laboratory). There velopment Center Inc, Deerfield, Illinois, with collaboration from is a possibility, however, that the open-label nature of this Affymax Inc, Palo Alto, California. study led to differential application of co-interventions Some data contained in this manuscript were presented in abstract (e.g., iron repletion), although there is no evidence to sug- form at the 2010 Annual Meeting American Society of Nephrology, gest that this occurred. In addition, the duration of the November 16–21, 2010, in Denver, Colorado. study was relatively short and there is a need for studies of peginesatide that are longer in duration to determine Disclosures fi safety and ef cacy after long-term treatment. S.F. is a member of advisory boards of Affymax, Rockwell, and The ability to administer an ESA less frequently offers Akebia and is on a speakers’ panel for AMAG Pharmaceuticals. F.L. is potential advantages. Results from a prospective observa- a member of advisory boards of Affymax, , GlaxoSmithKline, tional study indicated that, compared with a thrice-weekly Jansen, Pharmagenesis, Roche, Takeda, and Vifor Pharma, and is ESA, a once-monthly ESA may reduce injection-related fi a member of a safety committee of Sandoz. S.D.R. is a member of personnel time by 79% (18). Another potential bene tofa advisory boards of Hoffmann-La Roche, Sandoz, Takeda, and Vifor once-monthly ESA is that nurses could devote more time Pharma, and is a member of a steering committee of an Amgen anemia to patient assessment and education, which could improve trial. E.M. was a principal investigator for Affymax and Takeda. G.R., J. patient safety and satisfaction. O., and P.Q. are employees of Takeda Global Research & Development In conclusion, the results of this study indicated that Center Inc, Deerfield, Illinois. peginesatide at 4-week intervals maintained hemoglobin levels in the majority of both HD and CKD-ND patients after conversion from darbepoetin alfa. References 1. Zoccali C, Kramer A, Jager KJ: and end- stage renal disease - a review produced to contribute to the report Acknowledgments ’the status of health in the European Union: Towards a healthier We thank Steve Brunell for his medical writing support. Dr. Europe’. NDT Plus 3: 213–224, 2010 Brunell, an Affymax, Inc. consultant, prepared the preliminary draft 2. Mercadal L, Metzger M, Casadevall N, Haymann JP, Karras A, of the manuscript under the direction of the lead author, Dr. Steven Boffa JJ, Flamant M, Vrtovsnik F, Stengel B, Froissart M; Neph- Fishbane. 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