Peg in es a tide for Anemia in Patients with Chronic Kidney Disease Not Receiving Dialysis

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article Peg in es a tide for Anemia in Patients with Chronic Kidney Disease Not Receiving Dialysis Iain C. Macdougall, M.D., Robert Provenzano, M.D., Amit Sharma, M.D., Bruce S. Spinowitz, M.D., Rebecca J. Schmidt, D.O., Pablo E. Pergola, M.D., Ph.D., Raja I. Zabaneh, M.D., Sandra Tong-Starksen, M.D., Martha R. Mayo, Pharm.D., Hong Tang, M.S., Krishna R. Polu, M.D., Anne-Marie Duliege, M.D., and Steven Fishbane, M.D., for the PEARL Study Groups* A bs tr ac t From the Renal Unit, King s College Hospital, London (I.C.M.); St. Clair Specialty Physicians, Detroit (R.P.); the Boise Kidney and Hypertension Institute, Meridian, ID (A.S.); Nephrology Associates, Flushing (B.S.S.), and Hofstra North Shore LIJ School of Medicine, Great Neck (S.F.) both in New York; the Nephrology Department, West Virginia University School of Medicine, and the Robert C. Byrd Health Sciences Center, Morgantown, WV (R.J.S.); Renal Associates, San Antonio, TX (P.E.P.); Northwest Louisiana Nephrology Research, Shreveport (R.I.Z.); and Affymax, Palo Alto, CA (S.T.-S., M.R.M., H.T., K.R.P., A.-M.D.). Address reprint requests to Dr. Macdougall at the Renal Unit, King s College Hospital, London SE5 9RS, United Kingdom, or at iain.macdougall@ nhs.net. * Investigators for the PEARL (Peg in es a- tide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents) studies are listed in the Supplementary Appendix, available at NEJM.org. N Engl J Med 2013;368: DOI: /NEJMoa Copyright 2013 Massachusetts Medical Society. Background Peg in es a tide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peg in es a tide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis. Methods In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peg in es a tide once a month, at a starting dose of mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 µg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was 1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point. Results In both studies and at both starting doses, peg in es a tide was noninferior to dar bepo e tin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peg in es a tide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], 0.19 to 0.26) for the lower starting dose of peg in es a tide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, 0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for pegin es a tide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peg in es a tide. Conclusions The efficacy of peg in es a tide (administered monthly) was similar to that of dar bepo e tin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peg in esa tide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT [PEARL 1], NCT [PEARL 2], NCT [EMERALD 1], and NCT [EMERALD 2].) 320

2 The 1989 approval of recombinant human erythropoietin facilitated sustained correction of anemia in chronic kidney disease and freed many patients undergoing dialysis from dependence on transfusions. 1,2 Increases in hemoglobin levels from approximately 6 to 7 g per deciliter to approximately 11 to 12 g per deciliter improved symptoms, quality of life, and physical capacity. 3,4 Subsequent molecular modifications generated two erythropoiesis-stimulating agents (ESAs) with longer in vivo half-lives (darbepoetin alfa, which contains two extra N-linked carbohydrate chains, and continuous erythropoietin receptor activator, which has an added polyethylene glycol chain), offering the potential of less frequent administration. 5-7 Both are based on the endogenous erythropoietin molecule. 8 Peg in es a tide (Omontys, Affymax), a peptidebased ESA, 9,10 was approved in the United States in March 2012 for the treatment of anemia caused by chronic kidney disease in adults who are undergoing dialysis. Although peg in es a tide has no sequence homology with erythropoietin, 9 it stimulates the erythropoietin receptor, initiating a similar intracellular signaling cascade. 11 Peg ines a tide is pegylated, which enhances its biologic activity in vivo. 11 Phase 2 data suggested that treatment with peg in es a tide (0.019 to mg per kilogram of body weight, once a month) could maintain hemoglobin levels in patients with chronic kidney disease who were not receiving dialysis. 12 Among patients with chronic kidney disease who are not receiving dialysis, kidney function, 13 severity of anemia, 14 and underlying cardiovascular risk 15 vary widely. A study based on data from a large registry of patients with chronic kidney disease showed that the risk of cardiovascular events and hospitalization progressively increases as kidney function declines. 16 The role of ESAs in the treatment of anemia in patients not receiving dialysis has evolved as data from randomized, controlled trials have become available Data from the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, 17 in which patients received epoetin, showed an increase in a composite end point of death and cardiovascular events in the study group receiving a dose targeted to achieve higher hemoglobin levels (13.5 g per deciliter vs g per deciliter), whereas another study (the Trial to Reduce Cardiovascular Events with Aranesp Therapy, or TREAT), 19 a randomized, placebo-controlled trial evaluating the cardiovascular benefit with dar bepo e tin, showed that the risk of stroke increased by a factor of 2 when the targeted hemoglobin level was approximately 13 g per deciliter. Subsequently, warnings about these risks were added to ESA prescription information in the United States, and guidelines for initiating therapy in patients with chronic kidney disease who were not undergoing dialysis became stricter than the guidelines for patients who were undergoing dialysis. To evaluate the safety and efficacy of peg ines a tide, four randomized, clinical trials were conducted. Two of the studies included patients who were not receiving dialysis (PEARL 1 and 2, with PEARL denoting Peg in es a tide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents), and two included patients who were receiving hemodialysis (EMERALD 1 and 2, with EMERALD denoting Efficacy and Safety of Peg in es a tide for the Maintenance Treatment of Anemia in Patients with Chronic Renal Failure Who Were Receiving Hemodialysis and Were Previously Treated with Epoetin). These studies had a prespecified pooled composite safety end point, which included a head-to-head comparison of different ESAs to evaluate cardiovascular safety. The results of the PEARL studies are reported here; the results of the EMERALD studies and the pooled composite safety end point are reported elsewhere in this issue of the Journal. 20 Me thods Study Oversight We conducted two similarly designed, phase 3, randomized, active-treatment controlled, openlabel, noninferiority studies in the United States (PEARL 1 and 2) and in Europe (PEARL 2). The protocol was approved by the institutional review board or ethics committee at each study site or by the central institutional review board, and the studies were performed in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients provided written informed consent. The studies were funded by Affymax and Takeda Pharmaceutical (Osaka, Japan) and were designed collaboratively by the principal investi- 321

3 T h e n e w e ngl a nd j o u r na l o f m e dic i n e gators and Affymax. ICON Clinical Research was responsible for data management and for statistical analyses of individual study efficacy and safety. Statistical analyses of the composite safety end point were performed by Pacific Northwestern Statistical Consulting and analyses of integrated efficacy and safety were performed by Affymax. The principal investigators made the decision to submit the manuscript for publication, and all authors had full access to the data. The first author wrote the introduction and the Discussion section and oversaw all revisions; an Affymax employee and a contractor wrote the preliminary draft of the Methods and Results sections under the direction of the first author. All authors reviewed and edited the manuscript, vouch for the completeness and accuracy of the data and analyses, and testify to the fidelity of this report to the study protocols, which are available with the full text of this article at NEJM.org. Investigator agreements stated that after the date of the first publication of multicenter data or 36 months after study completion, investigators were free to publish study results and that Affymax could review manuscripts before submission for publication. Study Population Eligible patients with chronic kidney disease were 18 years of age or older, had an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m 2 of body-surface area, and were not expected to begin dialysis for at least 12 weeks after randomization. Other key inclusion criteria were two consecutively measured hemoglobin values between 8.0 and 11.0 g per deciliter in the 4 weeks preceding randomization and a value for transferrin saturation of 20% or more or a serum ferritin level of 100 ng per milliliter or more. Key exclusion criteria were previous long-term dialysis; bleeding or coagulation disorders, hematologic diseases, or causes of anemia other than chronic kidney disease; a scheduled kidney transplantation; poorly controlled hypertension; ESA therapy or blood transfusion within 12 weeks before randomization; and active cancer in the year preceding randomization (for details, see the Supplementary Appendix, available at NEJM.org). Study Procedures The first patient underwent randomization in October 2007, and follow-up of the last patient was completed in February Each study included a period of 4 weeks for screening, 24 weeks for correction, 12 weeks for evaluation, and 16 weeks or more of additional follow-up. Eligible patients were centrally allocated in a 1:1:1 ratio to receive peg in es a tide subcutaneously once every 4 weeks, starting at either mg per kilogram or 0.04 mg per kilogram of body weight, or dar bepo e tin once every 2 weeks, starting at 0.75 μg per kilogram. The goal was to increase and maintain hemoglobin levels between 11.0 g and 12.0 g per deciliter (see Table S1 in the Supplementary Appendix). In both PEARL 1 and PEARL 2, randomization was stratified according to mean level of hemoglobin at screening ( 10.4 g per deciliter or 10.5 g per deciliter) to ensure balance in efficacy variables at baseline and according to the New York Heart Association class of heart failure (no heart failure or class I vs. classes II, III, or IV) to help ensure balance in baseline cardiovascular risk. 21 In PEARL 2, randomization was also stratified according to geographic region. Hemoglobin measurements were performed at screening and at baseline and thereafter every 2 weeks (for the correction and evaluation periods) or every 4 weeks (for the longer-term follow-up period). At each visit, information was collected on adverse events, transfusions, phlebotomies, and concomitant medication use. Study End Points The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period. Secondary efficacy end points were the proportion of patients receiving a transfusion and the proportion of patients in whom there was a response in hemoglobin levels (see the Supplementary Appendix). Efficacy was also assessed as the mean change from baseline in hemoglobin levels during 4-week intervals. Cardiovascular risk was assessed with the use of a prospectively planned analysis of a composite safety end point consisting of death from any cause, stroke, myocardial infarction, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia (see the Supplementary Appendix). The identification and assessment of potential events were defined and designed prospectively to ensure that the treatment assignments and hemoglobin levels remained concealed from the event-review committee and to minimize investigator bias (see the Supplementary Appen- 322

4 dix). The prespecified primary analysis was the time to the first positively adjudicated event pooled across four studies: PEARL 1 and 2 and EMERALD 1 and 2 (in the latter two, patients received peg in es a tide or epoetin). Prespecified analyses were also performed according to the study population; the results in the population not receiving dialysis are reported here. Statistical Analysis The primary-analysis population for the assessment of safety comprised all patients who underwent randomization and who received at least one dose of the study drug (i.e., the modified intention-to-treat population). The primary efficacy analysis included patients in the primaryanalysis population who also had at least one hemoglobin measurement during the evaluation period. There was no imputation of missing data for the primary efficacy analysis. The primary efficacy end point was analyzed with an analysisof-variance cell means model to estimate the mean change from the baseline hemoglobin level to the mean level during the evaluation period within each randomization stratum. Estimates of treatment differences (peg in es a tide vs. dar bepo e tin) and corresponding two-sided 97.5% confidence intervals, with Bonferroni adjustment for group comparisons, were also calculated with the analysis-of-variance model. Because missing data were not imputed, a prespecified per-protocol population analysis and sensitivity analyses with imputation of missing values were performed to address the potential effects of premature withdrawal from the studies (see the Supplementary Appendix). Noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was 1.0 g per deciliter or higher (see the Supplementary Appendix). For the composite safety end point, we estimated that 553 patients with positively adjudicated events across the four trials would provide at least 89% power to exclude a hazard ratio of more than 1.3 with the use of a one-sided 95% confidence interval (see the Supplementary Appendix). Analyses of major adverse cardiovascular events (death from any cause, stroke, or myocardial infarction) were also performed. Sensitivity analyses were performed for the composite safety end point to assess the influence of study withdrawal and events occurring after the study drug was discontinued. R esult s Study Patients In PEARL 1, a total of 490 patients at 71 sites in the United States underwent randomization; in PEARL 2, a total of 493 patients at 43 sites in the United States and 19 sites in Europe underwent randomization. All of these patients received one or more doses of the study drug and were included in the primary-analysis population. A total of 118 patients in PEARL 1 withdrew from the study prematurely (including 79 of the 326 patients [24.2%] in the groups receiving either dose of peg in es a tide [peg in es a tide groups combined] and 39 of the 164 patients [23.8%] receiving darbe po e tin), and a total of 106 patients in PEARL 2 withdrew prematurely (including 82 of the 330 patients [24.8%] in the peg in es a tide groups combined and 24 of the 163 patients [14.7%] in the group receiving darbepoetin) (reasons for withdrawal are listed in Fig. 1A and 1B). At baseline, there were several differences in the incidence of coexisting conditions between the groups receiving peg in es a tide and the group receiving dar be poe tin; all coexisting conditions occurred at a higher rate in the groups receiving peg in es a tide (Table 1). The mean baseline hemoglobin level and iron status were similar across groups in both studies. The median duration of follow-up for the pegin es a tide groups combined and the groups receiving dar be po e tin were 81.4 weeks (interquartile range, 75.3 to 90.9) and 82.1 weeks (interquartile range, 75.1 to 90.0), respectively, in PEARL 1 and 67.9 weeks (interquartile range, 57.1 to 81.0) and 70.1 weeks (interquartile range, 60.1 to 84.1), respectively, in PEARL 2 (see the Supplementary Appendix for patient exposure). Doses were adjusted in accordance with the individual hemoglobin response and tended to converge over time in the peg in es a tide groups. The median of the mean dose administered per patient during longer-term follow-up (37 weeks and beyond) for the groups receiving the lower starting dose of peg in es a tide, the higher starting dose of peg ines a tide, and dar be po e tin was 1.6 mg, 1.9 mg, and 29.0 μg, respectively, in PEARL 1 and 1.5 mg, 1.6 mg, and 25.0 μg, respectively, in PEARL 2. Efficacy The mean (±SD) changes from the baseline hemoglobin levels to the mean level during the 12-week evaluation period for the group with the lower 323

5 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A PEARL Patients were screened 307 Were excluded 204 Did not meet entry criteria 45 Withdrew informed consent 17 Met exclusion criteria 41 Were withdrawn for other, unspecified reasons 490 Underwent randomization 161 Were assigned to and received peginesatide starting at mg/kg once monthly 165 Were assigned to and received peginesatide starting at 0.04 mg/kg once monthly 164 Were assigned to and received darbepoetin starting at 0.75 µg/kg every 2 wk 41 Prematurely discontinued the study 6 Died 12 Withdrew consent 8 Were lost to follow-up 15 Were withdrawn for other reasons 6 Started dialysis 4 Had adverse events 3 Had compliance issues 1 Underwent renal transplantation 1 Was at a site that elected to close study 38 Prematurely discontinued the study 12 Died 10 Withdrew consent 3 Were lost to follow-up 13 Were withdrawn for other reasons 4 Started dialysis 5 Had adverse events 2 Had compliance issues 2 Relocated 39 Prematurely discontinued the study 8 Died 10 Withdrew consent 5 Were lost to follow-up 16 Were withdrawn for other reasons 5 Started dialysis 2 Had adverse events 3 Had compliance issues 1 Underwent renal transplantation 1 Was withdrawn by investigator 4 Relocated 120 Completed the study 112 Were still receiving study drug 8 Were not receiving study drug 3 Had adverse events 3 Withdrew treatment consent 1 Had compliance issues 1 Started dialysis 127 Completed the study 119 Were still receiving study drug 8 Were not receiving study drug 4 Had adverse events 1 Withdrew treatment consent 1 Was withdrawn from treatment by investigator 1 Relocated 1 Started dialysis 125 Completed the study 118 Were still receiving study drug 7 Were not receiving study drug 2 Had adverse events 1 Underwent renal transplantation 1 Did not receive last scheduled dose 1 Had compliance issues 2 Were withdrawn from treatment by investigator Figure 1. Screening, Randomization, and Follow-up. Two similarly designed studies involving patients who were not undergoing dialysis were conducted: the Peg in es a tide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents (PEARL) 1 study (Panel A) and the PEARL 2 study (Panel B). Patients who discontinued either of the study drugs remained in the study for the collection of data relevant to the composite safety end point. Thus, discontinuation of the study drug was distinct from withdrawal from the study, and a separate reason for each was recorded and summarized. starting dose of peg in es a tide, the group with the higher starting dose of peg in es a tide, and the darbe po e tin group were 1.39±0.87 g per deciliter, 1.64±0.97 g per deciliter, and 1.37±0.86 g per deciliter, respectively, in PEARL 1 and 1.50±0.90 g per deciliter, 1.68±0.96 g per deciliter, and 1.35±1.00 g per deciliter, respectively, in PEARL 2. The noninferiority criterion was met: the mean differences in the hemoglobin level with peg in esa tide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], 0.19 to 0.26) for the lower starting dose of peg in es a tide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose; in 324

6 B PEARL Patients were screened 297 Were excluded 203 Did not meet entry criteria 40 Withdrew informed consent 25 Met exclusion criteria 29 Were withdrawn for other, unspecified reasons 493 Underwent randomization 167 Were assigned to and received peginesatide starting at mg/kg once monthly 163 Were assigned to and received peginesatide starting at 0.04 mg/kg once monthly 163 Were assigned to and received darbepoetin starting at 0.75 µg/kg every 2 wk 43 Prematurely discontinued the study 19 Died 8 Withdrew consent 4 Were lost to follow-up 12 Were withdrawn for other reasons 5 Were at a site where sponsor elected to close study 3 Had adverse events 2 Were withdrawn by investigator 1 Started dialysis 1 Relocated 39 Prematurely discontinued the study 11 Died 16 Withdrew consent 3 Were lost to follow-up 9 Were withdrawn for other reasons 2 Were at a site where sponsor elected to close study 1 Was withdrawn by investigator 2 Had compliance issues 4 Relocated 24 Prematurely discontinued the study 11 Died 6 Withdrew consent 3 Were lost to follow-up 4 Were withdrawn for other reasons 1 Was at a site where sponsor elected to close study 1 Was withdrawn by investigator 1 Had compliance issues 1 Underwent renal transplantation 124 Completed the study 119 Were still receiving study drug 5 Were not receiving study drug 3 Had adverse events 1 Underwent renal transplantation 1 Started dialysis 124 Completed the study 117 Were still receiving study drug 7 Were not receiving study drug 4 Had adverse events 1 Did not receive last scheduled dose 1 Had compliance issues 1 Relocated 139 Completed the study 132 Were still receiving study drug 7 Were not receiving study drug 2 Had adverse events 3 Withdrew treatment consent 2 Had compliance issues PEARL 2 they were 0.14 g per deciliter (97.5% CI, 0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. Mean hemoglobin levels were increased and maintained at points within the target range in all groups in both studies (Fig. 2). The proportion of patients receiving transfusions was similar in all groups in PEARL 1, but in PEARL 2, the proportion was higher in the groups receiving peg in es a tide (lower starting dose, 11.4%; higher starting dose, 10.4%) than in the group receiving dar be po e tin (4.9%) (see the Supplementary Appendix); for the two studies combined, 50% of transfusions in the group receiving the lower starting dose of peg in es a tide, 40% of those in the group receiving the higher starting dose, and 17% of those in the group receiving dar be po e tin were performed for the treatment of anemia of chronic kidney disease (Table S2 in the Supplementary Appendix). Iron status remained similar among groups in both studies (mean transferrin saturation, 27 to 30% at the end of the evaluation period), as did the proportion of patients receiving one or more doses of oral or intravenous iron (66 to 71% in PEARL 1 and 60 to 71% in PEARL 2) during the studies (Table S3 in the Supplementary Appendix). 325

7 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 1. Baseline Demographic and Clinical Characteristics of the Patients.* Characteristic PEARL 1 PEARL 2 Peginesatide, mg/kg (N = 161) Peginesatide, 0.04 mg/kg (N = 165) Peginesatide Groups Combined (N = 326) (N = 164) P Value Peginesatide, mg/kg (N = 167) Peginesatide, 0.04 mg/kg (N = 163) Peginesatide Groups Combined (N = 330) (N = 163) P Value Age yr 67.1± ± ± ± ± ± ± ± Male sex no. (%) 68 (42.2) 81 (49.1) 149 (45.7) 62 (37.8) (44.3) 67 (41.1) 141 (42.7) 64 (39.3) 0.47 Race no. (%) White 112 (69.6) 120 (72.7) 232 (71.2) 109 (66.5) 126 (75.4) 124 (76.1) 250 (75.8) 122 (74.8) Black 38 (23.6) 36 (21.8) 74 (22.7) 41 (25.0) 34 (20.4) 34 (20.9) 68 (20.6) 37 (22.7) Hemoglobin (g/dl) 10.1± ± ± ± ± ± ± ±0.7 Estimated GFR (ml/min/1.73 m 2 ) 27.2± ± ± ± ± ± ± ± Primary cause of chronic kidney disease no. (%) Diabetes 86 (53.4) 93 (56.4) 179 (54.9) 81 (49.4) 78 (46.7) 83 (50.9) 161 (48.8) 66 (40.5) Hypertension 51 (31.7) 50 (30.3) 101 (31.0) 59 (36.0) 54 (32.3) 48 (29.4) 102 (30.9) 56 (34.4) NYHA class no. (%) No heart failure or class I 137 (85.1) 139 (84.2) 276 (84.7) 140 (85.4) 133 (79.6) 129 (79.1) 262 (79.4) 130 (79.8) Class II, III, or IV 24 (14.9) 26 (15.8) 50 (15.3) 24 (14.6) 34 (20.4) 34 (20.9) 68 (20.6) 33 (20.2) History of cardiovascular risk factors no. (%) Diabetes 105 (65.2) 121 (73.3) 226 (69.3) 109 (66.5) (65.3) 109 (66.9)** 218 (66.1) 88 (54.0) Coronary artery disease 73 (45.3) 67 (40.6) 140 (42.9) 65 (39.6) (32.3) 70 (42.9) 124 (37.6) 60 (36.8) 0.87 Peripheral vascular disease 46 (28.6) 42 (25.5)** 88 (27.0) 25 (15.2) (26.9) 46 (28.2) 91 (27.6) 40 (24.5) 0.46 * Plus minus values are means ±SD unless otherwise noted. See Table S6 in the Supplementary Appendix for a more detailed list of baseline variables, none of which differed significantly across treatment groups in either study, except for the proportion of patients using dyslipidemic agents, which in PEARL 1 was higher in the peginesatide groups combined than in the darbepoetin group (74.2% vs. 65.9%, P = 0.05) and the proportion of patients using vitamin K antagonists, which in PEARL 1 was higher in the group receiving the lower starting dose of peginesatide (5.6%) and in the peginesatide groups combined (4.6%) than in the darbepoetin group (1.2%) (P = 0.03 and P = 0.05, respectively). In PEARL 2, the proportion of patients using vitamin K antagonists was higher in the group receiving the lower starting dose of peginesatide than in the darbepoetin group (8.4% vs. 3.1%, P = 0.04). NYHA denotes New York Heart Association, and PEARL Peginesatide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents. P values are for the comparison of the groups receiving peginesatide with the group receiving darbepoetin and were calculated with the use of analysis of variance for continuous variables and the Mantel Haenszel chi-square test for categorical variables, with adjustment for stratification factors. Race was determined from information in the case-report form. Statistical tests were not performed on stratification factors. Calculation of the estimated glomerular filtration rate (GFR) was based on the Modification of Diet in Renal Disease formula. P = 0.04 for the comparison of the lower starting dose of peginesatide with darbepoetin. ** P = 0.02 for the comparison of the higher starting dose of peginesatide with darbepoetin. P = for the comparison of the lower starting dose of peginesatide with darbepoetin. 326

8 A PEARL Mean Hemoglobin (g/dl) Peginesatide, LD Peginesatide, HD Weeks since Randomization No. of Patients Peginesatide, LD Peginesatide, HD B PEARL Mean Hemoglobin (g/dl) Peginesatide, LD Peginesatide, HD Weeks since Randomization No. of Patients Peginesatide, LD Peginesatide, HD Figure 2. Mean Hemoglobin Level According to Study Week. Data are shown for patients in the PEARL 1 study (Panel A) and the PEARL 2 study (Panel B). Dashed vertical lines indicate the evaluation period (weeks 25 through 36). Horizontal solid lines indicate the target range for hemoglobin (11 to 12 g per deciliter). I bars indicate standard errors. LD denotes lower starting dose, and HD higher starting dose. 327

9 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Patients without Event (%) No. at Risk Peginesatide Hazard ratio, 1.32 (95% CI, ) Days since Randomization Composite Safety End Point Peginesatide Figure 3. Kaplan Meier Curves for the Event-free Rate of the Composite Safety End Point. The curve illustrates the proportion of patients at each time point who had not had any of the following events: death from any cause, stroke, myocardial infarction, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia (all of which are components of the composite safety end point). Data from the PEARL 1 and PEARL 2 studies were pooled. The hazard ratio is for the comparison of peg in es a tide with darbepoetin With data from PEARL 1 and 2 combined (983 patients), events contributing to the composite safety end point occurred in 141 of 656 patients receiving peg in es a tide (21.5%) and 56 of 327 patients receiving dar be po e tin (17.1%). The hazard ratio with peg in es a tide relative to dar be po e tin was 1.32 (95% CI, 0.97 to 1.81) (Fig. 3) (see Fig. S1 in the Supplementary Appendix for the Kaplan Meier event-free rate according to study), with numerically higher event rates with peg in es a tide than with dar be po e tin in three categories: death (8.8% vs. 6.7%), unstable angina (2.4% vs. 0.9%), and arrhythmia (5.6% vs. 4.0%) (Table 2, and Fig. S2 in the Supplementary Appendix). A difference in the rate of sudden death was noted, occurring in 14 of the patients receiving peg in es a tide (2.1%) as compared with 1 patient receiving dar be po etin (0.3%); 13 of the 14 patients receiving peg ines a tide had diabetes, as did the 1 patient receiving dar be po e tin (Table S4 in the Supplementary Appendix). Differences in the rates of arrhythmia appeared to be related to atrial arrhythmias, predominantly atrial fibrillation; the incidence of ventricular arrhythmia was low and was similar among the groups (Table S5 in the Supplementary 12 4 Appendix). The sensitivity analysis evaluating the potential effect of premature withdrawals from the study showed results similar to those of the primary analysis (see the Supplementary Appendix). Imbalances were identified in several baseline variables (Table 1, and Table S6 in the Supplementary Appendix). A stepwise multivariate analysis (see the Supplementary Appendix) examining the combined influence of baseline factors (regardless of the magnitude of the imbalance) produced a hazard ratio for the composite safety end point of 1.20 (95% CI, 0.87 to 1.64). Sensitivity analyses excluding events occurring after the study drug was discontinued and sensitivity analyses of major cardiovascular events generally showed reduced hazard ratios but did not fully account for the differences observed between peg in es a tide and dar be po e tin (see Fig. S3 in the Supplementary Appendix). Adverse Events In pooled data from the PEARL studies, the proportion of patients who reported adverse events was similar in the peg in es a tide groups combined (93.6%) and in the dar be po e tin group (91.4%). There were no major differences (5 percentage points or more) between groups with regard to rates of individual events, with the exception of back pain, which was reported by 12.0% of patients receiving peg in es a tide, as compared with 6.7% of those receiving darbepoetin (Table S7 in the Supplementary Appendix). There were no clinically relevant differences in the incidence of adverse events known to be related to the ESA class of drugs (Table 2), including hypertensionrelated events (19.2% for peg in es a tide and 19.9% for dar be po e tin). Changes from baseline in blood pressure were similar in the peg in es a tide and darbe po e tin groups (Fig. S4 in the Supplementary Appendix), and there were no clinically relevant between-group differences in the intensification of antihypertensive medications. Serious adverse events were reported more frequently with peg in es a tide (48.5%) than with dar be po e tin (43.1%). No single event or organ system accounted for this difference; however, higher incidences (2 percentage points or more) of acute renal failure (8.5% vs. 4.3%) and anemia (3.5% vs. 1.5%) were observed with peg in es a tide than with darbepoetin (Table 2). Mean changes in the results of renal-function tests and in the proportion of patients with progression to dialy- 328

10 Table 2. Component Events of the Composite Safety End Point, Most Common Serious Adverse Events, and Adverse Events Associated with the Erythropoiesis-Stimulating-Agent (ESA) Class of Drugs. Event Peginesatide (N = 656) (N = 327) no. of patients (%) Component events of the composite safety end point* Death 58 (8.8) 22 (6.7) Cardiovascular 8 (1.2) 5 (1.5) Noncardiovascular 20 (3.0) 12 (3.7) Sudden 14 (2.1) 1 (0.3) Unknown cause 16 (2.4) 4 (1.2) Stroke 7 (1.1) 3 (0.9) Myocardial infarction 24 (3.7) 11 (3.4) Congestive heart failure 56 (8.5) 28 (8.6) Unstable angina 16 (2.4) 3 (0.9) Arrhythmia 37 (5.6) 13 (4.0) Serious adverse events occurring in 3% of patients in either group Congestive cardiac failure 56 (8.5) 26 (8.0) Acute renal failure 56 (8.5) 14 (4.3) Chronic renal failure 31 (4.7) 15 (4.6) Pneumonia 33 (5.0) 14 (4.3) Urinary tract infection 24 (3.7) 8 (2.4) Anemia 23 (3.5) 5 (1.5) Hypoglycemia 12 (1.8) 11 (3.4) Adverse-event categories associated with the ESA class of drugs Hypertension-related events 126 (19.2) 65 (19.9) Thromboembolic events Arterial 39 (5.9) 16 (4.9) Venous 14 (2.1) 6 (1.8) Complications related to vascular access 11 (1.7) 6 (1.8) Convulsions 8 (1.2) 1 (0.3) Infusion- or injection-related reactions 13 (2.0) 4 (1.2) Cancer 31 (4.7) 14 (4.3) * Component events of the composite safety end point were adjudicated by an independent, event-review committee whose members were unaware of the treatment assignments and hemoglobin measurements; patients could have more than one event. Sudden death was defined as nontraumatic or unexpected death within 1 hour after the onset of symptoms or unwitnessed death. The cause of death was classified as unknown if the primary cause could not be determined, including those cases in which there was insufficient information. There were no major differences (i.e., differences of³ 2 percentage points) between the pooled peginesatide and darbepo e tin groups with respect to serious adverse events, including those that were reported at a frequency of less than 3% in either group. Categories of adverse events associated with the ESA class of drugs were identified from the Medical Dictionary for Regulatory Activities (MedDRA) with the use of the Standardized MedDRA Query (SMQ); however, in the case of the categories of infusion- or injection-related reactions and complications related to vascular access, for which there are no suitable SMQs within MedDRA, the categories were identified according to sponsor-defined groups of preferred terms. This approach enabled the grouping of similar or related events that embodied similar clinical concepts. The proportion of patients reporting adverse events was similar for the pooled peginesatide group (93.6%) and the darbepoetin group (91.4%), with no major differences ( 5 percentage points) in any individual event between groups, with the exception of back pain (which occurred in 12.0% of patients receiving peginesatide and 6.7% of patients receiving darbepoetin). 329

11 T h e n e w e ngl a nd j o u r na l o f m e dic i n e sis or to stage 5 chronic kidney disease were similar with the two study drugs. Confirmed hemoglobin excursions (defined as two consecutive hemoglobin levels higher than 13 g per deciliter) occurred more frequently in patients receiving the higher starting dose of peg in es a tide (20.6%) than in those receiving the lower starting dose of peg in es a tide (12.8%) or those receiving dar be po e tin (10.8%) (Table S8 in the Supplementary Appendix). Among patients with composite safety end-point events, the percentage who also had hemoglobin excursions was similar across treatment groups (ranging from 8.5% among patients receiving darbepoetin to 11.5% among patients receiving either starting dose of peg ines a tide) (Table S9 in the Supplementary Appendix). Changes from baseline in the platelet count and potassium level were similar across treatment groups (Table S10 in the Supplementary Appendix). Among the patients treated with peg in es atide, 10 of 647 (1.5%) had detectable levels of drug-specific antibodies (4 patients in PEARL 1 and 6 in PEARL 2). These antibodies were neutralizing in 8 patients (3 in PEARL 1 and 5 in PEARL 2) in an in vitro assay (see the Supplementary Appendix). No cases of pure red-cell aplasia were reported. Discussion In this comparison of two ESAs in patients not receiving dialysis, an increase in composite safety end-point events, including sudden death, was observed with peg in es a tide. Previous randomized, controlled trials evaluating rates of death and cardiovascular events among patients with chronic kidney disease who were receiving ESAs but not dialysis showed unexpected evidence of harm when near-normal levels of hemoglobin (13 g per deciliter or higher) were targeted. 17,19 The hemoglobin targets used in patients receiving peg in es a tide or comparator ESAs in the phase 3 program were consistent with standard clinical care at the time (11 to 12 g per deciliter in the PEARL studies) but higher than current targets. After adjustment for baseline covariates, including diabetes, a multivariate model reduced the hazard ratio with peg in es a tide relative to dar be po e tin to 1.20, but it did not fully account for our findings. It is possible that factors related to peg in es atide exposure contributed to the findings in the PEARL study populations. In the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), darbepoetin exposure was associated with an increased risk of stroke, regardless of the hemoglobin response, 22 and a post hoc analysis in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial showed that higher-dose ESAs were associated with increased risks of death and cardiovascular events. 23 In the present studies, the same hemoglobin targets were used for all patients, regardless of the initial ESA dose, and doses converged in the pegin es a tide groups during longer-term follow-up. Furthermore, a difference in the rate of cardiovascular events was not observed for peg in es a tide relative to the comparator ESA in patients undergoing hemodialysis in the EMERALD studies, 20 a population at high cardiovascular risk, 24,25 in whom peg in es a tide doses were 2.5 to 3.0 times as high as the doses in PEARL 1 and 2. In the PEARL studies, the incidence of cardiovascular events with peg in es a tide did not appear to be related to initial exposure during correction of the hemoglobin level (i.e., when it was increasing) or during other treatment periods. Hemoglobin excursions occurred in more patients in the group receiving the higher starting dose of peg in es a tide than in the group receiving the lower starting dose of peg in es a tide or the group receiving darbepoetin, yet there were no major between-group differences in the proportion of patients with excursions among patients who had composite safety end-point events. The exposure hypothesis thus seems unlikely. Regarding the difference in the rate of sudden death between the peg in es a tide and dar be po e tin groups, no clinically relevant between-group differences were observed in potassium levels or platelet counts. Although the pathophysiology of sudden death in patients with chronic kidney disease is often attributable to ventricular arrhythmia precipitated by myocardial infarction, 25 there were no apparent between-group differences in adjudicated cases of myocardial infarction, congestive heart failure, or investigator-reported ventricular arrhythmias. This finding is consistent with studies in monkeys showing no evidence of a proarrhythmic potential with peg in es a tide. 26 Similarly, there were no clinically relevant between-group differences in blood pressure, hypertension-related events, or venous thromboembolism. Baseline 330

12 differences in diabetes, a known risk factor for sudden death in patients with chronic kidney disease, 25,27 may have contributed to the findings on sudden death; all but one of the sudden deaths occurred in patients with diabetes. A between-group difference was observed in the incidence of acute renal failure (8.5% in the two peg in es a tide groups combined vs. 4.3% in the dar be po e tin group). Laboratory measures of kidney function over time (e.g., creatinine level) were similar in the peg in es a tide and dar be po etin groups, and similar proportions of patients had progression to dialysis or stage 5 chronic kidney disease. The difference in the number of patients with acute renal failure, an event with heterogeneous pathophysiology, 28 warrants further study. In TREAT, 19 a protective effect of an ESA on kidney function (i.e., prolonged time to dialysis) was not observed in patients with chronic kidney disease and diabetes who were not undergoing dialysis. In both PEARL studies, the administration of peg in es a tide once a month increased and maintained hemoglobin at levels similar to those observed with the administration of dar be po e tin every 2 weeks. More than 89% of all patients did not require transfusions; however, in PEARL 2, the number of patients requiring transfusions was greater with peg in es a tide than with dar be po etin. Case evaluation revealed that in the majority of cases (57% in the peg in es a tide groups combined and 83% in the dar be po e tin group), the transfusions were required for reasons other than the treatment of anemia associated with chronic kidney disease, such as blood loss. Potential limitations of the PEARL studies include the open-label design, which could have biased the assessment of the softer end points (arrhythmia, congestive heart failure, and unstable angina). Nevertheless, efforts were made to minimize investigator bias, including the use of an independent committee (whose members were unaware of treatment assignments and hemoglobin levels) to adjudicate potential composite safety end-point events. The study population of patients not receiving dialysis, in PEARL 1 and 2, was smaller and had fewer patients with one or more events than the population of patients undergoing hemodialysis, in EMERALD 1 and 2 (197 patients vs. 375 patients), which led to a less precise estimate of the hazard ratio for the PEARL studies. The smaller study population and the randomization of patients in a 1:1:1 ratio in the PEARL studies may have contributed to the challenges of achieving balanced groups at baseline. Data on baseline levels of proteinuria, a strong predictor of cardiovascular risk in patients with chronic kidney disease, 29 were not collect ed; such data might have further informed our understanding of the observed differences. The effect of premature study withdrawals is also a potential limitation. However, the results of additional analyses, including an analysis of the primary efficacy end point in the per-protocol population and sensitivity analyses for efficacy and safety, were consistent with the results of the primary analyses. In conclusion, although our studies showed that monthly administration of peg in es a tide was as effective as administration of darbepoetin every 2 weeks in increasing and maintaining hemoglobin levels in patients with chronic kidney disease who were not receiving dialysis, there was an increase in cardiovascular events and deaths with peg in es a tide that was unexpected and remains unexplained, underscoring the need for additional data to clarify the benefit risk profile of peg in es a tide in this patient population. Supported by Affymax and Takeda Pharmaceutical. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Drs. Richard Stead and Paul Flyer for their many scientific contributions to the design, implementation, and analysis of the studies and for their insights on the interpretation of the results, and Julie Ann Obeid (of Affymax) and Laurie McClain (under contract with Affymax) for writing the preliminary drafts of the Methods and Results sections. References 1. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2: Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial. N Engl J Med 1987;316: Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase III multicenter clinical trial. Ann Intern Med 1989;111: Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990;335: [Erratum, Lancet 1990;335:614.] 5. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001;16:Suppl 3:

13 6. Kiss Z, Elliott S, Jedynasty K, Tesar V, Szegedi J. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact. Eur J Clin Pharmacol 2010;66: Macdougall IC. CERA (continuous erythropoietin-receptor activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 2005;4: Idem. Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol 2008;3: Woodburn KW, Holmes CP, Wilson SD, et al. Absorption, distribution, metabolism and excretion of peg in es a tide, a novel erythropoiesis-stimulating agent, in rats. Xenobiotica 2012;42: Livnah O, Stura EA, Johnson DL, et al. Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 Å. Science 1996;273: Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006; 34: Macdougall IC, Wiecek A, Tucker B, et al. Dose-finding study of peg in es a tide for anemia correction in chronic kidney disease patients. Clin J Am Soc Nephrol 2011;6: Eckardt K-U, Berns JS, Rocco MV, Kasiske BL. Definition and classification of CKD: the debate should be about patient prognosis a position statement from KDOQI and KDIGO. Am J Kidney Dis 2009;53: Finkelstein FO, Story K, Firanek C, et al. Health-related quality of life and hemoglobin levels in chronic kidney disease patients. Clin J Am Soc Nephrol 2009; 4: Chang A, Kramer H. Should egfr and albuminuria be added to the Framingham Risk Score? Chronic kidney disease and cardiovascular disease risk prediction. Nephron Clin Pract 2011;119(2): c171-c Go AS, Chertow GM, Fan D, Mc- Culloch CE, Hsu C-Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351: Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355: Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355: Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361: Fishbane S, Schiller B, Locatelli F, et al. Peg in es a tide in patients with anemia undergoing hemodialysis. N Engl J Med 2013;368: Postorino M, Marino C, Tripepi G, et al. Prognostic value of the New York Heart Association classification in end-stage renal disease. Nephrol Dial Transplant 2007;22: Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010;363: Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int 2008;74: U.S. Renal Data System Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Shamseddin MK, Parfrey PS. Sudden cardiac death in chronic kidney disease: epidemiology and prevention. Nat Rev Nephrol 2011;7: Woodburn KW, Wilson SD, Fong K-L, et al. Chronic preclinical safety evaluation of Hematide, a pegylated peptidic erythropoiesis stimulating agent, in monkeys. Haematologica 2008;93: Herzog CA, Stief JW, Collins AJ, Gilbertson DT. Cause-specific mortality of dialysis patients after coronary revascularization: why don t dialysis patients have better survival after coronary intervention? Nephrol Dial Transplant 2008; 23: Clarkson MR, Friedewald JJ, Eustace JA, Rabb H. Acute kidney injury. In: Brenner BM, ed. Brenner & Rector s The kidney. 8th ed. Philadelphia: Saunders Elsevier, 2007: Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108: Copyright 2013 Massachusetts Medical Society. nejm clinical practice center Explore a new page designed specifically for practicing clinicians, the NEJM Clinical Practice Center, at Find practice-changing research, reviews from our Clinical Practice series, a curated collection of clinical cases, and interactive features designed to hone your diagnostic skills. 332