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

Article

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

Iain C. Macdougall,* Andrzej Wiecek,† Beatriz Tucker,‡ Magdi Yaqoob,§ Ashraf Mikhail, Michal Nowicki,¶ Iain MacPhee,** Michal Mysliwiec,†† Olgierd Smolenski,‡‡ Władysław Sułowicz,§§ Martha Mayo, Carol Francisco, *Renal Unit, King’s Krishna R. Polu, Peter J. Schatz, and Anne-Marie Duliege College Hospital, London, United Kingdom; †Department Summary of Nephrology, Background and objectives Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis- Endocrinology and stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a popu- Metabolic Diseases, Medical University of lation of 139 nondialysis chronic kidney disease patients. Silesia, Katowice, Poland; ‡Mayday Design, setting, participants, & measurements Chronic kidney disease patients who were not on dialysis and University Hospital, not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug adminis- Croydon, United Kingdom; §Department tration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (dif- of Nephrology, ferent body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and Hypertension and frequency of administration (every 4 or 2 weeks). Kidney Transplant, Royal London Hospital, London, United Results Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship Kingdom; ʈRenal was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses pro- Medicine, Morriston duced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions Ͼ13 g/dl Hospital, Swansea, tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The United Kingdom; ¶Department of range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all co- Nephrology, horts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious Hypertension and event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were Kidney Transplant, consistent with those routinely observed in this patient population. Medical University of Lodz, Poland; **Renal Medicine, St. George’s Conclusions This study suggests that peginesatide administered every 4 weeks can increase and maintain Hospital, London, hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of United Kingdom; †† patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimu- Department of lating agent. Nephrology and Transplantation, Clin J Am Soc Nephrol 6: 2579–2586, 2011. doi: 10.2215/CJN.10831210 Wojewo´dzki Szpital Specjalistyczny, Bialystok, Poland; ‡‡Department of Introduction Peginesatide is a synthetic, PEGylated, investiga- Nephrology, Anemia in patients with chronic kidney disease tional, peptide-based ESA that acts via stimulation of Wojewo´dzki Szpital (CKD) is often accompanied by a decreased quality of the erythropoietin receptor (8). In a study of healthy Specjalistyczny, life and an increased risk of red blood cell (RBC) volunteers, peginesatide was well tolerated and associ- Krakow, Poland; §§Department of transfusions (1,2). The mainstay of treatment for this ated with a clinically and statistically significant increase Nephrology, Oddział condition is erythropoietin-replacement therapy with in hemoglobin (Hb) that was sustained for Ͼ1 month Kliniczny Kliniki an erythropoiesis-stimulating agent (ESA), which has (9). Because the amino acid sequence of peginesatide is Nefrologii Szpitala Uniwersyteckiego, been associated with an improved quality of life (3) unrelated to that of erythropoietin, peginesatide is un- Krakow, Poland; and and fewer RBC transfusions (4). Several ESAs are likely to induce a cross-reactive immune response ʈʈAffymax, Inc., Palo currently available in the United States and Europe against either endogenous or recombinant erythropoie- Alto, California for the correction of anemia in CKD, but these agents tin. Indeed, a clinical study of peginesatide showed that are approved for dosing three times per week (such as it increased the Hb in most patients with antierythro- Correspondence: Prof. Iain C. Macdougall, epoetin alfa) or dosing every 2 weeks (such as darbe- poietin antibody-mediated pure red cell aplasia (PRCA) Renal Unit, King’s poetin alfa) (5–7). Another ESA (methoxy polyethyl- from protein-based ESAs (10). College Hospital, ene glycol-epoetin beta) is approved and marketed These preliminary findings supported further London SE5 9RS, UK. for dosing every 2 weeks to once monthly in Europe. study in a broader population of nondialysis CKD Phone: 44-203-299- 6233; Fax: 44-203-299- These large protein-based molecules require complex patients who were anemic. Most patients in this study 6472; E-mail: manufacturing processes using recombinant DNA received every-4-weeks dosing with peginesatide iain.macdougall technology and mammalian cell lines. from the outset. The primary objective of the study @nhs.net www.cjasn.org Vol 6 November, 2011 Copyright © 2011 by the American Society of Nephrology 2579 2580 Clinical Journal of the American Society of Nephrology

was to determine the range of peginesatide doses that in a long-term extension study were followed for 28 days increase and maintain Hb between 11 and 13 g/dl, an after their last peginesatide dose, until the stabilization of acceptable Hb range when the study was conducted. The AEs, or until Hb concentration was Ͻ13.0 g/dl, whichever safety and tolerability of peginesatide were also evaluated. occurred later.

Materials and Methods Study Drug TM Study Population Peginesatide (Hematide ; Affymax, Inc., Palo Alto, The study included adult patients with CKD stage 3 or 4 CA) was supplied as a preservative-free, aseptically man- (estimated GFR of Յ60 ml/min per 1.73 m2). Before study ufactured, sterile parenteral isotonic phosphate-buffered drug administration, patients were required to have two solution in a single-use vial. Hb values from 9.0 to Ͻ11.0 g/dl and adequate iron stores (serum ferritin concentration Ն100 ng/ml and transferrin Assessments saturation [TSAT] Ն20%). The main exclusion criteria in- Pharmacodynamic response was assessed by the per- cluded ESA treatment in the 12 weeks before study drug centage of patients in each cohort who achieved a Hb administration and previous hemodialysis or peritoneal response, defined as a Hb increase of Ն1.0 g/dl from dialysis. A complete list of eligibility criteria is provided in baseline (mean of the three Hb values [two screening and Supplementary Table 1. one predose] collected most recently before the first peginesatide dose) and a Hb value of Ն11.0 g/dl at any time Study Design during the study. Other pharmacodynamic parameters This was a phase 2, multicenter, open-label, sequential, were the mean changes from baseline in Hb and reticulo- dose-finding study conducted at six sites in the United cyte counts, and the percentages of patients during the first Kingdom and seven sites in Poland. All of the sites re- 8 weeks of the study who experienced rapid rates of Hb Ͼ Ͼ ceived approval from their ethics committee/institutional increase ( 1 g/dl increase in any 2-week period or 2 review board, all of the patients provided written informed g/dl increase in any 4-week period) and elevated Hb ex- Ͼ consent, and the study was performed in accordance with cursions (Hb 13 g/dl). Hemoglobin data collected sub- the Declaration of Helsinki and the International Confer- sequent to a phlebotomy, or within 4 weeks after a RBC ence on Harmonisation Guidelines for Good Clinical Prac- transfusion, were excluded. tice. The study was registered with ClinicalTrials.gov Safety was assessed from AE reports. AE severity was (NCT00228436). graded according to the World Health Organization Tox- The study design allowed for multiple cohorts of pa- icity Criteria (grades 1 to 4; grades 1 and 2 were considered tients, with Յ15 patients sequentially enrolled in each. mild and moderate, respectively). The main serious AEs Patients received peginesatide treatment for Յ24 weeks. (SAEs) were fatal, life-threatening, or required hospitaliza- Ͼ Cohorts differed in starting peginesatide dose (body tion ( 24 hours). Each AE and SAE was assessed by the weight–based or absolute doses), route of administration investigators as being either related or unrelated to the (intravenous [IV] or subcutaneous [SC]), and frequency of study drug. Other safety end points included reasons for administration (every 4 weeks [Q4W] or every 2 weeks study withdrawal, number of phlebotomies and RBC [Q2W]). In the first cohort, SC peginesatide was adminis- transfusions, changes in clinical laboratory results and vital tered Q4W (0.05 mg/kg starting dose). The decision to add signs, and antibody evaluations. the next cohort in the sequence was made on the basis of predetermined criteria including the observed safety Statistical Analyses and pharmacologic response for this cohort. After week 5, This was an exploratory study intended to characterize each patient’s peginesatide dose was adjusted on the basis the preliminary efficacy and safety of peginesatide and of prespecified dosing guidelines (Supplementary Table 2). inform dose selection for future studies. Therefore, sample Enrollment of new patients and dosing of patients in a sizes were not determined by power calculations to eval- cohort was stopped if Ն3 patients had a grade 3 or 4 uate specific hypotheses. The number of patients per co- treatment-related adverse event (AE). A safety monitor, hort was considered sufficient to generate meaningful not a data and safety monitoring board, reviewed the pharmacodynamic and safety data to guide the design of clinical, laboratory, and safety data throughout the study. larger investigational studies. The results for cohorts with Hemoglobin, reticulocytes, and reticulocyte hemoglobin identical starting doses and dosing strategies were com- content were monitored weekly through week 13 and ev- bined for purposes of summarization. A cross-cohort mul- ery other week thereafter. AEs were monitored throughout tivariate regression analysis was performed to assess the the study. Vital signs, clinical laboratory parameters, and effect of administration of the first peginesatide dose and 12-lead electrocardiograms were assessed periodically dur- selected demographic and baseline characteristic variables ing the study. Blood samples for antibody evaluations on maximum Hb change from baseline before administra- were collected periodically during the study and tested tion of the second peginesatide dose. after study completion. Iron status, monitored by regular measurements of serum ferritin levels and TSAT, was rec- Results ommended to be maintained according to European Best Patient Disposition and Baseline Characteristics Practice Guidelines (11,12) with administration of supple- A total of 139 patients were enrolled in the study, which mental iron as needed to prevent iron deficiency and main- was conducted between September 2005 and November tain adequate iron stores. Patients not enrolling 2007 (Figure 1). Patients were assigned to one of 10 cohorts: Clin J Am Soc Nephrol 6: 2579–2586, November, 2011 Peginesatide in Anemia Correction, Macdougall et al. 2581

Figure 1. | Patient disposition. three cohorts with the identical starting dose, dose fre- Demographic and baseline characteristics are detailed in quency, and route of administration were combined (Co- Table 2. Patients had a mean (SD) age of 65 (14) years and hort A), for a total of eight cohorts for analysis (Table 1). Body were predominantly male (54%) and white (73%). The weight–based starting doses were investigated in Cohorts primary causes of CKD were diabetes (40%) or other (29%; A through F, whereas absolute starting doses were inves- mainly included interstitial nephritis or renovascular dis- tigated in Cohorts G and H. Q4W dosing was investigated ease). The mean (SD) estimated GFR was 25 (10) ml/min in Cohorts A, B, C, D, G, and H, whereas Q2W dosing was per 1.73 m2. investigated in Cohorts E and F. SC dosing was investigated in all cohorts except Cohort D (IV dosing). Two patients in Cohort E received all of their doses intrave- Pharmacodynamics Across all cohorts, 96% of patients achieved a Hb re- nously, in error, rather than subcutaneously. All of the sponse; a comparable proportion of patients in each cohort enrolled patients received at least one peginesatide dose achieved a Hb response (Table 3). Across all cohorts, the and were included in the analyses. Sixteen patients were mean (SD) Hb concentration increased by 1.4 (1.3) g/dl withdrawn from the study (Figure 1). from baseline to study end. A lower starting dose (0.025 mg/kg) of SC Q4W pegi- Table 1. Dosing cohorts nesatide (Cohort C) increased Hb more slowly than did a higher starting dose (0.05 mg/kg, Cohort A), suggesting a relationship between starting doses and Hb response rate Cohort n Peginesatide Dosing Route of Starting Dose Frequency Administration (Figure 2A). Similar initial increases in mean Hb levels from baseline were observed in Cohorts A (0.05 mg/kg SC A 45 0.05 mg/kg Q4W SC B 15 0.075 mg/kg Q4W SC Q4W starting dose) and B (0.075 mg/kg SC Q4W starting C 15 0.025 mg/kg Q4W SC dose; Figure 2A). Similar starting doses of body weight- D 15 0.05 mg/kg Q4W IV based and absolute-dose SC Q4W regimens (median start- E 15 0.025 mg/kg Q2W SCa ing doses of 3.8 and 4.0 mg for Cohorts A and G, respec- F 4 0.0375 mg/kg Q2W SC tively) resulted in comparable Hb responses (Figure 2A). A G 15 4.0 mg Q4W SC multivariate analysis was performed to evaluate the H 15 3.0 mg Q4W SC maximum Hb change from baseline before administration of the second dose, using the first dose and baseline Q4W, every 4 weeks; SC, subcutaneous; IV, intravenous; Q2W, demographics and characteristics as covariates; among every 2 weeks. all possible linear combinations of the baseline variables, a Because of dosing errors, two patients received their the best model for predicting maximum Hb change in- peginesatide doses via the intravenous route rather than the cluded only the first dose (P ϭ 0.02). Each cohort confi- subcutaneous route. dence interval (CI) did not include zero; Cohort G had 52Ciia ora fteAeia oit fNephrology of Society American the of Journal Clinical 2582

Table 2. Demographic and baseline characteristics

Cohort A Cohort B Cohort C Cohort D Cohort E Cohort F Cohort G Cohort H Total Characteristic (0.05 mg/kg SC (0.075 mg/kg SC (0.025 mg/kg SC (0.05 mg/kg IV (0.025 mg/kg SC (0.0375 mg/kg SC (4.0 mg SC (3.0 mg SC (n ϭ 139) Q4W n ϭ 45) Q4W n ϭ 15) Q4W n ϭ 15) Q4W n ϭ 15) Q2W n ϭ 15) Q2W n ϭ 4) Q4W n ϭ 15) Q4W n ϭ 15)

Age, mean (SD), years 64.8 (13.6) 64.7 (14.3) 63.9 (12.3) 59.9 (16.0) 62.5 (14.6) 68.3 (12.6) 68.7 (13.0) 65.7 (15.0) 64.5 (13.8) Men, n (%) 26 (57.8) 11 (73.3) 8 (53.3) 5 (33.3) 6 (40.0) 0 12 (80.0) 7 (46.7) 75 (54.0) Race, n (%) white 32 (71.1) 7 (46.7) 10 (66.7) 10 (66.7) 13 (86.7) 4 (100.0) 11 (73.3) 14 (93.3) 101 (72.7) black 7 (15.6) 3 (20.0) 2 (13.3) 1 (6.7) 1 (6.7) 0 1 (6.7) 0 15 (10.8) other 6 (13.3) 5 (33.3) 3 (20.0) 4 (26.7) 1 (6.7) 0 3 (20.0) 1 (6.7) 23 (16.5) Weight, mean (SD), kg 77.9 (16.3) 81.3 (13.8) 84.7 (26.0) 71.5 (17.4) 81.4 (23.9) 67.3 (21.0) 82.0 (19.7) 76.2 (16.7) 78.6 (18.8) Primary cause of CKD, n (%) diabetes 14 (31.1) 7 (46.7) 8 (53.3) 6 (40.0) 6 (40.0) 1 (25.0) 8 (53.3) 5 (33.3) 55 (39.6) hypertension 7 (15.6) 0 1 (6.7) 0 2 (13.3) 1 (25.0) 1 (6.7) 0 12 (8.6) polycystic kidney disease 5 (11.1) 0 1 (6.7) 0 0 0 1 (6.7) 1 (6.7) 8 (5.8) urologic 3 (6.7) 0 0 1 (6.7) 0 0 0 0 4 (2.9) autoimmune disease 1 (2.2) 0 0 0 1 (6.7) 0 0 1 (6.7) 3 (2.2) unknown 6 (13.3) 0 0 2 (13.3) 3 (20.0) 1 (25.0) 3 (20.0) 2 (13.3) 17 (12.2) othera 9 (20.0) 8 (53.3) 5 (33.3) 6 (40.0) 3 (20.0) 1 (25.0) 2 (13.3) 6 (40.0) 40 (28.8) eGFR, mean (SD), ml/min per 1.73 m2 24.4 (8.3) 26.9 (9.8) 25.7 (14.2) 25.7 (8.9) 24.9 (10.7) 17.8 (5.6) 25.5 (6.8) 25.3 (12.9) 25.0 (9.8) Hemoglobin, mean (SD), g/dl 10.3 (0.5) 10.2 (0.5) 10.2 (0.5) 10.0 (0.5) 10.1 (0.5) 10.3 (0.4) 10.1 (0.7) 10.1 (0.6) 10.2 (0.5)

SC, subcutaneous; Q4W, every 4 weeks; IV, intravenous; Q2W, every 2 weeks; CKD, chronic kidney disease; eGFR, estimated GFR. aMainly included interstitial nephritis or renovascular disease.

Table 3. Hemoglobin parameters, by cohort: hemoglobin response, rapid rates of increased hemoglobin, and hemoglobin excursions

Cohort A Cohort B Cohort C Cohort D Cohort E Cohort F Cohort G Cohort H Total Hemoglobin Parameter, n (%) (0.05 mg/kg SC (0.075 mg/kg SC (0.025 mg/kg SC (0.05 mg/kg IV (0.025 mg/kg SC (0.0375 mg/kg SC 4.0 mg (SC (3.0 mg SC (n ϭ 139) Q4W n ϭ 45) Q4W n ϭ 15) Q4W n ϭ 15) Q4W n ϭ 15) Q2W n ϭ 15) Q2W n ϭ 4) Q4W n ϭ 15) Q4W n ϭ 15)

Patients who achieved a Hb response 44 (97.8) 15 (100.0) 15 (100.0) 14 (93.3) 14 (93.3) 4 (100.0) 13 (86.7) 14 (93.3) 133 (95.7) Patients with Ͼ1 g/dl Hb increase 31 (68.9) 13 (86.7) 9 (60.0) 11 (73.3) 13 (86.7) 3 (75.0) 12 (80.0) 11 (73.3) 103 (74.1) during any 2-week perioda Patients with Ͼ2 g/dl Hb increase 12 (26.7) 3 (20.0) 0 (0) 5 (33.3) 12 (80.0) 1 (25.0) 4 (26.7) 3 (20.0) 40 (28.8) during any 4-week perioda Patients with Hb excursionsa,b 6 (13.3) 1 (6.7) 0 (0) 2 (13.3) 5 (33.3) 1 (25.0) 1 (6.7) 1 (6.7) 17 (12.2)

SC, subcutaneous; Q4W, every 4 weeks; IV, intravenous; Q2W, every 2 weeks; Hb, hemoglobin. aDuring the first 8 weeks of the study. bHemoglobin concentrations Ͼ13 g/dl on at least two consecutive measurements. Clin J Am Soc Nephrol 6: 2579–2586, November, 2011 Peginesatide in Anemia Correction, Macdougall et al. 2583

Figure 2. | Mean hemoglobin change from baseline. (A) In SC Q4W Cohorts. (B) With matched peginesatide starting doses delivered subcutaneously (Cohort A) or intravenously (Cohort D). (C) With equivalent (i.e., the same dose over a 4-week time period) peginesatide starting doses delivered Q4W (Cohort A) or Q2W (Cohort E). Q2W, every 2 weeks; Q4w, every 4 weeks. the largest change (1.59 g/dl, 95% CI 1.21 to 1.95), and Peginesatide Dosing Cohort C had the smallest change (0.91 g/dl, 95% CI 0.55 The median dose for the Q4W cohorts generally de- to 1.28). creased during the study (Figure 3), and the median final Identical starting doses of SC (Cohort A) and IV (Cohort dose ranged from 0.019 to 0.044 mg/kg. This effect was D) Q4W peginesatide resulted in comparable mean Hb particularly pronounced in the highest starting dose cohort levels (Figure 2B). Notably, the median doses in Cohorts A (Cohort B; 0.075 mg/kg) and was also evident in the Q2W and D were similar throughout the study (Figure 3), sug- cohorts. gesting that a given dose may produce a similar Hb response irrespective of the route of administration. Safety Hemoglobin concentrations of patients who received AEs were reported by 112 of 139 patients (81%); most of Q2W peginesatide (Cohort E) tended to increase more these patients (90 [65%]) had only AEs that were consid- rapidly, and to higher concentrations, than did those of ered mild to moderate in severity. The most frequently patients who received an equivalent (same total dose over reported AEs (occurring in Ն5% of patients) are detailed in a 4-week period) starting Q4W peginesatide dose (Cohort Table 4. AEs considered possibly related to peginesatide by A; Figure 2C). Rapid rates of Hb increase, particularly the investigators were reported in 16 (11.5%) patients; the Ͼ increases 2 g/dl during any 4-week period (e.g., 80.0% most common (occurring in Ն2 patients) were hyperten- Ͻ versus 26.7%, Cohorts E versus A, P 0.001), and Hb sion (n ϭ 9, 6.5%), arthritis (n ϭ 2, 1.4%), and headache excursions (e.g., 33.3% versus 13.3%, Cohorts E versus A, (n ϭ 2, 1.4%). ϭ P 0.12) generally occurred in more patients in the Q2W A total of 36 SAEs were reported by 27 of 139 patients than the Q4W cohorts (Table 3). Because of the higher (20%). The most frequently reported SAEs (occurring in Ն2 proportion of Hb excursions observed with Q2W admin- patients) were chronic renal failure (i.e., worsening of renal istration, enrollment in Cohort F was stopped on the basis function; n ϭ 6, 4.3%), bronchitis (n ϭ 2, 1.4%), and diabetic of sponsor judgment to prevent rapid rates of Hb increase, ketoacidosis (n ϭ 2, 1.4%). A single SAE (embolic cerebral and not because of AEs. These Cohort F patients had their infarction) was considered possibly related to peginesatide next dose reduced, and thereafter their dosing was per the by the investigator; see patient narrative in Supplementary protocol-specified dose-adjustment guidelines. Table 3. Two deaths occurred during the study, one caused by chronic renal failure and one caused by acute myocardial infarction and bronchitis. Neither death was reported as being related to peginesatide; see Supplementary Table 3 for patient narratives. Six patients were withdrawn from the study because of AEs. Two patients withdrew because of nonserious AEs (dizziness and nausea in one patient and skin necrosis in the other). Four patients withdrew because of SAEs (chronic renal failure, renal failure, multiple myeloma, and catheter site hematoma and peritonitis [after peritoneal dialysis]; none were considered related to peginesatide). A single patient in Cohort B underwent a phlebotomy (500 ml), 27 days after the second peginesatide dose, because of a Hb concentration of 15.2 g/dl. The patient’s Hb progressively decreased to 12.2 g/dl within 30 days after Figure 3. | Median peginesatide doses in the every-4-weeks cohorts, the phlebotomy. The patient’s third peginesatide dose was by injection. administered 30 days after the phlebotomy. Subsequent 2584 Clinical Journal of the American Society of Nephrology

peginesatide doses were delayed and/or decreased be- Ͼ

139) cause of Hb concentrations 12.5 g/dl. The patient did not ϭ Total 8 (5.8) 7 (5.0) 8 (5.8) have any AE considered possibly related to peginesatide ( n by the investigator. Five patients received RBC transfusions during the study (Cohort A, n ϭ 1; Cohort C, n ϭ 1; ϭ ϭ 15) Cohort G, n 2; and Cohort H, n 1), two patients ϭ

n because of anemia/low Hb concentrations and three pa- 3 (20.0) 10 (7.2) 1 (6.7) 0 2 (13.3) 9 (6.5) 1 (6.7) 3 (20.0) 8 (5.8) 1 (6.7) 10 (7.2) 2 (13.3) 14 (10.1) 1 (6.7) 18 (12.9) tients because of posthemorrhage anemia. Cohort H (3.0 mg SC Q4W Iron status was maintained throughout the study with the use of IV iron. For the cohorts that included Ն15 patients, 20 to 60% of patients per cohort received IV iron 15)

ϭ at some point during the study. Mean initial and end-of- n study values were 269 and 260 ng/ml, respectively, for 0 1 (6.7) 1 (6.7) 1 (6.7) 0 1 (6.7) 0 3 (20.0) 0 (0) Cohort G (4.0 mg SC

Q4W ferritin; 25.9 and 30.1%, respectively, for TSAT; and 32.8 and 33.4 pg, respectively, for reticulocyte hemoglobin content.

4) No patient had an electrocardiogram abnormality inter-

ϭ preted by the investigator as clinically significant that was n not present at screening. Alanine aminotransferase eleva- 2 (50.0) 1 (25.0) 0 0 1 (25.0) 1 (25.0) 1 (25.0) 1 (25.0) 1 (25.0) Cohort F

Q2W tions at least three times the upper limit of normal were

(0.0375 mg/kg SC observed once each in four patients; no SAEs were associated with these elevations (see Supplementary Table 3 for patient narratives). Other clinical laboratory tests and vital

15) sign assessments generally remained within normal limits ϭ

n and were similar to baseline values throughout the study. 0 0 4 (26.7) 1 (6.7) 3 (20.0) 1 (6.7) 0 5 (33.3) 3 (20.0) Peginesatide-specific antibodies were detected in two Cohort E

Q2W patients. The first patient was from Cohort B, and antibod- (0.025 mg/kg SC ies were first detected in the sample collected before the patient’s fifth Q4W peginesatide dose (week 17). At week

15) 25, the binding antibody titer reached 1:160, and a low, in

ϭ vitro neutralizing antibody titer (1:20) was recorded. The n 0 0 1 (6.7) 0 1 (6.7) 0 0 2 (13.3) 1 (6.7) neutralizing antibodies did not appear to affect the pa- Cohort D

Q4W tient’s Hb response (Hb at baseline, 10.7 g/dl; Hb at weeks (0.05 mg/kg IV 19 to 25, 11.7 to 11.9 g/dl) or safety profile. The second patient was from Cohort E, and antibodies were first detected in the sample collected before the patient’s twelfth 15)

ϭ Q2W peginesatide dose (week 25). At week 29, the binding n antibody titer reached 1:20, and a low, in vitro neutralizing 1 (6.7) 0 1 (6.7) 1 (6.7) 1 (6.7) 0 0 1 (6.7) 1 (6.7) Cohort C antibody titer (1:10) was recorded. The neutralizing anti- Q4W

(0.025 mg/kg SC bodies did not appear to affect the patient’s Hb response (Hb at baseline, 9.9 g/dl; Hb at weeks 25 to 29, 11.4 to 12.0 g/dl) or safety profile. This patient had a slight decrease in

15) Hb after discontinuation of peginesatide, but the Hb al- ϭ

n ways remained above 10 g/dl. The patient initiated darbe- 2 (13.3) 2 (13.3) 0 0 0 0 1 (6.7) 2 (13.3) 3 (20.0)

Cohort B poetin alfa treatment after discontinuation of peginesatide.

Q4W In both patients, the peginesatide-specific antibodies did (0.075 mg/kg SC not cross-react with erythropoietin. > 5% of patients) reported adverse events, by cohort 45)

ϭ Discussion n This phase 2 dose-finding study found that 96% of pa- 1 (2.2) 3 (6.7) 4 (8.9) 2 (4.4) 1 (2.2) 6 (13.3) 3 (6.7) 3 (6.7) Cohort A tients achieved an Hb response by study end. Moreover, Q4W (0.05 mg/kg SC mean Hb values across all cohorts increased by 1.4 g/dl from baseline to study end. These results indicate that different peginesatide starting doses and dosing strategies

(%) (e.g., IV or SC) can elicit a robust pharmacodynamic re- n sponse in nondialysis CKD patients who were recently naive to ESA treatment. Across all cohorts, the median peginesatide dose decreased during the study. This effect was particularly

Adverse Event, pronounced in cohorts with the highest starting doses. Table 4. Most frequently (occurring in SC, subcutaneous; Q4W, every 4 weeks; IV, intravenous; Q2W, every 2 weeks. Peripheral edema Chronic renal failure Increased blood pressure 2 (4.4) Urinary tract infection Nausea Back pain Nasopharyngitis Hypertension Diarrhea The doses required to maintain Hb in the target range Clin J Am Soc Nephrol 6: 2579–2586, November, 2011 Peginesatide in Anemia Correction, Macdougall et al. 2585

(final median doses of 0.019 to 0.044 mg/kg in the Q4W uscript were presented in abstract form at the 2007 and 2009 World cohorts) guided the selection of peginesatide starting Congress of Nephrology conferences, the 2006 and 2007 American doses for this patient population in phase 3 studies Society of Nephrology annual meetings, the 2006 and 2007 Con- (0.025 and 0.04 mg/kg). gresses of the European Renal Association-European Dialysis and Studies of epoetin alfa have demonstrated that lower Transplant Association, and the 2006 International Lu¨beck Confer- doses can be used with SC than with IV administration ence on the Pathophysiology and Pharmacology of Erythropoietin (13). The results from this study suggest that Hb responses and other Hemopoietic Growth Factors. The following investigators to comparable doses of IV and SC peginesatide may be participated in this study: Vipula DeSilva, Mayday University Hos- similar, which has also been shown with the long-acting pital, Croydon, United Kingdom; Simon Fletcher, University Hospi- ESAs, darbepoetin alfa (14–17) and methoxy polyethylene tals Coventry and Warwickshire NHS Trust, Coventry, United King- glycol-epoetin beta (18,19). Future studies are needed to dom; Kevin P. G. Harris, Leicester General Hospital, Leicester, evaluate the similarity of IV and SC dose requirements for United Kingdom; Iain C. Macdougall, King’s College Hospital, Lon- peginesatide. don, United Kingdom (lead investigator for the United Kingdom); The rate of Hb increase was higher, and there tended to Iain MacPhee, St. George’s Hospital, London, United Kingdom; be more Hb excursions Ͼ13 g/dl with Q2W peginesatide Ashraf I. Mikhail, Morriston Hospital, Swansea, United Kingdom; compared with an equivalent Q4W dose. This information Muhammad Magdi Yaqoob, The Royal London and St. Bar- helped inform the selection of a Q4W dosing interval in the tholomew’s Hospitals, London, United Kingdom; Michal Mysliwiec, phase 3 trials. Wojewodzki Szpital, Bialystok, Poland; Michal Nowicki, Sa- Most patients in this study (81%) experienced at least modzielny Publiczny Szpital Kliniczny, Lodz, Poland; Olgierd Smo- one AE with 90 (65%) patients experiencing only AEs lenski, Centrum Dializ Fresenius NephroCare, Krakow, Poland; Wla- considered mild to moderate in severity. The most com- dyslaw Sulowicz, Oddział Kliniczny Kliniki Nefrologii Szpitala mon AE considered possibly related to peginesatide by the Uniwersyteckiego, Krakow, Poland; Andrzej Wiecek, Medical Uni- investigators was hypertension. Of the 36 reported SAEs, a versity of Silesia, Katowice, Poland (lead investigator for Poland); single SAE (embolic cerebral infarction) was considered Richard J. Fluck, Derby City General Hospital, Derby, United King- possibly related to peginesatide by the investigator. The dom; Boleslaw Rutkowski, Klinika Nefrologii Transplantologii, AEs and SAEs reported in this study were consistent with Gdansk, Poland; Ryszard Gellert, IV Oddzial Chorob Wewnetrznych those observed in this patient population; however, this z Pododdzialem Nefrologicznym, Szpital, Warszawa, Poland; and study was not designed to definitively determine the Philip A. Kalra, Hope Hospital, Salford, United Kingdom. safety of peginesatide relative to an active control. Two patients developed peginesatide-neutralizing antibodies Disclosures during this study. The antibody titers were low and did Iain C. Macdougall has received consultancy fees, research sup- not appear to affect the patients’ Hb concentrations or port, and lecture honoraria from Amgen, Ortho Biotech, Roche, safety profiles; however, this study did not have long-term Affymax, Takeda, and Vifor Pharma. Andrzej Wiecek received follow-up of these patients. Importantly, given the lack of speakers fees from Amgen, Roche, and Hospira; was an Advisory immunological cross-reactivity of peginesatide with eryth- Board member of Affymax/Takeda, Bayer, Jannesen-Cilag, Roche, ropoietin (20), the potential risk of inducing antibody- and Hospira; and was an investigator for studies sponsored by mediated PRCA with peginesatide is extremely low. No Jannsen-Cilag, Roche, Affymax/Takeda, and Hospira. Ashraf patients with peginesatide-induced PRCA have been re- Mikhail was an investigator for studies sponsored by Amgen, ported during clinical trials. Cases of antibody-mediated Roche, Affymax/Takeda; received sponsorship to attend scientific PRCA have been described with protein-based ESAs, albeit meetings from Amgen, Roche, and Johnson & Johnson; and re- rarely (5,6). ceived consultancy fees from Amgen, Roche, Astellas, Takeda, and This study had several limitations: the sample size was Lipoxen. Olgierd Smolenski was an investigator for a clinical relatively small, follow-up was limited to the 24-week study sponsored by Amgen. Beatriz Tucker, Michal Nowicki, Iain study period, subjects were not randomized to the differ- MacPhee, Michal Mysliwiec, Władysław Sułowicz, and Magdi ent cohorts because the cohorts were enrolled sequentially, Yaqoob have nothing to disclose. Martha Mayo, Carol Francisco, and there was no control group. Hence, these results may Krishna Polu, Peter J. Schatz, and Anne-Marie Duliege are em- not be fully generalizable to the larger CKD population. ployees of Affymax, Inc. In conclusion, the results of this study show that Q4W peginesatide can increase and maintain Hb in nondialysis CKD patients. These results guided the dosing strategies References used in the phase 3 studies in nondialysis patients. 1. Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. 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