Summary
Background and objectives Peginesatide (Omontys) is a novel, synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent (ESA) that is designed to specifically stimulate the erythropoietin receptor. This study evaluated maintenance of hemoglobin levels in patients after conversion from darbepoetin alfa to once-monthly peginesatide.
Design, setting, participants, & measurements This open-label, multicenter study included 101 CKD patients, 52 of whom were receiving dialysis. The duration of the study was 24 weeks. The primary endpoint was the mean change in hemoglobin from baseline to the evaluation period (weeks 19–24). The study was conducted during the period from September 22, 2008 to December 24, 2009.
Results The mean change among hemodialysis patients was –0.42 g/dl (95% confidence interval, –0.65 to –0.19) and the mean change among CKD nondialysis patients was 0.49 g/dl (95% confidence interval, 0.26–0.71). The percentages of patients who maintained hemoglobin levels within ±1.0 g/dl of baseline values were as follows: 80.0% for hemodialysis and 68.1% for nondialysis, and73.3% for hemodialysis and 68.1% for nondialysis within the target range of 10.0–12.0 g/dl. Few patients received red blood cell transfusions (hemodialysis, 5.8%; nondialysis, 2.0%). Seventy-nine patients experienced adverse events, the majority of which were mild or moderate in severity. There were 40 serious adverse events and 2 deaths reported.
Conclusions In this study, once-monthly peginesatide resulted in a slight decrease in mean hemoglobin levels in individuals on hemodialysis and a small increase in individuals with CKD who were not on dialysis.
Introduction
CKD is a worldwide health problem with increasing incidence and prevalence (1). Anemia associated with CKD is primarily caused by the inability of the diseased kidneys to produce adequate amounts of endogenous erythropoietin (2). The prevalence of anemia increases with progressive deterioration of renal function, and anemia affects >90% of patients with ESRD (3).
Anemia is associated with increased mortality (4), increased likelihood of hospitalization (5), increased left ventricular hypertrophy and heart failure (6), and decreased quality of life (7,8). Erythropoiesis-stimulating agents (ESAs) are an effective treatment for CKD-associated anemia and have improved the management of anemia over alternatives such as transfusion. The use of ESAs has been associated with transfusion avoidance, decreased hospitalization, and—in some reports—an improved quality of life (9–12). In contrast, the use of ESAs to target near normal hemoglobin (Hb) levels for extended periods of time has been associated with adverse cardiovascular outcomes, an increased risk of death, and increase in thrombotic events (13–15). To date, all available ESAs have been recombinant erythropoietin proteins, and therefore have the potential to induce anti-erythropoietin antibodies and pure red cell aplasia (16). The first approved ESA, epoetin alfa, is administered up to three times per week (17). The frequent dosing requirement is often burdensome to patients and health care providers, and new agents allowing for less frequent dosing are desired. Less frequent dosing of ESAs could potentially allow more time for physicians and nurses to address other issues in patients (18); although this is particularly true in nondialysis patients, less frequent dosing could also decrease the time nurses spend preparing and injecting ESAs in dialysis patients. Darbepoetin alfa, although administered less frequently than epoetin alfa, is dosed up to once per week in dialysis patients (19). Although methoxy polyethylene glycol-epoetin β, a once-monthly ESA, is available in Europe (20) and in other parts of the world, it is currently not available in the United States; it is also a recombinant erythropoietin protein.
Peginesatide (Omontys) is a synthetic, PEGylated, peptide-based ESA that is designed to specifically stimulate the erythropoietin receptor. The amino acid sequence of peginesatide is unrelated to that of erythropoietin. The PEGylation of the peptide and its extended erythropoietic activity (21) allows for a once-monthly dosing interval. Results from the phase 3 peginesatide program have shown that peginesatide effectively maintained Hb levels after conversion from epoetin in CKD dialysis patients with once-monthly administration (22,23).
The purpose of this study was to demonstrate whether once-monthly peginesatide treatment could maintain Hb levels in CKD hemodialysis patients (HD) and CKD nondialysis patients (CKD-ND) after conversion from darbepoetin alfa treatment. The safety of peginesatide was also assessed.
Materials and Methods
Study Population
The study included adult HD and CKD-ND patients who were receiving stable doses of darbepoetin alfa for at least 8 weeks before enrollment. Patients were also required to have stable Hb levels and adequate iron stores (see Supplemental Table 1 for a list of key eligibility criteria). Key Hb and iron entry criteria included the following: four consecutive Hb values with a mean ≥10.0 and ≤12.0 g/dl during the screening period, with the difference between the mean of the first two consecutive Hb values and the mean of the last two consecutive values being ≤1.0 g/dl, and ferritin >100 ng/ml. The following comorbidities were excluded: known bleeding or coagulation disorder, poorly controlled hypertension within 4 weeks before enrollment, advanced chronic congestive heart failure (CHF) defined by New York Heart Association class III or IV, uncontrolled or symptomatic inflammatory disease, seizure disorder, or active malignancy. Patients provided written informed consent before participating in any study-specific procedures. The protocol was approved by the independent ethics committees of the participating centers (see protocol at ClinicalTrials.gov; identifier NCT00752609). The study was conducted in accordance with the Declaration of Helsinki (2002 version), the International Conference on Harmonization Good Clinical Practice Guidelines, and all applicable regulatory requirements.
Study Design
This was an open-label, multicenter, single-arm study to evaluate the conversion from darbepoetin alfa to peginesatide in HD and CKD-ND patients. The study consisted of a screening period (week −6 to week −1), enrollment (day 1/week 0), a titration period (weeks 0–18), and an evaluation period (weeks 19–24). Patients received their first dose of peginesatide during enrollment, which occurred on the day that the patient was to receive his or her next scheduled dose of darbepoetin alfa. Peginesatide starting doses were determined with the use of a tiered weight-based dose conversion table (Table 1). Peginesatide was administered via the same route (i.e., subcutaneous or intravenous) as each patient’s previous dose of darbepoetin alfa. Thereafter, peginesatide was administered at 4-week intervals throughout the study duration. During the titration and evaluation periods, peginesatide doses were adjusted according to the predetermined guidelines (Table 2) to maintain Hb levels in the range of 10.0–12.0 g/dl and within ±1.5 g/dl of baseline (i.e., the mean of the four most recent Hb values taken before enrollment and the value on the day of enrollment). Iron levels were recommended to be maintained according to the Kidney Disease Outcomes Quality Initiative treatment guidelines. Patient visits occurred every other week during the titration period and every week during the evaluation period.
Peginesatide starting doses
Regimen for dose adjustments
Study Drug
Peginesatide (Affymax Inc, Palo Alto, CA) was supplied as an aqueous, phosphate-buffered, isotonic, sorbitol solution (pH approximately 6.0). Each single-use glass vial contained 1 ml of solution at a peginesatide concentration of 10 mg/ml. The formulation included polysorbate 20 as a surfactant. Vials were stored at 2°C–8°C.
Assessments
At each study visit, Hb, concomitant medications, information about transfusions and therapeutic phlebotomies, and adverse events (AEs) were assessed. All reported AEs were graded by severity with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) (i.e., grades 1–5) (24). Events graded as 1 or 2 were considered mild and moderate, respectively. Each AE and serious adverse event (SAE) was assessed by the investigators as related or unrelated to the study drug. Each month, blood chemistry and hematology panel, serum pregnancy test, vital signs, and samples for assessment of peginesatide-specific antibodies were collected. Iron status evaluation and physical examination were performed every 12 weeks. Hb and all clinical laboratory tests were performed by a central laboratory.
Statistical Analyses
Patients who received at least one dose of the study drug were included in all analyses. For all results, HD and CKD-ND groups were listed separately. Baseline and demographic characteristics were summarized descriptively.
The primary efficacy endpoint was the mean change in Hb from baseline to the evaluation period (i.e., the mean of the Hb values from weeks 19 to 24). A two-sided 95% confidence interval (CI) of the estimated mean change from baseline in Hb was derived assuming that the variable follows a t-distribution. Secondary endpoints included the percentage of patients who had mean Hb values within the range of 10.0–12.0 g/dl during the evaluation period, the percentage of patients who had a change in Hb from baseline to the evaluation period within ±1.0 g/dl, and the percentage of patients who received red blood cell (RBC) transfusions during the titration and evaluation periods. For all secondary endpoints, a two-sided 95% CI of the percentage was calculated using the normal approximation with continuity correction. Primary and secondary endpoints were summarized descriptively. Median first and last doses of peginesatide were also summarized descriptively; doses of intravenous and subcutaneous peginesatide were listed separately for each group.
The safety evaluation included the incidence of AEs, AEs leading to withdrawal, the incidence of SAEs and deaths, the proportion of patients who received phlebotomies, the proportion of patients who had Hb excursions (i.e., two consecutive Hb values >12, >13, or >14 g/dl), clinical laboratory results, iron levels, vital signs, and peginesatide-specific antibodies. All safety results were summarized descriptively by group.
Results
Patient Disposition and Baseline and Demographic Characteristics
Patient disposition is provided in Figure 1. Of the 182 patients who were screened, a total of 102 patients were enrolled from 18 sites (10 in the United States, 3 in Italy, 3 in Australia, and 2 in the United Kingdom). One patient withdrew consent before receiving study treatment, leaving 101 patients for analysis (HD, n=52; CKD-ND, n=49). Ten patients discontinued from the study (HD, n=8; CKD-ND, n=2), four of them due to AEs.
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 nondialysis patients.
Baseline and demographic characteristics are detailed in Table 3. Mean baseline Hb values were similar for HD and CKD-ND patients, and diabetes was the most common primary cause of CKD in both groups. The majority of HD patients were on dialysis for >1 year at baseline. More HD patients had CHF than did CKD-ND patients. Median baseline ferritin levels in HD patients were more than twice that of patients not on dialysis; median transferrin saturation (TSAT) levels were similar in both groups.
Baseline and demographic characteristics
Efficacy Endpoints
The mean change in Hb from baseline to the evaluation period was 0.04 g/dl with a 95% CI of −0.14 to 0.23 g/dl. In the HD group, the mean (SD) change in Hb from baseline to the evaluation period was –0.42 (0.76) g/dl with a 95% CI of –0.65 to –0.19 (Table 4). In the CKD-ND group, the mean (SD) change in Hb from baseline to the evaluation period was 0.49 (0.77) g/dl with a 95% CI of 0.26–0.71 (Table 4). Over the course of the study, mean Hb values were in the range of 10.0–12.0 g/dl and they were maintained within ±1.0 g/dl from baseline in the majority of patients in both groups (Figure 2).
Primary and secondary endpoints
Mean (SD) hemoglobin change from baseline, by group. *Indicates a significant (P<0.05) change from baseline. HD, CKD hemodialysis patients; CKD-ND, CKD nondialysis patients.
Analysis of the secondary efficacy endpoints revealed that the majority of patients in both the HD and CKD-ND groups maintained Hb values within the range of 10.0–12.0 g/dl during the evaluation period (Table 4). The majority of patients in both groups maintained Hb values within ±1.0 g/dl of baseline during the evaluation period (Table 4). Few patients in either group received RBC transfusions during the study, including three patients in the HD group (one patient due to worsening anemia, one patient due to aortic valve replacement, and one patient due to multiple cardiovascular complications) and one patient in the CKD-ND group (one patient due to ARF) (Table 4).
Peginesatide Dosing
Because the HD group was receiving a higher mean baseline dose of darbepoetin alfa than the CKD-ND group (Table 3), the median starting dose of peginesatide was higher in the HD group than it was in the CKD-ND group (Table 5). This difference was maintained throughout the study, with the HD group having a higher median final dose of peginesatide than the CKD-ND group (Table 5).
Peginesatide doses, by group and route of administration
Safety
A total of 78.2% of patients reported at least one AE, most of which were assessed as either mild (50.3%) or moderate (39.6%) in severity. The most common AEs were diarrhea (15.4%), decreased appetite (13.5%), and nausea (11.5%) in the HD group and diarrhea (12.2%), upper respiratory tract infection (12.2%), and peripheral edema (12.2%) in the CKD-ND group. Other common AEs are presented in Table 6.
Most common (occurring in >5% of patients overall) adverse events, by group
AEs that led to study discontinuation occurred in two HD patients (vomiting related to nausea and decreased appetite; fatal ischemic cerebral infarction [detailed below]) and two CKD-ND patients (noncardiac chest pain; ARF). Four patients experienced AEs considered related to the study drug, including three HD patients (anemia; nausea, vomiting, and decreased appetite; cough) and one CKD-ND patient (hypotension). All of these AEs were mild or moderate in severity.
A total of 22 patients (HD, n=16; CKD-ND, n=6) reported 40 SAEs during the study. The most common SAEs (i.e., reported by >1 patient) were CHF (HD, n=1; CKD-ND, n=2), chest pain (HD, n=2), arteriovenous fistula thrombosis (HD, n=2), and hyperkalemia (HD, n=2). Two patients, both in the HD group, died during the study. One patient was a 69-year-old man who had an extensive history of smoking. This patient was hospitalized 5 weeks after his first dose of peginesatide because of a diagnosis of lung cancer. The patient received one additional dose of peginesatide, but died due to lung cancer. Baseline Hb was 10.6 g/dl and final Hb was 10.8 g/dl. The investigator considered the event unrelated to the study drug. The other death was in a 69-year-old woman with a history of peripheral vascular disease, pulmonary edema, cardiomyopathy, hypertension, and hyperlipidemia. Twelve days after the patient’s first 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. After discharge, the patient experienced a severe cerebral ischemic attack and was re-hospitalized. The patient did not attend her week 4 visit and was withdrawn from the study. The patient died due to cerebral ischemic attack 38 days after receiving her first and only dose of study drug. Hemoglobin level at enrollment was 12.3 g/dl and the final Hb level was 11.6 g/dl. The investigator considered the event and the outcome unrelated to the study drug because of the patient’s history of extensive peripheral and cardiovascular disease and other risk factors for stroke.
No therapeutic phlebotomies were required during the study.
During both the titration and evaluation periods, CKD-ND patients were more likely to experience a Hb excursion >12.0 g/dl than were HD patients (Table 7); excursions >13.0 g/dl or 14.0 g/dl were relatively infrequent (Table 7).
Hemoglobin excursions during the titration and evaluation periods, by group
Two patients in the HD group had liver enzymes >3 times the upper limit of normal. These elevations were temporary, were not associated with bilirubin elevations or clinical symptoms, and resolved without a change to the dose of study drug.
In the HD group, median (interquartile range [IQR]) serum ferritin was 366 (IQR, 391) ng/ml at baseline, which increased to 390 (IQR, 290) ng/ml at week 24; median TSAT was 29% (IQR, 19) at baseline, which increased to 39% (IQR, 19) at week 24. In the CKD-ND group, median serum ferritin was 174 (IQR, 131) ng/ml at baseline, which decreased to 110 (IQR, 90) ng/ml at week 24; median TSAT was 29% (IQR, 12) at baseline, which increased to 34% (IQR, 13) at week 24. None of these changes were statistically significant. Thirty-eight HD patients (73.1%) received iron supplementation during the study (intravenous, n=36 [69.2%]; oral, n=1 [1.9%]; route of administration missing, n=4 [7.7%]) and 23 CKD-ND patients (46.9%) received iron supplementation (intravenous, n=2 [4.1%]; oral, n=21 [42.9%]). Patients may have had more than one route of administration.
No patients developed peginesatide-specific antibodies during the study.
Discussion
Overall, the mean change in Hb from baseline to the evaluation period was 0.04 g/dl. During the evaluation period, mean Hb levels were within ±0.5 g/dl of baseline values and the majority of patients maintained Hb levels within ±1.0 g/dl of baseline and within the study target range of 10.0–12.0 g/dl. Overall, few patients received RBC transfusions. These data indicate that, after conversion from darbepoetin alfa, treatment response to peginesatide is within the range of what has been reported with other ESAs in current clinical use (25,26). Results of this study are also consistent with those of the phase 3 studies of peginesatide, which demonstrated that once-monthly peginesatide treatment maintained Hb levels in CKD patients on HD after conversion from epoetin treatment (22,23). The unique pharmacokinetic profile of peginesatide and its extended erythropoietic activity may explain the mechanism for the extended dosing interval.
There were some differences in Hb responses to peginesatide between the HD patients and CKD-ND patients, in that the mean Hb level decreased slightly in the HD group but increased slightly in the CKD-ND group from baseline 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, consistent with greater anemia severity in these patients, and lower doses of darbepoetin alfa in the CKD-ND group. During the study, median peginesatide doses were higher for the HD group and lower for the CKD-ND group. These results suggest that the peginesatide starting dose may have been lower than required for HD patients and higher than required for CKD-ND patients. These differences in treatment response may be explained by differences in baseline characteristics, anemia severity, and comorbidities between HD and CKD-ND patients. For example, the HD patients had a lower percentage of Black patients and a higher percentage of men, higher baseline serum ferritin and hsCRP levels, and a higher rate of CHF than did the CKD-ND group. Despite these differences, the results of this study show that peginesatide at 4-week intervals maintained Hb levels in the study target range of 10.0–12.0 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 during the titration and evaluation periods, likely a reflection of the higher-than-required starting doses that were used in the CKD-ND group. Excursions were more common during the titration period, as would be expected during a dose-adjustment interval (the titration period was also substantially longer than the evaluation period). Per the dose-adjustment guidelines, a dose decrease did not occur until a patient’s Hb level was ≥12.0 g/dl. Importantly, the incidence of sustained excursions greater than 13.0 or 14.0 g/dl was low.
Most AEs reported in this study were mild or moderate in severity and were generally typical of those experienced by patients with advanced CKD. No SAEs or deaths reported during the study were considered by the study investigators to be related to peginesatide, but the lack of randomization does not permit us to determine what proportion of the SAEs and deaths were due to the study drug. Because of safety concerns with the ESA class of drugs, deaths and cardiovascular events from this study were reviewed and no obvious safety signals in this regard were noted. No patients developed peginesatide-specific antibodies. Two patients developed fistula thromboses during the course of the study. Although the investigators assessed these AEs as unrelated to the study drug, it should be noted that fistula thromboses have been associated with the use of ESAs (13).
This study has several limitations. The study was a single-arm study, the sample size was relatively small, and the 24-week duration of the study did not allow for long-term evaluation of peginesatide. These limitations have been addressed in the phase 3 peginesatide development program (22,23). This was an open-label study and the primary endpoint was an objective measure (i.e., Hb levels, all of which were assayed at a central laboratory). There is a possibility, however, that the open-label nature of this study led to differential application of co-interventions (e.g., iron repletion), although there is no evidence to suggest that this occurred. In addition, the duration of the study was relatively short and there is a need for studies of peginesatide that are longer in duration to determine safety and efficacy after long-term treatment.
The ability to administer an ESA less frequently offers potential advantages. Results from a prospective observational study indicated that, compared with a thrice-weekly ESA, a once-monthly ESA may reduce injection-related personnel time by 79% (18). Another potential benefit of a once-monthly ESA is that nurses could devote more time to patient assessment and education, which could improve patient safety and satisfaction.
In conclusion, the results of this study indicated that peginesatide at 4-week intervals maintained hemoglobin levels in the majority of both HD and CKD-ND patients after conversion from darbepoetin alfa.
Disclosures
S.F. is a member of advisory boards of Affymax, Rockwell, and Akebia and is on a speakers’ panel for AMAG Pharmaceuticals. F.L. is a member of advisory boards of Affymax, Amgen, GlaxoSmithKline, Jansen, Pharmagenesis, Roche, Takeda, and Vifor Pharma, and is a member of a safety committee of Sandoz. S.D.R. is a member of advisory boards of Hoffmann-La Roche, Sandoz, Takeda, and Vifor Pharma, and is a member of a steering committee of an Amgen anemia trial. E.M. was a principal investigator for Affymax and Takeda. G.R., J.O., and P.Q. are employees of Takeda Global Research & Development Center Inc, Deerfield, Illinois.
Acknowledgments
We thank Steve Brunell for his medical writing support. Dr. Brunell, an Affymax, Inc. consultant, prepared the preliminary draft of the manuscript under the direction of the lead author, Dr. Steven Fishbane. Dr. Fishbane maintained full editorial control of the manuscript and its conclusions throughout its development. All authors had access to study data, contributed to the development of the manuscript, and approved the final version of the manuscript.
The following investigators participated in this study: Naveen Atray, FASN, Capital Nephrology Medical Group, Sacramento, California; Diogo Belo, California Institute of Renal Research, Chula Vista, California; Saroj Bhat, Fairlane Dialysis, Dearborn, Michigan; Giacomo Colussi, Azienda Ospedaliera, Ospedale Niguardo Cà Granda, Dipartimento di Nefrologia, Milan, Italy; Bruce Cooper, FRACP, MM (Clin Epi), Royal North Shore Hospital, Department of Renal Medicine, St Leonards, New South Wales, Australia; Alexander Disney, FRACP, The Queen Elizabeth Hospital, Renal Unit, Woodville, South Australia, Australia; Mohamed El-Shahawy, Academic Medical Research Institute, Los Angeles, California; Steven Fishbane, Winthrop University Hospital, Division of Nephrology and Hypertension, Mineola, New York; Giacomo Garibotto, Azienda Ospedaliera Universitaria “San Martino,” Genova, Italy; Christopher J. LeBrun, Nephrology Associates, Columbus, Mississippi; Francesco Locatelli, Azienda Ospedaliera Provinciale di Lecco “Ospedale Alessandro Manzoni,” Lecco, Italy; Edouard R. Martin, South Florida Research Institute, Lauderdale Lakes, Florida; Bhasker Rai Mehta, Arlington Nephrology, Arlington, Texas; Sandip Mitra, Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom; Nicholas R. Pritchard, Addenbrooke’s Hospital, Cambridge, United Kingdom; Bruce A. Pussell, GCHSM, Prince of Wales Hospital, Randwick, New South Wales, Australia; David A. Roer, Nephrology & Hypertension Associates, Middlebury, Connecticut; Simon D. Roger, Renal Research, Gosford, New South Wales, Australia; Michael Suranyi, Liverpool Hospital, Liverpool, New South Wales, Australia; Mark Thomas, Birmingham Heartlands Hospital, Birmingham, United Kingdom; Giuseppe Villa, U.O. di Nefrologia ed Emodialisi, dell’Istituto Scientifico di Pavia, Fondazione S. Maugeri-Clinica del Lavoro e della Riabilitazione (IRCCS), Pavia, Italy; Raja I. Zabaneh, Northwest Louisiana Nephrology, Shreveport, Louisiana.
This study was sponsored by Takeda Global Research & Development Center Inc, Deerfield, Illinois, with collaboration from Affymax Inc, Palo Alto, California.
Some data contained in this manuscript were presented in abstract form at the 2010 Annual Meeting American Society of Nephrology, November 16–21, 2010, in Denver, Colorado.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.03440412/-/DCSupplemental.
- Received April 5, 2012.
- Accepted November 8, 2012.
- Copyright © 2013 by the American Society of Nephrology
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