Peginesatide Rivals EPO as Anemia Treatment

Diedtra Henderson

January 25, 2013

Peginesatide taken once monthly was as safe and effective as epoetin taken 1 to 3 times per week in treating anemia suffered by patients with advanced chronic kidney disease who are undergoing hemodialysis, according to the findings of several open-label studies.

Steven Fishbane, MD, from Hofstra North Shore–Long Island Jewish School of Medicine, Great Neck, New York, and colleagues and reported pooled data from 4 studies in the January 24 issue of the New England Journal of Medicine.

An estimated 4.4 million Americans suffer from kidney disease, and the ailment ranks as the eighth leading cause of death, according to the National Center for Health Statistics. It is standard practice to prescribe erythropoiesis-stimulating agents (ESAs) for patients undergoing dialysis to partially correct anemia. Although ESAs increase hemoglobin levels, averting the need for blood transfusions, more intensive use can result in increased risk for adverse events such as myocardial infarction, stroke, other cardiovascular events, and death. Boxed warnings now caution about these risks and counsel healthcare practitioners to lower target hemoglobin levels.

In the Efficacy and Safety of Peginesatide for the Maintenance Treatment of Anemia in Patients with Chronic Renal Failure Who Were Receiving Hemodialysis and Were Previously Treated with Epoetin (EMERALD) 1 and EMERALD 2 studies, Dr. Fishbane and colleagues sought to compare the efficacy of peginesatide, a synthetic, pegylated, peptide-based ESA approved in March 2012 by the US Food and Drug Administration, with that of epoetin in US and European patients undergoing hemodialysis. The researchers pooled data from 4 studies, including 2 studies involving patients who were not undergoing dialysis, to study cardiovascular safety.

Patients who were at least 18 years of age with chronic kidney disease were enrolled in the 2 studies from September 2007 to January 2010. Patients were eligible if they had been undergoing hemodialysis for at least 3 months and had been receiving epoetin treatments continuously for at least 8 weeks. Twice as many patients were enrolled in the group that received peginesatide once every 4 weeks compared with the groups of US patients who continued receiving epoetin alfa and European patients who continued receiving epoetin beta treatments. Doses of both medications were adjusted to maintain the hemoglobin level between 10.0 and 12.0 g/dL for at least 52 weeks. Cardiovascular risk was determined by an adjudicated composite safety end point: death, stroke, myocardial infarction, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia.

Combining data from 693 patients in EMERALD 1 and 725 patients in EMERALD 2, the researchers determined that peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, −0.15 g/dL [95% confidence interval (CI), −0.30 to −0.01 g/dL] in EMERALD 1 and 0.10 g/dL [95% CI, −0.05 to 0.26 g/dL] in EMERALD 2). They also found no significant difference between peginesatide and comparator ESAs in the composite safety endpoint (hazard ratio [HR], 1.06; 95% CI, 0.89 - 1.26) in the 4 pooled studies (2591 patients) or in the EMERALD studies (HR, 0.95; 95% CI, 0.77 - 1.17).

"The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort," the authors write.

Eight patients developed neutralizing antibodies specific to peginesatide, which could blunt the medicine's efficacy. The authors suggest longer-term follow-up to gauge the frequency of antibody formation and its effect on patients' health.

Apples and Oranges?

Asked for independent comment, Jeffrey S. Berns, MD, professor of medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told Medscape Medical News that the study "certainly makes the case there is an option available now for less-frequent dosing than several times a week." Still, Dr. Berns would have preferred a study design that compared peginesatide with darbepoetin. Even though it is not labeled for such use, the drug is administered by nonprofit dialysis facilities once or twice a month to treat patients' anemia.

"It's appropriate to compare a monthly dosed drug to what we have in practice, which is epoetin dosed typically in dialysis patient 3 times a week," Dr. Berns told Medscape Medical News. Had darbepoetin been used as a comparator, "rather than apples and oranges, it would be comparing slightly different apples."

Because patients had "roughly clinically equivalent outcomes" taking peginesatide, he does not anticipate significant changes in the hemodialysis setting since decisions about ESAs "have been driven and will continue to be driven by economics.... I think the marketplace will determine where the drug finds its niche."

Among the study's limitations, the composite safety end point used to determine cardiovascular risk included soft end points, such as congestive heart failure; in this study population, adjudication of such events can be difficult. In addition, the open-label study design could have introduced bias and premature study withdrawals could have influenced results.

"Peginesatide, administered once a month, was similar to epoetin, administered one to three times a week, for the treatment of anemia in patients receiving hemodialysis," the authors conclude.

Support for this study was provided by Affymax and Takeda Pharmaceutical, which developed peginesatide. Several of the authors disclosed receiving consulting fees, payment for board membership, payment for developing educational presentations receiving institutional grants, serving as an expert witness before the US Food and Drug Administration, owning stock, and being employed by Affymax or Takeda. Authors also reported financial conflicts with other companies including Rockwell Medical, Akebia Therapeutics, Amgen, Janssen, Roche, Sandoz, Fresenius Medical Care, Pharmacosmos, DaVita, Abbott, Boehringer Ingelheim, Aethlon Medical, FibroGen, RoFAR, the Renal Research Institute, DSI Renal, Nephrology Associates, Celgene, Dynavax Technologies, Keryx Biopharmaceuticals, Merck, Mitsubishi, Otsuka, and Reata Pharmaceuticals. Dr. Berns was a member of the data and safety monitoring board for the EMERALD studies and is on the executive committee for a clinical trial for darbepoetin sponsored by Amgen.

N Engl J Med. 2013;368:307-319. Abstract