BACKGROUND: Peginesatide 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 peginesatide, 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 peginesatide once a month, at a starting dose of 0.025 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, peginesatide was 
noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The 
mean differences in the hemoglobin level with peginesatide 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 peginesatide 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 peginesatide 
relative to darbepoetin, with higher incidences of death, unstable angina, and 
arrhythmia with peginesatide.
CONCLUSIONS: The efficacy of peginesatide (administered monthly) was similar to 
that of darbepoetin (administered every 2 weeks) in increasing and maintaining 
hemoglobin levels. However, cardiovascular events and mortality were increased 
with peginesatide in patients with chronic kidney disease who were not 
undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; 
ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], 
NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).