ASN 2010: Peginesatide Associated with Increased Risk of CV Events

Investigators reported at Renal Week 2010, the American Society of Nephrology 43rd Annual Meeting and Scientific Exposition, that a pooled analysis of data from four clinical trials regarding the cardiovascular safety of the prospective drug peginesatide (Hematide) shows that the agent is essentially “noninferior” in its ability to increase hemoglobin when compared with darbepoetin and epoetin, two products commonly prescribed for treatment of anemia in patients with kidney disease.

But a review of composite safety endpoints defined for the trials also confirms earlier reported data that revealed peginesatide to be associated with a greater number of unstable angina, arrhythmia, and patient fatality events in chronic renal failure patients who have not progressed to the point where they require dialysis.

Last year, results from pivotal trials indicated that peginesatide was responsible for higher numbers of adverse events in pre-dialysis patients, prompting the drug’s makers to indicate they would gather more information and seek a modified route of FDA approval. The review to determine non-inferiority, based on an evaluation of composite safety endpoints sought to demonstrate that peginesatide is not inferior to comparable products on the market by more than a prespecified amount.

Previous clinical trials on the candidate peptide were divided into pre- and post-dialysis patient populations. PEARL 1 and PEARL 2 were both phase III randomized controlled trials designed to evaluate the safety and efficacy of peginesatide compared to darbepoetin alfa for anemia in chronic renal failure (CRF) patients not receiving dialysis, or who had not received treatment with erythropoiesis-stimulating agents.

PEARL 1 enrolled 490 American patients and PEARL 2 enrolled 493 American and European patients. They were randomized to receive either peginesatide in monthly starting doses of 0.025 or 0.04 mg/kg, or two-week starting doses of darbepoetin at 0.75 μg/kg, titrated to maintain hemoglobin levels of 11-12 g/dL. In both studies, peginesatide was found to be noninferior to darbepoetin in its increase of hemoglobin. But 21.6% of the peginesatide patients experienced adverse events, compared to 17.1% of patients receiving darbepoetin.

The drug fared better in two additional trials that focused on kidney disease patients undergoing dialysis, or who had previously been treated with Amgen’s epoetin alfa or beta. EMERALD 1 and 2 were phase III randomized controlled trials designed to test the safety and efficacy of peginesatide in such patients.

EMERALD 1 enrolled 803 American patients; EMERALD 2 enrolled 823 American and European patients. Patients who had received hemodialysis for three months and epoetin for eight weeks were randomized to receive peginesatide once monthly or epoetin one to three times weekly. The peginesatide starting dose was determined with a conversion table based on a screening of the epoetin doses, and doses were titrated to maintain target hemoglobin levels of 10-12 g/dL.

With regard to these trials, the pooled analysis reported at Renal Week 2010 concludes that peginesatide is noninferior to epoetin in the treatment of anemia in dialysis patients. Moreover, its safety profile is similar to that of epoetin in this population.