FDA advisory panel recommends darbepoetin alpha remain on market

The Cardiovascular and Renal Drugs Advisory Committee voted 15 to 1 to recommend keeping darbepoetin on the market, despite an increased risk for stroke with the drug documented in the TREAT trial.

Darbepoetin alpha (Aranesp, Amgen Inc.), an erythropoiesis-stimulating agent (ESA), was initially approved in 2001 for the treatment of anemia associated with chronic renal failure for patients both on and off dialysis. The TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) was designed to test darbepoetin with anemia associated with chronic kidney disease (CKD) and with type 2 diabetes. The objectives of the randomized, double-blind, placebo-controlled, multi-center, international trial was to demonstrate the benefit of darbepoetin treatment of the anemia to a target hemoglobin level of 13 g/dL by reducing the occurrence of either of two primary endpoints: the composite CV endpoint of all-cause mortality or a specified CV event (myocardial ischemia, chronic HF, MI and stroke); and the composite renal endpoint of all-cause mortality or progression to end-stage renal disease vs. placebo.

All subjects (n=4,038) of the trial were randomized to either subcutaneous treatment with darbepoetin (n=2,012) to achieve a hemoglobin level of 13 g/dL or to receive matching placebo injection (n=2,026). According to a press release, efficacy and safety favored the placebo group. The CV composite HR (1.05; 95%CI, 0.94-1.17) and the renal composite HR (1.05; 95% CI, 0.95-1.19) both slightly favored placebo.

Furthermore, the risk of stroke was nearly twofold higher in the darbepoetin group when compared to placebo (5% vs. 2.6%).

Following presentations by the sponsor and the FDA, the advisory panel voted not to recommend withdraw of the use of darbepoetin in patients with chronic kidney disease not on dialysis, with one member abstaining from voting.

“I voted no,” said Peter Kaboli, MD, MS, associate professor, University of Iowa Carver College of Medicine, Iowa City VA Medical Center, Iowa City, Iowa. “I believe the drug has considerable safety concerns, but to answer this question there is not compelling evidence that it should be withdrawn for any indication. More discussion is needed for where it should be modified.”

“Clearly, TREAT and the other trials suggest that the high-dose aggressive regimen is not desirable,” Allan Coukell, director, The Pew Prescription Project, Washington, said on his vote to recommend withdraw. “The current labeling of a goal of 10-12 g/dL seems to me still rather close to the aggressive treatment that we’ve seen. I don’t think we know how best to use this drug in this population, nor am I fully convinced that the control arm tells us how best to use it.”

While the FDA is not obligated to follow the recommendations provided by the advisory panel, it very often does.

In an additional question taken at the end of the meeting, the panel also voted 10-4 with 3 members abstaining to not recommend avoiding use of darbepoetin in all patients with CKD with a prior history of stroke.

“I voted no,” said Darren K. McGuire, M.D., associate professor of medicine, University of Texas Southwestern Medical Center, Dallas. “There is a real possibility that these patients would derive particular benefit of elevated hemoglobin compared with a lower one. One consideration is to do a written informed consent to initiate darbepoetin therapy.”

On his vote yes, David Stroncek, MD, chief of cell processing, department of transfusion medicine, Clinical Center, National Institutes of Health, Bethesda, Md, explained that while he did recommend to avoid using darbepoetin in all patients with a history of stroke, it shouldn’t be prohibited in these patients either. “If it is given, it should be given with appropriate discussion and informed consent,” he added. – by Brian Ellis

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