ADELPHI, Md. – The majority of a Food and Drug Administration advisory committee on Oct. 18 did not recommend changes in the way darbepoetin alfa is currently dosed for treating anemia in patients with chronic renal failure who are not on dialysis, based on the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study.
Watch Elizabeth Mechcatie's video report on Aranesp.
Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA) marketed as Aranesp by Amgen Inc., approved in 2001, is indicated for treating anemia associated with chronic renal failure, in patients who are or are not on dialysis. Darbepoetin is similar to epotin alfa (approved in 1989 and marketed as Epogen and as Procrit), but has a longer half life. (Amgen manufactures Aranesp and Epogen, and Epogen is licensed to Johnson and Johnson.) In 2007, a warning about a greater risk of death and serious CV events associated with targeting higher hemoglobin levels with ESAs, compared with targeting lower levels, was added to the drugs’ labeling.
At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee was asked to review data from the TREAT study of mostly female patients in their late 60s, with type 2 diabetes and chronic renal failure, who were not on dialysis, to evaluate whether targeting a hemoglobin level of 13 g/dL would reduce the risk of death, cardiovascular and renal outcomes, when compared to the control group of patients. No benefit on these outcomes was seen, although anemia was corrected. Those in the control group were given rescue therapy with darbepoetin once a month when hemoglobin dropped to below 9 g/dL, and treatment was stopped when hemoglobin increased to 9 g/dL or more.
Moreover, the rate of stroke was higher among those in the treatment group overall, compared with those in the control group (4% vs. 2%) and among those with a previous history of stroke, the rate of stroke was threefold higher in the treatment group (12% vs. 4%). Among the patients with a history of malignancy at baseline, the rate of death from malignancies during the study (but not necessarily related to the previous malignancy) was higher among those in the treatment group.
In the control group, the median hemoglobin level achieved was 10.6 g/dL and two-thirds of patients did not receive a blood transfusion, 54% did not require any rescue treatment, and 45% did not need a transfusion or rescue treatment.
But the panel voted 9 to 5 with 3 abstentions, against recommending that the regimen used in the TREAT control group be adopted as the dose for this group of patients. Those voting against recommending a change cited an inadequate amount of data and evidence to support a change, as well as concerns that some patients would suffer with the symptoms of low hemoglobin levels and not meet criteria for treatment.
A warning about the increased risk of stroke was added to the label of all ESAs in 2009. Most of the panel voted against recommending that darbepoetin should be avoided for all patients with chronic kidney disease who have a history of a stroke regardless of whether they were on dialysis. However, several voting no objected to the inclusion of patients with chronic kidney disease who were on dialysis in the FDA’s question, who were not in the TREAT trial. Panelists strongly recommended that patients who are treated with darbepoetin be provided with an adequate informed consent that fully explains the increased risk of stroke.
The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of possible conflicts of interest related to the topic of the meeting; in some cases, they receive a waiver, but not at this meeting.