Peginesatide: Any Better Than ESAs for Dialysis Patients?
Peginesatide: Any Better Than ESAs for Dialysis Patients?
Hello. This is Jeffrey Berns from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. I am Editor-in-Chief of Medscape Nephrology. It seems very likely that there is going to be a new player in the erythropoiesis-stimulating agent (ESA) field relatively soon.
In December of last year, a US Food and Drug Administration (FDA) advisory committee recommended approval of peginesatide (formerly known as Hematide) for the treatment of anemia in patients who are on dialysis. Peginesatide is a synthetic pegylated peptide that stimulates the erythropoietin receptor just like the native hormone erythropoietin and recombinant human erythropoietin, as well as darbepoetin alfa. However, it is produced using chemistry rather than recombinant DNA technology. Its amino acid sequence is completely different from erythropoietin's, both the hormone and the recombinant drug that we have been using for over 20 years for the treatment of anemia related to chronic kidney disease (CKD). It can be given by monthly injection intravenously or subcutaneously.
The primary data about peginesatide come from 4 studies that were done in the United States and Europe. Two of the studies were done in hemodialysis patients and 2 were done in patients with CKD. The CKD studies used darbepoetin as the comparator and the hemodialysis studies used epoetin alfa or -beta as the comparator. The investigators were looking for hemoglobin endpoints, keeping the hemoglobin level within target range in patients who started with hemoglobin levels above 10 g/dL. Then they looked at safety endpoints. The composite safety endpoint included first occurrence of death, stroke, myocardial infarction, congestive heart failure, unstable angina, or arrhythmia. A major adverse cardiac event endpoint looked at just stroke, death, and myocardial infarction.
In the study that looked at hemodialysis patients, the efficacy of peginesatide was not inferior. These were noninferiority studies, not superiority studies. Peginesatide was noninferior to epoetin alfa, with comparable transfusion rates and composite cardiovascular and major cardiovascular endpoint rates. It is for the indication of use in hemodialysis patients that the FDA will be considering peginesatide.
Unfortunately, and for reasons that I think remain incompletely explained, the CKD [study results were not as favorable]. Although efficacy was also noninferior to darbepoetin alfa, there were more transfusions, cardiovascular events, and mortality, with a hazard ratio of about 1.3 (a 30% higher event rate for these various adverse events). Although not all of them were statistically significant, the trend was certainly in the wrong direction in terms of favoring darbepoetin over peginesatide.
Of some note is that neutralizing antibodies occurred in a little over 1% of patients treated with peginesatide. We are all familiar with the occurrence of pure red cell aplasia (PRCA) and neutralizing antibodies to erythropoietin that occurred in almost epidemic form a number of years ago. Some of these antibodies have been neutralizing only in vitro, but it appears that some have also been neutralizing in patients with flawed hemoglobins, the need for transfusions, and so forth. If peginesatide does, in fact, get approved, which is very likely, we will have to see what the clinically significant occurrence rate of neutralizing antibodies will be. So far, it seems to be quite low.
It is interesting to note that peginesatide was used for the treatment of anemia in dialysis patients who had erythropoietin antibody-mediated PRCA, which was reported a number of years ago in the New England Journal of Medicine.
I think it is always nice to have some pharmacologic competition out there. This will be a monthly therapy by either intravenous or subcutaneous injection, potentially for hemodialysis patients. That is a specific indication for which FDA approval is being sought, and it seems likely that we will be seeing peginesatide on the market before long.
Thank you for listening. This is Jeffrey Berns, Editor-in-Chief of Medscape Nephrology.
Hello. This is Jeffrey Berns from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. I am Editor-in-Chief of Medscape Nephrology. It seems very likely that there is going to be a new player in the erythropoiesis-stimulating agent (ESA) field relatively soon.
In December of last year, a US Food and Drug Administration (FDA) advisory committee recommended approval of peginesatide (formerly known as Hematide) for the treatment of anemia in patients who are on dialysis. Peginesatide is a synthetic pegylated peptide that stimulates the erythropoietin receptor just like the native hormone erythropoietin and recombinant human erythropoietin, as well as darbepoetin alfa. However, it is produced using chemistry rather than recombinant DNA technology. Its amino acid sequence is completely different from erythropoietin's, both the hormone and the recombinant drug that we have been using for over 20 years for the treatment of anemia related to chronic kidney disease (CKD). It can be given by monthly injection intravenously or subcutaneously.
The primary data about peginesatide come from 4 studies that were done in the United States and Europe. Two of the studies were done in hemodialysis patients and 2 were done in patients with CKD. The CKD studies used darbepoetin as the comparator and the hemodialysis studies used epoetin alfa or -beta as the comparator. The investigators were looking for hemoglobin endpoints, keeping the hemoglobin level within target range in patients who started with hemoglobin levels above 10 g/dL. Then they looked at safety endpoints. The composite safety endpoint included first occurrence of death, stroke, myocardial infarction, congestive heart failure, unstable angina, or arrhythmia. A major adverse cardiac event endpoint looked at just stroke, death, and myocardial infarction.
In the study that looked at hemodialysis patients, the efficacy of peginesatide was not inferior. These were noninferiority studies, not superiority studies. Peginesatide was noninferior to epoetin alfa, with comparable transfusion rates and composite cardiovascular and major cardiovascular endpoint rates. It is for the indication of use in hemodialysis patients that the FDA will be considering peginesatide.
Unfortunately, and for reasons that I think remain incompletely explained, the CKD [study results were not as favorable]. Although efficacy was also noninferior to darbepoetin alfa, there were more transfusions, cardiovascular events, and mortality, with a hazard ratio of about 1.3 (a 30% higher event rate for these various adverse events). Although not all of them were statistically significant, the trend was certainly in the wrong direction in terms of favoring darbepoetin over peginesatide.
Of some note is that neutralizing antibodies occurred in a little over 1% of patients treated with peginesatide. We are all familiar with the occurrence of pure red cell aplasia (PRCA) and neutralizing antibodies to erythropoietin that occurred in almost epidemic form a number of years ago. Some of these antibodies have been neutralizing only in vitro, but it appears that some have also been neutralizing in patients with flawed hemoglobins, the need for transfusions, and so forth. If peginesatide does, in fact, get approved, which is very likely, we will have to see what the clinically significant occurrence rate of neutralizing antibodies will be. So far, it seems to be quite low.
It is interesting to note that peginesatide was used for the treatment of anemia in dialysis patients who had erythropoietin antibody-mediated PRCA, which was reported a number of years ago in the New England Journal of Medicine.
I think it is always nice to have some pharmacologic competition out there. This will be a monthly therapy by either intravenous or subcutaneous injection, potentially for hemodialysis patients. That is a specific indication for which FDA approval is being sought, and it seems likely that we will be seeing peginesatide on the market before long.
Thank you for listening. This is Jeffrey Berns, Editor-in-Chief of Medscape Nephrology.
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