DENVER—In patients with kidney disease, the investigational erythropoiesis-stimulating agent (ESA) peginesatide led to similar changes in hemoglobin as epoetin and darbepoetin. This finding, presented during the late-breaking clinical trial session here at the American Society of Nephrology Renal Week 2010, came from four Phase 3 randomized studies of a total of 2,610 patients.
“Patients have been greatly helped by the anemia treatments that have been available for chronic kidney disease, but unfortunately the current treatments have been somewhat inconvenient, both to patients and providers,” said principal investigator Steven Fishbane, MD, Professor of Medicine at the State University of New York at Stony Brook School of Medicine, in a phone interview.
“The results of this Phase 3 program for peginesatide indicate that, for the first time, there is an agent that in dialysis patients has a very consistent and clear spectrum of results that indicate excellent efficacy and safety even when administered once monthly, so that would be really important in terms of convenience of treatment.”
While the agent did have a comparable safety profile with epoetin in patients on dialysis, there were more safety events with peginesatide than with darbepoetin among patients with chronic kidney disease (CKD) who were not on dialysis.
“The safety signal is of concern in the CKD population, but in the hemodialysis population there was no safety signal, and that's encouraging,” said Rajiv Agarwal, MD, Professor of Medicine at Indiana University School of Medicine, who co-moderated the session during which the results were presented.
Peginesatide is a synthetic peptide-based ESA. “There is no structural homology to erythropoietin, and it binds to and stimulates the erythropoietin receptor, so this is an erythropoietin-mimetic agent,” Dr. Fishbane said during his presentation at the ASN meeting.
The agent was evaluated in two Phase 3 trials of patients on dialysis who were previously treated with epoetin—EMERALD 1 and EMERALD 2—and in two Phase 3 trials of non-dialysis patients with CKD who were not previously on anemia treatment—PEARL 1 and PEARL 2. EMERALD 1 and PEARL 1 were conducted in the United States, and EMERALD 2 and PEARL 2 in the United States and Europe.
Each dialysis study included 540 patients on monthly peginesatide and 270 patients on epoetin once to three times weekly, and each non-dialysis study included 330 patients on monthly peginesatide and 165 patients on darbepoetin alfa once every two weeks.
“This is the largest ESA study with a comparison of two active trial groups that evaluates efficacy and safety,” Dr. Fishbane said.
Efficacy was evaluated per study in terms of noninferiority, with a primary efficacy endpoint of the mean change in hemoglobin from baseline to the evaluation period.
In EMERALD 1, patients in the peginesatide group had a mean decrease in hemoglobin of 0.2 g/dL between baseline and Weeks 29-36, compared with a mean decrease of 0.1 g/dL in the epoetin group. In EMERALD 2, the mean decreases were 0.1 g/dL in the peginesatide group and 0.2 g/dL in the epoetin group.
“For the primary endpoint, noninferiority was very clearly met,” Dr. Fishbane said.
The secondary efficacy endpoint in the dialysis studies was the proportion of patients with a mean hemoglobin level within the target range of 10.0-12.0 g/dL during Weeks 29-36—63% in the peginesatide group and 72% in the epoetin group in EMERALD 1, and 64% in the peginesatide group and 66% in the epoetin group in EMERALD 2.
“That is virtually equivalent between the two groups,” Dr. Fishbane said. “A little bit of a difference in the EMERALD 1 study, but if you look at patients over time you'll see that the hemoglobin results were again virtually superimposable.”
In the non-dialysis studies, too, noninferiority was met for the primary efficacy endpoint, with hemoglobin increases of 1.4 g/dL to 1.7 g/dL in the peginesatide groups and 1.4 g/dL in the darbepoetin groups.
“The increase in hemoglobin from baseline to the evaluation period is almost exactly equivalent between the groups,” Dr. Fishbane said.
The proportions of non-dialysis patients reaching an increase in hemoglobin of at least 1 g/dL plus a hemoglobin level of at least 11 g/dL during Weeks 25-36 were also compared across the peginesatide and darbepoetin groups and shown to be similar, ranging from 91% to 95%.
In terms of transfusions, the percentages of patients receiving this intervention were similar for the peginesatide and epoetin groups in the EMERALD studies (8% to 10%) and for the peginesatide and darbepoetin groups in the PEARL 1 study (5% to 7%), but not for the two groups in the PEARL 2 study, where the percentage of patients who had a transfusion in the peginesatide group was about double that in the darbepoetin group.
“In non-dialysis we have this interesting and quirky finding that the rate of transfusion … was increased in the peginesatide group, so it's a little bit of an aberrant finding,” Dr. Fishbane said. “Why were there more transfusions among patients on peginesatide when there was such a clear demonstration of efficacy by any other measure that we could look at?”
For the safety analysis, data on a composite endpoint of death, stroke, myocardial infarction, congestive heart failure, unstable angina, and arrhythmia were pooled across all four studies.
Across these four studies, there were 1,625 events in 734 patients—385 patients in the peginesatide groups and 188 patients in the control groups, accounting for 22% of the total patient population in each.
The safety profile remained comparable across treatment types when data were evaluated for the dialysis studies alone, with 23% of the peginesatide patients and 24% of the epoetin patients having a composite safety event.
Among the non-dialysis patients, however, there was an imbalance in the safety endpoint, with 22% in the peginesatide groups and 17% in the darbepoetin groups having a composite safety event.
“From the first time that I heard this and in discussions with many of my colleagues, the question that comes up is: Is there any way that there could possibly be an intrinsic property of this drug that relates to the adverse findings in the non-dialysis population?” Dr. Fishbane said during a press conference at the ASN meeting.
“That seems so remarkably unlikely because of the dialysis study, where there was such a clean spectrum of findings—that is, no safety findings at all for a larger study that studied 1,600 patients in a much more fragile and vulnerable population—and if there were an intrinsic property of the drug that resulted in the safety issue in non-dialysis you would have had to have seen at least some signal of it.”
The non-dialysis studies did show some imbalances in baseline characteristics, Dr. Fishbane noted.
“When we look at the cardiovascular conditions at baseline, in the dialysis studies there were no differences that even strike in the least bit as being different, but I do have to note that despite the magic of randomization, there was some bad luck for peginesatide in the non-dialysis study. There was nothing that went against darbepoetin, but there were several things that went against the peginesatide group.”
But given the safety concerns in previous trials of ESAs in kidney disease, the burden on any clinical trial is to be very careful in not under-interpreting potential signals, said Ajay K. Singh, MBBS, MBA, Senior Nephrologist at Brigham and Women's Hospital, Associate Professor of Medicine at Harvard Medical School, and Chair of the Nephrology Times Editorial Board, during the question-and-answer session following the presentation.
“I am not aware of any single clinical trial that's ever been published where there hasn't been some imbalance that you see with regard to baseline characteristics,” he said. “If you look hard enough, by chance alone, there's almost always something. Do you not think that you'd want to be cautious in over-interpreting imbalances and things like that versus a potential reason for why we might see this difference in the non-dialysis population?”
Dr. Fishbane responded, “Dr. Singh is very correct that you don't want to over-interpret imbalances. … While randomization should do its magic, it often doesn't, but it almost always goes in both directions—little imbalances in both directions—and it is a remarkable, and I think unlucky, thing that in this non-dialysis study … that every potential relative covariance that could be important did go in the opposite direction. Nonetheless, totally sympathetic to your point.”
There isn't a clear mechanistic reason why the safety signal would be seen in one population but not the other, Dr. Singh noted in a phone interview.
“Having said that, we do know that we see a very heterogeneous type of clinical signal of adverse events when we use these drugs in patients.
“For example, in the TREAT study [Trial to Reduce Cardiovascular Events with Aranesp Therapy], with the use of darbepoetin there was a higher rate of stroke but no increased rate of heart failure or death, whereas in the CHOIR (Correction of Hemogloblin and Outcomes in Renal Insufficiency) study with epoetin alfa, there was a higher rate of heart failure and a higher rate of death, so could it be that this might be related to the type of agent and how this ESA agent interacts with the EPO [erythropoietin] receptors in different populations? I think that's an interesting area, but certainly an area of speculation.”
More research would be needed to clarify the safety signal seen in non-dialysis patients receiving peginesatide, noted Daniel W. Coyne, MD, EMERALD site investigator and Professor of Medicine in the Division of Renal Diseases at Washington University School of Medicine in St. Louis, in a phone interview.
“Although it does appear to be a marked imbalance in baseline risk that seemed to drive peginesatide looking worse than Aranesp [darbepoetin alfa], another large trial or two is really required to set that fear aside, and even if the drug were approved in that population, I think there'd be a lot of hesitancy to use it in the CKD population at this time.”
Affymax and Takeda confirmed in a Nov. 29 statement their plan to pursue approval of peginesatide for the treatment of anemia in patients on dialysis.
“We are only seeking an indication in the dialysis population at this time,” said Sylvia Wheeler, Vice President of Corporate Communications for Affymax, in a phone interview.
When asked if the companies expect to seek approval of the agent for the non-dialysis CKD population in the future, she said, “I can only tell you it's not in the plans right now. We'll continue to evaluate it and then reset expectations around that.”
If approved, peginesatide could offer the advantage of a more convenient dosing schedule.
“Based on the results of this Phase 3 program I want to be conservative in my interpretation and not imply that the Phase 3 results showed that the drug has either greater efficacy or greater safety than the existing available agents,” Dr. Fishbane said. “I think the great difference is the fact that this drug can be administered just once a month while maintaining excellent efficacy and safety, as well as very good hemoglobin stability.”