both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.
“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.
Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.
Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.
Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
A class with a history of safety concerns
The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.
And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.
In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.
“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.
He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.
In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.
Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.