Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both those who are dialysis dependent and those who are not, in a pair of phase 3 randomized trials that together included more than 6800 patients.
"Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and non-dialysis patients," said Ajay K. Singh, MBBS, who presented results from both studies at virtual Kidney Week 2021.
Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with nondialysis-dependent patients, ASCEND-ND, appeared online November 5 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 US Food and Drug Administration last July because of safety concerns, although it was approved in the EU.
And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that in patients with nondialysis-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," Wish said in an interview.
He cited in particular the data reported by Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by 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 1917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1935 patients treated with darbepoetin alfa, reported Singh, a nephrologist at Brigham and Women's Hospital in Boston, Massachusetts. 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 nondialysis-dependent CKD questions about indications and safety warrant further investigations," commented Patrick Parfrey, MD, in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
Safety Signals Seen for Cancers and Erosions
Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%) compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.
In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.
"The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis..., and post-marketing surveillance," wrote Parfrey, a nephrologist and professor at Memorial University of Newfoundland in St. John's, Canada.
Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Wish.
Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%) compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.
Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.
But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, "these things don't sink a drug. You deal with them in the drug's label," commented Wish.
During the FDA's advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.
Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.
Perhaps most importantly the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been "overdosed," resulting in faster increases in hemoglobin and higher peak levels.
Big Potential for Oral Anemia Treatment
In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.
US patients with CKD who do not require dialysis "often don't get treated for anemia because it is so cumbersome" to use ESAs on patients not treated at a centralized clinic, said Wish, medical director of the outpatient dialysis unit at Indiana University Hospital. "It's a logistical nightmare," he added.
On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.
Patients who receive an ESA during their three-times weekly dialysis session usually do very well. "It's not broken, and does not need to get fixed," Wish said.
ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.
Kidney Week 2021: American Society of Nephrology Annual Meeting. Presented November 5, 2021.
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. Follow him on Twitter @mitchelzoler.
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Cite this: Mitchel L. Zoler. Oral Daprodustat Safely Improves Anemia in Chronic Kidney Disease - Medscape - Nov 06, 2021.