Oral daprodustat on par with ESA for anaemia in CKD

The oral HIF-PHI* daprodustat was noninferior to standard treatment with erythropoiesis-stimulating agents (ESAs) for increasing haemoglobin levels to within target range, without increasing cardiovascular (CV) risk in patients with anaemia due to chronic kidney disease (CKD), regardless of whether they were dialysis dependent or not, according to the phase III ASCEND-D/-ND trials presented at ASN 2021.

“Anaemia is a problem for so many patients with CKD, and having to come to the hospital or give oneself a subcutaneous injection can become a bottleneck for treatment,” said lead author Dr Ajay Singh of Brigham and Women’s Hospital in Boston, Massachusetts, US. “Oral treatment has the power to be transformative for patient care.”

Also, many safety concerns over the use of ESAs have arisen recently. “The use of recombinant human erythropoietin and its derivatives for the treatment of anaemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events,” the researchers pointed out.

In the phase III ASCEND-D trial, 2,964 patients (median age 58–59 years, 57 percent male) with anaemia and CKD who were undergoing dialysis to receive oral daprodustat or an injectable ESA. The ESA given was either epoetin alfa for patients on haemodialysis or darbepoetin alfa for those undergoing peritoneal dialysis. [N Engl J Med 2021;doi:10.1056/NEJMoa2113379]

Haemoglobin levels rose by a mean of 0.28 g/dL in daprodustat-treated patients compared with 0.10 g/dL in those on ESA (mean adjusted difference, 0.18 g/dL; p<0.001) during the evaluation period from weeks 28 through 52 — thus meeting the prespecified margin for noninferiority between the two treatments.

In addition, daprodustat was also noninferior to ESA for the co-primary outcome of first major adverse cardiovascular event (MACE**), which occurred in 25.2 percent of patients in the daprodustat group compared with 26.7 percent in the ESA group over a median follow-up of 2.5 years (hazard ratio [HR], 0.93; p<0.001).

The team also reported on data of 3,872 patients (median age 67 years) not on dialysis in a separate trial, ASCEND-ND. [N Engl J Med 2021;doi:10.1056/NEJMoa2113380]

Similar findings were seen among these patients: haemoglobin levels rose by 0.74 g/dL in the daprodustat group compared with 0.66 g/dL in the ESA group (mean adjusted difference, 0.08; p<0.001) — again, meeting the prespecified noninferiority criteria.

The incidence of MACE was 19.5 percent in the daprodustat group vs 19.2 percent in the ESA group (HR, 1.03; p=0.005), also meeting the noninferiority criteria.

“We found that oral delivery of daprodustat worked just as well as conventional therapy — increasing and maintaining haemoglobin levels among non-dialysis patients and maintaining levels among patients on dialysis — and was just as safe,” Singh stated. “This could usher in a new way of treating people with kidney disease, avoiding injections while stimulating the body to produce red blood cells.”

While there were no apparent differences in adverse events (AEs), including serious AEs, between the two treatment groups, two AEs of special interest caught attention of experts. Specifically, oesophageal and gastric erosions as well as tumour progression/recurrence and cancer-related deaths were more common with daprodustat in patients not on dialysis — a signal not seen in patients who were dialysis dependent.

“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 investigation,” wrote Dr Patrick Parfrey from the Memorial University of Newfoundland, St. John's, Canada, in a linked editorial. [N Engl J Med 2021;doi:10.1056/NEJMe2117100]

“In these patients, a clinical indication for treatment should be more important than treatment because of a test result [ie, haemoglobin levels],” he added.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up,” Parfrey suggested, to which the study investigators also acknowledged that the duration of follow-up might not be sufficiently long to characterize the full risks.

*HIF PH: hypoxia-inducible factor prolyl hydroxylase inhibitor

**a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke.