Daprodustat Shows Favorable Safety in Treating Anemia in CKD With, Without Dialysis

Results of 2 late-stage studies were released at the American Society of Nephrology's Kidney Week 2021 showing the safety and potential of a new oral therapy for patients with anemia due to chronic kidney disease (CKD) both on dialysis and not on dialysis.

The phase 3 trials of daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), compared the safety and efficacy of the therapy treated with erythropoiesis stimulating agents (ESAs), which must be given via subcutaneous injection or as part of dialysis.

Daprodustat improved or maintained hemoglobin within target levels, without increased cardiovascular risk, when compared with ESAs, the current therapy. The 2 trials, ASCEND-D and ASCEND-ND, used a composite marker of time to first major adverse cardiovascular event (MACE) a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke.

Anemia is a common problem in CKD as damaged kidneys become dysfunctional in their ability to produce erythropoietin (EPO), the hormone that signals red blood cell production.

ESAs act as stand-ins for EPO to directly stimulate the production of red blood cells, but HIF-PHI drugs work stabilize proteins known as hypoxia inducible factors, coaxing the body to produce its own EPO and improving iron mobilization to the bone marrow.

Safety concerns about ESAs include possible increased risk of stroke, myocardial infarction, vascular access thrombosis, tumor progression, and death.

In the ASCEND trials, sponsored by the drugmaker, GlaxoSmithKline, ASCEND-D looked at daprodustat in patients with CKD on dialysis (ASCEND-D); ASCEND-ND examined patients with CKD not on dialysis.

ASCEND-D randomized 2964 patients to either daprodustat or ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The mean (SD) baseline hemoglobin level was 10.4 (1.0) g per deciliter overall. The mean change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28 (0.02) g per deciliter in the daprodustat group and 0.10 (0.02) g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% CI, 0.12-0.24.

During a median follow-up of 2.5 years, a MACE occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (HR, 0.93; 95% CI, 0.81-1.07).

In ASCEND-ND, 3872 patients were randomized together daprodustat or darbepoetin alfa. The mean baseline hemoglobin levels were similar in the 2 groups. The mean change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74 (0.02) g per deciliter in the daprodustat group and 0.66 (0.02) g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% CI, 0.03-0.13), meeting the prespecified noninferiority margin of −0.75 g per deciliter.

During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (HR, 1.03; 95% CI, 0.89-1.19), which meeting the prespecified noninferiority margin of 1.25.

In both trials, prespecified noninferiority margins were met and the percentages of patients with adverse events were similar in the 2 groups.

The trial had several limitations, besides its open-label design. HIF-PH inhibitors could have oncogenic or other potential long-term adverse effects, so longer term follow-up is needed. The ESAs in the trials were darbepoetin alfa and epoetin alfa, so findings may not be applicable to other ESAs. However, the trials had larger sample sizes than previous clinical trials of HIF-PH inhibitors.