ESA Hyporesponders More Likely to Receive Higher Doses of Daprodustat, ESA

Vivekanand Jha, MBBS, MD

Credit: The George Institute for Global Health

Patients categorized as erythropoiesis-stimulating agent hyporesponders (ESA-HR) were more likely to receive a higher assigned dose of daprodustat and ESA at week 52, according to a poster presented at the National Kidney Foundation (NKF) 2024 Spring Clinical Meeting.¹ Results also revealed that although the use of daprodustat in ESA-HR and non-ESA-HR patients were comparable, ESA-HR patients receiving ESAs could require different dose adjustment considerations compared with non-ESA-HR patients.

“ESA-HR is used to describe patients who do not achieve target hemoglobin levels despite higher than appropriate dosing based on body weight and is associated with a higher risk of morbidity and mortality,” wrote a team of investigators led by Vivekanand Jha, MBBS, MD, executive director at The George Institute for Global Health, India and chair of Global Kidney Health, Faculty of Medicine, Imperial College of London.

In a subgroup post hoc analysis of the phase 3, randomized, active-controlled, parallel-group, open-label, multicenter, event-driven ASCEND-D study, investigators assessed the dose and number of dose adjustments for daprodustat—an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of anemia in patients with chronic kidney disease (CKD) receiving dialysis for ≥ 4 months—or ESA. The cohort included patients stratified by response to ESA (ESA-HR or non-ESA-HR) or weight quartiles at baseline. Patient weight was split into < 63.0kg (Q1), < 63.0—74.7kg (Q2), < 74.7—88.5kg (Q3), and ≥ 88.5kg (Q4).

ESA-HR was defined as erythropoietin resistance index (ERI) ≥ 2.0U (units)/kg/week/g/L or a prior ESA dose (U/week) at baseline divided by the baseline estimated dry weight (kg) ≥ 450U/kg/week.

Patients were randomized 1:1 to receive either once-daily oral daprodustat or an injectable ESA. The median treatment dose at week 52, as well as the number of dose adjustments from the beginning of the trial to end of treatment (EoT) by ESA-HR status at baseline were assessed. Any differences in the percentage of patients with ≥ 10 dose adjustments—in either ESA-HR or non-ESA-HR groups—among each treatment arm were evaluated.

In total, 183 ESA-HR patients and 1284 non-ESA-HR patients received daprodustat, while 180 ESA-HR patients and 1279 non-ESA-HR patients were treated with ESA.

At the end of the study period, the median dose of daprodustat and ESA were higher among the ESA-HR cohort when compared with the non-ESA-HR group. Overall, the median number of dose adjustments were lower in those receiving daprodustat compared with ESA (2.58 vs 2.55 patient years, respectively).

Throughout the analysis, the percentage of patients with ≤ 2 dose adjustments were comparable between the ESA-HR group and the non-ESA-HR group for daprodustat (21% vs 17%, respectively) and ESA (20% vs 17%, respectively. Similarly, the percentage of patients with ≥ 10 dose adjustments were not significantly different in the ESA-HR and non-ESA-HR cohorts receiving daprodustat (27% vs 22%, respectively; P = .0556). However, these percentages were slightly higher in the ESA-HR arm vs the non-ESA-HR arm for those receiving ESA (41% vs 30%, respectively; P = .0020).

From day 1 to EoT, the percentage of patients requiring ≤ 2 dose adjustments were comparable among all weight quartiles for patients receiving either treatment. However, the percentage of patients needing ≥ 10 dose adjustments was higher in the weight quartile 1 (< 63.0kg) compared with other weight quartiles among both treatment arms.

The safety analyses by both ESA-HR and weight quartiles were similar to the coprimary major adverse cardiovascular events (MACE) analysis in the original study and showed little to no heterogeneity between subgroups.

References

1. ^{Jha V, Claggett B, Bhatt N, Jones-Leone A, et al. Daprodustat (dapro) dosing among prespecified subgroups including erythropoiesis-stimulating agent hyporesponders (ESA-HR) in dialysis-dependent patients (pts) in the ASCEND program. Poster presented at: National Kidney Foundation 2024 Spring Clinical Meeting (SCM). Long Beach, CA. May 14 – 18, 2024.}