Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients

Abstract

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysisdependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, −0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

“…Roxadustat, as compared to epoetin alfa treatment, previously resulted in approximately 5 times lower plasma erythropoietin concentrations, exposing patients to modest levels of endogenous erythropoietin within or near the physiologic range compared with epoetin alfa, which can increase levels to greater than 30 fold above normal [8, 32]. Because a similar trend toward increased DA doses compared with roxadustat doses in patients in the highest ERI quartile has also been observed in DD CKD patients, the consequences of these higher doses on clinical outcomes remain a research focus [25].…”

“…The endpoints of this post hoc analysis were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by the subgroup using the following factors chosen by expert opinion that have previously been associated with ESA hyporesponsiveness: the ESA resistance index (ERI) at baseline (quartile); iron repletion (ferritin <100 ng/mL and transferrin saturation [TSAT] <20%; ferritin <100 ng/mL and TSAT ≥20%; ferritin ≥100 ng/mL and TSAT <20%; ferritin ≥100 ng/mL and TSAT ≥20%) in the last 6 weeks; hs-CRP (nmol/L; <28.57, ≥28.57); presence of diabetes mellitus (DM) at baseline (with, without); eGFR (mL/min/1.73 m 2 ; ≥15, <15); CKD etiology (chronic glomerular nephritis [CGN], diabetic nephropathy [DN], nephrosclerosis [NS], and other); concomitant angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) use (yes, no); the geriatric nutritional risk index (GNRI) at baseline (quintile); and the prognostic nutritional index (PNI) at baseline (quartile) [25, 26]. Established cutoff values for select factors that denote increased risk for a diagnosis or harm or the upper limit of normal were used [27-31].…”

ESA, Iron Therapy and New Drugs: Are There New Perspectives in the Treatment of Anaemia?

“…Recently, Akizawa et al [ 78 ] performed a post-hoc analysis of a phase-3 RCT of Japanese HD patients to assess the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa dose needs. A significant increase in mean weight-adjusted dose needs at six weeks was observed for both roxadustat and darbepoetin alfa with increasing erythropoiesis responsive index (ERI), with a non-statistically significant trend of higher dose change with increasing ERI values for darbepoetin than roxadustat.…”

Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation

“… Currently available data on the effects of HIF-PHIs in ESA-hyporesponsive patients is inconclusive. 17,18,59  HIF-PHIs may have beneficial effects on iron absorption and mobilization, which could complement their effects on EPO production. Currently available data from phase 2 and 3 clinical trials offer evidence of improved iron utilization in patients treated with HIF-PHIs.…”

“…Phase 3 programs with 6 PHIs are ongoing or have been completed, the results of some of which have been published. [12][13][14][15][16][17][18][19][20] As of this writing 4 of these agents (roxadustat, vadadustat, daprodustat and enarodustat) have been licensed in Japan; roxadustat is licensed in China and Chile. Properties of the three PHIs with development programs in the US are summarized in Table 1.…”