Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES)

Abstract

Background: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD).

Methods: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed.

Results: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52-1.25), P = 0.339; MACE+: 0.90 (0.61-1.32), P = 0.583].

Conclusions: Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.

Keywords: anaemia; chronic kidney disease; erythropoietin; haemoglobin.

Graphical abstract

FIGURE 1

Study flow chart. After a ≤6-week screening period, eligible patients were randomized (1:1) to receive roxadustat or DA for up to 104 weeks during the treatment period. An initial correction period^a to achieve Hb ≥11.0 g/dL and Hb CFB ≥1.0 g/dL occurred in both groups. This was followed by a maintenance period^b with dosing aimed at achieving Hb levels between 10.0 and 12.0 g/dL. Initial DA dosing^c was weight-based. During a 4-week follow-up period, anaemia treatment was at the discretion of study investigators.

FIGURE 2

Patient disposition. Of 930 patients who signed informed consent, 616 were randomized (roxadustat, n = 323; DA, n = 293). A total of 424 [roxadustat group, n = 215 (66.6%); DA group, n = 209 (71.3%)] patients completed 2 years of treatment, whereas 33.4 and 28.7% of patients discontinued treatment in the roxadustat and DA groups, respectively.

FIGURE 3

Mean (95% CI) levels of Hb (PPS). Mean Hb levels are shown with dotted lines in reference to the aim of achieving Hb levels between 10.0 and 12.0 g/dL. EOT, end of treatment; EOS, end of study.

FIGURE 4

Mean (95% CI) levels of LDL by visit (FAS). BL LDL levels were comparable between groups, but patients in the roxadustat group had LDL levels below the upper limit of normal (ULN) and lower than the DA group throughout the treatment period.

FIGURE 5

Mean (95% CI) levels of serum ferritin (A) and TSAT (B) by visit (FAS). The serum ferritin levels were comparable between the treatment groups beginning at BL and continuing throughout the end of the study (EOS). The TSAT percentages were comparable between the treatment groups beginning at BL and continuing throughout the EOS, rising above the lower limit of normal between Weeks 8 and 12 and never approaching the upper limit of normal (ULN).