Safety and Efficacy of Vadadustat for the Treatment of CKD-Related Anemia within and outside the United States.

Abstract

BACKGROUND Vadadustat's global clinical program was comprised of four noninferiority trials comparing vadadustat and darbepoetin alfa for CKD-related anemia: two in dialysis-dependent (DD)-CKD and two in non-dialysis-dependent (NDD)-CKD. While vadadustat met prespecified noninferiority criteria for hematological efficacy globally, it did not meet noninferiority criteria for cardiovascular safety in the NDD-CKD trials. The trials considered regional differences in treatment practices, including hemoglobin targets within (10-11 g/dL) and outside the US (10-12 g/dL). METHODS To examine region-specific outcomes, we performed prespecified analyses for US and non-US patient subgroups from the vadadustat global program. The primary safety end point was first occurrence of MACE (death from any cause, or nonfatal myocardial infarction or stroke). The primary efficacy end point was change in hemoglobin from baseline to average values during weeks 24-36. RESULTS 4084/7399 (55%) randomized patients were enrolled in the US. In pooled analyses of all US patients, MACE risk was similar among vadadustat-treated and darbepoetin alfa-treated patients (hazard ratio [HR] 1.03; 95% CI 0.90-1.17). HRs were similar for US patients with DD-CKD (HR 1.00; 95% CI 0.84-1.18) and NDD-CKD (HR 1.06; 95% CI 0.87-1.29). In pooled analyses of non-US patients, MACE risk was numerically higher among vadadustat-treated patients (HR 1.12; 95% CI 0.94-1.33); the higher risk was primarily attributed to the NDD-CKD subgroup (HR 1.29; 95% CI 1.03-1.60). In the non-US DD-CKD subgroup, MACE risk was similar among vadadustat-treated and darbepoetin alfa-treated patients (HR 0.88; 95% CI 0.67-1.17). Changes in hemoglobin were similar among treatment groups in all regions, as were rates of treatment-emergent and serious adverse events. CONCLUSIONS In patients with DD-CKD, safety (vis-à-vis MACE) and efficacy (vis-à-vis change in hemoglobin) of vadadustat and darbepoetin alfa were similar when stratified by region (US versus non-US). In US patients with NDD-CKD, safety and efficacy of vadadustat and darbepoetin alfa were similar.