Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial

Abstract

<b><i>Background:</i></b> Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. <b><i>Methods:</i></b> Japanese patients not on dialysis (ND) (<i>N</i> = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin &#x3e;100 ng/mL or transferrin saturation &#x3e;20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25–250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40–52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. <b><i>Results:</i></b> Mean hemoglobin levels during weeks 40–52 were 12.0 g/dL in the daprodustat group (<i>n</i> = 108; 95% confidence interval [CI], 11.8–12.1) and 11.9 g/dL for CERA (<i>n</i> = 109; 95% CI 11.7–12.0); the difference between the groups was 0.1 g/dL (95% CI −0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of −1.0 g/dL. The mean hemoglobin level was within the target range (11.0–13.0 g/dL) during weeks 40–52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. <b><i>Conclusions:</i></b> Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.