Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia

Abstract

Background and objectivesDaprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.Design, setting, participants, & measurements This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants’ treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10–60 μg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40–52 in the intent-to-treat population.ResultsOf 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40–52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, −0.1 to 0.2 g/dl) was greater than the noninferiority criterion of −1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0–12.0 g/dl) during weeks 40–52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (−37%; 95% CI, −49 to −23) than with darbepoetin alfa (−20%; 95% CI, −36 to −1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.ConclusionsOral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40–52 in Japanese patients receiving hemodialysis switched from ESAs.Clinical Trial registry name and registration number201754, Clinicaltrials.gov, NCT02969655.

Profile of Daprodustat in the Treatment of Renal Anemia Due to Chronic Kidney Disease

“…Among Japanese hemodialysis patients who received ESA treatment, death and cancer progression were not reported during the 52-week study period. 28 Among the adverse events reported in ≥5% of patients per group, contusion and diarrhea were reported ≥5% more frequently in the daprodustat group than in the darbepoetin alfa group. Similar to a phase 2 study, 25 the incidence of hyperkalemia was reported in the daprodustat group (3%) compared to the darbepoetin alfa group (1%).…”

“…Akizawa et al conducted a 52-week, randomized, double-blind, phase 3 study to assess the noninferiority of daprodustat in maintaining the hemoglobin level among Japanese hemodialysis patients and its safety compared to darbepoetin alfa (NCT02969655). 28 Every participant received a stable dose of ESA treatment (darbepoetin alfa 10–60 µg/week, epoetin (including biosimilars) ≤9000 IU/week, or epoetin beta pegol up to 250 µg/4 weeks) at least 10 weeks before screening. Among 271 patients, 136 were randomized, receiving 4 mg daprdodustat with dose titration every 4 weeks based on a prespecified algorithm to achieve or maintain the target hemoglobin level (10–12 g/dl).…”

“…However, plasma VEGF level increased only when a high dose of daprodustat (50–100 mg) was administered to healthy participants, 19 and several phase 2 studies showed that daprodustat had no effect on circulating VEGF levels. 22–25 In addition, considering that ocular adverse events did not increase in phase 3 studies, 27 , 28 the therapeutic dose of daprodustat would not increase plasma VEGF levels.…”

“…Although the incidence of hyperkalemia increased in two phase 3 trials of roxadustat, 14 , 15 it had no significant increase in phase 3 studies that evaluate daprodustat efficacy for renal anemia among hemodialysis and non-hemodialysis-dependent CKD patients. 28 , 29 To confirm whether adverse event profile differences exist among several HIF-PH inhibitors, more detailed phase 3 or phase 4 studies of each HIF-PH inhibitor should be required.…”

A new insight into the treatment of renal anemia with HIF stabilizer

“…Other reports showed that daprodustat increased Hb in a dose-dependent manner in HD patients whose pretreatment average Hb value was less than 10 g/dL, and the secondary analysis showed that VEGF remained unchanged and the endogenous EPO concentration was within a physiological range (maximum EPO concentration < 50 mIU/mL). As for ESA resistance, Akizawa et al found that darbepoetin-αrDA), compared to daprodustat, required a broader range administration dose, suggesting that the ESA hyporesponsiveness is better controlled in the daprodustat-treated group [69]. In addition, there was basically no difference in the PK and the PD between Caucasian and Japanese with a slightly high AUC in the latter, which may be originated from the difference in body size [70].…”