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Clinical Trial
. 2021;52(1):26-35.
doi: 10.1159/000513103. Epub 2021 Feb 9.

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

Masaomi Nangaku  1 , Takayuki Hamano  2 , Tadao Akizawa  3 , Yoshiharu Tsubakihara  4 , Reiko Nagai  5 , Nobuhiko Okuda  6 , Kyo Kurata  7 , Takashi Nagakubo  8 , Nigel P Jones  9 , Yukihiro Endo  6 , Alexander R Cobitz  10
Affiliations
Clinical Trial

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

Masaomi Nangaku et al. Am J Nephrol. 2021.

Abstract

Background: 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.

Methods: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >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.

Results: Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT02791763.

Keywords: Anemia; Daprodustat; Hypoxia-inducible factor; Japanese; Nondialysis.

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Conflict of interest statement

M.N. has received grants and personal fees from Astellas Pharma Inc. (Astellas), Chugai Pharmaceutical Co. Ltd. (Chugai), Daiichi Sankyo Co. Ltd., GlaxoSmithKline (GSK), Kyowa Kirin Co. Ltd. (KKC), Mitsubishi Tanabe Pharma, and Torii Pharmaceutical Co. Ltd. (Torii); grants from Bayer Yakuhin Ltd. (Bayer), Ono Pharmaceutical Co. Ltd. (Ono), and Takeda Pharmaceutical Co. Ltd. (Takeda); and personal fees from AstraZeneca and JT Pharmaceuticals. T.H. has received grants and personal fees from Asahi Kasei Pharma Corporation, Bayer, Chugai, Kissei Pharmaceutical Co. Ltd. (Kissei), Otsuka Pharmaceutical Co. Ltd. (Otsuka), and Torii; grants, personal fees, and other from KKC, and Ono; personal fees and other from Astellas; grants from Eisai Co. Ltd., Fuso Pharmaceutical Industries Ltd. (Fuso), Takeda, and Terumo Corporation; and other from GSK. T.A. has received personal fees from Astellas, Bayer, Chugai, Fuso, GSK, JT Pharmaceuticals, KKC, Kissei, Nipro Corporation, Ono, Otsuka, Torii, and Sanwa Chemical Industrial Co. Ltd. Y.T. has received personal fees from Chugai, GSK, KKC, and Torii. R.N. is an employee of GSK. N.O., K.K., T.N., N.P.J., Y.E., and A.R.C. are employees of and hold equity stock in GSK.

Figures

Fig. 1
Fig. 1
Participant disposition. This study also evaluated efficacy and safety of daprodustat in a noncomparative cohort of Japanese peritoneal dialysis patients (ClinicalTrials.gov Identifier: NCT02791763). A total of 455 patients (ND and peritoneal dialysis) were screened. Of the 455 screened patients, 355 (78%) were enrolled. Of the 355 enrolled participants in this study, 299 were ND and 56 were on peritoneal dialysis. CERA, continuous erythropoietin receptor activator (epoetin beta pegol); Hgb, hemoglobin; ITT, intent-to-treat; ND, not on dialysis.
Fig. 2
Fig. 2
Mean hemoglobin level and 95% CIs by study treatment group (ITT population). Overall ITT (a); ESA-naïve participants (b); ESA users (c). Light gray dashed lines indicate target hemoglobin range. Orange solid lines represent time courses of values in daprodustat users. CI, confidence interval; CERA, continuous erythropoietin receptor activator (epoetin beta pegol); ESA, erythropoiesis-stimulating agent; ITT, intention-to-treat population.
Fig. 3
Fig. 3
Effect of daprodustat on iron metabolism (ITT population). Mean serum iron level (95% CI) (a); mean TIBC level (95% CI) (b); mean TSAT level (95% CI) (c); geometric mean ferritin level (95% CI) (d); geometric mean hepcidin level (95% CI) (e). Orange solid lines represent time courses of values in daprodustat users. aThe distribution in TSAT had been assumed to be skewed but was found not to be skewed after the data review; therefore, the post hoc analysis of TSAT was not based on transformed values. bThe distributions were skewed and required a log transformation for the analysis. The distribution in ferritin had been assumed not to be skewed but was found to be skewed after the data review; therefore, the analysis of ferritin based on a log transformation was done as a post hoc analysis. CERA, continuous erythropoietin receptor activator (epoetin beta pegol); CI, confidence interval; ITT, intention-to-treat; TIBC, total iron-binding capacity; TSAT, transferrin saturation.
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