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. 2024 Dec 20;11(1):49-62.
doi: 10.1159/000543193. eCollection 2025 Jan-Dec.

Enarodustat for the Treatment of Anemia in Chinese Patients with Non-Dialysis Chronic Kidney Disease: A Phase 3 Trial

Xin-Ling Liang  1 , Ren-Wei Huang  1 , Jian-Teng Xie  1 , Yan-Ning Zhang  2 , Yi-Nan Li  3 , Xiao-Nong Chen  4 , Tian-Jun Guan  5 , Hua Zhou  6 , Ping Fu  7 , Yun-Hua Liao  8 , Hui Xu  9 , Ai-Cheng Yang  10 , Hong-Wen Zhao  11 , Zi-Chen Liu  12 , Li-Li Yang  13 , Xue-Qing Yu  1
Affiliations

Enarodustat for the Treatment of Anemia in Chinese Patients with Non-Dialysis Chronic Kidney Disease: A Phase 3 Trial

Xin-Ling Liang et al. Kidney Dis (Basel). .

Abstract

Introduction: Renal anemia is a common complication among patients with non-dialysis chronic kidney disease (ND-CKD), and there remains an unmet need for more efficient and convenient daily oral medications to improve patient outcomes. This study aimed to evaluate the efficacy and safety of enarodustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, in treating anemia for ND-CKD patients.

Methods: This phase 3 study was conducted at 48 centers across China, enrolling 156 ND-CKD patients. Participants were randomly randomized in a 2:1 ratio to receive either enarodustat or placebo for an initial 8-week double-blind period, followed by a 16-week open-label period during which all patients received enarodustat.

Results: The primary endpoint was the mean change in hemoglobin (Hb) levels from baseline to the average level during weeks 7-9. Secondary endpoints focused on Hb concentration or treatment pattern, while exploratory endpoints assessed iron metabolism-related parameters. The mean (±SD) change in Hb levels from baseline to weeks 7-9 was 15.99 (±9.46) g/L in the enarodustat group, compared to -0.14 (±8.08) g/L in the placebo group, resulting in a mean difference of 16.00 (±1.54) g/L (p < 0.001). During weeks 7-9, 85.3% of patients in the enarodustat group achieved Hb levels ≥100 g/L with 86.0% maintaining this level during weeks 21-25. In the first 4 weeks, the Hb increased by 11.82 (±9.56) g/L in the enarodustat group. By week 9, the mean change in hepcidin level was -42.94 (±37.56) ng/mL in the enarodustat group, compared to +4.58 (±33.34) ng/mL in the placebo group. Enarodustat also improved other iron-related parameters and reduced the need for iron supplements. The safety profile of enarodustat was well tolerable with adverse events comparable to those of the placebo.

Conclusion: Enarodustat effectively corrected renal anemia with a manageable safety profile. Its once-daily oral administration offers convenience that may enhance the adherence. Enarodustat shows the potential as a promising therapy for anemic patients with ND-CKD.

Keywords: Anemia; Enarodustat; Hypoxia-inducible factor-prolyl hydroxylase inhibitor; Non-dialysis chronic kidney disease; Phase 3 trial.

Plain language summary

Anemia happens when the body does not have enough hemoglobin (Hb), which is a protein in red blood cells and responsible for carrying oxygen. Renal anemia is common in patients with non-dialysis chronic kidney disease (ND-CKD). This study looked at whether enarodustat, a new oral drug, could help treat anemia in these patients. The study involved 156 patients with ND-CKD. Some patients received enarodustat, while the others received a placebo (a tablet with no active ingredient but having the same appearance with enarodustat) for 8 weeks. During this period, no patients knew if they were taking the active drug, followed by another 16-week period during which all patients were certain to took enarodustat. The results showed that enarodustat significantly increased the levels of Hb compared to the placebo. Most patients receiving enarodustat reached target Hb levels, and this improvement continued over the following 16 weeks. The drug also helps with the way the body handles iron, which is important for producing red blood cells, reducing the need for additional iron treatments. The drug was generally well tolerated, with side effects similar to those of the placebo. Because enarodustat is a once-daily tablet, it looks easier for patients to use than drugs administered in other ways or with irregular frequency. The usage also potentially helps patients to stick to treatment. This study suggests that enarodustat could be a promising option for treating anemia in people with ND-CKD.

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Conflict of interest statement

Zi-Chen Liu and Li-Li Yang are employees of Shenzhen Salubris Pharmaceuticals Co., Ltd. The remaining authors declare no conflict of interest concerning the work.

Figures

Fig. 1.
Fig. 1.
Study design. The starting dose of enarodustat or placebo was 4 mg/day in the double-blind period, and the placebo group was switched to enarodustat treatment with a starting dose of 4 mg/day in the open-label period. The dose of study drugs was adjusted every 4 weeks in this study, mainly according to the hemoglobin concentration and its change during the past 4 weeks (online suppl. Table 1).
Fig. 2.
Fig. 2.
CONSORT flowchart of patient disposition. Nine patients (5.8%) withdrew during the double-blind period. In total, 30 patients (19.2%) withdrew during the study.
Fig. 3.
Fig. 3.
Changes in the Hb concentrations from baseline to weeks 7–9. The Hb level at weeks 7–9 was calculated as the average Hb level from weeks 7, 8, and 9.
Fig. 4.
Fig. 4.
Average hemoglobin levels (mean ± SD).
Fig. 5.
Fig. 5.
Doses and the distribution of dose ladders for the enarodustat group.
Fig. 6.
Fig. 6.
Proportion of patients receiving oral and intravenous (IV) iron supplements. In the enarodustat group, 47 patients were taking iron supplements at baseline, including 46 patients with oral iron and 2 patients with IV iron. No patient received IV iron in the double-blind period. In the open-label period, 12 patients received iron, including 12 patients with oral iron and 1 patient with IV iron. No patient initially randomized to the placebo group received IV iron from the baseline to the end of the study. IV, intravenous.
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