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.
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.
Enarodustat tablets significantly increased hemoglobin (Hb) levels in patients with non-dialysis chronic kidney disease (ND-CKD) compared to placebo.
Enarodustat improved iron metabolism, reducing the need for iron supplements.
Enarodustat was well tolerated, with a safety profile similar to the placebo. The once-daily oral administration potentially favors the convenience and adherence.
Introduction
Chronic kidney disease (CKD) is a global health challenge, affecting an estimated 9.1% of the population worldwide and 8.2% of adults in China, leading to significant morbidity and mortality [1, 2]. One of the major complications of CKD is renal anemia, primarily caused by reduced erythropoietin (EPO) production and iron deficiency. This condition is further exacerbated by impaired iron utilization driven by inflammation states, increased hepcidin, and uremic toxins [3].
In China, CKD poses a substantial burden, with an estimated 82 million adults affected [2]. Among non-dialysis CKD (ND-CKD) patients, the prevalence of renal anemia ranges from 28.5∼72.0% and it increases as CKD progresses [4]. Conditions such as diabetic nephropathy and hypertensive renal damage further contribute to this high prevalence and pose additional treatment challenges [4]. A previous study reported that only 39.8% of the anemic Chinese ND-CKD patients received EPO treatment, and just 27.1% were treated with iron supplements [5]. For predialysis patients in China, only 18.2%,11.6%, and 5.6% of patients achieved hemoglobin (Hb) levels of 100–110g/L, 110–120 g/L, and 120–130 g/L, respectively, underscoring the urgent need for more effective therapeutic options [4].
Traditional therapies for renal anemia, such as iron supplements and erythropoiesis-stimulating agents (ESAs), have several limitations. These treatments often come with gastrointestinal adverse effects, hypersensitivity reactions, and increased oxidative stress. ESAs can increase risks of cardiovascular events, hypertension, and thromboembolic events, particularly at higher doses. The subcutaneous or intravenous administration, along with complicated supply and storage requirements (e.g., refrigeration, no freezing, no shaking, protection form light), are very inconvenient for ND-CKD patients. These challenges highlight the need for new therapies that are not only effective but also more tolerable and convenient for patient use [1, 6‒9].
Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a promising new class of orally administered drugs for treating anemia in CKD patients. By stabilizing HIF levels, these drugs increase endogenous EPO production and improve iron metabolism [10]. Enarodustat, a novel HIF-PHI, has demonstrated efficacy in clinical trials in achieving and maintaining Hb levels within target ranges. It has been approved in Japan for both ND-CKD and dialysis-dependent CKD patients [11, 12]. Several guidance documents now recommend HIF-PHIs, including enarodustat, as a treatment option for ND-CKD patients [13‒15]. However, its efficacy and safety profile have not yet been established in China. This phase 3 trial aimed to evaluate the efficacy and safety of enarodustat in treating anemia for Chinese patients with ND-CKD and sought to provide a more effective and convenient treatment option for this population.
Methods
Study Design and Oversight
This study was a randomized, phase 3, double-blind, placebo-controlled, parallel-group, extended open-label, multicenter clinical trial conducted at 48 centers across China, targeting anemic ND-CKD patients. The study design included a 4-week screening period, an 8-week double-blind treatment period, a 16-week open-label extended treatment period, and a 2-week safety follow-up period (Fig. 1). During the open-label period, all patients, including those initially in the placebo group, received enarodustat. Following the screening visit, 12 visits were designed at weeks 1 (the baseline visit), 3, 5, 7, 8, 9, 11, 13, 17, 21, 25, and 27. The study was approved by the Institutional Review Board or Ethics Committee of study centers and conducted following the principles of the Declaration of Helsinki and applicable Chinese laws and regulations. All participants provided informed written consent.
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).
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).
Study Participants
Eligible participants were between 18 and 75 years old, diagnosed with stage 3–5 CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), not on dialysis, with Hb levels between 80 and 105 g/L (inclusive), and with serum ferritin > 100 μg/L or transferrin saturation (TSAT) > 20%. Participants had not received blood or red blood cell transfusion within 3 months before screening, nor had they received ESA treatment or HIF-PHIs for at least 8 weeks before randomization. Detailed inclusion and exclusion criteria are provided in online supplementary text (for all online suppl. material, see https://doi.org/10.1159/000543193) and the study registration information [16].
Randomization and Intervention
Eligible patients were randomly randomized in a 2:1 ratio to the enarodustat or placebo groups. Randomization was stratified by eGFR (<30 and ≥30 mL/min/1.73 m2), using a stratified block randomization method implemented in SAS software (version 9.4). The eGFR was calculated using the CKD-Epidemiology Collaboration (CKD-EPI) formula.
Patients in the enarodustat group received once-daily oral enarodustat tablets (Shenzhen Salubris Pharmaceuticals Co., Ltd) at an initial dose of 4 mg/day. Patients in the placebo group received once-daily oral placebo tablets during the first 8-week double-blind period and then switched to enarodustat (starting from 4 mg/day) during the 16-week open-label extension, referred to as the placebo/enarodustat group. The study drug doses were adjusted every 4 weeks at stepwise dose ladders of 1/2/4/6/8 mg/day based on the patient’s Hb concentration and the change of Hb concentration in the past 4 weeks (online suppl. Table 1), to achieve and maintain a Hb level of 100–120 g/L.
During the first 4 weeks, patients already taking oral iron supplements before screening were allowed to continue their regimen, while other subjects were not permitted to start oral iron. From week 5, iron supplements should be considered when ferritin was ≤ 100 μg/L or TSAT ≤ 20%. Oral iron was preferred, with IV iron reserved for cases where oral iron was intolerable or ineffective. Patients were closely monitored, and venous blood samples were collected for laboratory analysis.
Endpoints
The primary efficacy endpoint was the mean change in the Hb levels from baseline to the average level during weeks 7–9, calculated as the average Hb levels from weeks 7, 8, and 9, and compared between groups. Secondary efficacy endpoints included several measures related to Hb concentrations, drug dose, and treatment outcomes. Specifically, these eight endpoints were (1) Hb concentration at each visit; (2) the proportion of subjects achieving an average Hb level of ≥100 g/L during weeks 7–9 and weeks 21–25; (3) the cumulative proportion of subjects with Hb ≥ 100 g/L and an increase of ≥10 g/L from baseline at week 9; (4) the average Hb increase during the first 4 weeks of treatment, as measured at week 5; (5) the average dose of the drug used every 4 weeks for patients initially randomized to the enarodustat group and the proportion of different dose levels; (6) the number of drug dose adjustments during the open-label period; (7) the proportion of subjects who discontinued due to rescue treatment (including transfusion and ESA use) during the double-blind period; and (8) iron supplement usage during both the double-blind and open-label periods.
Exploratory endpoints focused on iron metabolism-related parameters, including the change of hepcidin and five additional parameters (serum iron, transferrin, total iron-binding capacity [TIBC], transferrin saturation [TSAT], and ferritin) during the treatment period. To ensure a comprehensive assessment of these endpoints, data analyses were conducted using the full analysis set during both the double-blind and open-label periods.
Safety and AEs
The safety analysis included monitoring adverse events (AEs), adverse drug reactions (ADRs), and conducting laboratory examinations, including lipid profiles and plasma vascular endothelial growth factor (VEGF) levels, throughout the double-blind and open-label periods, followed by a 2-week safety follow-up period. Comparisons between the enarodustat and placebo groups were primarily based on observations made during the double-blind period.
Statistical Analysis
The sample size was calculated to provide 94% power to detect a clinically significant mean difference of 7 g/L in Hb levels from baseline to weeks 7–9, assuming a common standard deviation (SD) of 10 g/L and a one-sided significance level of 0.025. To achieve this, a total of 150 patients were required, accounting for a 20% dropout rate. Participants were randomized in a 2:1 ratio, with 100 patients in the enarodustat group and 50 in the placebo group. Sample size calculations were performed using PASS16 software.
Quantitative data were analyzed using either a t test or the Wilcoxon rank-sum test, depending on the data distribution. Categorical data were compared using the chi-square test or Fisher’s exact test, as appropriate. All statistical tests comparing treatment groups were two tailed, with a 95% confidence interval and a significance level (p value) set at 0.05.
Efficacy analyses included patients who received at least one dose of the study drug and had at least one post-dose Hb concentration measurement. The primary efficacy endpoints were assessed using a mixed-effects model for repeated measures. Enarodustat was considered superior to placebo if the lower limit of the 95% confidence interval for the difference between groups exceeded 0 g/L. A sensitivity analysis of the primary endpoint was performed using an ANCOVA model, with the last observation carried forward method to handle missing Hb data. No imputing was applied to secondary endpoint analyses.
The safety analysis included all patients who received at least one dose of enarodustat or placebo after randomization. Safety data were analyzed using the safety set. The analyses were conducted using SAS software version 9.4, with statistical significance defined as p < 0.05. The study was registered with the Chinese clinical trial registry (ChiCTR2000040431) and ClinicalTrials.gov (NCT06016036).
Results
Patient Disposition
Between December 8, 2020, and February 21, 2022, a total of 372 patients were screened for the study, of whom 156 met the eligibility criteria and were enrolled (Fig. 2). These patients were randomized in a 2:1 ratio to receive either enarodustat (n = 103) or placebo (n = 53) during the double-blind period. During this period, 6 patients (5.8%) in the enarodustat group and 3 patients (5.7%) patients in the placebo group withdrew from the study.
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.
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.
In the open-label period, 16 patients (16.5%) and 5 patients (10.0%) withdrew from each group, leading to a total dropout rate of 19.2% (30/156). The main reasons for withdrawals were AEs, needing to receive dialysis or a kidney transplant, or the patient’s decision to discontinue participation. During the 2-week safety follow-up, all remaining patients (n = 126) were monitored for AEs and other safety concerns, with no further withdrawals occurring during this period.
Characteristics of Study Participants
The baseline characteristics were well balanced between the enarodustat and placebo groups (Table 1). Key characteristics such as age, gender distribution, body weight, body mass index, Hb concentration, and eGFR were similar across both groups.
Baseline characteristics of participants (FAS)
Characteristics . | Enarodustat (N = 103) . | Placebo (N = 52) . |
---|---|---|
Age, years | ||
Mean ± SD | 53.0±13.4 | 56.8±11.9 |
Median | 53.0 | 57.5 |
Age, n (%) | ||
<65 | 78 (75.7) | 37 (71.2) |
≥65 | 25 (24.3) | 15 (28.9) |
Gender, n (%) | ||
Male | 39 (37.9) | 23 (44.2) |
Female | 64 (62.1) | 29 (55.8) |
Body weight, kg | ||
Mean ± SD | 59.15±10.26 | 60.15±9.21 |
Median | 57.80 | 61.00 |
BMI, mean ± SD, kg/m2 | 22.8±3.7 | 22.4±2.5 |
Hb concentration, mean ± SD, g/dL | 93.83±6.14 | 93.81±6.05 |
Hb, n (%) | ||
<100 | 85 (82.5) | 42 (80.8) |
≥100 | 18 (17.5) | 10 (19.2) |
eGFR, mL/min/1.73 m2 | ||
Mean ± SD | 19.30±10.69 | 19.03±10.48 |
Median | 16.20 | 16.93 |
eGFR, mL/min/1.73 m2, n (%) | ||
<15 | 43 (41.7) | 24 (46.2) |
≥15 and <30 | 41 (39.8) | 19 (36.5) |
≥30 and <45 | 14 (13.6) | 7 (13.5) |
≥45 | 5 (4.9) | 2 (3.8) |
Causes of CKD, n (%) | ||
Primary glomerular disease | 42 (40.8) | 15 (28.9) |
Diabetic nephropathy | 20 (19.4) | 6 (11.5) |
Nephrosclerosis | 11 (10.7) | 10 (19.2) |
Others | 30 (29.1) | 21 (40.4) |
Iron parameters, mean ± SD | ||
Hepcidin, ng/mL | 74.40±43.50 | 77.29±52.01 |
Serum iron, μmol/L | 12.92±4.54 | 12.93±3.42 |
Transferrin, g/L | 2.11±0.33 | 1.96±0.37 |
TIBC, μmol/L | 48.38±8.19 | 46.22±8.60 |
TAST, % | 26.82±10.84 | 29.12±10.72 |
Ferritin, μg/L | 213.23±156.34 | 244.53±220.18 |
Abnormal CRP/hs-CRP level, n (%) | 17 (16.5) | 10 (19.2) |
History of smoking, n (%) | 22 (21.4) | 13 (25.0) |
History of alcohol consumption, n (%) | 21 (20.4) | 10 (19.2) |
Characteristics . | Enarodustat (N = 103) . | Placebo (N = 52) . |
---|---|---|
Age, years | ||
Mean ± SD | 53.0±13.4 | 56.8±11.9 |
Median | 53.0 | 57.5 |
Age, n (%) | ||
<65 | 78 (75.7) | 37 (71.2) |
≥65 | 25 (24.3) | 15 (28.9) |
Gender, n (%) | ||
Male | 39 (37.9) | 23 (44.2) |
Female | 64 (62.1) | 29 (55.8) |
Body weight, kg | ||
Mean ± SD | 59.15±10.26 | 60.15±9.21 |
Median | 57.80 | 61.00 |
BMI, mean ± SD, kg/m2 | 22.8±3.7 | 22.4±2.5 |
Hb concentration, mean ± SD, g/dL | 93.83±6.14 | 93.81±6.05 |
Hb, n (%) | ||
<100 | 85 (82.5) | 42 (80.8) |
≥100 | 18 (17.5) | 10 (19.2) |
eGFR, mL/min/1.73 m2 | ||
Mean ± SD | 19.30±10.69 | 19.03±10.48 |
Median | 16.20 | 16.93 |
eGFR, mL/min/1.73 m2, n (%) | ||
<15 | 43 (41.7) | 24 (46.2) |
≥15 and <30 | 41 (39.8) | 19 (36.5) |
≥30 and <45 | 14 (13.6) | 7 (13.5) |
≥45 | 5 (4.9) | 2 (3.8) |
Causes of CKD, n (%) | ||
Primary glomerular disease | 42 (40.8) | 15 (28.9) |
Diabetic nephropathy | 20 (19.4) | 6 (11.5) |
Nephrosclerosis | 11 (10.7) | 10 (19.2) |
Others | 30 (29.1) | 21 (40.4) |
Iron parameters, mean ± SD | ||
Hepcidin, ng/mL | 74.40±43.50 | 77.29±52.01 |
Serum iron, μmol/L | 12.92±4.54 | 12.93±3.42 |
Transferrin, g/L | 2.11±0.33 | 1.96±0.37 |
TIBC, μmol/L | 48.38±8.19 | 46.22±8.60 |
TAST, % | 26.82±10.84 | 29.12±10.72 |
Ferritin, μg/L | 213.23±156.34 | 244.53±220.18 |
Abnormal CRP/hs-CRP level, n (%) | 17 (16.5) | 10 (19.2) |
History of smoking, n (%) | 22 (21.4) | 13 (25.0) |
History of alcohol consumption, n (%) | 21 (20.4) | 10 (19.2) |
The baseline Hb concentration was derived from the mean of the last 3 central laboratory Hb concentrations before the first dose. eGFR was calculated with CKD-EPI formula. Either CRP or hs-CRP examination was selected according to the availability in each center.
FAS, full analysis set; SD, standard deviation; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; TIBC, total iron binding capacity; TSAT, transferrin saturation; CRP, C-reactive protein; hs-CRP, high-sensitivity C-reactive protein; BMI, body mass index.
The mean (±SD) baseline Hb levels were 93.83 (±6.14) g/L in the enarodustat group and 93.81 (±6.05) g/L in the placebo groups. Most patients had an eGFR below 30 mL/min/1.73 m2, with CKD stages 3, 4, and 5 evenly distributed between the two groups. The most common causes of CKD were primary glomerular disease, diabetic nephropathy, and nephrosclerosis. A small percentage of patients had a history of smoking or alcohol consumption. Overall, the trial sample was representative of the population with ND-CKD population (Table 1).
Primary Endpoints
During the double-blind period, the mean (±SD) change in Hb levels from baseline to weeks 7–9 was significantly higher in the enarodustat group (15.99 ± 9.46 g/L) compared to the placebo group (−0.14 ± 8.08 g/L) (Table 2). The difference between the groups was 16.00 (±1.54) g/L and was statistically significant (p < 0.001) (Fig. 3).
Mean changes in hemoglobin in the double-blind period (FAS)
Hemoglobin (mean ± SD), g/L . | Enarodustat (n = 103) . | Placebo (n = 52) . | ||
---|---|---|---|---|
value, g/L . | change from baseline, g/L . | value, g/L . | change from baseline, g/L . | |
Baseline | 93.83±6.14 | 93.81±6.05 | ||
Week 3 | 99.57±7.94 | 5.84±6.09 | 94.45±8.35 | 0.61±5.18 |
Week 5 | 105.58±10.77 | 11.82±9.56 | 95.45±10.22 | 1.58±7.56 |
Weeks 7–9 | 109.80±9.99 | 15.99±9.46 | 93.71±10.57 | −0.14±8.08 |
Hemoglobin (mean ± SD), g/L . | Enarodustat (n = 103) . | Placebo (n = 52) . | ||
---|---|---|---|---|
value, g/L . | change from baseline, g/L . | value, g/L . | change from baseline, g/L . | |
Baseline | 93.83±6.14 | 93.81±6.05 | ||
Week 3 | 99.57±7.94 | 5.84±6.09 | 94.45±8.35 | 0.61±5.18 |
Week 5 | 105.58±10.77 | 11.82±9.56 | 95.45±10.22 | 1.58±7.56 |
Weeks 7–9 | 109.80±9.99 | 15.99±9.46 | 93.71±10.57 | −0.14±8.08 |
Weeks 7–9, the mean Hb level was calculated as the average Hb levels from weeks 7, 8, and 9.
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.
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.
Secondary Endpoints
Figure 4 illustrates the Hb levels at each visit. During the double-blind period, the enarodustat group consistently increased Hb levels compared to the placebo group. By week 9, the mean (±SD) Hb level in the enarodustat group was 112.30 (±9.93) g/L, reflecting an increase of 18.52 (±9.86) g/L from baseline. In contrast, the placebo group achieved an average Hb level of 94.84 (±10.99) g/L, with a slight increase of 0.99 (±8.61) g/L from baseline. In the open-label period, the enarodustat group maintained the Hb levels. The placebo group experienced a significant increase in Hb levels after switching to enarodustat. By week 25, the mean (±SD) Hb level in the enarodustat group was 107.19 (±9.45) g/L, representing an increase of 13.22 (±10.40) g/L from baseline, while the placebo/enarodustat group achieved a Hb level of 116.51 (±10.75) g/L with an increase of 20.24 (±11.14) g/L from baseline.
During weeks 7–9, 85.3% of patients (87/102) in the enarodustat group achieved average Hb levels of ≥100 g/L, compared to 30% of patients (15/50) in the placebo group, with a significant difference between the groups (p < 0.001). During weeks 21–25, 86.0% of patients (74/86) in the enarodustat group maintained average Hb levels ≥100 g/L, while 93.6% of patients (44/47) in the placebo/enarodustat group achieved this level, with no significant difference between the groups (p > 0.05). By week 9, the cumulative percentage of patients having reached a Hb level ≥100 g/L and with an increase of ≥10 g/L from baseline was 83.5% (86/103) in the enarodustat group reflecting a good treatment response, compared to 11.5% (6/52) (p < 0.001) in the placebo group.
In the first 4 weeks of treatment, the mean (±SD) Hb increase was 11.82 (±9.56) g/L in the enarodustat group, compared to 1.58 (±7.56) g/L in the placebo group with a significant difference (p < 0.001). Regarding the dose, the enarodustat group received an average (±SD) daily dose of 3.92 (±0.67) mg during the double-blind period, which decreased to 2.98 (±1.89) mg during the open-label period. The placebo group had an average daily dose of 4.58 (±0.59) mg during the double-blind period. After switching to enarodustat in the open-label period, these patients received an average daily dose of 3.64 (±1.20) mg.
Figure 5 summarizes the enarodustat doses and the distribution of different dose ladders for patients initially randomized to the enarodustat group. Overall, the daily dose of enarodustat showed a downward trend over time. The average daily doses in every 4 weeks were 3.99 mg for weeks 1–4, 3.85 mg for weeks 5–9, 3.22 mg for weeks 9–13, 3.02 mg for weeks 13–17, 2.79 mg for weeks 17–21, and 2.92 mg for weeks 21–25. During the 16-week open-label period, the dose adjustments for enarodustat were relatively infrequent, with the enarodustat group and the placebo/enarodustat group averaging 1.5 ± 0.95 and 1.5 ± 0.91 times, respectively.
Doses and the distribution of dose ladders for the enarodustat group.
By week 9, no patient required rescue treatment of blood transfusions or ESA use. The proportion of patients receiving iron supplements significantly decreased in both groups in the open-label period (Fig. 6). In the enarodustat group, the proportion increased slightly from 45.6% (47/103) of patients at baseline to 49.5% (51/103) during the double-blind period, then significantly decreased to 12.4% (12/97) during the open-label period. A similar pattern was observed in the placebo group, where iron use remained stable from baseline (44.2%, 23/52) through the double-blind period (44.2%, 23/52) and declined to16.0% (8/50) during the open-label period.
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.
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.
Iron Parameters
During the double-blind period, patients in the enarodustat group experienced significant reductions in hepcidin levels compared to those in the placebo group (online suppl. Table 2). The mean (±SD) hepcidin level in the enarodustat group decreased from 74.40 (±43.50) ng/mL at baseline to 31.48 (±32.20) ng/mL by week 9, a decrease of 42.94 ng/mL, representing a significant reduction of 57.7% (p < 0.0001). In contrast, the placebo group showed a slight increase in hepcidin levels, from 77.29 (±52.01) ng/mL to 80.14 (±63.06) ng/mL, an increase of 4.58 ng/mL. By week 25, hepcidin levels were 53.94 (±36.14) ng/mL in the enarodustat group and 58.43 (±53.37) ng/mL in the placebo/enarodustat group.
We measured regular iron parameters in the enarodustat group during the whole study period (online suppl. Table 3). Serum iron levels increased slightly from 12.92 (±4.54) μmol/L at baseline to 13.31 (±5.60) μmol/L by week 9 and continued to rise to 15.71 (±4.83) by week 25. Transferrin levels increased from 2.11 (±0.33) g/L at baseline to 2.77 (±0.49) g/L by week 9, then slightly decreased to 2.48 (±0.46) g/L by week 25. TIBC increased from 48.38 (±8.19) μmol/L at baseline to 62.51 (±10.94) μmol/L by week 9, then decreased to 56.85 (±9.72) μmol/L by week 25. TSAT initially decreased from 26.82% at baseline to 21.56% by week 9, before rebounding to 28.01% by week 25. Ferritin levels showed a decline from 213.23 (±156.34) μg/L at baseline to 99.44 (±99.76) μg/L by week 9, before gradually increasing to 150.00 (±135.07) μg/L by week 25.
Safety and AEs
The overall incidence and distribution of AEs, serious adverse events, ADRs, and serious ADRs were similar between the enarodustat and placebo groups (Table 3; online suppl. Table 4, 5). During the double-blind period, the most frequently reported ADRs (with an incidence>1%) in the enarodustat group were nausea in 4 patients (3.9%), followed by vomiting, pruritus, fatigue, and elevated fibrin D-dimer levels, each reported in 2 patients (1.9%), comparing to various types of ADRs reported with an incidence of 1.9% in the placebo group. In the open-label period, the most frequently reported ADRs were elevated fibrin D-dimer in 3 patients (2.0%), followed by respiratory tract infection, hypertension, abnormal ECG T wave, and heart failure, each reported in 2 patients (1.4%). No treatment-related death occurred in this study.
Summary of safety profiles during the double-blind and open-label periods (SS)
. | Double-blind period, n (%) . | Open-label period, n (%) . | |
---|---|---|---|
enarodustat (N = 103) . | placebo (N = 53) . | enarodustat (N = 147) . | |
TEAEs | 80 (77.67) | 42 (79.25) | 126 (85.71) |
SAEs | 14 (13.59) | 5 (9.43) | 19 (12.93) |
AEs leading to study termination | 5 (4.85) | 1 (1.89) | 6 (4.08) |
ADRs | 19 (18.45) | 8 (15.09) | 21 (14.29) |
SADRs | 1 (0.97) | 0 (0.00) | 2 (1.36) |
ADRs leading to study termination | 0 (0.00) | 1 (1.89) | 1(0.68) |
. | Double-blind period, n (%) . | Open-label period, n (%) . | |
---|---|---|---|
enarodustat (N = 103) . | placebo (N = 53) . | enarodustat (N = 147) . | |
TEAEs | 80 (77.67) | 42 (79.25) | 126 (85.71) |
SAEs | 14 (13.59) | 5 (9.43) | 19 (12.93) |
AEs leading to study termination | 5 (4.85) | 1 (1.89) | 6 (4.08) |
ADRs | 19 (18.45) | 8 (15.09) | 21 (14.29) |
SADRs | 1 (0.97) | 0 (0.00) | 2 (1.36) |
ADRs leading to study termination | 0 (0.00) | 1 (1.89) | 1(0.68) |
ADR, adverse drug reaction; AE, adverse event; SADR, serious adverse drug reaction; SAE, serious adverse event; SS, safety set; TEAE, treatment-emergent adverse event.
Cardiovascular and thrombosis-related events were designated as adverse events of special interest (AESIs) in this study. During the 24-week treatment period, there were 15/103 (14.6%) patients in the enarodustat group and 6/52 (11.5%) patients in the placebo group reporting AESIs. Overall, 6/103 (5.8%) patients in the enarodustat group and 2/52 (3.8%) in the placebo group in the double-blind period, followed by 11/97 (11.3%) and 5/50 (10%) in each group in the open-label period, reported AESIs. The reported types were heart failure, thrombosis events, or severe hypertension. Among those, only 2 thrombosis AEs occurred in the enarodustat group. No AESIs of myocardial infarction or cerebrovascular accident were reported (Table 4). The incidence of hypertension as AEs was 4/103 (3.9%) in the enarodustat group and 2/53 (3.8%) in the placebo group during the double-blinded period and 6/147 (4.1%) during the open-label period. The incidence of hyperkalemia as AEs was 12/103 (11.7%) in the enarodustat group and 8/53 (15.1%) in the placebo group during the double-blind period and 22/147 (15.0%) during the open-label period.
Summary of the AESI
AESIsa . | Double-blind period, n (%) . | Open-label period, n (%) . | ||
---|---|---|---|---|
enarodustat (N = 103) . | placebo (N = 53) . | enarodustat (N = 97) . | placebo/enarodustat (N = 50) . | |
All patients | 6 (5.8) | 2 (3.8) | 11 (11.3) | 5(10.0) |
Heart failure | 1 (1.0) | 0 | 7 (7.2) | 2(4.0) |
Thrombosis eventsb | 2 (1.9) | 0 | 0 | 0 |
Acute coronary syndrome | 1 (1.0) | |||
Arteriovenous fistula occlusion | 1 (1.0) | |||
Severe hypertensionc | 3 (2.9) | 2 (3.8) | 5 (5.2) | 3 (6.0) |
AESIsa . | Double-blind period, n (%) . | Open-label period, n (%) . | ||
---|---|---|---|---|
enarodustat (N = 103) . | placebo (N = 53) . | enarodustat (N = 97) . | placebo/enarodustat (N = 50) . | |
All patients | 6 (5.8) | 2 (3.8) | 11 (11.3) | 5(10.0) |
Heart failure | 1 (1.0) | 0 | 7 (7.2) | 2(4.0) |
Thrombosis eventsb | 2 (1.9) | 0 | 0 | 0 |
Acute coronary syndrome | 1 (1.0) | |||
Arteriovenous fistula occlusion | 1 (1.0) | |||
Severe hypertensionc | 3 (2.9) | 2 (3.8) | 5 (5.2) | 3 (6.0) |
aAESI was defined as including myocardial infarction, heart failure, cerebrovascular accident, thrombosis events, or severe hypertension.
bAfter the treatment was ended, 1 patient reported arteriovenous fistula thrombosis and another patient reported jugular vein thrombosis in the enarodustat group in the safety follow-up period. The first patient had reported arteriovenous fistula occlusion in the double-blind period and reported heart failure in the open-label period. The second patient had reported heart failure in the open-label period.
cSevere hypertension includes “hypertension” or “renal hypertension” and CTCAE grade III or higher, or any of the following events: “hypertensive crisis,” “malignant hypertension,” “hypertensive encephalopathy,” “hypertensive cerebrovascular disease,” “hypertensive heart disease,” “hypertensive retinopathy.”
Laboratory and imaging examinations revealed no significant clinical changes. Specifically, no notable alterations were observed in VEGF, triglycerides, HDL, LDL, total cholesterol, albumin, vital signs, standard 12-lead ECG, chest X-rays, or fundus examinations throughout the study.
Discussion
This phase 3 trial is the first to validate the efficacy and safety of enarodustat for treating anemia in Chinese patients with ND-CKD. Our results demonstrate that enarodustat significantly increased Hb levels by 16.00 (±1.54) g/L compared to the placebo group during weeks 7–9 (p < 0.001). Over 85% of patients in the enarodustat group achieved a mean Hb level of ≥100 g/L at different treatment durations, including 85.3% during weeks 7–9 and 86.0% during weeks 21–25. The use of an innovative starting dose of 4 mg/day provided a satisfying average Hb increase in the first 4–8 weeks. The safety profile of enarodustat was comparable to placebo, demonstrating good tolerability and supporting its role as an effective therapeutic option for managing anemia in Chinese ND-CKD patients.
Enarodustat also significantly improved iron metabolism throughout the study. During the double-blind period, enarodustat effectively reduced hepcidin, TSAT, and ferritin levels, while increasing TIBC and serum iron levels. Although there were shifts in these trends during the open-label period, where transferrin and TIBC levels decreased while hepcidin, TSAT, and ferritin levels rebounded, serum iron remained elevated throughout the entire study. By week 25, serum iron, transferrin, TIBC, and TSAT levels were higher compared to baseline, while hepcidin and ferritin levels were lower, indicating improved iron absorption and utilization. This conclusion was also supported by both the ideal Hb levels and the significant reduction in iron supplements usage in both groups in the open-label period.
The decision to use a starting dose of 4 mg/day was based on evidence from Japanese phase 2 and 3 clinical trials, as well as practical considerations for treating renal anemia in China [4, 12, 17]. Previous fixed-dose studies showed that the dose of 2/4/6 mg/day delivered dose-dependent Hb increases, which is consistent with the linear pharmacokinetic characteristics of enarodustat in phase 1 trial in Chinese [18]. Guidelines recommend a monthly Hb increase of 10–20 g/L [4, 19]. The 2 mg seemed not to produce sufficient Hb increase, making it less effective for the rapid correction of anemia, while the 6 mg possibly brought higher Hb increases especially for untreated ND-CKD patients, which might increase the risk of thrombotic events [20]. Therefore, the 4 mg/day dose chosen strikes a balance between efficacy and safety, with the average Hb increase of 11.82 g/L during the first 4 weeks in this study falling within the recommended range.
Our findings are consistent with previous studies demonstrating the efficacy and safety of enarodustat in managing anemia in ND-CKD patients [12, 17]. For example, in the SYMPHONY ND and SYMPHONY ND-Long studies, 88.6% of patients achieved target Hb levels of 100–120 g/L after 24-week treatment, and 89.2% reached this range after 52-week treatment. The safety results in our study also align with previous studies. There were relatively low incidences of AEs of thrombosis, hypertension, and hyperkalemia, and no significant clinical changes in VEGF, supporting enarodustat’s favorable safety tolerability profile.
Enarodustat works by stabilizing HIF levels, which increases HIF-α and activates genes involved in erythropoiesis, iron metabolism, and angiogenesis [21‒23]. In this trial, enarodustat significantly increased Hb levels by stimulating endogenous EPO production in a physiological concentration range to enhance erythropoiesis [9, 18, 21]. Its effects on improving iron metabolism were demonstrated both by the dynamic changes of iron metabolism-related parameters and a reduction in iron supplements usage in this study. These multiple mechanisms contribute to the integrated efficacy, allowing it to treat anemia more efficiently with a manageable safety profile [9, 21‒23].
The strengths of this study include its prospective design, multicenter collaboration, and comprehensive evaluation of efficacy and safety outcomes. As the first pivotal phase 3 clinical trial of enarodustat conducted in China, this study supports its approval in China for treating anemia in ND-CKD, making it the second HIF-PHI drug approved in the country and the fourth globally. Enarodustat also offers convenience and shows the potential to enhance adherence, with its once-daily oral administration, simplified supply and storage requirements, simple dose ladders, and relatively low frequency for dose adjustments. However, the study has limitations, such as the absence of a control arm in the open-label period and a relatively short study duration. The efficacy and safety validated in the 8-week double-blind period need reinforcement with long-term evidence.
Salubris Co. has completed clinical trials of enarodustat in dialysis-dependent patients in China. The Center for Drug Evaluation (CDE) of China has accepted Salubris Co.’s application for expanding enarodustas’s indications for such population in 2024. Future research should focus on exploring the long-term benefits of enarodustat, particularly over 1 year, and its integration into clinical practice. Studies for hard endpoints, such as major adverse cardiovascular events and renal outcomes, head-to-head comparisons with ESAs and other HIF-PH inhibitors, and studies for efficacy in Chinese ND patients previously treated with ESAs or other HIF-PHIs should also be considered. These efforts will provide a comprehensive understanding of enarodustat’s role in managing anemia in CKD patients.
In conclusion, this phase 3 study confirms the efficacy and safety of enarodustat for treating anemia in Chinese patients with ND-CKD. Enarodustat demonstrated significant improvements in Hb levels and iron metabolism with good tolerability and a manageable safety profile. The once-daily oral administration and simple dose ladders are friendly for patients and potentially benefit the adherence of ND-CKD patients. Enarodustat is a promising treatment option for anemia in this population.
Acknowledgments
The authors thank all the patients, investigators, the 48 study centers (online supplementary Table 6) that participated in the study, and staff at these centers for their support.
Statement of Ethics
The study was approved by the Medical Ethics Committee of Guangdong General Hospital (Approval No. YW2020-061-04/06) and conducted following the principles of the Declaration of Helsinki and applicable Chinese laws and regulations. All participants provided informed written consent.
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.
Funding Sources
This work was sponsored by Shenzhen Salubris Pharmaceuticals Co., Ltd. The sponsor participated in the study design, study operation, data collection and analysis, interpretation, and writing of the manuscript. The corresponding authors and all the authors had access to all the study data and are responsible for this study’s accuracy and scientific validity. This manuscript was reported following the Good Publication Practice (GPP3) recommendations.
Author Contributions
Conceptualization: Xin-Ling Liang, Ren-Wei Huang, and Xue-Qing Yu; formal analysis: Zi-Chen Liu and Li-Li Yang; investigation: Xin-Ling Liang, Ren-Wei Huang, Jian-Teng Xie, Yan-Ning Zhang, Yi-Nan Li, Xiao-Nong Chen, Tian-Jun Guan, Hua Zhou, Ping Fu, Yun-Hua Liao, Hui Xu, Ai-Cheng Yang, Hong-Wen Zhao, and Xue-Qing Yu; methodology and writing – review and editing: Xin-Ling Liang, Ren-Wei Huang, Jian-Teng Xie, Yan-Ning Zhang, Yi-Nan Li, Xiao-Nong Chen, Tian-Jun Guan, Hua Zhou, Ping Fu, Yun-Hua Liao, Hui Xu, Ai-Cheng Yang, Hong-Wen Zhao, Zi-Chen Liu, Li-Li Yang, and Xue-Qing Yu; software: Zi-Chen Liu; visualization: Li-Li Yang; writing – original draft preparation: Xin-Ling Liang, Ren-Wei Huang, Li-Li Yang, and Xue-Qing Yu.
Additional Information
Xin-Ling Liang and Ren-Wei Huang contributed equally to this work.
Data Availability Statement
The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding authors X.-Q.Y. or L.-L.Y. upon reasonable request.