Abstract
Introduction
Enarodustat is an oral HIF-PHI for the treatment of chronic kidney disease anemia.
Methods
This phase 3, multicenter, randomized 24-week study assessed enarodustat’s noninferiority to rHuEPO for treating hemodialysis-dependent CKD (HD-CKD) anemia. Overall, 100 ESAs-treated patients were randomized 1:1 to enarodustat or rHuEPO for a 24-week treatment with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within target range 100–120 g/L. The primary efficacy endpoint was the between-group difference in mean Hb over weeks 20–24 (evaluation period [noninferiority margin: −10 g/L]). Safety was assessed by treatment-emergent adverse events (TEAEs).
Results
Of the 100 patients treated (enarodustat: 50; rHuEPO: 50), 93 completed the study. Demographic and baseline characteristics were comparable. During the evaluation period, the mean Hb level was 106.81 g/L in the enarodustat group and 99.68 g/L in the rHuEPO group. Enarodustat was noninferior to rHuEPO (least squares mean difference: 7.47 g/L [95% confidence interval: 4.17, 10.78]; p < 0.001). The mean Hb level in the enarodustat group remained within the target range throughout the treatment period, with a maintenance rate of 79.6% during weeks 20–24 versus 51.0% for rHuEPO. After switching from ESAs, the enarodustat group showed increased total iron-binding capacity, transferrin, and serum iron, decreased hepcidin by week 4, and increased RET% by week 2. TEAEs incidences were comparable (enarodustat: 90.0%, rHuEPO: 90.0%), with no additional safety concerns for enarodustat.
Conclusions
Enarodustat was noninferior to rHuEPO for the treatment of anemia in HD-CKD patients, with good safety and tolerability over 24 weeks.
Keywords: Anemia, Chronic kidney disease, Hemodialysis, Enarodustat, HIF-PHI
Introduction
Anemia frequently accompanies CKD. The global prevalence of CKD was 9.1% in 2017, affecting 700 million individuals, and the prevalence in China was 8.2% in 2018–2019 [1, 2]. CKD-related anemia correlates with heightened risks of cardiovascular (CV) disease, mortality, hospitalization, and diminished quality of life [3–6]. Current primary treatments for renal anemia, including ESAs and iron supplements often cause side effects such as gastrointestinal issues, allergic responses, and heightened oxidative stress [7–11]. Although ESAs are typically the first-line therapy for managing renal anemia [12], high doses of ESAs may also elevate CV risks, hypertension, and thrombosis [13]. Moreover, ESAs are administered parenterally and exhibit hyporesponsiveness in patients with inflammation [14]. These challenges emphasize the importance of developing therapies that are effective, convenient and reduce associated risks.
The hypoxia-inducible factor (HIF), a transcription factor responsive to oxygen levels, is crucial for erythropoiesis. Under normoxia, HIF prolyl hydroxylases degrade HIF-α subunits. Conversely, under hypoxia, the activity of these hydroxylases is diminished, allowing HIF-α to form dimers with HIF-β, thereby upregulating erythropoiesis, transferrin receptor expression, and iron absorption [15–18]. Enarodustat, a novel oral HIF-PHI, has demonstrated efficacy in clinical trials in achieving and maintaining Hb levels within target ranges [19–21]. It has been approved in Japan for treating anemia in CKD patients and in Korea for treating anemia in hemodialysis-dependent CKD patients. Enarodustat is also endorsed in several guidance documents as a potential treatment for hemodialysis-dependent CKD patients [22–24]. Thus, we hypothesize that enarodustat is effective and safe for the Chinese hemodialysis population, though this remains unconfirmed in China. This study was conducted to evaluate the efficacy and safety of enarodustat in the treatment of anemia in individuals with HD-CKD.
Methods
Study Design
This was a phase 3, multicenter, randomized, open-label study with rHuEPO as an active comparator (ClinicalTrials.gov: NCT06720025), conducted from September 2023 to June 2024 across 35 Chinese sites. Patients were randomized (1:1) to receive oral enarodustat or rHuEPO injections for up to 24 weeks without a formal washout period (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000550548). The study was divided into four stages: a screening period (2 weeks), an initial treatment period (4 weeks), a maintenance treatment period (20 weeks), and a follow-up period (2 weeks). It was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by the relevant Ethics Committee at each site, and all patients provided written informed consent. The conduct of the trial was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2025 checklist (see online suppl. material).
Study Population
In this study, eligible patients aged 18–75 with CKD anemia undergoing stable thrice-weekly HD for ≥12 weeks were included. Before randomization, patients had been receiving consistent ESAs (rHuEPO or darbepoetin alfa) for ≥4 weeks and at a stable weekly dose for ≥2 weeks. Eligible patients had pre-dialysis Hb levels of ≥95 g/L and <120 g/L and a ≤10 g/L difference (in absolute value) between two screening visits and transferrin saturation (TSAT) >20% or ferritin >75 μg/L. Further details of eligibility criteria are shown in online supplementary materials.
Study Drug Administration
Investigational Product
Patients were assigned 1:1 to either the enarodustat group with the initial dose of enarodustat 4 mg/day or the rHuEPO group with an initial total dose of ≤9,000 IU/week based on the prior regimen of ESAs before randomization (online suppl. Table 1). Doses were adjusted to maintain the Hb levels within 100–120 g/L. Enarodustat doses were evaluated every 2 or 4 weeks in accordance with the dose-adjusting rules (online suppl. Tables 2, 4) with a maximum dose of 8 mg/day. The dosage adjustment rules for rHuEPO are in online supplementary Tables 3 and 5.
Iron Administration
Patients already on oral iron therapy before screening may continue without dose adjustment, while others are not permitted oral iron during initial treatment. During maintenance, intravenous iron is allowed if TSAT <20% or ferritin <100 ng/mL (adjusted per Hb levels). Oral iron is preferred; intravenous iron may be used if oral therapy is ineffective or intolerable.
Study Outcomes
The primary efficacy endpoint was the difference in mean Hb (g/L) level between groups over weeks 20–24 (ΔHb20–24). The secondary efficacy endpoints included the proportion of patients with Hb levels within ±10 g/L of baseline at week 4; the proportion of the Hb level of 100–120 g/L during the evaluation period; Hb levels and changes in Hb levels from baseline during the screening period and at weeks 0, 2, 4, 8, 12, 16, 20, 22, 24, 26; prescribed dose and dose adjustments of the investigational product between visits and throughout the treatment period; usage of iron preparations; proportion of the Hb level out of the target range (≥100 g/L and <120 g/L) after week 4; proportion of the Hb level <80 g/L or ≥130 g/L after week 4; proportion of the Hb level increased by more than 20 g/L in any 4-week period until week 24.
Exploratory analyses included red blood cell test values, iron metabolism measures (serum iron, ferritin, transferrin, TIBC, TSAT), and the effect of C-reactive protein (CRP) levels on efficacy endpoints. Safety assessments included TEAEs, serious adverse events (SAEs), laboratory test findings, vital signs, electrocardiograms, chest X-rays, abdominal ultrasounds, and fundoscopy.
Statistical Methods
Sample Size
A sample size calculation was conducted to achieve 90% power to demonstrate the noninferiority of enarodustat to rHuEPO, assuming a standard deviation (SD) of 9.5 g/L and a difference of −3 g/L in ΔHb20–24; noninferiority was demonstrated if the lower limit of the 95% confidence interval (CI) of the difference in the least-squares mean of ΔHb20–24 between enarodustat and rHuEPO was above the noninferiority margin of −10 g/L [25, 26]. Considering an estimated dropout rate of 20%, the final required sample size was estimated to be 50 patients per treatment group. This calculation was performed using PASS 16 software.
Statistical Analyses
All statistical analyses were performed using SAS® version 9.4. The primary efficacy endpoint (ΔHb20–24) was analyzed by a mixed model of repeated measurements (MMRMs), with mean Hb level at weeks 20–24 and prior visits as dependent variables, baseline Hb level as a covariate, the treatment group, visit, and treatment-by-visit interaction as fixed effects. Missing data were handled using multiple imputation under the assumption of missing at random, and intercurrent events were addressed using a composite strategy in accordance with the ICH E9(R1) addendum on estimands. Noninferiority was concluded if the lower limit of the 95% CI of the difference was greater than −10 g/L. Secondary endpoints were analyzed using descriptive statistics.
Additionally, sensitivity and supplementary analyses were conducted to assess the robustness of the primary efficacy endpoint. These included analysis of covariance based on the primary estimand and MMRM with the site as a random effect for sensitivity analysis, and analysis of covariance without considering concomitant events for supplementary analysis to compare with the MMRM results. A tipping point analysis was conducted as a sensitivity analysis to evaluate the impact of missing data on the results. Efficacy was analyzed based on the full analysis set (FAS) with eligible patients who received study treatment; the handling of intercurrent events and strategies for the primary and secondary estimands complied with ICH E9(R1) guidelines. Safety was analyzed based on the safety set (SS), which included patients who received the study treatment.
Subgroup analyses, pre-specified for baseline dry weight, age, Hb level, C-reactive protein (CRP), and weekly dose of ESAs, were conducted to compare mean Hb concentrations and their 95% CIs during the evaluation phase (weeks 20–24) or at the end-of-treatment visit. Post hoc analyses assessed the primary efficacy endpoint across strata defined by sex, CKD etiology, history of dialysis, iron-status indices, intact PTH, phosphate binder at screening, and baseline Hb.
Efficacy was analyzed based on the FAS with patients meeting the inclusion criteria, receiving ≥1 dose of the study drug after randomization. Additionally, sensitivity and supplementary analyses were performed to evaluate the robustness of the primary efficacy endpoint. The endpoint analysis also considered the following intercurrent events and associated strategies, which were compliant with ICH E9(R1) guidelines. Safety was analyzed based on the SS with all patients receiving ≥1 dose of treatment after randomization.
Results
Patient Characteristics
Of 229 patients screened, 129 were excluded (124 due to protocol deviations, 5 due to withdrawal), and 100 were randomized to receive either enarodustat (n = 50) or rHuEPO (n = 50). A total of 93 patients completed the study (enarodustat, n = 46; rHuEPO, n = 47), while 7 patients discontinued (enarodustat, n = 4; rHuEPO, n = 3), as depicted in Figure 1. Among all randomized patients, the main reason for discontinuation was patient withdrawal (2 for each group). Overall, 98 patients were included in the FAS, with 1 patient excluded from each group for not meeting the inclusion criteria (1 patient without continuous 4-week ESAs treatment before screening in the rHuEPO group and 1 patient with variable rHuEPO dosage in 2 weeks before screening in the enarodustat group). Overall, 100 patients were included in the SS. Demographics and baseline characteristics were similar between the enarodustat and rHuEPO groups (Table 1).
Fig. 1.
Patient disposition.
Table 1.
Patient demographics and baseline characteristics (FAS)
| Parameters | Enarodustat (N = 49) | rHuEPO (N = 49) |
|---|---|---|
| Sex, n (%) | ||
| Male | 24 (49.0) | 31 (63.3) |
| Female | 25 (51.0) | 18 (36.7) |
| Age, years | ||
| Mean (SD) | 49.2 (10.57) | 51.4 (9.94) |
| Median | 48.0 | 52.0 |
| Min, max | 32, 74 | 30, 69 |
| Dry weight, kg | ||
| Mean (SD) | 58.18 (11.19) | 65.97 (12.46) |
| History of dialysis, years | ||
| Mean (SD) | 6.26 (5.26) | 5.441 (3.59) |
| Median | 5.25 | 5.50 |
| Min, max | 0.67, 22.9 | 0.86, 18 |
| Previous ESAs medication, n (%) | ||
| rHuEPO | 49 (100) | 48 (98.0) |
| DA | 0 | 1 (2.0) |
| Previous rHuEPO dose, IU/week | ||
| Mean (SD) | 5,928.6 (1,976.42) | 6,145.8 (2,360.94) |
| Hb, g/L | ||
| Mean (SD) | 107.43 (5.84) | 107.73 (4.81) |
| Oral iron, n (%) | ||
| Yes | 14 (28.6) | 14 (28.6) |
| Intravenous iron, n (%) | ||
| Yes | 25 (51.0) | 24 (49.0) |
| Serum iron, μmol/L | ||
| Median (Q1, Q3) | 13.07 (9.70, 18.80) | 13.84 (10.30, 16.70) |
| Ferritin, ng/mL | ||
| Median (Q1, Q3) | 219.00 (126.00, 416.62) | 248.10 (145.71, 508.60) |
| TSAT, % | ||
| Median (Q1, Q3) | 31.50 (23.00, 42.40) | 30.00 (24.10, 40.20) |
| Transferrin, g/L | ||
| Median (Q1, Q3) | 1.84 (1.56, 2.07) | 1.92 (1.58, 2.08) |
| C-reactive protein, n (%) | ||
| ≤ULN | 37 (75.5) | 31 (63.3) |
| Residual renal function, % | ||
| Present | 17 (34.7) | 12 (24.5) |
| SBP, mm Hg | ||
| Mean (SD) | 147.0 (15.45) | 148.1 (17.65) |
| DBP, mm Hg | ||
| Mean (SD) | 85.4 (11.89) | 84.2 (11.98) |
The baseline value of primary endpoint indicator Hb value was defined as the mean of the three pre-dose Hb levels tested by the central laboratory in V1, V2, and D1 during the screening period.
Treatment Compliance and Exposure
The mean (median, SD) treatment compliance was 98.74% (100.00, 4.96) in the enarodustat group and 99.06% (100.00, 3.46) in the rHuEPO group, respectively, in the FAS. The mean (median, SD) duration of exposure was 162.9 (22.31) days in the enarodustat group and 163.2 (21.25) days in the rHuEPO group. The mean (median, SD) dose during week 20 – Week 24 was 4.31 (4.00, 2.40) mg/day in the enarodustat group and 5,723.40 (5,500.00, 2,454.61) IU/week in the rHuEPO group in the SS.
Efficacy Outcomes
Primary Endpoint
In the FAS, the enarodustat group had a mean Hb level of 106.81 (95% CI, 104.62–108.99) g/L during weeks 20–24, within the target range of 100–120 g/L (Fig. 2). The mean ΔHb20–24 was −0.50 (95% CI, −2.94 to 1.94) g/L for enarodustat and −8.06 (95% CI, −10.50 to −5.62) g/L for rHuEPO. The estimated least-squares mean difference was 7.47 (95% CI, 4.17–10.78, p < 0.001) g/L, confirming enarodustat’s noninferiority to rHuEPO. Sensitivity analysis yielded similar results (online suppl. Table 12). A tipping point analysis with adjusting missing data negatively by −102.53 g/L caused the 95% CI lower bound to dip below the noninferiority margin (10 g/L). However, this adjustment was far from the actual mean Hb difference (7.63 g/L) and unrealistic. Thus, missing data are unlikely to affect the noninferiority conclusion, supporting the robustness of the results (online suppl. Fig. 2).
Fig. 2.
Hb levels over time: enarodustat and rHuEPO (FAS).
Secondary Endpoints
The enarodustat group received a mean dose of 4.33 mg/day during weeks 20–24 and 4.28 mg/day overall, with an average of 2.0 dose adjustments. The rHuEPO group received a mean dose of 5,819.15 IU/week during weeks 20–24 and 5,948.14 IU/week overall, with 2.5 dose adjustments on average (online suppl. Table 6). The enarodustat group maintained mean hemoglobin levels within the target range (100–120 g/L) throughout treatment, showing stability from baseline to the end of treatment (Fig. 2; online suppl. Table 7).
From week 0 to week 4, the enarodustat group experienced a mean Hb change of −0.3 g/L (SD, 10.61), compared to −1.5 g/L (SD, 6.73) in the rHuEPO group. At week 4, 69.4% (95% CI, 54.6%–81.7%) of the enarodustat group had Hb levels within ±10 g/L of baseline, compared to 87.8% (95% CI, 75.2%–95.4%) in the rHuEPO group.
The enarodustat group achieved a target Hb (100–120 g/L) maintenance rate of 79.6% (95% CI, 65.7%–89.8%) during weeks 20–24, higher than the 51.0% (95% CI, 36.3%–65.6%) observed in the rHuEPO group. Over 50% of enarodustat-treated patients maintained Hb levels within the target range at each visit.
After week 4, no patients in the enarodustat group experienced the Hb level of <80 g/L, compared to 1 (2.0%) patient in the rHuEPO group. Hb levels ≥130 g/L were observed in 4 patients (8.2%) in the enarodustat group and 2 patients (4.1%) in the rHuEPO group (online suppl. Tables 8, 9). The proportion of patients with Hb level increase of >20 g/L in any 4-week period until week 24 was 8.2% (4 patients) in the enarodustat group and 2.0% (1 patient) in the rHuEPO group (online suppl. Table 10).
Exploratory Outcomes
Iron-related test values: in the enarodustat group, serum iron and transferrin levels increased, peaking at weeks 2–4 and remaining elevated. TIBC also increased and maintained an upward trend. Ferritin and TSAT fluctuated initially and then declined. Hepcidin levels decreased obviously following treatment initiation and remained below baseline during maintenance. In the rHuEPO group, serum iron decreased gradually, while other iron parameters remained stable at baseline levels (online suppl. Fig. 4, online suppl. Table 16).
The mean dose of intravenous iron during the treatment period was 314.30 ± 219.170 mg in the enarodustat group and 989.30 ± 539.248 mg in the rHuEPO group. During the study, 40.8% (20/49) of patients in both the enarodustat group and the rHuEPO group received oral iron supplementation. Additionally, intravenous iron was administered to 12.2% (6/49) of patients in the enarodustat group and 14.3% (7/49) of patients in the rHuEPO group.
Red blood cell (RBC)-related test values: in the enarodustat group, RET% increased after treatment, peaking at week 2 and staying above baseline throughout the study. In the rHuEPO group, RET% remained stable. For hematocrit and RBC count, the enarodustat group maintained stability, while the rHuEPO group had slightly lower levels than baseline. Mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration levels remained stable in both groups throughout the study (online suppl. Fig. 5, online suppl. Table 15).
Subgroup Analysis
To assess the consistency of efficacy across different baseline levels, subgroup analyses were conducted based on the primary efficacy endpoint. The subgroups were defined by dry weight (<60 kg; ≥60 kg), age classification (<65 years; ≥65 years), baseline Hb stratification (<100 g/L; ≥100 g/L), CRP level (baseline CRP/hs-CRP ≤upper limit of normal [ULN]; baseline CRP/hs-CRP>ULN), and weekly total dose for rHuEPO levels at screening (<6,000 IU/week; ≥6,000 IU/week). Across all subgroups, the results aligned with the primary endpoint in the FAS, with no influencing factors identified, reinforcing the broad applicability and reliability of the treatment effect (online suppl. Table 11). Additionally, a post hoc subgroup analysis showed that various baseline factors (sex, CKD etiology, history of dialysis, iron-status indices, intact PTH, phosphate binder) had no significant impact on Hb levels during the evaluation period.
Safety Outcomes
Both groups showed comparable TEAE incidence (enarodustat: 90% [45/50]; rHuEPO: 90% [45/50]), predominantly mild. SAEs occurred in 12.0% (6/50) of enarodustat and 8.0% (4/50) of rHuEPO patients, with one drug-related SAE in the rHuEPO group. Treatment withdrawal due to TEAEs was rare (enarodustat: 4.0%; rHuEPO: 0%), and no deaths occurred. The most common adverse events (≥5% incidence) were hemodialysis complications (26.0% vs. 22.0%) and upper respiratory infections (20% in both groups), all deemed unrelated to treatment (Table 2).
Table 2.
Overview of TEAEs (SS)
| Parameter | Enarodustat (N = 50), n (%) | rHuEPO (N = 50), n (%) |
|---|---|---|
| TEAEsa | 45 (90.0) | 45 (90.0) |
| Drug-related TEAEs | 11 (22.0) | 8 (16.0) |
| Serious TEAEs | 6 (12.0) | 4 (8.0) |
| Drug-related serious TEAEsa | 0 | 1 (2.0) |
| TEAEs leading to withdrawal of treatment | 2 (4.0) | 0 |
| Drug-related TEAEs leading to withdrawal of treatment | 1 (2.0) | 0 |
| Deaths | 0 | 0 |
| TEAEs reported in ≥5% patients in either groupb | 34 (68.0) | 38 (76.0) |
| Hyperkalemia | 6 (12.0) | 7 (14.0) |
| Hypocalcemia | 4 (8.0) | 5 (10.0) |
| Hypermagnesemia | 6 (12.0) | 2 (4.0) |
| Hypoproteinemia | 6 (12.0) | 1 (2.0) |
| Hypercalcemia | 4 (8.0) | 2 (4.0) |
| Hypertriglyceridemia | 2 (4.0) | 3 (6.0) |
| Metabolic acidosis | 3 (6.0) | 1 (2.0) |
| Hyponatremia | 1 (2.0) | 3 (6.0) |
| Iron deficiency | 1 (2.0) | 3 (6.0) |
| Hemodialysis complication | 13 (26.0) | 11 (22.0) |
| Dialysis hypotension | 6 (12.0) | 3 (6.0) |
| Upper respiratory tract infection | 10 (20.0) | 10 (20.0) |
| Respiratory tract infection | 1 (2.0) | 4 (8.0) |
| Vomiting | 5 (10.0) | 1 (2.0) |
| Diarrhea | 1 (2.0) | 3 (6.0) |
| Cough | 1 (2.0) | 5 (10.0) |
| Renal cysts | 2 (4.0) | 3 (6.0) |
| Renal calculi | 3 (6.0) | 2 (4.0) |
| Occult blood positive | 1 (2.0) | 3 (6.0) |
| Dizziness | 3 (6.0) | 0 |
| Any AE related to study drug reported in ≥5% | 0 | 0 |
| AEs of special interestc | 3 (6.0) | 3 (6.0) |
| Injuries, poisoning, and procedural complications | 1 (2.0) | 2 (4.0) |
| Arteriovenous fistula occlusion | 1 (2.0) | 2 (4.0) |
| Cardiac disorders | 1 (2.0) | 1 (2.0) |
| Hypertensive heart disease | 0 | 1 (2.0) |
| Cardiac failure | 1 (2.0) | 0 |
| Product issues | 1 (2.0) | 0 |
| Thrombosis in device | 1 (2.0) | 0 |
| Nervous system disorders | 1 (2.0) | 0 |
| Cerebral artery stenosis | 1 (2.0) | 0 |
| Brainstem infarction | 1 (2.0) | 0 |
aTEAEs are defined as adverse events that occur after the first dose of the investigational product or that exist before the first dose of the investigational product but worsen after the first dose of the investigational product.
bMedDRA version 27.0 system organ class and preferred term.
cAEs of special interest (AESI): hypertension, thromboembolic event (stroke events include only infarctive stroke), angina pectoris, and cardiac failure. Among them, hypertension refers to serious hypertension.
At the end of treatment, the enarodustat group showed a significantly greater reduction in uric acid levels compared to the rHuEPO group. Additionally, enarodustat led to a larger decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (Δ = −3,156.20 pg/mL) than rHuEPO (Δ = 1,029.23 pg/mL), although this difference was not statistically significant (p = 0.162). Other clinical and laboratory parameters, including blood pressure (online suppl. Fig. 3), liver enzymes (ALT, AST, GGT, ALP, LDH), electrolytes (K), and biomarkers (VEGF, AFP, CA199), remained stable in both groups throughout the study (online suppl. Table 14).
Discussion
This multicenter, randomized, open-label, 24-week, phase 3 study compared the efficacy of enarodustat with rHuEPO in HD-CKD patients with renal anemia switching from ESAs. Enarodustat was as effective as rHuEPO in maintaining Hb levels within the target range during the evaluation period (106.81 g/L vs. 99.68 g/L), with rHuEPO’s level consistent with prior studies [27, 28]. Comparable Hb changes were observed at week 4 (−0.3 g/L vs. −1.5 g/L). The initial 4 mg/day dose of enarodustat kept Hb levels stable regardless of prior ESAs use. Throughout treatment, mean Hb levels were maintained within the target range with once-daily oral enarodustat, and the mean prescribed dose remained stable. Although some patients’ Hb levels exceeded the target range during the study (online suppl. Table 8), particularly with 4 patients experiencing Hb ≥130 g/L, mainly during weeks 4–8 (online suppl. Tables 8, 9), these levels gradually declined within 2–4 weeks after drug discontinuation or dosage reduction. This indicates that the impact of enarodustat on Hb levels diminishes within this timeframe. Moreover, there was no obvious increase in adverse events (Table 2), confirming the drug’s safety. The results indicated that the initial 4 mg once-daily dose and the dose adjustment criteria for enarodustat were reasonable, with a simple dosing schedule. To our knowledge, this is the first study that provides a comprehensive efficacy and safety profile of enarodustat in Chinese HD patients.
Subgroup analyses demonstrated that enarodustat’s efficacy is not influenced by patient weight, age, baseline ESAs dosage, or CRP levels. High CRP levels, indicating inflammation, are associated with poor ESAs response [29]. In this study, Hb levels remained consistent across different CRP levels, despite the high CRP group comprising about 30% of participants. These findings align with other HIF-PHI studies [30]. A post hoc subgroup analysis further confirmed that various baseline factors had no appreciable impact on Hb levels during the evaluation period (online suppl. Table 13).
HIF regulates oxygen homeostasis, affecting erythropoiesis, angiogenesis, energy metabolism, and iron metabolism [31]. Stabilizing HIF promotes erythropoiesis, increases erythroferrone, and suppresses hepcidin, which regulates iron levels [18, 32–34]. Elevated hepcidin in inflammation and CKD blocks iron release needed for red blood cell production [35, 36]. In this study, the enarodustat group had lower hepcidin and ferritin levels and higher TIBC, serum iron, and transferrin levels compared to the rHuEPO group, indicating improved iron utilization. This was supported by reduced intravenous iron use (online suppl. Table 17). Reticulocyte counts increased in the enarodustat group after week 2 and remained above baseline, showing effective erythropoietic performance. These results align with other studies [20, 37].
Enarodustat not only exhibited consistent efficacy but also demonstrated favorable safety and tolerability profiles. A potential concern regarding HIF-PHI is VEGF-related AEs. VEGF, as a HIF-target gene, is implicated in retinal/choroidal neovascularization and tumor growth [38]. In our study, no obvious changes in plasma VEGF or tumor markers such as AFP and CA199 were observed (online suppl. Table 14), and no drug-related tumors were reported. Notably, preclinical research found that a high dose of enarodustat (more than 10 times the amount needed for natural erythropoiesis) stimulated VEGF production, yet this elevation was not expected to impact tumor growth [39]. Moreover, drug-related retinal disorders were rare: maculopathy 2.0% (1/50) in the enarodustat group versus 0% in the rHuEPO group. For other concerns related to HIF-PHI, including hypertension, major CV events, embolic and thrombotic events, and hyperkalemia [40, 41], no apparent difference in frequency was noted between the enarodustat and rHuEPO groups.
Improvements have been observed in some indicators in the enarodustat group. NT-proBNP serves as an indicator of heart failure [42], and elevated levels of NT-proBNP are closely associated with an increased risk of CV events and mortality [43]. In the enarodustat group, NT-proBNP levels obviously decreased at week 24 (Δ = −3,156.20 pg/mL), while NT-proBNP levels increased slightly in the rHuEPO group (Δ = 1,029.23 pg/mL, p = 0.162). This finding aligns with other studies [44]. However, the precise underlying mechanisms for these differences remain to be elucidated. Additionally, there was no difference in the incidence of CV events between the two groups. Another difference is the uric acid level, uric acid dropped significantly more in the enarodustat group (Δ = −39.9 μmol/L) than in the rHuEPO group (Δ = −4.1 μmol/L, p < 0.01) at week 4 and stayed stable until treatment ended (online suppl. Table 14). This may be related to the slower decline in estimated glomerular filtration rate observed in the enarodustat group compared to the darbepoetin alfa in the SYMPHONY ND study [21].
This study has several limitations. First, the study’s limited sample size and brief duration precluded robust subgroup analyses; consequently, remaining subgroup analyses are exploratory and hypothesis generating rather than confirmatory and should also be interpreted with caution. Larger and longer-term studies – including extended RCTs and real-world evidence – are needed to assess HIF-PHI safety and definitively map enarodustat’s long-term benefit-risk profile; however, enrollment from 35 geographically dispersed Chinese centers strengthens external validity. Moreover, previous 52-week studies in Japan have demonstrated the long-term efficacy and safety of enarodustat in treating anemia in Japanese patients with chronic kidney disease, including those not on dialysis, as well as those undergoing hemodialysis or peritoneal dialysis [45–47]. Second, this study was not designed to detect significant differences in secondary endpoints. Third, this study lacks statistical power for definitive conclusions on overall safety, CV outcomes, and renal outcomes. In addition, the relatively high screen failure rate (54%) suggests our enrolled population represents a selected subgroup, potentially limiting generalizability to real-world practice where comorbidities are more prevalent. Lastly, our cohort consisted exclusively of Chinese maintenance hemodialysis patients whose mean age (50.3 ± 10.3 years) closely mirrors that documented in recent national registries [48, 49]. This demographic alignment underscores the real-world representativeness of the sample and supports external validity within China; nonetheless, extrapolation of our findings to older or ethnically distinct populations should be undertaken with caution.
Conclusion
This phase 3 trial established the noninferiority of enarodustat compared to rHuEPO for anemia treatment in patients undergoing hemodialysis over a 24-week period, with Hb levels being stable and within the target range.
Acknowledgments
The authors thank all investigators, participating centers, and study participants for their time, effort, and commitment to the study.
Statement of Ethics
All patients provided written informed consent prior to participation. This study was approved by the Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University (No. 2023-084-01) and was conducted in compliance with the ethical principles of the Declaration of Helsinki, the study protocol, and the Guidelines for Good Clinical Practice.
Conflict of Interest Statement
Shengmei Mu, Yuanyuan Chen, Xiaojuan Lian, and Zichen Liu are employees of Shenzhen Salubris Pharmaceuticals Co., Ltd. Other authors declare no conflict of interest.
Funding Sources
This work was sponsored by Shenzhen Salubris Pharmaceuticals Co., Ltd., China.
Author Contributions
Wei Chen, Haishan Wu, Zhen Ai, and Aiying Liu were responsible for conceptualizing and designing of the study. Aiying Liu, Hong Ye, Changyou Sun, Aicheng Yang, Wenli Chen, Zhihua Zheng, Caili Wang, Yuehong Li, Ning Cao, Cheng Wang, Yuou Xia, Hong Cheng, Ping Luo, Qiongqiong Yang, Yuehong Yan, Hua Zhou, Nan Mao, Zibo Xiong, Bicheng Liu, Daqing Hong, Qingping Chen, Bo Liang, Qun Luo, Yu Wang, Yongjun Shi, Xiaonong Chen, Li Zhou, Tiekun Yan, Bin Zhu, Jianwen Wang, Menghua Chen, Yongjun Zhu, Tianjun Guan, Song Wang, and Yuanwen Xu were responsible for patient screening, follow-up, and data acquisition, analysis, and interpretation. Shengmei Mu, Yuanyuan Chen, and Zichen Liu performed statistical analyses. Haishan Wu, Zhen Ai, Xiaojuan Lian, and Wei Chen were involved in drafting and revising the work to be published for important intellectual content. All authors critically reviewed and revised the manuscript and gave the final approval.
Funding Statement
This work was sponsored by Shenzhen Salubris Pharmaceuticals Co., Ltd., China.
Data Availability Statement
The data supporting the findings of this study are not publicly available due to privacy concerns regarding research participants. However, they are available from the corresponding author, Wei Chen, upon reasonable request.
Supplementary Material.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data supporting the findings of this study are not publicly available due to privacy concerns regarding research participants. However, they are available from the corresponding author, Wei Chen, upon reasonable request.
