Abstract
Introduction
This phase III trial assessed desidustat’s efficacy and safety compared with placebo for the treatment of anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD).
Methods
A multicenter, randomized, double-blind trial enrolled 152 NDD-CKD patients with anemia (101 desidustat, 51 placebo). Primary endpoint: hemoglobin (Hb) change from baseline to weeks 7–9. Secondary endpoints included Hb response rate (≥100 g/L), time to target Hb, and target Hb maintenance (100–120 g/L). Safety evaluated treatment-emergent adverse events (TEAEs). Exploratory endpoints analyzed Hb dynamics (weeks 21–25) and serum hepcidin levels (baseline-week 53).
Results
After 9 weeks of treatment, desidustat increased Hb level from 89.18 g/L to 105.66 g/L, whereas placebo decreased from 89.41 g/L to 88.51 g/L, with a mean difference of 17.52 g/L (95% confidence interval [CI]: 14.35–20.68) in the full analysis set. And in the per protocol set, desidustat increased Hb level from 88.86 g/L to 105.62 g/L, and placebo declined from 89.37 g/L to 87.57 g/L, with a mean difference of 18.39 g/L (95% CI: 15.39–21.39). Hb response rates were 85.15% vs. 23.53% (p < 0.001). Median time to target Hb was 30 days with desidustat vs. 0 days with placebo (p < 0.001). By week 9, desidustat maintained Hb within target range 51.68% of the time vs. 10.24% for placebo (p < 0.001). TEAE incidence was comparable between groups. During weeks 21–25, Hb rose further (desidustat: +21.26 g/L; placebo: +26.63 g/L). Serum hepcidin decreased sharply in desidustat by week 9 (−67.43 ng/mL vs. −6.38 ng/mL; placebo), though placebo showed delayed reduction by week 25 – levels equalized by week 53.
Conclusion
Desidustat significantly improved Hb levels and accelerated anemia correction in NDD-CKD patients versus placebo, with comparable safety.
Keywords: Desidustat, Anemia, Chronic kidney disease, Treatment, Safety, Hemoglobin
Introduction
Kidney disease has been an increasing global problem, and approximately 700 million people were estimated to have chronic kidney disease (CKD) worldwide [1]. Anemia is a common and serious complication, especially in non-dialysis-dependent CKD (NDD-CKD), with prevalence rising to 50%–80% in advanced stages [2–5]. It worsens quality of life, increases cardiovascular risk by elevating cardiac workload, and is linked to reduced physical endurance, higher hospitalization rates, and increased mortality [6–9]. Early detection and treatment are essential to improve outcomes.
Managing anemia in NDD-CKD remains challenging. Current therapies rely on erythropoiesis-stimulating agents (ESAs) and intravenous iron, both of which have limitations [10, 11]. ESAs can cause hypertension (in 20%–30% of patients), thrombotic events, and may accelerate renal decline at high doses [11, 12]. Up to 50% of patients respond poorly due to functional iron deficiency or inflammation [11]. As kidney function declines, maintaining stable hemoglobin (Hb) becomes increasingly complex [13], highlighting the need for safer, more effective treatments. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) offer a novel approach. By stabilizing HIF, they enhance erythropoietin production and improve iron utilization, promoting red blood cell formation through a mechanism that mimics the natural hypoxia response [14, 15]. This offers a physiologic alternative to ESAs and iron therapy.
Desidustat, an oral HIF-PHI, inhibits HIF-1α degradation in the kidneys, stimulating erythropoiesis similarly to ESAs but with improved convenience and adherence [16]. While early trials show promise, large-scale, multicenter randomized studies in NDD-CKD patients are lacking. This study evaluates the efficacy and safety of desidustat in this population, aiming to provide a new therapeutic option for those at high risk.
Methods and Materials
Study Design and Participants
In this phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial, participants with NDD-CKD-associated anemia were recruited from January 12, 2022, to July 31, 2024, at multiple research centers in China. The study was approved by the Ethics Committees of all participating centers and conducted by the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment. The inclusion criteria included: age 18–80 years, estimated glomerular filtration rate <60 mL/min/1.73 m2, Hb levels between 70 and 100 g/L at screening, and no prior use of ESAs within 6 weeks before randomization. The key exclusion criteria included a history of maintenance dialysis, recent intravenous iron supplementation or blood transfusions, active malignancies or severe liver disease, serum potassium ≥5.5 mmol/L, major cardiovascular events within the past 6 months, severe active infections, and known hypersensitivity to the study drug. A complete list of the inclusion and exclusion criteria is provided in online supplementary Table S1 (for all online suppl. material, see https://doi.org/10.1159/000551113).
A two-group parallel design was employed with a two-sided significance level (α) of 0.05 and 90% statistical power. Sample size estimation was informed by data from a randomized, double-blind, placebo-controlled phase II clinical trial conducted by Zydus Lifesciences Ltd. in India. In that study, the mean change in Hb from baseline after 6 weeks of treatment was 1.57 ± 1.07 g/dL in the 100 mg dose group and 0.46 ± 1.64 g/dL in the placebo group, yielding a between-group mean difference of 1.0 g/dL. The pooled standard deviation, calculated using the combined-variance method, was 1.4668 g/dL; thus, a conservative estimate of 1.5 g/dL was adopted for the sample size calculation. Participants were allocated to the treatment and control groups in a 2:1 ratio. Accounting for an anticipated 20% dropout rate, the required total sample size was determined to be 150 subjects.
Randomization and Masking
Randomization information for drug identification was generated by a randomization specialist using SAS 9.4 software (SAS Institute, Cary, NC, USA). This included determining the number of drug identifiers, the intergroup ratio (2:1), the block length, the number of blocks, and the seed numbers to create a blinded drug identifier list. The list was then imported into the Interactive Web Response System (IWRS). After the IWRS was configured and successfully tested, the randomization specialist generated the drug identifiers and prepared them for on-site blinding. The drug blinding was performed by an unblinded randomization specialist at a site designated by the sponsor. This specialist affixed labels with the drug identifiers to the corresponding drug packaging according to the randomization table. All study medications were indistinguishable in appearance and labeling, ensuring that both patients and investigators remained blinded.
Treatment
Following a maximum screening period of 4 weeks, eligible patients were randomly assigned in a 2:1 ratio to either the treatment group (desidustat) or the control group (placebo). During the first 8 weeks, patients received randomized treatment with either desidustat or placebo. From weeks 9 to 52, all patients received open-label oral desidustat, allowing for extended efficacy and safety follow-up. The starting dose of desidustat/placebo was 100 mg (four tablets), administered three times weekly at intervals of 1–2 days for a continuous period of 4 weeks. After this initial phase, dosage adjustments were made based on patients’ Hb levels and the rate of change; thereafter, adjustments could be made every 4 weeks according to Hb levels. If Hb levels dropped below 70 g/L at any visit during the first 4 weeks, dose escalation was permitted. If Hb levels reached ≥120 g/L, adjustments could be made at any time during the study. Dose modifications due to excessive erythropoiesis or adverse events could be based on unplanned Hb measurements assessed at the study site.
Outcomes
The primary efficacy endpoint was the change in the mean Hb level from baseline to weeks 7–9. Key secondary efficacy endpoints included the proportion of participants achieving a Hb response, defined as reaching target levels of 100–120 g/L at any point before week 9 or an increase in Hb levels of ≥10 g/L following treatment, the time to reach the target Hb level (≥100 g/L), the percentage of time spent within the target Hb range (100–120 g/L), and the proportion of participants requiring rescue therapy by week 9. The frequency and severity of adverse events, including serious adverse events, were compared between the treatment and control groups. Exploratory endpoints included changes in Hb and serum hepcidin levels. During the extended observation period (weeks 21–25), Hb levels were measured in patients from both the desidustat and desidustat (switched from placebo) groups. Data collection included baseline, week 21, and week 25 to evaluate changes in Hb levels during this period. Blood samples at each time point were analyzed using standardized laboratory methods. Concurrently, data on serum hepcidin level changes were collected at baseline, week 9, week 25, and week 53. Serum samples were obtained at each time point by the study sites and analyzed with standardized laboratory techniques. The same cohort of patients was used for all time points to ensure consistency and comparability of the hepcidin data.
Statistical Analysis
General Principles
Pharmacokinetic parameter analysis was conducted using a noncompartmental model in WinNonlin (version 8.3, Certara, Radnor, PA, USA). All other statistical analyses were performed using SAS (version 9.4). Continuous variables were summarized within each group, including the number of observations, the number of missing values, the mean, standard deviation, quartiles, and minimum and maximum values. Categorical variables were summarized within groups as counts, frequencies, percentages, and the number of missing values. Unless otherwise specified, all statistical tests were two-tailed with an alpha level of 0.05; p < 0.05 was considered statistically significant. For parametric data, between-group comparisons were conducted using t-tests or analysis of variance, whereas within-group comparisons (pre- and post-treatment) were performed using paired t-tests. For nonparametric data, the Wilcoxon rank-sum test or Friedman test was used for between-group comparisons, whereas the Wilcoxon signed rank test was used for within-group comparisons. For count data, between-group differences were analyzed using the chi-squared test, Fisher’s exact test, or Cochran-Mantel-Haenszel test differences were analyzed using the chi-squared test. In contrast, within-group differences were evaluated using McNemar’s chi-square test or binomial tests. For ordinal data, between-group differences were analyzed using rank-sum tests, whereas within-group differences were assessed using paired rank-sum tests.
Statistical Hypotheses
The null hypothesis (H0) was μ2 − μ1 = 0, and the alternative hypothesis (H1) was μ2 – μ1 ≠ 0. The study was designed to evaluate differences versus placebo, with the primary efficacy endpoint being the change in Hb levels from baseline to weeks 7–9, as measured at the central laboratory. In these hypotheses, μ1 and μ2 represent the changes in Hb levels in the placebo and desidustat groups, respectively. The probability of a type I error (two-sided) was set at α = 0.05. An analysis of covariance (ANCOVA) model was used to compare groups. A two-sided 95% confidence interval (CI) for the least-squares mean difference in Hb change (desidustat group – placebo group) exceeding zero was considered to indicate a statistically significant difference favoring the desidustat group. The completed CONSORT 2025 checklist is available as online supplementary Table S7.
Results
Patient Disposition
A total of 152 participants from 27 research centers were enrolled in the study, all of whom were included in the full analysis set (FAS). The desidustat group consisted of 101 participants, while the placebo group included 51 participants. After excluding 31 participants, 121 were included in the per protocol set (PPS), with 77 (76.24%) in the desidustat group and 44 (86.27%) in the placebo group (Fig. 1).
Fig. 1.
Study flowchart.
Baseline Characteristics of Study Participants
The baseline characteristics, including age, gender, ethnicity, body mass index, blood pressure, hyperkalemia + elevated blood potassium, hypocalcemia + decreased blood calcium, diabetes + type 2 diabetes, hypertension + renal hypertension, hyperphosphatemia, Hb concentration, and eGFR, were well balanced between the desidustat and placebo groups. The mean (±SD) baseline Hb levels were 89.18 ± 7.16 g/L in the desidustat group and 89.41 ± 6.86 g/L in the placebo group. The mean (±SD) eGFR was 16.78 ± 10.03 mL/min/1.73 m2 in the desidustat group and 17.32 ± 8.86 mL/min/1.73 m2 in the placebo group (Table 1).
Table 1.
Baseline characteristics of patients (full analysis set)
| Variable | | Desidustat group | Placebo group |
|---|---|---|---|
| (N = 101) | (N = 51) | ||
| Age, years | Mean (SD) | 55.9 (12.86) | 58.1 (12.80) |
| BMI, kg/mL | Mean (SD) | 23.358 (3.2705) | 23.474 (2.6555) |
| Gender, n (%) | |||
| Male | | 47 (46.53) | 23 (45.10) |
| Female | | 54 (53.47) | 28 (54.90) |
| Ethnicity, n (%) | |||
| Han | | 96 (95.05) | 47 (92.16) |
| Others | | 5 (4.95) | 4 (7.84) |
| Systolic blood pressure, mm Hg | Mean (SD) | 135.1 (17.17) | 135.1 (17.40) |
| Diastolic blood pressure, mm Hg | Mean (SD) | 80.7 (9.32) | 77.6 (10.87) |
| eGFR, mL/min/1.73 m2 | Mean (SD) | 16.774 (10.034) | 17.320 (8.859) |
| Median (Q1, Q3) | 13.560 (10.360, 19.150) | 14.460 (11.170, 24.150) | |
| Potassium, mmol/L | Mean (SD) | 4.848 (0.563) | 4.828 (0.609) |
| Median (Q1, Q3) | 4.870 (4.520, 5.190) | 4.830 (4.320, 5.230) | |
| Calcium, mmol/L | Mean (SD) | 2.263 (0.137) | 2.252 (0.143) |
| Median (Q1, Q3) | 2.260 (2.180, 2.360) | 2.260 (2.190, 2.350) | |
| Hb, g/L | Mean (SD) | 89.178 (7.164) | 89.405 (6.862) |
| Hyperkalemia + elevated blood potassium | n (%) | 30 (29.70) + 2 (1.98) | 13 (25.49) + 0 |
| Hypocalcemia + decreased blood calcium | n (%) | 14 (13.86) + 1 (0.99) | 5 (9.80) + 1 (1.96) |
| Diabetes + type 2 diabetes | n (%) | 9 (8.91) + 25 (24.75) | 7 (13.73) + 16 (31.37) |
| Hypertension + renal hypertension | n (%) | 92 (91.09) + 3 (2.97) | 42 (82.35) +5 (9.80) |
| Hyperphosphatemia | n (%) | 28 (27.72) | 15 (29.41) |
| Serum iron is normal | n (%) | 84 (83.17) | 40 (78.43) |
| Serum ferritin is normal | n (%) | 71 (70.30) | 39 (76.47) |
| Total iron binding capacity is normal | n (%) | 52 (51.49) | 22 (43.14) |
| Transferrin saturation is normal | n (%) | 75 (74.26) | 38 (74.51) |
Hb Levels from Baseline to Weeks 7–9
Both FAS and PPS analyses demonstrated that desidustat significantly increased Hb levels from baseline to weeks 7–9, while placebo showed minimal change or a slight decrease. In the FAS, desidustat rose Hb level from 89.18 g/L to 105.66 g/L, whereas placebo decreased from 89.41 g/L to 88.51 g/L, with a mean difference of 17.52 g/L (95% CI: 14.35–20.68). The PPS analysis yielded similar results: desidustat increased from 88.86 g/L to 105.62 g/L, and placebo declined from 89.37 g/L to 87.57 g/L, with a mean difference of 18.39 g/L (95% CI: 15.39–21.39). Significant improvements (p < 0.05) were observed at multiple time points (weeks 3, 5, 7, and 8) (Table 2; online suppl. Fig. 1–4). Hb response rates were substantially higher in the desidustat group: 85.15% (FAS) and 93.51% (PPS), compared to 23.53% and 22.73% in the placebo group, resulting in differences of 61.62% and 70.78%, respectively (p < 0.001) (Table 3).
Table 2.
Changes in Hb levels from baseline during weeks 7–9
| Datasets | | Desidustat group | Placebo group | Total | p value |
|---|---|---|---|---|---|
| (N = 101) | (N = 51) | (N = 152) | |||
| FAS | |||||
| Baseline, g/L | n (nmiss) | 101 (0) | 51 (0) | 152 (0) | 0.854* |
| Mean (SD) | 89.178 (7.1636) | 89.405 (6.8619) | 89.254 (7.0418) | | |
| Week 7–9, g/L | n (nmiss) | 88 (13) | 48 (3) | 136 (16) | <0.001* |
| Mean (SD) | 105.655 (9.0611) | 88.507 (12.0615) | 99.603 (13.0849) | | |
| Week 7–9 – baseline | n (nmiss) | 88 (13) | 48 (3) | 136 (16) | <0.001* |
| Mean (SD) | 16.436 (8.7905) | −1.229 (9.6541) | 10.201 (12.4112) | | |
| PPS | |||||
| Baseline, g/L | n (nmiss) | 77 (0) | 44 (0) | 121 (0) | 0.757* |
| Mean (SD) | 88.861 (7.2663) | 89.371 (6.8337) | 89.047 (7.0876) | | |
| Week 7–9, g/L | n (nmiss) | 77 (0) | 44 (0) | 121 (0) | <0.001 |
| Mean (SD) | 105.619 (9.2147) | 87.568 (9.3865) | 99.055 (12.7034) | | |
| Week 7–9 – baseline | n (nmiss) | 77 (0) | 44 (0) | 121 (0) | <0.001* |
| Mean (SD) | 16.758 (9.0484) | −1.803 (6.8842) | 10.008 (12.2155) | | |
Table 3.
Proportion of patients with Hb response through week 9 post-treatment
| Datasets | Desidustat group (N = 101) | Placebo group (N = 51) | Total (N = 152) | p value |
|---|---|---|---|---|
| FAS | ||||
| Hb response status at week 9 | ||||
| Respondersa, n (%) | 86 (85.15) | 12 (23.53) | 98 (64.47) | |
| Nonresponders, n (%) | 15 (14.85) | 39 (76.47) | 54 (35.53) | <0.001 |
| PPS | ||||
| Hb response status at week 9 | ||||
| Responders, n (%) | 72 (93.51) | 10 (22.73) | 82 (67.77) | |
| Nonresponders, n (%) | 5 (6.49) | 34 (77.27) | 39 (32.23) | <0.001 |
aThe Hb responders were defined as those who reached the target level of 100–120 g/L at any time up to week 9 or had an increase of 10 g/L or more in Hb after treatment.
For time to achieve target Hb levels, the desidustat group had a median of 30 days, with hazard ratios of 6.37 (FAS) and 6.84 (PPS), which increased to 8.23 and 8.89 after adjusting for baseline Hb, indicating an 8–9 times higher likelihood of success (p < 0.001) (Table 4). These results consistently confirm desidustat’s superiority over placebo. Hb and red blood cell count data from each study visit showed that deferasirox significantly improved anemia-related parameters (online suppl. Tables S3 and S4).
Table 4.
Time to achieve target Hb range
| Datasets | | Desidustat group (N = 101) | Placebo group (N = 51) | Total | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| FAS | |||||
| Time to reach target Hb level, days | n (censor) | 81 (11) | 11 (36) | <0.001 | 6.24 (3.31, 11.79) |
| PPS | |||||
| Time to reach target Hb level, days | n (censor) | 67 (10) | 9 (34) | <0.001 | 6.72 (3.33, 13.58) |
Percentage of Time within the Target Hb Range through Week 9
In the FAS analysis, the average percentage of time within the target Hb range for the desidustat group (97 participants) was 51.68% ± 34.37%, compared to 10.24% ± 23.39% in the placebo group. ANCOVA showed that the least-squares mean percentages were 51.77% for the desidustat group and 10.07% for the placebo group, resulting in a difference of 41.70% (95% CI: 32.65–50.76; p < 0.001), indicating that desidustat’s efficacy was significantly better than that of the placebo (Table 5). The PPS analysis produced similar results. The mean percentage of time within the target Hb range was 53.83% ± 33.59% in the desidustat group (77 participants) and 10.43% ± 24.19% in the placebo group (44 participants). ANCOVA revealed least-squares mean percentages of 54.25% for the desidustat group and 9.71% for the placebo group, with a between-group difference of 44.54% (95% CI: 34.75–54.33; p < 0.001; Table 5).
Table 5.
Percentage of time within target Hb range (%)
| Datasets | | Desidustat group (N = 101) | Placebo group (N = 51) | Total (N = 152) | p value |
|---|---|---|---|---|---|
| FAS | |||||
| Percentage of time within target Hb range, % | Mean (SD) | 51.678 (34.3727) | 10.243 (23.3879) | 37.400 (36.7153) | <0.001* |
| PPS | |||||
| Percentage of time within target Hb range, % | Mean (SD) | 53.830 (33.5892) | 10.432 (24.1927) | 38.049 (36.9287) | <0.001* |
Analysis of Treatment-Emergent Adverse Events
The safety analysis showed no statistically significant differences in overall adverse event profiles between the desidustat and placebo groups (Table 6). Specifically, 85.15% of patients in the desidustat group reported treatment-emergent adverse events (TEAEs), totaling 255 occurrences, compared with 84.31% (128 occurrences) in the placebo group (p = 0.892). For drug-related events, 28.71% (51 occurrences) of TEAEs in the desidustat group were considered related to the investigational drug, versus 27.45% (28 occurrences) in the placebo group (p = 0.870). There were no significant differences in the rates of serious adverse events (10.89% vs. 13.73%) and adverse events leading to withdrawal (3.96% vs. 5.88%) between the two groups. For high-grade adverse events, grade ≥3 TEAEs occurred in 22.77% of desidustat-treated patients (28 occurrences), with 5.94% classified as drug-related. In comparison, 19.61% of patients in the placebo group experienced grade ≥3 TEAEs (11 occurrences), including one drug-related event (1.96%). Despite a numerically higher number of drug-related high-grade events in the desidustat group, the between-group difference was not significant (p = 0.425). One death (0.99%) occurred in the desidustat group, which was determined to be unrelated to the investigational drug. No deaths occurred in the placebo group, and no drug-related deaths were reported in either group. Key safety indicators included three drug-related events leading to treatment discontinuation in the desidustat group (2.97%), involving seven distinct adverse events, primarily exacerbated severe anemia (2 cases) and persistent hypertension (1 case). In contrast, only one treatment withdrawal (1.96%) occurred in the placebo group, attributed to drug-related acute kidney injury. These findings highlight the importance of monitoring Hb fluctuations and managing blood pressure during treatment, consistent with the known safety profiles of other HIF-PHIs. Drug-related TEAEs classified by system organ and preferred terms were shown in online supplementary Table S2, and there was no statistically significant difference between the groups.
Table 6.
Analysis of treatment-emergent adverse events
| | Desidustat group (N = 101) | Placebo group (N = 51) | Total (N = 152) | p value | |||
|---|---|---|---|---|---|---|---|
| n (%) | events | n (%) | events | n (%) | events | ||
| TEAE | 86 (85.15) | 255 | 43 (84.31) | 128 | 129 (84.87) | 383 | 0.892 |
| Drug-related TEAE | 29 (28.71) | 51 | 14 (27.45) | 28 | 43 (28.29) | 79 | 0.870 |
| TEAE ≥ grade 3 | 23 (22.77) | 28 | 10 (19.61) | 11 | 33 (21.71) | 39 | 0.655 |
| Drug-related TEAE ≥ grade 3 | 6 (5.94) | 7 | 1 (1.96) | 1 | 7 (4.61) | 8 | 0.425* |
| Severe TEAE | 11 (10.89) | 15 | 7 (13.73) | 8 | 18 (11.84) | 23 | 0.610 |
| Drug-related severe TEAE | 3 (2.97) | 3 | 1 (1.96) | 1 | 4 (2.63) | 4 | >0.999* |
| TEAE leading to discontinuation | 4 (3.96) | 8 | 3 (5.88) | 4 | 7 (4.61) | 12 | 0.688* |
| Drug-related TEAE leading to discontinuation | 3 (2.97) | 7 | 1 (1.96) | 2 | 4 (2.63) | 9 | >0.999* |
| TEAE leading to death | 1 (0.99) | 1 | 0 | 0 | 1 (0.66) | 1 | >0.999* |
| Drug-related TEAE leading to death | 0 | 0 | 0 | 0 | 0 | 0 | – |
Treatment-emergent adverse events (TEAEs) refer to adverse events that occur after the administration of the investigational drug and up to the study’s conclusion. TEAEs deemed related to the investigational drug are those assessed as definitely, likely, or possibly related. Coding was performed according to the MedDRA 26.0/26.1 version. Intergroup comparisons were conducted using Chi-square/Fisher’s exact test, with results marked with “*” indicating Fisher’s exact test.
Exploratory Endpoints
Hb changes during weeks 21–25 were evaluated in both the desidustat group and the group that switched from placebo to desidustat (online suppl. Table S5). At baseline, mean Hb levels were 89.2 g/L in the desidustat group (N = 88) and 88.1 g/L in the placebo group (N = 44), with no significant difference between groups (p > 0.05). During weeks 21–25, Hb levels increased to 110.6 g/L in the desidustat group and 115.1 g/L in the switch group, representing mean increases of 21.26 g/L and 26.63 g/L from baseline, respectively.
Serum hepcidin dynamics were assessed at baseline and at weeks 9, 25, and 53 (online suppl. Table S6). Baseline hepcidin levels were higher in the desidustat group (120.18 ng/mL) compared to the placebo group (97.12 ng/mL). By week 9, hepcidin levels in the desidustat group declined sharply to 53.94 ng/mL (Δ = −67.43 ng/mL), whereas the placebo group showed only a modest decrease to 91.39 ng/mL (Δ = −6.38 ng/mL). At week 25, levels in the desidustat group partially rebounded to 75.54 ng/mL (Δ = −44.65 ng/mL), while the switch group reached 64.82 ng/mL (Δ = −25.84 ng/mL). By week 53, hepcidin levels stabilized at 63.71 ng/mL (Δ = −48.13 ng/mL) in the continued desidustat group and 61.33 ng/mL (Δ = −32.32 ng/mL) in the switch group. Overall, desidustat treatment was associated with a substantial and early reduction in serum hepcidin, followed by partial recovery and stabilization, whereas the placebo group exhibited minimal change. These patterns suggest a distinct biological response likely mediated by desidustat’s role in modulating iron metabolism during anemia therapy.
Discussion
This study was the first large-scale phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of desidustat in NDD-CKD patients in China. The results showed that desidustat could increase Hb levels and relieve anemia-related symptoms, with no significant safety differences between the desidustat and placebo groups. These findings provide strong clinical evidence supporting the use of desidustat and offer valuable insights into optimizing treatment strategies for anemia in NDD-CKD.
In this study, Hb levels increased in the desidustat group, whereas the placebo group experienced a slight decline in weeks 7–9. Covariance analysis further confirmed the statistical significance of this difference, with the 95% CIs for the change in Hb levels between the desidustat and placebo groups exceeding zero, reinforcing its therapeutic benefit. These findings support the efficacy of desidustat in improving Hb levels in NDD-CKD patients, consistent with other phase 3 clinical trials [17, 18]. In some cases, it may be even more effective than ESAs [16, 19].
The Hb response rate is a key measure for assessing the effectiveness of anemia treatments. In this study, the response rate was notably higher in the desidustat group compared to the placebo group. The ability of HIF-PHIs to stimulate erythropoiesis via a distinct pathway that mimics the body’s natural response to hypoxia may provide a more stable and lasting therapeutic effect than ESAs, leading to better Hb response outcomes [20]. A phase III study reported a significantly higher response rate for roxadustat compared to placebo, with roxadustat effectively raising Hb levels over a similar treatment period [21, 22]. Studies on vadadustat showed notable improvements in Hb levels and high response rates, further supporting the potential of HIF-PHIs as effective alternatives to traditional ESAs [23, 24].
Cox proportional hazards model analysis showed that patients in the desidustat group were much more likely to reach the target Hb level (over 100 g/L) than those in the placebo group, indicating that desidustat accelerates Hb recovery in patients with anemia. It was essential for relieving anemia symptoms and enhancing patients’ overall quality of life. Previous studies have reported that desidustat has demonstrated efficacy comparable to other HIF-PHIs, such as roxadustat and daprodustat, in raising Hb levels, supporting its potential for managing CKD [19, 25]. These results provide strong evidence for the clinical use of desidustat, especially in patients who need quick relief from anemia symptoms.
Long-term maintenance of Hb within the target range is a key indicator of anemia treatment effectiveness and essential for ensuring patients’ long-term health. Desidustat effectively sustained Hb levels within the target range. A clinical trial showed that desidustat significantly increased Hb levels within 6 weeks, with response rates across dosage groups surpassing those in the placebo group [26]. Additionally, desidustat demonstrated efficacy comparable to other HIF-PHIs, with timeframes to reach target Hb levels similar to those of other HIF-PHIs, further supporting its clinical usefulness [27]. These findings support the potential of desidustat for long-term use in the treatment of anemia in patients with NDD-CKD.
During the extended observation period of this study (weeks 21–25), both the desidustat group and the group that switched from placebo to desidustat showed significant increases in Hb levels; however, the increase in the desidustat group was relatively modest (21.26 g/L vs. 26.63 g/L). This difference may be due to dynamic changes in iron metabolism that affect Hb synthesis. In this study, serum hepcidin levels in the desidustat group dropped significantly by week 9 (−67.43 ng/mL), compared to a minimal change of −6.38 ng/mL in the placebo group. Elevated hepcidin levels can lead to iron-restricted erythropoiesis, primarily due to reduced intestinal absorption of elemental iron and impaired mobilization of iron from the reticuloendothelial system, and have been associated with increased mortality [28, 29]. As a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), roxadustat has been consistently shown in previous studies to reduce hepcidin levels relative to baseline in treated patients [30]. These findings align with the results observed in our study. This suggests that desidustat, like roxadustat, not only ameliorates anemia in patients with CKD but may also help mitigate adverse events associated with elevated hepcidin levels.
Safety remains a key factor when assessing any new therapeutic agent. In this study, the rate of TEAEs was similar between the desidustat and placebo groups, and serious adverse events occurred less frequently in the active treatment group. As a new HIF-PHI, desidustat showed a favorable safety profile compared to placebo. These safety findings are consistent with earlier research, further supporting the safety of desidustat for the treatment of anemia in patients with NDD-CKD and highlighting its potential for long-term use [31].
Despite these promising findings, several limitations must be recognized. First, the follow-up period in this study was relatively short, and long-term follow-up studies are necessary to assess the sustained effectiveness and safety of desidustat. Second, the study was conducted in a limited number of regions, which may restrict the generalizability of the results to other geographic areas. Therefore, multicenter trials involving a more diverse patient population are needed to confirm these findings. Additionally, although this study included several key endpoints, some clinically relevant parameters, such as cardiovascular event incidence, were not extensively examined. These factors are vital for a thorough evaluation of desidustat’s clinical utility.
In conclusion, this study indicates that desidustat effectively treats anemia associated with NDD-CKD by increasing Hb levels, reducing time to target levels, and improving Hb response rates. Based on eGFR analysis, the study population was predominantly classified as having CKD stage 4 or lower. Consequently, the generalizability and clinical applicability of the study findings to patients with CKD stage 5 might be limited. Additionally, desidustat was generally well tolerated and exhibited a favorable safety profile. These results support desidustat as a promising new treatment option for anemia, with significant implications for clinical practice.
Statement of Ethics
The study was approved by the Ethics Committee for Clinical Trials of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (KS2021549) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any funding.
Author Contributions
Conception of clinical research protocol and experimental design: Xuemei Li; data collection: Jie Ma, Xiangdong Yang, Xiaoyan Xiao, Changyou Sun, Qinghong Zhang, Caili Wang, Yan Xu, Jianrong Zhao, Aicheng Yang, Hong Cheng, Menghua Chen, Wenli Chen, Zhihua Zheng, Yongjun Shi, Zhanzheng Zhao, Zhenhua Yang, Lin Yang, Li Yao, Xiaoshi Zhong, Yilan Deng, Zuying Xiong, Xiaoping Yang, Chunjiang Zhang, Weiji Xie, Aiping Yin, Hua Zhou, Weihong Bi, Wenbin Li, Junxia Wang, Suhua Li, and Yuanyuan Yin; analysis and interpretation of data; manuscript editing and review: Xuemei Li, and Jie Ma.
Funding Statement
This study was not supported by any funding.
Data Availability Statement
The data supporting the findings of this study are not publicly available due to patient privacy protections but are available from the corresponding author upon 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 patient privacy protections but are available from the corresponding author upon request.
