Introduction
Chronic kidney disease (CKD) affects approximately 9.5% of the global population and accounts for 2.4% of worldwide mortality [1]. Both the incidence and prevalence are notably higher in upper–middle- and high-income countries, with Taiwan reporting the highest incidence globally at 529 cases per 1,000,000 people [1]. Among its complications, anemia is particularly common and clinically significant in both dialysis-dependent and non-dialysis-dependent (NDD) CKD. It is primarily driven by impaired iron homeostasis, reduced erythropoietin production, and chronic inflammation [2]. The prevalence of anemia in CKD patients is nearly double that of the general population (15.4% vs. 7.6%) and is often undertreated, particularly in those with NDD-CKD [3,4]. Current treatment strategies for iron deficiency anemia (IDA) include oral and intravenous (IV) iron supplementation [5,6]. However, conventional oral iron supplements, typically formulations of ferrous salts, are commonly associated with gastrointestinal (GI) adverse effects, while IV iron is associated with hypersensitivity reactions and infusion-related complications and has logistical challenges in routine clinical practice [5,6].
PBF-1681 (Panion & BF Biotech Inc.), a pharmaceutical-grade ferric citrate (FC) originally approved as a phosphate binder for CKD, has been shown to increase hemoglobin levels and replete iron reserves while correcting hyperphosphatemia in CKD patients [7–9]. Ferrous salts rely on gastric acid for conversion to ferric ions, a process that can contribute to oxidative stress and GI irritation. In contrast, FC is associated with improved tolerability and fewer adverse effects such as dyspepsia and gastritis [5,10]. Clinical trials have shown that FC improves hemoglobin, replenishes iron stores, and corrects iron-related parameters, such as ferritin, transferrin saturation (TSAT), and iron-binding capacity in CKD patients with IDA [11–13]. The iron and phosphate correcting effects of FC have been previously explored in Taiwanese and Japanese CKD patients on hemodialysis [8,14–18], but there is limited data on Asian NDD-CKD patients with IDA and normophosphatemia. Moreover, in clinical studies, patients often initiated therapy at 3 g/day with titration in increments of 3 g/day [8,12], resulting in higher doses than those generally tested for hyperphosphatemia management in CKD [7,8,11].
This study aimed to evaluate the efficacy and safety of FC at a lower daily dose of 2 g in Taiwanese patients with NDD-CKD and IDA. Participants were randomized to receive FC or placebo during a 16-week double-blind randomized period, which was then followed by an 8-week extension period. The primary endpoint was the change in hemoglobin levels, with secondary endpoints including alterations in iron and phosphate metabolism markers. Additional analyses explored the proportion of patients achieving target treatment responses and the effects of FC on relevant serum biomarkers. Safety was monitored throughout the 24-week study duration.
Methods
Study design
This was a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial conducted at 12 medical centers across Taiwan between November 2020 and December 2022. The study consisted of a 16-week randomized period of blinded treatment (with scheduled visits at weeks 2, 4, 8, 12, and 16), followed by an 8-week open-label extension period (with visits at weeks 18, 20, and 24).
During the study, participants underwent assessments at prespecified time points, including physical examinations, vital signs, complete blood counts, serum chemistry panels, iron parameters, and biomarker evaluations. All laboratory tests, except fibroblast growth factor 23 (FGF23), were performed at local sites following standard institutional protocols. Both intact and C-terminal FGF23 were measured centrally using enzyme-linked immunosorbent assays (Immutopics, Inc.) on plasma samples collected at baseline and weeks 8, 16, and 24. Most other assessments were conducted at each study visit (baseline; weeks 2, 4, 8, 12, 16, 18, 20, and 24). Exceptions included iPTH and serum bicarbonate, which were measured at baseline and weeks 8, 16, and 24, and serum aluminum, which was assessed at baseline, week 16, and week 24.
Study medications were dispensed on each visit except for the final visit (week 24). Dosing was adjusted based on hemoglobin and serum phosphate levels, and drug compliance was assessed through capsule counts from returned study medication.
Study participants
Eligible participants were adults (≥18 years) with 1) NDD-CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the four-variable Modification of Diet in Renal Disease equation; and 2) IDA, characterized by hemoglobin levels between 9.0 and 11.5 g/dL, serum ferritin <300 ng/mL, and TSAT <30%. The IDA criteria were selected based on the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in CKD, which recommends consideration of iron therapy in patients with TSAT ≤30% and ferritin ≤500 ng/mL [19]. The selected hemoglobin range targets patients with moderate anemia who may benefit from intervention while avoiding inclusion of individuals with severe anemia requiring urgent management. Similar criteria were also adopted in other clinical trials enrolling IDA patients with CKD [11,12]. To ensure balanced disease severity, enrollment of participants with advanced CKD (eGFR <15 mL/min, stage 5) was limited to less than 20% of the total study population.
Pregnant women were excluded from the study. Those of childbearing potential were required to use effective contraception or abstain from sexual activity for at least 28 days prior to receiving the study drug and for 30 days following the last dose of study drug.
Key exclusion criteria included: anemia due to causes other than iron deficiency; serum phosphate <3.0 mg/dL; treatment with IV iron, erythropoiesis-stimulating agents (ESAs), or blood transfusions within 4 weeks prior to screening; significant GI disorders (e.g., GI bleeding, inflammatory bowel disease); active infections requiring systemic treatment; history of active malignancy within the past 2 years; known allergy or intolerance to oral iron therapy; history of hemochromatosis; or a planned kidney transplant or initiation of dialysis within 24 weeks.
With 80% power and an anticipated dropout rate of approximately 30%, a total of 150 patients was determined to be sufficient to detect a statistically significant difference in the least squares (LS) mean change in hemoglobin levels of 0.84 ± 1.5 g/dL, based on estimates from a previous study [12].
Participants were randomized in a 1:1 ratio to receive PBF-1681 or placebo during the 16-week randomized period using a permuted block design via an interactive web response system. Randomization was stratified by age (>65 years vs. ≤65 years), baseline hemoglobin (>10.5 g/dL vs. ≤10.5 g/dL), and CKD stage (stage 3–4 vs. stage 5). Participants completing the 16-week randomized period were transitioned to open-label PBF-1681 (2 g/day) for the 8-week extension period.
Intervention and dosing
The investigational product, PBF-1681, contained 210 mg of ferric iron per tablet. Participants initially received a fixed dose of 2 g/day of PBF-1681 or placebo, administered as one tablet twice daily with meals. Dose titrations were performed at weeks 2, 4, 8, and 12 during the randomized period. All participants entering the extension period began treatment with PBF-1681 at 2 g/day starting at week 16, with dose titration at weeks 18 and 20.
For patients who did not achieve predefined treatment targets (defined as an increase in hemoglobin >1.0 g/dL from baseline during the randomized period or a hemoglobin >11.5 g/dL during the extension) and had a serum phosphate ≥3.0 mg/dL, the daily dose was increased by two tablets. No dose adjustment was made for participants who met these targets.
Additionally, if a participant’s serum phosphate level decreased to <2.5 mg/dL but remained ≥2.0 mg/dL at any time during the study, the dose was reduced by two tablets per day, or by one tablet per day if receiving two or fewer tablets.
Study endpoints
The primary endpoint was the mean change in hemoglobin from baseline to week 16, marking the end of the randomized period. A key secondary endpoint was the proportion of participants with an increase in hemoglobin of ≥1.0 g/dL at any time point from baseline through week 16 (end of randomized period).
Additional secondary endpoints included changes in TSAT, ferritin, and serum phosphate from baseline to week 16, as well as the proportion of participants who achieved a sustained hemoglobin increase of ≥0.75 g/dL over any continuous 4-week interval during the randomized period.
Important exploratory efficacy endpoints included the mean changes from baseline to week 16 in serum calcium, bicarbonate, aluminum, iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), hematocrit, intact parathyroid hormone, intact and C-terminal FGF23 (iFGF23 and cFGF23, respectively).
Safety assessments included the incidence, type, and severity of adverse events and serious adverse events, along with clinically significant changes in laboratory parameters, diagnostic tests, vital signs, and the occurrence of deaths.
Statistical analysis
Continuous variables were summarized as means ± standard deviations and compared using t tests, while categorical variables were presented as counts and frequencies and evaluated using the chi-square test. The primary, secondary, and exploratory endpoints (except for iPTH and FGF23) for the mean change from baseline to week 16 were analyzed using a mixed model for repeated measures (MMRM). The model included fixed effects for randomization stratification factors (age, screening hemoglobin, and disease stage), treatment-by-visit interaction, and fixed covariates of baseline and baseline measurement-by-visit interaction. All scheduled time points following randomization up to and including week 16 were incorporated in the analysis.
Two exploratory endpoints, changes in iPTH and FGF23, were analyzed using a two-sided non-parametric Wilcoxon rank-sum test, with the last observation carried forward used for imputation.
The proportion of participants achieving an increase in hemoglobin of ≥1.0 g/dL or a sustained increase in hemoglobin of ≥0.75 g/dL was analyzed using logistic regression. All statistical analyses were performed using SAS version 9.4 (Windows NT version; SAS Institute, Inc.), with a significance level set at a two-sided p < 0.05.
Ethics approval
The study protocol was approved by the Institutional Review Board at all participating study sites prior to initiation (No. Taipei Veterans General Hospital, #2019-08-031AU; Taipei Medical University-Shuang Ho Hospital, # N201909024; Kaohsiung Chang Gung Memorial Hospital, #201901538A4; Keelung Chang Gung Memorial Hospital, #201901538A4; Far Eastern Memorial Hospital, #108143-I; China Medical University Hospital, #CMUH108-REC3-132; Kaohsiung Medical University Chung-Ho Memorial Hospital, #KMUHIRB-F(I)-20190115; National Taiwan University Hospital, #201908083MSC; Taipei Medical University-Wan Fang Hospital, #N201909024; Taipei Medical University Hospital, #N201909024; Linkou Chang Gung Memorial Hospital, #201901538A4; National Cheng Kung University Hospital, #AB-CR-110-020), and was registered at www.clinicaltrial.gov (NCT04543812). Written informed consent was obtained from all participants prior to any study-related procedures. The trial was conducted in accordance with the Declaration of Helsinki and applicable regulatory requirements.
Results
Participant demographics
A total of 309 participants were screened, and 141 were randomized to receive either PBF-1681 (n = 71, mean age 62.4 years, 54.9% female) or placebo (n = 70, mean age 62.6 years, 61.4% female) (Fig. 1A). Of these, 114 participants completed the randomized period and entered the open-label extension period (54 in the PBF-1681 + PBF-1681 group and 60 in the placebo + PBF-1681 group). Overall, 106 participants completed the 24-week study (49 and 57 participants in each group, respectively). The primary reason for early withdrawal in both groups during the randomized period was voluntary dropout (Fig. 1A).
Data on all participants who were randomized and assigned to a treatment group were analyzed (Fig. 1B). A safety assessment was performed on the safety analysis set, consisting of all patients who received at least one dose of the study drug. Efficacy endpoints were analyzed using the efficacy analysis set, consisting of all participants who had the baseline measurement and at least one post-baseline measurement. One participant randomized to the placebo group did not receive any study drug during the randomized period, so this subject was excluded from both the safety and the efficacy analysis set. Another participant randomized to the placebo group took both the placebo and PBF-1681 in the randomized period. This subject was classified in the PBF-1681 group in the safety analysis set, but in the placebo group in the efficacy analysis set. In addition, two participants randomized to the PBF-1681 group had missing data. As a result, the safety analysis set included 140 patients, while the efficacy analysis set included 138 patients (Fig. 1B).
Demographic characteristics are summarized in Table 1. Demographic and baseline characteristics were generally well-balanced between the study groups at the start of the study. However, some iron-related parameters (ferritin, UIBC, and TIBC) were significantly higher in the PBF-1681 group compared to the placebo group. The two study groups were comparable in baseline age, hemoglobin levels (10.14 ± 0.73 g/dL vs. 10.11 ± 0.79 g/dL), and CKD stage distribution (stage 3 and 4, 85.9% vs. 87.1%), with fewer than 20% of patients in either group classified as having stage 5 CKD, in accordance with the study protocol. The most commonly reported comorbid condition was hypertension, followed by hyperlipidemia, gout, type 2 diabetes mellitus, essential hypertension, and diabetes mellitus.
During the randomized period, patients in the PBF-1681 group received a mean daily dose of 4.4 g of PBF-1681 tablets, while those in the placebo group received a mean daily dose of 5.3 g of placebo tablets. The proportion of participants with treatment compliance between ≥75% and ≤125% during the randomized period was similar between the two groups (93.1% in the PBF-1681 group and 97.1% in the placebo group; data not shown).
Primary efficacy outcome
As shown in Fig. 2, the baseline mean hemoglobin values were similar between the PBF-1681 and placebo groups. During the randomized period, there was an increasing trend in hemoglobin level in participants randomized to PBF-1681, while there was no change for participants in the placebo group. The treatment group difference was greater at each subsequent time point and was statistically significant as early as week 8. At week 16, the mean change in hemoglobin from baseline was significantly greater in participants in the PBF-1681 group than in the placebo group (LS mean difference, 0.62 g/dL; 95% CI, 0.32–0.92; p < 0.0001) (Table 2).
Secondary efficacy outcome
The hemoglobin-related secondary endpoints were consistent with the primary endpoint findings. The proportion of participants achieving an increase in hemoglobin of ≥1.0 g/dL at any point during the randomized period was higher in the PBF-1681 group than in the placebo group (37.7% vs. 21.7%, p = 0.0403; data not shown). Sustained hemoglobin responses, defined as an increase of ≥0.75 g/dL sustained over any 4-week interval during the randomized period, were also significantly more frequent in the PBF-1681 group (26.1% vs. 8.7%, p = 0.0091; data not shown).
Exploratory efficacy outcome
Results of key exploratory endpoints are summarized in Table 4. Compared to the placebo group, the PBF-1681 group showed significantly greater changes in hematocrit, serum iron, unsaturated and TIBCs, serum bicarbonate, intact parathyroid hormone (iPTH), and FGF23 (all p < 0.05). In contrast, serum aluminum and calcium levels were comparable between the two groups.
Safety assessment
PBF-1681 was generally well tolerated, with a safety profile consistent with previously published data of FC, showing no new or unexpected safety concerns throughout the study period. Treatment-emergent adverse events (TEAEs) occurred in 68.1% of participants in the PBF-1681 group and 61.8% in the placebo group during the randomized period (Table 5). The most common TEAEs in both groups fell under the GI disorders system organ class (47.2% and 35.3%), with diarrhea (18.1% vs. 2.9%) and discolored feces (11.1% vs. 2.9%) being more prevalent in the PBF-1681 group. In contrast, constipation was reported more frequently in participants who received a placebo (6.9% vs. 14.7%). Other common TEAEs observed in participants receiving PBF-1681 during the randomized period included events classified under general disorders and administration site conditions, infections and infestations, and investigations (16.7%, 11.1%, and 9.7%, respectively). TEAE that occurred in participants who received PBF-1681 at any time during the overall study period were not significantly different from those during the randomization phase (Table 5).
Discussion
This randomized, double-blind, placebo-controlled, multicenter phase III study demonstrated that PBF-1681 significantly increased hemoglobin levels in Taiwanese NDD-CKD participants with IDA. The treatment was well tolerated, with a safety profile consistent with its known pharmacologic properties. Overall, PBF-1681 demonstrated a favorable safety and efficacy profile over the 24-week treatment period.
Originally developed and approved as a phosphate binder indicated for hyperphosphatemia in CKD patients, the efficacy of FC in correcting serum phosphate and iron/anemia-related parameters have been compared to phosphate binders and iron supplements in clinical trials. Some of these studies were carried out in CKD patients with hyperphosphatemia, while others focused on CKD patients with IDA. Consistent with our findings, several meta-analysis studies have shown that FC reduces serum phosphate and increases hemoglobin levels compared to placebo [20,21]. Additionally, the cost-estimation analysis in these meta-analysis studies suggested that FC may be cost-saving by reducing hospitalization rates [20] and the need for ESAs and IV iron [20,21].
The hemoglobin improvements observed after 16 weeks of FC treatment in our study were comparable to those reported in previous randomized clinical trials conducted in NDD-CKD patients with IDA in the United States (placebo-adjusted hemoglobin increase, 0.67–0.84 g/dL) [12,22], despite the lower starting (2.0 g/day) and mean (4.4 g/day) daily doses of FC in our Taiwanese NDD-CKD cohort. Furthermore, both our study and earlier studies from the United States [11,12] consistently showed that a greater proportion of participants treated with FC achieved a clinically meaningful hemoglobin increase (≥1.0 g/dL) at any time point, along with a sustained response over multiple weeks. These consistent findings across diverse populations support both the immediate and durable efficacy of FC in managing IDA in NDD-CKD patients.
Improvements in hematocrit were consistent with the increases in hemoglobin further supporting the overall hematologic benefit of treatment. In a post-hoc subgroup analysis conducted during the randomized period by CKD stage (Supplementary Table 1, available online), we observed numerically greater hemoglobin improvements in the PBF-168 group compared to the placebo group across stages 3, 4, and 5. While statistical significance was only reached in stage 4 CKD (p < 0.001), this trend suggests the potential utility of PBF-1681 across the full spectrum of moderate-to-severe CKD. The lack of statistical significance in stages 3 and 5 was likely due to smaller sample sizes in these subgroups.
Although baseline ferritin, UIBC, and TIBC levels were significantly higher in the PBF-1681 group compared to the placebo group, the MMRM adjusted for baseline values of each parameter and their interactions with visit. This approach ensured that treatment-related changes in these endpoints were interpreted independently of any initial imbalance, supporting the robustness of the efficacy findings on the iron-related endpoints.
Upon entering the extension period, ferritin levels continued to rise in the PBF-1681 group, whereas TSAT reached a plateau. The observed divergence reflects physiological differences in iron storage and transport. Ferritin increased as absorbed iron exceeded erythropoietic needs, while TSAT stabilized due to transferrin’s limited binding capacity and regulatory control, including hepcidin-mediated modulation of iron absorption and release. These findings indicate effective iron repletion with PBF-1681 under homeostatic control, supporting the long-term safety of FC treatment in NDD-CKD patients.
FGF23 and iPTH are elevated in CKD primarily as a result of hyperphosphatemia and iron deficiency [23,24]. Elevated parathyroid hormone and FGF23 levels are associated with anemia, cardiovascular disease, and an increased risk of mortality in CKD patients, and thus the reduction of these biomarkers may confer clinical benefit in CKD patients [24]. A randomized, double-blind clinical trial conducted in NDD-CKD patients revealed that FC significantly reduces serum levels of iPTH, iFGF23, and cFGF23 compared to placebo [12]. The reduction in iFGF23 and cFGF23 was partially due to FC-driven improvements in iron balance and serum phosphate [23]. The present study also highlighted the short-term effects of PBF-1681 on FGF23 and iPTH. However, additional studies are needed to evaluate the long-term clinical significance of these findings in the NDD-CKD population.
This trial differs from earlier clinical trials in design, starting dose, and patient population. The beneficial effects of FC in American and Japanese NDD-CKD patients with IDA have been previously described [12,25]. In contrast, this study focuses on Taiwanese patients, with a moderate sample size, high compliance, and a low dropout rate. In addition, it used a lower PBF-1681 starting and titration dose, yet the improvements in primary and secondary study endpoints achieved were comparable to other studies, suggesting the feasibility of a potentially more cost-saving PBF-1681 regimen in Taiwanese patients.
Despite these strengths, this study has limitations. In this trial, patients were randomized to receive either a placebo or PBF-1681; however, the comparative efficacy of PBF-1681 vs. commonly used iron supplements, such as oral ferrous sulfate, ferric sulfate, or IV iron, has not yet been evaluated. Despite the sample size of this trial being moderate, studies with a larger sample size are warranted to confirm the current findings and ensure the generalizability of these findings. Finally, consistent with most studies in NDD-CKD patients, the treatment duration including the extension phase was limited to less than one year. Longer-term follow-up through clinical trials or real-world studies is warranted to confirm the sustained clinical and economic benefits of PBF-1681.
In conclusion, PBF-1681 significantly improved anemia and iron-related biomarkers in Taiwanese NDD-CKD patients with IDA, while demonstrating a safety profile consistent with its known pharmacologic risks. Further studies comparing PBF-1681 with standard iron therapies, and with longer follow-up periods, are warranted to fully establish its long-term clinical and economic value.
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