XOANACYL Film-coated tablet Ref.[115986] Active ingredients: Ferric citrate

Pharmacotherapeutic group: All other therapeutic products; drugs for treatment of hyperkalaemia and hyperphosphataemia
ATC code: V03AE08

Mechanism of action

This medicinal product contains ferric citrate coordination complex as the active substance, specifically designed to have a high surface area and a defined molar ratio of ferric iron to citrate. The high surface area of ferric citrate coordination complex impacts ferric iron solubility at physiological pH and allows part of ferric iron to be absorbed and supply iron to the metabolic pathway.

Ferric citrate coordination complex has a dual mechanism of action, one that is associated with providing a source of ferric iron and one associated with decreasing the absorption of phosphorous. The dual mechanism of action result in a direct impact on reducing functionally active intact fibroblast growth factor 23 (iFGF-23).

Following oral administration, soluble ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the gastrointestinal (GI) tract. After transport through the enterocytes into the blood, oxidized ferric iron circulates bound to the plasma protein transferrin, and can be incorporated into haemoglobin.

The non-absorbed part of the complex reacts with dietary phosphate in the GI tract and precipitates phosphate as ferric citrate phosphate complex. This compound is insoluble and is excreted in the stool, reducing the amount of phosphate that is absorbed from the GI tract. By binding phosphate in the GI tract and decreasing absorption, ferric citrate coordination complex lowers the levels of serum phosphorus. Following absorption, citrate is converted into bicarbonate by the tissues.

Clinical efficacy

Three pivotal clinical studies have been conducted to support the efficacy of ferric citrate coordination complex in the treatment of concomitant iron deficiency and elevated serum phosphorous in adult chronic kidney disease (CKD) patients. Two studies were in non-dialysis dependent (NDD) CKD patients and one study was in dialysis dependent (DD) CKD patients.

Study 1 (KRX-0502-204)

A total of 149 NDD CKD subjects with iron deficiency anaemia (haemoglobin >9.0 and <12.0 g/dL [>5.6 and <7.5 mmol/L], serum ferritin ≤300 ng/mL, transferrin saturation [TSAT] ≤30%, serum ferritin ≤300 ng/mL) and elevated serum phosphorous (≥4 and <6 mg/dL [≥1.3 and <1.9 mmol/L]) were randomised to receive either ferric citrate coordination complex (N=75) or placebo (N=74). The starting dose was 3 film-coated tablets/day which was titrated based on serum phosphorous levels; the maximum dose was 12 film-coated tablets/day.

The co-primary efficacy endpoint was change from baseline to Week 12 in TSAT and change from baseline to Week 12 in serum phosphorous. Key secondary efficacy endpoints included change from baseline to Week 12 in serum ferritin, haemoglobin and intact fibroblast growth factor-23 (iFGF-23).

At enrolment into the study 20.3%, 52.7% and 25.7% of subjects had Stage 3, 4 and 5 CKD, respectively. The mean age of subjects was 65.1 years (range 21 to 88 years; 56.1% ≥65 years) with the majority being Caucasian (77.7%) and female (64.9%). The mean daily dose of ferric citrate coordination complex was 5.1 film-coated tablets/day.

Primary and secondary endpoints relating to iron and phosphorous homeostasis are summarised in table 2.

Table 2. Study 1 - Summary of results from primary and key secondary endpoints:

A sequential hierarchal testing strategy was used for the primary and secondary efficacy endpoints.
CI=confidence interval; iFGF-23=intact fibroblast growth factor-23; SD=standard deviation; SE=standard error; TSAT=transferrin saturation.
[a] values can be estimated to mmol/L using conversion factor of 0.3229; [b] values can be estimated to mmol/L using conversion factor of 0.6206; [c] ANCOVA model with treatment as a fixed effect and baseline value as the covariate.

Study 2 (KRX-0502-306)

Subjects with NDD CKD and iron deficiency anaemia (haemoglobin ≥9.0 and ≤11.5 g/dL [≥5.6 and ≤7.1 mmol/L], serum ferritin ≤200 ng/mL and TSAT ≤25%) with serum phosphorous ≥3.5 mg/dL [≥1.1 mmol/L] were enrolled. A total of 234 subjects were randomised to receive either ferric citrate coordination complex (N=117) or placebo (N=117) for 16 weeks with a starting dose of 3 film-coated tablets/day which was subsequently titrated based on haemoglobin levels with a maximum dose of 12 film-coated tablets/day. At Week 16, subjects could enter an 8-week extension phase where all subjects received ferric citrate coordination complex at 3 film-coated tablets/day which could be titrated based on clinical response.

The primary efficacy endpoint was the percentage of haemoglobin responders, defined as a subject with an increase of ≥1.0 g/dL [0.62 mmol/L] at any point during the 16-week placebo-controlled phase. Secondary efficacy endpoints included both iron and phosphorous parameters: change from baseline to Week 16 in haemoglobin, TSAT, serum ferritin, percentage of subjects with sustained haemoglobin response (mean change ≥0.75 g/dL [0.47 mmol/L] over any 4-week time period during the 16-week placebo-controlled phase, provided ≥1.0 g/dL [0.62 mmol/L] was also attained during this period) and change from baseline to Week 16 in serum phosphorous.

At enrolment into the study 48.1%, 42.1% and 9.9% of subjects had Stage 3, 4 and 5 CKD, respectively. The mean age of subjects was 65.4 years (range 26 to 93 years; 58.8% ≥65 years) with the majority being Caucasian (68.7%) and female (63.1%). The mean daily dose of ferric citrate coordination complex was 5.0 film-coated tablets/day.

The primary and secondary endpoints are summarised in the following table.

Table 3. Summary of results from primary and secondary endpoints in Study 2:

A sequential hierarchal testing strategy was used for the primary and secondary efficacy endpoints.
CI=confidence interval; SD=standard deviation; SE=standard error; TSAT=transferrin saturation.
[a] values can be estimated to mmol/L using conversion factor of 0.6206; [b] values can be estimated to mmol/L using conversion factor 0.3229 [c] 2-sided chi-squared test; [d] mixed model repeated measures method with the terms of treatment, baseline value, week post-baseline, and treatment by week post-baseline interactions.

Study 3 (KRX-0502-304)

This study was an open-label active controlled study for 52 weeks followed by a 4-week placebo-controlled phase. Subjects with DD CKD (haemodialysis 3 times a week or peritoneal dialysis) with elevated phosphorous levels (serum phosphorous ≥6.0 mg/dL [≥1.9 mmol/L] after washout of existing phosphate binder), ferritin <1000 ng/mL and TSAT <50% were enrolled. Subjects were randomised (N=441) to receive either ferric citrate coordination complex (N=292) or an active control (N=149) in a 2:1 ratio. The active control group received calcium acetate, sevelamer carbonate, or a combination of these, which was administered based on the last dose administered prior to the start of the washout, or if not remaining on the same phosphate binder, per the prescribing information at the discretion of the investigator. Subjects could continue to receive intravenous iron and erythropoietin stimulating agents as clinically required. At baseline, there were 61% (265/438) and 82% (359/438) of the study population receiving intravenous iron and erythropoietin stimulating agents, respectively. The ferric citrate coordination complex group was administered 6 film-coated tablets/day and the dose titrated based on the serum phosphorous levels, with a maximum dose of 12 film-coated tablets/day. At the end of the 52-week active controlled phase, subjects who had received ferric citrate coordination complex were randomised to either continue to receive ferric citrate coordination complex or receive placebo for a further 4 weeks.

The mean subject age of the DD CKD subjects in the study was 54.4 years (range 19 to 90 years; 20.5% ≥65 years). The majority of subjects were African American/black (53.0%) and male (61.2%). During the 52-week active-controlled period, the mean daily dose of ferric citrate coordination complex was 8.8 film-coated tablets/day.

The primary efficacy endpoint evaluated the change from baseline to Week 12 in serum phosphorus for the ferric citrate coordination complex group compared to subjects who received sevelamer carbonate as a sole agent in the active control arm (N=78). The LS mean (95% CI) was -2.03 mg/dL (-2.21, -1.86) in the ferric citrate coordination complex group compared to -2.17 mg/dL (-2.51, -1.84) in the sevelamer carbonate group; with a LS mean for treatment difference of 0.14 mg/dL (95% CI for difference: -0.24, 0.52). This is approximately equivalent to mean decreases of -0.66 and -0.70 mmol/L in the ferric citrate coordination complex and sevelamer groups, respectively (difference of 0.04 mmol/L).

Secondary efficacy endpoints evaluated the treatment effect of ferric citrate coordination complex relative to the active control arm (all treatments) and were the change from baseline to Week 52 in serum ferritin, TSAT and the cumulative use to Week 52 of intravenous iron and ESA (median daily dose).

In the 4-week placebo-controlled phase, there was an increase in serum phosphorous in the group that was switched to placebo (LS mean [95% CI] from the Week 52 baseline to Week 56 of 1.86 mg/dL [1.57, 2.15]) and a continued decrease in the group that remained on ferric citrate coordination complex (-0.32 mg/dL [-0.61, -0.03]). The LS mean treatment difference was -2.18 (95% CI for difference: -2.59, -1.77), which was significant (p<0.0001).

Results from the secondary endpoints are summarised in the table below.

Table 4. Summary of results from secondary endpoints in Study 3:

A sequential hierarchal testing strategy was used for the primary and secondary efficacy endpoints.
CI=confidence interval; SD=standard deviation; SE=standard error; TSAT=transferrin saturation; ESA=erythropoietin stimulating agent
[a] includes calcium acetate, sevelamer carbonate, or a combination of these; [b] ANCOVA model with treatment as the fixed effect and study baseline as the covariate; [c] 2-sided Wilcoxon Rank Sum Test.

In a post-hoc analysis, there was a decrease in serum haemoglobin over 52 weeks in both treatment arms (see table below), which was less in the ferric citrate coordination complex arm.

Table 5. Summary of haemoglobin results in Study 3:

CI=confidence interval; SD=standard deviation; SE=standard error
[a] includes calcium acetate, sevelamer carbonate, or a combination of these; [b] values can be estimated to mmol/L using conversion factor of 0.6206; [c] ANCOVA model with treatment as fixed effect and study baseline value as the covariate

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with ferric citrate coordination complex in one or more subsets of the paediatric population in the treatment of iron deficiency anaemia in chronic kidney disease (CKD) with elevated serum phosphorus levels (see section 4.2 for information on paediatric use).