Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Akebia Europe Limited, c/o Matheson, 70 Sir John Rogersons Quay, Dublin 2, Ireland
Pharmacotherapeutic group: Drugs for treatment of hyperkalemia and hyperphosphatemia
ATC code: V03AE08
This medicine contains ferric citrate coordination complex as the active substance. The iron component reacts with dietary phosphate in the gastrointestinal (GI) tract and precipitates phosphate as ferric phosphate. 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, Fexeric lowers the levels of serum phosphorus. Following absorption, citrate is converted into bicarbonate by the tissues.
The ability of Fexeric to control serum phosphorus in CKD patients was principally evaluated in one long-term, pivotal Phase III trial (Study 304) in CKD 5D patients, and in one pivotal Phase II, 12 week, placebo-controlled trial (Study 204) in CKD ND patients with anaemia. Both studies were performed in North American and/or Asian patients. As a secondary endpoint in dialysis patients, and a co-primary endpoint in non-dialysis patients, the ability of Fexeric to increase iron stores was also evaluated.
In the pivotal dialysis study 304, following a 2-week washout period, 441 CKD 5D patients with hyperphosphatemia were randomised to receive Fexeric (n=292) or active control (sevelamer carbonate and/or calcium acetate; n=149) open-label for 52 weeks. The starting dose of Fexeric was 6 tablets/day (6 g/day), in divided doses with meals. The starting dose of active control was the patient’s dose prior to the washout period.
The dose of phosphate binder was titrated as needed to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl, to a maximum of 12 g/day. Non-inferiority to sevelamer carbonate was determined at Week 12. Following completion of the 52-week active-controlled period, patients were eligible to enter a 4-week placebo-controlled period in which they were re-randomized to receive Fexeric (n=96) or placebo (n=96).
After 12 weeks of treatment, the mean (± SD) change in serum phosphorus from baseline was −2.02 ± 2.0 mg/dl for Fexeric and −2.21 ± 2.18 mg/dl for sevelamer carbonate, demonstrating non-inferiority of Fexeric to sevelamer. During the overall 52-week active-controlled period, the decrease in serum phosphorus (approximately 2.0 mg/dl following up to a 2 week washout period) and the percentage of patients who achieved and maintained serum phosphorus ≤ 5.5 mg/dl (approximately 62%) were comparable in both the Fexeric and the active control groups (Table 3). During the subsequent 4-week placebo-controlled period, the serum phosphorus levels remained stable in patients receiving Fexeric (mean decrease of 0.24 mg/dl), whereas patients receiving placebo had a mean increase of 1.79 mg/dl (p<0.0001 for treatment difference).
In the pivotal non-dialysis study 204, a total of 148 CKD ND patients with hyperphosphatemia and iron deficiency anaemia received treatment with study drug; there were 141 patients in the intent-totreat population (Fexeric: 72 patients; Placebo: 69 patients). The starting dose of Fexeric was 3 tablets a day (3 g/day) in divided doses with meals and was adjusted as needed to a maximum of 12 g/day in order to maintain serum phosphorus levels between 3.0 and 3.5 mg/dl.
During the 12-week treatment period, patients treated with Fexeric had a significant decrease in serum phosphorus, compared to the placebo group (p<0.001 for treatment difference) (Table 3). Urinary phosphorus excretion and FGF-23 were also significantly decreased relative to baseline in the CKD ND patients treated with Fexeric compared to patients treated with placebo.
<bTable 3. Summary of efficacy parameters on phosphorus homeostasis at Week 12 and Week 52 in Study 304 (CKD 5D) and at Week 12 in Study 204 (CKD ND):
| Parameter | Study 304 (CKD 5D) | Study 204 (CKD ND) | ||
|---|---|---|---|---|
| Fexeric N=281 | Active Control N=146 | Fexeric N=72 | Placebo N=69 | |
| Baseline serum phosphorus (mean ± SD, mg/dl) | 7.41 ± 1.6 | 7.56 ± 1.7 | 4.5 ± 0.61 | 4.7 ± 0.60 |
| Serum phosphorus change from baseline at Week 12§ (mean ± SD, mg/dl) | −2.02 ± 2.0 | −2.22 ± 2.1 (−2.21 ± 2.2 for sevelamer only) | < −0.7 ± 0.61 | −0.3 ± 0.74 |
| Serum phosphorus change from baseline at Week 52 (mean ± SD, mg/dl) | −2.03 ± 2.0 | −2.18 ± 2.3 | NAP | |
| Proportion of serum phosphorus responders at Week 12 (%) | 60.9* | 63.7* | 69.4** | 27.5** |
| Proportion of serum phosphorus responders at Week 52 (%) | 62.3* | 63.0* | NAP | |
§ Primary endpoint in Study 304; Co-primary endpoint in Study 204.
* Proportion of patients achieving serum phosphorus ≤5.5 mg/dl in CKD 5D patients;
**Proportion of patients achieving serum phosphorus ≤4.0 mg/dl in CKD ND patients
NAP: not applicable; SD: standard deviation
In the pivotal dialysis study 304, CKD 5D patients treated with Fexeric, compared with patients treated with active control, had significantly higher increases in ferritin and TSAT levels after 52 weeks of treatment (Table 4), and significantly lower cumulative intravenous iron (96 versus 149 mg/month) and ESA use (7,713 versus 9,183 IU/week) during the same period. During the 52-week treatment period, haemoglobin remained relatively stable in the Fexeric group compared to the active control group (Table 4).
In the pivotal non-dialysis study 204 CKD ND patients treated with Fexeric had a significant increase in serum TSAT, ferritin and haemoglobin levels compared to the placebo group after 12 weeks of treatment (p<0.001 for treatment difference for each parameter) (Table 4).
Table 4. Summary of results on iron homeostasis at Week 12 and Week 52 in Study 304 (CKD 5D) and at Week 12 in Study 204 (CKD ND):
| Parameter | Study 304 (CKD 5D) | Study 204 (CKD ND) | ||
|---|---|---|---|---|
| Fexeric N=281 | Active Control N=146 | Fexeric N=72 | Placebo N=69 | |
| Baseline TSAT (mean ± SD, %) | 31.3 ± 11.2 | 30.8 ± 11.6 | 21.6 ± 7.4 | 21.0 ± 8.3 |
| TSAT change from baseline at Week 12§ (mean ± SD, %) | 8.8 ± 18.3 | 0.5 ±15.8 | 10.2 ± 12.5 | −1.0 ± 7.0 |
| TSAT change from baseline at Week 52 (mean ± SD, %) | 7.9 ± 18.3 | −1.0 ± 14.9 | NAP | |
| Baseline ferritin (mean ± SD, ng/ml) | 592.8 ± 292.9 | 609.5 ± 307.7 | 115.8 ± 83.1 | 110 ± 80.9 |
| Ferritin change from baseline at Week 12 (mean ± SD, ng/ml) | 162.7 ± 284.3 | 44.0 ± 270.4 | 73.5 ± 76.2 | −4.4 ± 47.5 |
| Ferritin change from baseline at Week 52 (mean ± SD, ng/ml) | 302.1 ± 433.7 | 22.4 ± 374.0 | NAP | |
| Proportion with ferritin >500 ng/ml at baseline | 166 (59.1%) | 87 (59.6%) | 0 | 0 |
| Proportion with ferritin >500 ng/ml at Week 12 | 174 (61.9%) | 86 (58.9%) | 3 (4.2%) | 0 |
| Proportion with ferritin >500 ng/ml at Week 52 | 160 (56.9%) | 63 (43.2%) | NAP | |
| Baseline Hgb (mean ± SD, g/dl) | 11.61 ± 1.24 | 11.71 ± 1.26 | 10.5 ± 0.81 | 10.6 ± 1.1 |
| Hgb change from baseline at Week 12 (mean ± SD, g/dl) | 0.19 ± 1.41 | −0.19 ± 1.53 | 0.4 ± 0.75 | −0.2 ± 0.91 |
| Hgb change from baseline at Week 52 (mean ± SD, g/dl) | −0.20 ± 1.34 | −0.55 ± 1.59 | NAP | |
§ Co-primary endpoint in Study 204.
All other parameters were secondary or exploratory endpoints in the two studies.
Hgb: haemoglobin; NAP: not applicable; SD: standard deviation; TSAT: transferrin saturation
The European Medicines Agency has deferred the obligation to submit the results of studies with Fexeric in in one or more subsets of the paediatric population in the treatment of hyperphosphataemia related to chronic kidney disease (see section 4.2 for information on paediatric use).
Of the 557 patients receiving Fexeric in the pooled safety population, there were 67 (12%) patients with evidence of liver dysfunction at baseline. These patients were treated according to the recommended dosing regimen without any safety concerns. There was no evidence of hepatic impairment or significant alteration of hepatic enzymes across the clinical studies with Fexeric, including the long-term studies.
Formal pharmacokinetic studies have not been performed due to the medicine’s predominantly localised primary mechanism of action in the GI tract.
Examination of serum iron storage parameters has shown that there is low systemic absorption of iron of approximately 1% from Fexeric.
The non clinical programme was based on 7 repeat dose toxicology studies in rats and dogs. The target organ for primary toxicity of ferric citrate is the GI tract, with evidence of mucosal erosion and acute to sub-acute inflammation of the GI tract in dogs at elevated doses. In iron replete dogs, microscopic and macroscopic findings in the liver were consistent with signs of iron accumulation.
Data on primary and secondary pharmacodynamics, safety pharmacology and pharmacokinetics of Fexeric were derived from the repeat dose toxicology studies, and did not reveal safety concerns for humans.
Information on genotoxicity, carcinogenic potential, toxicity to reproduction and development of ferric citrate was bridged from scientific literature. Data from carcinogenicity studies have shown that ferric citrate is not carcinogenic in mice and rats when administered intramuscularly or subcutaneously. Ferric citrate was neither mutagenic in the bacterial reverse mutation assay (Ames test) nor clastogenic in the chromosomal aberration test in Chinese hamster fibroblasts.
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