Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Norgine B.V., Antonio Vivaldistraat 150, 1083 HP Amsterdam, Netherlands
Pharmacotherapeutic group: Iron trivalent, oral preparation
ATC code: B03AB10
Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand. The complex is designed to provide, in a controlled way, utilisable iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins in the body (transferrin and ferritin, respectively). The complex dissociates on uptake from the gastro-intestinal tract and the complex itself does not enter the systemic circulation.
The safety and efficacy of Feraccru for the treatment of iron deficiency anaemia was studied in 128 patients (age range 18-76 years; 45 males and 83 females) with inactive to mildly active IBD (58 patients with Ulcerative Colitis [UC] and 70 patients with Crohn’s disease [CD]) and baseline Hb concentrations between 9.5 g/dL and 12/13 g/dL for females/males. Patients were enrolled in one combined randomised, placebo-controlled clinical study (AEGIS ½). 69% of the patients with UC had a SCCAI score ≤2 and 31% a SCCAI score of 3. 83% of the patients with CD had a CDAI-score <150 and 17% a CDAI-score >150-220. All patients had discontinued from prior oral ferrous product (OFP) treatment: more than 60% of the subjects stopped taking prior OFP due to adverse events. The median time since last dose of OFP was 22 months in the experimental group and 17 months in the placebo arm. 52% of the patients in AEGIS 1 and 33% in AEGIS 2 had a disease flare in the previous 6 months. The median (min-max) time since last disease flare was around 7 months (0.0-450 months). Subjects were randomised to receive either 30 mg Feraccru twice daily or a matched placebo control for 12 weeks. The difference between the change from baseline for Feraccru compared to placebo at week 12 was 2.25 g/dL (p<0.0001). Following completion of the 12-week placebo-controlled phase of the studies, all subjects were switched to Feraccru 30 mg twice daily open-label treatment for a further 52 weeks.
The results for the other key efficacy endpoints are shown in Table 2.
Table 2. Summary of Other Key Efficacy Endpoints (AEGIS ½):
| Endpoint | Hb change (g/dL) from Baseline* at Week 4 Mean (SE) | Hb change (g/dL) from Baseline* at Week 8 Mean (SE) | Proportion of subjects that achieved normalised Hb at Week 12 (%) | Proportion of subjects that achieved ≥1 g/dL change in Hb at Week 12 (%) | Proportion of subjects that achieved ≥2 g/dL change in Hb at Week 12 (%) |
| Feraccru (N=64) | 1.06 (0.08)*** | 1.79 (0.11)*** | 66 | 78 | 56 |
| Placebo (N=64) | 0.02 (0.08) | 0.06 (0.11) | 12 | 11 | 0 |
* Hb at Baseline mean (SE): Feraccru 11.0 (1.027) g/dL, Placebo 11.1 (0.851) g/dL; ***p<0.0001 compared to placebo group
An increase of ≥1 g/dL change in Hb at Week 12 was achieved in 90% and 69% of the ulcerative colitis (N=29) and Crohn’s Disease (N=35) subgroups, respectively. An increase of ≥2 g/dL change in Hb at Week 12 was achieved in 62% and 51% of the ulcerative colitis and Crohn’s Disease subgroups, respectively. Iron deficiency was also shown to be corrected by increase in ferritin levels in both studies. Mean ferritin (μg/L) levels in subjects taking feraccru improved steadily from baseline (mean 8.6 μg/L [SD 6.77]) to Week 12 (mean 26.0 μg/L [SD 30.57]), a mean overall improvement of 17.4 μg/L. Ferritin continued to rise over long-term treatment with Feraccru (mean 68.9 μg/L [SD 96.24] at 64 weeks, a mean overall improvement of 60.3 μg/L).
The efficacy, safety, tolerability and pharmacokinetics (PK) of Feraccru for the treatment of iron deficiency anaemia in adult subjects with chronic kidney disease (CKD) was studied in a phase III randomised placebo-controlled clinical study (AEGIS-CKD). 167 patients (age range 30-90 years; 50 males and 117 females) with an eGFR of 15 mL/min/1.73m² and <60 mL/min/1.73m² and baseline Hb 8.0 g/dL and <11.0 g/dL and ferritin <250 ng/mL with a transferrin saturation (TSAT) <25%, or ferritin <500 ng/mL with a TSAT of <15% were randomized 2:1 to receive either Feraccru 30 mg capsules twice daily or placebo twice daily for a treatment period of 16 weeks. This was followed by an open-label treatment phase, which included up to 36 weeks of treatment with Feraccru only.
Feraccru resulted in clinically and statistically significant increases in Hb compared to placebo during the double-blind 16-week treatment period. The least squares mean (LSM) change in Hb concentration from baseline to Week 16 was 0.50 g/dL for the ferric maltol group and -0.02 g/dL for the placebo group, with a statistically significant LSM difference of 0.52 (p=0.0149).
The LSM change in ferritin concentration from baseline to Week 16 with LOCF was 25.42 μg/L for the Feraccru group and -7.23 μg/L for the placebo group, with a statistically significant LSM difference of 32.65 (p=0.0007). Paediatric Studies
The European Medicines Agency has deferred the obligation to submit the results of studies with Feraccru in one or more subsets of the paediatric population in iron deficient anaemia (see section 4.2 for information on paediatric use).
The pharmacokinetic properties of Feraccru was assessed through measurement of plasma and urine concentrations of maltol and maltol glucuronide, together with serum iron parameters after a single dose and at steady state (after 1 week) in 24 subjects with iron deficiency, randomised to receive 30 mg, 60 mg or 90 mg Feraccru twice daily. Blood and urine samples were assayed for maltol and maltol glucuronide. Serum samples were assayed for iron parameters.
Maltol was transiently measured in plasma with a AUC0-t between 0.022 and 0.205 h.μg/mL across all dosing regimens and both study days. Non-clinical studies have shown that maltol is metabolised through UGT1A6 and by sulphation. It is not known if medical products that inhibit UGT enzymes have the potential to increase maltol concentration (see section 4.5). The maltol appeared to be rapidly metabolised to maltol glucuronide (AUC0-t between 9.83 and 30.9 h.μg/mL across all dosage regimens). Maximum maltol and maltol glucuronide concentrations were reached 1 to 1.5 hours after oral administration of Feraccru. Exposure to maltol glucuronide increased dose proportionally over the Feraccru 30 to 90 mg twice daily dosing range and there was no significant accumulation of either after 7 days treatment with Feraccru. Of the total maltol ingested, a mean of between 39.8% and 60.0% was excreted as maltol glucuronide. Peak transferrin saturation (TSAT) and total serum iron values were reached 1.5 to 3 hours after oral administration of Feraccru. Total serum iron concentrations and TSAT values were generally higher with increasing Feraccru doses. TSAT and total serum iron profiles were comparable between Day 1 and Day 8.
The pharmacokinetic properties of Feraccru were also investigated at steady state in 15 subjects who were already participating in the AEGIS1/2 study described above and who had been in the open-label treatment phase for at least 7 days (Feraccru 30 mg twice daily). Maltol was again transiently measured in plasma with a half-life of 0.7 hours, with a Cmax of 67.3 + 28.3 ng/mL. The maltol appeared to be rapidly metabolised to maltol glucuronide (Cmax = 4677 + 1613 ng/mL). Maximum maltol and maltol glucuronide concentrations were reached approximately 1 hour after oral administration of Feraccru. Maximum total iron serum concentrations were measured 1-2 hours after administration. The pharmacokinetic profiles of maltol/maltol glucuronide and iron parameters were independent of one another.
Non-clinical studies revealed no special hazard for humans based on repeated dose toxicity and local tolerance studies conducted with ferric maltol.
Deposition of iron in the reticulo-endothelial system, liver and spleen was recorded in dogs adminstered 250 mg/kg/day ferric maltol.
No reproductive and developmental toxicity or carcinogenicity studies have been conducted with ferric maltol.
Haemosiderin was observed in Kupffer cells of dogs administered 250 mg/kg/day maltol. At doses of 500 mg/kg/day testicular degeneration and toxic signs indicative of iron chelation were recorded. These effects were not observable in a second study in dogs receiving up to 300 mg/kg/day.
A possible potential genotoxic potential for maltol could not be fully ruled out. However, no carcinogenic effects were recorded in studies conducted in mice and rats receiving up to 400 mg/kg/day maltol.
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