MonoFer Mechanism of Action

Pharmacotherapeutic group: Iron parenteral preparation. ATC code: B03AC.
Pharmacology: Pharmacodynamics: The isomaltoside 1000 component of ferric derisomaltose consists of 3-5 glucose units with an average molecular weight of approximately 1000 Da. It has no detectable branching structures as evidenced by careful ¹³C and ¹H NMR spectroscopic analysis. Furthermore isomaltoside 1000 does not contain any reducing sugar residues, which can be involved in complex redox reactions.
Linear carbohydrates with a molecular weight of less than 1300 have been shown to not induce immune responses in vivo.
The Monofer formulation contains iron in a complex with isomaltoside 1000 that releases bioavailable iron to iron-binding proteins.
The iron is available in a non-ionic water-soluble form in an aqueous solution with pH between 5.0 and 7.0.
Evidence of a therapeutic response can be seen within a few days of administration of ferric derisomaltose as an increase in the reticulocyte count. Due to the release of bioavailable iron serum ferritin peaks within days after an intravenous dose of Monofer and slowly returns to baseline after weeks.
Clinical trials: The efficacy of Monofer has been studied in the different therapeutic areas necessitating intravenous iron to correct iron deficiency. The main trials are described in more detail as follows.
Iron deficiency anaemia outside CKD: The P-Monofer-IDA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 511 patients with IDA randomised 2:1 to either Monofer or iron sucrose. 90% of recruited patients were females. The dosing of Monofer was performed according to the Simplified Table as described under Dosage & Administration and dosing of iron sucrose was calculated according to Ganzoni and administered as 200 mg infusions. The primary endpoint was the proportion of patients with an Hb increase ≥2.0 g/L from baseline at any time between weeks 1 to 5. A higher proportion of patients treated with Monofer compared to iron sucrose reached the primary endpoint, 68.5% vs 51.6%, respectively (Full Analysis Set (FAS), p < 0.0001).
Nephrology: Non-dialysis-dependent chronic kidney disease: The P-Monofer-CKD-02 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 iron deficient non-dialysis dependent (NDD) chronic kidney disease (CKD) patients, randomised 2:1 to either Monofer or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. The patients in the Monofer group were randomised to infusion of 1000 mg single doses or bolus injections of 500 mg. The test for non-inferiority showed that Monofer was non-inferior to iron sulphate in its ability to increase Hb from baseline to week 4 in both FAS and PP datasets (FAS: difference estimate: 0.2216, 95% CI: 0.012:0.431, p < 0.0001; PP: difference estimate: 0.2176, 95% CI: 0.003:0.432, p < 0.0001) and also sustained a superior increase in Hb compared to oral iron from week 3 until the end of trial at week 8 (p=0.009 at week 3, p=0.04 at week 4, p=0.0004 at week 8, FAS).
Haemodialysis-dependent chronic kidney disease: The P-Monofer-CKD-03 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 haemodialysis patients randomised 2:1 to either Monofer or iron sucrose. Patients were randomised to either a single injection of 500 mg or 500 mg in split doses of Monofer or 500 mg iron sucrose in split doses. In the FAS of 341 subjects, a total of 187 (82.7%) subjects treated with ferric derisomaltose and 95 (82.6%) subjects treated with iron sucrose were able to maintain Hb between 95 and 125 g/L.
Oncology: Cancer related anaemia: The P-Monofer-CIA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 350 cancer patients with anaemia randomised 2:1 to either Monofer or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 12 weeks. The patients in the Monofer group were randomised to either an infusion of max 1000 mg single doses or bolus injections of 500 mg. The primary endpoint was change in Hb concentrations from baseline to week 4. The test for non-inferiority showed that Monofer was non-inferior to iron sulphate in its ability to increase Hb from baseline to week 4 in both FAS and PP datasets (FAS: difference estimate: 0.0161, 95% CI: -0.261:0.293, p = 0.0002; PP: difference estimate: -0.0071, 95% CI: -0.291:0.276, p = 0.0006).
Gastroenterology: Inflammatory bowel disease: The P-Monofer-IBD-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 338 inflammatory bowel disease (IBD) patients randomised 2:1 to receive either Monofer or oral iron sulphate administered as 100 mg elemental oral iron twice daily for 8 weeks (200 mg daily). The patients in the Monofer group were randomised to either an infusion of max 1000 mg single doses or bolus injections of 500 mg. The primary endpoint was change in Hb concentrations from baseline to week 8. A modified Ganzoni formula was used to calculate the IV iron need with a target Hb of only 130 g/L. Non-inferiority could not be statistically demonstrated on the primary endpoint (FAS: p = 0.0945). The study demonstrated an increase in Hb concentration from a mean of 96.4 g/L at baseline to 122.3 g/L at week 8 in subjects treated with Monofer and an increase from 96.1 g/L at baseline to 125.9 g/L at week 8 in subjects treated with oral iron sulphate. The dose-response relationship observed with Monofer suggests that the true iron demand of IV iron was underestimated by the modified Ganzoni formula.
Post-partum haemorrhage: The P-Monofer-PP-01 trial was an open-label, comparative, randomised, single-centre trial conducted in 200 healthy women with postpartum haemorrhage exceeding 700 mL within 48 hours after delivery. The women were randomised 1:1 to receive either a single dose of 1200 mg Monofer or standard medical care (i.e the majority of patients were prescribed oral iron). The primary endpoint was the aggregated change in physical fatigue within 12 weeks postpartum. The difference in aggregated change in physical fatigue score within 12 weeks postpartum was -0.97 (p=0.006), in favour of Monofer, although the estimated treatment difference was less than the pre-defined minimum clinically relevant difference of 1.8 required for claiming superiority.
Surgery: Non-anaemic patients undergoing cardiac surgery: The P-Monofer-CABG-01 trial was a double-blind, placebo-controlled, randomised, single-centre trial of 60 non-anaemic patients undergoing cardiac surgery (coronary artery bypass graft, valve replacement, or a combination thereof). The patients were randomized 1:1 to either 1000 mg Monofer administered perioperatively by infusion or placebo. The primary endpoint was to assess the change in Hb concentrations from baseline to 4 weeks postoperatively. One month after surgery, the decrease in haemoglobin concentration was less pronounced in the Monofer treated group, with an average of 126 g/L versus 118 g/L (p=0.012) and significantly more patients were non-anaemic in the Monofer treated group compared to the placebo group (38.5% versus 8.0%; p=0.019).
Pharmacokinetics: There is no data investigating the pharmacokinetics of single and multiple doses of MONOFER above 1000 mg.
Ferric derisomaltose displays inter-patient variability in PK parameters, including AUC and Tmax.
Distribution: Following intravenous administration, ferric derisomaltose or released free iron is taken up by the cells of the reticuloendothelial system (RES), particularly in the liver and spleen, from where iron is slowly released.
Metabolism: Circulating iron is removed from the plasma by cells of the RES. The iron binds available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, the transport molecule transferrin. This iron, which is subject to physiological control, replenishes haemoglobin (Hb) and depleted iron stores.
Excretion: After administration of a single dose of ferric derisomaltose of 100 to 1000 mg of iron in the pharmacokinetic studies, the iron injected or infused was cleared from the plasma with a half-life that ranged from 1 to 4 days. Renal elimination of iron was negligible.
Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, ferric derisomaltose is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.
Isomaltoside 1000 is either metabolised or excreted.
Toxicology: Preclinical safety data: Genotoxicity: Ferric derisomaltose was not genotoxic in a bacterial mutation assay, a chromosomal aberration test in human lymphocytes in vitro or a micronucleus assay in mice in vivo.
Carcinogenicity: Carcinogenicity studies were not conducted.