Intravenous ferric derisomaltose for the treatment of iron deficiency anemia

Abstract Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single‐infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.


| HISTORY OF THE DEVELOPMENT OF FERRIC DERISOMALTOSE
After the first parenteral iron formulation, ferric oxyhydroxide, was introduced in 1932, 1 the perception of toxicity in the medical community was so negative its use was abandoned. Remarkably, in 1952, Baird and Padmore introduced a high molecular weight (HMW) iron dextran (ImFeron, Fisons, Homes Chapel, UK), with a complex carbohydrate core binding elemental iron tightly allowing a larger dose to be administered in a much shorter period of time. Soon after the original approval for intra-muscular (IM) injection it was shown that the intravenous (IV) route was far less cumbersome, enabled the administration of complete doses in one visit, and was neither less efficacious nor more toxic than IM injections.
While safe and effective, infrequent infusion reactions were reported with HMW iron dextran. 2

,3 Misinterpretations of infusion
reactions and misinformation about their cause fomented an ongoing folklore of IV iron danger and resulted in inappropriate interventions with pressers and antihistamines, converting minor, self-limited reactions into serious adverse events (SAE). HMW iron dextran remained a minor product. In 1989, recombinant human erythropoietin (EPO) was approved for use in dialysis-associated anemia, yet 3 years later only 60% of patients on dialysis were being treated to target hemoglobin (Hb) concentrations and many not at all. Eschbach and colleagues 4 later reported marked improvement in EPO responsiveness with the addition of IV iron in the treatment paradigm for anemia chronic kidney disease (CKD) even with iron parameters consistent with iron repletion. The use of HMW iron dextran became standard in the dialysis community with rare SAEs.
In the early 1990s ImFeron was withdrawn from markets worldwide 5 and Schein Pharmaceuticals in Arizona released Pharmacosmos' low molecular weight (LMW) iron dextran (INFeD) for use in dialysis, which quickly became the principal parenteral product used in 475 000 patients on dialysis in the US. The SAEs associated with parenteral iron administration were vanishingly rare until 1996, when another HMW iron dextran (Dexferrum, American Regent, Shirley, NY) was released as a less expensive alternative to INFeD. In 1999, during a brief period when LMW iron dextran became unavailable for use in dialysis centers in the US, there was an 11-fold increase in SAE reports, using FDA's spontaneous adverse reporting system. 6 Novel parenteral iron formulations followed which supplanted the use of iron dextrans.  1.1 | Carbohydrate structure, labile iron, and parenteral iron toxicity The iron carbohydrate complexes in IS and FG are less stable and release more labile iron necessitating smaller doses to avoid toxicity. 9 Note, FDI has a short linear structure of linked glucose units that form an iron-carbohydrate matrix. The matrix structure has high iron stability that allows for rapid infusion (≥ 20 minutes) of a high dose and produces labile iron that represents <1% of the iron dose administered ( Figure 1). 10 Nonetheless, there is a persistent reticence among medical providers to utilize parenteral iron formulations. This is particularly true of those perceived to contain dextrans due to a misunderstood risk of serious or severe hypersensitivity reactions (HSR) despite evidence that classification of IV iron products as dextran-derived or nondextran derived has no clinical relevance. 11,12 Additionally, based on the preponderance of published evidence, most AEs attributed to parenteral iron are minor self-limited infusion reactions, due to nontransferrin-bound labile iron. These reactions usually consist of pressure in the chest or back, and facial flushing or tickling in the throat. These were first described by Fishbane et al, 13,14 published in a Lancet Clinical Update, 15 and more recently are posited by some to be non-allergic complement activation-related (CARPA) reactions. 16 To the uninitiated or inexperienced they may be misinterpreted as F I G U R E 1 Comparative labile iron pools of parenteral iron products. Labile iron adjusted with the surface/volume ratio of parenteral iron products. The surface to volume ratio is inversely proportional to the iron content. Master data for the figure are published. 9 Reprinted from Journal of pharmaceutical and biomedical analysis, 86, Fütterer S, Andrusenko I, Kolb U, Hofmeister W, Langguth P, Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X-ray powder diffraction (XRPD), 2013, with permission from Elsevier impending anaphylaxis, prompting unnecessary intervention with epinephrine or antihistamines, converting an otherwise minor, selflimited reaction into a hemodynamically significant SAE, ostensibly due to the intravenous iron. In contradistinction, these minor reactions resolve within minutes and patients may be re-challenged after symptoms subside with rare re-appearance of the minor reaction ( Figure 2). 11 Prophylactic medication with methylprednisolone has been shown to mitigate the arthralgia-myalgia syndrome that may occur following IV iron administration in a double-blind, randomized trial. 17 Prospective data supporting the use of steroid before rechallenging patients after a minor infusion reaction are lacking but we use it empirically based on the data above. However, prophylactic antihistamines commonly used in clinical practice can cause somnolence, diaphoresis, tachycardia and hypotension and in prospective studies were reported to be responsible for the majority of adverse events ostensibly associated with the administration of IV iron. 18 When antihistamines are used to treat minor reactions, they may induce vasoactive reactions treated with vasopressors which exacerbate the minor-infusion reaction. 16,19 The subsequent serious or severe HSR is often attributed to the IV iron further propagating the folklore of danger.

| Safety of ferric derisomaltose
The overall incidence of adverse drug reactions (ADRs) in the pooled safety analysis of FERWON trials was similar in the FDI (8.6%) and IS (9.0%) groups (p = .68). 22 Post-hoc analysis of recurrent ADRs showed that patients treated with FDI experienced fewer days with drug-related ADRs than those treated with IS (risk ratio 0.67 [95% CI: 0.56; 0.78] p < .001).

Serious or severe hypersensitivity reactions
In the FERWON trials non-inferiority of FDI in the adjudicated serious or severe HSR endpoint was met. 20 phosphate was expected to be most prevalent).

Biomarkers of serum phosphate homeostasis
The PHOSPHARE trials measured biomarkers of serum phosphate homeostasis which support the divergent hypophosphatemia results observed after FDI and FCM treatment. 26 Mechanistically, intact fibroblast growth factor 23 (iFGF23) causes hypophosphatemia by inducing urinary phosphate excretion and reducing biologically active vitamin D. 28,29 Reduced biologically active vitamin D limits dietary phosphate and calcium absorption. Reduced serum calcium produces secondary hyperparathyroidism and elevated levels of parathyroid F I G U R E 3 Comparative labile iron pools of parenteral iron products. (A) FGF23 is a circulating hormone that is synthesized primarily in osteocytes and osteoblasts, and is inactivated by cleavage. Under physiologic circumstances and following iron repletion, synthesis and cleavage are coupled to maintain circulating level within a set range. With iron deficiency, FGF23 gene transcription is increased, but additional synthesis of FGF23 is offset by increased cleavage to maintain normal circulating levels of active FGF23. (B) FCM appears to uncouple the balance between synthesis and inactivation, resulting in increased circulating intact FGF23. The mechanism is unknown, but proposed mechanisms include inhibition of cleavage in osteocytes or activation of FGF23 production in sites without the FGF23 cleavage apparatus. High circulating FGF23 directly inhibits phosphate reabsorption in the proximal tubules of the kidney, and reduces production of serum 1,25-dihydroxyvitamin D, which in turn reduces dietary phosphate and calcium absorption. Decreased serum calcium increases PTH production to maintain serum calcium homeostasis; PTH also inhibits phosphate reabsorption. The net result is increased phosphate excretion by the kidney and potential for hypophosphatemia. FCM, ferric carboxymaltose; FGF23, fibroblast growth factor-23; PTH, parathyroid hormone hormone can further promote urinary phosphate excretion (Figure 3).

Composite cardiovascular events
Evidence from a recent meta-analysis reported that IV iron improves outcomes in patients with heart failure. 30 Both CKD and chronic heart failure are often comorbid conditions and each has been reported to incur a greater cost when iron deficiency is present. 31,32 In the FERWON-IDA trial the incidence of composite cardiovascular events was consistent across IV iron treatments (0.8% in FDI and 1.2% in IS). 20 In patients with CKD in the FERWON-NEPHRO trial, those treated with FDI experienced significantly fewer composite cardiovascular events than those with IS (4.1% vs. 6.9%, respectively [p = .025]), and the time to first composite cardiovascular event was significantly longer (p = .019) with FDI. 21 The authors note the difficulty in explaining these differences in the timescale of an 8-week trial, but suggest that a combination of rapid iron repletion to support mitochondrial function and limited labile iron capable of generating oxidative stress following FDI may provide mechanistic support. 33 The pooled safety analysis confirmed a significantly lower incidence in

| Efficacy of ferric derisomaltose
Hemoglobin response The FDI treatment in FERWON-IDA produced a more rapid Hb response than did IS. 20

| Cost
As with the other formulations belonging to the newer generation of IV iron products, FDI is priced higher than the older generation of IV iron products (FG, IS, LMWD). Compared with other newer generation of IV iron products available in the US (Ferumoxitol and FCM), FDI's list price is currently at a premium per treatment course. Actual cost to patients for all IV iron formulations will depend upon insurance coverage and eligibility for patient assistance programs.

| CONCLUSIONS AND FUTURE DIRECTIONS
Oral iron remains frontline therapy for uncomplicated iron deficiency anemia without active bleeding. In situations of intolerance to oral iron, insufficient response to oral iron, IV iron is the preferred route of administration. In practice, the choice of IV iron treatment may reflect concerns about severe HSR reactions attributed to "dextran-based" IV iron formulations despite clear evidence that the classification has no clinical meaning for risk of HSR reactions. 11 In 2133 patients administered FDI across the FERWON and PHOSPHARE trials, serious or severe HSRs were observed in only seven patients (0.3%). These results were non-inferior to IS, an IV iron associated with a low risk for clinically serious or severe HSRs, and similar to FCM. The PHOSPHARE trials demonstrate a low risk of hypophosphatemia with FDI. Low risk for development of hypophosphatemia was also evident in the FERWON trials where the incidence of hypophosphatemia did not reach 4.0%. There were no reported cases of severe hypophosphatemia following FDI treatment and reported hypophosphatemia events were transient. The efficacy of a single 1000 mg dose of FDI in repletion of iron stores is also clear. In each of the trials FDI more rapidly restored iron parameters and improved fatigue compared to IS. These results are consistent with a prior randomized trial comparing FDI to IS that observed more rapid increases in Hb, s-ferritin, and TSAT after FDI treatment. 25 Single dose iron repletion increases convenience for both pro- Thomas G. DeLoughery https://orcid.org/0000-0002-5790-4700