Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial

Abstract

Background The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. Methods In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). Results A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: –0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. Conclusions Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.

Clinical data for intravenous iron – debunking the hype around hypersensitivity

“…In FIRM, for FCM and FER, respectively, ‘moderate HSRs’ were reported by 0.6% and 0.3%, ‘severe HSRs’ by 0.0% and 0.1%, and ‘moderate hypotension’ by 0.1% and 0.2% 9 . In FERWON, HSRs were experienced by six patients in the FDI group: nausea and abdominal pain; shortness of breath and tightness in the chest; acute asthma exacerbation; complement activation–related pseudo‐allergy; flushing, bronchospasm, angina pectoris, hypotension, dyspnea, and leukocytosis; and infusion reaction (each 0.05%), and two patients in the IS group: anaphylactic reaction (0.2%) 10,11 . In PHOSPHARE, HSRs in the FCM group were dyspnea and swelling (each 0.85%), and the HSR in the FDI group was swollen eyelid unilaterally (0.8%) 12 …”

“…Five RCTs were identified and included: FIRM: a Phase III, randomized, double‐blind trial comparing FCM with FER in iron deficiency anemia of any etiology (NCT02694978) 9 FERWON‐NEPHRO and FERWON‐IDA: two similarly designed Phase III, randomized, open‐label trials comparing FDI with IS in non‐dialysis‐dependent chronic kidney disease, and iron deficiency anemia of mixed etiologies, respectively (NCT02940860, NCT02940886) 10,11,13 PHOSPHARE‐IDA04 and PHOSPHARE‐IDA05: two identically designed Phase III, randomized, open‐label clinical trials comparing FDI with FCM in iron deficiency anemia of mixed etiologies (NCT03238911, NCT03237065) 12,13 …”

“…The FERWON studies (also designed in concert with the FDA) evaluated the incidence of serious or severe HSRs as a coprimary endpoint, alongside the change in hemoglobin 10,11 . In the PHOSPHARE studies, the incidence of serious or severe HSRs was evaluated as a secondary endpoint 12 .…”

“…In the FIRM and FERWON studies, the HSRs reported were confirmed and adjudicated by blinded independent committees 9–11 …”

“…Based on in vitro tests of possible antigens with monoclonal antibodies, Neiser and colleagues 6 hypothesized that IV iron products with dextran‐derived carbohydrate moieties (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than non‐dextran‐derived products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). However, “… in vitro tests of possible antigens with monoclonal antibodies can generally neither assess the risk of anaphylaxis in an individual patient, nor can they predict the numerical risk of such anaphylaxis in the clinical setting.” 7 Recently conducted, ‘gold‐standard’ randomized controlled trials (RCTs) now provide the high‐quality evidence for clinical outcome that is needed to reveal any differences between IV iron drugs with respect to risk of HSRs 8–12 …”