Iron pill safely fills iron stores in CKD patients with anaemia over long term

In patients with chronic kidney disease (CKD) and iron-deficiency anaemia (IDA), the orally administered ferric maltol appears to yield meaningful and sustained increases in haemoglobin and iron indices, with a low rate of treatment discontinuation due to adverse events (AEs), according to the results of the phase III AEGIS-CKD trial and open-label extension.

“Our study shows that ferric maltol 30 mg twice daily, which provides 60 mg of elemental iron/day, can increase haemoglobin by 0.7 g/dL over 52 weeks of treatment and is well tolerated with extended use in patients with stage 3 or 4 CKD,” the investigators said.

“Patients with stage 3 CKD may experience a greater treatment effect than those with stage 4 disease, whereas patients with lower ferritin levels at baseline appear to be more likely to benefit than those with higher levels, although the low number of patients with ferritin levels above 250 ng/mL makes this finding difficult to interpret,” they added.

AEGIS-CKD randomized 167 patients with stage 3/4 CKD (estimated glomerular filtration rate [eGFR] ≥15 to <60 mL/min/1.73 m²) and IDA (haemoglobin ≥8 to <11 g/dL) to receive oral ferric maltol 30 mg (n=111) or matching placebo capsules (n=56) twice daily for 16 weeks. After this, all patients received open-label ferric maltol 30 mg twice daily for another 36 weeks.

At week 16, the primary endpoint of improvement in haemoglobin levels was significantly greater with ferric maltol than placebo (least-squares mean difference, 0.5 g/dL, 95 percent confidence interval, 0.1–0.9; p=0.01). Ferritin, transferrin saturation (TSAT), and serum iron concentrations also increased with the study drug but declined with placebo (all p<0.05). [Am J Kidney Dis 2021;doi:10.1053/j.ajkd.2021.03.020]

In the open-label phase, the achieved increase in haemoglobin levels were sustained up to week 52 in patients continuing ferric maltol. Meanwhile, those who switched from placebo to ferric maltol showed an improvement that mirrored the change seen with the study drug during double-blind treatment.

“Haemoglobin levels were maintained above 10 g/dL over 52 weeks, a threshold value usually considered for initiation of erythropoietin therapy, in these patients with baseline moderate to severe kidney failure,” the investigators noted. “Iron indices (transferrin, TSAT, and serum iron) improved more slowly over the course of the trial than haemoglobin concentrations, with gradual but steady increases noted up to week 24.”

The above suggests that ferric maltol seems to deliver immediate iron for erythropoiesis (reflected by the rise in haemoglobin at weeks 4 and 8), while replenishing iron stores over the longer term (indicated by the increase in ferritin from week 8 onwards), the investigators pointed out.

“Haemoglobin may be a good early indicator of response to ferric maltol,” they said, adding that even when there is no sign of an early gain, iron stores are restored over time, and patients may therefore benefit from prolonged treatment.

“The duration of ferric maltol treatment will depend on the severity of iron deficiency; generally, at least 12 weeks of treatment is required, but treatment should be continued as long as needed to replenish iron stores in the body and to support erythropoiesis, as assessed by blood tests,” according to the investigators. [tinyurl.com/ydupxp2t]

Easy on the stomach

In terms of safety, ferric maltol was well tolerated. Gastrointestinal disorders were more common among patients who initially received and continued the study drug (double-blind phase: 41 percent vs 30 percent; open-label phase: 56 percent vs 46 percent).

AEs led to treatment withdrawal in seven patients in the ferric maltol arm and in five patients in the placebo arm (9 percent) receiving placebo during double-blind treatment, and 11 patients (9 percent) during the open-label extension.

Iron-replacement therapies are used to replenish iron stores and correct anaemia in IDA. Iron drips are given in cases where patients fail or cannot tolerate oral agents or when the iron deficiency is far beyond what can be delivered with oral preparations. [Kidney Int Suppl 2013;3:1-150; Gut 2011;60:1309-1316]

“However, intravenous administration may be limited by venous access problems, injection site reactions, and, rarely, anaphylaxis,” the investigators noted. [J Am Soc Nephrol 2007;18:382-393; Hemodial Int 2017;21:S125-S131]

On the other hand, the iron in oral ferrous (Fe2+) compounds tends to be poorly and variably absorbed, they added. “As a result, oral ferrous compounds are associated with gastrointestinal AEs such as nausea, epigastric discomfort, and constipation, which can limit tolerance and reduce adherence.” [Dig Dis Sci 2010;55:548-559; Nephrol Dial Transplant 2014;29:2075-2084]

Meanwhile, ferric maltol remains strongly chelated in the intestinal lumen until the point of absorption, when the greater affinity of iron for the iron transport receptor on the surface of luminal enterocytes promotes dissociation from maltol. [Aliment Pharmacol Ther 1998;12:845-848; Br J Pharmacol 1991;102:723-729]

“Thus, there is no free iron in the gut to generate hydroxyl radicals, minimizing the risk of gastrointestinal toxicity. Uptake of iron from ferric maltol is saturable and dependent on the expression of iron transport receptors,” the investigators explained. [Expert Opin Pharmacother 2015;16:2859-2867]

“A drug such as ferric maltol that is able to replace and restore iron, that is orally administered, and that patients are able to tolerate will provide a clinically relevant treatment option for patients with moderate to severe CKD and anaemia due to iron deficiency,” they said.