A Look at Recent Novel Iron Replacement Therapies for the Treatment of Anemia in CKD

The advent of novel oral and IV therapies for treating iron deficiency has opened up more possibilities for the millions of patients with chronic kidney disease (CKD) who have anemia. In a new paper, a group of researchers has outlined the advancements.

Noting each of their benefits, the researchers also caution that to better characterize the safety and efficacy of the options, there’s a need for further investigation among larger patient pools.

Oral options

Traditional oral iron supplementation options include ferrous salts, ferrous gluconate, ferrous succinate, and iron polymaltose. Four recent advancements in particular have stood out to the researchers.

“These modern iron formulations are associated with greater efficacy and fewer adverse effects than traditional iron preparations and are more effective at increasing Hgb levels,” wrote the researchers.

One of these options—ferric citrate (FC)—is currently indicated for use in controlling serum phosphate levels in adult patient with CKD who are on dialysis and as an oral iron supplement for iron deficient patients with non-dialysis-dependent CKD. The approval followed several phase 3 studies showing that the supplement could mostly be absorbed by the gastrointestinal (GI) tract, resulting in improvements in iron status and hemoglobin (Hgb) levels. Several other clinical trials have indicated that FC is effective in lowering serum phosphate levels among various forms and stages of CKD.

Ferric maltol offers an option with increased bioavailability and reduced GI toxicity and is currently approved for the treatment of adult patients with iron deficiency anemia and inflammatory bowel disease. The iron complex consists of a stable trivalent iron complex bound with 3 maltol ligands.

Heme iron polypeptide (HIP), a new-generation oral iron, uses the heme porphyrin ring to supply iron to absorption sites through a membrane protein, heme carrier protein 1, on the intestinal mucosa. Data from randomized clinical trials have shown that the iron has improved bioavailability and tolerability compared with nonheme iron, although the data have also shown that its effects on Hgb level, transferrin saturation, and required erythropoietin dose in patients are not significantly different than those of IV iron or oral nonheme iron. According to the researchers, the treatment also comes with increased costs.

A fourth iron—sucrosomial iron (SI)—has a unique structure allowing iron absorption through various channels including endocytosis, the paracellular pathway, and the M cells of Peyer’s patches. The researchers did note that there is a lack of evidence supporting the long-term efficacy and safety of SI.

IV options

IV options—used for patients who are intolerant to oral options or who are undergoing hemodialysis—have gained 3 new-generation compounds: ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose. All 3 options offer high stability of the carbohydrate shell, preventing uncontrolled release of toxic free iron, thus allowing complete replacement doses in 1 or 2 infusions. The options also have low immunological activity, allowing for quick administration as a single infusion without a need for a testing dose.

The potential of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors

According to the researchers, “HIF prolyl hydroxylase (HIF-PH) inhibitors, also known as HIF stabilizers, have been introduced for treating renal anemia, primarily through the stimulation of endogenous EPO production. Without the use of ESAs, the administration of HIF-PH inhibitors can increase Hgb levels in patients with CKD, which implies that the pathogenesis of renal anemia is not only caused by insufficient EPO production but also the defective translation of the EPO gene.”

These inhibitors may have several advantages over ESA treatments, including being able to be administered orally and potentially being able to activate several target genes other than the EPO gene, allowing for iron absorption by the GI tract, mobilization form macrophages into the circulation, and transportation of the transferrin-bound iron to bone marrow for erythropoiesis. The treatments are also expected to be lower in cost.

There are several clinical trials, including some in phase 3, assessing several of these inhibitors, including roxadustat, vadadustat, and daprodustat.

Reference

Lee K, Ho Y, Tarng D. Iron therapy in chronic kidney disease: days of future past. Int. J Mol Sci. 2021;22(3):1008.