Roxadustat (FG-4592)

Abstract

Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb#10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean6SD baseline Hb was 8.361.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by $2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean6SEM maximal change in Hb from baseline (DHb max ), the primary endpoint, was 3.160.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, DHb max was similar and larger than in the no-iron group. Hb response (increase in Hb of $1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

The HIF System Response to ESA Therapy in CKD‐Anemia

“…The most promising are the PHD inhibitors (Table 1) with several compounds already under evaluation in clinical trials. Some of these compounds showed to be well tolerated, corrected anemia in non-dialysis CKD and incident dialysis patients without increasing blood pressure, and also reduced serum hepcidin levels [70][71][72][73]. However, regarding their effects in reducing cardiovascular events and slowing the progression of the renal disease, no data are still available from human studies.…”

A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat

“…Roxadustat offers a novel way of utilizing the body's natural compensatory mechanisms in response to hypoxia [4,12,14,15]. Hypoxia-inducible factors (HIF) are transcription factors that regulate expression of genes that stimulate erythropoiesis.…”

“…An open label, randomized study evaluated the effect of roxadustat therapy on anemia in dialysis patients and the exogenous iron requirements [4]. A total of 60 patients were enrolled: 24 patients undergoing hemodialysis (HD) received no exogenous iron supplement, 12 HD patients and 12 peritoneal dialysis patients received oral iron and 12HD were given intravenous (IV) iron.…”

“…Roxadustat was well tolerated in Phase II trials and most documented adverse events were typical for patients with CKD [4,12]. Common documented side effects were diarrhea, headache, back pain, fatigue, increases in blood pressure and liver enzymes [4,12,15].…”

“…Other causes of anemia in CKD are iron deficiency and inflammation. Anemia may be present in all stages of CKD and increases in prevalence as CKD progresses [2,4]. Current treatment of anemia includes iron replacement and use of Erythropoeitin (EPO) analogs.…”