Biomolecules and Biomedicine · 9 authors, 2 centres
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Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, effectively treats renal anemia by increasing hemoglobin and reducing hepcidin, even in patients with inflammation. However, it raises safety concerns, particularly cardiovascular risks such as thrombosis and pulmonary hypertension, and its long-term effects on other organs require further study. The review highlights both the therapeutic potential and the need for cautious patient selection and dosing.
**Background:** Anemia in chronic kidney disease (CKD) is primarily due to erythropoietin (EPO) deficiency, and conventional erythropoiesis-stimulating agents (ESAs) have adverse effects like hypertension and thrombosis. Roxadustat (FG-4592), a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), offers a novel oral approach by stabilizing HIF-α, thereby increasing endogenous EPO and improving iron metabolism. This review summarizes roxadustat's effects on multiple organs and its safety profile.
**Methods:** This is a narrative review of published clinical trials, preclinical studies, and mechanistic investigations. It synthesizes data from key clinical trials (e.g., NCT02174627 on 2781 NDD-CKD patients, a trial on 1043 dialysis patients comparing roxadustat to epoetin alfa) and numerous animal and cell-based studies. The review covers effects on renal anemia, cardiovascular, respiratory, neurological, ophthalmic, metabolic, and neoplastic diseases.
**Key Results:** In NDD-CKD patients, roxadustat raised hemoglobin and reduced RBC transfusion rates, even in 411 patients with elevated C-reactive protein (CRP). In dialysis patients, hemoglobin response was similar to epoetin alfa (88.4% vs 88.2%), but hepcidin remained lower. However, serious adverse events were higher with roxadustat vs epoetin alfa (14.2% vs 10%), including cardiac/vascular disorders (~3.5%). Arteriovenous fistula thrombosis occurred in 9.0% vs 7.3%. Roxadustat also showed benefits in lower-risk myelodysplastic syndrome (transfusion independence) and pure red cell aplasia. Preclinically, it protected against ischemia-reperfusion kidney injury, reduced myocardial fibrosis, and improved lung development in bronchopulmonary dysplasia models. In ophthalmology, it promoted meibomian gland differentiation and reduced oxygen-induced retinopathy of prematurity. However, HIF stabilization may exacerbate diabetic retinopathy, age-related macular degeneration, and polycystic kidney disease cysts. Roxadustat also increased infection incidence and showed potential for rhabdomyolysis.
**Clinical Implications:** Roxadustat is a promising oral alternative to ESAs for renal anemia, especially in patients with inflammation or EPO resistance. Its multi-target effects offer potential benefits in cardiovascular, respiratory, and neurological diseases, but also raise safety concerns, particularly cardiovascular events and tumor risk. Careful patient selection, dosing (lower doses may reduce adverse effects), and monitoring for thrombosis, hypertension, and cyst enlargement are essential. Long-term, large-scale trials are needed to clarify risks and optimize use in diverse populations.