Roxadustat: Not just for anemia

Abstract

Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.

Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications

“…In particular, for dialysis dependent (DD) patients, roxadustat had a higher cardiovascular risk than epoetin alfa; for NDD patients, roxadustat had a higher cardiovascular risk than placebo. Therefore, the FDA refused to approve the listing of roxadustat in the United States (Zhu et al, 2022). In two phase 3 studies in Japanese patients with anaemia and dialysis-dependent CKD, the most common treatment-emergent adverse events (AEs) with roxadustat included nasopharyngitis, back pain, diarrhoea, vomiting (Dhillon, 2019;Akizawa et al, 2020a).…”

Open‐label, Phase 2 study of roxadustat for the treatment of anemia in patients receiving chemotherapy for non‐myeloid malignancies

“…[6][7][8][9][10] Through stabilization of HIF-α, roxadustat also promotes angiogenesis via activation of the vascular endothelial growth factor (VEGF) pathway. 11 However, roxadustat did not enhance oncogenesis in non-clinical studies, including VEGF-dependent mouse models, nor is there evidence of sustained increases in systemic VEGF levels in clinical studies of HIF-PH inhibitors. [12][13][14] Roxadustat is approved to treat anemia of CKD in China, Japan, Chile, South Korea, Europe, and the UK, 6,[15][16][17] and is currently being investigated as a treatment for anemia caused by myelodysplastic syndrome in an ongoing Phase 3, global, randomized, double-blind, placebo-controlled study.…”

Roxadustat (FG-4592) abated lipopolysaccharides-induced depressive-like symptoms via PI3K signaling

“…Lipopolysaccharides-induced depression is associated with inflammation ( Ali et al, 2020a ), and FG-4592 has shown anti-inflammatory action by reducing cytokine levels in the animal model ( Akizawa et al, 2019 ; Liu et al, 2021 ; Zhu et al, 2022 ). Besides, the HIF-1 anti-inflammatory mechanism is largely unknown.…”

“…Furthermore, prolyl hydroxylases (PHDs) regulate HIF-1 under different conditions ( Appelhoff et al, 2004 ), whose underlying mechanisms have not been explored in LPS-induced stress conditions. Similarly, the HIF-1 anti-inflammatory consensus has not been currently elucidated ( Zhu et al, 2022 ). Therefore, we aimed to determine whether LPS-altered HIF-1 signaling can affect depressive symptoms coinciding with neuroinflammation and synaptic defects.…”

“…FG-4592 showed considerable protection against other hypoxia-related disorders, including cancer, fibrosis, and chronic inflammation. Besides, in the sepsis animal model, Roxadustattreatment significantly reduced the cytokines, including IL-1β, IL-6, and TNF-α (Akizawa et al, 2019;Liu et al, 2021;Zhu et al, 2022). Furthermore, prolyl hydroxylases (PHDs) regulate HIF-1 under different conditions (Appelhoff et al, 2004), whose underlying mechanisms have not been explored in LPS-induced stress conditions.…”