Can Prolyl Hydroxylase Inhibition Treat EPO-Deficient Anemia of Renal Failure With Fewer Vascular Complications Than EPO Itself?

 A Phase 3, Multicenter, Randomized, Open-label, Active-Controlled Study of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in Dialysis Patients

 NCT02174731

 AstraZeneca Research and Development

 AstraZeneca in collaboration with FibroGen

 Multiple sites in the United States and other countries.

 1,425

 This is a phase III safety and efficacy trial that compares the time to first occurrence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke in dialyzed subjects with renal failure whose anemias are treated with the prolyl hydroxylase inhibitor, roxadustat, with that of individuals treated with the active control, recombinant human erythropoietin (rhEPO). Dialyzed patients with renal failure who are anemic and either treated with rhEPO or a rhEPO-associated erythropoiesis-stimulating agent (ESA) are randomized 1:1 to receive roxadustat or rhEPO. Both groups have a target hemoglobin range of 11 ± 1 g/dL. Secondary outcomes are changes in mean hemoglobin from baseline, time to rescue therapy with rhEPO or red blood cell transfusion, and time to other major vascular events including vascular access thrombosis, deep vein thrombosis, pulmonary embolism, hypertensive emergency, and heart failure or unstable angina requiring hospitalization.Rationale: The cloning of EPO has allowed for the large-scale production of rhEPO for clinical use, most successfully in anemic patients with renal failure. Peritubular interstitial cells in the kidney cortex produce the large majority of EPO, and most patients with renal failure develop anemia secondary to deficient EPO production by their diseased kidneys, although iron deficiency and decreased iron mobilization due to increased inflammatory cytokines contribute to renal failure anemia.¹  Along with successful treatment of the anemia in renal disease patients, rhEPO treatment also causes an increased incidence of exacerbated hypertension and adverse cardiovascular events, including myocardial infarctions and strokes, especially when the anemia correction approaches normal hemoglobin levels.² The cloning of EPO also led to the discovery of specific sequences termed hypoxia responsive elements in the 5ʹ and 3ʹ flanking regions of the EPO gene that bind the transcription factor, hypoxia inducible factor (HIF). HIF regulates the enhanced EPO production resulting from tissue hypoxia caused by anemia. The HIF1α or HIF2α component of the HIF transcription factor complex is rapidly degraded under normoxic conditions when it is hydroxylated on two specific prolines by three HIF hydroxylases that have non-heme ferrous iron at their active sites.^3,4  These enzymes use molecular oxygen and the Krebs cycle intermediate α-ketoglutarate as cosubstrates in reactions that hydroxylate HIF and oxidatively decarboxylate α-ketoglutarate to succinate. Thus, HIF hydroxylases act as hypoxia sensors at an interface of oxygenation and energy metabolism.⁴  Prolyl hydroxylated HIFα components are recognized by von Hippel-Lindau protein (pVHL), which mediates their polyubiquitination with subsequent proteasomal degradation. Under hypoxic conditions, HIF1α and HIF2α are not hydroxylated due to decreased oxygen availability. Nonhydroxylated HIF1α or HIF2α dimerizes with constitutively produced HIFβ and forms the active HIF complex that induces target gene transcription. Although EPO is produced mainly in renal cortical interstitial cells, HIF is produced in all cells. HIF2α mediates EPO transcription, but HIF1α and HIF2α can induce transcription of many genes in a wide variety of cells, including those encoding proteins that 1) increase iron absorption and mobilization (duodenal cytochrome b, divalent metal transporter-1, transferrin, transferrin receptor, and heme oxygenase-1),¹  2) shift energy metabolism from aerobic to anaerobic (glucose transporters, glycolytic enzymes, and lactate dehydrogenase),^3,4  and 3) promote neovascular development (vascular endothelial growth factor and angiopoietins).³ 

Compared with rhEPO administration in anemic renal failure patients, HIFα stabilization by prolyl hydroxylase inhibition with subsequent increases in endogenous EPO production has an additional potential advantage of improving iron absorption and mobilization, thereby facilitating anemia correction. Furthermore, HIF-mediated neovascular activity has been associated with decreased cardiac damage from myocardial ischemia,³  suggesting that the cardiovascular complications accompanying anemia correction in patients with renal failure might be decreased with prolyl hydroxylation inhibition compared with rhEPO administration. These potential advantages of prolyl hydroxylase inhibitors are accompanied by potential drawbacks. pVHL mutations that increase HIF activity and cause polycythemia in von Hippel-Lindau and Chuvash polycythemia syndromes are associated with increased microvascular tumors, pulmonary hypertension, and cerebrovascular disease.^1,3,4  Increased HIF activity with its enhancement of anaerobic metabolism is associated with aggressive growth of malignancies.^3,4  Neovascular activity from increased HIF may accelerate tumor vessel growth in patients with unrecognized malignancies and may exacerbate retinopathy in diabetics, who represent a significant proportion of patients with renal failure.

 In a phase I trial, an orally administered analogue of α-ketoglutarate competitively inhibited HIF prolyl hydroxylases and increased plasma EPO levels of patients with renal failure.⁵  Preliminary results from a phase II clinical trial of roxadustat, another oral α-ketoglutarate analogue inhibitor of prolyl hydroxylases, showed increased EPO levels and maintenance of target hemoglobin.⁶  The ongoing phase III roxadustat trial [NCT02174731] will have a target hemoglobin range that is less than that seen in previous rhEPO clinical trials associated with increased vascular events, but the outcome should help determine whether HIF prolyl hydroxylase inhibition decreases the incidence of vascular events compared with rhEPO administration during the treatment of renal failure anemia. Furthermore, the trial may help determine whether any of the potential drawbacks of prolyl hydroxylase inhibition will be problematic.