Editor’s note: This is the third part in a three part series on treating anemia in CKD and ESRD patients. Part one covered trends in ESA therapy and part two covered trends in iron therapy.
It has been increasingly recognized that anemia in patients with CKD is due to a combination of erythropoietin (EPO) deficiency and functional iron deficiency (FID). The EPO deficiency is a blunted but not absent (even in anephric patients) response in EPO production to the degree of anemia. FID is a combination of impaired iron mobilization from stores in the reticuloendothelial system and inadequate delivery to the bone marrow to support the increase in red blood cell (RBC) production induced by treatment with erythropoietic stimulating agents (ESAs).
An emerging approach to the treatment of EPO deficiency in anemic patients with CKD is the use of agents which stimulate the production of endogenous EPO in renal and non-renal tissues. It is proposed that such a strategy might decrease adverse outcomes by producing a more consistent (though not necessarily continuous) physiologic level of EPO to stimulate RBC production. This contrasts with the high intermittent blood levels of EPO or EPO-like hormone that result from pharmacologic administration of exogenous ESAs.
One class of agents being developed works to stabilize hypoxia-inducible factor (HIF) by inhibiting the prolyl hydroxylase (PH) enzymes which degrade HIF under normal conditions of tissue oxygenation. During hypoxia, HIF-PH activity is physiologically suppressed, allowing HIF to accumulate and directly stimulate endogenous EPO production and upregulate iron delivery to the bone marrow. It is hypothesized that the consistent but non-continuous low-level stimulation of HIF activity by HIF-PH inhibitors improves erythropoiesis while minimizing some of the undesirable downstream effects of continuous HIF stimulation such as angiogenesis.
There are currently four HIF-PHIs undergoing clinical trials in the U.S.
Roxadustat (FG-4592). Roxadustat is being developed by Fibrogen and co-marketed by AstraZeneca and Astellas. Four phase 2 studies of roxadustat in patients with CKD and ESRD have been published at the time of this writing, four additional phase 2 studies have been completed, and 13 phase 3 studies are underway worldwide, according to clinicaltrials.gov. In one published phase 2 study, incident HD patients treated with roxadustat at titrated doses increased mean Hb levels by >2 g/dL within seven weeks regardless of iron repletion status, which is promising in patients with side effects from IV or oral iron.
In another phase 2 study maintenance HD patients treated with ESAs were randomized to roxadustat or to continue ESAs. Patients randomized to roxadustat had a higher rate of maintaining target Hb level. In a double blinded placebo-controlled phase 2 study in patients with non-dialysis CKD, roxadustat produced an increase in Hb levels, decrease in hepcidin and ferritin levels, and increase in total iron binding capacity levels, suggesting an improvement in iron mobilization that contributed to the increase RBC production. Total cholesterol levels decreased in a dose-dependent manner with roxadustat, the mechanism for which is not understood.
In a fourth published Phase 2 study of roxadustat in patients with non-dialysis CKD, quality of life measures significantly improved over baseline values, particularly among patients with low baseline scores. Adverse events from roxadustat were consistent with background disease in the ESRD population and none of the serious adverse events in the non-dialysis CKD patients was attributed to study drug. Unlike the other HIF-PHIs discussed below which are administered once daily, roxadustat has a longer half-life and is administered three times weekly.
Vadadustat (AKB-6548). Vadadustat is being developed by Akebia and co-marketed by Otsuka. Only one phase 2 study of vadadustat has been published as of this writing; two have appeared in abstract form and one more has been completed. Three phase 3 studies of vadadustat in patients with CKD are currently underway, two in dialysis patients (INNO2VATE) and one in non-dialysis CKD patients (PRO2TECT).
The published study is a placebo randomized, double-blind, placebo-controlled study in non-dialysis CKD patients, stratified by ESA naïve with Hb <10.5 g/dl, previously treated with ESA Hb <10.5 g/dL, and currently treated with ESA Hb >9.5 to <12.0 g/dL. ESA was discontinued in the third group. In the study, 59% of vadadustat treated patients achieved a successful Hb response (defined as either mean Hb >11 g/dL or increase in Hb by >1.2 g/dL from baseline) compared to 10.3% in the placebo-treated group (p<0.0001). Vadadustat treatment was associated with decreased ferritin and hepcidin levels and increased total iron binding capacity, suggesting that improved iron mobilization contributed to the Hb response. Side effects in vadadustat treated patients were not significantly higher than in patients receiving placebo.
Daprodustat (GSK-1278863). Daprodustat is being developed by GlaxoSmithKline. Four phase 2 studies of daprodustat have been published as of this writing and an additional four phase 2 studies have been completed. Two phase 3 studies of daprodustat in CKD, peritoneal dialysis and HD patients in Japan are underway according to clinicaltrials.gov.
Published phase 2 studies of daprodustat demonstrate that a 5 mg daily dose increased Hb levels by a mean of 1 mg/dL in ESA-naïve patients and maintained Hb levels in patients previously treated with ESAs. Higher doses led to an unacceptably high number of patients with Hb levels >13 g/dL. Daprodustat decreased ferritin levels and increased total iron binding capacity but did not decrease hepcidin levels in the published studies. As with roxadustat, daprodustat decreases total cholesterol levels. Like other agents in its class, the most common side effect of daprodustat in phase 2 studies was nausea.
Molidustat (BAY 85-3934). Molidustat is being developed by Bayer. Three phase 2 studies on molidustat in kidney disease patients have been completed; none has been published but two have appeared in abstract form as of this writing. There are two additional active phase 2 studies but no phase three studies underway, according to clinicaltrials.gov. In a phase 2b randomized, double-blind, placebo-controlled study of fixed does of molidustat in anemic ESA-naïve non-dialysis CKD patients, the most common reason for molidustat discontinuation was Hb >13 g/dL or increasing Hb >1 g/dL in two weeks. Its effects on iron metabolism and inflammatory markers have yet to be reported.
Non-erythropoietic downstream effects of HIF activation
Activation of HIF, due to decreased oxygen delivery to tissues, is the body’s major defense against hypoxia. HIF stimulates EPO gene expression and improves iron mobilization due to its effects on transferrin, ceruloplasmin and transferrin receptor 1. It also increases the intestinal absorption of iron by upregulating duodenal cytochrome b and divalent metal transporter-1. EPO production induced by HIF leads to the production by erythroblasts of erythroferrone, which downregulates hepcidin production by the liver.
In its role to adapt the body to decreased availability of oxygen, HIF also has effects on mitochondrial metabolism, anaerobic metabolism, glucose metabolism, cell growth, cell differentiation and angiogenesis. Through their stimulation of endogenous HIF, PHIs simulate a hypoxic cellular environment and it remains unclear what the long-term effects of these other consequences of HIF activation will be. Under physiologic conditions, HIF-induced angiogenesis is mediated by vascular endothelial growth factor (VEGF). In addition to promoting angiogenesis and increasing vascular permeability, VEGF also affects tumor stem cell function as well as tumor initiation.
There is a theoretical concern that HIF stabilization may increase the risk of neoplasia and diabetic retinopathy. However, in phase 2 studies of vadadustat and daprodusat there was no change in VEGF over the dose range planned for phase 3 clinical trials.