fg-4592 and Anemia

Roxadustat (ROX) is a new medication for anemia as a complication of chronic kidney disease (CKD). Our meta-analysis aims to evaluate the efficacy and safety of ROX, especially on the cardiovascular risks, for anemia in NDD-CKD patients.. Electronic databases were searched systematically from inception to July 2021 to look for randomized control trials (RCTs) that evaluated ROX NDD-CKD patients. Hemoglobin level and iron utilization parameters, including ferritin, serum iron, transferrin saturation (TSAT), total iron-binding capacity (TIBC), transferrin, and hepcidin were analyzed for efficacy. Pooled risk ratios (RRs) and standardized mean differences (SMDs) were calculated and presented with their 95% confidential intervals (CIs).. Nine RCTs included a total of 3,175 patients in the ROX group and 2,446 patients in the control group. When compared the control group, ROX increased Hb level significantly (SMD: 1.65; 95% CI: 1.08, 2.22; P< 0.00001) and improved iron utilization parameters by decreasing ferritin (SMD: -0.32; 95% CI: -0.51, -0.14; P = 0.0006), TSAT (SMD: -0.19; 95% CI: -0.32, -0.07; P = 0.003), and hepcidin (SMD: -0.74; 95% CI: -1.09, -0.39; P< 0.0001) and increasing TIBC (SMD: 0.99; 95% CI: 0.76, 1.22; P< 0.00001) and transferrin (SMD: 1.20; 95% CI: 0.70, 1.71; P< 0.00001). As for safety, ROX was associated with higher serious adverse effects (RR: 1.07; 95% CI: 1.01, 1.13; P = 0.01), deep venous thrombosis (DVT) (RR: 3.80; 95% CI: 1.5, 9.64; P = 0.08), and hypertension (HTN) (RR: 1.37; 95% CI: 1.13, 1.65; P = 0.001).. We concluded that ROX increased Hb level and improved iron utilization parameters in NDD-CKD patients, but ROX was associated with higher serious adverse effects, especially DVT and HTN. Our results support the use of ROX for NDD-CKD patients with anemia. However, higher-quality RCTs are still needed to ensure its safety and risk of thrombosis.

Topics: Anemia; Ferritins; Glycine; Hepcidins; Humans; Iron; Isoquinolines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Transferrin

The effect of roxadustat on iron homeostasis in patients with chronic kidney disease (CKD) is unclear. This study aimed to evaluate the efficacy of roxadustat for the treatment of iron metabolism disorders in dialysis-dependent (DD) and non-dialysis-dependent (NDD) CKD patients.. We searched the PubMed, Embase, China National Knowledge Internet and Web of Science databases for randomized controlled trials (RCTs). The primary outcomes were changes in serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), ferritin, transferrin, and hepcidin. The secondary outcomes included the changes in hemoglobin (Hb) and the incidences of adverse events (AEs) and severe adverse events (SAEs).. Twelve RCTs comprising 4976 participants were included. Compared to the control group, increases in the serum iron (SMD = 0.21, 95% CI: 0.15 to 0.27, P < 0.00001), TIBC (SMD = 1.02, 95% CI: 0.82 to 1.22, P < 0.00001) and transferrin levels (WMD = 0.55, 95% CI: 0.41 to 0.69, P < 0.00001) were found in the roxadustat group. Compared to the control group, decreases in the ferritin levels (WMD = -37.82, 95% CI: -59.89 to -15.74, P = 0.0008) and hepcidin levels (WMD = -24.04, 95% CI: -36.28 to -11.79, P = 0.0001) were observed in the roxadustat group. The meta-analysis showed that roxadustat significantly increases Hb levels (WMD = 0.77, 95% CI: 0.42 to 1.12, P < 0.0001). The incidences of AEs and SAEs in the roxadustat group was significantly higher than that in the control group (RR = 1.03, 95% CI: 1.00 to 1.07, P = 0.04; RR = 1.08, 95% CI: 1.00 to 1.15, P = 0.04).. Our findings suggest that roxadustat could effectively improve iron metabolism in patients with CKD.

Topics: Anemia; Ferritins; Glycine; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Renal Insufficiency, Chronic; Transferrins

Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety.. PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when. A total of 842 articles were retrieved, and 16 trials in the 15 articles were finally included. Roxadustat treatment significantly increased Hb levels. Iron (SMD 1.43, 95% CI 0.31 to 2.55), total iron-binding capacity (SMD 2.06, 95% CI 0.91 to 3.22), ferritin (WMD 21.33, 95% CI 3.04 to 39.62), transferrin saturation (SMD 4.17, 95% CI 3.90 to 4.45), and LDL-cholesterol (SMD -0.64, 95% CI -0.73 to -0.55) showed statistical significance in dialysis-dependent (DD) study. And hepcidin (SMD -1.56, 95% CI -2.63 to -0.50), transferrin (SMD 1.80, 95% CI 1.53 to 2.06), total iron-binding capacity (SMD 1.62, 95% CI 1.39 to 1.86), total cholesterol (SMD -0.88, 95% CI -1.68 to -0.09), ferritin (WMD -52.68, 95% CI -62.68 to -42.67), transferrin saturation (SMD -5.57, 95% CI -7.47 to -3.68), and LDL-cholesterol (SMD -0.85, 95% CI -1.37 to -0.34) showed statistical significance in not dialysis-dependent (NDD) study. In terms of safety, roxadustat treatment did not increase risk of total adverse events either in dialysis-dependent or not dialysis-dependent patients.. Roxadustat can effectively improve anemia in patients with chronic kidney disease. There was no significant difference in total adverse events compared with the control group.

Topics: Anemia; Cholesterol; Ferritins; Humans; Iron; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Transferrin

Renal anaemia is a common complication of chronic kidney disease (CKD). Roxadustat is the first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia. In this systematic review, we aimed to investigate the efficacy and safety of roxadustat in the treatment of anaemia in CKD patients.. PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases were searched from their inception to February 2021 for randomised controlled trials (RCTs) that compared the efficacy and safety of roxadustat to those of an erythropoiesis-stimulating agent (ESA) or a placebo in treating anaemia in CKD patients.. Nine RCTs involving 2743 patients were found. The meta-analysis showed that roxadustat increased haemoglobin (Hb) level by 0.91 g/dL (95% confidence interval [CI]: 0.47-1.34, P < .05), transferrin level by 0.50 mg/dL (95% CI: 0.34-0.65, P < .05), and total iron-binding capacity by 50.64 μg/dL (95% CI: 36.21-65.07, P < .05) in CKD patients. Decreases in hepcidin (mean difference [MD] = -23.16, 95% CI: -37.12 to -9.19, P < .05) and ferritin (MD = -38.35, 95% CI: -67.41 to -9.29, P < .05) levels were also observed. There was no significant difference in the incidence of adverse events (AEs) (OR: 1.12, 95% CI: 0.95-1.32, P = .17) between the roxadustat and control groups; however, the incidence of serious AEs in the roxadustat group was significantly higher than that in the ESA group (OR: 1.33, 95% CI: 1.06-1.68, P < .05).. Roxadustat can significantly improve renal anaemia in CKD patients by increasing Hb level and iron metabolism. However, attention must be paid to the risk of SAEs during treatment.

Topics: Anemia; Female; Glycine; Hematinics; Humans; Iron; Isoquinolines; Male; Renal Dialysis; Renal Insufficiency, Chronic

To investigate current treatment practices for anemia in patients with chronic kidney disease (CKD), issues surrounding current treatment practices, and the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) that are currently in clinical trials. Treatment of anemia in patients with CKD has traditionally included iron supplementation and erythropoiesis-stimulating agents (ESAs). However, due to adverse cardiovascular (CV) events and hypo-responsiveness to ESA therapy, new agents are currently in clinical trials to treat anemia in patients with CKD. The HIF-PHIs stimulate erythropoiesis and regulate iron metabolism and are attractive alternatives to iron supplementation and ESAs.

Topics: Anemia; Barbiturates; Forecasting; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Practice Patterns, Physicians'; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) is an increasing public health issue. Anemia, which is a complication of CKD, is associated with reduced quality of life and increased morbidity and mortality. Currently quite a few clinical studies have been conducted to compare roxadustat with epoetin alfa [all for dialysis-dependent (DD) patients] or placebo [all for nondialysis-dependent (NDD) patients]. Our meta-analysis aimed to investigate the efficacy and safety of roxadustat for anemia in patients with CKD.. We thoroughly searched eight electronic resource databases for randomized controlled trials (RCTs) comparing the efficacy and safety between roxadustat versus epoetin alfa or placebo for the treatment of anemia in patients with CKD.. Four Phase 2 and two Phase 3 studies with 1010 participants were included. Hemoglobin (Hb) and transferrin levels were increased significantly in the roxadustat group versus those in the placebo {standard mean difference [SMD] 1.57 [95% confidence interval (CI) 1.17-1.98]; SMD 1.81 [95% CI 1.53-2.08]; respectively, both low-quality evidence} or epoetin alfa group [SMD 0.47 (95% CI 0.02-0.93), very low-quality evidence; SMD 1.05 (95% CI 0.81-1.29), low-quality evidence; respectively]. Hepcidin levels were reduced significantly in the roxadustat group versus those in the placebo [SMD -1.72 (95% CI -3.03 to -0.41), very low-quality evidence] or epoetin alfa group [SMD -0.23 (95% CI -0.43 to -0.02), low-quality evidence]. Ferritin and serum transferrin saturation (TSAT) levels were reduced significantly in the roxadustat group versus those in the placebo group [SMD -0.82 (95% CI -1.31 to -0.33); SMD -0.54 (95% CI -0.76 to -0.32), respectively; both low-quality evidence] and ferritin and TSAT levels in the roxadustat group were comparable to those in the epoetin alfa group [SMD 0.02 (95% CI -0.18-0.21); SMD 0.15 (95% CI -0.04-0.35), respectively, both low-quality evidence]. As for safety, the incidence of adverse events (AEs) in the roxadustat group was insignificantly different from that of the placebo group [risk ratio (RR) 0.99 (95% CI 0.83-1.18); P = 0.89, very low-quality evidence]. But the incidence of AEs in the roxadustat group was significantly higher than that in the epoetin alfa group [RR 1.25 (95% CI 1.01-1.54); P = 0.04, low-quality evidence]. There was no significant association between roxadustat and the incidence of serious AEs (SAEs) for both NDD and DD patients [RR 1.08 (95% CI 0.51-2.28) and RR 1.43 (95% CI 0.85-2.40), respectively, both very low-quality evidence].. In this meta-analysis of RCTs, we found evidence that after the oral administration of roxadustat, NDD patients' Hb levels were increased effectively and DD patients' Hb levels were maintained effectively. The risk of SAEs was not observed with the short-term use of roxadustat. These findings support roxadustat for the treatment of anemia in patients with CKD.

Topics: Anemia; Glycine; Humans; Isoquinolines; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is a common complication for patients with kidney disease. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is a newly approved oral drug for anemia. We performed this study to build evidence regarding efficacy and safety of roxadustat in kidney disease patients with or without dialysis.. We searched the databases of PubMed, Embase, Cochrane library and clinicaltrials.gov from the inception to July 20, 2020. The randomized controlled trials (RCTs) which compared roxadustat with placebo or other therapies in the treatment of anemia in kidney disease patients were included. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan5.3 and stata13.0 software.. Eight RCTs with 1010 patients were included in our analysis. We found that roxadustat significantly increased hemoglobin (Hb) level (1.10 g/dL, 95% CI [0.52 g/dL, 1.67 g/dL], p = 0.0002), total iron-binding capacity (TIBC) (58.71 µg/dL, 95% CI [44.10 µg/dL, 73.32 µg/dL], p < 0.00001), iron level (9.28 µg/dL, 95% CI [0.11 µg/dL, 18.45 µg/dL], p = 0.05) compared with control group in kidney disease patients. In addition, our result showed that a significant reduction in hepcidin level (- 31.96 ng/mL, 95% CI [- 35.05 ng/mL, - 28.87 ng/mL], p < 0.00001), ferritin (- 44.82 ng/mL, 95% CI [- 64.42 ng/mL, - 25.23 ng/mL], p < 0.00001) was associated with roxadustat. No difference was found between roxadustat and control group in terms of oral iron supplementation, adverse events (AEs), serious adverse events (SAEs), infection, myocardial infraction, stroke, heart failure and death.. Roxadustat has higher mean Hb level than placebo or EPO. Due to the short follow-up period and the lack of critical data, more RCTs are needed to prove long-term safety and effectiveness of roxadustat in the future.

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Insufficiency, Chronic; Treatment Outcome

In patients with chronic kidney disease (CKD), anemia develops gradually, which is primarily due to an inadequate synthesis of erythropoietin by the kidneys, as well as to iron disorders in the body, blood loss, shortened erythrocyte survival and inflammation. The currently accepted treatment employs iron, vitamin B12, folic acid supplementation and the use of erythropoiesis stimulants, which are administered only parenterally. Research is currently underway on the new erythropoiesis drugs that can be orally administered, i.e., hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI) inhibitors which temporarily block propyl hydroxylase [PHD] catalysis and promote a transient increase in the expression of genes regulated by HIF, including kidney and liver erythropoietin [EPO]. Roxadustat is the first oral drug in this class and a potent HIF-PHD inhibitor, exerted to treat anemia in patients with CKD. In phase 1, 2 and 3 studies with CKD-affected patients, roxadustat was more effective to stimulate erythropoiesis for anemia correction than previously used drugs. Roxadustat can be orally given, unlike other erythropoiesis drugs with parenteral administration only, which grants roxadustat a considerable advantage. Our paper presents the results of studies with roxadustat applied for the treatment of anemia in CKD patients with or without dialysis. We are currently not yet able to know the exact role of roxadustat in the treatment of anemia in patients with CKD, but time will tell. It is possible that roxadustat has benefits an iron metabolism and cardiovascular risk.

Topics: Anemia; Glycine; Humans; Isoquinolines; Prolyl Hydroxylases; Renal Insufficiency, Chronic

Recombinant human erythropoietin (rHuEPO) has been used worldwide for treatment of renal anaemia due to its good curative effect. However, rHuEPO treatment is associated with a rare but severe complication because of the development of anti-EPO antibodies, which are difficult to treat. Currently, the main treatments for the anti-EPO antibodies include withdrawing the rHuEPO, providing blood transfusions and administrating steroid-based immunosuppressive agents. Although the above methods can alleviate anti-EPO-related anaemia, there are obvious side-effects such as decreased immunity and an increased risk of infection. Therefore, accurately identifying anti-EPO-related anaemia and effectively treating this complication is worth exploring. This current case report describes a 49-year-old female patient with chronic kidney disease that received rHuEPO subcutaneously and then developed anti-EPO antibody-mediated renal anaemia with her haemoglobin levels dropping to 37 g/l. The patient refused to be treated with steroids, so she received 120 mg roxadustat administered orally every 72 h and her Hb level increased to 110 g/l over a few months. This current case report demonstrates that roxadustat can be used to successfully treat anti-EPO antibody-mediated renal anaemia without the use of steroid-based immunosuppressants.

Topics: Anemia; Erythropoietin; Female; Glycine; Humans; Isoquinolines; Middle Aged; Recombinant Proteins

Chronic kidney disease is a global public health problem, anemia is the most common complication of chronic kidney disease. Roxadustat is a new drug that can be used to treat renal anemia by oral administration.. We conducted a comprehensive computerized search of the China Knowledge Network (CNKI), VIP (VIP), Wanfang, China Biomedical (CBM), PubMed, Embase, and the Cochrane Library databases. We collected clinical randomized controlled trials (RCTs) published on roxadustat in the treatment of anemia of kidney disease. According to the inclusion and exclusion criteria, the included studies were subject to screening and quality evaluation, and RevMan 5.3 software was used for meta-analysis.. A total of 7 RCTs involving 997 patients with anemia of kidney disease were included. The results of meta-analysis showed that compared with the treatment effect of the erythropoietin (EPO) group, in the roxadustat group there were significant increases in the amount of hemoglobin [mean difference (MD) =11.70, 95% confidence interval (CI): 0.41 to 22.99, P=0.04], hemoglobin overall response rate [odds ratio (OR) =1.97, 95% CI: 1.7 to 3.33, P=0.01], serum iron [standardized mean difference (SMD) =0.39, 95% CI: 0.23 to 0.55, P<0.00001], transferrin saturation (MD =6.09, 95% CI: 5.36 to 6.82, P<0.0001), transferrin (MD =0.36, 95% CI: 0.28 to 0.44, P<0.00001], total iron binding capacity (SMD =0.63, 95% CI: 0.47 to 0.79, P<0.00001) and significantly reduced hepcidin (MD =-29.04, 95% CI: -51.61 to -6.47, P=0.01). There was no significant difference in adverse reactions between groups (OR =1.06, 95% CI: 0.30 to 3.74, P=0.93).. Roxadustat can effectively improve the anemia status of patients with CKD without increasing adverse reactions. Due to limitations of the number and quality of the included studies, further verification is required through the multi-center, large sample-sized, and high-quality RCTs in the future.

Topics: Anemia; China; Glycine; Humans; Isoquinolines

Anemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia.. We searched publications online and conducted a meta-analysis and calculated relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences (MD) with 95% CIs for continuous data.. Roxadustat elevated the serum Hb levels in a manner similar to that observed for ESAs. Roxadustat raised the Hb levels more significantly than the placebo and showed a higher Hb response rate than the placebo group in NDD patients. Roxadustat is a safe and effective drug for anemia in CKD patients.

Topics: Anemia; Animals; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

This study aimed to assess the efficacy, tolerance, and cost-effectiveness of roxadustat treatment for anemia in patients with chronic kidney disease not receiving dialysis (CKD ND).. A meta-analysis was conducted to evaluate the clinical efficacy and tolerance of roxadustat for the correction of anemia associated with CKD ND, and a Markov model was developed to evaluate the cost-effectiveness of roxadustat compared with a placebo.. The meta-analysis results showed that compared with a placebo, roxadustat treatment was associated with a remarkably higher rate of clinical response and the differences in the rate of adverse events between these two regimens were not significant. Moreover, roxadustat treatment (70 mg, three times per week) provided an additional 0.49 QALYs at a cost of $12,526 in the time horizon of 5 years, resulting in an ICER of $25,563 per QALY, with approximately 60% probability to be cost-effective at a $29,295 per QALY willingness-to-pay (WTP) threshold from the perspective of Chinese medical system.. For the treatment of anemia in Chinese patients with CKD ND, roxadustat is much more effective than a placebo; moreover, it is cost-effective at conventional WTP thresholds.

Topics: Anemia; Cost-Benefit Analysis; Glycine; Humans; Isoquinolines; Markov Chains; Quality-Adjusted Life Years; Renal Insufficiency, Chronic; Treatment Outcome

Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug.

Topics: Anemia; Animals; Drug Discovery; Erythropoietin; Glycine; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

Topics: Anemia; Barbiturates; Glycine; Humans; Isoquinolines; Picolinic Acids; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic; Treatment Outcome

Roxadustat (Ai Rui Zhuo

Topics: Anemia; China; Drug Approval; Erythropoiesis; Erythropoietin; Glycine; Hepcidins; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Renal Dialysis

Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional, and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia-inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent a novel pharmacological treatment of anemia associated with chronic diseases. Many orally active PHD inhibitors like roxadustat, molidustat, vadadustat, and desidustat are in late phase clinical trials. This review discusses the role of PHD inhibitors in the treatment of anemia associated with chronic diseases.

Topics: Anemia; Genetic Diseases, Inborn; Humans; Inflammatory Bowel Diseases; Neoplasms; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.

Topics: Anemia; Barbiturates; Clinical Trials as Topic; Erythropoiesis; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Isoquinolines; Picolinic Acids; Prolyl-Hydroxylase Inhibitors; Renal Dialysis

Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses.. This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.

Topics: Anemia; Animals; Barbiturates; Blood Pressure; Disease Models, Animal; Drug Design; Drug Interactions; Glycine; Hepcidins; Humans; Hypoxia-Inducible Factor 1; Inflammation; Isoquinolines; Kidney Failure, Chronic; Picolinic Acids; Protein Domains; Pyrazoles; Triazoles

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

Topics: Anemia; Barbiturates; Clinical Trials as Topic; Enzyme Inhibitors; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Pyrazoles; Renal Insufficiency, Chronic; Triazoles

This article informs the reader of the current information available on a novel therapeutic agent and new class of drug for the treatment of anemia. The data show promising results for alternative erythropoietin-stimulating agents and offers a time line of when Phase III data will be available. The information on this new drug and new drug class will change how nephrologists approach treating anemia within their patients.

Topics: Anemia; Glycine; Hematinics; Humans; Isoquinolines; Renal Insufficiency, Chronic

Anemia is one of the major complications of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) have been the mainstay of renal anemia treatment. However, there are several safety drawbacks, and a safer and more effective alternative treatment has been sought.. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been developed as a novel orally active therapeutic agent for renal anemia. HIF-PHIs stimulate endogenous EPO and optimize iron utilization. Roxadustat is a first-in-class HIF-PHI for the treatment of anemia in CKD patients approved in China, Japan, South Korea, and Chile. The authors herein evaluate the pharmacology of roxadustat and give their expert perspectives on its use.. Phase 3 clinical trials have demonstrated that roxadustat effectively increases and maintains hemoglobin (Hb) levels in both nondialysis-dependent and dialysis-dependent CKD patients. Roxadustat also improved iron metabolism and reduced intravenous (IV) iron requirements. However, pooled analyses of phase 3 studies have revealed frequent thromboembolic events in the roxadustat group, which might be attributed to rapid changes in Hb and inadequate iron supplementation. Roxadustat is an attractive alternative treatment especially for patients with ESA hyporesponsive due to impaired iron utilization, and so appropriate selection of target patients and its proper use are crucially important.

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Insufficiency, Chronic

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.

Topics: Aged; Anemia; Double-Blind Method; Female; Glycine; Humans; Isoquinolines; Male; Middle Aged; Myelodysplastic Syndromes; Placebo Effect; Treatment Outcome

The present study aimed to explore the efficacy and safety of roxadustat in patients with renal anemia and erythropoietin (EPO) hyporesponsive who are receiving continuous ambulatory peritoneal dialysis (CAPD).. This is a single center, before and after treatment, self-controlled study; 55 CAPD patients with renal anemia and EPO hyporesponsiveness were enrolled. The main follow-up parameters included routine blood, liver and kidney function, electrolyte, blood lipid, high-sensitivity C-reactive protein, and iron tests. Serum samples were used to determine interleukin-6 and tumor necrosis factor-α levels via enzyme linked immunosorbent assay. The Modified Quantitative Subjective Global Assessment Score and Malnutrition-Inflammation Score before and after treatment, and adverse events during treatment were recorded. The follow-up observation time was 12 weeks. Preliminary data 12-24 weeks before the enrollment as well as post-follow-up data at 36 weeks were also collected.. Fifty patients completed the 12-week follow-up. The hemoglobin levels were 8.0 ± 1.2 g/dL at baseline and 11.2 ± 2.0 g/dL after 12 weeks of roxadustat treatment. The hemoglobin increases at all measured time points and was statistically significant compared with the baseline value (P < .05). The overall hemoglobin response rate (hemoglobin increase ≥ 1.0 g/dL) was 80%, and 50% of the patients reached the hemoglobin target (hemoglobin ≥ 11.0 g/dL) at 12 weeks. Transferrin was higher at 12 weeks (2.2 ± 0.5 g/L) than at baseline (1.7 ± 0.5 g/L) (P < .05), while serum ferritin levels slightly decreased compared with the baseline value (P > .05). The median high-sensitivity C-reactive protein level and other inflammation-related indicators, such as white blood cell counts, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, interleukin-6, and tumor necrosis factor-α, were not significantly different from their baseline values. Nutrition-related biochemical indices such as albumin, creatinine, and blood lipids were also not significantly changed. The Modified Quantitative Subjective Global Assessment Score and Malnutrition-Inflammation Score were slightly lower at 12 weeks than at baseline. No serious adverse events were observed during the follow-up period. Post-follow-up data revealed a maintained hemoglobin level in patients who remained on roxadustat treatment while those switched back to EPO treatment after 12 weeks resulted in a decreased hemoglobin at 36 weeks.. In patients with EPO hyporesponsiveness on CAPD, roxadustat can efficiently and safely improve anemia and nutritional status without promoting inflammation.

Topics: Anemia; C-Reactive Protein; Erythropoietin; Glycine; Hemoglobins; Humans; Inflammation; Interleukin-6; Isoquinolines; Malnutrition; Peritoneal Dialysis; Pilot Projects; Prospective Studies; Renal Dialysis; Tumor Necrosis Factor-alpha

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in patients with non-dialysis-dependent (NDD) CKD evaluated disease state-related parameters among patients with and without diabetes mellitus who received roxadustat. In the 1517-CL-0310 study (NCT02988973), roxadustat was noninferior to darbepoetin alfa for change in average hemoglobin levels at Weeks 18-24 from baseline who received roxadustat.. Patients enrolled in the 1517-CL-0310 study who received roxadustat were included in this post hoc analysis. Hematologic (hemoglobin, reticulocyte/erythrocyte ratio, mean corpuscular volume [MCV], and mean corpuscular hemoglobin [MCH]), iron-related (ferritin, total iron-binding capacity, transferrin, ceruloplasmin, and hepcidin), metabolic (HbA1c, glycated albumin, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), and renal (eGFR) parameters were summarized descriptively by visit through Week 52.. Among 201 included patients, 105 (52.2%) and 96 (47.8%) were in the Diabetes and No Diabetes subgroups, respectively. There were no clinically meaningful differences through Week 52 for most hematologic, iron-related, metabolic, or renal parameters between patients in the Diabetes and No Diabetes subgroups. MCV and MCH remained lower and HbA1c and glycated albumin remained higher in patients in the Diabetes subgroup through Week 52. Both subgroups experienced a similar benefit from roxadustat in maintaining hemoglobin levels in the target range of 10-12 g/dL.. Roxadustat maintained hemoglobin levels in the target range with similar clinical parameters irrespective of diabetes mellitus presence at baseline.

Topics: Anemia; Cholesterol; Diabetes Mellitus; Glycated Hemoglobin; Glycine; Hemoglobins; Humans; Iron; Isoquinolines; Japan; Renal Insufficiency, Chronic

Roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, promotes erythropoiesis and regulates iron metabolism. This study investigated the efficacy and safety of roxadustat in Chinese patients with anemia on peritoneal dialysis (PD).. One hundred and twenty-nine patients were randomized and treated with roxadustat (n = 86) or erythropoiesis-stimulating agents (ESAs) (n = 43) for 24 weeks. The primary end points were the mean hemoglobin (Hb) level at week 24, the change in average Hb levels from baseline to week 24, and the cumulative response rate throughout the treatment period. The secondary end points included changes in hepcidin and iron indices and serum lipid levels. Subgroup analysis examined the effect of inflammatory status on the efficacy of Hb. Safety was assessed as the occurrence of emergent adverse events after treatment.. The mean average Hb levels at week 24 and average change in Hb levels from baseline to week 24 were 11.5 g/dL and 2.5 g/dL in the roxadustat group and 11.2 g/dL and 2.2 g/dL in the ESAs group, respectively. The cumulative response rate was 96% in the roxadustat group and 92% in the ESAs group at week 24. Roxadustat decreased hepcidin levels and increased total iron-binding capacity. The decreases in total cholesterol and low-density lipoprotein cholesterol were greater with roxadustat than with ESAs. Roxadustat-induced Hb increases were independent of baseline C-reactive protein levels. Common adverse events included hyperkalemia, hypertension, and insomnia.. Roxadustat effectively corrected and maintained target Hb levels in Chinese PD patients. This trial was registered in the Chinese Clinical Trial Register (ChiCTR2000035054).

Topics: Anemia; Glycine; Hemoglobins; Humans; Isoquinolines; Peritoneal Dialysis; Renal Insufficiency, Chronic

Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months.. Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively.. Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea.. Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.

Topics: Anemia; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Kidney Failure, Chronic; Renal Dialysis; Renal Insufficiency, Chronic; Research Design

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness.. Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated.. Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses.. The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Female; Glycine; Hematinics; Humans; Isoquinolines; Japan; Male; Middle Aged; Renal Insufficiency, Chronic

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycine; Hematinics; Humans; Isoquinolines; Japan; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Young Adult

We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis.. HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28-52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >-0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference -15%). Adverse events were monitored.. The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28-52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI -0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups.. Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia.. This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3-5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)-hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration-change in Hb from BL to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined.. A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48-58.93] and change in Hb from BL [roxadustat - placebo: +1.692 (95% CI 1.52-1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%).. Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.

Topics: Anemia; Double-Blind Method; Glycine; Hemoglobins; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD).. This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed.. Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52-1.25), P = 0.339; MACE+: 0.90 (0.61-1.32), P = 0.583].. Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.

Topics: Anemia; Calcium Carbonate; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Magnesium; Renal Dialysis; Renal Insufficiency, Chronic

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.. Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports.. A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).

Topics: Adult; Aged; Aged, 80 and over; Anemia; Contusions; Darbepoetin alfa; Diarrhea; Double-Blind Method; Female; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Japan; Male; Middle Aged; Nasopharyngitis; Renal Dialysis; Renal Insufficiency, Chronic; Retinal Hemorrhage; Time Factors; Transferrin; Vomiting; Young Adult

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD).. Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan.. Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study.. Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events.. Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Dialysis; Female; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Japan; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic; Treatment Outcome

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before dialysis on day 8. Maximum plasma concentration and area under the plasma concentration-time curve for patients receiving roxadustat were slightly more than dose proportional and elimination half-life ranged from 14.7 to 19.4 hours. Roxadustat was highly protein bound (99%) in plasma, and dialysis contributed a small fraction of the total clearance: only 4.56% and 3.04% of roxadustat recovered from the 1 and 2 mg/kg dose groups, respectively. Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1- and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment- or dose-related trends in adverse event incidence.

Topics: Administration, Oral; Adult; Aged; Anemia; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoiesis; Erythropoietin; Female; Glycine; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Kidney Failure, Chronic; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Treatment Outcome

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed to treat anemia in chronic kidney disease (CKD) patients. This Phase 3, randomized, open-label, 24-week study investigated the efficacy and safety of roxadustat in Japanese CKD patients with anemia on peritoneal dialysis (PD) who were previously treated or not treated with erythropoiesis stimulating agents (ESAs). Patients not previously receiving ESA (ESA-Naïve group) were randomized to roxadustat at a starting dose of 50 or 70 mg three times weekly; patients previously receiving ESA (ESA-Converted group) switched from ESA to roxadustat 70 or 100 mg three times weekly depending on the prior ESA dose. Outcomes included maintenance rate of average hemoglobin (Hb) level within 10-12 g/dL at weeks 18-24, cumulative response rate at end of treatment (Hb thresholds, 10.0 g/dL or 10.5 g/dL; Hb increase, ≥1.0 g/dL), and average Hb levels at weeks 18-24. Safety was assessed by occurrence of treatment-emergent adverse events (TEAEs). Fifty-six patients were enrolled (ESA-Naïve, n = 13; ESA-Converted, n = 43). Maintenance rates (weeks 18-24) were 92.3% (95% CI: 64.0-99.8; ESA-Naïve) and 74.4% (95% CI: 58.8-86.5; ESA-Converted). Cumulative response rate was 100.0% in the ESA-Naïve group. Average Hb levels (weeks 18-24) were 11.05 g/dL (95% CI: 10.67-11.42; ESA-Naïve) and 10.93 g/dL (95% CI: 10.73-11.13; ESA-Converted). Common TEAEs included nasopharyngitis and back pain. Roxadustat was well tolerated and effective in maintaining target Hb levels in CKD patients on PD who were previously treated or not treated with ESA.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Female; Glycine; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Peritoneal Dialysis; Renal Insufficiency, Chronic

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94.44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions.

Topics: Administration, Oral; Adsorption; Adult; Anemia; Area Under Curve; Charcoal; Cross-Over Studies; Drug Interactions; Erythropoiesis; Food-Drug Interactions; Glycine; Healthy Volunteers; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients.. In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10-12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb ≥ 10.0 g/dL and increase in Hb from baseline ≥ 1 g/dL) and mean Hb and change from baseline in Hb at weeks 18-24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events.. Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was - 0.052 (0.142) for placebo and + 0.200 (0.160), + 0.453 (0.256), and + 0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively (p < 0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups (p < 0.001). Change in Hb from baseline at weeks 18-24 was - 0.17 (0.61) for placebo and + 1.10 (0.71), + 1.33 (0.82), and + 1.55 (0.88) g/dL for roxadustat TIW groups (p < 0.001). No deaths or major adverse cardiac events occurred with roxadustat.. Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients.. ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered).. Astellas Pharma Inc.

Topics: Adult; Aged; Anemia; Chronic Disease; Double-Blind Method; Female; Glycine; Humans; Isoquinolines; Japan; Male; Middle Aged; Placebo Effect; Renal Insufficiency, Chronic

Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis.. In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9.. During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period.. In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).

Topics: Acidosis; Adult; Aged; Anemia; Cholesterol; Double-Blind Method; Female; Glycine; Hematinics; Hemoglobins; Humans; Hyperkalemia; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Insufficiency, Chronic

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.. In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.. A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.. Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).

Topics: Adult; Aged; Analysis of Variance; Anemia; Cholesterol; Double-Blind Method; Epoetin Alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hyperkalemia; Hypertension; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic

FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD).. In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed.. In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects.. FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Double-Blind Method; Female; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

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. Mean±SD baseline Hb was 8.3±1.0 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. Mean±SEM maximal change in Hb from baseline (ΔHb(max)), the primary endpoint, was 3.1±0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, ΔHb(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.

Topics: Anemia; Female; Glycine; Hepcidins; Humans; Isoquinolines; Male; Middle Aged; Peritoneal Dialysis; Renal Dialysis

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin.. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study.. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa.. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited.. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2).. Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset).. Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised.. Short treatment duration and small sample size.. In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Epoetin Alfa; Female; Glycine; Hematinics; Humans; Isoquinolines; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors; Treatment Outcome; Young Adult

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD.. The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events.. Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported.. In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; C-Reactive Protein; Cholesterol; Enzyme Inhibitors; Female; Glycine; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Insufficiency, Chronic

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects.. NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity.. Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo.. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial.. Clintrials.gov #NCT00761657.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Glycine; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Prognosis; Renal Dialysis; Renal Insufficiency, Chronic; Single-Blind Method; Young Adult

Topics: Anemia; Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney Diseases; Mice; Mice, Inbred C57BL; Procollagen-Proline Dioxygenase; Prolyl-Hydroxylase Inhibitors; Pyridines

Topics: Aged; Anemia; Blood Transfusion; Disease Management; Female; Glycine; Hematinics; Hematopoiesis; Humans; Isoquinolines; Myelodysplastic Syndromes; Signal Transduction

Inhibition of the prolyl-4-hydroxylase domain (PHD) enzymes, leading to the stabilization of hypoxia-inducible factor (HIF) α as well as to the stimulation of erythropoietin (Epo) synthesis, is the functional mechanism of the new anti-anemia drug roxadustat. Little is known about the effects of roxadustat on the Epo-producing cell pool. To gain further insights into the function of PHD inhibitors, we characterized the abundance of mesenchymal stem cell (MSC)-like cells after roxadustat treatment of mice. The number of Sca-1

Topics: Anemia; Animals; Erythropoietin; Glycine; Hypoxia; Isoquinolines; Kidney; Mice; Procollagen-Proline Dioxygenase; Prolyl Hydroxylases

Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has been reported to be effective in treating conservative renal failure and renal anemia in patients undergoing dialysis. Nonetheless, its effect on posttransplant anemia (PTA) has not yet been analyzed.. This study was conducted in accordance with the 1975 Declaration of Helsinki, as revised in 2013. Roxadustat was administered in 31 patients with a hemoglobin level ≤11 g/dL after renal transplant. The mean hemoglobin, serum iron, ferritin, and low-density lipoprotein (LDL) cholesterol levels and the estimated glomerular filtration rate at 4, 8, 12, 16, and 20 weeks after administration were compared with those before administration.. The average (standard deviation) hemoglobin level in 25 patients (6 patients dropped out) increased from 9.8 (0.78) g/dL before administration to 12.1 (1.44) g/dL (P < .001) after 12 weeks of roxadustat administration. The mean ferritin level in patients decreased from 107.6 (84.95) ng/mL before administration to 51.7 (44.04) ng/mL (P = .022) after 8 weeks of roxadustat administration. The mean LDL cholesterol level decreased from 114.1 (31.67) mg/dL before administration to 78.7 (18.26) mg/dL (P = .0012) after 8 weeks of roxadustat administration. Complications observed in patients after roxadustat administration included reduced hemoglobin levels in 3 patients, gastrointestinal symptoms in 2 patients, and myocardial infarction in 1 patient.. Hemoglobin levels significantly increased, whereas ferritin and LDL cholesterol levels significantly decreased in patients with PTA after roxadustat administration. Roxadustat seems to be an effective treatment for patients with PTA; however, the blood clotting tendency due to iron deficiency should be monitored in patients.

Topics: Anemia; Cholesterol, LDL; Ferritins; Glycine; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agent (ESA) hyporesponsiveness is an important cause for the undertreatment of anaemia. A decrease in haemoglobin (Hb) levels was observed during the initial stage of the conversion from ESA to roxadustat. The study aims to investigate the effectiveness and safety of adding roxadustat to an ESA for the treatment of ESA-hyporesponsive anaemia in patients on peritoneal dialysis (PD).. Patients on PD with ESA-hyporesponsive anaemia were enrolled from January 2020 to April 2020 with a 24-week follow-up period. Patients were treated with roxadustat at a starting dose of 50 or 100 mg thrice weekly without changing the ESA dose. Roxadustat and ESA dose adjustments were made as needed to maintain Hb levels within 11.0 to 13.0 g/dl. Efficacy outcomes and safety were assessed.. Nine patients were recruited in the study. Both the cumulative responsive rate and maintenance rate of Hb > 11 g/dl were 100%. Six patients required ESA dose reduction from ≥15,000 UI/week to ≤7000 IU/week at week 24. No drug-related severe adverse events were observed in this study.. The addition of roxadustat effectively and smoothly corrected anaemia in patients who were hyporesponsive to ESA, and permitted reduction of the ESA dose.

Topics: Anemia; Erythropoiesis; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Peritoneal Dialysis; Renal Dialysis

Current studies have limited data on long-term treatment safety and medication compliance of roxadustat for renal anemia in peritoneal dialysis (PD) patients. We aimed to analyze the long-term efficacy, safety, and medication compliance of roxadustat in the treatment of renal anemia in patients with PD who discontinued recombinant human erythropoietin (rhEPO) treatment due to the corona virus disease 2019 (COVID-19) outbreak.. We retrospectively collected patients who were switched from rhEPO to roxadustat in our hospital due to the pandemic. The criteria for subject inclusion: aged >18 years with a dialysis vintage >3 months, without malignant tumor, no severe cardiovascular and cerebrovascular diseases, and not combined hemodialysis. Patients were followed up until the end of December 2021. Hemoglobin (Hb), red blood cell (RBC) and hematocrit (Hct) were recorded at baseline, month 1-12 and month 20, and iron parameters at baseline, 3, 6, 9, 12, and 20 months were collected. The Morisky Medication Adherence Scale-8 (MMAS-8) was used to score medication compliance during rhEPO treatment and roxadustat treatment, and adverse reactions occurred during treatment were collected. The efficacy and medication compliance of roxadustat were analyzed using Wilcoxon rank sum test or t-test.. The median follow-up time was 21.1 (20.6, 21.7) months. After 1 month of treatment, the Hb level was significantly increased by 9.4 g/L (95% CI: 6.0-12.8 g/L) compared with the baseline, follow up at 20 months showed the Hb level had remained stable, increased by 20.7 g/L (95% CI: 15.9-25.4 g/L) compared with before treatment. At the beginning of treatment, total iron binding capacity increased, transferrin saturation and serum ferritin decreased, serum iron remained stable during treatment. During roxadustat treatment, no patient discontinued treatment due to the pandemic, and the Morisky score was improved compared with that during rhEPO treatment [5.75 (4.25, 6.00) vs. 6.75 (5.75, 7.00), P=0.000]. There were no serious adverse events associated with roxadustat were observed.. Roxadustat can effectively improve anemia and had good tolerance in patients undergoing PD who have difficult using rhEPO, and the medication compliance was better than rhEPO during the COVID-19.

Topics: Anemia; Chronic Disease; COVID-19; Glycine; Humans; Iron; Isoquinolines; Medication Adherence; Pandemics; Peritoneal Dialysis; Renal Dialysis; Retrospective Studies

We investigated the effect of roxadustat on factors associated with renal fibrosis and efficacy. After giving roxadustat, it can change the expression of HIF-1

Topics: Anemia; Fibrosis; Glycine; Hemoglobins; Hepcidins; Humans; Isoquinolines; Kidney Diseases; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

The objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters.. A total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software.. Roxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed.

Topics: Anemia; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer

Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD).. Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported.. Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa.. In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Topics: Anemia; Clinical Trials, Phase III as Topic; Epoetin Alfa; Erythropoietin; Ferritins; Glycine; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Our objective was to develop a population pharmacokinetic (PK) model to describe roxadustat plasma concentrations in Japanese dialysis-dependent chronic kidney disease (DD-CKD) patients with renal anaemia and to identify the covariate factors that affect exposure of roxadustat.. In total, 367 patients (male, 256; female, 111) contributing 1285 concentration values from 4 clinical studies were analysed using a nonlinear mixed-effects modelling approach. Candidate covariates included clinical characteristics hypothesized to affect roxadustat clearance and bioavailability, such as demographics, hepatic parameters and concomitant drugs.. The roxadustat PK data in Japanese DD-CKD patients with renal anaemia were well described by a 2-compartment disposition model with first-order absorption and interindividual variability on clearance, central volume of distribution and absorption rate constant. Age was identified as a significant covariate on clearance. PK profiles of haemodialysis and peritoneal dialysis patients were comparable. Eighty-two percent of patients were administered at least 1 phosphate binder (PB). The effect of PBs on roxadustat concentration was modelled as a decrease in bioavailability. Staggered administration of PBs reduced the effect on roxadustat bioavailability. The clinical impact of all covariates on roxadustat PK was mild and manageable as the roxadustat dose was titrated based on haemoglobin level and administered starting from a low dose.. Roxadustat PK in Japanese DD-CKD patients were successfully described by a population PK model. The identified key covariates included coadministration of PBs on the roxadustat bioavailability and age on clearance of roxadustat.

Topics: Anemia; Female; Glycine; Humans; Isoquinolines; Japan; Male; Renal Dialysis; Renal Insufficiency, Chronic

To observe the efficacy and safety of roxadustat, an inhibitor of proline hydroxylase, in renal allograft anemia patients.. This prospective study collected the clinical data of renal transplant patients treated with roxadustat for anemia at the Kidney Disease Center of the First Affiliated Hospital of Zhejiang University from April to August 2020. The patients were followed up every 2 weeks, and the changes in their hemoglobin index and any adverse reactions were recorded during 10 weeks of treatment. The efficacy of roxadustat for treatment of anemia after kidney transplantation was analyzed by comparing the change and increase in average hemoglobin levels before and after treatment. Rates of treatment response and achievement of the standard hemoglobin level were statistically analyzed. In addition, any potential adverse events and the glomerular filtration rate were recorded for 10 weeks to assess the safety of roxadustat in renal allograft anemia patients.. After 10 weeks of roxadustat treatment, the mean hemoglobin level was 10.4±3.9 g/dL, which was significantly higher than at baseline. Over the entire period, treatment was observed to have a therapeutic effect at weeks 2-4, with mean hemoglobin levels increasing as treatment time increased. At the 10-week endpoint, the percentage of patients reaching the standard hemoglobin level and exhibiting a response to treatment was 52.4% and 71.4%, respectively. During the treatment, there was no rejection, and the glomerular filtration rate was stable. Only one person showed symptoms of fatigue, and there were no other obvious adverse reactions reported.. Roxadustat significantly improves hemoglobin levels and can be safely used in renal transplant anemia patients.

Topics: Allografts; Anemia; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Kidney Transplantation; Prospective Studies; Renal Insufficiency, Chronic

In this case, we share a case of one of our patients developed rhabdomyolysis after he was administered roxadustat to treat anaemia caused by chronic renal failure.. More than 1.2 million people died from chronic kidney damage (CKD) globally, in 2017. Anaemia is a common complication of CKD. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Roxadustat is often used to treat anaemia caused by renal failure. Its adverse effects include high blood pressure, myocardial infarction, heart failure, high potassium, and dizziness; however, there are no reports about rhabdomyolysis associated with roxadustat.. Physicians should be alert about the occurrence of rhabdomyolysis when roxadustat is used.

Topics: Anemia; Glycine; Humans; Isoquinolines; Male; Renal Insufficiency, Chronic; Rhabdomyolysis

Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear.. This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes.. The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question.. The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .

Topics: Anemia; Clinical Protocols; Cohort Studies; Glycine; Humans; Isoquinolines; Multicenter Studies as Topic; Observational Studies as Topic; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Research Design

Erythropoietin (EPO) is a crucial hormone for erythropoiesis and produced by adult kidneys. Insufficient EPO production in chronic kidney disease (CKD) can cause renal anemia. Although hypoxia-inducible factors (HIFs) are known as a main regulator, the mechanisms of EPO production have not been fully elucidated. In this study, we aimed to examine the roles of retinoic acid (RA) in EPO production using EPO-producing cells derived from human induced pluripotent stem cells (hiPSC-EPO cells) that we previously established. RA augmented EPO production by hiPSC-EPO cells under hypoxia or by treatment with prolyl hydroxylase domain-containing protein (PHD) inhibitors that upregulate HIF signals. Combination treatment with RA and a PHD inhibitor improved renal anemia in vitamin A-depleted CKD model mice. Our findings using hiPSC-EPO cells and CKD model mice may contribute to clarifying the EPO production mechanism and developing efficient therapies for renal anemia.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Drug Evaluation, Preclinical; Drug Therapy, Combination; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Induced Pluripotent Stem Cells; Isoquinolines; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Tretinoin

Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) is a novel choice for the treatment of renal anemia, and an oral HIF-PH inhibitor roxadustat was approved for renal anemia. Roxadustat has high affinity to thyroid hormone receptor beta, which may affect thyroid hormone homeostasis.. We present here a patient undergoing hemodialysis with primary hypothyroidism receiving levothyroxine replacement, who showed decreased free thyroxine (FT4) and thyroid stimulating hormone (TSH) after starting roxadustat. Pituitary stimulation test revealed selective suppression of TSH secretion. Recovery of TSH and FT4 levels after stopping roxadustat suggested the suppression of TSH was reversible.. Physicians should pay special attention to thyroid hormone abnormalities in treatment with roxadustat.

Topics: Aged; Anemia; Glycine; Humans; Isoquinolines; Male; Renal Dialysis; Renal Insufficiency; Thyrotropin

Topics: Anemia; Glycine; Humans; Isoquinolines; Pneumonia; Renal Insufficiency, Chronic; Urinary Tract Infections

Roxadustat (Evrenzo

Topics: Anemia; Animals; Glycine; Humans; Isoquinolines; Japan; Rats; Renal Insufficiency, Chronic; Tablets

Topics: Adverse Drug Reaction Reporting Systems; Anemia; Barbiturates; Female; Gastrointestinal Hemorrhage; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Topics: Anemia; Ficus; Glycine; Humans; Isoquinolines; Renal Insufficiency, Chronic

Erythropoietin (EPO) production in the kidney is regulated by the oxygen-sensing transcription factor HIF-1α, which is degraded under normoxic conditions by HIF-prolyl hydroxylase (HIF-PHD). Inhibition of HIF-PHD by roxadustat leads to increased EPO production, better iron absorption, and amelioration of anemia in chronic kidney disease (CKD).

Topics: Anemia; Glycine; Humans; Hypoxia-Inducible Factor 1; Isoquinolines; Kidney; Prolyl Hydroxylases; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Prolyl Hydroxylases; Renal Dialysis; Renal Insufficiency, Chronic

Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Erythropoiesis; Erythropoietin; Glycine; Haplorhini; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Rats; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Insufficiency, Chronic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Insufficiency, Chronic

Topics: Activin Receptors, Type II; Anemia; Female; Glycine; Humans; Immunoglobulin Fc Fragments; Isoquinolines; Myelodysplastic Syndromes; Oligonucleotides; Recombinant Fusion Proteins

Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Glycine; Humans; Isoquinolines; Japan; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Glycine; Humans; Isoquinolines; Japan; Renal Dialysis; Renal Insufficiency, Chronic

Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, and then switched to Rox. We measured erythrocyte, reticulocyte indices, and iron-related factors at every HD during the first two weeks after the treatment switch (Days 0-14) and again on Days 21 and 28. We measured erythropoietin (EPO) concentration every week and examined their changes from Day-0 values. The same variables were measured in 15 HD patients who continued DA at every HD for one week. Iron-related factors were also measured on Days 14 and 28. In the Rox group, hepcidin significantly decreased from Day 2. The reticulocyte hemoglobin content (CHr) significantly increased on Day 4, but decreased with a significant increase in reticulocyte count from Day 7. Log

Topics: Aged; Aged, 80 and over; Anemia; Cell Count; Darbepoetin alfa; Drug Substitution; Erythrocytes; Erythropoietin; Female; Ferritins; Gene Expression Regulation; Glycine; Hematinics; Hematopoiesis; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Reticulocytes; Transferrin; Treatment Outcome

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis

Topics: Aged; Anemia; Dose-Response Relationship, Drug; Echocardiography, Doppler; Female; Glycine; Humans; Hypertension, Pulmonary; Isoquinolines; Radiography, Thoracic

Topics: Anemia; Glycine; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.

Topics: Acetic Acid; Administration, Oral; Anemia; Animals; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Molecular Structure; Prolyl-Hydroxylase Inhibitors; Rats; Renal Insufficiency, Chronic; Structure-Activity Relationship

Topics: Administration, Oral; Anemia; Animals; Cisplatin; Click Chemistry; Erythropoietin; Female; Fluorescence Polarization; Glycine; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Prolyl-Hydroxylase Inhibitors; Rats, Sprague-Dawley; Structure-Activity Relationship; Triazoles

Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia-inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies.

Topics: Anemia; Animals; Cardiovascular Diseases; Erythropoietin; Glycine; Hematinics; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

Topics: Administration, Oral; Anemia; Animals; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Structure; Pyridazines; Pyrimidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors regulated by oxygen-dependent prolyl hydroxylase domain (PHD) enzymes and are key to cell adaptation to low oxygen. The hematopoietic stem cell (HSC) niche in the bone marrow is highly heterogeneous in terms of microvasculature and thus oxygen concentration. The importance of hypoxia and HIFs in the hematopoietic environment is becoming increasingly recognized. Many small compounds that inhibit PHDs have been developed, enabling HIFs to be pharmacologically stabilized in an oxygen-independent manner. The use of PHD inhibitors for therapeutic intervention in hematopoiesis is being increasingly investigated. PHD inhibitors are well established to increase erythropoietin production to correct anemia in hemodialysis patients. Pharmacological stabilization of HIF-1α protein with PHD inhibitors is also emerging as an important regulator of HSC proliferation and self-renewal. Administration of PHD inhibitors increases quiescence and decreases proliferation of HSCs in the bone marrow in vivo, thereby protecting them from high doses of irradiation and accelerating hematological recovery. Recent findings also show that stabilization of HIF-1α increases mobilization of HSCs in response to granulocyte colony-stimulating factor and plerixafor, suggesting that PHD inhibitors could be useful agents to increase mobilization success in patients requiring transplantation. These findings highlight the importance of the hypoxia-sensing pathway and HIFs in clinical hematology.

Topics: Amino Acids, Dicarboxylic; Anemia; Apoptosis Regulatory Proteins; Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Glycine; Hematology; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Isoquinolines; Repressor Proteins; Signal Transduction; Stem Cell Transplantation

Topics: Anemia; Clinical Trials, Phase III as Topic; Cooperative Behavior; Drug Design; Drug Industry; Enzyme Inhibitors; Glycine; Humans; Isoquinolines; Procollagen-Proline Dioxygenase; Renal Insufficiency, Chronic

Topics: Anemia; Drug Industry; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Renal Insufficiency, Chronic