Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease.
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ABSTRACT:
SUBMITTER: Haase VH
PROVIDER: S-EPMC7983025 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundErythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats.ObjectiveTo evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD).AnimalsTwenty-one client-owned CKD cats (4-17 years old) with anemia.MethodsMulticenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline.ResultsControl group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, -0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups.Conclusions and clinical importanceDaily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment.
| S-EPMC10800191 | biostudies-literature
Project description:Objective: This study aimed to explore the global research status, hot topics, and future prospects in the field of the hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) by bibliometric analysis. Methods: The literatures about HIF-PHI were downloaded from the Web of Science Core Collection and Pubmed database from inceptions to January.10th. 2022. The VOSviewer 1.6.18 was used to explore the bibliometric networks and research priorities of HIF-PHI. Results: A total of 409 papers about HIF-PHI were included, involving 1,674 authors from 548 institutions in 43 countries. The number of HIF-PHI literatures showed an upward trend, with steady growth from 2016 to 2020 and rapid growth in 2021. Tadao Akizawa, Masaomi Nangaku and Alexander R Cobitz published the most literatures. The United States, Japan and China contributed the most publications. The three most contributed institutions are Astellas Pharma Inc., the Showa University and Glaxosmithkline. Therapeutic Apheresis and Dialysis, American Journal of Nephrology and Clinical Pharmacology in Drug Development are the most productive journals. The main hot topics of HIF-PHI field are anemia, chronic kidney disease, hif-phi, epoetin and roxadustat. Conclusion: The United States and Japan are dominant in the field of HIF-PHI research. The discovery and clinical application of HIF-PHI is a great boon for patients with renal anemia. However, due to the short clinical application time of HIF-PHI, and its long-term efficacy and safety still need time to prove. In addition, more cooperation should be carried out between European and American countries and Asian countries to better prove the clinical value of HIF-PHI.
| S-EPMC9549679 | biostudies-literature
Project description:We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.
| S-EPMC6296170 | biostudies-literature
Project description:Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.
| S-EPMC4814173 | biostudies-literature
Project description: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.
| S-EPMC4891748 | biostudies-literature
Project description: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.
| S-EPMC5837707 | biostudies-literature
Project description:Anemia is a complication of chronic kidney disease (CKD), primarily due to insufficient secretion of erythropoietin (EPO) by the kidney. Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with chronic kidney disease. A poor response to ESAs has been associated with inflammation. Inflammation can affect erythrocytes and its production in many ways, but mainly through the inflammatory cytokine IL-6 to stimulate the synthesis of hepcidin in the liver. Hepcidin causes iron insufficiency, which causes erythrocytes to fail to mature normally. In addition, inhibition of bone marrow erythroid precursor cells by inflammatory cytokines such as IL-1 and TNF-? also affects bone marrow hematopoiesis. These cytokines are also important factors leading to EPO resistance. Roxadustat is a new drug for the treatment of renal anemia. In addition to promoting the production of EPO, clinical trials have shown that it can significantly reduce hepcidin and can potentially be used for the treatment of inflammation-induced anemia in CKD.
| S-EPMC7423837 | biostudies-literature
Project description:Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIFα subunit. Thieno[2,3-d]pyrimidine 8 identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo[4,3-d]pyrimidine 13 as the lead compound of orally bioavailable HIF-PHD inhibitors. Conversion of the benzyl moiety in 13 gave pyrazolopyrimidine 19 with high solubility and bioavailability, which increased hemoglobin levels in anemic model rats after repeated oral administration. It was shown that pyrazolo[4,3-d]pyrimidine derivatives are promising therapeutic agents for renal anemia through the inhibition of HIF-PHD.
| S-EPMC7357221 | biostudies-literature
Project description:Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.
| S-EPMC7946011 | biostudies-literature
Project description:Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-alpha subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 A resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.
| S-EPMC1502536 | biostudies-literature