scholarly journals The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease

2021 ◽  
pp. 1574-1579
Author(s):  
Ryujiro Hara ◽  
Naoki Goto ◽  
Daisuke Furuya ◽  
Toshihiko Kitahara ◽  
Hiroki Numata ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Hypoxia Inducible Factor ◽  
Underlying Disease ◽  
Efficacy And Safety ◽  
Renal Anaemia ◽  
Treatment Target ◽  
Endogenous Erythropoietin ◽  
Erythropoietin Production

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

scholarly journals Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies

2019 ◽  
Vol 49 (4) ◽  
pp. 271-280 ◽  
Author(s):  
Tadao Akizawa ◽  
Iain C. Macdougall ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Gerald Staedtler ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Efficacy And Safety ◽  
Open Label ◽  
Multicenter Studies ◽  
Parallel Group ◽  
The Mean ◽  
Term Management

Background: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. Methods: Both studies were parallel-group, open-label, multicenter studies of ≤36 months’ duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). Results: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient’s overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. Conclusions: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

scholarly journals Anemia in Chronic Kidney Disease : Role of Hypoxia Inducible Factor Stabilizer

2021 ◽  
Vol 5 (3) ◽  
pp. 395-400
Author(s):  
Emilia ◽  
Zulkhair Ali
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Hypoxia Inducible Factor ◽  
Iron Availability ◽  
Current Standard ◽  
Erythropoietin Production ◽  
Significant Harm ◽  
Erythropoietin Deficiency

A B S T R A C TAnemia contributes to increased morbidity and mortality in chronic kidney diseasepatients. The pathogenesis of anemia in these patients is multifactorial, but thecontribution of erythropoietin deficiency becomes greater as glomerular filtrationrate declines which related to decreased nephron mass. The current standard ofcare includes supplemental iron, erythropoiesis-stimulating agents (ESA), and redblood cell transfusions, although each has drawbacks. Lately, concern has arisenfollowing randomized clinical trials showing that higher hemoglobin targets and/orhigh ESA doses may cause significant harm including increasing cardiovascular andthrombotic events, and even death. Recent experimental and clinical studies showthe promising efficacy of hypoxia inducible factor (HIF) stabilizer which stimulatesendogenous erythropoietin production and enhance iron availability.

scholarly journals Effects of Molidustat in the Treatment of Anemia in CKD

2018 ◽  
Vol 14 (1) ◽  
pp. 28-39 ◽  
Author(s):  
Iain C. Macdougall ◽  
Tadao Akizawa ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Thilo Krueger
Keyword(s):  
Oral Treatment ◽  
Hypoxia Inducible Factor ◽  
Mean Value ◽  
Fixed Dose ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
Endogenous Erythropoietin ◽  
Dose Trial

Background and objectivesThe efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on dialysis (DaIly orAL treatment increasing endOGenoUs Erythropoietin [DIALOGUE] 1 and 2) and in those who are on dialysis (DIALOGUE 4).Design, setting, participants, & measurementsDIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and 75 mg once daily; 25 and 50 mg twice daily). DIALOGUE 2 and 4 were open-label, variable-dose trials, in which treatment was switched from darbepoetin (DIAGLOGUE 2) or epoetin (DIALOGUE 4) to molidustat or continued with the original agents. Starting molidustat ranged between 25–75 and 25–150 mg daily in DIAGLOGUE 2 and 4, respectively, and could be titrated to maintain hemoglobin levels within predefined target ranges. The primary end point was the change in hemoglobin level between baseline and the mean value from the last 4 weeks of the treatment period.ResultsIn DIAGLOGUE 1 (n=121), molidustat treatment was associated with estimated increases in mean hemoglobin levels of 1.4–2.0 g/dl. In DIAGLOGUE 2 (n=124), hemoglobin levels were maintained within the target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels between molidustat and darbepoetin treatments of up to 0.6 g/dl. In DIAGLOGUE 4 (n=199), hemoglobin levels were maintained within the target range after switching to molidustat 75 and 150 mg, with estimated differences in mean change between molidustat and epoetin treatment of −0.1 and 0.4 g/dl. Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity.ConclusionsThe overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables the progression of its development into phase 3.

scholarly journals Hypoxia inducible factor stabilizers: a promising treatment for chronic kidney disease

2020 ◽  
Vol 9 (11) ◽  
pp. 1766
Author(s):  
Koushiki Mani ◽  
Johnny Karini ◽  
Kuntolika Mani ◽  
Ananya Amrit
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Supplementation ◽  
Hypoxia Inducible Factor ◽  
Renal Anemia ◽  
Erythropoietin Production ◽  
Cell Life ◽  
Oxygen Sensitive ◽  
Promising Treatment ◽  
Hif Pathway

Anemia in chronic kidney disease (CKD) is a very common complication. The two main factors contributing to the development of anemia in CKD is decreased erythropoietin production and iron deficiency. Other factors that might play a role in the pathogenesis of renal anemia are: chronic inflammation leading to increased hepcidin, uremic toxins, and shorter red blood cell life span. The mainstay of treatment is iron supplementation, blood transfusion and erythropoietin stimulating agents (ESA). The discovery of hypoxia inducible factor (HIF) pathway has opened a new chapter in the treatment of anemia in CKD. The oxygen-sensitive HIF pathway plays a prominent role in the control of erythropoiesis and iron metabolism. HIF stabilizers are a new set of drugs that inhibits prolyl hydroxylase domain (PHD) proteins which are key regulators of HIF activity. Several such compounds are being developed to revolutionize the treatment of renal anemia.

scholarly journals The efficacy and safety of an oral iron chelating agent, deferasirox, for iron overload in a patient with chronic kidney disease and myelodysplastic syndrome

2009 ◽  
Vol 42 (11) ◽  
pp. 865-869
Author(s):  
Shinji Fukui ◽  
Kazumasa Torimoto ◽  
Yoriaki Kagebayashi ◽  
Katsuhiko Morimoto ◽  
Soichi Yamaguchi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Myelodysplastic Syndrome ◽  
Iron Overload ◽  
Chelating Agent ◽  
Oral Iron ◽  
Efficacy And Safety

scholarly journals Anemia in Chronic Kidney Disease : Role of Hypoxia Inducible Factor Stabilizer

2021 ◽  
Vol 5 (5) ◽  
pp. 462-467
Author(s):  
Emilia ◽  
Zulkhair Ali
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Randomized Clinical Trials ◽  
Hypoxia Inducible Factor ◽  
Standard Of Care ◽  
Current Standard ◽  
Endogenous Erythropoietin ◽  
Red Blood Cell Transfusions ◽  
Erythropoietin Deficiency

Anemia contributes to increased morbidity and mortality in chronic kidney disease patients. The pathogenesis of anemia in these patients is multifactorial, but the contribution of erythropoietin deficiency becomes greater as glomerular filtration rate declines which related to decreased nephron mass. The current standard of care includes supplemental iron, erythropoiesis-stimulating agents (ESA), and red blood cell transfusions, although each has drawbacks. Lately, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm including increasing cardiovascular and thrombotic events, and even death. Recent experimental and clinical studies show the promising efficacy of hypoxia inducible factor (HIF) stabilizer which stimulates endogenous erythropoietin production and enhance iron availability.

Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease?

2019 ◽  
Vol 35 (6) ◽  
pp. 926-932 ◽  
Author(s):  
Francesco Locatelli ◽  
Lucia Del Vecchio
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Adverse Outcomes ◽  
The Body ◽  
Phase Iii ◽  
Endogenous Erythropoietin ◽  
Potential Alternative

Abstract Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.

scholarly journals Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Jose Portolés ◽  
Leyre Martín ◽  
José Jesús Broseta ◽  
Aleix Cases
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Intravenous Iron ◽  
Great Expectations ◽  
Functional Iron Deficiency ◽  
Endogenous Erythropoietin ◽  
The One

Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.

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