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Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects.

Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U - PLoS ONE (2014)

Bottom Line: Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production.Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system.Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

View Article: PubMed Central - PubMed

Affiliation: Cardiology/Hematology, Acute Care Research, Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.

ABSTRACT
Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

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Characterization of the in vivo activity of BAY 85-3934 (in male Wistar rats).Data are presented as means ± SEM. (A) Increase in plasma erythropoietin (EPO) at 4 h and (B) reticulocytes (as a proportion of red blood cells [RBCs]) at 72 h following single oral dosing of BAY 85-3934. Data were pooled from two sequential experiments (n = 2×5 animals per group). *p<0.05, **p<0.01, and ***p<0.001; unpaired t-test, sequentially pairwise-applied to dose groups and corresponding vehicle group. (C) Change in packed cell volume (PCV) during once-daily dosing with BAY 85-3934 (n = 12 animals per group). **p<0.01 and ***p<0.001; two-way ANOVA with Dunnett’s multiple comparison test versus vehicle group. (D) Induction of erythropoiesis after subcutaneous administration of recombinant human EPO (rhEPO) twice weekly or BAY 85-3934 (2.5 mg/kg) once daily (n = 10 animals per group). *p<0.001 compared with control (t-test) at day 30. (E) BAY 85-3934 plasma levels, kidney EPO relative mRNA expression, and plasma EPO levels after oral administration of BAY 85-3934 (5 mg/kg) (n = 5 animals per group). (F) Relative mRNA expression levels of HIF target genes in rat kidney after administration of BAY 85-3934 (5 mg/kg). Baseline expression was set at 1 (n = 5 animals per group; error bars not show for clarity of presentation). For definition of gene symbols, see Table 1.
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pone-0111838-g002: Characterization of the in vivo activity of BAY 85-3934 (in male Wistar rats).Data are presented as means ± SEM. (A) Increase in plasma erythropoietin (EPO) at 4 h and (B) reticulocytes (as a proportion of red blood cells [RBCs]) at 72 h following single oral dosing of BAY 85-3934. Data were pooled from two sequential experiments (n = 2×5 animals per group). *p<0.05, **p<0.01, and ***p<0.001; unpaired t-test, sequentially pairwise-applied to dose groups and corresponding vehicle group. (C) Change in packed cell volume (PCV) during once-daily dosing with BAY 85-3934 (n = 12 animals per group). **p<0.01 and ***p<0.001; two-way ANOVA with Dunnett’s multiple comparison test versus vehicle group. (D) Induction of erythropoiesis after subcutaneous administration of recombinant human EPO (rhEPO) twice weekly or BAY 85-3934 (2.5 mg/kg) once daily (n = 10 animals per group). *p<0.001 compared with control (t-test) at day 30. (E) BAY 85-3934 plasma levels, kidney EPO relative mRNA expression, and plasma EPO levels after oral administration of BAY 85-3934 (5 mg/kg) (n = 5 animals per group). (F) Relative mRNA expression levels of HIF target genes in rat kidney after administration of BAY 85-3934 (5 mg/kg). Baseline expression was set at 1 (n = 5 animals per group; error bars not show for clarity of presentation). For definition of gene symbols, see Table 1.

Mentions: Experiments were conducted in male Wistar rats to assess the threshold doses for EPO induction and the erythropoietic activity of BAY 85-3934. Following a single oral administration of BAY 85-3934, EPO was statistically significantly induced at doses of 1.25 mg/kg and above (Fig. 2A). EPO induction was maximal at doses of 500 mg/kg and above, and these plasma concentrations were maintained for over 48 h following administration (data not shown). Induction of EPO after single-dose administration was followed by a dose-dependent increase in the proportion of reticulocytes at doses of 1.25 mg/kg and above (Fig. 2B).


Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects.

Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U - PLoS ONE (2014)

Characterization of the in vivo activity of BAY 85-3934 (in male Wistar rats).Data are presented as means ± SEM. (A) Increase in plasma erythropoietin (EPO) at 4 h and (B) reticulocytes (as a proportion of red blood cells [RBCs]) at 72 h following single oral dosing of BAY 85-3934. Data were pooled from two sequential experiments (n = 2×5 animals per group). *p<0.05, **p<0.01, and ***p<0.001; unpaired t-test, sequentially pairwise-applied to dose groups and corresponding vehicle group. (C) Change in packed cell volume (PCV) during once-daily dosing with BAY 85-3934 (n = 12 animals per group). **p<0.01 and ***p<0.001; two-way ANOVA with Dunnett’s multiple comparison test versus vehicle group. (D) Induction of erythropoiesis after subcutaneous administration of recombinant human EPO (rhEPO) twice weekly or BAY 85-3934 (2.5 mg/kg) once daily (n = 10 animals per group). *p<0.001 compared with control (t-test) at day 30. (E) BAY 85-3934 plasma levels, kidney EPO relative mRNA expression, and plasma EPO levels after oral administration of BAY 85-3934 (5 mg/kg) (n = 5 animals per group). (F) Relative mRNA expression levels of HIF target genes in rat kidney after administration of BAY 85-3934 (5 mg/kg). Baseline expression was set at 1 (n = 5 animals per group; error bars not show for clarity of presentation). For definition of gene symbols, see Table 1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4230943&req=5

pone-0111838-g002: Characterization of the in vivo activity of BAY 85-3934 (in male Wistar rats).Data are presented as means ± SEM. (A) Increase in plasma erythropoietin (EPO) at 4 h and (B) reticulocytes (as a proportion of red blood cells [RBCs]) at 72 h following single oral dosing of BAY 85-3934. Data were pooled from two sequential experiments (n = 2×5 animals per group). *p<0.05, **p<0.01, and ***p<0.001; unpaired t-test, sequentially pairwise-applied to dose groups and corresponding vehicle group. (C) Change in packed cell volume (PCV) during once-daily dosing with BAY 85-3934 (n = 12 animals per group). **p<0.01 and ***p<0.001; two-way ANOVA with Dunnett’s multiple comparison test versus vehicle group. (D) Induction of erythropoiesis after subcutaneous administration of recombinant human EPO (rhEPO) twice weekly or BAY 85-3934 (2.5 mg/kg) once daily (n = 10 animals per group). *p<0.001 compared with control (t-test) at day 30. (E) BAY 85-3934 plasma levels, kidney EPO relative mRNA expression, and plasma EPO levels after oral administration of BAY 85-3934 (5 mg/kg) (n = 5 animals per group). (F) Relative mRNA expression levels of HIF target genes in rat kidney after administration of BAY 85-3934 (5 mg/kg). Baseline expression was set at 1 (n = 5 animals per group; error bars not show for clarity of presentation). For definition of gene symbols, see Table 1.
Mentions: Experiments were conducted in male Wistar rats to assess the threshold doses for EPO induction and the erythropoietic activity of BAY 85-3934. Following a single oral administration of BAY 85-3934, EPO was statistically significantly induced at doses of 1.25 mg/kg and above (Fig. 2A). EPO induction was maximal at doses of 500 mg/kg and above, and these plasma concentrations were maintained for over 48 h following administration (data not shown). Induction of EPO after single-dose administration was followed by a dose-dependent increase in the proportion of reticulocytes at doses of 1.25 mg/kg and above (Fig. 2B).

Bottom Line: Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production.Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system.Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

View Article: PubMed Central - PubMed

Affiliation: Cardiology/Hematology, Acute Care Research, Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.

ABSTRACT
Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

Show MeSH
Related in: MedlinePlus