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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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Effect of BAY 85-3934, erythropoietin (EPO), and enalapril in the rat subtotal nephrectomy model.Data are presented as means ± SEM. (A) Packed cell volume (PCV), (B) systolic blood pressure (SBP), and (C) prorenin following oral administration of BAY 85-3934 (2.5 mg/kg or 5 mg/kg once daily) or rhEPO (100 IU/kg s.c. twice weekly) for 5 weeks, compared with control and sham-operated animals (n = 4–6 animals per group). Efficacy of BAY 85-3934 sodium (80 ppm), enalapril (30 ppm), and a combination of both, administered in drinking water for 5 weeks, on (D) PCV, (E) SBP (at 4 weeks), and (F) prorenin (n = 9–10 animals per group). *p<0.05, **p<0.01, ***p<0.001; one-way ANOVA followed by Dunnett’s multiple comparison test to corresponding sham or control group for (A), (C), (D), and (E), and Bonferroni’s multiple comparison test to corresponding sham or control group for (B) and (F).
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pone-0111838-g006: Effect of BAY 85-3934, erythropoietin (EPO), and enalapril in the rat subtotal nephrectomy model.Data are presented as means ± SEM. (A) Packed cell volume (PCV), (B) systolic blood pressure (SBP), and (C) prorenin following oral administration of BAY 85-3934 (2.5 mg/kg or 5 mg/kg once daily) or rhEPO (100 IU/kg s.c. twice weekly) for 5 weeks, compared with control and sham-operated animals (n = 4–6 animals per group). Efficacy of BAY 85-3934 sodium (80 ppm), enalapril (30 ppm), and a combination of both, administered in drinking water for 5 weeks, on (D) PCV, (E) SBP (at 4 weeks), and (F) prorenin (n = 9–10 animals per group). *p<0.05, **p<0.01, ***p<0.001; one-way ANOVA followed by Dunnett’s multiple comparison test to corresponding sham or control group for (A), (C), (D), and (E), and Bonferroni’s multiple comparison test to corresponding sham or control group for (B) and (F).

Mentions: Subtotal nephrectomy resulted in a mild reduction in mean hematocrit, and an increase in mean systolic blood pressure as determined by tail cuff measurement (Fig. 6A, B). Treatment with rhEPO or BAY 85-3934 (2.5 mg/kg and 5 mg/kg) significantly increased mean PCV (Fig. 6A). In fact, 2 weeks after onset of treatment, animals in the 5 mg/kg group were switched to treatment with 2.5 mg/kg because their mean PCV had exceeded 50%.


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)

Effect of BAY 85-3934, erythropoietin (EPO), and enalapril in the rat subtotal nephrectomy model.Data are presented as means ± SEM. (A) Packed cell volume (PCV), (B) systolic blood pressure (SBP), and (C) prorenin following oral administration of BAY 85-3934 (2.5 mg/kg or 5 mg/kg once daily) or rhEPO (100 IU/kg s.c. twice weekly) for 5 weeks, compared with control and sham-operated animals (n = 4–6 animals per group). Efficacy of BAY 85-3934 sodium (80 ppm), enalapril (30 ppm), and a combination of both, administered in drinking water for 5 weeks, on (D) PCV, (E) SBP (at 4 weeks), and (F) prorenin (n = 9–10 animals per group). *p<0.05, **p<0.01, ***p<0.001; one-way ANOVA followed by Dunnett’s multiple comparison test to corresponding sham or control group for (A), (C), (D), and (E), and Bonferroni’s multiple comparison test to corresponding sham or control group for (B) and (F).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4230943&req=5

pone-0111838-g006: Effect of BAY 85-3934, erythropoietin (EPO), and enalapril in the rat subtotal nephrectomy model.Data are presented as means ± SEM. (A) Packed cell volume (PCV), (B) systolic blood pressure (SBP), and (C) prorenin following oral administration of BAY 85-3934 (2.5 mg/kg or 5 mg/kg once daily) or rhEPO (100 IU/kg s.c. twice weekly) for 5 weeks, compared with control and sham-operated animals (n = 4–6 animals per group). Efficacy of BAY 85-3934 sodium (80 ppm), enalapril (30 ppm), and a combination of both, administered in drinking water for 5 weeks, on (D) PCV, (E) SBP (at 4 weeks), and (F) prorenin (n = 9–10 animals per group). *p<0.05, **p<0.01, ***p<0.001; one-way ANOVA followed by Dunnett’s multiple comparison test to corresponding sham or control group for (A), (C), (D), and (E), and Bonferroni’s multiple comparison test to corresponding sham or control group for (B) and (F).
Mentions: Subtotal nephrectomy resulted in a mild reduction in mean hematocrit, and an increase in mean systolic blood pressure as determined by tail cuff measurement (Fig. 6A, B). Treatment with rhEPO or BAY 85-3934 (2.5 mg/kg and 5 mg/kg) significantly increased mean PCV (Fig. 6A). In fact, 2 weeks after onset of treatment, animals in the 5 mg/kg group were switched to treatment with 2.5 mg/kg because their mean PCV had exceeded 50%.

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