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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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Effects of BAY 85-3934 or recombinant human erythropoietin (rhEPO) on erythropoietic parameters in cynomolgus monkeys.Data are presented as means ± SEM. (A) Plasma erythropoietin (EPO) concentrations after repeat oral administration of BAY 85-3934 (n = 6 animals per group). (B) Plasma EPO concentrations after a single s.c. administration of rhEPO (100 IU/kg) or a single oral dose of BAY 85-3934 (1.5 mg/kg) (n = 3 animals per group). (C) Erythropoietic parameters (hemoglobin [HGB], red blood cells [RBCs], and reticulocytes) after s.c. administration of rhEPO twice weekly (100 IU/kg) for 2 weeks or BAY 85-3934 (1.5 mg/kg) once daily for 2 weeks (n = 3 animals per group).
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pone-0111838-g003: Effects of BAY 85-3934 or recombinant human erythropoietin (rhEPO) on erythropoietic parameters in cynomolgus monkeys.Data are presented as means ± SEM. (A) Plasma erythropoietin (EPO) concentrations after repeat oral administration of BAY 85-3934 (n = 6 animals per group). (B) Plasma EPO concentrations after a single s.c. administration of rhEPO (100 IU/kg) or a single oral dose of BAY 85-3934 (1.5 mg/kg) (n = 3 animals per group). (C) Erythropoietic parameters (hemoglobin [HGB], red blood cells [RBCs], and reticulocytes) after s.c. administration of rhEPO twice weekly (100 IU/kg) for 2 weeks or BAY 85-3934 (1.5 mg/kg) once daily for 2 weeks (n = 3 animals per group).

Mentions: A multiple-dose study in cynomolgus monkeys was conducted to evaluate whether repeat administration of BAY 85-3934 would result in EPO accumulation and/or adaptation of the EPO response. EPO was significantly induced 7 h after administration of BAY 85-3934 (1.5 mg/kg) in all animals, and showed a clear increase after the 0.5 mg/kg dose in females (Fig. 3A). In all groups, EPO concentrations had returned to baseline concentrations 24 h after administration of the study drug. Notably, there was no adaptation of the EPO response after repeated dosing in any of the treated animals. Platelet and white blood cell counts were unchanged. With respect to EPO induction, the 0.5 mg/kg dose was determined as the minimal effective dose in this study, although statistical significance versus control animals was not reached in this small and heterogeneous animal cohort.


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)

Effects of BAY 85-3934 or recombinant human erythropoietin (rhEPO) on erythropoietic parameters in cynomolgus monkeys.Data are presented as means ± SEM. (A) Plasma erythropoietin (EPO) concentrations after repeat oral administration of BAY 85-3934 (n = 6 animals per group). (B) Plasma EPO concentrations after a single s.c. administration of rhEPO (100 IU/kg) or a single oral dose of BAY 85-3934 (1.5 mg/kg) (n = 3 animals per group). (C) Erythropoietic parameters (hemoglobin [HGB], red blood cells [RBCs], and reticulocytes) after s.c. administration of rhEPO twice weekly (100 IU/kg) for 2 weeks or BAY 85-3934 (1.5 mg/kg) once daily for 2 weeks (n = 3 animals per group).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111838-g003: Effects of BAY 85-3934 or recombinant human erythropoietin (rhEPO) on erythropoietic parameters in cynomolgus monkeys.Data are presented as means ± SEM. (A) Plasma erythropoietin (EPO) concentrations after repeat oral administration of BAY 85-3934 (n = 6 animals per group). (B) Plasma EPO concentrations after a single s.c. administration of rhEPO (100 IU/kg) or a single oral dose of BAY 85-3934 (1.5 mg/kg) (n = 3 animals per group). (C) Erythropoietic parameters (hemoglobin [HGB], red blood cells [RBCs], and reticulocytes) after s.c. administration of rhEPO twice weekly (100 IU/kg) for 2 weeks or BAY 85-3934 (1.5 mg/kg) once daily for 2 weeks (n = 3 animals per group).
Mentions: A multiple-dose study in cynomolgus monkeys was conducted to evaluate whether repeat administration of BAY 85-3934 would result in EPO accumulation and/or adaptation of the EPO response. EPO was significantly induced 7 h after administration of BAY 85-3934 (1.5 mg/kg) in all animals, and showed a clear increase after the 0.5 mg/kg dose in females (Fig. 3A). In all groups, EPO concentrations had returned to baseline concentrations 24 h after administration of the study drug. Notably, there was no adaptation of the EPO response after repeated dosing in any of the treated animals. Platelet and white blood cell counts were unchanged. With respect to EPO induction, the 0.5 mg/kg dose was determined as the minimal effective dose in this study, although statistical significance versus control animals was not reached in this small and heterogeneous animal cohort.

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