Mimicking Hypoxia to Treat Anemia: HIF-Stabilizer BAY 85-3934 (Molidustat) Stimulates Erythropoietin Production without Hypertensive Effects

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.

Anaemia of Chronic Kidney Disease: What We Know Now

“…Similar small preclinical and clinical studies have demonstrated some pleiotropic effects of this class of drug (molidustat corrected anaemia in rat studies and also helped normalise blood pressure; daprodustat was shown to improve cholesterol levels) (82,83). Advantages of this new class of drug include oral administration, low immunogenicity, product stability and possibly lower costs as well as potential cardiovascular benefits (84).…”

Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients

“…However, emerging evidence supports a blood pressure-lowering effect of PHD inhibitors (noted with 3 separate agents) equivalent to that achieved by enalapril [73,74,75]. …”

The HIF System Response to ESA Therapy in CKD‐Anemia

“…The most promising are the PHD inhibitors (Table 1) with several compounds already under evaluation in clinical trials. Some of these compounds showed to be well tolerated, corrected anemia in non-dialysis CKD and incident dialysis patients without increasing blood pressure, and also reduced serum hepcidin levels [70][71][72][73]. However, regarding their effects in reducing cardiovascular events and slowing the progression of the renal disease, no data are still available from human studies.…”