A new approach to influencing the renin-angiotensin-aldosterone system: aldosterone synthase inhibitor badrostat

The problem of treatment of resistant arterial hypertension (AH) is related to the fact that in patients who received at least three antihypertensive drugs, including a renin-angiotensin-aldosterone system (RAAS) inhibitor, a calcium channel blocker and a diuretic in the maximum tolerated doses, the target level of blood pressure (BP) is not achieved (BP≥140/90 mm Hg). Guidelines for the AH treatment recommend adding the mineralocorticoid receptor antagonist spironolactone as a fourth agent to pharmacotherapy because the mechanisms underlying resistant hypertension are associated with persistent excess fluid retention. However, the use of mineralocorticoid receptor antagonists (spironolactone, eplerenone) has a number of disadvantages associated with the possibility of reducing the effectiveness of the feedback mechanism and the development of side effects (hyperkalemia, sexual disorders), which limits their use in resistant hypertension. A new approach to influencing the RAAS is associated with the search for drugs that have a more selective effect on aldosterone - inhibition of aldosterone synthase. Recent publications present the results of studies of a new aldosterone synthase inhibitor, bacdrostat, intended for the treatment of diseases with elevated aldosterone levels. According to the results of phase 1 trials on healthy volunteers, bacdrostat showed a dose-dependent decrease in plasma aldosterone levels in the dose range of 1.5-10.0 mg. A BrigHTN phase 2 trial on evaluation of the efficacy of bacdrostat in patients with resistant hypertension, in which bacdrostat was used at doses of 0.5 mg, 1.0, 2.0 mg/day within 12 weeks, was recently completed. The study was terminated earlier than expected due to a significant difference in systolic BP reduction at the 2 mg dose compared with placebo after 12 weeks of therapy (-11.0 mmHg; P=0.003). There were no serious side effects and cases of adrenal insufficiency. Further research in area of target organ protection in hypertensive patients may pave the way for increased use of aldosterone synthase inhibitors.