Aldosterone Synthase Inhibitors and the Treatment of Essential Hypertension

Approximately 10% of hypertensive patients have treatment-resistant hypertension defined as uncontrolled hypertension despite taking effective doses of 3 classes of antihypertensive drugs including a calcium channel blocker, thiazide diuretic, and an angiotensin-converting enzyme inhibitor or angiotensin-2 receptor blocker. The Pathway-2 study of treatment-resistant hypertensives randomized to receive an additional low dose of spironolactone demonstrated that addition of the mineralocorticoid receptor (MR) antagonist lowered the blood pressure (BP) more effectively than placebo, bisoprolol, or doxazosin. The extent of BP lowering by spironolactone was predicted by the baseline aldosterone–renin ratio (1). Aldosterone excess is common in patients with treatment-resistant hypertension and about 20% of these patients meet current criteria for primary aldosteronism (PA) (2). The importance of aldosterone synthesis in primary hypertension was demonstrated several decades ago by lowering the BP of patients with low renin hypertension with aminoglutethimide, an inhibitor of the mitochondrial side chain cleavage enzyme (CYP11A1) (3). Only aldosterone levels significantly decreased; those of deoxycorticosterone, cortisol, and other steroids were unchanged or increased (3). Spironolactone, the most used MR antagonist, has significant adverse effects including hyperkalemia and off-target effects through the androgen and progesterone receptors. Newer more selective MR antagonists including eplerenone and finerenone are less effective antihypertensives. An alternative approach to treat hypertension due to inappropriate aldosterone levels is to target its synthesis.

The CYP11B2 catalyzes the last and unique step in aldosterone production within the adrenal zona glomerulosa. CYP11B2 is 93% homologous with the far more abundant CYP11B1 required for cortisol production within the zona fasciculata, significantly complicating the development of sufficiently specific CYP11B2 antagonists. Another impediment to the development of specific CYP11B2 inhibitors for human use has been that most compounds in development inhibit the human and monkey CYP11B2, but not the rat or mouse enzyme, thus limiting preclinical studies (4). The fungicide derivative fadrozole, an aromatase inhibitor originally used for advanced breast cancer, also inhibits the CYP11B2 and CYP11B1 enzymes. The D-enantiomer of fadrozole is more selective for CYP11B2 than for the aromatase, but also inhibits the CYP11B1, albeit with 6-fold greater affinity for CYP11B2 (4). Structural modifications led to the development of LC1699 (osilodrostat) with a selectivity of 10:1 for CYP11B2 compared with CYP11B1. LC1699 was tested as a treatment of PA, but a significant number of patients developed adrenal insufficiency, so it was repurposed for the treatment of endogenous Cushing syndrome (5).

The first CYP11B2 inhibitor to reach phase 1 and 2 clinical trial is RO6836191 (Baxdrostat), a potent, long acting and specific inhibitor of CYP11B2 with a 100:1 specificity compared with CYP11B1 (6, 7). In the phase 1 clinical trial, Baxdrostat was shown to be safe and to reduce aldosterone by 51% to 73% doses between 0.5 and 5 mg/day in healthy normotensive individuals (7). In the phase 2 BrigHTN trial, patients with a BP greater than 130/80 on stable doses of 3 antihypertensive medications received placebo, 0.5, 1, or 2 mg/day of Baxrostat and followed for 12 weeks (6). Patients with secondary hypertension except for PA were excluded (6 supplement). MR antagonists, if used, were discontinued before the trial. Each treatment group comprised 67 to 70 patients. Urinary free aldosterone was significantly decreased from a baseline of 431 ± 399 ng aldosterone/g creatinine/day by all doses of Baxdrostat. Reductions were −187, −180, and −273 ng aldosterone/g creatinine, with 0.5, 1, or 2 mg/day of Baxrostat, respectively. BP decreased significantly with 1 and 2 mg/day. The number of patients diagnosed with PA and whether they were distributed equally among the 3 treatment groups was not mentioned.

The prevalence of PA diagnosed using the criteria of urinary excretion of aldosterone >12 μg/24 hour while on a high-salt diet in individuals with low plasma renin activity was found to be 22% in patients with treatment-resistant hypertension (2). Significantly, a diagnosis of PA was almost as frequent in patients with less severe hypertension and occurred in a lower but substantial number of normotensive individuals (2). The level of urinary aldosterone excretion in this cohort was a continuum, suggesting a significant role for aldosterone in the development of the hypertension even in those who do not fulfill current criteria for PA.

The pathophysiology of inappropriate MR activation is complex. The MR has similar affinity for cortisol as for aldosterone and mediates effects in addition to those related to hemodynamic and electrolyte homeostasis in nonepithelial tissues where cortisol is most often its physiological ligand, including cognition and the stress response in the brain (8). By targeting aldosterone excess, not its receptor, CYP11B2 inhibitors like Baxdrostat should be better alternatives to MR inhibitors in the treatment sequelae of aldosterone excess including hypertension. Notwithstanding, there are pathological consequences of ligand-independent MR activation associated with inflammation and oxidative stress that are less well understood in which MR antagonists remain the most appropriate treatment (8).

It is curious that while all the doses of Baxdrostat in the BrigHTN trial lowered aldosterone synthesis significantly, only the higher doses were more effective in lowering systolic and diastolic BP. All the requisite enzymes for aldosterone synthesis from cholesterol are expressed in the human and rat cardiovascular centers of the hypothalamus and aldosterone synthesis has been demonstrated by the rat brain ex vivo and in vivo where it is hypothesized to have autocrine or paracrine effects. Moreover, central administration of Cyp11b2 inhibitors normalize the BP in hypertensive Dahl salt-sensitive rats (8). While all doses used in the BrigHTN trial lowered circulating aldosterone levels similarly, only the higher ones lowered the BP significantly. One might speculate that Baxdrostat at higher concentrations surmounted the blood–brain barrier and inhibited local aldosterone synthesis and its autocrine or paracrine effects on central BP control.

In summary, selective CYP11B2 antagonists should be valuable adjuncts for the control of treatment-resistant low renin hypertension, as well as primary and secondary hyperaldosteronism. Aldosterone synthase inhibitors have an advantage over MR antagonists in that they spare functions of the MR normally mediated by cortisol, however, they will not replace the MR antagonists completely, particularly in conditions driven by inappropriate ligand-independent activation of the MR (8).

Abbreviations

BP

blood pressure

MR

mineralocorticoid receptor

PA

primary aldosteronism

Funding

Dr. Gomez-Sanchez is supported by National Heart, Lung and Blood Institute grant R01 HL144847, National Institutes of General Medical Sciences U54 GM115428, and Department of Veteran Affairs BX00468.

Disclosures

None.