Discussion
primary aldosteronism, baxdrostat-induced decreases, BP reduction, MR, hypertension
PRIMARY ALDOSTERONISM, HYPERTENSION
Consistent with the single ascending dose study results [One of the challenges of aldosterone synthase inhibition is to achieve high selectivity for the enzyme, which shares 93% homology to cortisol synthase [Lack of specificity for aldosterone synthase has resulted in the discontinuation of LCI699, which was previously being developed for the treatment of hypertension [Baxdrostat decreased plasma aldosterone levels under both low-salt and normal-salt diet conditions; the 2.5-mg baxdrostat dose used in both low- and normal-salt conditions showed a similar effect on lowering plasma aldosterone levels. The low-salt diet subjects of cohorts 1 and 2 also underwent an ACTH challenge to further stimulate aldosterone and cortisol levels prior to receiving baxdrostat. Baxdrostat suppressed plasma aldosterone levels while having no meaningful effect on cortisol, even in the presence of the ACTH challenge, further supporting the selectivity of baxdrostat to inhibit aldosterone synthase.As expected, the inhibition of aldosterone synthase by baxdrostat resulted in an increase in the aldosterone precursor 11-deoxycorticosterone under both normal- and low-salt diet conditions. However, the magnitude of increase was modest (~2- to 3-fold) compared to what has previously been observed for LCI699, where 11-deoxycorticosterone levels increased up to 10-fold [Although the study was conducted in healthy volunteers, the apparent diuretic effect, the slight trends toward mild baxdrostat-induced decreases in orthostatic BP, and the moderate increases in orthostatic heart rate indicate that baxdrostat represents a promising treatment for the negative health impact of elevated aldosterone. It is difficult to predict how the observed 51 to 73% reduction in plasma aldosterone will translate to BP reduction in patients with primary aldosteronism or uncontrolled or treatment-resistant hypertension; however, further studies in these patient populations will help elucidate this relationship.There are potential benefits of selective aldosterone synthase inhibition vs. MR antagonism. For example, due to the hypothalamic-pituitary axis feedback loop, blocking MRs activates the RAAS, leading to a compensatory increase in aldosterone, which could overcome the blockade by MR antagonists [The relatively small sample size for each treatment group is a limitation of the current study. Because it was conducted in healthy subjects, the clinical relevance of these findings needs to be investigated in patients who have uncontrolled or treatment-resistant hypertension or primary aldosteronism. As expected, we were unable to detect BP changes in our healthy subjects and therefore were not able to definitively identify the efficacious dose range for patients with hypertension or primary aldosteronism. Moreover, the relationship between the magnitude of aldosterone lowering and BP lowering is not yet defined. For these reasons, further study is needed to understand the dose-response for lowering BP in these patients, including the possibility of additional higher doses.