Lorundrostat may expand treatment toolbox for uncontrolled hypertension

Aldosterone synthase inhibition with lorundrostat confers substantial blood pressure (BP)-lowering benefit in people with uncontrolled hypertension, while having a favourable safety profile, according to data from the phase II Target-HTN trial.

The drug reduced both serum aldosterone and BP levels after 8 weeks of treatment, the investigators said. “The 50-mg once-daily dose of lorundrostat lowered office BP to a similar degree as the 100-mg once-daily dose but resulted in fewer adverse events, including fewer episodes of hyperkalaemia.”

Specifically, in the group of participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL), all five doses of lorundrostat produced greater reductions in the primary study endpoint of automated office systolic BP compared with placebo: −14.1 mm Hg with 100 mg once daily, −13.2 mm Hg with 50 mg once daily, −6.9 mm Hg with 12.5 mg once daily, −10.1 mm Hg with 25 mg twice daily, and −13.8 mm Hg with 12.5 mg twice daily vs −4.1 mm Hg with placebo. [JAMA  2023;330:1140-1150]

Lorundrostat notably showed superiority over placebo for lowering automated office systolic BP at the 50-mg once-daily (least-squares mean difference, −9.6 mm Hg, 90 percent confidence interval [CI], −15.8 to −3.4; p=0.01) and the 100-mg once-daily doses (least-squares mean difference, −7.8 mm Hg, 90 percent CI, −14.1 to −1.5; p=0.04).

Meanwhile, in the exploratory group of participants without suppressed PRA, 100-mg once-daily lorundrostat reduced systolic BP by 11.4 mm Hg, which was similar to that seen among participants with suppressed PRA receiving the same dose.

In terms of safety, more than half of the participants (55 percent) experienced any adverse event (AE) during the trial, with most AEs being mild. There were three serious AEs recorded, one of which was deemed related to treatment. Specifically, one participant without suppressed PRA who received 100 mg once daily of lorundrostat had worsening of hyponatraemia that led to treatment withdrawal.

Additionally, six participants experienced elevations in serum potassium >6.0 mmol/L, which was corrected with dose reduction or drug discontinuation. None of the participants developed cortisol insufficiency.

“The trial results support further study of lorundrostat as a treatment for uncontrolled hypertension,” the investigators said.

Aldosterone suppression

Several studies suggest that individuals with obesity tend to produce too much of the hormone aldosterone due to the inability of their bodies to regulate aldosterone production normally owing, in turn, to abnormalities in the production of adipokines. [Circulation 2018;137:1614-1631; Hypertension 2016;67:1020-1028]

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnoea and metabolic syndrome, and has been shown to damage the heart and blood vessels. Yet, this condition is often undiagnosed in people with hypertension. [Ann Intern Med 2020;173:10-20; Hypertension 2022;79:726-735; Front Endocrinol 2023;13:1016804; Ann Intern Med 2020;173:10-20; Ann Intern Med 2021;174:289-297]

Recent guidelines for treating resistant hypertension recommend the use of mineralocorticoid receptor antagonists (MRAs), in addition to a three-drug regimen of a thiazide-type diuretic, a dihydropyridine calcium channel blocker, and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, for treating hypertension in patients in whom aldosterone excess plays a major role.  [Hypertension 2018;72:e53-e90; Lancet 2015;386:2059-2068; Am J Hypertens 2017;30:103-109]

However, MRAs such as spironolactone can cause side effects related to the drugs’ antiandrogenic and progestogenic properties, according to the investigators. Additionally, MRAs do not block the nongenomic effects of aldosterone, which can lead to increased sympathetic activity, problems with blood sugar control, and increased blood vessel constriction and stiffness. [Endocrinology 2006;147:5564-5567; Hypertension 2006;47:312-318]

Unlike MRAs, aldosterone synthase inhibitors such as lorundrostat work by blocking the production of aldosterone via inhibition of aldosterone synthase and averts the antiandrogenic and progestogenic-related side effects associated with MRAs.

“Lorundrostat has a relatively short half-life, and once-daily dosing resulted in a 25-percent lower mean change in serum potassium when 50 mg once daily was compared with 25 mg twice daily,” the investigators noted.

“This suggests that allowing an overnight period of escape from aldosterone suppression may have safety benefits when compared with aldosterone synthase inhibitors or aldosterone receptor blockers with longer half-lives, which has active metabolites with half-lives exceeding 24 hours,” they added.

Study population

Target-HTN included an initial cohort of 163 participants with suppressed plasma renin and elevated plasma aldosterone (cohort 1) and an exploratory cohort of 37 participants with PRA >1.0 ng/mL/h (cohort 2). These 200 participants had a mean age of 65.7 years, with 60 percent being women, 36 percent being Black or African American, and 48 percent having a body mass index of >30 kg/m². Cohort 1 participants had a mean baseline systolic BP of 142.2 mm Hg and a mean diastolic BP of 81.5 mm Hg, whereas cohort 2 participants had a mean baseline systolic BP of 139.1 mm Hg and diastolic BP of 79.1 mm Hg.

The cohort 1 participants were randomly assigned to placebo or one of five dosages of lorundrostat (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomly assigned to treatment with placebo or lorundrostat 100 mg once daily.