Novel aldosterone synthase inhibitor safely lowers BP in uncontrolled hypertension
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Key takeaways:
- Once-daily lorundrostat, an aldosterone synthase inhibitor, significantly decreased automated office systolic BP vs. placebo.
- BP reduction was greatest among people with hypertension and concomitant obesity.
An investigational aldosterone synthase inhibitor was associated with clinically significant reductions in automated office BP for people with uncontrolled hypertension, with the greatest effects seen in people with concomitant obesity.
Data from the Target-HTN trial, presented at the American Heart Association Hypertension Scientific Sessions, also demonstrated that lorundrostat (Mineralys) was safe for people with suppressed renin, according to Luke J. Laffin, MD, co-director of the Center for Blood Pressure Disorders at Cleveland Clinic, told Healio.
“We know that aldosterone not only raises BP but it is detrimental to our vasculature and kidneys,” Laffin told Healio. “Increasingly, we as a field in hypertension are understanding that excess aldosterone plays a role in a lot of patients with hypertension. Currently available mineralocorticoid receptor antagonist therapies like spironolactone and eplerenone can help, but newer drugs, such as lorundrostat, will probably be more beneficial in the long term.”
Role of elevated aldosterone
Laffin and colleagues analyzed data from 163 adults with uncontrolled hypertension (taking two or more antihypertensive medications), suppressed plasma renin (plasma renin activity [PRA] 1 ng/mL per hour) and elevated plasma aldosterone ( 1 ng/dL), as well as a cohort of 37 adults with uncontrolled hypertension and PRA greater than 1 ng/mL per hour, all enrolled from July 2021 to June 2022. Researchers randomly assigned participants placebo or one of five doses of lorundrostat in the initial cohort: 12.5 mg, 50 mg or 100 mg once daily, or 12.5 mg or 25 mg twice daily. In the second cohort, researchers randomly assigned participants to lorundrostat 100 mg once daily or placebo. The primary endpoint was a change in automated office systolic BP from baseline to 8 weeks.
The findings were simultaneously published in JAMA.
Researchers observed mean changes in office systolic BP of –14.1 mm Hg with 100 mg lorundrostat, –13.2 mm Hg with 50 mg lorundrostat, –6.9 mm Hg with 12.5 mg lorundrostat and –4.1 mm Hg with placebo. Participants who received twice-daily doses of 25 mg and 12.5 mg lorundrostat experienced mean reductions in systolic BP of –10.1 mm Hg and –13.8 mm Hg, respectively. The least-square mean difference between placebo and lorundrostat in systolic BP was –9.6 mm Hg for the 50 mg daily dose (90% CI, –15.8 to –3.4; P = .01) and –7.8 mm Hg for the 100 mg daily dose (90% CI, –14.1 to –1.5; P = .04).
Participants without suppressed PRA saw a mean reduction in systolic BP of 11.4 mm Hg with the 100 mg once-daily dose, which Laffin noted was similar to the BP reduction seen among participants with suppressed PRA who received the same dose.
“The second cohort was an exploratory cohort,” Laffin said during an interview. “We said, ‘This drug is probably effective not just in those with suppressed plasma renin, so what is like in people who do not have suppressed plasma renin?’ And it was essentially the same.”
Greater effects in people with obesity
In a prespecified subgroup that included people with obesity, the researchers observed a greater BP lowering in response to lorundrostat. Those with a BMI of 30 kg/m2 or greater randomly assigned 50 mg lorundrostat once daily had a mean –16.7 mm Hg change in systolic BP compared with placebo (90% CI, –25.5 to –7.9), whereas those with a BMI of 30 kg/m2 or greater assigned a 100 mg once-daily dose had a –12.3 mm Hg change in systolic BP (90% CI, –21.6 to –3.1) compared with placebo. BP changes were attenuated among those not taking a diuretic.
“That was a very significant reduction in the 100 mg and 50 mg once-daily doses, and that speaks to this idea that there is dysregulation of aldosterone among people with obesity,” Laffin said. “Can we think about these people as being in a large ‘bucket’ and can we more directly target that underlying mechanism, allowing for a more effective therapy with fewer side effects than spironolactone or eplerenone, for example?”
Six participants experienced an increase in serum potassium above 6 mmol/L that resolved with dose reduction or drug discontinuation. Laffin said there were no instances of cortisol insufficiency, which initially was a concern with the therapy.
“This showed that at the highest doses of lorundrostat, there was safety and efficacy, so significant BP lowering of almost 10 mm Hg compared with placebo,” Laffin told Healio.
Researchers are now enrolling for the ADVANCE-HTN trial, a second phase 2 trial that will assess the 50 mg dose of lorundrostat along with standard background therapy compared with placebo. A larger phase 3 study as well as a study assessing the drug in people with chronic kidney disease are also in the planning stages, Laffin said.
Reference:
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Laffin LJ, et al. Abstract 113. Presented at: American Heart Association Hypertension Scientific Sessions; Sept. 7-10, 2023; Boston.
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