‘New Dawn’ for Aldosterone as a Drug Target in Hypertension?

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2 randomized clinical trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the drug reduced automated office sitting systolic blood pressure significantly more than placebo (9.6 mm Hg at 50 mg; 7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” said study investigator Steven Nissen, MD, academic director of the Heart Vascular & Thoracic Institute at Cleveland Clinic, Cleveland, Ohio. theheart.org | Medscape Cardiology. Lorundrostat represents a “new class” of antihypertensives that “appear to be safe and we are seeing very large reductions in blood pressure.”

Results from the Target-HTN study were published online September 10 in Journal of the American Medical Association to coincide with the presentation at the American Heart Association (AHA) 2023 Hypertension Scientific Sessions.

The contribution of aldosterone is “very underestimated”

Excess aldosterone production contributes to uncontrolled blood pressure in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.

“The contribution of aldosterone to uncontrolled hypertension is greatly underestimated,” said first author and study presenter Luke Laffin, MD, also of the Cleveland Clinic. theheart.org | Medscape Cardiology.

Aldosterone synthase inhibitors are a new class of blood pressure-lowering medications that decrease aldosterone production. Lorundrostat is one of two agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The randomized, placebo-controlled, dose-ranging Target-HTN trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese, and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity (PRA) at baseline (PRA 1.0 ng/mL/h) and elevated plasma aldosterone (1.0 ng/mL/h) dL) and a second cohort of 37 adults with PRA > 1.0 ng/mL/h.

Participants were randomized to receive 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, participants were randomly assigned (1:6) to receive placebo or lorundrostat 100 mg once daily. The primary endpoint was the change in automated in-office systolic blood pressure from baseline to week 8.

Among participants with suppressed PRA, after 8 weeks of treatment, changes in office systolic blood pressure of 14.1, 13.2, and 6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg of lorundrostat once daily, respectively, compared to a change of 4.1 mm Hg with placebo.

Reductions in systolic blood pressure in subjects receiving twice daily doses of 25 mg and 12.5 mg of lorundrostat were 10.1 and 13.8 mm Hg, respectively.

Among participants without suppressed ARP, lorundrostat 100 mg once daily decreased systolic blood pressure by 11.4 mm Hg, similar to the reduction in blood pressure in those with suppressed ARP who received the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP reduction in response to lorundrostat.

There were no cases of cortisol insufficiency. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that were corrected by dose reduction or drug discontinuation.

The rise in serum potassium is “expected and manageable,” Laffin said theheart.org | Medscape Cardiology. “Whenever you stop aldosterone production, you will have to have an increase in serum potassium, but it is very manageable and not something to worry about.”

A phase 2 trial in 300 adults with uncontrolled hypertension is underway. The trial will evaluate the blood pressure-lowering effects of lorundrostat, administered in the context of a standardized antihypertensive medication regimen. A larger phase 3 study will begin before the end of the year.

“New Dawn” for aldosterone-targeted therapies

The author of an editorial in JAMA notes that more than 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for aldosterone-targeted therapies.”

“There is now real potential to provide more targeted treatment for patients in whom excess aldosterone is known to contribute to their clinical condition and influence their clinical outcome, namely those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and many with yet-to-be-diagnosed primary aldosteronism,” says Bryan Williams, MD, University College London, UK.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Laffin reported that Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, Cleveland Clinic’s academic research organization, receives payment for services related to other Mineralys clinical trials. Laffin also reported receiving personal fees from Medtronic, Lilly and Crispr Therapeutics, grants from AstraZeneca, and stock options from LucidAct Health and Gordy Health.

Nissen reported receiving grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Williams reported to be the unpaid chairman of the steering committee that is designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

JAMA. Published online September 10, 2023. Full text, Editorial

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