Thursday, 21 Sep 2023

New Dawn for Aldosterone as 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 controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic blood pressure significantly more than placebo (−9.6 mm Hg with 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,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at Cleveland Clinic, Cleveland, Ohio, told | Medscape Cardiology. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

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

Aldosterone’s Contribution “Vastly Underappreciated”

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

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, told | Medscape Cardiology.

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

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age 66; 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/dL) and a second cohort of 37 adults with PRA > 1.0 ng/mL/h.

Participants were randomly assigned to 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 placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic blood pressure from baseline to week 8.

Among participants with suppressed PRA, following 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 once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic blood pressure in individuals 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 PRA, lorundrostat 100 mg once daily decreased systolic blood pressure by 11.4 mm Hg, similar to blood pressure reduction in those with suppressed PRA receiving the same dose.

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

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Laffin told | Medscape Cardiology. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

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

“New Dawn” for Therapies Targeting Aldosterone

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

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

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

Nissen reported receipt of 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 being the unremunerated chair of the steering committee 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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