Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension
Authors: Laffin Luke J. , Rodman David , Luther James M. , Vaidya Anand , Weir Matthew R. , Rajicic Natasa , Slingsby B. T. , Nissen Steven E. ,   Target-HTN Investigators, Beasley Richard , Budoff Matthew , Carr George , Carroll Michael , Cevallos Yepez Jose , Chhabra Anil , Cole Frank , Dunn Leonard , Eaves William , Ebuh Valentine , Estevez Roger , Gould Glenn , Hong Matthew , Iteld Bruce , Jain Mahendra , Kemp Charles , Kennelly Christina , Kleiner Mark , Kutner Mark , Laffin Luke , Lambert Joseph , Ledesma Gilbert , Lee Keung , Lentz John , Lupovitch Steven , Luther  James , Lynn Lon , Marquez Obadias , Mazhar Mobeen , Morin David , Neutel Joel , Oppong Yaa , Osorio Merlin , Patron Andres , Pharr Walter , Ponce de Leon Mercedes , Rodriguez-Ables Lilia , Rosen Jeffrey , Sachmechi Issac , Surowitz Ronald , Wadsworth Larkin , Wayne Jeffrey , Zafar Zahid 
Published: September 2023

Importance

Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.

Objective

To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials.

Design, Setting, and Participants

Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h.

Interventions

Participants were randomized to placebo or 1 of 5 dosages 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 randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.

Main Outcomes and Measures

The primary end point was change in automated office systolic blood pressure from baseline to study week 8.

Results

Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of −14.1, −13.2, −6.9, and −4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed 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. The least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mm Hg (90% CI, −15.8 to −3.4 mm Hg; P = .01) for the 50-mg once-daily dose and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred.

Conclusions and Relevance

Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.

Trial Registration

ClinicalTrials.gov Identifier: NCT05001945