Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension
Author:
Laffin Luke J.12, Rodman David3, Luther James M.4, Vaidya Anand5, Weir Matthew R.6, Rajicic Natasa7, Slingsby B. T.3, Nissen Steven E.12, Beasley Richard8, Budoff Matthew8, Carr George8, Carroll Michael8, Cevallos Yepez Jose8, Chhabra Anil8, Cole Frank8, Dunn Leonard8, Eaves William8, Ebuh Valentine8, Estevez Roger8, Gould Glenn8, Hong Matthew8, Iteld Bruce8, Jain Mahendra8, Kemp Charles8, Kennelly Christina8, Kleiner Mark8, Kutner Mark8, Laffin Luke8, Lambert Joseph8, Ledesma Gilbert8, Lee Keung8, Lentz John8, Lupovitch Steven8, Luther James8, Lynn Lon8, Marquez Obadias8, Mazhar Mobeen8, Morin David8, Neutel Joel8, Oppong Yaa8, Osorio Merlin8, Patron Andres8, Pharr Walter8, Ponce de Leon Mercedes8, Rodriguez-Ables Lilia8, Rosen Jeffrey8, Sachmechi Issac8, Surowitz Ronald8, Wadsworth Larkin8, Wayne Jeffrey8, Zafar Zahid8,
Affiliation:
1. Cleveland Clinic Foundation, Cleveland, Ohio 2. C5 Research, Cleveland Clinic Foundation, Cleveland, Ohio 3. Mineralys Therapeutics, Radnor, Pennsylvania 4. Vanderbilt University Medical Center, Nashville, Tennessee 5. Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 6. University of Maryland School of Medicine, Baltimore 7. Cytel, Cambridge, Massachusetts 8. for the Target-HTN Investigators
Abstract
ImportanceExcess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.ObjectiveTo 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 ParticipantsRandomized, 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.InterventionsParticipants 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 MeasuresThe primary end point was change in automated office systolic blood pressure from baseline to study week 8.ResultsBetween 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 RelevanceAmong individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.Trial RegistrationClinicalTrials.gov Identifier: NCT05001945
Publisher
American Medical Association (AMA)
Cited by
13 articles.
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