Phase II Advance-HTN Trial Shows Lorundrostat Significantly Lowers Blood Pressure in Treatment-Resistant Hypertension
Lorundrostat, a selective aldosterone synthase inhibitor, significantly reduced systolic blood pressure in patients with uncontrolled and treatment-resistant hypertension in the Phase II Advance-HTN trial, indicating its potential as a safer, more effective alternative to current therapies.
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Findings from the 12-week Phase II Advance-HTN trial (NCT05769608) show that lorundrostat significantly lowered systolic blood pressure (SBP) in patients with uncontrolled and treatment-resistant hypertension. These results, published by The New England Journal of Medicine, support the approach of targeting aldosterone production and avoiding other adrenal steroid pathways, which may improve efficacy with a more favorable safety profile compared to current approved treatments for this patient population.1,2
“Uncontrolled hypertension remains a leading cause of cardiovascular complications and death from cardiovascular disease,” the study authors wrote. “Despite the use of multidrug regimens, reaching recommended blood-pressure targets remains elusive for many patients. Among patients with uncontrolled, treatment-resistant hypertension, aldosterone dysregulation is increasingly recognized as a driver of persistent blood-pressure elevation.”1
Lorundrostat is a highly selective aldosterone synthase inhibitor that investigators hypothesize may be effective in lowering blood pressure by directly targeting aldosterone biosynthesis with fewer adverse events than mineralocorticoid receptor antagonists. Findings from the randomized, placebo-controlled, dose-ranging Target-HTN trial (NCT05001945) published by the Journal of the American Medical Association found that lorundrostat safely and effectively lowered blood pressure in patients with hypertension who are refractory to standard treatments.3,4
Trial Design
The multicenter, double-blind, randomized, placebo-controlled Advance-HTN trial enrolled 285 patients currently on a regimen of two to five antihypertensive medications with a blood-pressure measurement of 140/90 mm Hg or higher. Patients had a mean age of 60 years and 53% were Black.
Patients with an average 24-hour ambulatory blood pressure of 130/80 mm Hg or higher were assigned to either the placebo cohort (n = 95), lorundrostat at a stable dose of 50 mg daily (n = 94), or a dose adjustment cohort with lorundrostat administered at a starting dose of 50 mg daily and increased to 100 mg daily if SBP was 130 mm Hg or higher after four weeks (n = 96).
The trial’s primary endpoint was change in 24-hour average SBP from baseline to week 12, determined by least-squares mean difference from placebo in each lorundrostat dosing cohort. Secondary endpoints included change in 24-hour average SBP from baseline to week four, as determined by placebo-adjusted change in the combined lorundrostat dosing cohorts.
At the end of the 12-week period, the least-squares mean change in 24-hour average SBP was −15.4 mm Hg in the stable-dose cohort, −13.9 mm Hg in the dose-adjustment cohort, and −7.4 mm Hg in the placebo cohort.
Placebo-adjusted change in blood pressure was −7.9 mm Hg (97.5% confidence interval [CI], −13.3 to −2.6) in the stable-dose cohort and −6.5 mm Hg (97.5% CI, −11.8 to −1.2) in the dose-adjustment cohort. Placebo-adjusted change in 24-hour average SBP from baseline to week four across the lorundrostat dosing cohorts was −5.3 mm Hg (95% CI, −8.4 to −2.3). In terms of safety, serious adverse events considered to be related to lorundrostat occurred in three participants, with two in the stable-dose cohort and one in the dose-adjustment cohort.
“Aldosterone synthase inhibition may address the aldosterone breakthrough that occurs with long-term use of angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers and is a risk factor for the progression of renal and cardiovascular diseases,” the study authors wrote. “Aldosterone synthase inhibitors thus hold promise for the treatment of heart failure and chronic kidney disease. Trials of another aldosterone synthase inhibitor, vicadrostat, in which cardiovascular and kidney outcomes are being evaluated are ongoing.”1
References
1. Laffin L., et al. Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension. N Engl J Med 2025; doi/full/10.1056/NEJMoa2501440.
2. A Pivotal Study to Evaluate the Efficacy of Lorundrostat in Subjects with Uncontrolled Hypertension on a Standardized Antihypertensive Medication Regimen. ClinicalTrials.gov. Updated February 18, 2025. Accessed April 24, 2025. https://clinicaltrials.gov/study/NCT05769608
3. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. JAMA. 2023;330(12):1140–1150. doi:10.1001/jama.2023.16029
4. Trial on the Safety and Efficacy of MLS-101 in Patients With Uncontrolled Hypertension (Target-HTN). ClinicalTrials.gov. January 5, 2024. https://clinicaltrials.gov/study/NCT05001945
