Phase IIb study supports lorundrostat for treatment-resistant hypertension

The phase IIb Advance-HTN trial shows the blood pressure (BP)-lowering effect of lorundrostat in patients with uncontrolled and treatment-resistant hypertension (HTN).

“Lorundrostat was associated with greater reductions in 24-hour average BP than placebo in [these patients],” said the researchers.

The least-squares mean changes in 24-hour average systolic BP (SBP) were -15.4 and -13.9 mm Hg in the respective stable-dose and dose-adjustment arms, whereas with placebo, the corresponding change was -7.4 mm Hg. The placebo-adjusted changes in BP were -7.9 mm Hg (p=0.001) in the stable-dose arm and -6.5 mm Hg (p=0.006) in the dose-adjustment arm.

Participants in the stable-dose arm received lorundrostat 50 mg daily. Those in the dose-adjustment arm received lorundrostat 50 mg daily as a starting dose, which was increased to 100 mg daily if the SBP was ≥130 mm Hg after 4 weeks. [N Engl J Med 2025;392:1813-1823]

According to the investigators, these effects underpin the hypothesis that aldosterone plays a vital role in the pathogenesis of HTN. [N Engl J Med 2023;388:464-467] “In patients with uncontrolled, treatment-resistant HTN, aldosterone dysregulation is increasingly recognized as a driver of persistent BP elevation. Aldosterone promotes sodium retention, volume expansion, and vascular remodeling, all of which contribute to sustained HTN and end-organ damage.”

Lorundrostat is a highly selective aldosterone synthase inhibitor that may be an effective treatment by directly targeting aldosterone biosynthesis, they said. By inhibiting aldosterone production while sparing other adrenal steroid pathways, lorundrostat may offer better efficacy and have fewer adverse events (AEs) than current therapeutic approaches targeting aldosterone, which may be limited by their off-target effects, compensatory increases in serum aldosterone levels, and patient acceptability issues. [J Endocrinol 2017;234:T125-T140]

Other endpoints

Week 4 saw a placebo-adjusted change in 24-hour average SBP of -5.3 mm Hg (p<0.001) among those receiving lorundrostat, and more lorundrostat vs placebo recipients with SBP <125 mm Hg (41 percent vs 18 percent; odds ratio, 3.3; p<0.001).

Among patients on lorundrostat 100 mg daily after week 4, the mean change in office SBP at week 12 was -17.5 mm Hg (p<0.001).

Safety-wise, the death due to arteriosclerosis in the dose-adjustment arm was deemed unrelated to the drug. Of the 16 participants who experienced serious AEs, three had drug-related events.

“The safety profile of lorundrostat appeared acceptable, with AEs consistent with the known effects of targeting the renin-angiotensin-aldosterone system – an increased risk of hyperkalaemia and hyponatremia and decreases in the eGFR,” the investigators said.

Important study characteristics

Eligible participants stopped their antihypertensive drugs and started a standardized regimen. Those on two antihypertensives at enrolment were assigned to olmesartan 40 mg QD with indapamide 2.5 mg or hydrochlorothiazide 25 mg. For those on 3–5 antihypertensives, amlodipine 10 mg daily was incorporated into the standard regimen. Lower doses of olmesartan (20 mg), amlodipine (5 mg), or both, were allowed at the local investigators’ discretion.

After 3 weeks of the standardized regimen with a concurrent single-blind run-in period (all participants were also given placebo), ambulatory BP monitoring (ABPM) over 24 hours was performed.

Participants (n=285; mean age 60 years, 60 percent men) whose BP remained uncontrolled (defined as 24-hour average SBP of 130–180 mm Hg or 24-hour average diastolic BP of >80 mm Hg) were then randomized 1:1:1 to the stable-dose, dose-adjustment, or placebo arms. ABPM was done at weeks 4 and 12.

According to the researchers, the standardized regimen and ABPM are two important attributes of the trial. “Inadequate medication doses and the ‘white coat effect’  may result in HTN being falsely classified as treatment-resistant. With a standardized regimen and ABPM, a large percentage of screened participants were ineligible for randomization because BP control had been achieved.”

Despite the lack of direct comparison between lorundrostat and alternative antihypertensives and the short study duration, the ongoing open-label extension trial is anticipated to shed light on lorundrostat’s longer-term effect in this population.