Lorundrostat for uncontrolled hypertension hits efficacy, safety targets in phase III trial

Twelve weeks of treatment with the aldosterone synthase inhibitor lorundrostat proved efficacious and safe for lowering blood pressure (BP) in adults with uncontrolled hypertension, including those who were resistant to treatment, according to the phase III Launch-HTN trial.

The primary endpoint of office systolic BP at week 6 decreased with a significantly greater magnitude for participants in the pooled 50-mg lorundrostat group than for those in the placebo group (mean change, –16.9 vs −7.9 mm Hg; mean difference, −9.1 mm Hg, 95 percent confidence interval [CI], −13.3 to −4.9; p<0.001). [JAMA 2025;doi:10.1001/jama.2025.9413]

Participants in the pooled 50-mg lorundrostat group had threefold greater odds of achieving an office systolic BP of <130 mm Hg at week 6 compared with those in the placebo group (44.1 percent vs 24.1 percent; odds ratio, 3.4, 95 percent CI, 1.5–7.8; p=0.003).

Furthermore, the reduction in office systolic BP at week 6 was consistently higher in the pooled 50-mg lorundrostat group vs the placebo group among participants taking at least three background antihypertensive medications (mean difference, −9.0 mm Hg, 97.5 percent CI, −14.0 to −4.1; p<0.001). Similar results were seen across all BMI ranges in the trial, with 91.6 percent of the participants having a BMI of at least 25 kg/m².

For the subset of participants who received lorundrostat at 50 for the first 6 weeks and were then escalated to 100 mg for another 6 weeks, office systolic BP dropped by a mean of 10.2 mm Hg (97.5 percent CI, −14.3 to −6.1; p<0.001) more compared with those who received placebo.

In terms of safety, treatment-emergent adverse events (AEs) occurred in around half of the overall population, with most being mild or moderate in severity. Serious AEs occurred in 22 participants, including one that was considered to be related to treatment. One participant in the placebo group died after week 6 (unrelated to treatment).

AEs of special interest, such as hyponatremia, hyperkalemia, and reduction in kidney function occurred more frequently with lorundrostat vs placebo. In the group of participants who received 50 mg lorundrostat for 12 weeks, treatment discontinuation occurred in two participants (0.37 percent) due to hyperkalemia, in two (0.37 percent) due to hyponatremia, and in three (0.56 percent) due to reduction in kidney function.

In the group of those who received 50 mg lorundrostat for 6 weeks with possible escalation to 100 mg in the next 6 weeks, two participants discontinued treatment due to hyperkalemia (0.37 percent) and hyponatremia (0.37 percent), respectively. In the group of placebo-treated participants, there were no treatment discontinuations due to special interest AEs.

“The current trial is the third clinical trial of lorundrostat in participants with uncontrolled hypertension, [with the other two being the phases II and III Target-HTN and Advance-HTN trials, respectively.] The degree and trajectory of BP reduction, the similar tolerability and safety profiles, and the use of a maximally effective dose of lorundrostat (50 mg/d) were observed across the three trials,” according to the investigators. [JAMA. 2023;330(12):1140-1150; N Engl J Med. 2025;392(18):1813-1823]

“In the Advance-HTN trial and in the current Launch-HTN trial, the reduction in BP at week 12 was maintained. The changes in office BP measurements in the current trial were expectedly greater than those observed with 24-hour ambulatory BP measurements in the Advance-HTN trial. Participants in the Advance-HTN trial were placed on a standardized antihypertensive regimen that included a high-dose angiotensin receptor blocker prior to randomization; greater increases in serum potassium level and decreases in eGFR were observed compared with those in the current trial,” they said.

The investigators also emphasized that they minimized the variable nature of office BP measurement in Launch-HTN by (1) obtaining measurements prior to the intake of morning medications, (2) using unattended BP measurements to limit the white-coat effect, and (3) using the mean of repeated BP measurements to reduce intraindividual variability.

Conducted at 159 clinic sites across 13 countries, Launch-HTN included 1,083 adult participants (mean age 61.6 years, 46.9 percent female, 67.7 percent White, 63.3 percent had obesity). These patients were randomly assigned to receive 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d for another 6 weeks (n=270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n=541), or daily placebo for 12 weeks (n=272).

The prespecified criteria for lorundrostat dose escalation included systolic BP of at least 130 mm Hg, potassium level of not more than 4.8 mmol/L, sodium level of at least 135 mmol/L, eGFR of greater than 45 mL/min/1.73 m², and less than a 25-percent reduction in eGFR. A total of 92 participants met these criteria and received lorundrostat at 100 mg per day from weeks 7 to 12.

At baseline, 432 participants overall (39.9 percent) were taking two prescribed antihypertensive medications, and 651 (60.1 percent) were taking three or more.