The novel aldosterone inhibitor works, but longer-term safety data are needed before the drug might be approved.
Lorundrostat (Mineralys Therapeutics), a novel aldosterone synthase inhibitor, can substantially lower blood pressure in patients with uncontrolled and treatment-resistant hypertension, according to new findings from the phase IIb Advance-HTN trial.
After 12 weeks of treatment with lorundrostat 50 mg daily, the average 24-hour ambulatory systolic blood pressure was reduced from baseline (primary endpoint) by a mean of 15.4 mg Hg. All patients were already receiving two to five antihypertensive medications yet still displayed an office BP measurement of 130/90 mm Hg after undergoing a 3-week run-in regimen of two or three standardized antihypertensives.
Previous research with this medication has shown good efficacy, especially among patients with obesity. It joins a cadre of drugs under development for resistant hypertension, including another aldosterone synthase inhibitor, baxdrostat (CinCor Pharma)—which failed to show a benefit over placebo in the phase II HALO trial but did do so previously in BrigHTN—and aprocitentan (Tryvio; Idorsia Pharmaceuticals), an endothelin receptor antagonist that was approved by the US Food and Drug Administration last year for uncontrolled hypertension.
These new data show that lorundrostat compares favorably with other aldosterone synthase inhibitors in the pipeline, lead author Luke Laffin, MD (Cleveland Clinic Foundation, OH), told TCTMD.
“It’s clearly the furthest along,” he said, adding that it gets at the root cause of hypertension for most patients. “It’s a little bit different than the siRNAs against angiotensinogen, for example, or renal denervation, which address a different reason for blood pressure elevation. I think that there’s probably a role for this amongst patients with resistant hypertension.”
If physicians can be certain that aldosterone is driving the increase in blood pressure, lorundrostat could be used earlier, possibly as third-line drug agent, said Laffin.
“The positive news from this sort of trial is that it’s another option for treating patients,” Morris Brown, MD (Queen Mary University of London, England), the senior investigator for BrigHTN, told TCTMD. “There are a bunch of side effects [with currently available hypertension medications], especially with spironolactone, and if phase III programs and beyond tell us that these drugs are better tolerated,” they might win out over other options, he said. “But that’s still to be determined.”
A unique facet of Advance-HTN is that its design directed patients through a 3-week run-in phase of a standardized hypertension regimen, according to Eugenia Gianos, MD (Northwell Health, New York, NY), who serves as chair for the American College of Cardiology’s Council for Cardiovascular Disease Prevention.
“This allows for a more homogenous population to test the drug in,” she told TCTMD. “The efficacy is similar to other available agents, but with a unique mechanism, allowing it to be used as an add-on agent for resistant hypertension, which can be challenging to treat.”
Advance-HTN Findings
In Advance-HTN, which was published online last week in the New England Journal of Medicine and previously presented at the 2025 American College of Cardiology Scientific Session, Laffin and colleagues randomized 285 patients with uncontrolled hypertension (mean age 60 years; 60% male; 53% Black) to receive a stable 50 mg daily dose of lorundrostat (n = 94), a dose-adjusted regimen of lorundrostat that started at 50 mg daily and increased to 100 mg daily at 4 weeks if the systolic BP remained 130 mg Hg or higher (n = 96), or placebo (n = 95). Notably, the researchers screened 2,617 participants and gave the standardized 3-week treatment regimen to 936 of them during the trial’s run-in period, which took place between March 2023 and October 2024.
Twelve weeks after randomization, the least-squares mean change in 24-hour average systolic BP in the stable-dose, dose-adjusted, and placebo groups was -15.4 mm Hg, -13.9 mm Hg, and -7.4 mm Hg, respectively. The placebo-adjusted change in BP was -7.9 mm Hg for those in the stable-dose group and -6.5 mm Hg for those in the dose-adjustment group, of whom 20% had their dose adjusted after 4 weeks.
When the lorundrostat groups were combined, the placebo-adjusted change in 24-hour average systolic BP from baseline through 4 weeks was -5.3 mm Hg. More of the patients taking lorundrostat than those taking placebo had a systolic BP below 125 mm Hg at 4 weeks (41% vs 18%; OR 3.3; 95% CI 1.4-7.8). There was no difference in the effect of the drug across the body mass index spectrum.
Sixteen patients experienced serious adverse events, with three deemed related to the trial drug. Five patients from the stable-dose group (5%) and seven from the dose-adjustment group (7%) had potassium levels above 6.0 mmol/L. Adverse events were consistent with the effects of targeting the renin–angiotensin–aldosterone system, such as an increased risk of hyperkalemia and hyponatremia and decreases in eGFR, say researchers.
Laffin pointed out the strengths of the study, including its run-in period as well as the use of the “gold standard” 24-hour ambulatory BP monitoring instead of office-based BP measurements. The study also included a high proportion of Black patients, a population that has a high prevalence of primary aldosteronism, noted Brown.
“They’re a group who would stand to benefit a lot from this drug,” he said.
Next: Safety
The drug’s manufacturer has already announced positive topline results for its phase III Launch-HTN trial of lorundrostat, but the full dataset is still forthcoming.
“All the trials are remarkably consistent in terms of blood pressure lowering that they show efficacy, so there’s not a lot of open questions necessarily about this drug,” Laffin said, adding that future avenues of investigation include the potential effects on heart failure or kidney disease. With longer-term safety data, he’s hopeful the drug could be submitted for regulatory approval.
“Longer trials will allow for continued safety evaluation, although the increased risk of hyperkalemia can be managed by early assessment as is currently done with mineralocorticoids,” Gianos added.
Brown agreed. “It’s all down now to phase III [data] to tell us about tolerability of the drug,” he said, adding that he’d like to see multiple drugs in this class approved for use. “It’s just generally good to have more than one new drug, they sort of nudge each other along [and it] increases the amount of noise and helps get physicians used to it being a new drug class.”