Lorundrostat Shows Continued Promise Against Uncontrolled Hypertension

An investigational drug that inhibits aldosterone production significantly lowered 24-hour blood pressure (BP) among patients with uncontrolled and resistant hypertension that remained out of control despite expert treatment. So conclude investigators with the phase 2b Advance-HTN study of lorundrostat, whose results were reported in a late-breaking clinical trials presentation at the American College of Cardiology’s 2025 Scientific Session.

“This pivotal confirmatory study found that lorundrostat lowered 24-hour average systolic blood pressure by about 8 mm Hg beyond levels obtained with placebo,” says Cleveland Clinic cardiologist Luke Laffin, MD, who presented findings from the multicenter study. “This result was achieved in expertly treated patients who were taking an optimal standardized antihypertensive regimen. In other words, they were patients with uncontrolled and truly treatment-resistant hypertension.”

Advance-HTN also demonstrated lorundrostat to be safe, with low rates of hyperkalemia and hyponatremia. And it showed that a strategy of dose escalation from 50 to 100 mg did not achieve greater BP control than 50 mg but was associated with more adverse events.

“Additionally, this study’s use of 24-hour ambulatory blood pressure monitoring strengthens findings from previous studies of lorundrostat that used office-based monitoring, as ambulatory monitoring is a better predictor of future cardiovascular and kidney risk,” Dr. Laffin notes. “New therapies for hypertension, and particularly resistant hypertension, are needed, so these results are encouraging.”

A new mechanism for hypertension treatment

Lorundrostat is the first in a novel class of agents known as aldosterone synthase inhibitors. Elevated levels of aldosterone, a mineralocorticoid hormone, have been implicated in hypertension pathogenesis by promoting retention of sodium and water and thereby increasing blood volume.

When a standard three-drug antihypertensive regimen (thiazide diuretic, calcium channel blocker and ACE inhibitor/angiotensin receptor blocker) does not sufficiently lower BP, a mineralocorticoid receptor antagonist, most commonly spironolactone, can be added. While spironolactone reduces BP by binding to intracellular aldosterone receptors, its clinical utility is often constrained by adverse effects. Moreover, mineralocorticoid receptor antagonists can paradoxically increase circulating aldosterone, potentially exacerbating nongenomic aldosterone effects including sympathetic hyperactivation, glucose homeostasis disruption and vascular dysfunction.

Aldosterone synthase inhibitors represent a new pharmacologic approach. Rather than blocking the mineralocorticoid receptor, they block aldosterone production. Unlike earlier compounds in this class (such as osilodrostat, which affected cortisol production), lorundrostat offers more targeted inhibition. Its mechanism resembles that of baxdrostat, another aldosterone synthase inhibitor that has also shown promise in early clinical investigations.

A careful study design to ensure resistant hypertension

Advance-HTN builds on positive results from Target-HTN, a phase 2 dose-finding study also led by Dr. Laffin. The new investigation included adults on two to five antihypertensive medications with serum sodium level ≥ 135 mmol/L, serum potassium ≤ 5.0 mmol/L and estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m².

After initial screening to confirm that enrollees had an office systolic BP of 140 to 180 mm Hg or an office diastolic BP of 90 to 110 mm Hg, qualifying patients entered a three-week single-blind run-in phase during which they were switched to a standardized antihypertensive regimen of indapamide 2.5 mg daily (or hydrochlorothiazide 25 mg daily), olmesartan 40 mg daily and amlodipine 10 mg daily.

“Indapamide is a more potent diuretic than hydrochlorothiazide, which is used in most other studies, so we feel our study’s use of indapamide in most patients is a strength that reflects optimal therapy for resistant hypertension,” Dr. Laffin notes.

After the three-week run-in, patients were assessed with 24-hour ambulatory BP monitoring, and only those with a systolic BP of 130 to 180 mm Hg or a diastolic BP of 80 mm Hg or higher continued into the study’s 12-week double-blind randomized phase. These patients were assigned to receive one of the following (in addition to the background standardized antihypertensive regimen):

• Placebo (n = 94)
• Lorundrostat 50 mg daily (n = 94)
• Lorundrostat 50 mg daily with titration to 100 mg daily at four weeks if systolic BP remained uncontrolled and patients still met specific criteria for sodium, potassium and eGFR (n = 94)

The randomized study population had a mean age of 60 years and was 40% female and 53% Black. The mean body mass index was 32 kg/m².

Key findings

The study’s primary endpoint was the change in systolic BP from baseline to week 12. On this measure, the reduction in the placebo group (7.4 mm Hg) was significantly exceeded in both the lorundrostat 50 mg group (15.4 mm Hg; P = .001 vs. placebo) and the lorundrostat 50 to 100 mg group (13.9 mm Hg; P = .006 vs. placebo).

Results on key secondary endpoints included the following:

• At four weeks, the reduction in 24-hour average systolic BP was significantly greater in the combined lorundrostat groups than in the placebo group (11.5 mm Hg vs. 6.2 mm Hg; P <.001). “This shows that the relative reduction with lorundrostat is achieved fairly quickly but that the drug generally doesn’t achieve maximum efficacy at four weeks,” Dr. Laffin comments.
• At four weeks, the proportion of patients with 24-hour average systolic BP below 125 mm Hg was 42% in the combined lorundrostat groups versus 18% in the placebo group (odds ratio = 3.3 [95% CI, 1.7-6.5]; P < .001).

No relationship between body mass index and BP reduction was observed.

Safety analysis showed lorundrostat to be generally well tolerated, with any trends toward adverse events being highly consistent with those of other drugs that impact the renin-angiotensin-aldosterone system. Hyperkalemia and hyponatremia occurred in 5% and 9%, respectively, of patients in the lorundrostat 50 mg group versus 0% and 6%, respectively, of placebo recipients.

Rates of adverse events were numerically higher among patients in the lorundrostat 50 to 100 mg group than in the lorundrostat 50 mg group. “Given this slightly higher rate of adverse events with the titration strategy without any accompanying blood pressure improvement, there does not appear to be a benefit from dose titration with lorundrostat,” Dr. Laffin observes.

Promising potential for a new drug class

Dr. Laffin says Advance-HTN is notable because it included a large proportion of Black patients (53%) and lorundrostat’s efficacy was similar in the study’s Black and non-Black participants. “Black individuals have a higher burden of resistant hypertension and of cardiovascular morbidity and mortality from uncontrolled hypertension,” he explains. “It’s important that clinical trials test new therapies in high-risk populations who stand to benefit most, and this study has done that.”

Results from the phase 3 Launch-HTN study of lorundrostat are expected to be formally presented later this year. If they are consistent with those of Advance-HTN, the drug should have adequate efficacy results for a regulatory filing in the U.S. Long-term safety follow-up is continuing via open-label extensions of both studies.

Lorundrostat is the furthest along of three aldosterone synthase inhibitors that are currently in clinical development. “There is great potential for these drugs that target aldosterone production,” Dr. Laffin says. “Not only do they reduce blood pressure, but they also theoretically reduce overall cardiovascular risk because we know that excess aldosterone causes a variety of adverse vascular effects.”

“This is a very promising new approach to treating uncontrolled hypertension,” adds Steven Nissen, MD, senior author of Advance-HTN and Chief Academic Officer of Cleveland Clinic’s Heart, Vascular and Thoracic Institute. “Many patients cannot achieve target blood pressure levels despite use of multiple drugs, or they do not tolerate existing treatments. If approved, lorundrostat will provide an additional therapeutic option to enable physicians to bring more of these patients under control and help avoid the serious complications of uncontrolled hypertension.”

For more from Dr. Laffin on the Advance-HTN trial and its implications, listen to the below episode of Cleveland Clinic's Cardiac Consult podcast.