September 11, 2023

Lorundrostat Safely Lowers Blood Pressure in Uncontrolled Hypertension in Phase 2 Trial

Results inform dose selection for further trials of the aldosterone synthase inhibitor

Middle-aged overweight Hispanic woman having her blood pressure checked

Lorundrostat (MLS-101) ― an investigational medication that works by lowering aldosterone production ― safely and effectively lowered blood pressure (BP) in patients with hypertension refractory to standard medical treatment. So reported investigators with the placebo-controlled Target-HTN phase 2 clinical trial in a late-breaking clinical trials session at the American Heart Association Hypertension Scientific Sessions 2023. The study was simultaneously published in the Journal of the American Medical Association.

Advertisement

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

“We saw a very robust blood pressure lowering response, particularly in study participants with obesity, a major driver of hypertension in this country,” says first author and study presenter Luke Laffin, MD, staff cardiologist in Cleveland Clinic’s Section of Preventive Cardiology. “Lorundrostat has the potential to become an important new tool to help this hard-to-treat population and others with uncontrolled hypertension.”

Possible new way to treat hypertension

Excess aldosterone has been implicated in contributing to hypertension in patients with obesity, metabolic syndrome and obstructive sleep apnea. In such individuals, the normal feedback loop of elevated aldosterone leading to increased renin activity ― which inhibits further aldosterone synthesis ― is disrupted.

If the standard three-drug regimen for treating hypertension (a thiazide diuretic, a calcium channel blocker, and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) does not adequately control BP, a mineralocorticoid receptor antagonist (MRA), typically spironolactone, is added. While spironolactone binds intracellular aldosterone receptors, leading to BP lowering, its use is limited by side effects. In addition, circulating aldosterone levels may actually increase as a result of receptor blocking, enhancing nongenomic effects of aldosterone and leading to excess sympathetic activation, disrupted glucose homeostasis and negative vascular effects.

Lorundrostat is in a novel class of drugs that lower aldosterone by inhibiting aldosterone synthase rather than blocking mineralocorticoid receptors. The orally administered medication has the potential to lower BP without the adverse effects of an MRA. The first aldosterone synthase inhibitor, osilodrostat, interfered with cortisol production. Baxdrostat, a more specific drug similar to lorundrostat, has performed well in a phase 2 clinical trial.

The current Target-HTN trial (NCT05001945) was designed to test lorundrostat’s safety and efficacy, especially among patients with suppressed renin activity, and to help determine dosages for future trials.

“The development of lorundrostat is important because no new class of blood pressure-lowering drugs has been introduced for many years,” says the study’s senior author, Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute. “Blood pressure is difficult to control in some patients, particularly those with obesity and diabetes, so new options will be valuable.”

Advertisement

A dose-ranging study design with two target groups

The prospective, randomized, double-blind Target-HTN study was conducted at 43 U.S. sites, including Cleveland Clinic. The Cleveland Clinic Coordinating Center for Clinical Research (C5Research) independently confirmed the primary endpoint analysis.

To qualify for participation, patients had to have a minimum systolic BP of 130 mmHg despite taking at least two antihypertensive medications. The study’s 200 patients were enrolled into two cohorts, with the initial cohort (cohort 1) consisting of patients with suppressed plasma renin activity (≤ 1.0 ng/mL/h) and elevated serum aldosterone (> 1.0 ng/dL) and a subsequent smaller cohort (cohort 2) consisting of patients without suppressed plasma renin activity (> 1.0 ng/mL/h). The cohorts were treated as follows:

  • Cohort 1 (n = 163; mean baseline BP of 142.2/81.5 mmHg): Participants were randomized in equal numbers to placebo or one of five lorundrostat doses (12.5 mg, 50 mg or 100 mg once daily or 12.5 mg or 25 mg twice daily) for eight weeks.
  • Cohort 2 (n = 37; mean baseline BP of 139.1/79.1 mmHg):In a 1:6 ratio, patients were randomized to placebo or 100 mg lorundrostat once daily for eight weeks. This small cohort was considered exploratory to see if patients without suppressed plasma renin activity might also respond to the drug; no formal statistical analysis was performed.

Patients continued their existing background antihypertensive medications during study treatment. Mean age of the overall study population was 65.7 years, 60% were women, 48% were Hispanic and 36% were Black.

Nearly half of participants (48%) had a body mass index of more than 30 kg/m2 and 40% had type 2 diabetes.

All participants underwent a two-week placebo run-in period. After randomization, they were monitored with automated office BP measurements weekly throughout the study. The primary efficacy endpoint was change in systolic BP from baseline to week 8.

Results

Key efficacy findings were as follows:

Advertisement
  • In cohort 1, observed reductions from baseline in systolic BP were 14.1 and 13.2 mmHg with lorundrostat 100 mg and 50 mg once daily, respectively, compared with 4.1 mmHg with placebo. The least square mean difference in systolic BP change versus placebo was −9.6 mmHg for lorundrostat 50 mg once daily (90% CI, −15.8 to −3.4; P = 0.01) and −7.8 mmHg for lorundrostat 100 mg once daily (90% CI, −14.1 to −1.5; P = 0.04).
  • Reductions in systolic BP with the twice-daily dosages, relative to placebo, were similar to those with the once-daily regimens.
  • In cohort 2 (patients without suppressed plasma renin activity), lorundrostat 100 mg once daily reduced systolic BP by 11.4 mmHg.
  • Patients with obesity had the largest BP-lowering response from lorundrostat.

Most adverse events were classified as mild. No cases of cortisol insufficiency occurred. One serious adverse event was believed to be treatment-related: a patient in cohort 2 on lorundrostat 100 mg developed worsening hyponatremia, requiring drug discontinuation. Mean serum potassium increases were similar across all doses of lorundrostat. Serum potassium rose above 6.0 mmol/L in six patients but was corrected with dose reduction or drug discontinuation and required no further intervention.

“The 50-mg daily dose lowered blood pressure to a similar degree as 100 mg, but with fewer adverse events,” Dr. Laffin observes.

Keep an eye out for further trials

Dr. Laffin notes two trials using lorundrostat that Cleveland Clinic and C5Research are helping to lead:

  • ADVANCE-HTN (NCT05769608) is testing the use of lorundrostat as add-on therapy to standardized background treatment of uncontrolled and resistant hypertension. About 300 participants are being randomized to placebo, lorundrostat 50 mg once daily, or lorundrostat 50 mg daily with titration at four weeks to 100 mg daily as needed. The 12-week trial is currently enrolling patients and is expected to issue preliminary results in 2024.
  • A larger phase 3 international trial of lorundrostat is expected to begin enrolling participants soon, with early results anticipated in mid-2025.

“Target-HTN has found lorundrostat to be well tolerated and to confer significant and clinically meaningful blood pressure reduction in patients with hypertension refractory to standard therapy,” Dr. Laffin summarizes. “These findings suggest that a targeted approach to blood pressure management might be useful, especially for those with elevated aldosterone.”

Related Articles

photo of grains and niacin supplement pills
February 20, 2024
Link Discovered Between Excess Niacin and Cardiovascular Disease

Newly identified pathway may explain the so-called niacin paradox

19-HVI-1792159; Steven Nissen, M.D., M.A.C.C.; Mike Viars
January 4, 2024
Lipoprotein(a): Progress on One of the Last Untreatable Frontiers of Cardiovascular Risk

It's time to increase testing for this major cardiovascular risk factor in advance of new therapies

illustration showing action of a GLP-1 receptor agonist
November 20, 2023
Semaglutide Shows Secondary Cardiovascular Prevention Benefits in Patients Without Diabetes

Findings establish overweight/obesity as a modifiable risk factor for cardiovascular disease

23-HVI-4317309_lipoprotein(a)_650x450
November 13, 2023
Novel siRNA Reduces Lipoprotein(a) by More Than 90% for 48 Weeks

Undetectable levels achieved for nearly nine months in phase 1 trial

illustration of coronary artery with calcified plaque
September 26, 2023
Coronary Artery Calcium Scoring Improves Accuracy of Cardiovascular Risk Screening

Observational study supports adding CAC score to traditional risk factors for precision medicine approach

23-HVI-3606662_calcium-scoring_650x450
March 8, 2023
Coronary Artery Calcium Correlates With Carotid Plaque but Not Significant Carotid Stenosis

Retrospective findings from an executive health program spur interest in broader studies

23-HVI-3606661_atherosclerosis_650x450
March 7, 2023
Targeting Inflammation Is Best Way to Reduce Residual Risk in Statin-Treated Patients, Study Suggests

Inflammation found more predictive of events than LDL-C in pooled analysis of RCTs

23-HVI-3606660_LDL-cholesterol-particles_650x450
March 4, 2023
CLEAR Outcomes: Bempedoic Acid Reduces Cardiovascular Events in Statin-Intolerant Patients

Findings bolster the oral drug as an option for primary and secondary prevention

Ad