Lorundrostat Shows Promise for Treatment-Resistant Hypertension: Results from Advance-HTN Trial

Lorundrostat, a novel aldosterone synthase inhibitor, is emerging as a potent therapy for patients with treatment-resistant hypertension. In the phase IIb Advance-HTN trial, lorundrostat demonstrated significant blood pressure (BP) reduction in patients who were already on multiple antihypertensive medications.

Key Findings from the Advance-HTN Trial

• 15.4 mm Hg drop in 24-hour systolic BP after 12 weeks of treatment with 50 mg daily lorundrostat.

• Patients included in the study had persistent office BP readings ≥130/90 mm Hg despite two to five antihypertensive agents.

• Lorundrostat outperformed placebo significantly, with placebo-adjusted BP drops of:

  • −7.9 mm Hg in the stable-dose group

  • −6.5 mm Hg in the dose-adjustment group

• 41% of patients on lorundrostat achieved systolic BP <125 mm Hg at 4 weeks versus 18% with placebo.

• Drug efficacy was independent of BMI—a key advantage in diverse patient populations.

Study Design Enhancements

• A standardized 3-week run-in phase ensured patients had optimized background therapy.

• The trial used 24-hour ambulatory BP monitoring, a gold standard, rather than relying solely on clinic measurements.

• A large number of Black participants were included, a group with a higher incidence of primary aldosteronism, which lorundrostat specifically targets.

Safety Considerations

• Adverse events were consistent with RAAS (renin-angiotensin-aldosterone system) modulation:

  • Hyperkalemia (serum K⁺ > 6.0 mmol/L) in 5-7% of treated patients

  • Mild drops in eGFR and occurrences of hyponatremia

• Serious adverse events were few and manageable with close monitoring.

• Longer-term safety remains under investigation in ongoing phase III studies.

Why Lorundrostat May Be a Game-Changer

• Targets the root hormonal cause of hypertension—aldosterone excess.

• Offers a new mechanism compared to beta-blockers, calcium channel blockers, or diuretics.

• Could serve as an earlier-line option in patients with confirmed aldosterone-driven hypertension.

• Potential for broader use in conditions like heart failure or chronic kidney disease pending further research.

What’s Next?

• Awaiting phase III data for regulatory approval.

• Emphasis now lies on tolerability, long-term efficacy, and comparison with existing agents like spironolactone.

• If approved, lorundrostat could become a go-to add-on agent in challenging hypertension cases, particularly when aldosterone plays a central role.

Summary Points

• Lorundrostat lowers BP by blocking aldosterone synthesis at the adrenal level.

• Leads to less sodium reabsorption and fluid retention, reducing BP.

• May cause hyperkalemia, so electrolytes must be monitored.

• Ideal candidate for patients with resistant hypertension and suspected aldosterone excess.