In a phase II dose-finding trial, researchers have discovered that a highly selective aldosterone synthase inhibitor successfully reduces blood pressure (BP) in individuals with uncontrolled hypertension. This finding is especially significant for hypertensive patients with suppressed renin levels, as they are theoretically the group most likely to benefit from reducing aldosterone production. The trial, known as Target-HTN, revealed that patients who received lorundrostat 50 mg or 100 mg once daily experienced reductions in automated office systolic BP up to 14.1 mm Hg after 8 weeks. This improvement was significant compared to the placebo group, which only saw a 4-mm Hg reduction. The study findings also indicated that the subgroup of patients with obesity experienced the greatest BP lowering effect. These findings were presented at the 2023 Hypertension conference hosted by the American Heart Association.
Interestingly, even among patients without suppressed renin levels, a daily dose of 100 mg of lorundrostat reduced systolic BP by 11.4 mm Hg. The researchers concluded that lorundrostat was well-tolerated, with small expected increases in serum potassium and declines in estimated glomerular filtration rate (eGFR), suggesting a favorable safety profile. Particularly, the 50-mg once-daily dose demonstrated fewer adverse events, including fewer episodes of hyperkalemia. These findings support the need for further studies on lorundrostat as a potential treatment for uncontrolled hypertension.
Lorundrostat belongs to a new class of antihypertensives in development, specifically designed to reduce excess aldosterone synthesis that contributes to high blood pressure. This development is crucial as there have been no new classes of blood pressure-lowering drugs introduced in many years. According to Steven Nissen, MD, from Cleveland Clinic, controlling blood pressure can be challenging, especially in patients with obesity and diabetes. Therefore, new options such as lorundrostat would provide valuable alternatives for these patients.
Another selective aldosterone synthase inhibitor, baxdrostat, did not demonstrate consistent results for blood pressure lowering in a phase II study known as HALO. Some attribute the failure of baxdrostat to beat placebo to issues with patient adherence to therapy. Dexfadrostat, a third agent in this class, is currently in early-phase testing. Unlike mineralocorticoid receptor antagonists like spironolactone, aldosterone synthase inhibitors target aldosterone synthesis upstream, offering potential benefits for conditions such as hyperaldosteronism and obesity-associated hypertension without hormonal adverse effects.
Bryan Williams, MD, from University College London, commented that there is now a real potential to provide better-targeted treatment for patients whose clinical conditions and outcomes are influenced by aldosterone excess. This includes patients with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and those with undiagnosed primary aldosteronism. Williams highlighted that blood cortisol and potassium levels are two safety outcomes particularly relevant to this new class of drugs. In Target-HTN, six patients experienced increases in serum potassium above 6.0 mmol/L, which were corrected through dose reduction or drug discontinuation. However, no instances of cortisol insufficiency occurred. Williams noted that more significant increases in potassium would be expected in patients with advanced kidney disease.
Luke Laffin, MD, also from Cleveland Clinic and a co-author of the study, expressed optimism regarding the results of lorundrostat, especially among patients with obesity-associated hypertension. The ongoing ADVANCE-HTN pivotal trial aims to evaluate lorundrostat as an add-on therapy for 300 individuals with uncontrolled or resistant hypertension. In addition, a larger phase III trial is being planned for reporting in 2025 by the drug-maker Mineralys Therapeutics.
The Target-HTN trial was conducted at 43 sites across the United States. Initial enrollment included 163 participants with suppressed renin levels and elevated plasma aldosterone, who were randomized to receive placebo or one of five lorundrostat doses. Subsequent enrollment involved 37 participants with renin levels greater than 1.0 ng/mL/h, who were randomized to receive placebo or lorundrostat 100 mg once daily. The average age of the participants was 65.7, with 60% being women. The racial composition of the participants was 36% Black and 48% Hispanic. Nearly half of the participants had a BMI over 30, indicating obesity. The study had a small sample size, which limits the generalizability of the findings for each tested dose of lorundrostat.
The phase II Target-HTN trial has demonstrated the potential efficacy of lorundrostat, a highly selective aldosterone synthase inhibitor, in reducing blood pressure, particularly in hypertensive patients with suppressed renin and obesity-associated hypertension. The favorable safety profile of lorundrostat makes it a promising candidate for further investigation and potential treatment of uncontrolled hypertension. The ongoing ADVANCE-HTN trial and planned phase III trial will provide additional insights into the effectiveness of lorundrostat as an add-on therapy for individuals with uncontrolled or resistant hypertension. With the introduction of new classes of blood pressure-lowering drugs, there is hope for better-targeted treatment for patients whose clinical conditions are influenced by excess aldosterone synthesis.
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