Lorundrostat Shows Promise in Drug-Resistant Hypertension
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on June 4th, 2025
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Despite the use of multidrug regimens, many patients with hypertension continue to struggle with blood pressure control. Emerging research suggests that aldosterone dysregulation may be a key driver of treatment-resistant hypertension. With funding from Mineralys Therapeutics, a study was conducted to evaluate lorundrostat, an aldosterone synthase inhibitor, for managing blood pressure in this population.
The phase 2 clinical trial enrolled 285 patients diagnosed with hypertension who were already on two or three antihypertensive medications. Despite these therapies, participants had poorly controlled blood pressure, with an average 24-hour ambulatory systolic/diastolic pressure of 141/86 mmHg. To standardize treatment, existing medications were discontinued and replaced with a combination regimen including olmesartan, indapamide, hydrochlorothiazide, and amlodipine, tailored by the treating physician. Participants were then randomized to receive either a placebo or lorundrostat, administered daily at a fixed 50 mg dose or titrated to 100 mg after four weeks.
Lorundrostat works by inhibiting aldosterone synthase, the adrenal enzyme responsible for aldosterone production—a hormone that increases sodium reabsorption and raises blood pressure. Unlike mineralocorticoid receptor antagonists, which block aldosterone’s effects but leave its levels unchanged (often leading to off-target side effects), lorundrostat directly suppresses hormone synthesis.
After 12 weeks, lorundrostat significantly reduced systolic blood pressure by approximately 8 mmHg compared to placebo, after adjusting for confounding variables. However, the treatment was associated with increased rates of hyponatremia and hyperkalemia. A decline in estimated glomerular filtration rate (eGFR) was also observed, though the long-term renal effects of lorundrostat and similar agents remain to be fully understood. Other aldosterone synthase inhibitors, such as baxdrostat (tested) and vicadrostat (under study), may offer opportunities for comparative trials to better define their therapeutic niches.
The phase 2 clinical trial enrolled 285 patients diagnosed with hypertension who were already on two or three antihypertensive medications. Despite these therapies, participants had poorly controlled blood pressure, with an average 24-hour ambulatory systolic/diastolic pressure of 141/86 mmHg. To standardize treatment, existing medications were discontinued and replaced with a combination regimen including olmesartan, indapamide, hydrochlorothiazide, and amlodipine, tailored by the treating physician. Participants were then randomized to receive either a placebo or lorundrostat, administered daily at a fixed 50 mg dose or titrated to 100 mg after four weeks.
Lorundrostat works by inhibiting aldosterone synthase, the adrenal enzyme responsible for aldosterone production—a hormone that increases sodium reabsorption and raises blood pressure. Unlike mineralocorticoid receptor antagonists, which block aldosterone’s effects but leave its levels unchanged (often leading to off-target side effects), lorundrostat directly suppresses hormone synthesis.
After 12 weeks, lorundrostat significantly reduced systolic blood pressure by approximately 8 mmHg compared to placebo, after adjusting for confounding variables. However, the treatment was associated with increased rates of hyponatremia and hyperkalemia. A decline in estimated glomerular filtration rate (eGFR) was also observed, though the long-term renal effects of lorundrostat and similar agents remain to be fully understood. Other aldosterone synthase inhibitors, such as baxdrostat (tested) and vicadrostat (under study), may offer opportunities for comparative trials to better define their therapeutic niches.