By Lucy Piper, medwireNews Reporter
medwireNews: Lorundrostat, a selective aldosterone synthase inhibitor, shows blood pressure (BP)-lowering potential in people with uncontrolled and treatment-resistant hypertension, according to the Advance-HTN trial.
The results showed a significant 7.9 mmHg greater reduction in average 24-hour ambulatory systolic BP after 12 weeks of treatment with lorundrostat at a daily dose of 50 mg versus placebo, and a significant 6.5 mmHg greater reduction with a starting daily dose of 50 mg, increasing to 100 mg at 4 weeks if systolic BP remained at 130 mmHg or above.
“By inhibiting aldosterone production while sparing other adrenal steroid pathways, lorundrostat may offer better efficacy and have fewer adverse effects than existing approved therapies”, suggest Steven Nissen (Cleveland Clinic Foundation, Ohio, USA) and fellow Advance-HTN investigators.
The phase 2b, multicentre study involved 926 adults who were receiving stable doses of two to five antihypertensives and had a blood pressure of 140/190 mmHg or higher measured during an office visit. To be eligible, they had to have an estimated glomerular filtration rate (eGFR) of 45 mL/min per 1.73 m3 or above, a serum potassium level below 5.0 mmol/L and a serum sodium level above 135 mmol/L.
Prior to randomization, the patients discontinued their hypertensives and started a standardized 3-week treatment regimen of olmesartan 40.0 mg/day, along with indapamide 2.5 mg or hydrochlorothiazide 25.0 mg if they were taking two antihypertensives, and with additional amlodipine 10 mg/day if they were taking three to five antihypertensives.
After the 3 weeks, 285 of the patients still had uncontrolled hypertension (average 24-hour systolic BP 130–180 mmHg or diastolic BP >80 mmHg) and were randomly assigned to receive lorundrostat, at the stable 50 mg/day dose for the full 12 weeks or adjusted to 100 mg/day after 4 weeks, or placebo for 12 weeks.
The mean age of the participants was 60 years, 60% were men and 53% were Black. This relatively high proportion of Black individuals reflects the “disproportionate burden of treatment-resistant hypertension” that exists in such patients in the USA, note the researchers. In all, 20% of patients received the adjusted dose of lorundrostat.
After 12 weeks, 282 patients – 94 in each group – were available for analysis. Among those receiving lorundrostat, the least squares mean reduction in average 24-hour ambulatory systolic BP was 15.4 mmHg for patients receiving the stable dose and 13.9 mmHg for those receiving the adjusted dose, which was significantly greater than the 7.4 mmHg reduction achieved by those taking placebo.
A treatment effect was evident from 4 weeks, with the reduction in average 24-hour systolic BP at this timepoint – a key secondary endpoint – a significant 5.3 mmHg greater among patients in the combined lorundrostat group than those in the placebo group. And patients taking lorundrostat were 3.3-times more likely to have a systolic BP below 125 mmHg at 4 weeks than those taking placebo.
“The observed efficacy reinforces the concept that aldosterone plays an important role in the pathogenesis of hypertension”, say the investigators.
They note that “the safety profile of lorundrostat appeared to be acceptable, with adverse events consistent with the known effects of targeting the renin–angiotensin–aldosterone system — an increased risk of hyperkalaemia and hyponatremia and decreases in the eGFR.”
Dose modifications due to hyperkalaemia (potassium ≥5.5 mmol/L) occurred in 5% of participants taking stable-dose lorundrostat and 7% of those taking the adjusted dose, compared with none of the placebo-treated patients. Those due to hyponatremia (serum sodium <135 mmol/L) occurred in a respective 9%, 11% and 6%, and due to eGFR reductions (<30 mL/min per 1.73 m2 or >25%) in 3%, 7% and 3%.
Serious adverse events occurred in six patients in the stable lorundrostat group, eight patients in the dose-adjusted lorundrostat group, and two patients in the placebo group, with three considered related to lorundrostat. There was also one death due to arteriosclerosis in the dose-adjusted lorundrostat arm, but this was deemed unrelated to the trial drug.
Nissen et al acknowledge the limitations of the short study duration and the lack of comparison with alternative hypertensives, such as mineralocorticoid receptor antagonists. They point out that the longer-term effects of lorundrostat “are expected to be assessed in an ongoing open-label extension trial (NCT05968430).”
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N Engl J Med 2025; doi:10.1056/NEJMoa2501440