The investigational, highly selective aldosterone synthase inhibitor baxdrostat has shown significant reductions in blood pressure compared with placebo at 12 weeks in patients with uncontrolled or treatment-resistant hypertension, a phase 3 clinical trial has found.
Findings from the international BAXHTN trial, led by University College London, England, were exclusively presented at the European Society of Cardiology Congress 2025, and simultaneously published in the New England Journal of Medicine.
Globally, hypertension is estimated to affect 1.3 billion people and is uncontrolled or treatment-resistant in around half of cases. Patients living with hypertension have a much greater risk of heart attack, stroke, kidney disease and premature death.
Addressing aldosterone dysregulation has been a key effort in hypertension research over several decades and has proved difficult to achieve. Baxdrostat was one of the first therapies to selectively block aldosterone production, showing meaningful blood pressure reductions in uncontrolled or resistant hypertension.
As such, the recent BaxHTN trial assessed the efficacy and safety of baxdrostat 1 mg or 2 mg taken as a once-daily pill in a broad group of patients whose blood pressure was uncontrolled despite being on multiple medications.
Assessing baxdrostat efficacy
Almost 800 patients participated in this phase 3 doubled-blind, randomised, placebo-controlled trial across 214 clinical sites worldwide.
Eligible patients were adults with seated systolic blood pressure (SBP) between 140mmHg and less than 170mmHg, despite the receipt of stable treatment with two antihypertensive medications (uncontrolled hypertension) or three or more such medications (resistant hypertension), including a diuretic for more than four weeks before screening.
Part one of the trial was a 12-week double-blind period in which 796 patients were randomly assigned 1:1:1 to receive baxdrostat 1mg, baxdrostat 2mg or a placebo once daily.
The primary efficacy endpoint was the difference in mean change from baseline in seated SBP at Week 12 with baxdrostat (1mg or 2mg separately) or placebo.
Part two was a 12-week open-label period in which patients were randomised for a second time, with 483 patients receiving baxdrostat 2mg and 245 receiving the standard of care.
Part three was a double-blind randomised withdrawal period in which 257 patients from the baxdrostat 2mg group were re-randomised 2:1 to baxdrostat 2mg or placebo for eight weeks.
In total, 974 patients received at least one dose of baxdrostat and were analysed in part one. They had a mean age of 62 years and 39% were female. A total of 27% had uncontrolled hypertension and 73% had resistant hypertension.
At baseline, the mean seated SBP and diastolic blood pressure (DBP) were 149mmHg and 85mmHg, respectively. The median number of antihypertensive medications was three.
For the primary endpoint at Week 12, placebo-adjusted reductions in seated SBP from baseline were -8.7mmHg for the 1mg dose and -9.8mmHg for the 2mg dose (both p<0.0001). Changes with baxdrostat were consistent across prespecified subgroups, including uncontrolled and resistant hypertension.
Substantial reduction in systolic blood pressure
After 12 weeks, patients taking baxdrostat (1mg or 2mg once daily in pill form) saw their blood pressure fall by around 9-10mmHg more than the placebo group. This was a reduction large enough to cut cardiovascular risk, the study authors noted.
Four in 10 patients reached healthy blood pressure levels, compared with fewer than two in 10 in the placebo group.
Principal investigator Professor Bryan Williams, chair of medicine at University College London (UCL) and a consultant physician at University College London Hospital, said: ‘Achieving a nearly 10mmHG reduction in systolic blood pressure with baxdrostat in the BaxHTN phase 3 trial is exciting, as this level of reduction is linked to substantially lower risk of heart attack, stroke, heart failure and kidney disease.
‘These data show that aldosterone plays a greater role in hard-to-control hypertension than previously recognised, underscoring the importance of baxdrostat’s novel mechanism of action, and potential impact for the millions of people living with hard-to-control hypertension despite being on multiple treatments.’
Sustained blood pressure control and safety profile
In an exploratory analysis, mean ambulatory 24-hour and night-time average SBP reductions were substantial with baxdrostat 2mg (placebo-adjusted reductions of -16.9mmHg and -11.7mmHg, respectively) after 12 weeks of treatment.
After three months, the proportion of patients with controlled SBP (<130mmHg) was 39.4% with baxdrostat 1mg, 40% with baxdrostat 2mg, and 18.7% with the placebo.
Seated SBP at the end of part two of the trial – when all patients had received baxdrostat 2mg – was 133mmHg. At the end of the eight-week randomised withdrawal period (part three), patients who received a placebo/standard of care had a mean SBP increase (+1.4mmHg), while those who continued on baxdrostat 2mg had a further reduction (-3.7mmHg; p=0.0016).
Serious adverse events were reported in 1.9% of patients in the baxdrostat 1mg group, 3.4% in the baxdrostat 2mg group and 2.7% in the placebo group over 12 weeks in part one of the trial.
Hyperkalaemia led to discontinuation in 0.8% of patients on baxdrostat 1mg and 1.5% on baxdrostat 2mg, with confirmed hyperkalaemia >6mmol/l occurring in 1% of patients in both baxdrostat groups. There were no reports of adrenocortical insufficiency.
Baxdrostat offers important advancement
‘These BaxHTN trial findings are an important advance in treatment and in our understanding of the cause of hard-to-control blood pressure,’ Professor Williams said.
‘In patients with uncontrolled or resistant hypertension, the addition of baxdrostat 1mg or 2mg once daily to background antihypertensive therapy led to clinically meaningful reductions in systolic blood pressure, which persisted up to 32 weeks, with no unanticipated safety findings.
‘This suggests that aldosterone is playing an important role in causing difficult to control blood pressure in millions of patients and offers hope for more effective treatment in the future.’
Indeed, according to the researchers, as many as half a billion people could benefit from baxdrostat globally, with 10 million of those in the UK.
This article was originally published by our sister publication Hospital Healthcare Europe.
