Effect of Baxdrostat on Ambulatory Blood Pressure in Patients with Resistant Hypertension (Bax24): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial

Phase 3, randomised, double-blind, placebo-controlled trial

N= 217

To assess the effect of baxdrostat, a selective aldosterone synthase inhibitor, on ambulatory blood pressure in patients with resistant hypertension

Baxdrostat (n= 108)

Placebo (n= 109)

Adults (aged ≥18 years) with seated systolic blood pressure (SBP) ≥140 mm Hg and <170 mm Hg, despite receiving three or more antihypertensive medications, including a diuretic, with 24 h ambulatory SBP ≥130 mm Hg

SBP levels ≥170 mm Hg, use of mineralocorticoid receptor antagonists or potassium-sparing diuretics within 4 weeks of screening, uncontrolled diabetes, secondary hypertension, cardiovascular or cerebrovascular events within the previous 6 months, persistent atrial fibrillation

Patients entered a 2-week placebo run-in, then eligible patients were randomized 1:1 to baxdrostat 2 mg or placebo once daily, added to background antihypertensive therapy. Randomization was stratified by baseline mean ambulatory SBP <140 or ≥140 mm Hg. Background antihypertensive medications were continued and could not be changed unless seated SBP exceeded 170 mm Hg or DBP exceeded 105 mm Hg. Blood pressure was assessed with seated office BP and 24-hour ambulatory BP monitoring at baseline and week 12 after witnessed intake of background therapy and study drug. Ambulatory BP monitoring required ≥20 hours of recordings, ≥70% of readings recorded, and no more than 2 consecutive missing hours. The primary analysis used ANCOVA in treated patients with valid ambulatory SBP at baseline and week 12; missing or invalid ambulatory SBP measurements were not imputed. Safety was assessed in all treated patients through adverse events, vital signs, laboratory monitoring, and adverse events of special interest.

March 1, 2024, to April 16, 2025

Primary: Change in 24 h ambulatory SBP from baseline to week 12

Secondary: Change in night-time and daytime ambulatory SBP, seated SBP, proportion of patients reaching 24 h ambulatory SBP <130 mm Hg, change in 24 h, night-time, and daytime ambulatory DBP, change in seated DBP, proportion of patients reaching nocturnal SBP dipping of at least 10%

Baxdrostat group (n= 108)

60.0 (52.0–67.0)

70 (65%)

86 (80%)

32.4 (28.4 to 36.1)

Ambulatory systolic blood pressure, 24 h average, mm Hg

140.5 ± 8.4

Seated systolic blood pressure, mm Hg

146.9 ± 12.0

eGFR, mL/min per 1·73 m²

86.3 ± 18.1

Abbreviations: IQR, interquartile range; BMI, body mass index; eGFR, estimated glomerular filtration rate.

Baxdrostat group (n= 108)

-16.6 mm Hg (95% CI -18.8 to -14.3)

-16.0 mm Hg (95% CI -18.6 to -13.4)

-16.8 mm Hg (95% CI -19.2 to -14.4)

-14.9 mm Hg (95% CI -18.2 to -11.6)

Adverse events occurred in 56 (52%) of 108 patients in the baxdrostat group and 40 (37%) of 109 patients in the placebo group. A confirmed potassium level of more than 6 mmol/L occurred in three (3%) of the 108 baxdrostat recipients and in none of the placebo recipients.

In conclusion, in the Bax24 trial, the addition of 2 mg baxdrostat daily to background antihypertensive therapy for patients with true resistant hypertension confirmed by ambulatory blood pressure monitoring resulted in substantial reductions in 24 h and night-time ambulatory SBP at 12 weeks compared with placebo. Although steroidal (spironolactone and eplerenone) and non-steroidal (finerenone) mineralocorticoid receptor antagonists have demonstrated clinical benefits in selected populations with heart failure or chronic kidney disease, selective aldosterone synthase inhibitors such as baxdrostat represent a promising new treatment strategy for patients with hard-to-control hypertension. Dedicated outcomes trials will be needed to determine whether these blood pressure reductions translate into improved long-term cardiovascular and renal outcomes.

This rigorously designed phase 3 trial used ambulatory BP confirmation, a placebo run-in, witnessed medication intake before ambulatory BP assessments, and stable background antihypertensive therapy, strengthening confidence that the observed BP reductions reflect a true baxdrostat effect in resistant hypertension. Limitations include short treatment duration, exclusion of many screened patients, relatively preserved baseline kidney function, and limited representation of women and Black patients, which may affect generalizability and understate hyperkalaemia risk in higher-risk clinical populations.

Baxdrostat Efficacy and Safety in Uncontrolled and Resistant Hypertension

Multinational, randomized, double-blind, placebo-controlled phase 3 trial

N= 794

To test the efficacy and safety of baxdrostat, an aldosterone synthase inhibitor, in patients with uncontrolled or resistant hypertension

Baxdrostat 1mg (n= 264)

Baxdrostat 2mg (n= 266)

Placebo (n= 264)

Men and women aged ≥18 years with uncontrolled or resistant hypertension, defined by a mean seated-systolic blood pressure (SBP) ≥140 mmHg and <170 mmHg despite treatment with maximally tolerated doses of either 2 (uncontrolled hypertension) or ≥3 (resistant hypertension) antihypertensive medications of different classes, including a diuretic, for ≥4 weeks before screening

Not specified in the provided text

Participants completed a 2-week single-blind placebo run-in while continuing stable background antihypertensive therapy. Eligible participants were randomized 1:1:1 to baxdrostat 1 mg, baxdrostat 2 mg, or placebo once daily for 12 weeks, stratified by baseline hypertension status and baseline seated-SBP. Background antihypertensive therapy generally remained unchanged during double-blind periods unless rescue therapy was needed for seated-SBP >170 mmHg or DBP >105 mmHg. During part 1, participants were assessed monthly before study medication ingestion; seated BP, vital signs, medication list, and adverse events were recorded. Blood samples included serum creatinine, sodium, baxdrostat levels, aldosterone, plasma renin activity, and potassium. Modified intention-to-treat populations were used, and BP analyses used ANCOVA with treatment and hypertension status as factors and baseline BP as covariate.

12 weeks for the primary endpoint assessment

Primary: Change in seated-SBP from baseline to week 12

Secondary: Change in seated-SBP from week 24 to week 32, change in seated-SBP in the resistant hypertension subpopulation, change in seated-DBP from baseline to week 12, achieving seated-SBP <130 mmHg at week 12

Baxdrostat 1mg (n= 264)

149/87

Baxdrostat 1mg (n= 264)

-14.5 (95% CI, -16.5 to -12.5)

At week 12, least-squares mean seated systolic blood pressure decreased by 14.5 mmHg with baxdrostat 1 mg and 15.7 mmHg with baxdrostat 2 mg versus 5.8 mmHg with placebo, corresponding to placebo-corrected reductions of 8.7 mmHg and 9.8 mmHg, respectively (both p< 0.0001).

In the resistant hypertension subgroup, placebo-corrected seated systolic blood pressure reductions were 9.1 mmHg with baxdrostat 1 mg and 9.8 mmHg with baxdrostat 2 mg (both P<0.0001). Baxdrostat also reduced seated diastolic blood pressure versus placebo by 3.3 mmHg with 1 mg (p= 0.0008) and 3.9 mmHg with 2 mg (p< 0.0001), and a greater proportion of participants achieved seated systolic blood pressure <130 mmHg at week 12 with baxdrostat 1 mg (39.4%) and 2 mg (40.0%) than placebo (18.7%; both p< 0.0001).

During randomized withdrawal, continued baxdrostat 2 mg was associated with a 3.7-mmHg reduction in seated systolic blood pressure from week 24 to week 32, compared with a 1.4-mmHg increase after withdrawal to placebo, for a placebo-corrected difference of 5.1 mmHg (p= 0.0016).

Hyperkalemia (potassium levels >5.5mmol/l) occurred in 6.1% with baxdrostat 1mg, 11.1% with baxdrostat 2mg, and 0.4% with placebo. Hyponatremia and hypotension were also reported more frequently in the baxdrostat groups compared to placebo.

Baxdrostat added to background therapy resulted in a reduction in seated-SBP at 12 weeks compared with placebo in patients with uncontrolled or resistant hypertension.

This large phase 3 trial was strengthened by its randomized, double-blind, placebo-controlled design, prespecified BP endpoints, monthly safety monitoring, and inclusion of both uncontrolled and resistant hypertension populations. Baxdrostat produced clinically meaningful seated-SBP reductions over 12 weeks, but treatment was associated with more hyperkalemia, hyponatremia, and eGFR decline than placebo, making electrolyte and renal monitoring important in clinical interpretation.

Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension

Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial

N= 274

To examine the efficacy and safety of baxdrostat in patients with treatment-resistant hypertension

Placebo (n= 69)

Baxdrostat 0.5 mg (n= 69)

Baxdrostat 1 mg (n= 70)

Baxdrostat 2 mg (n= 67)

Men and women aged 18 years or older, receiving stable doses of at least three antihypertensive medications (including a diuretic), with a mean blood pressure of at least 130/80 mm Hg while seated

Mean seated systolic blood pressure (SBP) of at least 180 mm Hg or diastolic blood pressure (DBP) of at least 110 mm Hg, estimated GFR of less than 45 ml/min/1.73 m2, and uncontrolled diabetes

Patients were randomly assigned to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) or placebo once daily for 12 weeks. Blood pressure was measured as the average of three measurements using an automated in-office monitor. The primary endpoint was the change in systolic blood pressure from baseline to week 12.

12 weeks

Primary: Change in systolic blood pressure from baseline to week 12

Secondary: Change in diastolic blood pressure, percentage of patients with blood pressure <130/80 mm Hg at week 12

Baxdrostat, 1 mg (n= 70)

Mean age, years

Male 

Race

White

Black

Hispanic or Latinx

51 (74%)

16 (23%)

30 (43%)

45 (65%)

22 (32%)

33 (48%)

48 (69%)

20 (29%)

23 (33%)

47 (70%)

19 (28%)

32 (48%)

Body mass index

Seated SBP, mmHg

Seated DBP, mmHg

Placebo (n= 69)

Change in SBP, mmHg

Change in DBP, mmHg

No deaths occurred during the trial. Baxdrostat-related increases in potassium levels to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and re-initiation of the drug. Common adverse events included urinary tract infections, hyperkalemia, headache, and fatigue.

Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. Baxdrostat generally had an acceptable side-effect profile, and none of the patients discontinued the trial because of hyperkalemia.

The study demonstrated significant reductions in blood pressure with baxdrostat, highlighting its potential as a treatment for resistant hypertension. However, the trial was not designed to test long-term benefits and risks, nor to compare baxdrostat with other antihypertensive agents. The inclusion of patients with high adherence may limit generalizability to the broader population of patients with treatment-resistant hypertension.

Efficacy and Safety of Baxdrostat in Participants with CKD and Uncontrolled Hypertension

Randomized, double-blind, placebo-controlled, multicenter trial

N= 195

To evaluate the efficacy and safety of baxdrostat, an aldosterone synthase inhibitor, in participants with CKD and uncontrolled hypertension

Baxdrostat low-dose (n= 65)

Baxdrostat high-dose (n= 64)

Placebo (n= 66)

Participants aged ≥18 years with an eGFR of 25–75 ml/min per 1.73 m², a urine albumin-creatinine ratio of ≥100 mg/g, and a mean seated office systolic BP between 140 and 180 mm Hg without diabetes or between 130 and 180 mm Hg with type 2 diabetes, taking an ACE inhibitor or ARB at the maximum tolerated daily dose for >4 weeks before screening

Participants with type 1 diabetes, glycosylated hemoglobin >10.5% at screening, or concomitantly treated with MRAs or potassium-sparing diuretics

Participants were randomized to baxdrostat low-dose (0.5 mg up-titrated to 1 mg), high-dose (2 mg up-titrated to 4 mg), or placebo for 26 weeks. The primary endpoint was change from baseline in mean seated office systolic BP at week 26. Secondary endpoints included changes by high-dose or low-dose baxdrostat. Safety was assessed by treatment-emergent adverse events, particularly hyperkalemia.

April 29, 2022, to May 2, 2024

Primary: Change in mean seated office systolic BP at week 26

Secondary: Change in systolic BP by high-dose or low-dose baxdrostat, proportion achieving systolic BP <130 mm Hg, change in UACR, change in eGFR

Baxdrostat High-Dose (n= 64)

67 ± 13

23 (35%)

41 (63%)

150.7 ± 13.3

Mean eGFR, ml/min per 1.73 m²

59 (89%)

p-value

-9.0 (-15.1 to -2.9)

-52.0% (-66.8 to -30.6)

Hyperkalemia was the most frequent treatment-emergent adverse event, occurring in 41% of participants in the baxdrostat pooled group compared to 5% in the placebo group. Other common adverse events included increased blood creatinine levels.

Baxdrostat reduced systolic BP in participants with CKD and uncontrolled hypertension. Hyperkalemia was reported more commonly as an adverse event with baxdrostat versus placebo.

This randomized, double-blind, placebo-controlled trial provides clinically relevant evidence that baxdrostat lowers seated office SBP in a high-risk CKD population already treated with ACE inhibitor or ARB therapy. Interpretation is limited by the modest sample size, lack of ambulatory BP monitoring, and late protocol changes to potassium-related titration rules; the high rate of hyperkalemia, especially with high-dose baxdrostat, is a key practical safety consideration for future CKD use.

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers

Phase 1, randomized, double-blind, multiple ascending dose study

N= 54

To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of baxdrostat following oral dosing once daily for 10 days in subjects with a normal- or low-salt diet

2.5 mg baxdrostat (n= 9), placebo (n= 3) on a low-salt diet

5.0 mg baxdrostat (n= 9), placebo (n= 3) on a low-salt diet

1.5 mg baxdrostat (n= 9), placebo (n= 3) on a normal-salt diet

2.5 mg baxdrostat (n= 6), placebo (n= 2) on a normal-salt diet

0.5 mg baxdrostat (n= 9), placebo (n= 3) on a normal-salt diet

Subjects aged 18-55 years, in good health based on medical and psychiatric history, physical examination, electrocardiograph (ECG), orthostatic vital signs, and routine laboratory tests; nonsmokers with body mass index (BMI) ≥18 and ≤30 kg/m2; appropriate response to cortisol stimulation or normal cortisol level during the inpatient run-in period

Personal or family history of long QT syndrome, complex ventricular arrhythmias, or family history of sudden death; clinically significant arrhythmias; prolonged QTcF (>450 ms); seated BP > 150/90 mm Hg or <90/50 mm Hg; resting heart rate >100 bpm or <50 bpm; postural tachycardia or orthostatic hypotension; serum potassium greater than the upper limit of normal and serum sodium less than the lower limit of normal

Subjects were randomized 3:1 to baxdrostat or placebo once daily for 10 days. Cohorts 1 and 2 received low-salt diets; cohorts 3 to 5 received normal-salt diets. Cohort 1 initially received 50 to 60 mEq sodium/day during run-in, modified to 65 to 70 mEq/day after decreases in sodium were observed before study drug exposure. Cohort 2 received up to 65 to 70 mEq sodium/day throughout. Normal-salt cohorts received 100 to 104 mEq sodium/day. All diets included 70 to 100 mEq potassium/day. After screening up to 28 days, subjects completed a 5-day inpatient run-in with controlled standardized diet and baseline pharmacodynamic assessments, followed by a 15-day inpatient period: 10 days of study drug/placebo dosing plus 5 additional days of blood and urine sampling. Dosing occurred in the morning; days 1 and 10 dosing followed an overnight fast, with fasting for at least 4 hours afterward. Cohorts 1 and 2 underwent ACTH challenge at baseline, 1 hour after the first dose, and 1 hour after the final dose.

10 days of treatment with a follow-up visit 3 ± 1 days after clinic discharge

Primary: Safety, tolerability, pharmacokinetics, and pharmacodynamics of baxdrostat

Secondary: Dose-dependent reduction in plasma aldosterone, lack of effect on cortisol

Baseline Characteristics

Study participants were generally middle-aged, healthy volunteers, with mean ages ranging from 37.0 to 44.8 years across treatment groups and mean BMI values ranging from 24.3 to 26.9 kg/m². Overall, most participants were male (70%), Black or African American (50%), and not Hispanic or Latino (88%).

Baseline characteristics were generally balanced across treatment groups with respect to sex and race, although the small cohort sizes resulted in some numerical variation between groups, such as female representation ranging from 11.1% to 50.0% and White participants ranging from 33.3% to 66.7% across cohorts.

Results

Baxdrostat demonstrated dose-proportional pharmacokinetics, with plasma concentrations increasing proportionally across ascending doses, peak concentrations occurring within 4 hours, and a mean half-life of approximately 26 to 31 hours, supporting once-daily dosing.

Pharmacodynamically, baxdrostat produced dose-dependent reductions in plasma aldosterone at doses ≥1.5 mg under both low-salt and normal-salt diet conditions, with sustained day 10 reductions of approximately 51% to 73%. Baxdrostat had no meaningful effect on plasma cortisol, including in low-salt cohorts undergoing ACTH challenge, supporting selectivity for aldosterone synthase.

Safety findings were favorable, with no deaths, serious adverse events, or adverse event-related discontinuations; all treatment-emergent adverse events in baxdrostat recipients were mild, most commonly headache, postural dizziness, and dizziness.

There were no deaths or serious adverse events. All treatment-emergent adverse events in subjects receiving baxdrostat were mild. Common adverse events included headache, postural dizziness, and dizziness

Oral administration of baxdrostat was safe and well tolerated in all subjects and resulted in dose-proportional increases in plasma baxdrostat with a half-life that supports once-daily dosing. The dose-dependent decrease in plasma aldosterone at doses ≥1.5 mg and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase and support continued study in ongoing phase 2 clinical trials evaluating the efficacy and safety of baxdrostat for treatment-resistant or uncontrolled hypertension and primary aldosteronism.

This phase 1 study supports baxdrostat’s biologic plausibility as a selective aldosterone synthase inhibitor, with dose-dependent aldosterone suppression and no meaningful cortisol suppression after 10 days. However, the study was small, enrolled healthy volunteers rather than patients with hypertension or primary aldosteronism, and was not designed to evaluate blood pressure efficacy, limiting direct clinical applicability.