Baxdrostat: looking to BrigHTN the outlook for treatment-resistant hypertension

Baxdrostat: looking to BrigHTN the outlook for treatment-resistant hypertension
Drew Paszotta, PharmD
Geritom Medical, Inc.

Background: Elevated blood pressure has been identified as the leading risk factor for cardiovascular disease, stroke, disability, and death. In the United States, about 10% of adults with hypertension (10 to 12 million) have treatment-resistant hypertension, defined as elevated blood pressure while on at least three antihypertensive medications of different classes, including a diuretic. Currently, spironolactone–a mineralocorticoid receptor antagonist–is recommended by the American Heart Association for treatment-resistant hypertension, but the potential for adverse effects limits its use. Despite a variety of antihypertensive medication options available, 40-50% of patients with hypertension remain inadequately treated. As a highly selective inhibitor of aldosterone synthase, baxdrostat prevents the body from producing aldosterone (rather than blocking the mineralocorticoid receptor), making it an intriguing option for treatment-resistant hypertension due to a more limited side effect profile.

Purpose: The purpose of this study was to examine the safety and efficacy of baxdrostat treatment for patients diagnosed with treatment-resistant hypertension.

Study Design: BrigHTN is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase II trial that assigned patients to receive 0.5 mg, 1 mg, or 2 mg of once-daily baxdrostat or placebo. Participants were eligible to enroll if they were at least 18 years old, taking stable doses of at least three antihypertensive medications, including one diuretic, and had a mean blood pressure of at least 130/80 mmHg. Key exclusion criteria were mean seated systolic blood pressures of at least 180 mmHg or diastolic blood pressure of at least 110 mmHg, eGFR of <45 mL/min/1.73m2, and uncontrolled diabetes. Patients receiving mineralocorticoid receptor antagonists and potassium sparing diuretics were required to discontinue these medications four weeks prior to randomization. Eligible participants entered a 2-week run-in period and patients with at least 70% adherence, as determined by pill counts, underwent randomization. The primary efficacy endpoint evaluated was the change in the mean seated systolic blood pressure from baseline to the end of the 12-week treatment period. The secondary efficacy endpoints included the change in seated diastolic blood pressure and the percentage of patients with a seated blood pressure of <130/80 mmHg at the end of the 12-week period. The safety endpoints evaluated were adverse effects of special interest, vital signs, and results of laboratory tests, electrocardiography, and physical examinations.

Results: The trial ran from July 30, 2020 to June 14, 2022 and 274 patients were included in the modified intention-to-treat analysis. Each trial group consisted of similar demographic and clinical characteristics at baseline. Approximately 44% of the patients were female, and mean patient age was 62 years old. The study population represented 70% White, 28% Black, 2% Asian, <1% American Indian or Alaska Native, and 43% identified as Hispanic or Latinx adults. The modified intention-to-treat analysis of the primary outcome showed that baxdrostat treatment was associated with dose-dependent changes in mean reduction of systolic blood pressure of -20.3 + 2.1 mmHg, -17.5 + 2.0 mmHg, and -12.1 +1.9 mmHg at the 2 mg, 1 mg, and 0.5 mg doses, respectively, compared with placebo which had a -9.4 mmHg mean change in systolic blood pressure. Statistical significance was met for the 1 mg (P=0.003) and 2 mg (P<0.001) baxdrostat groups. Hypothesis testing was not performed for the secondary efficacy endpoint of change in mean diastolic blood pressure. No deaths occurred throughout the trial and a higher percentage of patients in the baxdrostat 1 mg and 2 mg groups experienced adverse events (52% and 48%) than in the 0.5 mg and placebo groups (35% and 41%), although hypothesis testing was not performed. Most were considered mild (62%) and investigators determined 89% were unrelated to baxdrostat or placebo. The most common adverse effects that occurred in 5% or more of patients were urinary tract infections, hyperkalemia, headache, and fatigue. No patients discontinued the trial because of hyperkalemia and there were 10 adverse events of special interest: one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Conclusion: In the BrigHTN trial, baxdrostat 1 mg and 2 mg displayed significant, dose-related reductions in the mean systolic blood pressures at week 12. Further studies are needed to confirm the benefit beyond 12 weeks and the long-term safety profile, and head-to-head studies are necessary to determine its place in therapy. Impacting millions of adults in the United States, treatment-resistant hypertension remains difficult to control with the current treatment options. Promising results from this phase II trial lend hope that baxdrostat will BrigHTN the outlook for treatment-resistant hypertension.

Key Point: Baxdrostat is an aldosterone synthase inhibitor that showed promising blood pressure-lowering efficacy in a phase II trial of individuals with treatment-resistant hypertension. While the initial results are encouraging, comparison with other antihypertensives, especially mineralocorticoid receptor antagonists such as spironolactone and eplerenone, will be the real benchmark for the safety and efficacy of this medication.


  1. Freeman MW, Halvorsen YD, Marshall W, Pater M, Isaacsohn J, Pearce C, Murphy B, Alp N, Srivastava A, Bhatt DL, Brown MJ; BrigHTN Investigators. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2022 Nov 7. doi: 10.1056/NEJMoa2213169. Epub ahead of print. PMID: 36342143.
  2. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 2018;72(5):e53- e90