Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension (BaxHTN)

Authors, Journal, Affiliations, Type, DOI

• Authors: John M. Flack, Michel Azizi, Jenifer M. Brown, Jamie P. Dwyer, Jakub Fronczek, Erika S.W. Jones, Daniel S. Olsson, Shira Perl, Hirotaka Shibata, Ji-Guang Wang, Ulrica Wilderäng, Janet Wittes, Bryan Williams, for the BaxHTN Investigators
• Journal: New England Journal of Medicine, 2025;393:1363-74. Published August 30, 2025.
• Affiliations: Multinational — Southern Illinois University; Université Paris Cité; Brigham and Women's Hospital; University of Utah; AstraZeneca (Warsaw, Mölndal, Gaithersburg); Groote Schuur Hospital (Cape Town); Oita University; Shanghai Jiao Tong University; UCL Institute of Cardiovascular Science
• Type: Phase 3, multinational, double-blind, randomised, placebo-controlled trial (n=794; 214 clinical sites)
• Funded by AstraZeneca
• DOI: https://doi.org/10.1056/NEJMoa2507109

Overview

BaxHTN randomised 794 patients with uncontrolled (≥2 antihypertensives) or resistant hypertension (≥3 including diuretic) and seated SBP 135–170 mmHg to baxdrostat 1 mg, 2 mg, or placebo once daily for 12 weeks on top of stable background therapy. Both doses significantly reduced seated SBP versus placebo (placebo-corrected: −8.7 mmHg with 1 mg and −9.8 mmHg with 2 mg; P<0.001 for both). An 8-week randomised withdrawal phase confirmed a slow BP offset after drug cessation, consistent with persistent effects on sodium homeostasis. Key safety concerns were dose-dependent hyperkalemia and hyponatremia and a reversible eGFR dip; no adrenal insufficiency occurred.

Keywords

Baxdrostat, aldosterone synthase inhibitor, resistant hypertension, uncontrolled hypertension, phase 3, randomised controlled trial, aldosterone, mineralocorticoid receptor antagonist, hyperkalemia, blood pressure

Key Takeaways

Background and Rationale

• Inappropriately elevated aldosterone production (relative to sodium status) is a key driver of hard-to-control hypertension and hypertension-mediated organ damage.
• Mineralocorticoid receptor antagonists (MRAs) block aldosterone's receptor-mediated effects but are underused due to dose-dependent side effects; MRAs also induce counter-regulatory increases in renin and circulating aldosterone that may stimulate MR-independent effects.
• Baxdrostat directly inhibits CYP11B2 (aldosterone synthase), blocking the final three steps of aldosterone biosynthesis; plasma half-life ~30 hours permits once-daily dosing.
• Phase 2 precedents: BrigHTN (resistant HT, positive) and HALO (uncontrolled HT, neutral at 8 weeks). BaxHTN used a broader population and a 12-week period.

Trial Design

• Phase 3, 214 sites, multinational, 52 weeks total structured as 4 sequential parts. Part 1 (weeks 0–12): double-blind 1:1:1 RCT — primary endpoint reported here.
• Enrolled: seated SBP 140–<170 mmHg on ≥2 antihypertensives (uncontrolled) or ≥3 including diuretic (resistant); 2-week run-in to confirm adherence (≥80% tablet count).
• Randomisation stratified by HT status (uncontrolled vs resistant) and baseline SBP (<145 vs ≥145 mmHg).
• Part 3 (weeks 24–32): 8-week double-blind randomised-withdrawal of 2-mg baxdrostat vs placebo among patients who had completed 12 weeks open-label baxdrostat (Part 2) — key secondary endpoint.

Primary Endpoint — Seated SBP at Week 12

• Placebo: −5.8 mmHg (95% CI −7.9 to −3.8)
• 1-mg baxdrostat: −14.5 mmHg; placebo-corrected difference −8.7 mmHg (95% CI −11.5 to −5.8; P<0.001)
• 2-mg baxdrostat: −15.7 mmHg; placebo-corrected difference −9.8 mmHg (95% CI −12.6 to −7.0; P<0.001)
• Consistent across prespecified subgroups (uncontrolled vs resistant, baseline SBP, sex, age, race, region)

Secondary Endpoints

• Resistant-HT subpopulation: placebo-corrected SBP difference −9.1 mmHg (1 mg) and −9.8 mmHg (2 mg); P<0.001 for both
• Diastolic BP placebo-corrected: −3.3 mmHg (1 mg, P=0.001) and −3.9 mmHg (2 mg, P<0.001)
• BP control (SBP <130 mmHg) at week 12: 39.4% (1 mg) and 40.0% (2 mg) vs 18.7% placebo; OR ~2.9 for both (P<0.001)
• Randomised withdrawal (part 3): 2-mg baxdrostat −3.7 mmHg vs placebo +1.4 mmHg; estimated difference −5.1 mmHg (95% CI −8.3 to −1.9; P=0.002) — confirms sustained effect on BP regulation

Safety

• Serious adverse events: 1.9% (1 mg), 3.4% (2 mg), 2.7% (placebo) — similar across groups
• Any adverse events: 47.3% (1 mg), 44.7% (2 mg), 41.3% (placebo); most mild
• Hyperkalemia (K >5.5 mmol/L): 6.1% (1 mg), 11.1% (2 mg) vs 0.4% placebo
• Potassium >6.0 mmol/L: 2.3% (1 mg), 3.0% (2 mg) vs 0.4% placebo; clinical intervention for hyperkalemia in 2.7% (1 mg) and 7.9% (2 mg)
• Hyponatremia (Na <135 mmol/L): 19.1% (1 mg), 22.8% (2 mg) vs 7.0% placebo; most asymptomatic; medical intervention required in 0.8% (1 mg) and 2.3% (2 mg)
• eGFR decline: mean −7.0 ml/min/1.73m² (both doses) vs −0.1 (placebo); occurred early and stabilised; reversed toward baseline during randomised withdrawal; consistent with hemodynamic effect of BP lowering on renal perfusion
• No adrenal insufficiency reported

Mechanistic Insights

• Baxdrostat reduced serum aldosterone and increased plasma renin activity, suggesting aldosterone breakthrough contributes to hard-to-control hypertension even in patients already receiving RAASi
• Slow BP offset after withdrawal (despite ~1-week drug clearance) — may reflect persistent effects on sodium homeostasis or reversal of aldosterone-mediated vascular and sympathetic nervous system damage
• Class comparator lorundrostat (Launch-HTN, JAMA 2025) showed −9.1 mmHg at 6 weeks — consistent ASI class effect

Limitations of the Document

• Ambulatory BP measured in only a small subset (34/214 sites); 24-hour ABPM data very limited
• Female and Black patient representation below real-world proportions (7% Black overall; 36% in North America subgroup)
• Medication adherence not measured by direct biomarker methods throughout (pill count + plasma baxdrostat levels used as proxies)
• 12-week duration insufficient to assess hard cardiovascular outcomes (MI, stroke, death)
• Funded by AstraZeneca; data collected and analysed by AstraZeneca representatives; no independent academic data management
• No active comparator arm — no head-to-head comparison with spironolactone or other MRAs

Key Concepts Mentioned

• concepts/Aldosterone-Synthase-Inhibitors — primary drug class; baxdrostat mechanism, BaxHTN Phase 3 data, comparison with lorundrostat and MRAs

Key Entities Mentioned

• entities/Hypertension — primary disease entity; resistant and uncontrolled hypertension

Wiki Pages Updated

• Created: wiki/sources/baxdrostat-baxhtn-nejm-2025.md
• Created: wiki/concepts/Aldosterone-Synthase-Inhibitors.md
• Updated: wiki/entities/Hypertension.md
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md