Written and Reviewed By: Vikas Londhe MPharm
A recently concluded The phase 3 BaxHTN trial, published in the New England Journal of Medicine (2025), evaluated the efficacy and safety of baxdrostat in patients with uncontrolled and resistant hypertension who failed other antihypertensive treatments. Baxdrostat, a selective aldosterone synthase inhibitor, offers a novel strategy by directly reducing aldosterone production. Hypertension that remains uncontrolled despite treatment with multiple medications can have a major challenge in clinical management of the blood pressure. Patients with resistant hypertension are at high risk of cardiovascular complications.
Aldosterone and Resistant Hypertension
Aldosterone is a hormone that regulates blood pressure by controlling salt and water balance in the body. When its production is abnormally high, it pushes the kidneys to retain sodium and water, while increasing potassium loss. This imbalance leads to persistent elevation of blood pressure and contributes to organ damage over time. Excess aldosterone is now recognized as a key factor of uncontrolled and resistant hypertension.
Traditional therapies such as mineralocorticoid receptor antagonists (MRAs), including spironolactone and eplerenone, attempt to block aldosterone’s action at its receptor. These agents found to be effective in controlling blood pressure but often trigger side effects like hyperkalemia and kidney function decline. As a result, many patients cannot tolerate MRAs on long term, limiting their use in clinical practice.
Baxdrostat, however targeting aldosterone but it works differently; instead of blocking the receptor, it directly inhibits aldosterone synthase, the enzyme responsible for the final steps in aldosterone production, lowering aldosterone level at its source. This mechanism makes it particularly valuable in patients, whose hypertension remains uncontrolled despite multiple drug classes, including those with resistant disease.
Trial Design
The BaxHTN study was a multinational, double-blind, randomized, placebo-controlled trial. It included adults with a mean seated systolic blood pressure (SBP) of 140 to <170 mmHg despite therapy with at least two antihypertensive drugs (uncontrolled hypertension) or three or more drugs, including a diuretic (resistant hypertension). After a 2-week placebo run-in, patients with seated SBP ≥135 mmHg were randomized to once-daily Baxdrostat 1 mg, Baxdrostat 2 mg, or placebo, in addition to background therapy.
The primary endpoint was the change in seated SBP at 12 weeks. Secondary endpoints included effects in the resistant hypertension subgroup, changes in diastolic pressure, the proportion of patients reaching SBP <130 mmHg, and outcomes during a randomized withdrawal phase.
Results
A total of 796 patients were randomized, and 794 received treatment. Baseline mean blood pressure was 149/87 mmHg across groups.
At 12 weeks, Baxdrostat produced substantial reductions in SBP compared with placebo:
- 1 mg Baxdrostat: –14.5 mmHg (placebo-corrected difference –8.7 mmHg)
- 2 mg Baxdrostat: –15.7 mmHg (placebo-corrected difference –9.8 mmHg)
- Placebo: –5.8 mmHg
Both Baxdrostat doses achieved statistically significant improvements (P<0.001). Importantly, effects were consistent across prespecified subgroups, including patients with resistant hypertension.
During the randomized-withdrawal phase, patients switched from Baxdrostat to placebo showed a rise in SBP, confirming the drug’s effect.
Safety Profile
Adverse events were reported in 41–47% of patients across groups, with most being mild. The most common included hyperkalemia, hyponatremia, hypotension, muscle spasms, and dizziness.
- Hyperkalemia (>6.0 mmol/L) occurred in 2.3% of the 1 mg group, 3 % of the 2 mg group, and 0.4% with placebo.
- Hyponatremia (<132 mmol/L) was observed in 5.7% in 1 mg group and up to 8% in 2 mg group of Baxdrostat-treated patients compared with 1.1% on placebo.
- Estimated GFR declined modestly (–7 mL/min/1.73 m² with Baxdrostat vs –0.1 with placebo) but returned toward baseline after drug withdrawal, suggesting a hemodynamic effect.
- No cases of adrenal insufficiency were reported.
Overall, safety findings were consistent with the expected pharmacological profile of aldosterone synthase inhibition.
Interpretation
The BaxHTN trial provides robust phase 3 evidence that Baxdrostat significantly lowers systolic blood pressure in patients with both uncontrolled and resistant hypertension. The extent of reduction (about 9–10 mmHg beyond placebo) is clinically meaningful, given that even a 5 mmHg decrease is associated with reduced cardiovascular risk.
While safety concerns such as hyperkalemia and hyponatremia warrant monitoring, most events were manageable. The drug’s once-daily dosing and targeted mechanism make it a promising alternative to mineralocorticoid receptor antagonists, especially for patients who cannot tolerate spironolactone or eplerenone.
Conclusion
Baxdrostat represents an important therapeutic advance for patients with difficult-to-control hypertension. Its ability to safely and effectively lower blood pressure across a broad population highlights the central role of aldosterone in hypertension pathophysiology. Ongoing studies will further clarify its long-term safety and potential to reduce cardiovascular events.
References
John M. Flack, Michel Azizi, Jenifer M. Brown, Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension, New England Journal of Medicine, published on August 30, 2025, DOI: 10.1056/NEJMoa2507109
Baxdrostat demonstrated statistically significant and clinically meaningful reduction in systolic blood pressure in patients with hard-to-control hypertension in the BaxHTN Phase III trial, 30 Aug 2025, AstraZeneca, https://www.astrazeneca.com/media-centre/press-releases/2025/baxdrostat-demonstrated-statistically-significant-clinically-meaningful-reduction-sbp-patients-hard-control-hypertension-baxhtn-phase-iii-trial.html