Rationale and design of phase 3 trial for baxdrostat, a novel highly selective aldosterone synthetase inhibitor

Objective: Aldosterone is a key driver of cardiorenal disease as well as hard-to-treat hypertension. Highly selective aldosterone synthase inhibitors (ASI) are a new class of anti-hypertensive therapy that hold great promise for management of blood pressure (BP), having demonstrated BP lowering in a proof-of-concept study. The rationale for and design of a phase 3 trial with the novel ASI baxdrostat are described here. Design and method: The international, multicenter, randomized, double-blind, placebo-controlled phase 3 BaxHTN trial (NCT06034743) will enroll approximately 720 adults with uncontrolled or resistant hypertension defined as seated office systolic BP greater than/equal to 135 mmHg despite 2+ antihypertensives including a diuretic, serum potassium 3.5-5.0 mmol/L, and eGFR greater than/equal to 45mL/min/1.73m2. Given the need to address long-term efficacy but limit placebo use due to the risks of uncontrolled hypertension, the study will have 4 sequential parts following placebo run-in: 1) 12-week double-blind period, 1:1:1 randomization to baxdrostat 2 mg, baxdrostat 1 mg, or placebo; 2) 12-week open label period, re-randomization of the placebo and 1 mg arms to 2 mg or standard-of-care; 3) 8-week randomized withdrawal period to 2 mg or placebo; and 4) 20-week open label period. The primary endpoint will be the change in office systolic BP from baseline to 12 weeks. Adverse events will be evaluated under independent data monitoring committee supervision. Results: Results are expected in late 2025. Conclusions: The phase 3 BaxHTN trial design will allow assessing the safety of baxdrostat and its effect on BP in patients with uncontrolled or resistant hypertension. Results are expected in late 2025.