Baxdrostat in patients with uncontrolled hypertension

In the placebo-controlled phase 2 HALO trial, baxdrostat did not achieve a statistically significant change from baseline in mean seated systolic blood pressure (SBP) in patients with uncontrolled hypertension. The placebo effect in this study was substantial. In a post-hoc analysis, SBP was significantly lowered in patients adherent to the highest dose of 2 mg.

The results of the phase 2 HALO study (NCT05137002) were highly anticipated since there have not been any new agents to treat uncontrolled hypertension in well over a decade, said Dr Deepak Bhatt (Icahn School of Medicine at Mount Sinai, NY, USA) [1]. Baxdrostat is a highly selective aldosterone synthase inhibitor. Its efficacy and safety were evaluated in the randomised, double-blind, placebo-controlled, multicentre, phase 2 HALO trial. The participants had to be on a stable regimen of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), an ACEi/ARB plus a thiazide diuretic, or an ACEi/ARB plus a calcium channel blocker, and have a mean seated SBP ≥140 mmHg. The primary endpoint was change from baseline in mean seated SBP after 8 weeks of treatment. A total of 249 patients were randomised 1:1:1:1 to baxdrostat 0.5 mg, 1 mg, 2 mg, or placebo; 227 completed the trial.

The primary endpoint was not met with any baxdrostat dose. SBP change was -17.0, -16.0, and -19.8 mmHg in the 0.5 mg, 1 mg, and 2 mg groups, respectively, but there was also a large decrease (-16.6 mmHg) in the placebo group (see Figure).

Figure: Placebo-corrected change from baseline in mean seated SBP at 8 weeks [1]



Similarly, none of the baxdrostat doses were associated with a significant difference in placebo-corrected diastolic blood pressure (DBP), which was a secondary endpoint. Change in DBP at 8 weeks did not significantly differ either; nor did the percentage of patients achieving a seated SBP response <130 mmHg at 8 weeks. Baxdrostat significantly reduced serum aldosterone levels at all doses. The treatment was well tolerated.

Dr Bhatt explained that a post-hoc analysis was done in patients who were adherent to the highest baxdrostat dose of 2 mg. The reason was that 20 of 54 (36%) patients in the 2 mg arm who completed 8 weeks of treatment had baxdrostat levels <0.2 ng/dL, indicating non-adherence (despite dosing records by pill count showing >95% adherence in all groups). This subgroup analysis suggested a placebo-corrected SBP reduction of 7.9 mmHg in patients adherent to baxdrostat 2 mg.

1. Bhatt DL, et al. Results from a phase 2, double-blind, placebo-controlled trial evaluating the efficacy and safety of baxdrostat in patients with uncontrolled hypertension. Session 403-08, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.

 

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Posted on 7 June, 2023