New Antihypertensive Stumbles in Phase 2 Study: HALO

A phase 2 study of a new class of antihypertensive agent, baxdrostat (CinCor Pharma/AstraZeneca), failed to show a significant reduction in blood pressure compared with placebo, but the trial was marred by a large placebo effect and nonadherence in the group taking the highest dose of the active drug.

The HALO study results were presented by Deepak Bhatt, MD, director of Mount Sinai Heart, New York City, at the recent American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023.

Bhatt noted that development of the drug is continuing.

“My prediction is that in the resistant hypertension population — where there is so much unmet need — this drug will end up being a useful addition to the armamentarium,” he concluded.

Bhatt noted that baxdrostat (CIN-107) is a highly selective aldosterone synthase inhibitor that has shown a sustained, dose-dependent reduction of plasma aldosterone by >70% without reducing cortisol. In a previous phase 2 study, (BrigHTN), baxdrostat reduced systolic blood pressure (SBP) by 11 mm Hg more than placebo in patients with treatment-resistant hypertension.

The current HALO study is another phase 2 trial looking at the safety and efficacy of baxdrostat in patients with uncontrolled hypertension.

The study enrolled 249 patients on a stable regimen of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB), an ACEi/ARB plus a thiazide diuretic, or an ACEi/ARB plus a calcium blocker, and a mean seated systolic blood pressure ≥140 mm Hg (baseline systolic pressure was 146-148 mm Hg).

The patients were randomly assigned to one of three different once-daily doses of baxdrostat (0.5 mg, 1 mg or 2 mg) or placebo.

Results showed that the primary endpoint of placebo-corrected systolic blood pressure change at 8 weeks was not met at any baxdrostat dose, but there was a large decrease in systolic blood pressure in the placebo group.

The systolic blood pressure reductions were 17 mm Hg in the 0.5 mg baxdrostat group, 16 mm Hg in the 1 mg group, 19.8 mm Hg in the 2 mg group, and 16.6 mm Hg in the placebo group.

Similar results were seen for diastolic pressure, which was reduced by 5.8, 5.0, and 5.4 mmHg in the three baxdrostat groups vs 5.9 mm Hg in the placebo group.

Bhatt noted that adverse events were largely similar across the four groups. Adverse events of special interest were hypotension (which occurred in 1 patient in the baxdrostat 0.5 mg group vs 0 on placebo); elevated potassium levels (3 patients in the 2 mg group and 1 patient in the 1 mg group vs 1 patient on placebo); and low sodium levels (1 patient in the 1 mg group vs 0 on placebo).

Bhatt reported that these adverse effects were reversed in all six baxdrostat patients experiencing them — four patients after interruption of treatment, and in two cases after cessation of treatment. 

He also pointed out that 20 patients (36%) in the 2 mg baxdrostat group had less than 1% of the expected blood levels of the drug, indicating nonadherence. Post-hoc analysis excluding these patients demonstrated a significant systolic blood pressure reduction in the 2 mg group (-24.3 mm Hg vs -16.4 mm Hg with placebo).

“I believe this post-hoc analysis to be true. We have good biological rationale for this, and in other analyses we have shown clear relationship between accrual drug levels and effect,” Bhatt commented.   

Discussing the trial at the ACC session, Nanette Wenger, MD, Emory  University School of Medicine, whose career in cardiology has spanned more than 50 years, agreed that the marked reduction in blood pressure in the placebo group and nonadherence in the high dose baxdrostat group probably contributed to lack of significant results.

Wenger, who at age 92 has been a women’s health pioneer and a trailblazer in the field of cardiology, said she was still excited about this drug.

“Hypertension and poor hypertension control are major problems worldwide and we have not had a new class of antihypertensive drug in well over a decade, so here is a possibility for intervention,” she noted.

She added that baxdrostat seemed to have a “reasonable” safety profile in patients with preserved kidney function, and is “another potential, either to add to a regimen for patients with resistant hypertension, or possibly even as an upstream drug for patients with hypertension.”

Bhatt noted there are still two ongoing phase 2 trials with the drug: one in chronic kidney disease and one in primary aldosteronism; AstraZeneca, which has now acquired the drug from CinCor, is planning a phase 3 trial in resistant hypertension.

The HALO study was funded by CinCor. Bhatt reports receiving research funding from CinCor and AstraZeneca.

American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023: Featured Clinical Research. Presented March 4, 2023.

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