HALO Misses End Point, but Optimism Remains for Baxdrostat in Resistant Hypertension

The investigational hypertension therapy baxdrostat reduced systolic blood pressure (SBP) in the phase 2 HALO trial, although the results did not reach statistical significance, according to findings presented Saturday at the 72nd American College of Cardiology (ACC) Scientific Session Together With World Congress of Cardiology.¹ However, both HALO’s lead investigator and another expert were optimistic about baxdrostat, one of a new class of antihypertensive drugs, thanks to a deeper dive into the trial and other recent data.

Deepak L. Bhatt, MD, MPH, director of Mount Sinai Heart and the Dr Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, outlined the results for HALO in a packed Featured Clinical Science session, where he explained that a post-hoc analysis revealed that a cluster of patients in one of the study arms was nonadherent; when results for adherent patients in this arm were calculated, they showed that SBP was reduced.

Baxdrostat is a highly selective aldosterone synthase inhibitor; according to Bhatt, phase 1 studies showed that the therapy caused a sustained, dose-dependent reduction in plasma aldosterone by more than 70% without reducing cortisol. Previously, results for a separate phase 2 study, called BrigHTN, found that baxdrostat reduced SBP 11 mm Hg more than placebo in patients with resistant hypertension. Those findings recently appeared in the New England Journal of Medicine.²

On January 9, 2023, AstraZeneca acquired CinCor, the developer of baxdrostsat, for $1.3 billion, citing baxdrostat’s potential to become a complementary therapy to dapagliflozin (Farxiga), its sodium glucose co-transporter 2 inhibitor.

BrighHTN evaluated patients whose SBP was at least 180 mm Hg or diastolic blood pressure (DBP) was at least 110 mm Hg; these patients also had uncontrolled diabetes and an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m² of body surface area.

Patients in HALO had uncontrolled SBP, but at a lower range: 140 to 180 mm Hg. HALO also excluded patients with a body mass index above 50 kg/m² and an eGFR below 30mL/min/1.73 m². Across the arms of the study, between 33% and 46% of patients had diabetes.

HALO was designed to measure safety and efficacy of baxdrostat in patents taking up to 2 antihypertensive agents at maximally tolerated doses; the trial randomized 249 patients to 1 of 4 groups: baxdrostat at 0.5 mg (n = 63), 1 mg (n = 62), and 2 mg (n = 60) doses, and placebo (n = 64).

The trial enrolled patients on a stable regimen of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), an ACE inhibitor/ARB plus a thiazide diuretic, or an ACE inhibitor/ARB plus a calcium channel blocker. The primary end point was the change from baseline in mean seated SBP after 8 weeks of treatment. Secondary end points included changes in DBP, aldosterone, and renin levels.

The study population was diverse; the mean age across the 4 arms ranged from 59 to 61 years. The percentage of women across the arms ranged from 40% to 55%; Black patients made up about a quarter of participants, and those of Hispanic ethnicity accounted for about one half.

Results showed the following:

• The primary end point of placebo-corrected SBP change was not met at any baxdrostat dose; there was a large decrease in SBP noted in the placebo group
• There was no significant difference in placebo-corrected DBP change; there was a large decrease in DBP noted in the placebo group
• The percentage of patients achieving SBP less than 130 mm Hg at 8 weeks, by group: placebo, 56.3%; 0.5 mg, 57.1% (odds ratio [OR], 0.97; P = .92); 1 mg, 53.2% (OR, 0.85; P = .65); 2 mg, 71.1% (OR, 1.77; P = .10)
• The drug was generally well tolerated; 4 patients across the arms taking the study drug developed hyperkalemia, 5 had dose changes, and 2 had to discontinue taking the study drug

In looking for explanations of the findings, Bhatt noted that compared with the BrigHTN trial, HALO lasted only 8 weeks, not 12; HALO was also a study of “modest” size. But Bhatt also pointed to the post-hoc analysis, which found that site records that showed 95% medication adherence simply did not square with serum evidence that showed patients clustered at a few sites were not taking the study drug; this affected results for 2-mg arm in particular.

Twenty-two patients withdrew or were lost to follow-up after randomization and were not included in the analysis: 4 from the placebo arm, 8 from the 0.5-mg arm, 4 from the 1-mg arm, and 6 from the 2-mg arm.

About 1.3 billion people have hypertension, and reducing its incidence 33% by 2030 is a priority of the World Health Organization. Uncontrolled hypertension increases the risk of heart attack, kidney disease, cognitive decline, and other comorbidities.

“We’ve not had a new antihyperclassive class of drugs in well over a decade,” noted Nanette Wenger, MD, professor of medicine, Division of Cardiology, Emory University School of Medicine, who was a commenter on the results. Despite HALO not meeting its primary end point, Wenger said, there is cause for optimism. A future trial may examine ways to coach patients to ensure they take the study medication, she said.

A phase 3 trial for baxdrostat is planned, Bhatt said. The underlying biological mechanism behind baxdrostat is the best case for the therapy. “In the large phase 3 trial, that'll give us a much more precise estimate of efficacy, of course, and also safety,” he said. “My prediction is that in the resistant hypertension population—where there's such a great unmet need—it will end up being a useful addition to the armamentarium.”

References

1. Bhatt DL, Halvorsen YD, Marshall W, et al. HALO: Results from a phase 3, double-blind, placebo-controlled trial evaluating the efficacy and safety of baxdrostat in patients with uncontrolled hypertension. Presented at: 72nd American College of Cardiology Scientific Sessions Together With World Congress of Cardiology; New Orleans, LA; March 4-6, 2023. Abstract 23-LBCT-20864.

2. Freeman MW, Halvorsen YD, Marshall W, et al. Phase 2 trial of baxdrostat for treatment-resistant hypertension. N Engl J Med. 2023;388(5):395-405. doi:10.1056/NEJMoa2213169