Novel Antihypertensive Stumbles Over Early-Phase Hurdle

NEW ORLEANS — A phase II trial with baxdrostat failed to replicate the impressive blood-pressure lowering seen in a similar trial with the novel antihypertensive for treatment-resistant hypertension.

Placebo-corrected systolic blood pressure reduction was not significant at any baxdrostat dose in the HALO trial, reported Deepak Bhatt, MD, MPH, of Mount Sinai Heart in New York City, at the American College of Cardiology (ACC) annual meeting.

While the drug reduced mean seated systolic blood pressure by 16.0-19.8 mm Hg across the doses tested, the placebo group had a 16.6-mm Hg improvement from baseline to week 8 as well, rendering the primary endpoint of placebo-corrected change insignificant.

The secondary endpoint of diastolic blood pressure followed a similar pattern, with small, insignificant differences that if anything favored placebo.

In the prior phase II BrighHTN trial, baxdrostat reduced systolic blood pressure by 11 and 8.1 mm Hg more than placebo in the two higher dose groups.

The drug, which is in a new class of highly selective aldosterone synthase inhibitors, did decrease serum aldosterone and increase plasma renin activity as expected compared with placebo in HALO.

A post hoc analysis to understand why the trial failed despite high pill-count based adherence showed that 36% of the baxdrostat patients in the highest, 2-mg dose group (20 of 54) were actually not adherent based on plasma levels less than 1% of expected.

“I wonder where the pills actually went,” quipped ACC session moderator Kim Eagle, MD, of the University of Michigan in Ann Arbor.

“Probably they were flushed,” said Bhatt. “In fairness, it wasn’t across the trial. It was clustered at a few sites for this happening. I think it points to issues potentially of having to be really careful about site selection and providing enough support for patients to navigate a complex medical regimen.”

Of course, the adherence problem does not explain the placebo effect, Eagle told MedPage Today. “The placebo effect may well be that by enrolling in a trial, the patient is also taking their other meds for hypertension. Recall that the patients were already supposed to be taking several antihypertensives.”

Nevertheless, he called it compelling that, in “patients who were taking the larger dose and who had evidence of adherence by blood levels, the drug clearly seems to work.”

In that post hoc analysis of patients who had at least 1% of the expected plasma level of baxdrostat suggesting that they took the drug as assigned, the 2-mg group had a 24.3 mm Hg reduction in systolic blood pressure compared with 7.9 mm Hg in the placebo group, which was a significant difference at P<0.01.

Study discussant Nanette Wenger, MD, of Emory University School of Medicine in Atlanta, also expressed enthusiasm despite the trial failure.

“We have not had a new antihypertensive class of drugs in well over a decade,” she said. Given the “reasonable” safety profile in a trial phase that really is only designed to show reasonable safety and enough promise to move to phase III, she concluded: “This is another potential [agent] either to add to a regimen for patients with resistant hypertension, or, should it be shown to be effective, possibly even as an upstream drug for patients with hypertension.”

Bhatt pointed to two ongoing phase II trials (one in chronic kidney disease, the other in primary aldosteronism) and drug developer AstraZeneca’s announcement of plans for a phase III trial in resistant hypertension.

“I think we have good biological rationale,” he said, pointing also to the post hoc analysis results. “But will know for sure in the phase III trial planned. It will give us a much more precise estimate of efficacy, of course, and also safety. My prediction is the resistant hypertension population, where there is such a great unmet need, it will end up being a useful addition to the armamentarium.”

Limitations were the phase II design with modest size; inclusion of U.S patients only, although racially and ethnically diverse; and suboptimal adherence clustered at some sites.

HALO included 249 participants with a mean seated systolic blood pressure of 140-180 mm Hg at baseline despite treatment with a stable regimen of an ACE inhibitor or one of those drugs plus a thiazide diuretic or a calcium channel blocker. They were randomized to placebo or a 0.5-, 1.0-, or 2.0-mg dose of baxdrostat for 8 weeks.

Of the participants, 26% were Black, 53% were Hispanic or Latino, and around half were women.

The drug had similar adverse-event rates overall compared with placebo. The sole serious adverse event was a death in the 2.0-mg baxdrostat group due to acute respiratory failure following a diagnosis of COVID-19 at 30 days after the last dose of study drug.

Of the adverse events of special interest, rates were the same across the lower dose and placebo groups, at 1.6% each, and 6.7% in the 2.0-mg dose group. All six of those baxdrostat patients recovered, four after dose interruption and two after discontinuation.

Subgroup analysis suggested some difference in impact by ethnicity, but Bhatt suggested interpreting with caution due to the multiple subgroup comparisons in a modest-sized phase II trial.