Add-on baxdrostat shows promise for hard-to-control BP

In the phase III BaxHTN trial, the highly selective and potent aldosterone synthase inhibitor baxdrostat efficiently controls blood pressure (BP) when added to background antihypertensive therapy for the treatment of uncontrolled or treatment-resistant hypertension (HTN).

“[At week 12,] I was pleased to see that we only had a modest effect in those randomized to placebo (least-squares mean [LSM] change, -5.8 mm Hg), which has often been a hazard in many trials on resistant HTN,” said Professor Bryan Williams from the University College London, UK, during a Hot Line session at ESC 2025.

“In patients receiving baxdrostat 1 mg, we saw a very substantial reduction in [seated] systolic BP (SBP; LSM, -14.5 mm Hg). In patients receiving baxdrostat 2 mg, there was a numerically greater reduction in [seated SBP] (LSM, -15.7 mm Hg),” he continued, amidst a resounding applause.

Between-group comparisons led to placebo-corrected differences of -8.7 mm Hg (baxdrostat 1 mg) and -9.8 mm Hg (baxdrostat 2 mg). Both comparisons yielded p-values of <0.0001. [Williams, et al, ESC 2025]

Williams added that there was no evidence of any heterogeneity in response across all patient groups, including those with uncontrolled and resistant HTN.

By week 24, seated SBP was 133 mg Hg in both arms. Eight weeks after (end of study part 3), there was a modest increase in SBP among placebo recipients and further reductions among those on baxdrostat 2 mg (LSM change, +1.4 vs -3.7 mm Hg; p=0.0016). “The difference between groups was highly significant. Interestingly, there was a slow offset of the effect of baxdrostat on SBP and continued BP lowering out to 32 weeks,” said Williams.

Exploratory endpoint: Ambulatory BP

Week 12 also saw substantial differences in ambulatory 24-h average SBP between the baxdrostat and placebo arms (placebo-corrected difference, -14.6 mm Hg [baxdrostat 1 mg] and -16.9 mm Hg [baxdrostat 2 mg]). This pattern was similarly seen for ambulatory nighttime average SBP (placebo-corrected difference, -11.7 mm Hg [baxdrostat, pooled]).

“[Although] this analysis was conducted in a small group of patients … I think the results are remarkable. There was no placebo effect, which we often do not see in ambulatory BP studies. The nighttime BP was substantially lowered with baxdrostat, which was consistent with its long duration of action,” said Williams.

Serum aldosterone

Expectedly, baxdrostat suppressed the circulating levels of serum aldosterone concentrations at week 12 by 60 percent with the 1-mg dose (from 7.9 to 3.2 ng/dL) and 65 percent with the 2-mg dose (from 7.2 to 2.5 ng/dL).

“Interestingly, during randomized withdrawal, those continuing baxdrostat still had that >60-percent suppression of aldosterone levels throughout to 32 weeks. For those who had withdrawn treatment, even by the end of 8 weeks, there was only a modest elevation in the aldosterone level, and it never returned to baseline level,” Williams said.

“Aldosterone is a well-known driver of HTN, but for decades, scientists have struggled to block its production in a precise way … Mineralocorticoid receptor antagonists can be used to block receptor-mediated aldosterone effects, but dose-dependent adverse effects have limited their clinical utility,” Williams noted. “Baxdrostat is one of the first therapies to do so selectively, showing meaningful BP reductions in uncontrolled or resistant HTN.”

Study profile

The study included adults with a mean seated SBP of ≥140 to <170 mm Hg despite treatment with maximally tolerated doses of 2 (uncontrolled HTN) or ≥3 (resistant HTN) antihypertensives, including a diuretic, for ≥4 weeks before screening.

In the 12-week double-blind (DB) phase, 796 participants were randomized 1:1:1 to baxdrostat 1 or 2 mg or placebo QD. In the ensuing 12-week open-label period, baxdrostat 2-mg recipients continued their regimen, those on the 1-mg dose were randomized 4:1 to standard of care (SoC) or baxdrostat 2 mg, while those on placebo were randomized 1:4 to SoC or baxdrostat 2 mg. In part 3 (8-week DB randomized withdrawal period), participants on baxdrostat 2 mg were rerandomized 2:1 to continue baxdrostat or switch to placebo.

The full analysis set comprised 794 patients (mean age 61 years, 62 percent men, 26 percent Asian) who received at least one dose of baxdrostat. Of these, 73 percent had resistant HTN, while the rest had uncontrolled HTN. Mean baseline BP was 149/87 mm Hg. Participants had a median of three background antihypertensives. Almost all were on a background diuretic. Ninety percent were on an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker.

Safety data

The rates of any severe adverse event (AE) with baxdrostat 1 and 2 mg were low (1.1 and 2.6 percent, respectively), as were the incidences of discontinuation due to hyperkalaemia (0.8 percent and 1.5 percent). Only 1 percent of baxdrostat recipients had confirmed serum potassium >6 mmol/L.

AEs were mostly mild. There were no reports of any adrenal insufficiency. The most common AE of special interest with baxdrostat 1 and 2 mg was hyperkalaemia (2.7 percent and 7.9 percent, respectively), followed by hypotension (1.9 percent and 2.3 percent) and hyponatraemia (0.8 percent and 2.3 percent).

The greatest challenge in HTN clinics

According to discussant Professor Tomasz Guzik from the University of Edinburgh, UK, “uncontrolled and resistant HTN probably remain the greatest challenge in HTN clinics”.

As the BP reductions occurred in patients who were already on a median of three drugs, baxdrostat represents a new medication that clinically lowers BP on top of an already intensive therapy, he noted.

The most interesting finding, Guzik highlighted, is the minimal rise in BP when the drug was stopped during the washout phase. “This indicates that there is minimal rebound despite drug clearance. So, we are not dealing with a drug-on-drug-off effect. The resetting of some pathophysiological mechanisms … shows that we are dealing with a medication that efficiently lowers BP and actually changes the underlying disease trajectory.”

May benefit a broader population

Given that the trial successfully recruited patients across different subgroups around the world, Williams noted that this underlines the potential of baxdrostat to extend its efficacy to a broad population of HTN patients. “[Moreover, looking] at the heterogeneity data, there was no evidence of any selected group that responded more than the other – they all responded to treatment.”

He added that once patients with difficult-to-control BP start to use baxdrostat and realize that it is highly effective, it might move up towards earlier treatment.

Overall, the findings are an important advance in treatment and in the understanding of the cause of hard-to-control BP, Williams noted in the press release. “I think this is great news for doctors because they [would prefer] drugs that will lower BP in all their patients … and for patients because it is an opportunity to improve on where we are at the moment.”