Effect of baxdrostat on ambulatory blood pressure in patients with resistant hypertension (Bax24): a phase 3, randomised, double-blind, placebo-controlled trial

The Lancet · 2026-03-01 · 5 citations

BACKGROUND: Aldosterone dysregulation is an important contributor in the pathogenesis of hard-to-control hypertension. We aimed to assess the effect of baxdrostat, a selective aldosterone synthase inhibitor, on ambulatory blood pressure in patients with resistant hypertension. METHODS: The Bax24 international, phase 3, randomised, double-blind, placebo-controlled trial recruited adults (aged ≥18 years) with seated systolic blood pressure (SBP) ≥140 mm Hg and <170 mm Hg, despite receiving three or more antihypertensive medications, including a diuretic, from 79 clinical sites (primary, secondary, and tertiary centres, in addition to research centres) in 22 countries. Following a 2-week placebo run-in period, patients with 24 h ambulatory SBP ≥130 mm Hg were randomly assigned (1:1) to receive 2 mg baxdrostat or placebo orally once daily for 12 weeks, in addition to background therapy (stratified by baseline ambulatory SBP <140 mm Hg or ≥140 mm Hg). Investigators, patients, and trial staff were masked to treatment assignment. The primary endpoint was change in 24 h ambulatory SBP from baseline to week 12, assessed by analysis of covariance in patients administered at least one dose of study medication with valid ambulatory SBP measurement at baseline and week 12. Missing or invalid ambulatory SBP measurements were not imputed. The safety analysis included all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT06168409, and is complete. FINDINGS: Between March 1, 2024, and April 16, 2025, 854 patients were screened, 636 were excluded (437 before the placebo run-in and 199 during the placebo run-in) and 217 were randomly assigned to and received baxdrostat (n=108) or placebo (n=109). 140 patients (65%) were male, 77 (35%) patients were female, and 170 patients (78%) were White. The median age was 60·0 years (IQR 51·0-68·0). At 12 weeks, the change from baseline in the least-squares mean 24 h ambulatory SBP was -16·6 mm Hg (95% CI -18·8 to -14·3) in the baxdrostat group (n=89) and -2·6 mm Hg (-4·7 to -0·4) in the placebo group (n=95); the estimated placebo-corrected difference was -14·0 mm Hg (-17·2 to -10·8; p<0·0001). Adverse events occurred in 56 (52%) of 108 patients in the baxdrostat group and 40 (37%) of 109 patients in the placebo group. A confirmed potassium level of more than 6 mmol/L occurred in three (3%) of the 108 baxdrostat recipients and in none of the placebo recipients. INTERPRETATION: Baxdrostat significantly reduced 24 h ambulatory SBP versus placebo in patients with resistant hypertension, providing further evidence of the potential of aldosterone synthase inhibition for treatment of hard-to-control hypertension. FUNDING: AstraZeneca.

Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension

New England Journal of Medicine · 2026-01-14

WCN26-3177 BASELINE CHARACTERISTICS OF PARTICIPANTS IN BAXASIA: PHASE 3 STUDY OF THE ALDOSTERONE SYNTHASE INHIBITOR BAXDROSTAT IN ADULTS WITH UNCONTROLLED OR RESISTANT HYPERTENSION PRIMARILY FROM ASIA

Kidney International Reports · 2026-03-25

Pharmacological blood-pressure lowering for the prevention of cardiovascular disease and death across the full spectrum of chronic kidney disease severity: an individual-participant data meta-analysis

The Lancet · 2026-04-01

<h2>Summary</h2><h3>Background</h3> Individuals with chronic kidney disease (CKD), particularly those at more advanced stages, have been systematically under-represented in randomised controlled trials (RCTs) of blood-pressure-lowering treatment due to safety concerns, leading to a persistent paucity of evidence for cardiovascular risk management in this high-risk group. We investigated the effect of blood-pressure-lowering treatment on the risk of major cardiovascular disease and death across the full spectrum of CKD stages and by key clinical subgroups. <h3>Methods</h3> We conducted a one-stage meta-analysis of individual-participant data from RCTs in which participants were randomly assigned to a blood-pressure-lowering therapy versus a comparator. We used RCTs collated in the Blood Pressure Lowering Treatment Trialists' Collaboration dataset, published at any time in any language, which were eligible for inclusion if they had at least 1000 person-years of follow-up per arm, baseline blood-pressure and creatinine measurements, and time-to-event outcomes; those with unclear randomisation procedures or restricted to heart failure or acute care settings were excluded. Participants with a documented history of heart failure or extreme creatinine values were excluded. No age criteria were applied. The primary outcome was major cardiovascular events, defined as a composite of fatal or non-fatal stroke, ischaemic heart disease, or hospitalisation for, or death from, heart failure. Relative treatment effects were estimated with a stratified Cox proportional hazards model. Heterogeneity of treatment effects was evaluated across prespecified subgroups defined by CKD status, CKD stage (1–5), diabetes, proteinuria, and baseline blood pressure. A stratified network meta-analysis was performed to examine whether treatment effects differed by defined subgroups within each of five principal antihypertensive drug classes. The systematic review was registered in PROSPERO (CRD42018099283). <h3>Findings</h3> From 52 RCTs (363 684 participants), a total of 285 124 participants from 46 randomised trials met the eligibility criteria; 116 145 (40·7%) were women, 168 979 (59·3%) were men, 59 185 (20·7%) had CKD at baseline, and 86 067 (30·2%) had type 2 diabetes. During a median follow-up of 4·4 years (IQR 3·2–5·1), a 5 mm Hg reduction in systolic blood pressure reduced the risk of major cardiovascular disease in individuals with CKD (hazard ratio [HR] 0·91 [95% CI 0·87–0·94]) and without CKD (0·90 [0·88–0·93]; p_interaction>0·99). Furthermore, these observed relative risk reductions were consistent across all CKD stages, including severe stages 4–5 (p_interaction>0·99). Similar treatment effects were observed by proteinuria status and across blood-pressure categories, down to <120/70 mm Hg. However, the relative treatment effect in individuals with CKD was notably attenuated among those with coexisting diabetes (HR 0·96 [95% CI 0·90–1·02]) compared with those without (0·88 [0·84–0·93]; p_interaction=0·044). The stratified analysis within each drug class showed that the class-specific effects of antihypertensive agents versus placebo on cardiovascular disease risk remained unchanged across the investigated subgroups. <h3>Interpretation</h3> In the context of cardiovascular risk reduction, the relative benefit of blood-pressure lowering in patients with CKD is similar to that in individuals without CKD, with consistent efficacy across all CKD stages, blood-pressure thresholds, and proteinuria status. However, notably, this relative benefit is attenuated in patients with CKD and concomitant diabetes, underscoring the requirement for adapted therapeutic strategies in this high-risk subgroup. Moreover, the class-specific effects of principal antihypertensives in CKD mirror those observed in the broader population, independent of CKD stage or proteinuria status. <h3>Funding</h3> British Heart Foundation.

WCN26-3663 BAXHTN – EFFICACY AND SAFETY OF THE ALDOSTERONE SYNTHASE INHIBITOR BAXDROSTAT IN PATIENTS WITH UNCONTROLLED OR RESISTANT HYPERTENSION

Kidney International Reports · 2026-03-25

A double-blind, randomized, placebo-controlled, phase 2 trial examined the efficacy and safety of monlunabant in adults with diabetic kidney disease

Kidney International · 2026-03-20

INTRODUCTION: Diabetic kidney disease (DKD) is a significant complication of diabetes, and an unmet need remains for new therapeutic options. Here, we investigated the efficacy and safety of monlunabant, a second-generation cannabinoid receptor 1 inverse agonist, in individuals with DKD. METHODS: This phase 2, randomized, double-blind, placebo-controlled, multicenter study, enrolled adults with DKD. Participants were randomized (1:1:1) to receive oral tablets of monlunabant 10 mg or 25 mg, or placebo once daily for 16 weeks. The primary endpoint was the change in urine albumin-to-creatinine ratio (UACR) from baseline to week 16. Secondary endpoints included changes in urine protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR). RESULTS: In total, 254 participants formed the full analysis set (85, 86, and 83 in the 10 mg, 25 mg, and placebo groups, respectively). At week 16, the estimated geometric least squares mean ratios to baseline for UACR were 0.58, 0.51, and 0.71 in the 10 mg, 25 mg, and placebo groups, respectively. Monlunabant 25 mg did not show statistically significant differences compared to placebo (estimated treatment ratio [ETR] 0.72, 95% confidence interval (0.46 to 1.14)). Therefore, formal testing was not performed for 10 mg compared to placebo (ETR 0.82 (0.53 to 1.27)). Secondary endpoints showed similar trends, with no differences in UPCR or eGFR, when compared to placebo. The most frequently reported adverse events were mild to moderate gastrointestinal disorders, driven by nausea, vomiting, and diarrhea. Participant withdrawals increased with monlunabant dose. CONCLUSIONS: Our study failed to establish proof of concept of monlunabant in DKD, as the effect on UACR at week 16 was not significantly different from placebo. However, greater than anticipated variability and a large placebo response affect interpretation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT05514548.

Midazolam Dosing During CRRT: A Combined Ex Vivo and Physiologically‐Based Pharmacokinetic Approach

CPT Pharmacometrics & Systems Pharmacology · 2026-04-25

Children supported with continuous renal replacement therapy have high mortality rates ranging from 30% to 70%. The cause of this high mortality is multifactorial and includes ineffective drug dosing and altered drug pharmacokinetics. Changes in drug exposure can result from (1) underlying disease; and (2) direct drug interaction and/or clearance by the circuit. The extent to which these effects interact and modify drug pharmacokinetics is currently unknown for most drugs. As a result, there is little guidance on drug dosing in this population. We have developed a combined ex vivo and physiologically-based pharmacokinetic modeling approach to mechanistically model midazolam concentrations in pediatric patients on continuous renal replacement therapy. Published models were scaled to children and modified to incorporate patient-specific physiological changes due to critical illness including residual renal function, hematocrit, albumin levels, and inflammation-induced downregulation of drug metabolizing enzymes. A compartment representing the dialysis circuit was created, parameterized using ex vivo data, and added to the full child physiological based pharmacokinetic model. The child model was then used to predict drug exposure in children undergoing continuous renal replacement therapy. Observed data from an ongoing opportunistic pharmacokinetic study were used to validate the models. The midazolam continuous renal replacement therapy models accurately represented drug concentrations and were used to predict optimal drug dosing. Model informed dosing for all age groups fell within the standard dosing range suggesting no changes are needed during continuous renal replacement therapy.

Blood pressure lowering in isolated diastolic hypertension and cardiovascular risk: an individual patient data meta-analysis

European Heart Journal · 2025-11-11 · 3 citations

BACKGROUND AND AIMS: Blood pressure (BP) lowering reduces cardiovascular disease (CVD) risk; however, the benefits of treating patients with normal systolic BP but elevated diastolic BP remain uncertain. METHODS: Data from 51 randomized controlled trials were pooled to compare BP-lowering effects in participants with and without isolated diastolic hypertension (IDH), defined as systolic BP < 130 mmHg and diastolic BP ≥ 80 mmHg. Treatment effects were stratified across baseline diastolic BP categories (range < 60 to ≥90 mmHg) among individuals with baseline systolic BP < 130 mmHg. Fixed-effect one-stage individual participant data meta-analyses were used, and Cox proportional hazard models, stratified by trial, were applied to analyse the data. RESULTS: Among 358 325 participants, 15 845 (4.4%) had IDH. At a median follow-up of 4.2 years, a 5 mmHg reduction in systolic BP reduced the risk of major cardiovascular events similarly in individuals with IDH [hazard ratio 0.91; 95% confidence interval (CI) 0.82-1.01] and those without IDH (hazard ratio 0.90; 95% CI 0.89-0.92; P for interaction = 1.00). Analyses by baseline diastolic BP showed no evidence of heterogeneity in treatment effects among individuals with baseline systolic BP < 130 mmHg (P for interaction = .26). Relative treatment effects were not statistically different by CVD history, age, prior medication use, and BP measurement methods. CONCLUSIONS: The study found no evidence to suggest that pharmacological BP-lowering therapy in individuals with IDH is less or more effective than in those without IDH. Relative risk reductions also did not diminish in those with lower diastolic BP, down to <60 mmHg at baseline. No meaningful differences across various clinical phenotypes were detected.

Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension

New England Journal of Medicine · 2025-08-30 · 87 citations

BACKGROUND: Aldosterone dysregulation plays an important pathogenic role in hard-to-control hypertension. In several studies, baxdrostat, an aldosterone synthase inhibitor, reduced the seated systolic blood pressure of patients with uncontrolled or resistant hypertension. METHODS: In this phase 3, multinational, double-blind, randomized, placebo-controlled trial, we recruited patients with a seated systolic blood pressure of between 140 mm Hg and less than 170 mm Hg despite the receipt of stable treatment with two antihypertensive medications (uncontrolled hypertension) or three or more such medications (resistant hypertension), including a diuretic. After a 2-week placebo run-in period, we randomly assigned patients with a seated systolic blood pressure of 135 mm Hg or more in a 1:1:1 ratio to receive baxdrostat at a dose of 1 mg, baxdrostat at a dose of 2 mg, or placebo once daily for 12 weeks. The primary end point was the change in seated systolic blood pressure from baseline to week 12. RESULTS: A total of 796 patients underwent randomization and 794 received 1-mg baxdrostat (264 patients), 2-mg baxdrostat (266 patients), or placebo (264 patients) in addition to background therapy. At 12 weeks, the change from baseline in the least-squares mean seated systolic blood pressure was -14.5 mm Hg (95% confidence interval [CI], -16.5 to -12.5) with 1-mg baxdrostat, -15.7 mm Hg (95% CI, -17.6 to -13.7) with 2-mg baxdrostat, and -5.8 mm Hg (95% CI, -7.9 to -3.8) with placebo. The estimated difference from placebo (placebo-corrected difference) was -8.7 mm Hg (95% CI, -11.5 to -5.8) with 1-mg baxdrostat and -9.8 mm Hg (95% CI, -12.6 to -7.0) with 2-mg baxdrostat (P<0.001 for both comparisons). A potassium level of more than 6.0 mmol per liter was reported in 6 patients (2.3%) with 1-mg baxdrostat, in 8 patients (3.0%) with 2-mg baxdrostat, and in 1 patient (0.4%) with placebo. CONCLUSIONS: Among patients with uncontrolled or resistant hypertension, the addition of baxdrostat to background therapy resulted in a significantly lower seated systolic blood pressure at 12 weeks than placebo. (Funded by AstraZeneca and others; BaxHTN ClinicalTrials.gov number, NCT06034743.).

Baxdrostat for uncontrolled and resistant hypertension: rationale and design of the Phase 3 clinical trials BaxHTN, BaxAsia, and Bax24

Hypertension Research · 2025-08-24 · 10 citations

Inappropriately elevated aldosterone is a common feature of uncontrolled hypertension (uHTN) and resistant hypertension (rHTN), and is a major pathophysiological driver of adverse cardiorenal outcomes beyond elevated blood pressure (BP). Baxdrostat is a selective aldosterone synthase inhibitor that has demonstrated dose-dependent seated office systolic BP (SBP) lowering in a Phase 2 trial of patients with rHTN. Here, we report the design of the baxdrostat hypertension Phase 3 program. BaxHTN (NCT06034743), BaxAsia (NCT06344104), and Bax24 (NCT06168409) are randomized, multi-national, double-blind, placebo-controlled Phase 3 trials evaluating the efficacy and safety of baxdrostat 1 and/or 2 mg versus placebo. BaxHTN includes patients with uHTN or rHTN, BaxAsia includes patients with uHTN or rHTN primarily from Asia, and Bax24 includes patients with rHTN. Eligibility criteria include age ≥18 years, mean seated office SBP of ≥140 mmHg to <170 mmHg at screening, and ≥2 antihypertensive treatments of different classes for ≥4 weeks before screening. BaxHTN and BaxAsia have four sequential periods following placebo run-in: 12-week double-blind; 12-week open-label; 8-week randomized withdrawal; 20-week open-label. Bax24 has a placebo run-in and 12-week double-blind period. Primary endpoints are changes from baseline to Week 12 in mean seated office SBP (BaxHTN and BaxAsia) and ambulatory 24-h average SBP (Bax24). Safety and tolerability are also assessed. The Baxdrostat hypertension Phase 3 program will assess efficacy, long-term sustained effect, and safety profile in patients with hypertension across multiple geographies. The trials will evaluate the BP lowering efficacy of aldosterone synthase inhibition as a novel treatment for uHTN and rHTN.