Key Points
Question
Is the aldosterone synthase inhibitor lorundrostat more effective than placebo in reducing blood pressure in participants with uncontrolled hypertension, including treatment-resistant hypertension, taking 2 to 5 prescribed antihypertensive medications?
Findings
In this randomized clinical trial, 50 mg of lorundrostat once daily significantly reduced automated office systolic blood pressure (by 16.9 mm Hg) vs placebo (by 7.9 mm Hg) at week 6 in participants taking 2 or more prescribed antihypertensive medications. Lorundrostat was associated with a low incidence of hyperkalemia and was well tolerated.
Meaning
These data support the use of lorundrostat as a treatment option for participants with uncontrolled hypertension, including treatment-resistant hypertension.
Abstract
Importance
Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension.
Objective
To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension.
Design, Setting, and Participants
In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025.
Intervention
Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n = 270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n = 541), or daily placebo for 12 weeks (n = 272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR.
Main Outcome and Measures
The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function.
Results
Of the 1083 participants, the mean age was 61.6 years (SD, 10.3 years), 508 (46.9%) were female, 311 (28.7%) were Black or African American, 733 (67.7%) were White, and 685 (63.3%) had a body mass index of 30 or greater (obesity). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more. For the pooled 50 mg of lorundrostat group (n = 808), the least-squares mean change in automated office systolic BP at week 6 was −16.9 mm Hg (95% CI, −19.0 to −14.9 mm Hg) vs −7.9 mm Hg (95% CI, −11.5 to −4.2 mm Hg) for the placebo group (least-squares mean difference, −9.1 mm Hg [95% CI, −13.3 to −4.9 mm Hg]; P < .001). Hyponatremia, hyperkalemia, and reduction in kidney function were reported more often with lorundrostat vs placebo. In the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 participant (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function. In the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 participants (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function. Treatment-emergent adverse events occurred in 49.9% of participants (538/1078) and were mostly mild or moderate in severity.
Conclusions and Relevance
The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension.
Trial Registration
ClinicalTrials.gov Identifier: NCT06153693
This randomized clinical trial compares the efficacy and safety of lorundrostat for lowering blood pressure when added to a prescribed antihypertensive regimen of 2 to 5 medications vs placebo among participants with uncontrolled hypertension, including those with treatment-resistant hypertension.
Introduction
Hypertension affects 1 in 3 adults globally and is the leading modifiable risk factor for cardiovascular disease.1,2 Despite the availability of multiple antihypertensive treatment options, more than 40% of adults with hypertension do not have adequate blood pressure (BP) control.3 Uncontrolled hypertension confers an elevated risk of end-organ damage as well as all-cause and cardiovascular mortality. This is particularly true among patients with treatment-resistant hypertension, which is defined as an inability to achieve a target BP despite treatment with at least 3 antihypertensive medications of different classes, including a diuretic, a renin-angiotensin system blocker, and a long-acting calcium channel blocker or β-blocker.4,5,6
There is increasing awareness that primary aldosteronism and the secondary causes of increased aldosterone production, including obesity and aldosterone breakthrough, contribute significantly to elevated BP and a lack of BP control among patients with hypertension.7,8 Collectively these disease states may be termed aldosterone dysregulation and some estimates suggest 30% of patients with hypertension have dysregulated aldosterone production, many of whom are undiagnosed and untreated.9 However, aldosterone-targeted antihypertensive medication is underused worldwide in the treatment of hypertension. Mineralocorticoid receptor antagonists (MRAs), the only currently available aldosterone-targeted antihypertensive class, are recommended as a fourth-line add-on treatment for patients with treatment-resistant hypertension in both European and US BP guidelines.10
Aldosterone synthase inhibitors target aldosterone synthesis in the adrenal glands and extra-adrenal tissues.11 Aldosterone synthase inhibitors reduced BP in initial trials. Recently, several aldosterone synthase inhibitors with improved selectivity, including lorundrostat, have entered late-stage clinical development.12,13,14,15,16,17 Two phase 2 trials of lorundrostat have been completed. The dose-finding, phase 2 Target-HTN trial14 of lorundrostat included participants with hypertension who were taking 2 to 3 or more antihypertensive medications and demonstrated a significant reduction in systolic BP. Use of lorundrostat was associated with modest effects on serum potassium level and selective suppression of aldosterone, and no effects on adrenocorticotropic hormone–stimulated cortisol production. The Advance-HTN trial,18 a 12-week placebo-controlled trial including 285 participants with confirmed uncontrolled hypertension, demonstrated clinically meaningful reductions in 24-hour ambulatory BP.
The phase 3 Launch-HTN randomized clinical trial evaluated the efficacy, tolerability, and safety of lorundrostat in participants with uncontrolled hypertension, including those with apparent treatment-resistant hypertension.
Methods
Trial Design, Organization, and Oversight
The current double-blind, placebo-controlled randomized clinical trial screened participants at 159 sites across 13 countries. The participants were recruited by investigators from primary and secondary care clinics. Additional information appears in the eMethods in Supplement 1 and in the trial protocol (versions of the trial protocol appear in Supplements 2-4).
The trial was composed of 3 phases: screening, a 2-week single-blind placebo run-in, and a 12-week randomized, double-blind treatment phase (eFigure 1 in Supplement 1). Upon completion, participants had the option to enroll in an open-label extension trial of lorundrostat or participate in a 2-week safety follow-up. Participants continued taking their prescribed antihypertensive medications for the duration of the trial.
All participants provided written informed consent before enrollment. The trial protocol was approved by an institutional review board or independent ethics committee at each site. The trial was conducted in accordance with the principles of the Declaration of Helsinki19 and the Good Clinical Practice guidelines of the International Council for Harmonization. An independent, unblinded data and safety monitoring committee assessed the study. This report followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.
Trial Population
Males or females aged 18 years or older with an unattended automated office systolic BP of 135 to 180 mm Hg and diastolic BP of 65 to 110 mm Hg or an isolated automated office diastolic BP of 90 to 110 mm Hg while taking stable doses of 2 to 5 prescribed antihypertensive medications (including a thiazide or thiazide-like diuretic) were eligible for inclusion. The key exclusion criteria were an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2, a serum potassium level of greater than 5.0 mmol/L at screening or greater than 4.8 mmol/L at randomization, and a serum sodium level of less than 135 mmol/L at screening. The use of epithelial sodium channel inhibitors, MRAs, and potassium-sparing diuretics was prohibited 4 weeks prior to screening to trial completion. The full inclusion and exclusion criteria appear in the eMethods in Supplement 1. Sex and race were self-reported and this information was collected to examine the potential significant effects of sex and race on BP outcomes.
Trial Procedures
After the screening phase, eligible participants proceeded to a 2-week single-blind placebo run-in phase (Figure 1). Upon confirmation of eligibility for randomization after the placebo run-in phase, participants were randomly assigned in a 1:2:1 ratio to receive 50 mg of lorundrostat for 6 weeks and then possibly 100 mg for 6 weeks (n = 270) if they met prespecified criteria at week 6 (the prespecified criteria were office systolic BP ≥130 mm Hg, serum potassium level ≤4.8 mmol/L, serum sodium level ≥135 mmol/L, eGFR >45 mL/min/1.73 m2, and <25% reduction in eGFR from baseline), 50 mg of lorundrostat once daily for 12 weeks (n = 541), or placebo once daily for 12 weeks (n = 272).
Figure 1. Flow of Participants Through the Launch-HTN Trial.
aThe most frequent reasons were current use of treatment (or anticipated treatment) with any of the prohibited medications described in the trial protocol within a specified time frame (n = 15); had a condition that would preclude participation in the study (based on the opinion of the investigator) (n = 14); and had current, known, or presumed orthostatic hypotension (n = 9).
bParticipants were escalated to 100 mg of lorundrostat once daily after week 6 if all the following prespecified criteria were met at week 6: had an automated office systolic blood pressure of 130 mm Hg or greater; had a potassium level of less than 4.8 mmol/L; had a sodium level greater than 135 mmol/L; had an estimated glomerular filtration rate (eGFR) greater than 45 mL/min/1.73 m2; and had less than a 25% reduction in eGFR from randomization. Of the 270 participants randomized to 50 mg of lorundrostat once daily, 92 (34.1%) were escalated to the 100-mg dose.
cIncluded participants who received at least 1 dose of trial drug according to treatment assignment at randomization.
dIncluded participants who received at least 1 dose of trial drug according to the actual treatment they received.
The participants in the lorundrostat group who did not meet all of the prespecified criteria at week 6 continued to receive the 50-mg dose for the remaining 6 weeks of double-blind treatment. The trial medication dose could be reduced, temporarily withheld, or permanently discontinued for safety concerns at the discretion of the investigators. Random permuted block sizes of 4 and 8 were used for randomization, which was stratified by geography (Australia, Canada, Europe, and the US). The randomization sequence was implemented using the Rave RTSM (a randomization and trial supply management system manufactured by Medidata).
The placebo tablets were identical in color, shape, and packaging to the tablets containing lorundrostat. Participants took 2 tablets at each dosing to ensure blinding of dose escalation after week 6. The treatment assignment was masked to participants, investigators, individuals assessing the outcomes, and individuals analyzing the data until the final database lock. Lorundrostat or matching placebo tablets were administered orally once daily at approximately the same time each morning. Participants were reminded about taking their trial medication using a smartphone application (AiCure).20 Unattended, automated office BP was assessed at screening, at randomization (baseline), at weeks 2, 4, 6, 8, and 12 during the double-blind treatment phase, and at an optional safety follow-up visit.
Each site was provided with an identical automated oscillometric BP device (MicroLife WatchBP Office AFIB), training, and an instruction manual for collecting BP measurements. All BP was measured with an appropriately sized cuff on the same arm of the participant throughout the trial at approximately the same time, preferably in the morning. After an initial 5-minute rest phase, 5 unattended seated measurements were performed with a 1-minute break between each reading; the last 4 measurements were used to calculate the mean and reduce within-participant variance in measuring BP.21 A standing measurement followed the seated measurements to monitor for orthostatic hypotension.
Trial Outcomes
The primary efficacy outcome was the change in office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. The key secondary outcomes controlled for multiplicity and included the proportion of participants with an office systolic BP of less than 130 mm Hg at week 6; change in office systolic BP at week 6 in participants taking 2 prescribed antihypertensive medications or taking 3 or more prescribed antihypertensive medications; change in office systolic BP from baseline by continuous body mass index (BMI; calculated as weight in kilograms divided by height in meters squared); change in office systolic BP at week 12; and change in office systolic BP from baseline at week 12 in participants who met prespecified criteria and were escalated from 50 mg to 100 mg of lorundrostat after week 6 (eTable 1 in Supplement 1). Efficacy evaluations at week 6 included participants in both lorundrostat groups because both groups were randomized to receive 50 mg of lorundrostat for the first 6 weeks.
Safety was assessed as the proportion of participants having received at least 1 dose of trial medication experiencing any treatment-emergent adverse events. Prespecified adverse events of special interest included dose reduction, interruption, or discontinuation due to hyperkalemia, hyponatremia, and reduction in kidney function (decline in eGFR) as well as treatment discontinuation due to glucocorticoid deficiency, symptomatic hypotension, severely elevated BP, or overdose of trial drug or prescribed antihypertensive medications.
Sample Size Calculation and Power
The sample size of 1000 participants randomized to 1 of 3 treatment groups in a 1:2:1 ratio had 95% power to detect a difference of 3.7 mm Hg in office systolic BP between lorundrostat (n = 750) and placebo (n = 250) at a 1-sided α level of .025, assuming a common SD of 14 mm Hg for change in office systolic BP. This sample size allowed robust safety monitoring.
Statistical Analysis
The primary estimand followed the treatment policy approach by using all observed efficacy data regardless of possible treatment discontinuation. The primary outcome was analyzed on 1000 multiple imputed data using analysis of covariance with categorical factors for treatment, geographic region or country (randomization stratification factor), and treatment interaction with geographic region or country and using baseline office systolic BP as a covariate. Canada and the US were merged into 1 geographic stratum because only 3 participants were randomized in Canada. The Kenward-Roger degrees of freedom adjustment was used and the estimates were derived applying the Rubin rule. Additional details regarding the imputation methods and sensitivity analyses appear in eTables 2 and 3 in Supplement 1. Versions of the statistical analysis plan appear in Supplements 5-7.
The secondary outcomes were analyzed on multiple imputed data using the analysis methods described in eTable 2 in Supplement 1. A graphical testing approach was used to control multiplicity for the secondary efficacy outcomes (eFigure 2 in Supplement 1). The CIs for the secondary outcomes were adjusted for multiplicity.
Results
Trial Participants
Between November 24, 2023, and September 16, 2024, 3161 participants were screened, 1575 entered the placebo-run in phase, and 1083 were randomized to the double-blind treatment phase (the mean age was 61.6 years [SD, 10.3 years], 508 [46.9%] were female, 311 [28.7%] were Black or African American, 733 [67.7%] were White, and 685 [63.3%] had a BMI of ≥30 [obesity]). Of the 1083 participants randomized, 1078 received at least 1 dose of 50 mg/d of lorundrostat for 6 weeks with the potential dose increase to 100 mg/d (n = 270), 50 mg/d of lorundrostat for 12 weeks (n = 538), or daily placebo for 12 weeks (n = 270) (Figure 1). The last date of follow-up was January 24, 2025. The randomized groups were comparable for the baseline demographic and clinical characteristics (Table 1). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more.
Table 1. Participant Demographics and Characteristics at Randomization (Baseline) in the Intention-to-Treat Population.
| Lorundrostat | Placebo (n = 272) | ||
|---|---|---|---|
| 50 mg and then 100 mg (n = 270)a | 50 mg (n = 541) | ||
| Age, mean (SD), y | 61.4 (10.3) | 61.7 (10.6) | 61.8 (10.4) |
| Sex, No. (%) | |||
| Male | 142 (52.6) | 294 (54.3) | 139 (51.1) |
| Female | 128 (47.4) | 247 (45.7) | 133 (48.9) |
| Race, No. (%)b,c | (n = 267) | (n = 535) | |
| American Indian or Alaska Native | 1 (0.4) | 0 | 0 |
| Asian | 4 (1.5) | 14 (2.6) | 6 (2.2) |
| Black or African American | 72 (26.7) | 152 (28.1) | 87 (32.0) |
| Native Hawaiian or Other Pacific Islander | 0 | 1 (0.2) | 1 (0.4) |
| White | 190 (70.4) | 366 (67.7) | 177 (65.1) |
| Hispanic or Latino ethnicity, No. (%)b | 102 (37.8) | 191 (35.3) | 101 (37.1) |
| Body mass indexd | |||
| Mean (SD) | 32.8 (6.7) | 33.0 (6.9) | 32.6 (7.4) |
| ≥30 (obesity), No. (%) | 166 (61.5) | 351 (64.9) | 168 (61.8) |
| Estimated glomerular filtration rate at randomization | |||
| Mean (SD), mL/min/1.73 m2 | 92.8 (17.6) | 90.1 (17.8) | 91.2 (16.4) |
| ≥60 mL/min/1.73 m2, No. (%) | 255 (94.4) | 500 (92.9) | 260 (96.3) |
| Diabetes, No. (%) | 76 (28.2) | 173 (32.2) | 89 (33.0) |
| Prescribed and reported use, No. (%) | |||
| Taking 2 antihypertensive medications | 106 (39.3) | 213 (39.4) | 113 (41.5) |
| Taking ≥3 antihypertensive medications | 164 (60.7) | 328 (60.6) | 159 (58.5) |
| Antihypertensive drug class, No. (%) | |||
| Thiazide or thiazide-like diuretic | 259 (95.9) | 520 (96.1) | 259 (95.2) |
| ACE inhibitor or ARB | 237 (87.8) | 467 (86.3) | 225 (82.7) |
| Calcium channel blocker | 140 (51.9) | 278 (51.4) | 135 (49.6) |
| Other medication use, No. (%) | |||
| Glucagon-like peptide-1 receptor agonists | 13 (4.8) | 30 (5.6) | 9 (3.3) |
| Sodium-glucose cotransporter 2 inhibitors | 14 (5.2) | 21 (3.9) | 13 (4.8) |
| Systolic blood pressure, mean (SD), mm Hg | 146.6 (11.1) | 149.0 (12.2) | 148.8 (12.2) |
| No. (%) | |||
| <140 | 83 (30.7) | 137 (25.3) | 73 (26.8) |
| 140-<160 | 152 (56.3) | 294 (54.3) | 144 (52.9) |
| ≥160 | 35 (13.0) | 110 (20.3) | 55 (20.2) |
| Diastolic blood pressure, mean (SD), mm Hg | 86.3 (9.2) | 87.8 (9.0) | 87.1 (9.1) |
| No. (%) | |||
| <80 | 63 (23.3) | 105 (19.4) | 61 (22.4) |
| 80-<90 | 117 (43.3) | 200 (37.0) | 105 (38.6) |
| ≥90 | 90 (33.3) | 236 (43.6) | 106 (39.0) |
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
After receiving 50 mg/d of lorundrostat for 6 weeks, 92 participants met the following prespecified criteria at week 6 for systolic blood pressure (≥130 mm Hg) and levels of potassium (≤4.8 mmol/L), sodium (≥135 mmol/L), and estimated glomerular filtration rate (>45 mL/min/1.73 m2 and <25% reduction from baseline) and received 100 mg/d of lorundrostat for the next 6 weeks.
Self-reported.
There were 2 participants in the 50 mg of lorundrostat group and 1 participant in the placebo group who reported having more than 1 race.
Calculated as weight in kilograms divided by height in meters squared.
Primary Outcome
The least-squares mean change in office systolic BP at week 6 was −16.9 mm Hg (95% CI, −19.0 to −14.9 mm Hg) for the pooled 50 mg of lorundrostat group vs −7.9 mm Hg (95% CI, −11.5 to −4.2 mm Hg) for the placebo group (least-squares between-group mean difference, −9.1 mm Hg [95% CI, −13.3 to −4.9 mm Hg], P < .001; Table 2 and Figure 2). The efficacy of lorundrostat for lowering BP was consistent across age, sex, race, BMI, and number of prescribed antihypertensive medications participants were taking (Figure 3).
Table 2. Primary and Secondary Blood Pressure (BP) Outcomes and Prespecified Exploratory BP Outcomes.
| Lorundrostata | Placebo | Lorundrostat vs placebo | ||||||
|---|---|---|---|---|---|---|---|---|
| BP measured in office, mean (SD)b | Least-squares mean change (95% CI)b | BP measured in office, mean (SD) | Least-squares mean change (95% CI)b | |||||
| Baseline (n = 808)b |
Follow-up (n = 808)b |
Baseline (n = 270)b |
Follow-up (n = 270)b |
Least-squares mean difference (95% CI)b | P value | |||
| Primary outcome | ||||||||
| Systolic BP, baseline to 6 wk | 148.2 (11.9) | 133.6 (15.3) | −16.9 (−19.0 to −14.9) | 148.6 (12.1) | 140.7 (15.0) | −7.9 (−11.5 to −4.2) | −9.1 (−13.3 to −4.9) | <.001 |
| Secondary outcomes | ||||||||
| Systolic BP, baseline to 6 wk | ||||||||
| <130 mm Hg, No. (%)c | 20 (2.5) | 356 (44.1) | NA | NA | 65 (24.1) | NA | 3.4 (1.5 to 7.8)d | .003 |
| By prescribed and reported use | ||||||||
| Taking 2 antihypertensive drugs | (n = 318) 147.6 (11.5) |
(n = 318) 134.2 (14.9) |
−16.1 (−19.1 to −13.0)e | (n = 112) 148.0 (11.3) |
(n = 112) 141.4 (14.4) |
−7.2 (−11.7 to −2.8) | −8.8 (−14.8 to −2.9)e | <.001 |
| Taking ≥3 antihypertensive drugs | (n = 490) 148.6 (12.1) |
(n = 490) 133.2 (15.6) |
−17.2 (−19.6 to −14.7)e | (n = 158) 149.0 (12.6) |
(n = 158) 140.4 (15.5) |
−8.1 (−12.4 to −3.8)e | −9.0 (−14.0 to −4.1)e | <.001 |
| By body mass index ≥30 (obesity) | 0.07 (−0.10 to 0.24)f | 0.21 (−0.05 to 0.48)f | 0.15 (−0.46 to 0.17)f | |||||
| Systolic BP, baseline to 12 wk | ||||||||
| By escalated dose groupg | (n = 270) 146.6 (11.1) |
(n = 270) 131.9 (14.3) |
−15.7 (−19.3 to −12.2) | 148.6 (12.1) | 141.2 (15.4) | −7.3 (−11.1 to −3.5) | −8.4 (−13.6 to −3.2) | .002 |
| Within-participant analysish | (n = 92) 148.3 (12.4) |
(n = 92) 138.1 (14.8) |
−10.2 (−14.3 to −6.1)e | NA | NA | NA | NA | <.001 |
| Prespecified exploratory outcomes | ||||||||
| Diastolic BP, baseline to 6 wk | 87.3 (9.1) | 79.9 (10.4) | −8.6 (−9.9 to −7.3) | 87.1 (9.0) | 83.2 (10.1) | −5.2 (−7.4 to −3.0) | −3.4 (−5.9 to −0.8) | .01 |
| Systolic BP, baseline to 12 wk | (n = 538) 149.1 (12.2) |
(n = 538) 132.5 (16.0) |
−19.0 (−21.6 to −16.3) | 148.6 (12.1) | 141.2 (15.4) | −7.3 (−11.1 to −3.5) | −11.6 (−16.3 to −7.0) | <.001 |
Abbreviation: NA, not applicable.
The data for lorundrostat were pooled (n = 808) and included the 538 participants from the 50-mg only group plus the 270 participants in the 50-mg dose group with the 100-mg escalation option.
Unless otherwise indicated by a different sample size or with a footnote. For example, the data may not be expressed as mean (SD), the total number of participants may be different from the number in the column heading, or the data may not be expressed as least-squares mean difference (95% CI).
The estimated proportions are based on multiple imputed data. The observed data were 332/755 (44.0%) for lorundrostat vs 62/257 (24.1%) for placebo.
Data are expressed as odds ratio (95% CI).
Data are expressed as least-squares mean change or difference (97.5% CI).
Data are expressed as regression slope coefficient (95% CI).
After receiving 50 mg/d of lorundrostat for 6 weeks, 92 participants met the following prespecified criteria at week 6 for systolic blood pressure (≥130 mm Hg) and levels of potassium (≤4.8 mmol/L), sodium (≥135 mmol/L), and estimated glomerular filtration rate (>45 mL/min/1.73 m2 and <25% reduction from baseline) and received 100 mg/d of lorundrostat for the next 6 weeks.
Met prespecified criteria at 6 weeks; after 6 weeks, only these participants received the escalated dose of 100 mg/d of lorundrostat.
Figure 2. Changes in Office Blood Pressure From Randomization (Baseline) to Week 6.
The box plots demonstrate the median (thick horizontal line), mean (circle), IQR (box top and bottom), and the maximum and minimum blood pressure (whiskers). The mean data were calculated using the last 4 of 5 blood pressure measurements at the baseline visit and at the week 6 visit.
Figure 3. Subgroup Analyses of Office Blood Pressure Changes From Randomization (Baseline) to Week 6.
aThe data for lorundrostat were pooled (n = 808) and included the 538 participants from the 50-mg only group plus the 270 participants in the 50-mg dose group with the 100-mg escalation option.
bIncluded the categories of American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander.
cCalculated as weight in kilograms divided by height in meters squared.
Secondary Outcomes
The results from the secondary efficacy outcomes appear in Table 2. An office systolic BP of less than 130 mm Hg at week 6 was achieved by 44.1% of participants in the pooled 50 mg of lorundrostat group vs 24.1% of participants in the placebo group (odds ratio, 3.4 [95% CI, 1.5 to 7.8]; P = .003). Compared with placebo, the least-squares mean change in office systolic BP at week 6 was −8.8 mm Hg (97.5% CI, −14.8 to −2.9 mm Hg; P < .001) for participants in the pooled 50 mg of lorundrostat group taking 2 prescribed antihypertensive medications. Compared with placebo, the least-squares mean change in office systolic BP at week 6 was −9.0 mm Hg (97.5% CI, −14.0 to −4.1 mm Hg; P < .001) for participants in the pooled 50 mg of lorundrostat group taking 3 or more antihypertensive medications. A comparable reduction in office systolic BP was observed across the continuum of BMI represented in the trial; 91.6% of participants had a BMI of 25 or greater.
Compared with placebo, the least-squares mean change in office systolic BP at week 12 was −8.4 mm Hg (95% CI, −13.6 to −3.2 mm Hg; P = .002) for participants randomized to 50 mg of lorundrostat for 6 weeks and then possibly 100 mg for 6 weeks. Compared with placebo, the least-squares mean change in office systolic BP at week 12 was −10.2 mm Hg (97.5% CI, −14.3 to −6.1 mm Hg; P < .001) for the 92 participants who escalated from 50 mg of lorundrostat to 100 mg.
The prespecified exploratory outcome of least-squares mean change in automated office diastolic BP with 50 mg of lorundrostat at week 6 and least-squares mean difference vs placebo appears in Table 2 and in eFigure 3 in Supplement 1. The prespecified exploratory outcome of least-squares mean change in automated office systolic BP observed with 50 mg of lorundrostat at week 12 and least-squares mean difference vs placebo appears in Table 2 and in eFigure 4 in Supplement 1.
Safety Outcomes
Treatment-emergent adverse events were experienced by 49.9% of participants (538/1078) and were mostly mild or moderate in severity (Table 3). Serious adverse events occurred in 22 participants and included 1 event that was considered to be related to treatment. One participant in the placebo group died after week 6 (unrelated to treatment). A serum potassium level of greater than 6.0 mmol/L occurred in 4 participants (1.5%) randomized to 50 mg of lorundrostat group with possible dose escalation to 100 mg, in 6 participants (1.1%) randomized to 50 mg of lorundrostat, and in 2 participants (0.7%) randomized to placebo (eTable 4 in Supplement 1). The mean serum potassium level increased in the 2 lorundrostat groups but remained within normal range (eFigure 5 in Supplement 1).
Table 3. Summary of Adverse Events.
| No. (%) | |||
|---|---|---|---|
| Lorundrostat | Placebo (n = 270) | ||
| 50 mg and then 100 mg (n = 270)a | 50 mg (n = 538) | ||
| Died | 0 | 0 | 1 (0.4) |
| Serious adverse event | 2 (0.7) | 12 (2.2) | 8 (3.0) |
| Treatment-emergent adverse event | |||
| Severe | 6 (2.2) | 9 (1.7) | 8 (3.0) |
| Moderate | 30 (11.1) | 100 (18.6) | 31 (11.5) |
| Mild | 115 (42.6) | 180 (33.5) | 59 (21.9) |
| Special interest adverse event | |||
| Severely elevated blood pressureb | 2 (0.7) | 10 (1.9) | 11 (4.1) |
| Hypotension with symptoms | 5 (1.9) | 11 (2.0) | 1 (0.4) |
| Hyperkalemiac | 7 (2.6) | 11 (2.0) | 1 (0.4) |
| Hyponatremiac | 28 (10.4) | 37 (6.9) | 9 (3.3) |
| Glucocorticoid deficiencyd | 0 | 0 | 3 (1.1) |
| Reduction in estimated glomerular filtration ratec | 9 (3.3) | 16 (3.0) | 2 (0.7) |
After receiving 50 mg/d of lorundrostat for 6 weeks, 92 participants met the following prespecified criteria at week 6 for systolic blood pressure (≥130 mm Hg) and levels of potassium (≤4.8 mmol/L), sodium (≥135 mmol/L), and estimated glomerular filtration rate (>45 mL/min/1.73 m2 and <25% reduction from baseline) and received 100 mg/d of lorundrostat for the next 6 weeks.
Defined as systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 110 mm Hg.
Trial drug had to be modified due to the adverse event (dose reduction, interruption, or discontinuation).
Confirmed by adrenocorticotropic hormone (cosyntropin or regional equivalent) stimulation test; trial drug was discontinued.
Creatinine-based eGFR decreased by 9.3% from baseline to week 12 in the 2 lorundrostat groups and increased by 0.4% in the placebo group. Using the cystatin-C–based eGFR formula, eGFR decreased by 5.2% in the 50 mg of lorundrostat group with possible escalation to 100 mg, decreased by 4.1% in the 50 mg of lorundrostat group, and increased by 3.4% in the placebo group. At week 12, the geometric mean for serum cortisol increased by 4.2% from baseline in the 50 mg of lorundrostat group with possible escalation to 100 mg, increased by 5.0% in the 50 mg of lorundrostat group, and decreased by 2.0% in the placebo group. The shift in cortisol level from 25 μd/dL or less at baseline to greater than 25 μd/dL at week 12 occurred in 2/243 participants (0.8%) in the 50 mg of lorundrostat group with possible escalation to 100 mg, in 2/487 participants (0.4%) in the 50 mg of lorundrostat group, and in none of the participants in the placebo group.
The treatment-emergent adverse event of glucocorticoid insufficiency was reported in 0 participants in the 50 mg of lorundrostat group with possible escalation to 100 mg, in 3 participants (0.56%) in the 50 mg of lorundrostat group, and in 5 participants (1.9%) in the placebo group. No participants treated with lorundrostat experienced a glucocorticoid deficiency (confirmed by stimulation testing; Table 3). There were no reports of hyperadrenocorticism. Among participants in the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function (decline in eGFR). Among participants in the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function (decline in eGFR). Among participants in the placebo group, there were no treatment discontinuations due to hyperkalemia, hyponatremia, or reduction in kidney function.
Discussion
This phase 3 trial of lorundrostat demonstrated a reduction in office systolic BP after 6 weeks of treatment when participants were given a dose of 50 mg daily. The reductions in BP were maintained over 12 weeks. Increasing the 50-mg/d dose of lorundrostat to 100 mg/d provided no additional benefit to participants who did not reach the goal BP using the 50-mg/d dose.
The current trial aimed to minimize the variable nature of office BP measurement by (1) obtaining measurements prior to the intake of morning medications, (2) using unattended BP measurements to limit the white-coat effect, and (3) using the mean of repeated BP measurements to reduce intraindividual variability. In addition, the current trial used a smartphone application20 to remind participants to take their trial medication daily. The trial recruited a diverse population, which is reflected in the high proportion of female, Black or African American, and elderly participants.
Dysregulated aldosterone and a state of fluid overload are consistent features of treatment-resistant hypertension and related cardiovascular morbidities (such as heart failure and chronic kidney disease).22 In the current guidelines and treatment regimens, MRAs are recommended for patients with apparent or confirmed treatment-resistant hypertension.4,5 However, MRAs are underused due to safety concerns with hyperkalemia and, in the case of spironolactone, chemotype-specific androgenic effects.23 The PATHWAY-2 study10 of spironolactone demonstrated a reduction of 8.7 mm Hg in systolic BP measured at home in patients with treatment-resistant hypertension vs placebo.
Lorundrostat at a dose of 50 mg once daily was generally well tolerated. Treatment-emergent adverse events were mostly mild, transient, and resolved without intervention. The prespecified adverse events of hyponatremia, hyperkalemia, and reduction in kidney function (decline in eGFR) were reported more with lorundrostat compared with placebo; however, few treatment discontinuations occurred due to these events. There were no lorundrostat-treated participants with confirmed glucocorticoid deficiency vs 3 placebo-treated participants with confirmed glucocorticoid deficiency.
The observed decline in eGFR (assessed using the cystatin C–based eGFR formula to correct for falsely elevated creatinine due to competition between lorundrostat and creatinine for MATE [multidrug and toxin extrusion] 1–dependent transport) after initiation of lorundrostat was expected. An acute, reversible decline in eGFR of similar or greater magnitude has also been observed with renin-angiotensin-aldosterone system inhibitors and sodium glucose cotransporter inhibitors.24 The acute decline in eGFR reflects a lowering of intraglomerular pressure that predicts long-term kidney protection when it coincides with BP reduction.24,25
The current trial is the third clinical trial of lorundrostat in participants with uncontrolled hypertension. The degree and trajectory of BP reduction, the similar tolerability and safety profiles, and the use of a maximally effective dose of lorundrostat (50 mg/d) were observed across the 3 trials. In the Advance-HTN trial18 and in the current Launch-HTN trial, the reduction in BP at week 12 was maintained. The changes in office BP measurements in the current trial were expectedly greater than those observed with 24-hour ambulatory BP measurements in the Advance-HTN trial.26 Participants in the Advance-HTN trial18 were placed on a standardized antihypertensive regimen that included a high-dose angiotensin receptor blocker prior to randomization; greater increases in serum potassium level and decreases in eGFR were observed compared with those in the current trial. The BrigHTN phase 2 trial15,27 of baxdrostat, which is an alternative aldosterone synthase inhibitor, reported similar safety and efficacy findings.
Limitations
This trial has limitations. First, the efficacy and safety of lorundrostat compared with placebo was evaluated for only 12 weeks. This is consistent with US Food and Drug Administration guidance limiting placebo-controlled studies of antihypertensive medications for this duration. However, eligible participants had the option to continue in an open-label extension trial (NCT05968430), which intends to provide safety and efficacy information relevant to longer-term use of lorundrostat.
Second, although ambulatory BP measurement is the gold standard for assessment of BP, unattended office BP was used as the primary outcome measure to reflect usual clinical practice. Importantly, the phase 2 Advance-HTN trial18 of lorundrostat used 24-hour ambulatory BP measurements and, compared with placebo, demonstrated similar patterns of BP lowering after 12 weeks of treatment.
Third, the current trial compared the efficacy of lorundrostat vs placebo, but the trial did not include an active comparator.
Conclusions
The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension.
eMethods
eFigure 1. Study Design
eFigure 2. Multiplicity Adjustment
eFigure 3. Change in Automated Office Diastolic Blood Pressure at Week 6
eFigure 4. Change in automated office systolic blood pressure at Week 12 (A) and change from baseline in automated office systolic blood pressure throughout the trial (B)
eFigure 5. Serum Potassium During the Treatment Period
eTable 1. Overview of Statistical Hypotheses for Primary and Secondary Endpoints and Approach to Multiple Imputation
eTable 2. Analytic Approach to Secondary Endpoints
eTable 3. Sensitivity Analyses for the Primary End Point (Change in AO Systolic Blood Pressure at Week 6)
eTable 4. Participants With One or More Chemistry Analyte Values with Elevated or Low Values Meeting Specified Levels for Serum Sodium and Serum Potassium Levels
eLists
Trial protocol version 3.1
Trial protocol version 3.0
Trial protocol version 2.1
Statistical analysis plan, windowing addendum 1
Statistical analysis plan, amendment 2
Statistical analysis plan, multiple imputation addendum 1
Nonauthor collaborators
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods
eFigure 1. Study Design
eFigure 2. Multiplicity Adjustment
eFigure 3. Change in Automated Office Diastolic Blood Pressure at Week 6
eFigure 4. Change in automated office systolic blood pressure at Week 12 (A) and change from baseline in automated office systolic blood pressure throughout the trial (B)
eFigure 5. Serum Potassium During the Treatment Period
eTable 1. Overview of Statistical Hypotheses for Primary and Secondary Endpoints and Approach to Multiple Imputation
eTable 2. Analytic Approach to Secondary Endpoints
eTable 3. Sensitivity Analyses for the Primary End Point (Change in AO Systolic Blood Pressure at Week 6)
eTable 4. Participants With One or More Chemistry Analyte Values with Elevated or Low Values Meeting Specified Levels for Serum Sodium and Serum Potassium Levels
eLists
Trial protocol version 3.1
Trial protocol version 3.0
Trial protocol version 2.1
Statistical analysis plan, windowing addendum 1
Statistical analysis plan, amendment 2
Statistical analysis plan, multiple imputation addendum 1
Nonauthor collaborators
Data sharing statement
