Lorundrostat Shows Promise in Phase 2 Trial for Uncontrolled, Resistant Hypertension

Luke Laffin, MD
Credit: Cleveland Clinic

Results of a phase 2 trial examining use of lorundrostat, an aldosterone synthase inhibitor being developed by Mineralys Therapeutics, suggest the agent could reduce aldosterone synthesis and lower blood pressure in people with uncontrolled or resistant hypertension.

A randomized, placebo-controlled, dose-ranging trial named Target-HTN, results of the study suggest treatment with lorundrostat at doses of 50mg and 100 mg once daily led to a statistically and clinically significant reduction of systolic blood pressure, with this effect most apparent in people with hypertension and concomitant obesity.¹

“Despite the multitude of currently available treatments, half of all patients treated for hypertension are not able to reach their blood pressure goal. Up to 25 percent of all people with hypertension exhibit abnormal aldosterone levels,” said Luke Laffin, MD, lead investigator and co-director of the Center for Blood Pressure Disorders in the Heart, Vascular, and Thoracic Institute at Cleveland Clinic.² “Importantly, the Target-HTN study of lorundrostat demonstrated data compelling enough to warrant its advancement into late-stage clinical trials, representing a first-in-class milestone that will further the goal of understanding a new way of treating uncontrolled and treatment-resistant hypertension that takes the underlying causes into account.”

A prospective, multicenter phase 2 trial, Target-HTN was conducted at 43 sites across the US and enrolled a population of patients aged 18 years or older, with a systolic automated office blood pressure (AOBP) of 130 mmHg or greater while taking 2 or more antihypertensive medications for at least 4 weeks at maximum tolerated doses. The trial was designed with 2 cohorts, with those included in the initial cohort randomized to placebo or 1 of 5 dosages of lorundrostat and those included in cohort 2 randomized in a 1:6 ratio to placebo or lorundrostat 100 mg once daily.¹

Of note, initial doses of lorundrostat administered in cohort 1 were 12.5 mg, 50 mg, or 100 mg once daily or 12.5 or 25 mg twice daily. Additionally, the initial cohort consisted of participants with plasma renin activity equal to or less than 1.0 ng/mL/h and plasma aldosterone of 1.0 ng/dL or greater. With enrollment occurring from July 2021 through June 2022, a total of 200 patients underwent randomization. Of the 200 individuals included, 163 were part of the initial cohort and 37 participants with plasma renin activity greater than 1.0 ng/mL/h were enrolled as part of cohort 2.¹

The overall study population had a mean age of 65.7 (Standard Deviation [SD], 10.2) years, 60% were women, 36% were Black or African American, and 48% were of Hispanic or Latino ethnicity. Baseline analysis revealed 48% of participants had a BMI of 30 kg/m2 or greater at time of randomization. Investigators also pointed out 40% had type 2 diabetes and 42% were using 3 or more antihypertensive medications. Among cohort 1, the mean baseline systolic AOBP was 142.2 (SD, 12.5) mmHg and a mean diastolic AOBP was 81.5 (SD, 9.7) mmHg. Among cohort 2, the mean baseline systolic blood pressure of 139.1 (SD, 8.7) mmHg and diastolic blood pressure of 79.1 (SD, 9.7) mmHg.¹

The primary endpoint of interest for the trial was change in AOBP from baseline to week 8. Secondary endpoints of interest in the trial included changes in diastolic AOBP, 24-hour ambulatory blood pressure monitoring changes, and the proportion of participants achieving an AOBP less than 130/80 mmHg at week 7 or 8.¹

Among cohort 1, which included patients with suppressed plasma renin activity, changes in systolic AOBP from baseline to week 8 were −14.1, −13.2, −6.9, and −4.1 mmHg among the 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Analysis of the twice-daily doses indicated reduction of −10.1 and −13.8 mmHg was observed for the 25 mg and 12.5 mg groups, respectively. Investigators highlighted the least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mmHg (90% Confidence Interval [CI], −15.8 to −3.4 mm Hg; P = .01) for the 50-mg once-daily dose and −7.8 mmHg (90% CI, −14.1 to −1.5 mmHg; P = .04) for 100 mg daily.¹

Among cohort 2, 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed plasma renin activity receiving the same dose. When assessing safety outcomes, results suggested 6 participants experienced increases in serum potassium greater than 6.0 mmol/L, which was corrected with dose reduction or drug discontinuation. Additionally, there were no instances of cortisol insufficiency observed in the trial.¹

"We believe this trial confirms the link between obesity, excess aldosterone production and hypertension. Based on the beneficial response observed in Target-HTN, our recently initiated pivotal program lays the groundwork to facilitate identification of patients who may benefit from an aldosterone-targeted therapy like lorundrostat,” said David Rodman, MD, chief medical officer for Mineralys.²

In an editorial comment, Bryan Williams, MD, chair of Medicine at University College London, expressed excitement about the prospect of novel therapies addressing excess aldosterone.³

“More than 70 years after the first isolation of electrocortin, there is a new dawn for therapies targeting aldosterone,” Williams wrote.³ “There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism.”

References:

1. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. JAMA. Published online September 10, 2023. doi:10.1001/jama.2023.16029
2. Mineralys Therapeutics announces JAMA publication of full target-HTN phase 2 trial results for LORUNDROSTAT in uncontrolled and treatment-resistant hypertension. Mineralys Therapeutics, Inc. September 10, 2023. Accessed September 13, 2023. https://ir.mineralystx.com/news-events/press-releases/detail/26/mineralys-therapeutics-announces-jama-publication-of-full.
3. Williams B. A New Dawn for Aldosterone as a Therapeutic Target in Hypertension. JAMA. Published online September 10, 2023. doi:10.1001/jama.2023.17087