Selective aldosterone synthase inhibitor effective in uncontrolled hypertension

Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial

Literature - Laffin LJ, Rodman D, Luther JM, et al. - JAMA. 2023 Sep 26;330(12):1140-1150. doi: 10.1001/jama.2023.16029

Introduction and methods

Background

Although contemporary guidance recommend MRAs as part of the treatment regimen for resistant hypertension [1], hormonal adverse effects hinder their wider use. Moreover, MRAs do not block the nongenomic effects of aldosterone, which may lead to increased sympathetic nervous system activation and stimulate vascular contractility and stiffness [2,3]. Interestingly, aldosterone production can also be reduced by inhibition of aldosterone synthase, thereby potentially avoiding these adverse effects.

Aim of the study

The authors investigated the safety and efficacy of different doses of lorundrostat, a selective inhibitor of aldosterone synthase, compared with placebo in patients with uncontrolled hypertension, with a specific focus on blood pressure (BP) reduction among participants with obesity or suppressed renin.

Methods

The Target-HTN (Trial on the Safety and Efficacy of MLS-101 (Lorundrostat) in Patients With Uncontrolled Hypertension) trial was a multicenter, prospective, double-blind, placebo-controlled, dose-ranging, phase 2 RCT conducted in the USA in which 200 adults with automated office systolic BP (SBP) ≥130 mmHg while taking ≥2 antihypertensive medications at maximally tolerated doses were enrolled. Key exclusion criteria included orthostatic hypotension, T1D, and concomitant use of an MRA or epithelial sodium channel inhibitor.

Cohort 1 comprised 163 participants with plasma renin activity (PRA) ≤1.0 ng/mL per hour and plasma aldosterone ≥1.0 ng/dL, who were randomized in a 1:1:1:1:1:1 ratio to lorundrostat (12.5 mg once daily, 50 mg once daily, 100 mg once daily, 12.5 mg twice daily, or 25 mg twice daily) or placebo for 8 weeks. In cohort 2, 37 participants with PRA >1.0 ng/mL per hour were randomized in a 6:1 ratio to lorundrostat 100 mg once daily or placebo for 8 weeks.

At baseline and prior to the 8-week visit, 24-hour ambulatory BP monitoring was performed.

Outcomes

The primary endpoint was change in automated office SBP from baseline to 8 weeks. Secondary efficacy endpoints included the change in automated office diastolic BP, the change in 24-hour ambulatory BP, and the proportion of participants achieving automated office BP <130/80 mmHg at 7 or 8 weeks.

Additional safety and pharmacodynamic biomarker endpoints included changes in PRA, serum aldosterone, cortisol, and potassium, and eGFR. Prespecified adverse events of special interest were incidence of hyperkalemia with dose modification, hypotension with symptoms, and adrenocortical insufficiency.

All cohort 2 analyses were exploratory in nature.

Main results

Primary endpoint

  • In cohort 1, the least-squares (LS) mean change in automated office SBP from baseline to 8 weeks was –5.6 mmHg (SE: 3.2) for lorundrostat 12.5 mg once daily, –13.7 mmHg (SE: 2.7) for lorundrostat 50 mg once daily, –11.9 mmHg (SE: 2.8) for 100 mg once daily, –11.3 mmHg (SE: 3.2) for lorundrostat 12.5 mg twice daily, –11.1 mmHg (SE: 2.7) for lorundrostat 25 mg twice daily, and –4.1 mmHg (SE: 2.6) for placebo.
  • Significant placebo-corrected LS mean changes were observed for the 50-mg once-daily dose (–9.6 mmHg; 90%CI: –15.8 to –3.4; P=0.01) and 100-mg once-daily dose (–7.8 mmHg; 90%CI: –14.1 to –1.5; P=0.04).
  • In the exploratory cohort 2, the LS mean change at 8 weeks was 11.4 mmHg (SE: 2.5) for lorundrostat 100 mg once daily. The LS mean systolic automated office BP difference between both 100-mg once-daily cohorts was 0.74 mmHg (90%CI: −5.4 to 6.9).
  • Exploratory subgroup analyses showed that in patients with BMI >30 kg/m², lorundrostat 50 mg once daily resulted in a change in automated office SBP of −16.7 mmHg (90%CI: −25.5 to −7.9) compared with placebo, while lorundrostat 100 mg once daily led to a placebo-corrected change of −12.3 mmHg (90%CI: −21.6 to −3.1).
  • Similar placebo-corrected changes in automated office SBP were seen in participants taking a thiazide-type diuretic who were randomized to lorundrostat 50 mg once daily (−12.9 mmHg; 90%CI: −21.2 to −4.7) or 100 mg once daily (–10.0 mmHg; 90%CI: −21.2 to −1.6).

Secondary endpoints

  • Only lorundrostat 50 mg once daily showed a significant placebo-corrected LS mean change in automated office diastolic BP compared with placebo (–5.5 mmHg; 90%CI: −9.4 to −1.5; P=0.02).
  • There were no significant differences in the proportion of participants with automated office BP <130/80 mmHg at the end of the trial between the lorundrostat treatment groups and placebo.

Pharmacodynamic biomarker endpoints

  • In cohort 1, mean changes in serum aldosterone were –1.05 ng/dL (SD: 4.33), –2.56 ng/dL (SD: 3.72), and –2.88 ng/dL (SD: 4.44) for the lorundrostat 12.5-mg, 50-mg, and 100-mg once-daily doses, respectively, –2.42 ng/dL (SD: 2.78) and –3.39 ng/dL (SD: 4.22) for the lorundrostat 12.5-mg and 25-mg twice-daily doses, respectively, and 0.14 ng/dL (SD: 3.68) for placebo.
  • In cohort 2, the mean serum aldosterone change was –1.19 ng/dL (SD: 5.38) for lorundrostat 100 mg once daily.
  • In cohort 1, anticipated increases in PRA were seen, ranging from 0.78 (SD: 3.44) to 4.65 ng/mL per hour (SD: 11.27), as well as small increases in serum cortisol.

Safety endpoints

  • A total of 110 participants (55%) experienced any adverse event, most of which were classified as mild. There were 3 serious adverse events, 1 of which (worsening of hyponatremia) was deemed to be treatment-related.
  • During the trial, 13 lorundrostat-treated patients showed serum potassium >5.5 mmol/L and 6 had serum potassium >6.0 mmol/L, which was corrected with dose reduction or drug discontinuation. Hypotension was experienced by 3 lorundrostat-treated patients, and no adrenocortical insufficiency was observed.

Conclusion

Treatment with lorundrostat 50 or 100 mg once daily reduced automated office SBP compared with placebo in patients with uncontrolled hypertension, particularly in those with concomitant obesity. The authors attribute the ineffectiveness of the lower doses of lorundrostat to its relatively short half-life. Overall, the selective aldosterone synthase inhibitor was well tolerated and did not lead to adrenocortical insufficiency.

References

1. Carey RM, Calhoun DA, Bakris GL, et al; American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Genomic and Precision Medicine, Council on Peripheral Vascular Disease, Council on Quality of Care and Outcomes Research, and Stroke Council. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72(5):e53-e90. doi:10.1161/HYP.0000000000000084

2. Funder JW. Minireview: aldosterone and the cardiovascular system: genomic and nongenomic effects. Endocrinology. 2006;147(12):5564-5567. doi:10.1210/en.2006-0826

3. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47(3):312-318. doi:10.1161/01.HYP.0000201443.63240.a7

Find this article online at JAMA.

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