First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor

Abstract

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t_1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

FIGURE 1

(a) Lorundrostat and lorundrostat hydrobromide chemical structures. PK profile (b) SAD administration of lorundrostat by dose group, and (c) MAD administration of lorundrostat by dose group and day. Data shown as mean ± SE. MAD, multiple ascending dose; PK, pharmacokinetic; SAD, single ascending dose; SE, standard error.

FIGURE 2

(a) Aldosterone time profile for SAD administration of lorundrostat by dose group (Day ‐1 is the day prior to dosing, reflecting normal circadian rhythm and Day 1 is the day of dosing, showing suppression of plasma aldosterone; mean ± SE). Part 1 SAD (b) aldosterone AUC_0–24 and (c) cortisol AUC_0–72 by dose group. (d) MAD administration of lorundrostat by dose group (Day −1 is the day prior to initiating dosing, reflecting normal circadian rhythm and Day 7 is the final day of dosing, showing suppression of plasma aldosterone up to 16 h post‐dose; mean ± SE). All PD analyses used the PD analysis set (all participants who received at least one dose of study drug, had at least one post‐dose PD assessment, and PD data considered sufficient and interpretable). In Panels (b) and (c), dots within the box plots indicate mean, horizontal lines indicate median, whiskers indicate minimum and maximum values, and dots outside the box plots indicate outliers. Panel (d) Day ‐1 represents PAC over time in the MAD portion of the study over a 24‐h period. Similar to what was observed in the SAD, the normal circadian rhythm of aldosterone that ranges from ~40–150 ng/dL is observed. Panel (d) Day 7 shows suppression of aldosterone in all active doses followed by an increase at the end of the dosing interval to values that are observed in the MAD pre‐dose data, and also in the SAD portion, up to 150 ng/dL. AUC, area under the curve; AUC_0–24, area under the curve from 0 to 24 h; AUC_0–72, area under the curve from 0 to 72 h; PD, pharmacodynamic; SAD, single ascending dose; SE, standard error; MAD, multiple ascending dose.

FIGURE 3

Effect of lorundrostat on (a) plasma renin activity, (b) 11‐DOC, and (c) serum potassium in part 2 MAD study. Effect of lorundrostat on (d) renal sodium handling in SAD study. Data shown as mean ± SE. Panel (c) Within 2 days of initiation of lorundrostat treatment, serum potassium rose in all three dose cohorts (part 2) by group mean values ranging from 0.28 to 0.38 mmol/L and remained elevated throughout the remainder of the 7 days of treatment. There was a maximum mean increase of 0.44 mmol/L after 40 mg on Day 8, 0.6 mmol/L after 120 mg on Day 7, and 0.48 mmol/L after 360 mg on Day 6. None of the subjects reached the stopping criterion for potassium of 6.0 mmol/L. MAD, multiple ascending dose; SAD, single ascending dose; SE, standard error.