Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study)

Abstract

Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02890173.

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

“…In the present study, no gynecomastia or breast pain was reported; however, one female patient did report menorrhagia during treatment with esaxerenone 5 mg/day. In clinical studies of esaxerenone [28,29], no sex hormone receptor-related AEs or menorrhagia were observed in any patients treated with esaxerenone.…”

“…Esaxerenone is an oral nonsteroidal MR blocker with high MR-binding specificity [26]. Data from clinical studies [27][28][29] have shown that esaxerenone inhibits MR activity, is well tolerated and reduces BP in a dose-dependent manner in Japanese patients with essential hypertension. The phase 3 study [29] also showed that esaxerenone 2.5 mg/day was noninferior to eplerenone 50 mg/day and that esaxerenone at 5 mg/day exhibited superior BP-lowering effects over esaxerenone at 2.5 mg/day.…”

“…Data from clinical studies [27][28][29] have shown that esaxerenone inhibits MR activity, is well tolerated and reduces BP in a dose-dependent manner in Japanese patients with essential hypertension. The phase 3 study [29] also showed that esaxerenone 2.5 mg/day was noninferior to eplerenone 50 mg/day and that esaxerenone at 5 mg/day exhibited superior BP-lowering effects over esaxerenone at 2.5 mg/day. In a study of esaxerenone in patients with moderate renal dysfunction with diabetes with albuminuria [30], incremental dose escalation starting from a low dose was able to manage serum K + elevations and renal function safely while exerting antihypertensive effects.…”

Effects of itraconazole and rifampicin on the single‐dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects

“…The half‐maximal inhibitory concentration of esaxerenone for the transcriptional activity of human MR is 3.7 nM, and its potency was superior to that of spironolactone and eplerenone, whose half‐maximal inhibitory concentrations were 66 and 970 nM, respectively 1 . The clinical efficacy of esaxerenone for essential hypertension was demonstrated in a recent double‐blind phase 3 study, 2 in which esaxerenone 2.5 mg d −1 was shown to be noninferior to eplerenone 50 mg d −1 ; furthermore, the esaxerenone 5 mg d −1 dosage was superior to the 2.5 mg d −1 dosage 2 . Both dosages of esaxerenone demonstrated efficacy in lowering blood pressure (BP) and were well tolerated 2 …”

“…The clinical efficacy of esaxerenone for essential hypertension was demonstrated in a recent double‐blind phase 3 study, 2 in which esaxerenone 2.5 mg d −1 was shown to be noninferior to eplerenone 50 mg d −1 ; furthermore, the esaxerenone 5 mg d −1 dosage was superior to the 2.5 mg d −1 dosage 2 . Both dosages of esaxerenone demonstrated efficacy in lowering blood pressure (BP) and were well tolerated 2 …”