Safety Of Esaxerenone Research Articles

Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin‐to‐creatinine ratio 30 to <300 mg/gCr (−4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin–angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

Efficacy and safety of esaxerenone (CS-3150) in primary hypertension: a meta-analysis.

This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched for articles published until April 18, 2023. The outcomes included were diastolic blood pressure (DBP), systolic blood pressure (SBP), 24 h DBP, 24 h SBP, and adverse events. The meta-analysis was conducted using RevMan 5.3. This study included three trials. CS-3150 5 mg had a greater effect on lowering the SBP, DBP, 24 h SBP, and 24 h DBP than either CS-3150 2.5 mg or eplerenone 50 mg. In contrast, CS-3150 2.5 mg and eplerenone 50 mg showed no significant difference in lowering DBP, SBP, 24 h DBP, and 24 h SBP. Moreover, adverse events occurred at comparable rates in the three groups. CS-3150 (especially CS-3150 5 mg) is an effective and safe treatment for primary hypertension; which can reduce blood pressure and alleviate hypertensive symptoms.

Exposure-response analysis of the efficacy and safety of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with or without diabetic kidney disease

BackgroundEsaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK+). MethodsThe relationships between model-derived individual esaxerenone exposure and efficacy (blood pressure [BP]) and safety (increased sK+) were evaluated using multivariate linear regression and Cox regression analyses, respectively, using data from 1453 hypertensive patients with or without diabetic kidney disease in five clinical studies. ResultsExposure-efficacy analyses demonstrated that higher exposure was linearly associated with greater BP reduction over the investigated dose range. Exposure-safety analyses showed that higher exposure was associated with a higher risk of increased sK+ under a fixed-dosing regimen; higher baseline sK+ and lower baseline estimated glomerular filtration rate (eGFR) were influential covariates. Model-based simulations suggested that fewer occurrences of increased sK+ are expected under the up-titration regimen (from 1.25 to 5 mg) relative to the fixed-dosing regimen (5 mg) in patients with different combinations of these covariates. ConclusionsThe exposure-response analyses supported the esaxerenone recommended doses and the safety benefits of using the up-titration regimen.

PS-P15-9: EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON HOME BLOOD PRESSURE AND CARDIAC HYPERTROPHY IN HYPERTENSIVE PATIENTS WITH LVH (ESES-LVH STUDY)

Objective: Cardiac hypertrophy is a prognostic factor in hypertensive patients, and attenuation of the hypertrophy with sustained antihypertensive treatment is important to delay the progression to heart failure. Although most classes of antihypertensive agents have evidence of cardiac hypertrophy regression, there is insufficient evidence for mineralocorticoid receptor blockers (MRB); only one report states that MRB has a more pronounced regressive effect when used in combination with a renin-angiotensin system (RAS) inhibitor. Esaxerenone is a novel selective nonsteroidal MRB which has been recently approved for the treatment of hypertension, to date however, there is little evidence of the effectiveness and safety of esaxerenone in hypertensive patients with cardiac hypertrophy. The study was aimed to evaluate the effectiveness and safety of esaxerenone in Japanese hypertensive patients with left ventricular hypertrophy (LVH) whose blood pressure (BP) was inadequately controlled with a RAS inhibitor or calcium channel blocker (CCB). Design and method: ESES-LVH study (jRCTs071190043) was a multicenter, open-label, interventional study. Main inclusion criteria were hypertensive patients (20 years) with morning and bedtime home BP: 135–159 mmHg systolic BP (SBP) and/or 85–99 mmHg diastolic BP (DBP) taking a RAS inhibitor or CCB, and patients with LVH (diagnosed with echocardiography, ECG, or left ventricular mass index [LVMI]). Over the 24-week study period, the initial dose of esaxerenone was started at 1.25 or 2.5 mg/day, and increased to 5 mg/day at weeks 4 and 8, based on the individual patient's condition. The primary endpoints were change from baseline in morning home BP, and change and %change in LVMI, at the end of treatment (EOT). Secondary endpoints included changes in bedtime home and office BP, proportion of patients achieving target BP, changes in echocardiographic parameters, and safety variables including adverse events, eGFR, and serum potassium levels. Results: Baseline characteristics of the 58 enrolled patients were mean age, 64.8 years; male, 70.7%; RAS inhibitor/CCB, 32.8/67.2%; mean morning home SBP/DBP, 142.8/85.0 mmHg; mean LVMI 118.1 g/m2; left ventricular ejection fraction 62.8%; serum potassium level 4.1 mEq/L; and mean eGFRcreat 71.3 mL/min/1.73m2. Mean change from baseline at EOT was -11.5/-4.7 mmHg in the morning home BP, and mean change and % change in LVMI were -9.9 g/m2 and-8.5%, respectively (p &lt; 0.001 each). Detailed effectiveness and safety results will be presented. Conclusions: ESES-LVH study will provide the first clinical evidence of not only the antihypertensive and LVH-regressive effects of esaxerenone, but also its safety in Japanese hypertensive patients with cardiac hypertrophy.

PS-P15-8: EFFICACY AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES AND RECEIVING SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS (EAGLE-DH STUDY)

Objective: Hypertensive patients with type 2 diabetes mellitus (T2DM) who respond inadequately to antihypertensive therapy are at high risk for cardiorenal events and require effective treatment options. Clinical trials have shown that esaxerenone, a non-steroidal mineralocorticoid receptor blocker, has favorable antihypertensive and renoprotective effects in hypertensive patients with various characteristics including T2DM and albuminuria. However, clinical evidence is lacking regarding the concomitant use of esaxerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors in hypertensive patients with T2DM. The study aimed to evaluate the efficacy and safety of esaxerenone and SGLT2 inhibitor combination therapy in Japanese hypertensive patients with T2DM who had an inadequate response to blood pressure (BP)-lowering treatment with renin angiotensin system (RAS) inhibitor or calcium channel blocker (CCB) monotherapy or combined therapy. Design and method: EAGLE-DH (jRCTs031200273) was a multicenter, open-label, interventional study in hypertensive patients (age, ≧ 20 years) with T2DM. Inclusion criteria were previous use of antihypertensive therapy (a RAS inhibitor, CCB, or RAS inhibitor plus CCB) and oral hypoglycemic drugs (a SGLT2 inhibitor with or without one or two other oral hypoglycemic drugs) for ≧ 12 weeks; morning home systolic BP (SBP) 125 to &lt; 160 mmHg and/or diastolic BP (DBP) 75 to &lt; 100 mmHg; and eGFRcreat ≧ 30 mL/min/1.73m2 at baseline. Over the 24-week study period, esaxerenone dose was started at 1.25 or 2.5 mg/day, and based on the individual patient's condition, the dose could be titrated at weeks 4 and 8 to a maximum of 5 mg/day. The primary endpoints were change in morning home BP from baseline to weeks 12 and 24. Secondary endpoints included change in bedtime home BP and office BP, proportion of patients achieving target SBP/DBP (home, &lt; 125/75 mmHg; office, &lt; 130/80 mmHg), change in urine albumin-to-creatinine ratio (UACR), and safety variables including adverse events, eGFR, and serum potassium. Results: The study population comprised 93 patients. Baseline characteristics were mean age, 66.3 years; male, 68.8%; mean morning home SBP/DBP, 136.4/82.3 mmHg; mean UACR 145.3 mg/g creatinine; one RAS inhibitor use, 33.3%; one CCB inhibitor use, 19.4%; RAS inhibitor plus CCB, 47.3%; mean HbA1c 6.8%; mean serum potassium, 4.2 mEq/L; and mean eGFRcreat 66.8 mL/min/1.73m2. Efficacy and safety results will be presented at the conference. Conclusions: EAGLE-DH will provide the first evidence from clinical practice for the efficacy of esaxerenone plus SGLT2 inhibitor in reducing morning/bedtime home and office BP with improving albuminuria as well as for its safety profile in Japanese hypertensive patients with T2DM.

PS-P15-7: EFFECT OF ESAXERENONE ON UNCONTROLLED NOCTURNAL HYPERTENSION FIRST EVALUATED BY 2 UPPER-ARM/WRIST HOME MONITORING DEVICES (EARLY-NH STUDY)

Objective: Nocturnal hypertension is one of the phenotypes of masked hypertension, which affects 30–50% of hypertensive patients, and it cannot be adequately controlled with a single agent. The mineralocorticoid receptor (MR) is activated in an aldosterone-independent manner in diabetes, obesity, salt sensitivity, and excessive salt intake. As all of these conditions are associated with nocturnal hypertension, MR blockers which exert not only antihypertensive but also organ-protective effects are considered the optimal antihypertensive option. Recently, we have developed 2 types (upper-arm and wrist) of nocturnal home blood pressure (BP) monitoring (HBPM) devices. Using these devices, we evaluated the effects of esaxerenone on nighttime home BP and organ damage (UACR and NT-proBNP) in uncontrolled nocturnal hypertensive patients on medication using one drug, either angiotensin receptor blocker (ARB) or calcium channel blocker (CCB). Design and method: EARLY-NH study (jRCTs031200364) was a multicenter, open-label, interventional study in nocturnal hypertensive patients. Nighttime BP was automatically measured at 2, 3, and 4AM with upper-arm (OMRON HEM-9700T), and wrist (OMRON HEM-9601T) HBPM devices. The BP data were electronically collected. Inclusion criteria were: 1) aged ≧ 20 years, 2) receiving one ARB or CCB, 3) nighttime home systolic BP (SBP) ≧ 120 mmHg. Over the 12-week study period, esaxerenone was started at the initial dose of 1.25 or 2.5 mg/day, and could be titrated up to 5 mg/day at weeks 4 and 8, based on the individual patient's condition. The primary efficacy endpoint was the change from baseline in nighttime home BP [SBP and diastolic BP (DBP)] measured by the upper-arm device at week 12. Secondary endpoints included changes in nighttime home BP measured by the wrist device, and levels and control rate of office and home BPs, %change in UACR and NT-proBNP, and safety variables including adverse events, eGFR, and serum potassium. Results: The 93 patients with uncontrolled nocturnal hypertension were successfully enrolled [age: 67.6 years; man: 50.5%; ARB/CCB: 48.4/51.6%; nighttime home SBP/DBP (upper-arm: 132.4/78.4 mmHg; wrist: 130.4/73.1 mmHg); morning home SBP/DBP: 143.8/86.7 mmHg; office SBP/DBP: 147.2/84.1 mmHg; UACR: 110.4 mg/gCr; NT-proBNP: 83.7 pg/mL; serum potassium: 4.0 mEq/L; eGFR: 69.7 mL/min/1.73m2]. Results for the efficacy, safety, and exploratory analysis will be presented. Conclusions: EARLY-NH study will provide the first clinical evidence of the efficacy and safety of esaxerenone on uncontrolled nocturnal hypertension evaluated by 2 newly developed different upper-arm and wrist HBPM and on organ damage. These results will contribute to digital management of hypertension using home BP.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

IntroductionClinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment.MethodsIn this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety.ResultsIn total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (− 11.6/− 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (− 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was − 4.8 mL/min/1.73 m2.ConclusionEsaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction.Clinical Trial RegistrationjRCTs06119002.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02294-z.

Clinical Pharmacokinetics and Pharmacodynamics of Esaxerenone, a Novel Mineralocorticoid Receptor Antagonist: A Review.

Esaxerenone is a selective, nonsteroidal, high-affinity mineralocorticoid receptor antagonist recently approved in Japan for the treatment of hypertension. It has high oral biovailability, a large volume of distribution, and is primarly metabolized in liver and excreted in bile. Esaxerenone is an efficient antihypertensive, whether given alone or as add-on therapy. The antihypertensive effect is accompanied by renoprotective action, which is being further investigated in current clinical trials. Due to its relatively long half-life and high affinity for the mineralocorticoid receptor, esaxerenone is administered once daily and in low absolute doses. The safety of esaxerenone is considerable, since hyperkalemia is not frequent and, when it does appear, not sustained. Endocrine adverse events, which frequently occur with steroidal mineralocorticoid receptor antagonists, are extremely rare with esaxerenone. Although the risk of clinically significant drug-drug interactions is not high, esaxerenone treatment should start with low doses, with subsequent titration to achieve the optimal clinical effect, all while monitoring serum potassium and paying attention to concomitant therapy with drugs that may induce or inhibit esaxerenone metabolism. This review article offers comprehensive information about the pharmacodynamics and pharmacokinetics of esaxerenone in humans, which should help clinicians to more precisely tailor esaxerenone dosing regimens to their patients.

Rationale and Design of the Efficacy and Safety of Esaxerenone in Hypertensive Patients With Left Ventricular Hypertrophy (ESES-LVH) Study ― Protocol for a Multicenter, Open-Label, Exploratory Interventional Study ―

Background: The complication of left ventricular (LV) hypertrophy (LVH) is associated with increased incidence of major cardiovascular events. Hypertension is an independent risk factor among several factors contributing to the development of LVH, and thus appropriate treatment of both hypertension and LVH reduces the risk of developing heart failure. Mineralocorticoid-receptor blockers (MRBs) have been reported to improve the prognosis of LVH, but use of currently available MRBs is limited by adverse events. Esaxerenone is a novel selective nonsteroidal MRB recently approved for treatment of hypertension. Although the renoprotective effect of esaxerenone has been demonstrated in both preclinical and clinical studies, little data is available in terms of its cardioprotective effects. Methods and Results: This multicenter, open-label, exploratory interventional study was designed to evaluate the safety and efficacy of esaxerenone in combination with renin-angiotensin system (RAS) inhibitors or calcium-channel blockers (CCBs). Eligible criteria are hypertensive patients with LVH, and target blood pressure (BP) not reached with an RAS inhibitor or a CCB. The primary endpoints are change from baseline in seated home BP (early morning systolic/diastolic BPs), and change and %change from baseline in the LV mass index at the end of treatment. Conclusions: This study will provide the first clinical evidence of the antihypertensive effect and safety of esaxerenone in hypertensive patients with LVH.

Abstract 9146: Efficacy and Safety of Esaxerenone in Hypertensive Patients with Heart Failure with Reduced Ejection Fraction

Introduction: Esaxerenone, a mineralocorticoid receptor blocker (MRB), is a new antihypertensive agent. However, esaxerenone-related data with respect to hypertension with heart failure are limited. Hypothesis: Esaxerenone is safe and effective for hypertensive patients with heart failure with reduced ejection fraction (HFrEF). Methods: Hypertensive patients with HFrEF treated with esaxerenone were retrospectively analyzed at two timepoints (short-term: 35±15 days; mid-term: 167±45 days) for hyperkalemia (K + &gt;5.5 mEq/L), worsening renal function (WRF; estimated glomerular filtration rate (eGFR) reduction by &gt;20%), and hypotension (systolic blood pressure &lt;90 mmHg) along with brain natriuretic peptide (BNP) level. Patients administered esaxerenone as their first MRB (first-MRB cohort, n=20) and those who converted from another MRB (conversion cohort, n=30) were separately analyzed as sub analysis. Results: Fifty patients (56±10 years old, 37 males) were enrolled in this study. At the short-term assessment, hyperkalemia or hypotension was not observed at a dose of 2.0±0.9 mg/day. Seven patients (14%) showed WRF. K + and serum creatinine (Cre) were elevated (4.12±0.41 to 4.25±0.39 mmol/L, p =0.07, and 0.95±0.34 to 1.01±0.34 mg/dL, p =0.01, respectively), and eGFR was significantly reduced (66.9±19.6 to 62.4±19.7 mL/min/1.73 m 2 , p =0.006). At the mid-term assessment, there were no significant changes regarding K + , Cre and eGFR compared to those at the short-term. BNP levels were consistently lowered at the short-term and mid-term assessment. Sub analysis at the short-term assessment showed the changes in K + , Cre, and eGFR were significant in the first-MRB cohort, while they were not significant in the conversion cohort. Conclusions: Esaxerenone was safe for hypertensive patients with HFrEF. Hyperkalemia and hypotension were rarely noted while eGFR was significantly reduced. Moreover, esaxerenone was effective for HFrEF with respect to BNP levels.

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study

BackgroundEsaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine).MethodsWe conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin–angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline.ResultsUACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was − 8.3 mL/min/1.73 m2 at week 24.ConclusionsEsaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine.Clinical trial registrationJapicCTI-173696

BLOOD PRESSURE LOWERING EFFECTS AND SAFETY OF ESEXERENONE, NEWLY AVAILABLE MINERALOCORTICOID RECEPTOR BLOCKER

Objective: Esaxerenone (CS-3150) is a novel, highly potent, selective and long acting non-steroidal mineralocorticoid receptor (MR) blocker with MR blocking action of IC50 3.7 nM, other steroid hormone receptors blocking action of IC50 &gt;5000 nM and half life loss of 18.6 hours. The authors aimed to investigate blood pressure (BP)-lowering ability and safety of esaxerenone in resistant hypertensive patients by add-on or by replacement from spironolactone or eplerenone. Design and method: This study was designed as a prospective observational study in 230 patients, approved by the local ethical committee and followed for 12 weeks. In add-on group, 52 resistant hypertensive patients, whose office BP was &gt; 130/80 (&lt;75 years old) or 140/90 (&gt;75 years old) treated with at least three hypertensive agents (CCBs, RAS inhibitors and diuretics) according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019), were treated by the add-on use of esaxerenone. In replacement group, 208 resistant hypertensive patients, whose BP was controlled by at least 4 antihypertensive drugs including spironolactone or eplerenone, were medicated with esaxerenone by replacement from spironolactone or eplerenone. Results: In add-on group, both systolic and diastolic BP were significantly lowered from 139 ± 16 / 82 ± 14 mmHg (means ± SD) to 129 ± 16 / 79 ± 12 mmHg (p &lt; 0.0001 and p = 0.0185, respectively) with mean esaxerenone dose of 1.44 mg. In replacement group, systolic BP was significantly lowered from 126 ± 16 mmHg (means ± SD) to 120 ± 14 mmHg (p &lt; 0.0001), but diastolic BP was not, with mean esaxerenone dose of 1.58 mg once a day, which was changed from mean spironolactone and eplerenone doses of 34 and 58 mg, respectively. In add-on group, serum potassium concentration was significantly increased from 4.18 ± 0.46 to 4.40 ± 0.58 mmol/L and eGFR was decreased from 74.2 ± 23.9 to 66.9 ± 24.0, but those in replacement group were not significantly changed. Conclusions: This study suggested that esaxerenone has more potent BP lowering ability than spironolactone or eplerenone especially in systolic BP and has the equivalent safety.

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

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

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] −17.7 [−20.6, −14.7] and −9.5 [−11.7, −7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin–angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin–angiotensin system inhibitor.

Efficacy and safety of esaxerenone (CS-3150) for the treatment of essential hypertension: a phase 2 randomized, placebo-controlled, double-blind study

This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50–100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose–response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of −7.0 (−9.5 to −4.6)/−3.8 (−5.2 to −2.4) mmHg in the placebo group, and −10.7 (−13.2 to −8.2)/−5.0 (−6.4 to −3.6) mmHg, −14.3 (−16.8 to −11.9)/−7.6 (−9.1 to −6.2) mmHg, and −20.6 (−23.0 to −18.2)/ −10.4 (−11.8 to −9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was −17.4 (−19.9 to −15.0)/−8.5 (−9.9 to −7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.