Esaxerenone

Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial

Background and objectives: Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group. Design, setting, participants, & measurements: In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (n=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≡30% reduction from baseline on two consecutive occasions). Results: Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; P<0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≡300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≡6.0 or ≡5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation. Conclusions: Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.

Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease

The steroidal mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone, decrease blood pressure, and attenuate the progression of chronic kidney disease (CKD). However, their use is limited by the fear of inducing hyperkalemia, gynecomastia, impotence, and amenorrhea. Esaxerenone is a novel nonsteroidal MR blocker (MRB) that has been recently developed. In vitro studies have revealed that esaxerenone has a high potency and selectivity for MR compared with spironolactone and eplerenone. Further studies have shown that esaxerenone elicits a strong blood pressure-lowering effect in hypertensive animals. Following the results from phase III clinical trials that esaxerenone is an effective and well-tolerated MRB in Japanese hypertensive patients, esaxerenone became clinically available in Japan from May 2019 for hypertensive patients. Thus, esaxerenone is a promising treatment option for patients with hypertension. In addition, both preclinical studies and phase II clinical trials have shown that esaxerenone elicits renoprotection independent of its antihypertensive effect. Recently, a phase III clinical trial (ESAX-DN study) has also demonstrated the safety and efficacy of esaxerenone in patients with type 2 diabetes and microalbuminuria. These data support future clinical development of esaxerenone for the treatment of renal disease.

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

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.

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.

Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet

Background: Esaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (MR) blocker. MR activation plays a crucial role in the development of cardiovascular and metabolic diseases. In this study, we investigated the effects of esaxerenone on various metabolic parameters in mice.
Materials and methods: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed male C57BL/6 mice. Mice fed a normal diet (ND) served as controls. Glucose and insulin tolerance, plasma lipid levels, and transaminase levels were assessed as metabolic parameters. Macrophage accumulation in the adipose tissue was evaluated using histological analysis. 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used for in vitro experiments. Gene expression and insulin signaling were examined using quantitative RT-PCR and western blotting, respectively.
Results: HFD successfully induced insulin resistance compared with that in ND. Esaxerenone ameliorated insulin resistance (P < 0.05) without altering other metabolic parameters, such as the lipid profile. Esaxerenone administration tended to decrease plasma transaminase levels compared with those in the non-treated group. In the adipose tissue, esaxerenone decreased macrophage accumulation (P < 0.05) and increased the expression levels of adiponectin and PPAR污. Aldosterone significantly decreased the expression levels of PPAR污 and adiponectin in 3T3-L1 adipocytes. Furthermore, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P < 0.01). These effects were ameliorated by pretreatment with esaxerenone.
Conclusion: Esaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.