Daiichi Sankyo Announces Successful Completion of Pivotal Phase 3 Trial of Esaxerenone in Early Diabetic Kidney Disease

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Today (November 8), Daiichi Sankyo announced that the pivotal Phase III clinical study evaluating esaxerenone for the treatment of early diabetic nephropathy in patients with type 2 diabetes had met its primary endpoint.

This was a randomized, double-blind, two-arm, parallel-group comparative study conducted to evaluate the efficacy and safety of esaxerenone in patients with type 2 diabetes mellitus and microalbuminuria who were receiving treatment with an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor. The study was conducted at 135 clinical trial sites in Japan and enrolled a total of 455 patients. The primary endpoint was the proportion of patients achieving remission to normoalbuminuria after 52 weeks of treatment, and the secondary endpoints were the percent changes in the urine albumin-to-creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR).

The results showed that, compared with placebo, esaxerenone significantly increased the UACR remission rate (22.1% vs. 4.0%) and significantly reduced UACR (-58.3% vs. +8.3%). Regarding secondary endpoints, progression from early-stage to overt diabetic nephropathy was significantly reduced in the esaxerenone treatment group (1.4% vs. 7.5%). No new safety concerns were identified in the study. Hyperkalemia was confirmed in 8.8% of patients in the esaxerenone group, compared with 2.2% in the placebo group; potassium levels returned to normal after discontinuation of the drug.

Remarks:

Early diabetic nephropathy refers to type 2 diabetes accompanied by microalbuminuria, defined in this study as 45 ≤ UACR < 300 mg/g·Cr;

UACR Remission is defined as simultaneously meeting the criteria for restoration to and maintenance of the normal UACR range: two consecutive UACR measurements <30 mg/g·Cr (normal albuminuria) at the end of treatment, with a ≥30% reduction from baseline.

Overt diabetic nephropathy is defined as an increase in urinary albumin-to-creatinine ratio (UACR) to ≥300 mg/g･Cr in patients with type 2 diabetes.

In terms of incidence and mortality, diabetic nephropathy is one of the most important long-term complications in patients with diabetes. Approximately 50% of patients with type 2 diabetes show evidence of progressing to diabetic nephropathy. In Japan, diabetic nephropathy is the leading cause of dialysis (42.5% in 2017).

Multifactorial intensive therapy, including the control of blood glucose, lipids, and blood pressure, as well as the use of angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, is recommended in multiple treatment guidelines to suppress the onset and progression of early diabetic kidney disease. However, the efficacy of these conventional therapies is suboptimal, resulting in a clear unmet need for additional therapeutic agents. The progression of diabetic kidney disease to advanced stages is associated with an increased risk of dialysis and cardiovascular events. The inhibitory effect of pharmacological interventions on diabetic kidney disease at advanced stages remains unclear. To mitigate the deterioration of renal function, promoting remission to normoalbuminuria in the early stages of diabetic kidney disease is a desirable strategy.

Molecular Structure of Esaxerenone (Source: medchemexpress.cn)

Esaxerenone is an oral, non-steroidal, selective, novel mineralocorticoid receptor (MR) blocker. Recent reports indicate that aldosterone is considered a potent mediator of organ damage, and esaxerenone may play a role in preventing such organ damage.

Esaxerenone is one of the compounds discovered through a research collaboration between Daiichi Sankyo and the US pharmaceutical company Exelixis, signed in March 2006, and subsequently developed by Daiichi Sankyo. In January 2018, Daiichi Sankyo submitted a new drug application in Japan for esaxerenone for the treatment of hypertension. In January this year, esaxerenone tablets at doses of 1.25 mg, 2.5 mg, and 5 mg were approved.

Reference Source: Daiichi Sankyo Announces Positive Results from ESAX-DN Phase 3 Study in Japan of Esaxerenone in Patients with Diabetic Nephropathy