Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study

Takashi Wada, Masaya Inagaki, Toru Yoshinari, Ryuji Terata, Naoko Totsuka, Miki Gotou, Gaia Hashimoto, Takashi Wada, Masaya Inagaki, Toru Yoshinari, Ryuji Terata, Naoko Totsuka, Miki Gotou, Gaia Hashimoto

Abstract

Background: We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN).

Methods: The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs).

Results: In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not.

Conclusion: The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable.

Clinical trial registration: NCT02517320 (dose-response study) and NCT02676401 (extension study).

Keywords: Apararenone; Diabetic kidney disease; Diabetic nephropathy; Dose-finding study; Fibrosis; Mineralocorticoid receptor antagonists.

Conflict of interest statement

Takashi Wada has received advisory fees and lecture fees from Mitsubishi Tanabe Pharma Corporation. Masaya Inagaki, Toru Yoshinari, Ryuji Terata, Naoko Totsuka, Miki Gotou and Gaia Hashimoto are employees of Mitsubishi Tanabe Pharma Corporation.

Figures

Fig. 1
Fig. 1
Percent change from baseline in UACR at 24 weeks after randomization (in all patients and stratified by concomitant ACE-I/ARB use). ACE-I angiotensin-converting enzyme inhibitors, ARB angiotensin II receptor blocker, CI confidence interval, LOCF last observation carried forward, LS least squares, UACR urine albumin to creatine ratio
Fig. 2
Fig. 2
a UACR remission rate at each time point up to 52 weeks after randomization. UACR urine albumin to creatine ratio. Placebo group data from the 24-week dose–response study only. Apararenone treatment data from the 24-week dose–response study and the 28-week extension study. b Time-course of percent changes from baseline in UACR up to 52 weeks after randomization. CI confidence interval, FU follow-up, UACR urine albumin to creatine ratio. Geometric LS mean (95% CI). Placebo group data from the 24-week dose–response study only. Apararenone treatment data from the 24-week dose–response study and the 28-week extension study
Fig. 3
Fig. 3
Change in blood pressure at 24 weeks after randomization (in all patients and stratified by baseline SBP and DBP). Mean (standard deviation). DBP diastolic blood pressure, SBP systolic blood pressure
Fig. 4
Fig. 4
Time-course of percent changes from baseline in eGFR up to 52 weeks after randomization. eGFR estimated glomerular filtration rate, FU follow-up, SD standard deviation, Q1 first quartile, Q3 third quartile. Median (Q1/Q3). Placebo group data from the 24-week dose–response study only. Apararenone treatment data from the 24-week dose–response study and the 28-week extension study
Fig. 5
Fig. 5
Time-course of changes from baseline in serum potassium level (measured at a central laboratory) up to 52 weeks after randomization. Mean (95% CI). CI confidence interval, FU follow-up, SD standard deviation. Placebo group data from the 24-week dose–response study only. Apararenone treatment data from the 24-week dose–response study and the 28-week extension study

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