Efficacy and safety of apararenone (MT‐3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study

Abstract

Aim To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). Methods In this multicenter, randomized, double‐blind, placebo‐controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end‐point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end‐points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. Results Forty‐eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was −3.0% and −13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen‐3 N‐terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis‐4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. Conclusions In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti‐inflammatory and antifibrotic effects of apararenone.

Placebo effect on progression and regression in NASH: Evidence from a meta‐analysis

“…Forty-three RCTs consisting of 2649 placebo participants were included in this metaanalysis and systematic review (Figure 1). Of these, 20 trials were conducted in North America, [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] five in Europe, [4953] four in Asia, [54][55][56][57] and one in Brazil and Turkey, respectively, [58,59] while 12 trials were multinational studies. [60][61][62][63][64][65][66][67][68][69][70][71] Of the 43 included studies, 19 were single-center trials, and 24 were multicenter trials.…”

Meta‐analysis: analysis of mechanistic pathways in the treatment of non‐alcoholic steatohepatitis. Evidence from a Bayesian network meta‐analysis

“…A total of 49 RCTs comprising of 5586 participants were included in this meta‐analysis (Supplementary material 2). There were 16 experiment groups evaluating medications classified under the inflammation subset, 17‐31 26 groups under the energy subset, 18,32‐56 nine groups under the bile acid subset 54,57‐64 and three groups under the fibrosis subset 8,65 . Majority of the included RCTs had placebo as the control group with exception of three articles with Pioglitazone, 21 Simtzutumab 25 and vitamin E as control 29 .…”

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

“…These results indicate that 19 exhibits a more potent MR antagonist activity than eplerenone in the in vivo animal study. The excellent antagonistic activity of 19 toward MR encouraged us to advance this compound for clinical development; phase II trials of 19 for diabetic nephropathy and NASH have been completed. , …”

“…Therefore, in order to overcome these issues, the development of selective and potent MRAs is required, and extensive research has been conducted to identify novel nonsteroidal MRAs. , Compared with steroidal MRAs, nonsteroidal MRAs characterized by high MR selectivity are suggested to reduce the risk of hyperkalemia. − As a result of the compound optimization, some compounds have reached the stage of clinical development. − Notably, the most advanced compounds in this context are esaxerenone (CS-3150), which received marketing approval in Japan for the treatment of hypertension in 2019, finerenone (BAY94-8862), which was approved in the United States for the treatment of chronic kidney disease associated with type 2 diabetes in 2021, apararenone (MT-3995), KBP-5074, and AZD9977 (Figure ). In this article, we describe the design and discovery of 19 (apararenone: MT-3995), as well as the pharmacological profile of the said compound, which has completed phase II clinical trials for diabetic nephropathy and NASH, wherein it proved to be a highly selective and potent nonsteroidal MRA. − …”