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

Takeshi Okanoue; Michiie Sakamoto; Kenichi Harada; Masaya Inagaki; Naoko Totsuka; Gaia Hashimoto; Hiromitsu Kumada

doi:10.1111/hepr.13695

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

Hepatol Res. 2021 Sep;51(9):943-956. doi: 10.1111/hepr.13695. Epub 2021 Aug 5.

Authors

Takeshi Okanoue¹, Michiie Sakamoto², Kenichi Harada³, Masaya Inagaki⁴, Naoko Totsuka⁵, Gaia Hashimoto⁵, Hiromitsu Kumada⁶

Affiliations

¹ Department of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan.
² Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
³ Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
⁴ Data Science Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
⁵ Clinical Research and Development II Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
⁶ Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

PMID: 34260795
DOI: 10.1111/hepr.13695

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.

Keywords: alanine aminotransferase; clinical trial; fibrosis; mineralocorticoid receptor antagonist; nonalcoholic steatohepatitis; phase II.

Grants and funding

Mitsubishi Tanabe Pharma Corporation