Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease

Abstract

Background: Pemafibrate is a novel, selective peroxisome proliferator-activated receptor α modulator (SPPARMα). In mice, Pemafibrate improved the histological features of non-alcoholic steatohepatitis (NASH). In patients with dyslipidaemia, it improved serum alanine aminotransferase (ALT).

Aims: To evaluate the efficacy and safety of Pemafibrate in patients with high-risk, non-alcoholic fatty liver disease (NAFLD).

Methods: This double-blind, placebo-controlled, randomised multicentre, phase 2 trial randomised 118 patients (1:1) to either 0.2 mg Pemafibrate or placebo, orally, twice daily for 72 weeks. The key inclusion criteria included liver fat content of ≥10% by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF); liver stiffness of ≥2.5 kPa, by magnetic resonance elastography (MRE); and elevated ALT levels. The primary endpoint was the percentage change in MRI-PDFF from baseline to week 24. The secondary endpoints included MRE-based liver stiffness, ALT, serum liver fibrosis markers and lipid parameters.

Results: There was no significant difference between the groups in the primary endpoint (-5.3% vs -4.2%; treatment difference -1.0%, P = 0.85). However, MRE-based liver stiffness significantly decreased compared to placebo at week 48 (treatment difference -5.7%, P = 0.036), and was maintained at week 72 (treatment difference -6.2%, P = 0.024), with significant reduction in ALT and LDL-C. Adverse events were comparable between the treatment groups and therapy was well tolerated.

Conclusions: Pemafibrate did not decrease liver fat content but had significant reduction in MRE-based liver stiffness. Pemafibrate may be a promising therapeutic agent for NAFLD/NASH, and also be a candidate for combination therapy with agents that reduce liver fat content. ClinicalTrials.gov, number: NCT03350165.

FIGURE 1

Flow diagram of patient disposition

FIGURE 2

Percentage change from baseline to 72 weeks in liver fat content by MRI‐PDFF (A) and liver stiffness by MRE (B). Data are expressed as least square mean. Error bars show 95% CI. *P < 0.05 vs placebo. Representative images of MRE of a patient (C). ROIs, the areas surrounded by yellow line, were set in the right lobe of the liver in accordance with the instruction in the prespecified manual [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Measured levels of liver (A‐D) and renal function (E, F) markers over 72 weeks. Data are expressed as mean. Error bars show SD. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ‐glutamyl transpeptidase; ALP, alkaline phosphatase; eGFR, estimated glomerular filtration rate [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Measured levels of lipid markers over 72 weeks. Data are expressed as mean. Error bars show SD. TC, total cholesterol; LDL‐C, low‐density lipoprotein‐cholesterol; HDL‐C, high‐density lipoprotein‐cholesterol; TG, triglyceride [Colour figure can be viewed at wileyonlinelibrary.com]