Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review

Table 3 Studies of pan peroxisome proliferator-activated receptor agonists in the treatment of non-alcoholic fatty liver disease

Ref.	Human or animal	Study design	Number of participants	Key inclusion criteria	Investigational product/dose	Study endpoints	Key findings
Abitbol et al[21], 2016	Human	Double-blind, randomized, placebo-controlled, parallel-group study. Duration: 4 wk	n = 45	Patients with biopsy-confirmed NASH and type 2 diabetes on stable doses of metformin	IVA337 (Lanifibranor). Placebo vs IVA337 (400, 800, or 1200 mg daily)	Metabolic effects of IVA337 in diabetic patients	Reduction in triglycerides by 32% and ALT by 10% (P < 0.05)
Cooreman et al[14], 2022	Human	Post-hoc analysis of the phase 2b NATIVE study. Duration: 24 wk	n = 247	Patients with non-cirrhotic biopsy-confirmed NASH	Lanifibranor Placebo vs Lanifibranor (800 or 1200 mg daily)	Effect of Lanifibranor on glycemic control and NASH markers. Efficacy in NASH was measured with SAF score and fibrosis staging	NASH resolution and fibrosis improvement in the treatment group vs placebo was 26% vs 7%, respectively, and a 41% reduction of HbA1c from baseline (P < 0.001)
Francque et al[18], 2021	Human	Randomized, double-blind, placebo-controlled, phase 2b trial. Duration: 24 wk	n = 247	Patients with noncirrhotic, highly active NASH (SAF ≥ 1 or higher for steatosis, hepatocellular ballooning, and lobular inflammation on liver biopsy)	Lanifibranor Placebo vs Lanifibranor (800 or 1200 mg daily)	Decrease of at least 2 points in the SAF score without worsening of fibrosis	48% of patients in the 800 mg group and 55% in the 1200 mg group had a decrease of at least 2 points in the SAF score vs 33% in the placebo group (P = 0.007)
An et al[22], 2017	Animal	Duration: 3 wk	n = 5	Genetically obese mice	MHY2013: Control vs 5 mg/kg daily	Reduction of hepatic steatosis measured via liver triglycerides on biopsy	Liver triglycerides were 10 mg/100 mg of protein in the control vs 7 mg/100 mg of protein in the treatment group (P < 0.05)
An et al[25], 2018	Animal	Duration: 3 wk	n = 6	Aged model mice	MHY2013: Control vs MHY2013 (1 or 3-5 mg/kg daily)	Evaluate the attenuation of hepatic lipid accumulation measured by liver biopsy	The ratio of liver weight/body weight was 0.035, 0.03, and 0.025 in control, 1 and 3-5 mg/kg groups, respectively (P < 0.01)
Barbosa-da-Silva et al[16], 2015	Animal	Duration: 4 wk	n = 20	High-fat diet mice (n = 10 per group)	Bezafibrate: Control vs 100 mg/kg daily	Effect of Bezafibrate on hepatic lipid metabolism measured by liver TG and steatosis on biopsy	Reduction in TG levels and liver steatosis of 30% and 50%, respectively, in the treatment group (P < 0.0001)
Boubia et al[19], 2018	Animal	Duration: 3 wk	n = 16	CCI4-induced liver fibrosis in mice (n = 8 per group)	Lanifibranor: Control vs 30 mg/kg daily	Efficacy of Lanifibranor in reducing fibrosis in NASH measured by hepatic collagen on biopsy	Reduction in hepatic collagen deposition from 0.6% of the area to 0.3% in the control vs treatment group (P < 0.01)
Lefere et al[15], 2020	Animal	Duration: 6 wk	n = 16	Choline-deficient high-fat diet-induced NASH mouse model (n = 8). Isolated hepatic macrophages (n = 8)	Lanifibranor Control vs 30 mg/kg daily	Effect on NAFLD measured by the NAFLD activity score, fibrosis by the Sirus red staining, and hepatic macrophages assessed by IHC	Reduction of NAFLD activity score from 6 to 2 in the treatment vs control group (P < 0.0001), collagen by 5% to 3% (P < 0.01), and liver macrophages from 22% to 8% (P < 0.0001)
Møllerhøj et al[20], 2022	Animal	Duration: 12 wk	n = 13	Gubra-Amylin NASH diet-induced obese mouse with biopsy-confirmed NASH	Lanifibranor: Control vs 30 mg/kg daily	Change in NAS and fibrosis stage measured on biopsy	At least a 2-point improvement in the steatosis score, and only 20% of hepatocytes had lipid droplets vs 80% in the control group (P < 0.001). 50% of mice had a 1-point improvement in fibrosis (P < 0.05)
Nagasawa et al[17], 2006	Animal	Duration: 5 wk	n = 7	Choline-deficient high-fat diet-induced NASH mouse model	Benzafibrate: Control vs Benzafibrate (50, 100 mg/kg daily)	Effect on hepatic lipid content and histopathological changes measured on biopsy by the number of activated hepatic stellate cells	Liver TG was 25, 20, and 55 mg/g in the 50, 100 mg/kg vs placebo groups, respectively (P < 0.01). The activated hepatic stellate cells were 11 number/15 fields vs 1 number/15 fields, respectively
Wettstein et al[24], 2017	Animal	Duration: 3 wk	n = 20	Choline-deficient high-fat diet-induced model of NASH in mice (n = 10 per group)	IVA337 (Lanifibranor) Control vs 30 mg/kg daily	Evaluate the effects of IVA337 on hepatic features associated with NASH measured by hepatic lipid droplet count and lobular inflammation foci count	Prevention of steatosis in 98% of mice and inflammation in 75% of mice (P < 0.001)

ALT: Alanine transaminase; NASH: Non-alcoholic steatohepatitis; n: Number; TG: Triglycerides; CCL4: Carbon tetrachloride; SAF: Steatosis activity fibrosis; NAFLD: Non-alcoholic fatty liver disease; NAS: NAFLD activity score; IHC: Immunohistochemistry.