Randomised clinical trial: a leucine‐metformin‐sildenafil combination (NS‐0200) vs placebo in patients with non‐alcoholic fatty liver disease

Summary Background Sirtuin 1 (Sirt1) is suppressed in non‐alcoholic fatty liver disease (NAFLD), while its’ stimulation or overexpression results in reduced disease severity in pre‐clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS‐0200), which was effective in a mouse model of non‐alcoholic steatohepatitis (NASH). Aim To report the results from a Phase 2, randomised clinical trial of of NS‐0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging‐proton‐density fat fraction (MRI‐PDFF)). Methods Subjects were randomised to placebo, low‐dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI‐PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). Results In the full cohort, active treatments did not separate from placebo. High dose NS‐0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P