2. Academic Validation
  3. Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease

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

  • Aliment Pharmacol Ther. 2018 Jun;47(12):1639-1651. doi: 10.1111/apt.14674.
N Chalasani 1,  R Vuppalanchi 1,  M Rinella 2,  M S Middleton 3,  M S Siddiqui 4,  A S Barritt 4th 5,  O Kolterman 6,  O Flores 6,  C Alonso 7,  M Iruarrizaga-Lejarreta 7,  R Gil-Redondo 7,  C B Sirlin 3,  M B Zemel 6
Affiliations

Affiliations

  • 1 Indiana University School of Medicine, Indianapolis, IN, USA.
  • 2 Northwestern University, Chicago, IL, USA.
  • 3 University of California at San Diego, San Diego, CA, USA.
  • 4 Virginia Commonwealth University, Richmond, VA, USA.
  • 5 University of North Carolina, Chapel Hill, NC, USA.
  • 6 NuSirt Biopharma, Nashville, TN, USA.
  • 7 OWL Metabolomics, Derio, Spain.
PMID: 29696666 DOI: 10.1111/apt.14674
Abstract

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 < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation.

Conclusion: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).

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