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

Naga Chalasani, Raj Vuppalanchi, M. Rinella, M. S. Middleton, M. S. Siddiqui, A. S. Barritt, O. Kolterman, O. Flores, C. Alonso, M. Iruarrizaga-Lejarreta, R. Gil-Redondo, C. B. Sirlin, M. B. Zemel

Research output: Contribution to journalArticle

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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).

Original languageEnglish (US)
Pages (from-to)1639-1651
Number of pages13
JournalAlimentary Pharmacology and Therapeutics
Volume47
Issue number12
DOIs
StatePublished - Jun 1 2018

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Metformin
Leucine
Randomized Controlled Trials
Fats
Placebos
Alanine Transaminase
Sirtuin 1
Liver
Fatty Liver
Protons
Magnetic Resonance Imaging
AMP-Activated Protein Kinases
Lipid Metabolism
Compliance
Non-alcoholic Fatty Liver Disease
Sildenafil Citrate
Up-Regulation
Fatty Acids
Lipids
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Randomised clinical trial : a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. / Chalasani, Naga; Vuppalanchi, Raj; Rinella, M.; Middleton, M. S.; Siddiqui, M. S.; Barritt, A. S.; Kolterman, O.; Flores, O.; Alonso, C.; Iruarrizaga-Lejarreta, M.; Gil-Redondo, R.; Sirlin, C. B.; Zemel, M. B.

In: Alimentary Pharmacology and Therapeutics, Vol. 47, No. 12, 01.06.2018, p. 1639-1651.

Research output: Contribution to journalArticle

Chalasani, N, Vuppalanchi, R, Rinella, M, Middleton, MS, Siddiqui, MS, Barritt, AS, Kolterman, O, Flores, O, Alonso, C, Iruarrizaga-Lejarreta, M, Gil-Redondo, R, Sirlin, CB & Zemel, MB 2018, 'Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease', Alimentary Pharmacology and Therapeutics, vol. 47, no. 12, pp. 1639-1651. https://doi.org/10.1111/apt.14674
Chalasani, Naga ; Vuppalanchi, Raj ; Rinella, M. ; Middleton, M. S. ; Siddiqui, M. S. ; Barritt, A. S. ; Kolterman, O. ; Flores, O. ; Alonso, C. ; Iruarrizaga-Lejarreta, M. ; Gil-Redondo, R. ; Sirlin, C. B. ; Zemel, M. B. / Randomised clinical trial : a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. In: Alimentary Pharmacology and Therapeutics. 2018 ; Vol. 47, No. 12. pp. 1639-1651.
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T2 - a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease

AU - Chalasani, Naga

AU - Vuppalanchi, Raj

AU - Rinella, M.

AU - Middleton, M. S.

AU - Siddiqui, M. S.

AU - Barritt, A. S.

AU - Kolterman, O.

AU - Flores, O.

AU - Alonso, C.

AU - Iruarrizaga-Lejarreta, M.

AU - Gil-Redondo, R.

AU - Sirlin, C. B.

AU - Zemel, M. B.

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N2 - 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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