A Randomized, Double-blind, Placebo-controlled Study of Effects of Two Fixed-dose Leucine-sildenafil Combinations (NS-0300) or Two Fixed-dose Leucine-sildenafil-metformin Combinations (NS-0200) Versus Placebo on Body Weight in Obesity

This is a 24-week study to evaluate the effects of two fixed-dose combinations of leucine and sildenafil or two fixed-dose combinations of leucine, sildenafil and metformin compared to placebo. The primary objective of this study is to evaluate the percentage change in body weight in subjects from Baseline/Visit 2 (Day 1) to Study Termination/Visit 8 (Day 168/Week 24).

Start Date08 Jan 2018

Sponsor / Collaborator

NuSirt Biopharma, Inc.

NCT02546609 / CompletedPhase 2

A Randomized, Blinded, Placebo-Controlled Study To Evaluate The Effect Fixed-Dose Leucine, Metformin, Sildenafil Combinations(NS-0200) Versus Placebo On Hepatic Fat Assessed By MRI In Non Alcoholic Fatty Liver Disease Patients

The goal of this study is to determine if NS-0200 can reduce the amount of liver fat in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). This study will compare two doses of NS-0200 to placebo in NAFLD patients.

Start Date19 Nov 2015

Sponsor / Collaborator

NuSirt Biopharma, Inc.

NCT02435277 / CompletedPhase 2

An Extension of Protocol NS-0100-01 to Evaluate the Safety and Effect of Various Fixed-Dose Leucine and Metformin Combinations (NS-0100) Versus Standard Metformin Mono-therapy on Glycemic Control in Subjects With Type 2 Diabetes

Study NS-0100-01E is an extension of Study NS-01-0100 designed to assess safety and longer term effect (i.e., additional 8 weeks) of various fixed-dose leucine and metformin combinations (NS-0100) versus standard metformin monotherapy on glycemic control in subjects with type 2 diabetes using HbA1c as the primary endpoint.

Start Date01 Oct 2014

Sponsor / Collaborator

NuSirt Biopharma, Inc.

100 Clinical Results associated with NuSirt Biopharma, Inc.

0 Patents (Medical) associated with NuSirt Biopharma, Inc.

Literatures (Medical) associated with NuSirt Biopharma, Inc.

01 Nov 2016·MetabolismQ1 · MEDICINE

Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans

Q1 · MEDICINE

Article

Author: Bruckbauer, Antje ; Zemel, Michael B ; Banerjee, Jheelam

BACKGROUNDWe have previously shown leucine (Leu) to activate Sirt1 by lowering its K_M for NAD⁺, thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin sensitivity and glycemic control while achieving ~80% dose-reduction in diet-induced obese mice. Accordingly, we sought here to define the mechanism of this interaction.METHODSMuscle cells C2C12 and liver cells HepG2 were used to test the effect of Met-Leu on Sirt1 activation. Caenorhabditis elegans was used for glucose utilization and life span studies.RESULTSLeu (0.5mmol/L)+Met (50-100μmol/L) synergistically activated Sirt1 (p<0.001) at low (≤100μmol/L) NAD⁺ levels while Met exerted no independent effect. This was associated with an increase in AMPK and ACC, phosphorylation, and increased fatty acid oxidation, which was prevented by AMPK or Sirt inhibition or silencing. Met-Leu also increased P-IRS1/IRS1 and P-AKT/AKT and in insulin-independent glucose disposal in myotubes (~50%, p<0.002) evident within 30 min as well as a 60% reduction in insulin EC₅₀. In addition, in HepG2 liver cells nuclear CREB regulated transcription coactivator 2 (CRTC2) protein expression and phosphorylation of glycogen synthase was decreased, while glycogen synthase kinase phosphorylation was increased indicating decreased gluconeogenesis and glycogen synthesis. We utilized C. elegans to assess the metabolic consequences of this interaction. Exposure to high glucose impaired glucose utilization and shortened life span by ~25%, while addition of Leu+Met to high glucose worms increased median and maximal life span by 29 and 15%, respectively (p=0.023), restored normal glucose utilization and increased fat oxidation ~two-fold (p<0.005), while metformin exerted no independent effect at any concentration (0.1-0.5mmol/L).CONCLUSIONThus, Leu and Met synergize to enable Sirt1 activation at low NAD⁺ concentrations (typical of energy replete states). Sirt1 and AMPK activations are required for Met-Leu's full action, which result in improvements in energy metabolism and insulin sensitivity.

01 Jan 2016·International Journal of Hepatology

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Article

Author: Bruckbauer, Antje ; Shi, Hang ; Banerjee, Jheelam ; Fu, Lizhi ; Xue, Bingzhong ; Li, Fenfen ; Cao, Qiang ; Zemel, Michael B. ; Wu, Rui ; Cui, Xin

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.

01 Nov 2015·MetabolismQ1 · MEDICINE

Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice

Q1 · MEDICINE

Article

Author: Bruckbauer, Antje ; Cao, Qiang ; Zemel, Michael B ; Li, Fenfen ; Shi, Hang ; Fu, Lizhi ; Xue, Bingzhong ; Cui, Xin ; Wu, Rui

BACKGROUNDLeucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice.METHODSMice were fed high leucine (24 g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50 g/kg diet) or therapeutic levels of metformin (1.5 g/kg diet; ~300 mg/kg body weight).RESULTSHigh-fat diet produced a 10-fold increase in inguinal fat pad weight and 25% increase in liver weight, histologically confirmed as steatosis. The leucine-metformin combinations reduced fat pad mass, normalized liver weight, liver and plasma lipids and inflammatory markers (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. Moreover, the highest sub-therapeutic levels of metformin with leucine exerted significantly greater effects than therapeutic levels of metformin and fully reversed hepatic steatosis. These effects were mediated by upregulation of hepatic AMPK and associated changes in lipogenic gene expression (fatty acid synthase, stearoyl CoA desaturase, acetyl CoA carboxylase) in the liver.CONCLUSIONA low-dose leucine-metformin combination exerts comparable effects on adiposity to therapeutic doses of metformin and fully reverses hepatic steatosis in diet-induced-obese mice.

100 Deals associated with NuSirt Biopharma, Inc.

100 Translational Medicine associated with NuSirt Biopharma, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Leucine/Sildenafil ( PDE5A )	Obesity More	Pending
Sildenafil/Metformin/Leucine ( PDE5A x PRKAB1 )	Obesity More	Pending

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