2046-P: NS-0200 (Leucine-Metformin-Sildenafil) Reduces Weight in Obese Subjects: A 24-Week Randomized Trial
Authors: ZEMEL MICHAEL B. , KOLTERMAN ORVILLE G. , FLORES OMAR , FLEMING GILBERT ALEXANDER , GREENWAY FRANK L. 
Published: June 2019

We previously showed leucine to activate the SIrt1/AMPK/NO pathway and to synergize with other activators of this pathway, and developed NS-0200 (leucine-metformin-sildenafil combination) to treat diseases of energy dysregulation. During a previous trial of NS-0200 of nonalcoholic fatty liver disease we noted significant weight loss induced by NS-0200. Accordingly, we have conducted a 24-week placebo-controlled double-blind trial in 258 weight-stable obese subjects to evaluate the effects of leucine (1.1 g) + sildenafil (1 or 4 mg) with or without metformin (500 mg) administered b.i.d. on weight loss in the absence of lifestyle modification; data presented are for the 202 per-protocol completers. Leu/Met/Sil 1.0 or 4.0 mg and Leu/Sil 4.0 mg produced significant weight loss, while LeuSil 1.0 mg did not. Leu/Met/Sil 1.0 mg exerted the greatest effect (2% placebo-adjusted weight loss, p&lt;0.01), with a greater effect in subjects with BMI&lt;40 (2.9% weight loss, 23% of subjects achieved ≥ 5% weight loss). Markedly greater effects were found in African-American (AA) subjects (6% weight loss, p&lt;0.01) and those with BMI 35-39.9 (4.2% weight loss, p&lt;0.001). These sub-group differences were explained, in part, by differences in baseline insulin and insulin resistance. 71% of AA had insulin ≥ 8 mU/L and HOMAIR&gt;2, vs. 42% in Caucasians, and Leu/Met/Sil 1.0 resulted in a 61% decrease in both insulin and HOMAIR(p&lt;0.009) in AA. Similarly, treated subjects with BMI 35-39.9 had ∼two-fold elevations in insulin and HOMAIR vs. those with BMI&lt;35, and 77% had insulin ≥ 8 mU/L and HOMAIR&gt;2 (p=0.017); those with elevated insulin at baseline lost ∼twice as much weight as those with lower insulin (-3.8 vs. -1.8%), and 30% of this subgroup achieved 5% weight loss vs. 6% of placebo. These data indicate NS-0200 results in significant 6-month weight loss, especially in insulin-resistant subjects, and suggest therapeutic utility for obese insulin-resistant individuals.

Disclosure
M.B. Zemel: Board Member; Self; NuSirt Biopharma, Inc. Employee; Self; NuSirt Biopharma, Inc. Stock/Shareholder; Self; NuSirt Biopharma, Inc. O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. O. Flores: None. G. Fleming: Advisory Panel; Self; ADOCIA, Biocon. Consultant; Self; Enanta Pharmaceuticals, Inc., InsuLine Medical Ltd., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Merck KGaA, Oramed Pharmaceuticals, Orgenesis Ltd., Sanofi. Employee; Self; Tolerion, Inc. F.L. Greenway: Advisory Panel; Self; BAROnova, Gelesis, Jenny Craig - Curves, Novartis Pharmaceuticals Corporation, NuSirt Biopharma, Inc., Zafgen, Inc. Consultant; Self; Academic Technology Ventures, Basic Research, General Nutrition Corporation, Melior Discoveries. Research Support; Self; Microbiome Therapeutics. Stock/Shareholder; Self; Plensat, Slim Health Nutrition. Other Relationship; Self; Neuroquest.

Funding
NuSirt Biopharma, Inc.