1. Michael B. Zemel, Ph.D. Chief Scientific Officer NuSirt Biopharma
NS-WM-01 Investigator Meeting:
Scientific Rationale& Clinical
Michael B. Zemel, Ph.D.
Chief Scientific Officer
NuSirt Biopharma

2. NuSirt Targets Sirt1 & AMPK
Sirt1 & AMPK: Regulators of energy metabolism
Activated by caloric restriction
Inhibited by high-fat or calorically-dense diet
Sirt1 activation mimics physiological effects of caloric restriction
Increases mitochondrial biogenesis & lipid oxidation
Inhibits lipid synthesis and storage
Increases insulin sensitivity
Reduces adipose tissue-mediated inflammation

3. Molecular Synergy Between Leucine and Sirt1
Sirt1 activity
NAD+ concentration
Leucine
Enables synergy with Sirtuin
Pathway activators to:
 Lipid oxidation
 Lipid synthesis
 Lipid storage
 Adipose tissue Inflammation
Leucine lowers NAD+ activation energy for sirtuins. Robust synergy at very low concentrations of sirtuin activators mimics the effects of caloric restriction (high NAD+).

4. Integrated Mechanism of Action Targets Obesity & Co-morbidities

5. Sirt1, AMPK and eNOS: Interactive Targets of Leu-Sil & Leu-Met-Sil

6. Sirt1 Pathway Activation Shifts Energy Disposition

7. Clinical Study Results: NS-0200-01

8. Leu-Met-Sil Induces Weight Loss in Obese Subjects

9. Leu-Met-Sil Induces Weight Loss in Obese NAFLD Subjects with Elevated Liver Enzymes

10. Leu-Met-Sil Reduces Liver Fat in Obese NAFLD Subjects with Elevated Liver Enzymes

11. Leu-Met-Sil Induces Weight Loss in Obese Subjects with Elevated Triglycerides

12. Leu-Met-Sil Reduces Triglycerides in Obese Hypertriglyceridemic Subjects

13. Leu-Met-Sil Reduces Blood Pressure in Obese Subjects
Effects shown: Obese patients on anti-hypertensive Rx;
Comparable effect in full cohort

14. Leu-Met-Sil vs. Leu-Sil

15. Dose Rationale
Leucine: Sufficient to increase plasma leucine to ~0.5 mM
Activates Sirt1 without affecting mTOR
1.1 g b.i.d.
Metformin: Optimal dose determination for insulin sensitivity from previous clinical trial
500 mg b.i.d.
Sildenafil: Activation of eNOS with little or no effect on PDE5
1 – 4 mg b.i.d.

16. Summary
Leu-Sil with or without metformin: Synergistic activation of Sirt1/AMPK/eNOS signaling (calorie restriction mimetic)
Clinical data: Leu-Met-Sil in NS induced weight loss & improvement in co-morbidities in absence of caloric restriction
Preclinical data suggests Leu-Sil is equal to or better than Leu-Met-Sil for weight management, but no clinical data available on Leu-Sil
Clinical comparison in NS-WM-01
Sildenafil clinical dose-optimization in NS-WM-01

17. Questions?