The Effect Of NS-0200 and NS-0300 Versus Placebo on Weight In Obesity

This is a randomized, 24-week, placebo-controlled, double-blind 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. Subjects meeting all the inclusion
criteria and no exclusion criteria will be randomized to one of five study arms.

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)
receiving two fixed-dose combinations of leucine and sildenafil or two fixed-dose
combinations of leucine, sildenafil and metformin compared to placebo. Secondary objectives
will also assess changes in absolute body weight, percentage of patients with ≥5% body weight
loss, change in waist circumference, change in HbA1c, change in fasting glucose, change in
blood lipids such as cholesterol, LDL, HDL, triglycerides, change in blood pressure and
changes in in C-reactive protein. In addition this study will evaluate the safety and
tolerability of NS-0200 and NS-0300.

Patients will have one screening visits which will determine their eligibility based on lab
tests. Once qualified, patients will be randomly assigned to either one of the treatment
groups or the placebo control group and monitored for a total of 24 weeks. Patients will
return to the clinic each month for lab tests, and routine examinations.

Inclusion Criteria:

1. Age ≥18 and ≤65 at study entry.

2. Is male, or female and, if female, meets all of the following criteria:

1. Not breastfeeding

2. Post-menopausal or negative serum pregnancy test result (human chorionic
gonadotropin, beta subunit [β-hCG]) at Screening/Visit 1 (Day-7/Week-1) (not
required for hysterectomized females)

3. If of childbearing potential (including peri-menopausal women who have had a
menstrual period within one year) must practice and be willing to continue to
practice appropriate birth control (defined as a method which results in a low
failure rate, i.e., less than 1% per year, when used consistently and correctly,
such as double barrier methods [male condom with spermicide, with or without
cervical cap or diaphragm], implants, injectables, oral contraceptives [must have
been using for at least the last 3 months], some intrauterine contraceptive
devices, tubal ligation, or in an established relationship with a vasectomized or
same sex partner) during the entire duration of the study

3. Stable body weight (±5%) and health over the last 3 months.

4. Has a BMI between 30 kg/m2 and 45 kg/m2

5. Stable diet within the last three months

6. Subjects on antidepressants, excluding those listed in the exclusion criteria, must
have been on a stable dose regiment for at least 3 months prior to study enrollment
and maintain stable dose during the study

7. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either
normal, not clinically significant or with abnormalities consistent with obesity

8. Is able to read, understand, and sign the informed consent forms (ICF) and, when
applicable, an authorization to use and disclose protected health information form
(consistent with Health Insurance Portability and Accountability Act of 1996 [HIPAA]
legislation), communicate with the investigator, and understand and comply with
protocol requirements.

Exclusion Criteria:

1. Diagnosis of diabetes or on a diabetes medication

2. HbA1c ≥6.5% at Screening/Visit 1 (Day-7/Week-1)

3. Severe renal impairment (eGFR < 45 mg/mL/1.73 m2) and/or patients with acute or
chronic metabolic acidosis. Acidosis is defined as >25mmol/L computed without K.

Normal is 8- 16, but acidosis is >25

4. Use of any of the following medications in the eight weeks prior to entering screening
for study participation and during the study:

1. Use of any anti-diabetes medication including metformin and any combination drug
that contains metformin

2. Sildenafil

3. Tadalafil

4. Vardenafil

5. OCT2/MATE inhibitors (e.g. cimetidine, quinidine, and pyrimethamine)

6. Riociguat (guanylate cyclase stimulant)

7. Alpha blockers

8. Nitrates (e.g. oral nitrates, sublingual nitroglycerine and nitroglycerine
patches)

9. Potent CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, nefazodone,
itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir,
nelfinavir, ritonavir, saquinavir, tipranavir)

10. All antihypertensive medications

11. Medications associated with weight changes

- Drugs approved for the treatment of obesity

- Cypropheptadine or medroxyprogesterone

- Atypical anti-psychotic drugs

- Tricyclic antidepressants

- Lithium, MAO's, glucocorticoids

- SSRI's or SNRI's

- Antiepileptic drugs

- Systemic corticosteroids

- Stimulants e.g. amphetamines

12. Any dietary supplement that is labeled for weight management or maintenance of
healthy weight

5. Diagnosis or evidence of eating disorders

6. ≥ 5% weight change in the last 3 months

7. Subjects who have had bariatric surgery

8. An infection requiring antibiotic treatment within the last 30 days

9. Any chronic inflammatory disease, e.g. inflammatory bowel disease rheumatoid
arthritis, vasculitis, systemic lupus erythematosus

10. Diseases interfering with metabolism (including metabolism of branched chain amino
acids) and/or ingestive behavior (myxedema, Cushing's disease, diabetes,
schizophrenia, major psychoses, maple syrup urine disease, unmanaged depression etc.)

11. History of alcohol abuse (defined ≥ 21 drinks per week for males and > 14 drinks per
week for females), within the past 3 months or failure on urinary drug screen

12. History of substance abuse (including alcohol abuse as defined above) in the past 12
months or a positive screen for drugs (opioids without a prescription), including
marijuana, of abuse or alcohol at screening.

13. Has received any investigational drug within 3 months of Screening.

14. Has donated blood within 3 months before Screening or is planning to donate blood
during the study (due to HbA1c reading at screening)

15. Other medical conditions that may diminish life expectancy to <2 years, including
known cancers

16. Have been diagnosed with metastatic carcinomas in the last 5 years

17. Has known allergies or hypersensitivity to metformin, sildenafil or leucine

18. Have suffered myocardial infarction, stroke, arrhythmia in the last 6 months

19. Resting hypotension (BP <90/50 mmHg) or severe hypertension (BP >170/110 mmHg) If both
or one of the parameters for diastolic or systolic BP is meet

20. Cardiac failure or coronary artery disease causing unstable angina

21. History or evidence at screening of left ventricular outflow obstruction (e.g., aortic
stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired
autonomic control of blood pressure

22. At risk for priapism due to anatomical deformation of the penis (e.g., angulation,
cavernosal fibrosis, Peyronie's disease) or other conditions that predispose to
priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia)

23. Clinical evidence of hepatic impairment and/or ALT/AST >5X ULN

24. Is an immediate family member (spouse, parent, child, or sibling; biological or
legally adopted) of personnel directly affiliated with the study at the clinical study
site, or NuSirt Biopharma.

25. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or
designee responsible for the conduct of the study).