Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR1-365

INTERVENTION: Part 1 includes 5 dosing cohorts with 8 subjects in each cohort, 6 subjects to be treated with SIR1‐365 and 2 subjects with placebo. Two subjects to be enrolled in each of the 5 dosing cohorts will be treated first (one subject with SIR1‐365 and another subject with matching placebo). If there is no significant safety concern within 48 hours after dosing in those two subjects, the rest of the subjects in the dose cohort will then be treated at the same time with a single oral dose of either placebo or SIR1‐365. Subjects in cohorts 1‐5 will receive a single 10mg, 30mg, 100mg, 200mg or 300mg oral dose of SIR1‐365 or placebo instead of SIR1‐365. Dose escalation will not occur until a decision is made by the Safety Review Committee based on the review of safety and tolerability data from the previous dose cohort. Each subject will remain in the study unit for 5 days. Part 2 will include 3 dosing cohorts with 10 subjects in each cohort. Eight subjects will be treated with SIR1‐365 and two subjects with placebo in each cohort. Subjects enrolled in the Part 2 2nd cohort, will have one CSF sample collected during Days 5‐9. The three doses for Part 2 will be decided after the completion of Part 1. The potential dose range for Part 2 is 10‐300mg. Each subject will receive oral administrations of either placebo or SIR1‐365 to be administered twice daily for 10 days. Each subject will remain in the study unit for 14 days. All Part 1 and Part 2 subjects will complete 1 additional outpatient visit for safety assessment. Study staff will instruct subjects to take the study medication exactly as instructed as compliance is necessary for subject safety and for the validity of the study. CONDITION: Inflammatory and Immune System ‐ Other inflammatory or immune system disorders Neurodegenerative disease;inflammatory disease; ; Neurodegenerative disease ; inflammatory disease Neurological ‐ Alzheimer's disease Neurological ‐ Multiple sclerosis Neurological ‐ Neurodegenerative diseases Neurological ‐ Other neurological disorders Neurological ‐ Parkinson's disease Renal and Urogenital ‐ Other renal and urogenital disorders SECONDARY OUTCOME: Pharmacodynamics: plasma samples from each subject to be enrolled in one of the cohorts in Part 2 (to be selected after PK data is available) will be used for the measurements of a common cytokine panel and IL‐33.[Part 1 Blood: Day 1: pre‐dose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 hours after morning dose. ; Days 2‐4 ; Part 2: Day 1: pre‐dose, 0.5, 1, 2, 4, 6, 9, 9.5, 10, 11, 13, 15 and 18 hours after morning dose. ; Days 2‐9: one sample within 30 min prior to the morning and evening dosing, respectively every day ; Days 10‐13: pre‐dose, 0.5, 1, 2, 4, 6, 9, 9.5, 10, 11, 13, 15, 18, 24, 36, 48, 60 and 72 hours after morning dose on Day 10.] INCLUSION CRITERIA: 1. Are capable of signing informed consent form (ICF) and complying with study procedures; 2. Women of childbearing potential (WOCBP) must have a negative pregnancy test and be practicing a medically acceptable method of contraception. All male patients with female partners of child‐bearing potential must use two acceptable methods of contraception, during and for 3 months after participation in the study. 4. Able to abstain from the consumption of alcohol and any alcohol‐containing products from 48 hours before dosing through the end of the study; 5. Able to limit the consumption of coffee and any caffeine‐containing products to four cups a day during the study; 6. Body mass index (BMI) of 18 to 32 kg/m2 inclusive and body weight not le PRIMARY OUTCOME: Pharmacokinetics: The plasma concentration time data for SIR1‐365 will be analyzed using non‐compartmental methods. Actual dosing and sampling times will be used for analyses. The primary PK parameters of interest include Cmax, Tmax, t1/2, AUClast, AUCinf, CL/F and Vd/F for plasma, when possible. Additional parameters may be estimated and reported, as appropriate.[Part 1 Blood: Day 1: pre‐dose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 hours after morning dose.; Days 2‐4; Part 1 Urine: pre‐dose, 0‐4, 4‐8, 8‐12 and 12‐24 hours post dose.; Part 2: Day 1: pre‐dose, 0.5, 1, 2, 4, 6, 9, 9.5, 10, 11, 13, 15 and 18 hours after morning dose.; Days 2‐9: one sample within 30 min prior to the morning and evening dosing, respectively every day; Days 10‐13: pre‐dose, 0.5, 1, 2, 4, 6, 9, 9.5, 10, 11, 13, 15, 18, 24, 36, 48, 60 and 72 hours after morning dose on Day 10; Subjects enrolled in the 2nd cohort, will have one CSF sample collected during Days 5‐9. A blood PK sample will be collected around 30 minutes after collection of the CSF sample.; ] Safety (e.g., Adverse Events (AE), Serious Adverse Events (SAE), Vital Signs Measurements, 12‐lead Electrocardiogram (ECG) Results, Clinical Laboratory Results, Physical Examination Findings).; ; Clinical Laboratory tests include:; ‐ Blood haematology ; ‐ Blood chemistry; ‐ Blood coagulation ; ‐ Blood serology (HIV, Hepatitis B and C); ‐ Urinalysis; ‐ Serum and urine pregnancy test (women of child bearing age) ; ; A complete physical examination will include but not limited to the evaluation of the following organs or body systems: skin; head, eyes, ears, nose, and throat; thyroid; respiratory, cardiovascular, and central nervous systems; abdomen (liver and spleen); lymph nodes; and extremities.[Part 1 ‐ Baseline (Day ‐1) and Days 1, 2, 3, 4 and 11 after intervention. A complete physical examination will be completed at screening (including weight and height), baseline and day 4. All other safety assessments are completed at all scheduled visits including screening, except for the following:; Serum pregnancy (hCG) test: Screening,; Urine pregnancy test: Day ‐1,; HIV, hepatitis B & C test: Screening; ; Part 2 ‐ Baseline (Day ‐1) and Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 20 after intervention. A complete physical examination will be completed at screening (including weight and height), baseline and day 13. Vital Signs Measurements will be completed at all scheduled visits including screening. 12‐lead Electrocardiogram (ECG) and Clinical Laboratory tests will be completed at screening, baseline and Days 1, 4, 7, 10, 13 and 20 except for the following:; Serum pregnancy (hCG) test: Screening; Urine pregnancy test: Day ‐1; HIV, hepatitis B & C test: Screening] 3. Nonsmoker, defined as not having smoked more than 2 cigarettes a day during the 6 months before screening. During the study, subject should be able to limit the use of tobacco products to 2 cigarettes a day;