Phase 1, Randomized, Placebo-controlled, Double-blind, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability and Pharmacokinetics of NB-4746 in Healthy Volunteers

INTERVENTION: This is a single center, double‐blind randomized placebo‐controlled study to assess the safety, tolerability and pharmacokinetics of NB‐4746 in healthy volunteers. A total of 66 subjects will be enrolled sequentially into 6 ascending single dose and 3 ascending multiple dose cohorts. Subjects will only be allowed to enrol in one cohort. Part A ‐ Single Escalating Dose: Study participants will be randomly assigned to receive a single dose of NB‐4746 or placebo administered as an oral solution on day 1. There will be 6 ascending dose cohorts in Part A with 7 participants per cohort. The proposed dose levels for cohorts 1 through to 6 are 50, 100, 175, 300, 450 and 600mg as a single oral dose. Participants must fast for at least 10 hours prior to administration. Administration will occur under supervision. Sentinel dosing will occur within each cohort, whereby on Day 1, the first 2 subjects will receive NB‐4746 or placebo as assigned per the 1:1 randomization schedule. A minimum of 48 hours following sentinel dosing, following safety assessment by the Principal Investigator (PI), the remaining 5 subjects in each cohort will be randomly assigned to receive NB‐4746 or placebo in a 4:1 ratio. A Safety Review Committee (SRC) will review the safety and 24‐hour PK data together in a blinded manner and approve or deny escalation to the next higher dose. Each follow‐on cohort will not commence dosing until a minimum of 6 subjects from the prior cohort have completed their in‐house/confinement period. Part B ‐ Multiple Ascending Doses: Study participants will be randomly assigned to receive multiple doses of NB‐4746 or placebo administered as an oral solution for 10 days. NB‐4746 or placebo will be administered once on day 1 (single dos CONDITION: Amyotrophic lateral sclerosis (ALS); ; Amyotrophic lateral sclerosis (ALS) Neurological ‐ Neurodegenerative diseases INCLUSION CRITERIA: ‐ Male and post‐menopausal females aged >/=18 years and < /=65 years old at the time of signing informed consent. ‐ Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (ECG). ‐ Nonsmoker and/or ex‐smoker who has discontinued smoking and/or the use of nicotine containing products for at least 3 months prior to first dose of study drug. ‐ Body mass inde Xwithin the range 18 to 30 kg/m2 inclusive. ‐ Females must be either postmenopausal for >/=1 year (or with FSH >/=40 mIU/mL at screening if postmenopausal for < 1 year) or surgically sterile (having undergone bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months. However, to protect against the transfer of the study drug in any bodily fluids, male partners of female subjects (whether postmenopausal or surgically sterile) must use a barrier form (e.g., condom) PRIMARY OUTCOME: To evaluate the safety and tolerability of multiple escalating oral doses of NB 4746 in healthy subjects. ; Safety will be measured by routine clinical and laboratory procedures including blood samples to assess hematology, liver function, renal function and blood chemistry; urinalysis; physical examination; 24 hour urine collection; collection of vital signs including measurement of blood pressure measured using an automated sphygmomanometer, heart rate, respiratory rate and temperature; ECG and recording treatment‐emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in accordance with Common Terminology Criteria for Adverse Events (CTCAE v5.0). [Following enrolment into the study and administration of the first dose of study drug participants will undergo vital signs measurements comprising temperature, heart rate, respiratory rate and blood pressure at 1, 2, 4, 8 and 12 hours post dose on day 1, 3, 7 and 10; 24 hours after day 10 dosing, day 14 and EOS (day 18). A complete physical examination will occur on day 14 and EOS, a focused physical examination will be performed on day 1 (predose), days 3, 5, 7 and day 10 if clinically indicated and body weight measured on days 2, 4, 7 and 10. Clinical laboratory tests including chemistry, hematology and urinalysis will be collected during screening and predose on day 1, 3, 7, 10, 14 and at EOS. Serum electrolyte levels will be collected 2 hours post AM dose from Days 1‐10 (inclusive). Triplicate 12‐lead ECG recordings will be obtained during screening, predose and 1, 2, 4, 8 and 12 hours post dose (AM dose) on days 1, 3, 7, and 10; 24 hours after day 10 dosing, on day 14, and at EOS. ECG will also be obtained pre‐dose and 2 hours post AM dose on days 2, 4,5, 6, 8 and 9. 24‐hour urine collection will be conducted daily on days 1 to 13. All AE and SAE information will be collected from signing of the informed consent form until the EOS visit.] To evaluate the safety and tolerability of single escalating oral doses of NB 4746 in healthy subjects. ; Safety will be measured by routine clinical and laboratory procedures including blood samples to assess hematology, liver function, renal function and blood chemistry; urinalysis; physical examination; 24 hour urine collection; collection of vital signs including measurement of blood pressure measured using an automated sphygmomanometer, heart rate, respiratory rate and temperature; ECG and recording treatment‐emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in accordance with Common Terminology Criteria for Adverse Events (CTCAE v5.0). [Following enrolment into the study and administration of the first dose of study drug participants will undergo vital signs measurements comprising temperature, heart rate, respiratory rate and blood pressure at 0.5, 1, 2, 4 and 8 hours post dose on day 1, 24 hours post dose on day 2, 48 hours post dose on day 3 and 72 hours post dose on day 4 and EOS (End of Study/day 8). A complete physical examination will occur on day 4 and EOS, a focused physical examination will be performed on day 1 (predose), day 2 and day 3 if clinically indicated. Clinical laboratory tests including chemistry, hematology and urinalysis will be collected during screening and on day 1 (predose), 24 hours post dose on day 2, day 4 and EOS. Serum electrolyte levels will be collected pre‐dose, 0.5, 1, 2, 4, 8 and 24‐hours post‐dose on day 1. Triplicate 12‐lead ECG recordings will be obtained during screening, on day 1 (predose), 0.5, 1, 2, 4, 8 hours post dose on day 1, 24 hours post dose on day 2, 48 hours post dose on day 3, and 72 hours post dose on day 4 and EOS. 24‐hour urine collection will be conducted on days 1, 2 and 3. All AE and SAE information will be collected from signing of the informed consent form until the EOS visit.] SECONDARY OUTCOME: To determine markers of CYP3A activity after multiple escalating oral doses in healthy subjects. ; ; Urine 6beta‐OH cortisol/cortisol ratio will be examined. [Urine will be analyzed for 6beta‐OH cortisol/cortisol ratio (a CYP3A activity marker) on Day ‐1, and Day 1 and Day 10 from the 24‐hour urine collection. ] To estimate the pharmacokinetic (PK) profile of NB‐4746 after single, escalating oral doses in healthy subjects. ; ; Plasma PK parameters include Cma X(maximum plasma concentration), tma X(time to maximum plasma concentration), AUC0‐inf (area under the curve from time 0 to infinity), AUC0‐last (area under the curve to the last concentration), AUC0‐12 (area under the curve from time 0 to 12 hours), AUC0‐24 (area under the curve from time 0 to 24 hours), Terminal half‐life (t½), CL/F (apparent clearance following oral administration). ; [Sampling for PK plasma parameters will occur at the following time points: predose, 05, 1, 2, 4, 6, 8, 12, 16, 24, 32, 40, 48, 56 and 72 hours post dose.] To estimate the PK profile of NB‐4746 after multiple escalating oral doses in healthy subjects. ; ; Plasma PK parameters include Cma X(maximum plasma concentration), tma X(time to maximum plasma concentration), AUC0‐inf (area under the curve from time 0 to infinity), AUC0‐last (area under the curve to the last concentration), AUC0‐12 (area under the curve from time 0 to 12 hours), AUC0‐24 (area under the curve from time 0 to 24 hours), Terminal half‐life (t½), CL/F (apparent clearance following oral administration). ; [Sampling for PK plasma parameters will occur at the following time points: predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 post dose on day 1; predose and 2 hours after first daily dose on days 3, 5, and 7; and predose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 32, 48, 56, 72, 80, and 96 hours post dose on day 10.] To estimate the urinary excretion of unchanged drug (NB‐4746) after multiple escalating oral doses in healthy subjects. ; ; Parameters include Ae0‐24 (amount excreted from time 0 to 24 hours) on day 9.[Urine will be analyzed for drug levels (amount excreted) on Day 9.]