A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GRX-917 in Healthy Subjects

INTERVENTION: Approximately 76 healthy men or women will be enrolled in this study. There will be two parts to the study. In the first part of the study approximately 40 healthy men and women will be enrolled in up to 5 single ascending dose cohorts comprising 8 subjects each. Subjects within each cohort will be randomised to receive a single dose of either oral GRX‐917 (6 subjects) or oral placebo (2 subjects). All cohorts will be started with sentinel dosing. All doses will be administered under direct observation in the Phase 1 unit. The doses for each cohort are shown below Cohort 1: 25mg Cohort 2: 50mg Cohort 3: 100mg Cohort 4: 250mg Cohort 5: 500mg In the second part of the study approximately 36 healthy men and women will be enrolled into up to 3 multiple ascending dose cohorts comprising 12 subjects each. Subjects within each cohort will be randomised to receive multiple doses of either oral GRX‐917 (9 subjects) or oral placebo (3 subjects). Each dose regimen will be administered for 7 days (13 total doses); dosing every 12 hours on Day 1 through Day 6 with a single last dose given on Day 7. All doses will be administered under direct observation in the Phase 1 unit. The doses for each cohort are shown below Cohort 1: 100mg every 12 hours Cohort 2: 200mg every 12 hours Cohort 3: 300mg every 12 hours CONDITION: Anxiety; ; Anxiety Mental Health ‐ Depression PRIMARY OUTCOME: To evaluate the safety of multiple doses of GRX‐917 when compared with placebo in healthy volunteers through the assessment of: treatment‐emergent adverse events assessed through regular solicitation of volunteers and review of physical examination data, vital sign data including blood pressure measured using a digital blood pressure monitor, heart rate measured as beats per minute, temperature and respiratory rate measured as breaths per minute, ECG data and clinical laboratory assessments of blood and urine: hematology (standard panel), chemistry (standard panel) and urinalysis (standard panel)[Treatment‐emergent adverse events will be collected from the time of signing the informed consent form through the final follow‐up visit which is on Day 17,; Physical examinations will be conducted at screening, on Day ‐1, Day 3, Day 5, Day 9 and Day 17..; Clinical laboratory assessments of blood and urine will be collected at screening, on Day ‐1, Day 2, Day 3, Day 5, Day 7, Day 8 and Day 17. ; ECGs will be collected at screening, and pre‐dose and 4 hours post dose on Day 1, Day 3 , Day 5, and Day 7, prior to discharge on Day 9 and on Day 17; Continuous telemetry will be collected for at least 16 hours prior to dosing and until 24 hours after the last dosing on Day 7. ; Vital signs will be collected at screening, on Day ‐1, within 2 hours prior to and 2, 4, 8 and 12 hours after the first dose of study drug on Days 1 to 7, on Day 8 at 24 hours post‐dose, and Day 9 prior to discharge and on Day 17.; Sedation will be scored on Day 1 pre‐dose and at 2, 4, 8, and 12, hours post first dose on Days 1 to 7, on Day 8, on Day 9 and on Day 17. ] To evaluate the safety of single doses of GRX‐917 when compared with placebo in healthy volunteers through the assessment of: treatment‐emergent adverse events assessed through regular solicitation of volunteers and review of physical examination data, vital sign data including blood pressure measured using a digital blood pressure monitor, heart rate measured as beats per minute, temperature assessed using a digital thermometer and respiratory rate measured using a manual counting of breaths per minute, sedation scored on the Ramsay sedation scale, ECG data including continuous telemetry, and clinical laboratory assessments of blood and urine: hematology (standard panel), chemistry (standard panel) and urinalysis (standard panel)[Treatment‐emergent adverse events will be collected from the time of signing the informed consent form through the final follow‐up visit which is on Day 11 for Cohorts 1, 2, 4, and 5, and on Day 25 for Cohort 3,; Physical examinations in Cohort 1, 2, 4 and 5 will be conducted at screening, on Day ‐1, Day 3, and Day 11. Physical examinations in Cohort 3 will be conducted at screening, on Day ‐1, Day 3, Day 14, Day 17 and Day 25.; Clinical laboratory assessments of blood and urine in Cohort 1, 2, 4 and 5 will be collected at screening, on Day ‐1, Day 2, and Day 11. Clinical laboratory assessments of blood and urine in Cohort 3 will be collected at screening, on Day ‐1, Day 2, Day 14, Day 16 and Day 25. ; ECGs in Cohort 1, 2, 4 and 5 will be collected at screening, pre‐dose on Day 1, and at 4, and 24 hours post dose, and on Day 11. ECGs in Cohort 3 will be collected at screening, on Day 1 pre‐dose and at 4, and 24 hours post dose, on Day 15 pre‐dose and at 4, and 24 hours post dose, and on Day 25.; Continuous telemetry in Cohorts 1, 2, 4 and 5 will be collected for at least 16 hours prior to dosing and for 24 hours after dosing on Day 1 pre‐dose. Continuous telemetry in Cohort 3 will be collected for at least 16 hours prior to dosing and for 24 hours after dosing on Day 1 and on Day 15. ; Vital signs in Cohorts 1, 2, 4 and 5 will be collected at screening, on Day ‐1, on Day 1 pre‐dose and 1, 2, 4, 8, 12, 24 and 48 hours post dose, and on Day 11. Vital signs in Cohort 3 will be collected at screening, on Day ‐1, on Day 1 pre‐dose and 1, 2, 4, 8, 12, 24 and 48 hours post dose, on Day 14, on Day 15 pre‐dose and 1, 2, 4, 8, 12, 24 and 48 hours post dose and on Day 25.; In Cohort 1, 2, 4, and 5 sedation will be scored on Day 1 pre‐dose and at 1, 2, 4, 8, 12, 24 and 48 hours post dose and on Day 11. In Cohort 3, sedation will be scored on Day 1 pre‐dose and at 1, 2, 4, 8, 12, 24 and 48 hours post dose, on Day 15 pre‐dose and at 1, 2, 4, 8, 12, 24 and 48 hours post dose and on Day 25.] SECONDARY OUTCOME: Quantitative electroencephalogram changes measured through power spectral analysis after a single oral dose of GRX‐917[Recordings collected pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8 and 12 hours after the first dose of GRX‐917. ] This outcome is a composite outcome of the plasma concentrations of GRX‐917 and its key metabolite after a single oral dose of GRX‐917[In Cohorts, 1, 2, 4 and 5, samples will be collected on Day 1 pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8 and 12 hours after dosing. A 24‐hour post dosing sample will be collected on Day 2 and a 48‐hour post dosing sample will be collected on Day 3 prior to discharge. Additional samples will be collected on Day 5, Day 7, Day 9 and on Day 11. ; INCLUSION CRITERIA: 1. Aged between 18 and 55 years of age at time of consent 2. Male or female and meet the following conditions: a. Female participants must be of non‐childbearing potential, or, b. If of childbearing potential, be non‐pregnant or lactating and agree to use highly effective contraception from screening through 30 days post‐ dose. Hormonal forms of contraception are contraindicated in this study. c. Male participants, if engaging in sexual intercourse with a female partner of childbearing potential, must be willing to use highly effective contraception from screening through 90 days post‐dose and agree not to donate sperm during this period. 3. Is judged to be in good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests performed at the screening visit and/or before the first dose of study drug. 4. Weigh at least 50 kg at the time of screening 5. Have a body mass index (BMI) between 18. ; In Cohort 3, samples will be collected on Day 1 pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8 and 12 hours after dosing. A 24‐hour post dosing sample will be collected on Day 2 and a 48‐hour post dosing sample will be collected on Day 3 prior to discharge. Additional samples will be collected on Day 5, Day 7, Day 9. On Day 15 a sample will be collected pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8 and 12 hours after dosing. A 24‐hour post dosing sample will be collected on Day 16 and a 48‐hour post dosing sample will be collected on Day 17 prior to discharge. Additional samples will be collected on Day 19, Day 21, Day 23 and Day 25.] This outcome is a composite outcome of the plasma concentrations of GRX‐917 and its key metabolite after multiple oral doses of GRX‐917[On Day 1, samples will be collected pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8, 10 and 12 hours after dosing. A 24‐hour post dosing sample will be collected prior to the first study drug dose on Day 2. On Day 4, Day 5, and Day 6, samples will be collected immediately prior to the first dose of study drug for that day. On Day 7, samples will be collected pre‐dose and then at 30 and 60 minutes, and 2, 4, 6, 8, 10 and 12 hours after dosing. A 24‐hour post dosing sample will be collected on Day 8 and a 48‐hour sample will be collected on Day 9 prior to discharge. Additional samples will be collected on Day 11, Day 13, Day 15 and on Day 17.] This outcome is a composite outcome of the urine concentrations of GRX‐917 and its key metabolite after a single oral dose of GRX‐917[On Day 1, urine will be collected predose and then pooled urine will be collected at 0‐4, 4‐8, 8‐12, 12‐24 and 24‐48 hours after dosing.] This outcome is a composite outcome of the urine concentrations of GRX‐917 and its key metabolite after multiple oral doses of GRX‐917[On Day 1, urine will be collected predose and then pooled urine will be collected at 0‐4, 4‐8, and 8‐12 hours after dosing. On Day 7, pooled urine will be collected at 0‐4, 4‐8, and 8‐12 hours after the final dose of study drug.]