A Three Part, Randomized, Double-Blind, Placebo-Controlled, Phase I Study to evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of GXV-001 in Healthy Volunteers

INTERVENTION: This is a randomised double‐blind, placebo controlled, ascending dose, multi‐cohort trial. The study will be conducted in two parts: Part A: A single ascending dose (SAD) part where dose levels will be evaluated in a sequential manner starting at the proposed lowest dose level in healthy volunteers. 40 healthy volunteers will be enrolled in a total of 5 cohorts. Each cohort will enrol 8 participants with 6 participants randomized to receive GXV‐001 and 2 participants randomized to receive placebo. GXV‐001 will be provided as an oral solution. The starting dose, dose increments and dose range to be evaluated are based on available nonclinical data. In Part A, GXV‐001 dose levels in the range of 3 to 200 mg are planned to be investigated. Single dose of double blinded GXV‐001 or placebo administered on Day 1. Part B: A multiple ascending dose (MAD) part where dose levels and final numbers of subjects will be evaluated depending on SAD results in healthy volunteers. Up to 48 healthy volunteers will be enrolled in a total of 3 cohorts. Each cohort will enrol a minimum of 8 and a maximum of 16 participants with up to 12 participants randomised to receive GXV‐001 and 4 participants randomized to receive placebo depending on the variability of exposure and pharmacodynamic (PD) assessments in Part A. The starting dose for each cohort in Part B will be selected following completion of Part A based upon safety/tolerability/PK and available biomarker data. A dose level will only be evaluated in Part B if determined to be safe and tolerable in Part A. GXV‐001 or placebo administered once daily (QD) for 7 days (total of 7 doses). The GXV‐001 and placebo doses to be administered to participants will be dissolved in CONDITION: Human Genetics and Inherited Disorders ‐ Other human genetics and inherited disorders Mental Health ‐ Other mental health disorders Rett Syndrome; Fragile X Syndrome;Neurodevelopmental disorders; ; Rett Syndrome ; Fragile X Syndrome ; Neurodevelopmental disorders Neurological ‐ Other neurological disorders SECONDARY OUTCOME: To assess the PK of GXV‐001 in urine following administration of a 7‐day repeat oral doses in healthy adult volunteers[Urine PK endpoints include (but are not limited to): Cumulative amount of unchanged drug excreted in urine (Ae), Renal clearance (CLr). ; Timepoints: Day 1 & Day 7: pre‐dose, 0 to 12 hours post‐dose, 12 to 24 hours post‐dose ; Timepoints: Day 1 and Day 7: pre‐dose, 0, 0.5, 1, 2, 4, 6, 12 and 24 hours post dose, Day 2 to Day 6: pre‐dose ; ] To assess the PK of GXV‐001 in urine following administration of a single oral dose in healthy adult volunteers[Urine PK endpoints include (but are not limited to): Cumulative amount of unchanged drug excreted in urine (Ae), Renal clearance (CLr). ; Timepoints: Day 1: pre‐dose, 0 to 12 hours post‐dose, 12 to 24 hours post‐dose ; ] To assess the pharmacokinetics (PK) of GXV‐001 in plasma following administration of single oral doses in healthy volunteers.[PK parameters to be calculated include (but are not limited to): Maximum observed plasma concentration (Cmax), Time to Cmax (Tmax), Area under the plasma concentration‐time curve from time 0 to time of last quantifiable concentration (AUC0‐t), Area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC0‐inf), Apparent terminal elimination half‐life (T1/2), Terminal elimination rate constant (Terminal elimination rate constant (kel), Apparent clearance (CL/F), Apparent volume of distribution (Vz/F) ; Timepoints: Day 1: pre‐dose, 0, 0.5, 1, 2, 4, 6, 12 and 24 hours post dose] INCLUSION CRITERIA: Healthy volunteers will be included in Part A or Part B of the study if they satisfy all the following criteria: 2. Assessed to have a usual sleeping pattern that meets the following criteria as judged by the PI following discussion with the participant: PRIMARY OUTCOME: To assess the safety and tolerability of single oral doses of GXV‐001 in healthy volunteers.[Measured by change from baseline and where appropriate overtime include:; • Incidence, severity, and relationship of AEs/SAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE) (Version 5). Timepoints: Monitored continuously from Day ‐1 (Check‐in) to Day 6, and Day 7 End of Study (EOS)/Early Termination Visit (ETV) ; • Change in vital signs, Blood pressure and heart rate is assessed using a sphygmomanometer and e‐Celsius Performance used to measure temperature of participants under controlled conditions.. Timepoints: Screening, Day ‐1 (Check‐in) and Day 1 (pre‐dose, 1,2,4 and 12 hours post‐dose), Day 2 (24 hours post dose) and Day 7 EOS/ETV; • Change in electrocardiogram (ECG) parameters – 12 Lead ECG usedin triplicate and single. Timepoints: Screening, Day ‐1 (Check‐in) and Day 1 (pre‐dose, 1, 4 and 12 hours post‐dose), Day 2 (24 hours post dose) and Day 7 EOS/ETV ; • Change in clinical laboratory parameters (haematology, serum chemistry, coagulation (blood samples) and urinalysis (urine sample) Timepoints: Screening, Day ‐1 (Check‐in), Day 1 (1 hour post‐dose), Day 2 (24 hours post‐dose) and Day 7 EOS/ETV] To assess the safety and tolerability of 7‐day repeat oral doses of GXV‐001 in healthy volunteers.[Measured by change from baseline and where appropriate overtime include:; • Incidence, severity, and relationship of AEs/SAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE) (Version 5). Timepoints: Monitored continuously from Day ‐1 (Check‐in) to Day 7, Day 8, Day 9 to Day 14, and Day 15 EOS/ETV; • Change in vital signs, Blood pressure and heart rate is assessed using a sphygmomanometer and e‐Celsius Performance used to measure temperature of participants under controlled conditions. Timepoints: Screening, Day ‐1 (Check‐in), Day 1 and Day 7 (pre‐dose, 1,2,4 and 12 hours post‐dose), Day 2 to Day 6 (pre‐dose) and Day 15 EOS/ETV; • Change in electrocardiogram (ECG) parameters – 12 Lead ECG used in triplicate and single. Timepoints: Screening, Day ‐1 (Check‐in) (pre‐dose, 1, 4 and 12 hours post‐dose), Day 1 and Day 7 (pre‐dose,1 4 and 12 hours post dose), Day 2 to Day 6 (pre‐dose) and Day 15 EOS/ETV; • Change in clinical laboratory parameters (haematology, serum chemistry, coagulation (blood samples) and urinalysis (urine sample) Timepoints: Screening, Day ‐1 (Check‐in), Day 1 (1 hour post‐dose), Daily for Day 2 to Day 6 (pre‐dose), Day 8 and Day 15 EOS/ETV; ] 1. Participants must have given written informed consent before any study‐related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects; a. no use of sleep aids (homeopathic/natural remedies such as over‐the‐counter melatonin, valerian and sleep vitamins) during last 3 months, b. generally regular bedtime between 10 pm and midnight, c. generally regular wake up times between 6 am and 9 am, d. sleep latency time usually no longer than 1 hour e. generally, sleep duration of 6‐10 hours per day. 3. Willingness to comply with a structured sleeping pattern for 7 days prior to drug administration and d ; ] To assess the pharmacokinetics (PK) of GXV‐001 in plasma following administration of 7‐day repeat oral doses in healthy volunteers.[PK parameters to be calculated include (but are not limited to): Maximum observed plasma concentration (Cmax), Time to Cmax (Tmax), Trough concentrations, Minimum observed concentration Cmin (Day 7, Part B only), Area under the plasma concentration‐time curve from time 0 to time of last quantifiable concentration (AUC0‐t), Area under the plasma concentration‐time curve from time 0 to tau (AUCtau), Area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC0‐inf), Apparent terminal elimination half‐life (T1/2), Terminal elimination rate constant (Terminal elimination rate constant (kel), Apparent clearance (CL/F), Apparent steady state volume of distribution (Vss/F) following multiple oral administration, Accumulation ratio of AUCtau, Accumulation ratio of Cmax