A Phase I Randomised, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Effect of Food on the Bioavailability of SKY-0515 in Healthy Volunteers and Patients with Huntington’s Disease

INTERVENTION: This study will be conducted in three parts: ‐ Part A: Single Ascending Dose (SAD) and food effect part in healthy participants ‐ Part B: Multiple Ascending Dose (MAD) in healthy participants ‐ Part C: has 2 parts ‐ Part C (i) a non‐interventional observational part and Part C (ii) multiple dose part in Huntington's Disease (HD) patients. Parts A & B are listed on previously registered trial ACTRN12623001161617. Part C is being listed in this trial application. Part C (i): Participants will be required to attend 2 clinic visits over a period of 28 days. Health information and blood samples will be collected at these 2 visits. No treatment is given in this part of the study. Upto 50 participants will be enrolled. Following completion of Part C [i], participants will be invited to participate in the treatment portion of the study ‐ Part C [ii], based on eligibility. Part C (ii): Two dose levels (high and low‐dose level) of study drug SKY‐0515‐001 in the range of 1 mg to 16 mg will be evaluated. Final dose levels will be determined from results of Part A & B. A single dose of SKY‐0515 or placebo will be administered orally once daily on Days 1 to 28 (inclusive); 28 doses total. Participants will maintain a diary to record exact date and time of dose administration. Enrolled HD patients will be randomised to 3 parallel treatment arms at 2:3:3 ratio: ‐ Arm 1: Placebo (n=6) ‐ Arm 2: Low dose SKY‐0515 (n=9) ‐ Arm 3: High dose SKY‐0515 (n=9) CONDITION: Human Genetics and Inherited Disorders ‐ Other human genetics and inherited disorders Huntington’s Disease; ; Huntington’s Disease SECONDARY OUTCOME: Part C (ii) only: To measure the pharmacokinetics of SKY‐0515 in plasma in HD patients[Pharmacokinetic endpoints include plasma concentration time curves, maximum observed plasma concentration, time to maximum plasma concentration, terminal half‐life. Blood plasma samples will be collected Pre dose on Day 1, 8, 15, 22 and 28; Post dose on Day 1 at 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs; Day 28 at 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 24hrs; anytime at end of study visit on Day 56. ] PRIMARY OUTCOME: Part C (i) only: To explore the natural variability of Huntington's Disease (HD) markers, Huntington (HTT) mRNA (messenger Ribonucleic Acid) and protein levels in HD patients. ; This is a composite outcome. [Blood samples will be collected to measure levels of HTT mRNA, total HTT protein and other HD markers. Blood samples will be collected at Day 1 and Day 28 at any time during the visit to site. Part C (i) is non‐interventional. ] Part C (ii) only: To investigate the safety and tolerability of SKY‐0515 in Huntington's Disease (HD) patients[This is the first clinical trial in which the study drug is being tested in humans and possible side effects are unknown. Any adverse events during the course of the study will be monitored and standard safety tests such as vital signs, lab tests (haematology, serum chemistry, coagulation and urinalysis), ECG will be monitored for any clinically significant changes. Endpoints to investigate safety and tolerability include:; ‐ Incidence, severity and relationship of adverse events (AEs) and serious adverse events (SAEs); ‐ Change from baseline in vital signs; ‐ Change from baseline in electrocardiogram (ECG) parameters; ‐ Change from baseline in clinical lab parameters (haematology, serum chemistry, coagulation and urinalysis); ‐ Mental Health: Columbia‐Suicide Severity Scale (C‐SSRS) ‐ Adverse events will be assessed continuously as they are reported or observed and reviewed at Clinic visits on Screening, and post commencement of treatment on Day 1, Day 8, Day 15, Day 22, Day 28, Followup visit on Day 29 and End of study visit on Day 56; ; ‐Vital signs: Blood pressure, heart rate and temperature will be measured at Screening, and post commencement of treatment on Day 1, Day 8, Day 15, Day 22, Day 28, Followup visit on Day 29 and End of study visit on Day 56; ; ‐ECG ‐ recordings will be obtained at Screening, and post commencement of treatment on Day 1, Day 15, Day 28, and End of study visit on Day 56; ; ‐Clinical lab parameters (haematology, serum chemistry, coagulation and urinalysis) will be assessed at Screening, and post commencement of treatment on Day 1, Day 15, Day 28, and End of study visit on Day 56; ; ‐ Columbia‐Suicide Severity Scale (C‐SSRS) questionnaire will be completed at Screening, and post commencement of treatment on Day 15 and End of study visit at Day 56; ] INCLUSION CRITERIA: Part C (i): 1. Must have given written informed consent 2. Males and females, aged between 25 and 65 years. 3. Confirmed diagnosis of HD as defined by: a. Genetically confirmed HD diagnosis by direct DNA testing. CAG repeat length greater than or equal to 40, and b. Huntington’s Disease Integrated Staging System (HD‐ISS) Stage 1: CAG greater than or equal to 40 & biomarker of pathogenesis. Atrophy identified in caudate volumetric magnetic resonance imaging (vMRI) and putamen vMRI, or c. HD‐ISS Stage 2: CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom. Total Motor Score (TMS) greater than 6; Independence Score (IS) equal to 100 and Total Functional Capacity (TFC) equal to 13, or d. HD‐ISS Stage 3 (Mild): CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom & functional change. TMS greater than 6, IS greater than or equal to 70, and TFC greater than or equal to 8. Part C (ii): 1.