First in human study of multiple doses of a novel drug PTC607 to assess its safety and tolerability in healthy participants

INTERVENTION: This is a multiple ascending dose study in healthy volunteers. It will consist of up to 3 sequential cohorts of 8 participants each. In each cohort, participants will be randomised to receive multiple doses of either PTC607 or placebo in tablet formulation in a 3:1 ration (6 participants will receive PTC607 and 2 will receive placebo) with food for 14 days. The following dose regimens have been selected: ‐ Cohort 3.1: 15 mg PTC607 or matching placebo once daily for 14 consecutive days ‐ Cohort 3.2: 30 mg PTC607 or matching placebo once daily for 14 consecutive days ‐ Cohort 3.3: depending on pharmacokinetics data from cohorts 3.1 and 3.2, either 30 mg or 60 mg PTC607/placebo every other day for 14 days (7 doses in total). The Safety Review Committee will meet to review the results of each cohort prior to proceeding to the following cohort in this study. Healthy participants will stay in the clinical research unit for 18 consecutive nights and will take study drug with food between 8:00 am and 11:00 am under direct supervision of the clinical research unit staff. The study drug and matching placebo will be taken with 240 mL of water. Monitoring the adherence to the intervention may include mouth checks. CONDITION: Human Genetics and Inherited Disorders ‐ Other human genetics and inherited disorders Huntington's Disease; ; Huntington's Disease Neurological ‐ Neurodegenerative diseases SECONDARY OUTCOME: Effect of PTC607 administered for 14 days on HTT protein level in the blood of healthy participants.[Summary statistics (n, mean, median, standard deviation, minimum, maximum) and changes from baseline for HTT protein level in whole blood. One sample will be collected anytime after check in on Day ‐1 prior to commencement of PTC607 immediately after collection of PK samples. ; For Cohort 3.1 and 3.2, HTT samples will be collected on Day 1 of commencement of PTC607 at pre‐dose and 12 hours post‐dose. On Day2 through Day 13 post commencement of PTC607, pre‐dose. On Day 14 post commencement of PTC607, HTT samples will be collected at pre‐dose and 12, 24, 48, 72 and 96 hours post‐dose. ; For Cohort 3.3, HTT samples will be collected on Day 1 of commencement of PTC607 at pre‐dose and 12 hours post‐dose. ON Day 2 through Day 12 post commencement of PTC607 at pre‐dose or approximately the same time of dose administration. On Day 13 post commencement of PTC607, HTT samples will be collected at pre‐dose and 12, 24, 48, 72 and 96 hours post‐dose. ] Effect of PTC607 administered for 14 days on huntingtin (HTT) pre‐mRNA splicing level in the blood of healthy participants.[Summary statistics (n, mean, median, standard deviation, minimum, maximum) and changes from baseline for HTT mRNA level in whole blood. One sample will be collected anytime after check in on Day ‐1 before commencement of PTC607 for all cohorts. ; For Cohort 3.1 and Cohort 3.2, mRNA samples will be collected on Day 1 of commencing PTC607 pre‐dose at ‐60 and ‐30 minutes and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post‐dose and 24 hours (prior to dose on Day 2 post commencement of PTC607). On Day 2 through Day 13 post commencement of PTC607 at pre‐dose (within 30 minutes) and 4 hours post‐dose. The 24h sample following first dose could serve as the pre‐dose sample for Day 2 post commencement of PTC607. On last day of dosing (Day 14 post commencement of PTC607) at pre‐dose (within 30 minutes) and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post‐dose; 24 and 36 hours (Day 15 post commencement of PTC607), 48 and 60 hours (Day 16 post commencement of PTC607); 72 hours (Day 17 post commencement of PTC607); and 96 hours (Day 18 post commencement of PTC607). ; For Cohort 3.3, mRNA samples will be collected on Day 1 of commencement of PTC607 pre‐dose at ‐60 and ‐30 minutes and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post‐dose; 24 and 36 hours (Day 2 post commencement of PTC607); and 48 hours (Day 3 post commencement of PTC607, prior to the second dose). On Day 3 through Day 12 post commencement of PTC607 at pre‐dose and 4 hours (if dose is administered) or at approximately the same time of dose administration (if no dose treatment on the day). The 48h sample following first dose could serve as the pre‐dose sample for Day 3 post commencement of PTC607. On Day 13 post commencement of PTC607 (the seventh dose administration) at pre‐dose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post‐dose; 24 and 36 hours (Day 14 post commencement of PTC607); 48 and 60 hours (Day 15 post commencement of PTC607); 72 hours (Day 16 post commencement of PTC607); and 96 hours (Day 17 post commencement of PTC607).] Pharmacokinetics (PK) of PTC607 following multiple doses in healthy participants[Phoeni XWinNonlin software in the non‐compartmental model. The following parameters will be measured: Cmax, AUC, Ctrough, Cavg, T1/2, LAMBDAz, CL/F, Vz/F, ARauc, ARma XFor Cohort 3.1 and Cohort 3.2, PK samples will be collected on Day 1 of commencement of PTC607 at pre‐dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post‐dose and 24 hours (prior to dose on Day 2). ; On Day 2 through Day 13 post commencement of PTC607 at pre‐dose (within 30 minutes) and 4 hours post‐dose. The 24h sample following first dose could serve as the pre‐dose sample for Day 2. On last day of dosing (Day 14 post commencement of PTC607) at pre‐dose (within 30 minutes) and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post‐dose; 24 and 36 hours (Day 15 post commencement of PTC607); 48 and 60 hours (Day 16 post commencement of PTC607); 72 hours (Day 17 post commencement of PTC607); and 96 hours (Day 18 post commencement of PTC607). ; For Cohort 3.3, PK samples will be collected on Day 1 of commencement of PTC607 at pre‐dose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post‐dose; 24 and 36 hours (Day 2 post commencement of PTC607); and 48 hours (Day 3 post commencement of PTC607, prior to ; the second dose). On Day 3 through Day 12 post commencement of PTC607, at approximately the same time of dose administration (prior dose if no dose treatment on the day) or at pre‐dose (within 30 minutes) and 4 hours (only if dose is to be administered on the day). On Day 13 post commencement of PTC607 (the seventh dose administration) at pre‐dose (within 30 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post‐dose; 24 and 36 hours (Day 14 post commencement of PTC607); 48 and 60 hours (Day 15 post commencement of PTC607); 72 hours (Day 16 post commencement of PTC607); and 96 hours (Day 17 post commencement of PTC607).] INCLUSION CRITERIA: 1. Healthy males and females aged 18 to 65 years inclusive at Screening. 2. Participants able to provide informed consent. 3. Body mass inde Xof greater than or equal to 18.5 and less than or equal to 30 kg/m2 with a body weight of greater than or equal to 50 kg for male participants and a body weight of greater than or equal to 45 kg for female participants at Screening. 4. Generally healthy as determined by the investigator based on medical evaluation, including medical history, physical examination, laboratory test results, ECG and vital signs. 5. Male participants must be willing to use 2 acceptable contraceptive methods for the duration of the study and for a minimum of 6 months after the last dose and female participants of childbearing potential must be willing to use 2 acceptable contraceptive methods for the duration of the study and for a minimum of 30 days after the last dose. Postmenopausal female participants must have had greater th PRIMARY OUTCOME: Safety and tolerability of multiple‐ascending doses of PTC607 administered for 14 days in healthy participants through review of:; ‐ vital signs ; ‐ electrocardiogram parameters; ‐ clinical safety laboratory test results: ; ‐ suicidal ideation and suicidal behaviour; ‐ treatment‐emergent adverse events (TEAE); ‐ treatment‐emergent adverse events leading to premature discontinuation of study drug[Vital signs: (blood pressure and heart rate assessed by sphygmomanometer, body temperature by thermometer).; Electrocardiogram parameters: 12‐lead ECG and Holter monitoring; Clinical safety laboratory test results: serum chemistry (including liver function tests, electrolytes, glucose, kidney function tests, cholesterol and triglycerides), full blood count and coagulation tests will be assessed using whole blood samples; urinalysis will be assessed using urine samples.; Suicidal ideation and suicidal behaviour will assessed via completion of the Columbia‐Suicide Severity Rating Scale; TEAEs (including those leading to discontinuation of study drug): via interviews, physical examinations and review of clinical safety laboratory test results and ECG reports; Vital signs: Screening (once between Day ‐28 to Day ‐2 before commencement of PTC607), admission (once on Day ‐1 before commencement of PTC607), once pre‐dose every day on Days 1 to 14 post‐commencement of PTC607, once on discharge day (Day 18 post‐commencement of PTC607 for cohorts 3.1 and 3.2 or Day 17 post‐commencement of PTC607 for cohort 3.3); Electrocardiogram parameters: ; ‐ 12 lead ECG: Screening (single measurement between Day ‐28 to ‐2 before commencement of PTC607), single measurement on admission (Day ‐1 before commencement of PTC607); triplicate measurements at 60 min, 45 min and 30 min pre‐dose and 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post‐dose on Day 1 and Day 14 (Cohorts 3.1 and 3.2)/Day 13 (Cohort 3.3) post commencement of PTC607.; ‐ Holter monitoring: continuously for 24 hours from pre‐dose on Day 1 and Day 14 (Cohorts 3.1 and 3.2)/Day 13 (Cohort 3.3)]