A Phase 1 single and multiple ascending dose study of YA-101 in Healthy Subjects

INTERVENTION: This is a phase 1 study consisting of Part 1 Part 2. Besides the one food effect (FE) cohort, each cohort in Part 1 Part 2 is randomized, placebo‐controlled, double‐blinded to establish safety and tolerability in healthy volunteers (HV) following single ascending dose (SAD) and multiple ascending dose (MAD). FE is a single cohort, cross‐over, 2‐period study planned to evaluate the effect of food on the PK profile of open‐label YA‐101. ‐ Part 1 will assess the safety, tolerability, and PK of YA‐101 administered to healthy adult volunteers as a single‐ascending dose (HV SAD) ‐ Part 2 will assess the safety, tolerability, and PK of YA‐101 administered to healthy adult volunteers as multiple‐ascending doses (HV MAD), and as a single dose administered with and without food to assess food effect (HV FE). Investigational Product: YA‐101 Dose form: Suspension Route of Administration: Oral Dose (mg/day): Starting dose for HV SAD Cohort 1 is based on the human equivalent dose (HED) calculated from the NOAEL reported in the 28‐day GLP rat toxicity study, with application of an appropriate safety factor. SAD: Starting dose for Cohort 1 is starting at 900mg and escalating to a maximum of 9600mg of YA‐101. Subsequent dose levels for Cohort 2 and Cohort 3 will be determined based on the emerging safety, tolerability, and PK data in the preceding cohort(s).Dose frequency: once per day FE: HV FE doses will be determined based on the emerging safety, tolerability, and PK data from SAD cohorts. In the fed state, a high‐fat (approximately 50% of total caloric content of the meal) and high‐calorie (approximately 800 to 1000 calories) meal is provided before dosing. YA‐101 suspension will be administered within 30 minutes after the completion of mea CONDITION: Multiple System Atrophy ; ; Multiple System Atrophy; Neurological ‐ Neurodegenerative diseases INCLUSION CRITERIA: 1. Subjects 18 to 65 years of age (inclusive) and in good state of health. 2. Must be able to communicate and participate in the whole study. 3. Must provide written informed consent. PRIMARY OUTCOME: To evaluate the effect of food on the PK profile of YA‐101 following a single dose of YA‐101 in healthy volunteers in fed and fasted states determined by the changes in the plasma and urine PK parameters. ; ; Plasma parameters tthat will be assesses include Tmax(time to reach maximum plasma concentration), Cmax (mamximum plasma concentration), and AUC0‐last (Area under curve from 0 to last measurable concentration). ; Urine PK parameter include cumulative amount of drug excreted in urine (Ae), percent fraction of drug recovered in urine (Fe) and renal clearance (CLr)[ Plasma PK samples to be collected at the following time points: pre‐dose Day 1, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours Day 1 post‐dose. Day 2 collection is the 24 hours post Day 1 collection for PK. PK samples will also be collected at pre‐dose Day 4, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours Day 4 post‐dose. Day 5 collection is the 24 hours post Day 4 collection for PK. ; ; PK urine collection: will be collected on Day 1 and Day 4 pre‐dose at (‐6 to 0 hours), and at (0‐6), (6‐12), (12‐24) hour intervals post‐dose.] To evaluate the safety and tolerability of YA‐101 following multiple ascending oral administration in healthy volunteers.; ; These will be assesed by monitoring‐ ; ‐Incidence and severity of AES ‐ AEs and SAEs will be assessed for severity and causality (relationship of the event to the investigational product) by the study investigator using the specified grading definitions Common Terminology Criteria for Adverse Events (CTCAE) (V5.0) as 5 grades. ; ; ‐Changes in clinical laboratory parameters including blood tests for hematology, blood biochemistry and coagulation; using urine sample for urinaurinalysis ; ; ‐Changes in the elctrocardiogram (ECG) findings ; ; ‐Change in vital signs measurements. Vital signs will include mesurement of heart rate, respiration rate, systolic and diastolic blood pressure, and oral temperature using EarlyVue VS30 or Vital Signs Monitor 53NTO devices.[ Adverse Events (AEs) and Serious Adverse events (SAEs) : MAD‐ Screening, Day ‐1, Days 1 to 15, and Day 21 post first‐dose administration. ; ; Safety Laboratory assessments: MAD‐ Screening, Day ‐1, Days 1 to 15, and Day 21 post first‐dose administration. ; ; ECG: MAD‐ Screening, Day ‐1, Days 1 to 15, and Day 21 (±2) post first‐dose administration or ET.; ; Vital Signs: MAD‐ Screening, Day ‐1, Days 1 to 15, and Day 21 (±2) post first‐dose administration or ET.; ] To evaluate the safety and tolerability of YA‐101 following single ascending oral administration in healthy volunteers.; ; These will be assesed by monitoring‐ ; ‐Incidence and severity of AES ‐ AEs and SAEs will be assessed for severity and causality (relationship of the event to the investigational product) by the study investigator using the specified grading definitions Common Terminology Criteria for Adverse Events (CTCAE) (V5.0) as 5 grades. ; ; ‐Changes in clinical laboratory parameters including blood tests for hematology, blood biochemistry and coagulation; using urine sample for urinaurinalysis ; ; ‐Changes in the elctrocardiogram (ECG) findings ; ; ‐Change in vital signs measurements. Vital signs will include mesurement of heart rate, respiration rate, systolic and diastolic blood pressure, and oral temperature using EarlyVue VS30 or Vital Signs Monitor 53NTO devices.[ Adverse Events (AEs) and Serious Adverse events (SAEs) : SAD‐ Screening, Day ‐1, Day 1, Day 2, and Day 8 post last dose administration; ; ; Safety Laboratory assessments: SAD‐ Screening, Day ‐1, Day 1, Day 2, and Day 8 (±2) post last dose administration or Early Termination (ET); ; ; ECG: SAD‐ Screening, Day ‐1, Day 1, Day 2, and Day 8 (±2) post last dose administration or ET; ; ; Vital Signs: SAD‐ Screening, Day ‐1, Day 1, Day 2, and Day 8 (±2) post last dose administration or ET; ; ; ] SECONDARY OUTCOME: Characterize the pharmacokinetic (PK) prole of YA‐01 in healthy participants after multiple ascending doses with urine and plasma samples. ; Plasma parameters which will be assessed include ‐ t1/2 (apparent terminal half‐life ), Tma X(time to reach maximum plasma concentration), Cma X(mamximum plasma concentration), and AUC0‐last (Area under curve from 0 to last measurable concentration) ; ; Urine PK parameters including, but not limited to, cumulative amount of drug excreted in urine (Ae), percent fraction of drug recovered in urine (Fe) and renal clearance (CLr) will be assessed.[ For MAD cohorts‐ ; ‐Blood samples for PK analyses will be collected on Day 1, Day 3, Day 7: pre‐dose, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 after the morning dose, and pre‐dose. Day 14: pre‐dose, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours after the morning dose. Day 15: 24 hours after the morning dose on Day 14.; Days 2,4‐6, 8‐13: pre‐dose. ; ‐Urine samples will be collected on Day 1 pre‐dose at (‐6 to 0 hours), and at (0‐6), (6‐12) hour intervals post‐dose of morning dose and at (0‐12) hours post‐dose of evening dose. Urine samples will also be collected on Day 7 and Day 14 at (0‐6), (6‐12) hour intervals post‐dose of morning dose and on Day 7 at (0‐12) hours post‐dose of evening dose.] Characterize the pharmacokinetic (PK) prole of YA‐01 in healthy participants after single ascending doses with urine and plasma samples. ; Plasma parameters which will be assessed include ‐ t1/2 (apparent terminal half‐life ), Tma X(time to reach maximum plasma concentration), Cma X(mamximum plasma concentration), and AUC0‐last (Area under curve from 0 to last measurable concentration) ; ; Urine PK parameters including, but not limited to, cumulative amount of drug excreted in urine (Ae), percent fraction of drug recovered in urine (Fe) and renal clearance (CLr) will be assessed. [ For the SAD cohorts‐ ; ‐Blood samples for PK analyses will be collected at pre‐dose, and at 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post‐dose. Day 2 collection is the 24 hours post Day 1 collection for PK. ; ‐urine sample will be collected on Day 1 pre‐dose at (‐6 to 0 hours), and at (0‐6), (6‐12), (12‐24) hour intervals post‐dose. ; ; ]