Safety and tolerability Phase I study of a new immunomodulatory drug in healthy participants after single and repeat doses.

INTERVENTION: Part A, Single Ascending Dose (SAD), involves the oral capsule administration of 0.5 mg up to 24 mg (proposed dose levels are 0.5mg, 2mg, 6mg, 12mg, 24mg) of AK‐119, each participant consuming one dose only. The one selected dose cohort will return for a food effect evaluation after at least a 7‐day wash‐out. The selected dose cohort will participate in a two‐way crossover design and return to the clinical unit to receive AK‐119/placebo administration of the same for evaluation of the food effect after a washout of at least 7 days. Subjects will undergo the same study assessments in Period 2 as in Period 1, byby the Safety Review Committee (SRC), and will have their follow‐up assessment visit 7 days after dose administration in their second period. Subjects will be randomised to receive either no breakfast or a high fat breakfast on the first period and the alternate breakfast in the second period. The cohort and dose selected for the food effect evaluation may be changed after review of the safety data from the first two cohorts of Part A. This part of the study can be conducted in parallel to the higher determined dosing for the subsequent groups. Part B, Multiple Ascending Dose (MAD): up to 16 (2 cohorts) of healthy volunteers will be dosed daily for seven days. Part C, Multiple Ascending Dose (MAD): One cohort of up to 8 healthy volunteers will be dosed daily for up to 28 days. The dose levels for Parts B and C will be selected following review of safety and pharmacodynamics data from the preceding part(s) of the study. Drug will be administrated at the site under supervision of trained staff monitoring adherence. CONDITION: Inflammatory and Immune System ‐ Autoimmune diseases Multiple Sclerosis; ; Multiple Sclerosis PRIMARY OUTCOME: To determine the food effect on AK‐119 absorption when administered as a single dose (Part A) in one cohort of healthy volunteers in Part A. The study will include AK‐119 pharmacokinetics (AUC, T1/2, Tmax, Cmax) as assessed by plasma assay or Absolute lymphocyte count as assessed by serum assay. [The blood samples for pharmacokinetics at pre‐dose and 30 minutes and 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose; the pharmacodynamic blood samples to determine the absolute lymphocyte count (ALC) at pre‐dose, 2, 4, 6, 8, 12, 16, and 24 hours post‐dose;; the pre‐dose urine sample for pharmacokinetics (within 30 minutes prior to Investigational Product administration) and bulk urine samples over the collection periods of 0‐4, 4‐12, 12‐24 and 24‐48 hours post dose.; ] To determine the safety and tolerability of ascending dose levels of AK‐119 when administered as a single dose (Part A) and multiple oral doses (Part B & C) to healthy volunteers. The study assessments will include: vital signs, triplicate 12‐lead ECGs, 24‐hour holter monitoring, telemetry, blood and urine samples for laboratory, pharmacokinetic (PK) and pharmacodynamic (PD) assessments, review of concomitant medications and adverse events (AE). [The primary timepoints are for Part A: Days 1, 2‐3, 4 and 7 after a single dose: for Part B; Days 1, 2‐7, 8‐9, 10 and 14 after multiple oral dosing for 7 days: for Part C: Days 1, 2‐28 and 35 after multiple dosing for 28 days.] ; ; ; [Secondary time points: 0 (pre‐dose) 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours post‐dose.] INCLUSION CRITERIA: Healthy volunteer subjects eligible for inclusion in this study have to fulfil all of the following INCLUSION CRITERIA: 1. Male and female subjects 18‐55 years of age, inclusive, at the time of screening 2. Able to provide written informed consent prior to the performance of any study specific procedures 3. Subjects with a BMI between 18.0 and 30.0 kg/m2, inclusive 4. A 12‐lead ECG at screening or pre‐dose assessment that, in the opinion of the investigator, has no abnormalities that compromise subject’s safety in this study. SECONDARY OUTCOME: Multiple‐dose, once daily for 28 days, AK‐119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method. [At 0 (pre‐dose), 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post Day 1 dose, pre‐dose on Days 3, 5, 8, 15, 22 and 28 and post dose 2, 4, 6, 8, 12, 16, 24 hrs post Day 28 dose] Multiple‐dose, once daily for 28 days, AK‐119 urine pharmacokinetics The urine concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method. [At 0‐4, 4‐12, 12‐24 hours post‐dose on Day 1 and Day 8, 15, 22, 28.] Multiple‐dose, once daily for 7 days, AK‐119 plasma pharmacodynamics, by Absolute lymphocyte count assessed by serum assay. [ ‐24, ‐22, ‐20, ‐18, ‐16, ‐12, ‐8 hrs and immediately before pre‐dose, 2, 4, 6, 8, 12, 16 hours post dose on Day 1, pre‐dose on Days 2‐6 and on Day 7 pre‐dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 168 hours post dose (timings may be adjusted on review of ALC response from Part A) ; ] Multiple‐dose, once daily for 728 days, AK‐119 plasma pharmacodynamics, Absolute lymphocyte count assessed by serum assay. [‐24, ‐22, ‐20, ‐18, ‐16, ‐12, ‐8 hrs and immediately before pre‐dose, 2, 4, 6, 8, 12, 16 hours post dose on Day 1; pre dose on Days 2, 3, 4, 5, 8, 15, 22; pre‐dose on 28 Day dose, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose of Day 28 (timings may be adjusted on review of ALC response from Parts A and B)] Multiple‐dose, once daily for seven days, AK‐119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method. [Blood samples collected at 0 (pre‐dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16 hours post dose on Day 1, immediately prior to dosing on days 2‐ 7; post dose on day 7 at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours .] Multiple‐dose, once daily for seven days, AK‐119 urine pharmacokinetics The urine concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method. [At predose, 0‐4, 4‐12, 12‐24 and 24‐48 hours after dosing on Days 1 and 7 .] Single‐dose AK‐119 urine pharmacokinetics. The urine concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method [At pre‐dose, 0‐4, 4‐12, 12‐24 and 24‐48 hours post‐dose.] Single‐dose AK‐119 plasma pharmacodynamics, by Absolute lymphocyte count assessed by serum assay. [‐24, ‐22, ‐20, ‐18, ‐16, ‐12, ‐8 hrs and immediately before pre‐dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 168 hours.] Single‐dose AK‐119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography‐tandem mass spectrometry method. 5. Female subjects of non‐childbearing potential, defined as (1) having a documented tubal ligation at least 6 weeks prior to dosing; (2) having had a surgical bilateral oophorectomy (with or without hysterectomy); (3) at least 12 months of spontaneous amenorrhoea with follicle stimulating hormone (FSH) > 40 MIU/ml. 6. Female subjects of child‐bearing potential with negative serum pregnancy test at screening and