A study of the safety and pharmacokinetics and pharmacodynamics of the LOXL2 inhibitor PXS-5338K in healthy male subjects given single and repeated doses.

INTERVENTION: PXS‐5338K has been developed to be an anti‐fibrotic medication for once daily oral administration in patients for the treatment of NASH (non‐alcoholic steatohepatitis) and other fibrosis based diseases. Subjects will be randomised to receive PXS‐5338K (active) or matching placebo in single ascending doses (SAD) or multiple ascending doses (MAD). PXS‐5388K will be in a capsule form and will be administered orally followed by 200ml of water. Dose levels for SAD will begin at 10 mg and increase to 400 mg over 6 Cohorts. Dose for each cohort are as follows: Cohort 1 – PXS‐5338K = 10 mg Cohort 2 – PXS‐5338K = 30 mg Cohort 3 – PXS‐5338K = 60 mg Cohort 4 – PXS‐5338K = 100 mg Cohort 5 – PXS‐5338K = 200 mg Cohort 6 – PXS‐5338K = 400 mg The doses for the MAD phase will be chosen based on the safety/tolerability data collected from the SAD phase. Cohort 7, Cohort 8 and Cohort 9 of MAD study will be planned following consideration of safety, tolerability and PK assessment of preceding SAD and/or repeat dose cohorts. However the most likely doses for MAD study will be between 60 and 200 mg for 14 days once daily. For the SAD, there will be outpatient visits on Day 3 and 4. For the MAD Phase, follow up visits will be done on Day, 16, 17 and 18. The Exit Evaluation visit will be done at Day 5 for the SAD and Day 21 for the MAD. CONDITION: Nonalcoholic steatohepatitis (NASH) Other fibrotic diseases PRIMARY OUTCOME: To evaluate the safety and tolerability of single ascending or repeated oral doses of PXS‐5338K SECONDARY OUTCOME: Assessment of plasma pharmacodynamic parameters after single and repeat dosing of PXS‐5338K. ; ; Serum levels of LOXL2 and target engagement of LOXL2 by PXS‐5338K To evaluate plasma pharmacokinetic parameters after single and repeat oral dosing of PXS‐5338K ; ; For SAD, PK parameters to be determined will include: ; 1. AUC (0‐24) and AUC (0‐inf) ; 2. Cmax – maximum concentration ; 3. Tmax – time to maximum observed plasma drug concentration ; 4. t1/2 – Terminal half‐life ; ; For MAD, PK parameters to be determined will include: ; 1. Cmax, Tmax, AUC (0‐24), AUC (0‐inf) on Day 1 ; 2. Cmax, Tmax, AUC (0‐24), t1/2 on Day 7 and 14. ; 3. Accumulation ratio, AUC (0‐24, Day 7/14)/ AUC (0‐24, Day 1) along with ; Cmax (Day 7/14)/ Cmax (Day 1) INCLUSION CRITERIA: 1. Male and aged between 18 and 60 years (inclusive). 2. Body Mass Index (BMI) between 18.5 kg/m2 and 30 kg/m2 inclusive. 3. No clinically relevant abnormality in an ECG; QTcF (QTc Fredericia’s correction) less than or equal to 450 ms, PR interval of 120‐210 ms and a QRS duration less than or equal to 120 ms. 4. Adequate venous access in the left or right arm to allow collection of a number of blood samples. 5. Agrees to use a condom, and in the case of partner who is potentially childbearing at least one other method of contraception, from Screening and until 30 days after administration of the study drug. Agreed methods of contraception may include approved birth control pills, patches, implants or injections by the subject’s partner, use of an IUD (intra uterine device) by the subject’s partner and/or surgical sterilisation of the participant (vasectomy at least six months prior to dosing). 6. Have given written informed consent to participate