Tu1883 HIGHER TROUGH GOLIMUMAB LEVELS ARE ASSOCIATED WITH EARLY CLINICAL AND BIOCHEMICAL RESPONSE; EARLY RESULTS OF THE GOAL-ARC STUDY

Background: LC51-0255 is a potent, selective, and orally available sphingosine-1-phosphate receptor 1 (S1P1) modulator which exerts anti-inflammatory effect by internalizing S1P1 receptors, leading to sequestration of immune cells to peripheral lymphoid organs.The objective of this study was to evaluate the safety, tolerability and pharmacokinetic (PK)/ pharmacodynamic (PD) characteristics of multiple ascending doses of LC51-0255 as a potential treatment of auto-immune diseases such as ulcerative colitis (UC).Methods: A randomized, double-blind, placebo-controlled, multiple dosing (0.25 mg, 0.5 mg, 1 mg, 1.5 mg and 2 mg, once daily for 21 days), dose-escalation phase 1 study was conducted in healthy male volunteers aged 19-45 years.A total of 50 subjects were randomly assigned and received either LC51-0255 or placebo (10 subjects in each dose group, in 4:1 ratio).Safety assessment included adverse event (AE), electrocardiogram, laboratory tests, Holter monitoring, vital signs, physical examination, pulmonary function test and ophthalmologic test.Blood and urine samples were collected for PK/PD assessments.Results: All AEs were mild in severity except one moderate AE, and no case of study discontinuation due to AEs occurred.The most common AE was bradycardia, and all bradycardia events were resolved without any action.There was a serious adverse event (diverticulitis) in a subject who received multiple doses of LC51-0255 1 mg, and the event was resolved after medication treatments.No clinically significant abnormalities were observed in clinical laboratory test, pulmonary function test and ophthalmologic test.Systemic exposure of LC51-0255 was dose-proportional after multiple dosing, with the mean area under the plasma concentration time curves during dosing interval at steady state ranging from 229 to 2060 µgxh/L.The peak plasma concentration at steady state was observed at 4-4.5 hours post-dose, and the mean elimination half-life was 76-95 hours, making it suitable for once daily administration.The fraction excreted into urine ranged from 0.01 to 0.3 % across dose levels, indicating that renal excretion was not the major route of elimination.The absolute lymphocyte count (ALC), a PD biomarker, decreased dose-dependently with the mean maximum decrease in ALC from baseline ranging from 62 to 88%.All dose levels reached its maximum PD effect at 6 hours post-dose.ALC recovered to baseline within 14 days of discontinuation.Conclusions: LC51-0255 was well tolerated in healthy subjects when administered once daily for 21 days at dose levels ranging from 0.25mg to 2mg.Systemic exposure was doseproportional and PK profile was favorable for once daily regimen.ALC displayed a dosedependent reduction.These results support further evaluation of LC51-0255 in a phase 2 study to determine the safe and efficacious dose in UC patients. Tu1882