AGA Abstracts 43:e47. 4. Liberzon A, et al . Cell Syst 2015; 1:417–425. 5. Barbie DA, et al . Nature 2009; 462:108–112. Tu1881 SAFETY, PHARMACOKINETICS AND IMMUNE MODULATORY PROPERTIES OF LC51-0255, AN ORAL, SELECTIVE SPHINGOSINE 1- PHOSPHATE 1 (S1P1) RECEPTOR MODULATOR, IN HEALTHY VOLUNTEERS Inyoung Hwang, Sang won Lee, Seonhui Jeon, Yujin Lee, Kyung-Sang Yu 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 dose- proportional and PK profile was favorable for once daily regimen. ALC displayed a dose- dependent 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 GB004, A NOVEL PROLYL HYDROXYLASE INHIBITOR FOR INFLAMMATOYR BOWEL DISEASE, LEADS TO GUT-TARGETED HIF- 1ALPHA PATHWAY ENGAGEMENT IN A MULTIPLE DOSE STUDY IN HEATHY SUBJECTS Barrett G. Levesque, Kristen Taylor Meadows, Akshay Buch, Michael Flynn, Kevin Peters, Allan Olson, Jinshan Shen, Debbie Slee, Courtney Van Biene, Richard Aranda, Niels Vande Casteele, Gregory J. Opiteck Background: GB004 is a small molecule prolyl hydroxylase inhibitor that stabilizes hypoxia inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1 α stabilization. GB004 is in clinical development for treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies. Methods: This was a randomized, double- blind, placebo-controlled, multiple dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to first dose and at Day 8. Colonic tissue concentrations of S-1202 AGA Abstracts GB004 and HIF pathway target genes were determined. Results: Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%, 10/ 32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 hours for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed. Conclusions: This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed. Tu1883 HIGHER TROUGH GOLIMUMAB LEVELS ARE ASSOCIATED WITH EARLY CLINICAL AND BIOCHEMICAL RESPONSE; EARLY RESULTS OF THE GOAL-ARC STUDY Ciara Egan, Fiona Jones, Juliette Sheridan, Carolann Coe, Doran Peter, Garret Cullen, Jan Leyden, Marie Galligan, Jane McCarthy, Aoibhlinn M. O'Toole, David Kevans, Laurence Egan, Glen Doherty Introduction Golimumab (GLM) is an anti-TNF monoclonal antibody licensed for the treat- ment of Ulcerative Colitis. Higher trough levels are associated with enhanced response to therapy. (GOAL-ARC) is a randomized multi-centered trial of the impact of personalised dosing of Golimumab based on inflammatory burden (assessed by FCP - faecal calprotectin) and therapeutic drug monitoring versus standard of care (with dosing according to label) commencing at week 6 of therapy.1 In order to validate the concept we examined the baseline and week 6 characteristics of the first 50% of patients enrolled. Aim To examine the induction data from GOAL-ARC and identify how we can improve outcomes of patients treated with Golimumab Methods 77 patient were enrolled; all participants had a diagnosis of UC, with moderate to severe disease activity (Mayo 6-12), with an endoscopic sub- score of ≥2. The study protocol is available for review (https://clinicaltrials.gov/ct2/show/ NCT02687724). Clinical response was defined as a decrease in modified partial mayo score of ≥2 points or a decrease of ≥30% from baseline. GLM was administered at 200mg at week 0, 100mg at week 2 in all patients in advance of week 6 assessment. Induction data was analysed to week 6 including FCP, modified partial mayo scores and week 6 trough GLM levels. Results Week 6 data is available in 63 patients. Clinical response was achieved in 60%. The median modified partial mayo score decreased from 4(IQR 3-5) at baseline to 2(IQR 1-4) at week 6 (p<0.001). Median FCP reduced from 1335 (IQR 432-2354) at baseline to 222 (IQR 16-1139) at week 6 (p=0.008). Higher week 6 drug levels were associated with clinical response. Median level in the responder group was 4.96μg/ml(IQR 3.5-6.2) compared to 2.6μg/ml(IQR 2.1-4.2) in the non responder group.(p=0.003) Higher drug levels were also significantly associated with lower calprotectin levels. (p=0.001) Patients with a FCP <150( biochemically inactive) had median trough level 0f 5.57μg/ml versus those with a FCP >150(biochemically active) who had a median trough level of 3.3μg/ml Conclusion Early results of GOAL-ARC demonstrate the majority (60%) of UC patients treated with GLM show early clinical response (by week 6). Significant improvements are observed in modified partial Mayo scores and FCP by week 6, with higher drug levels being significantly associated with achieving clinical and biochemical response. Our multi centre, real world experience has shown comparable results to those seen in the PURSUIT induction studies.