estimated ERRs from the logistic regression modeling for either end point were positive(P<.10), these ERR slope estimates were less steep than those in the exploratory plots. Withingroups, defined by quartiles of baseline covariates between Caverage values of 32 to 85 μg/mL (5th and 95th percentiles), the average probability of clinical response and clinicalremission increased by 15% and 10%, respectively. On average, patients with lower baselineCRP levels and no prior anti-TNF-α use have a higher probability of clinical remissionwhether receiving placebo or VDZ. The likelihood ratio statistic of the 2-way interactionanalysis was not significantly different for either clinical response (2.49; P=.647) or remission(5.47; P=.243), indicating no dependence of the VDZ ERRs on baseline covariates. Conclu-sions: A positive ERR exists for both clinical response and clinical remission in patients withCD after 6 weeks of induction therapy with VDZ 300 mg; however, any ERR derived fromplots or tables of observed data may provide an overestimation of the true VDZ ERR.Furthermore, the VDZ ERR was not found to be dependent on any of the covariates tested.

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Indirect Comparison of Adalimumab, Infliximab, and Golimumab inUlcerative Colitis: Cost Per Remitter AnalysisYifei Liu, William Reichmann, Dendy Macaulay, Song Wang, Martha Skup, ParvezMulani, Jingdong Chao

Background: Adalimumab (ADA), infliximab (IFX), and golimumab (GLM) have been shownto induce and maintain clinical remission in patients with moderate to severe ulcerativecolitis (UC).1-3 To date, a head-to-head randomised clinical trial comparing these therapieshas not been conducted. In the absence of a direct comparison, we conducted an indirectcomparison of remission rates of anti-tumour necrosis factor-Naive patients based on datain clinical trials1-3 (ULTRA 2 [NCT00408629], ACT 1 [NCT00036439], and PURSUIT-M[NCT00488631]) using a Bayesian network meta-analysis (NMA) framework, and calculatedcost per remitter associated with ADA, IFX, and GLM. Methods: In ULTRA 2, patientsreceived placebo or ADA 160 mg/80 mg at weeks 0/2 and then 40 mg every other weekthrough week 52. In ACT 1, patients received placebo or IFX (5 mg/kg) intravenously atweeks 0, 2, and 6 and then every 8 weeks through week 46. In PURSUIT-M, patients whoresponded to GLM induction therapy (intravenous GLM 1, 2, or 4 mg/kg at week 0 orsubcutaneous GLM 100/50, 200/100, or 400/200 mg at weeks 0/2) received placebo orGLM 100 mg every 4 weeks through week 52. In all 3 trials, clinical remission was definedas a total Mayo score of ≤2 points, with no individual subscore >1 point. Clinical remissionwas assessed at week 52 in the ADA trial and week 54 in the IFX and GLM trials. UsingNMA methodology,4 the relative efficacy of each biologic therapy was derived in terms ofincremental remission rates between the biologic therapy and placebo. Treatment costsincluded drug and administration costs according to the respective Food and Drug Adminis-tration prescribing labels. Costs for those on ADA were weighted by the week-8 remissionrate from ULTRA 2, while costs for those on IFX and GLM assumed that patients were ondrug for the entire 1-year period. Results: NMA-estimated 1-year remission rates in UCwere 30.1%, 36.7%, 28.0%, and 17.4% in for ADA-, IFX-, GLM-, and placebo-treatedpatients, respectively. Differences in remission rates for ADA vs placebo, IFX vs placebo,and GLM vs placebo were 12.7% (95% credible interval [CrI]: 0.3%, 26.3%), 19.3% (95%CrI: 5.9%; 33.7%), and 10.6% (95% CrI: 1.2%, 21.2%), respectively. One-year treatmentcosts per incremental remitter were $116,596 (95% CrI: $35,188, $573,117), $127,357(95% CrI: $58,051, $301,541), and $399,447 (95% CrI: $138,445, $1,554,453) for ADA,IFX, and GLM, respectively. Conclusion: The 1-year cost per remitter in UC was numericallylower but not statistically significant for ADA-treated patients compared to IFX- and GLM-treated patients. References: 1Sandborn WJ, et al. Gastroenterology. 2012;142:257-65. 2Rut-geerts P, et al. N Engl J Med. 2005;353:2462-76. 3Sandborn WJ, et al. Gastroenterology.2013;pii:S0016-5085(13)00846-9. 4Liu Y, et al. Adv Ther. 2012;29:620-34.

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Cognitive Behavioural Therapy (CBT) Influences Innate and AdaptiveInflammatory Responsiveness in IBD Patients With Clinical RemissionSustained Over 6 Months: A Randomised Control TrialPatrick A. Hughes, Antonina A. Mikocka-Walus, Melissa Moretta, Amelia N. Pilichiewicz,Peter A. Bampton, Jane M. Andrews

Background: Inflammatory Bowel Disease (IBD) is characterised by a relapsing and remittingdisease course, with overt inflammation during flares. Psychological stress is proposed toinfluence IBD disease course, yet there is no convincing data on whether psychotherapy is aneffective treatment. CBT is a type of psychotherapy with the most evidence for improvement ofcoping with stress. We aimed to investigate whether CBT prolongs disease remission inpatients with quiescent IBD and/or influenced circulating cytokine profiles as a surrogatefor inflammatory propensity. Methods: 29 clinically established IBD patients in remissionfor ≥ 3 months were enrolled in a pilot randomised control trial and received either standardmedical care alone (Placebo) (N=17)), or with a 10 week period of CBT in addition (+CBT(N=12)). Blood was taken at entry (visit 1 (V1)) and at 6 months (visit 2(V2)) and peripheralblood mononuclear cells (PBMC) isolated by density centrifugation. PBMC were culturedin media only overnight or in the presence of either LPS overnight to stimulate innateimmune responses or PMA/ionomycin for 4 hours to stimulate adaptive immune responses.Cytokine concentrations in cultured supernatants were determined via multiplex assay (18plex; eBioscience) and compared between visit 1 and visit 2 for placebo and CBT groups.Results: Patients were classified as remissive (R) or not remissive (NR) based on clinicalrecurrence over the 6 months of observation. The number of +CBT and Placebo patientsthat remained in remission over the 6 months was similar: 58% (7/12) +CBT patients,compared to 53% (9/17) Placebo patients (p=NS). LPS stimulation increased the concentra-tion of GMCSF, IL-1β, IL-10, IL-18, IL-22, IL-23, IL-27 and TNF-α compared to concentra-tions in unstimulated media and PMA/ionomycin stimulation increased the concentration ofIFN-γ, IL-2, IL-4, IL-13, IL-21, IL-22 and TNF-α compared to concentrations in unstimulatedmedia in Placebo and +CBT patients. However, CBT reduced LPS stimulated concentrationsof GMCSF, IL-18 and TNF-α, and PMA/ionomycin stimulated concentrations of IFN-γ, IL-2, IL-13, IL-18, IL-21, IL-22 and TNF-α in +CBT-R but not Placebo-R. Further, at studyentry (V1), the concentration of LPS stimulated GMCSF and IL-18 and PMA/ionomycin

S-593 AGA Abstracts

stimulated IFN-γ, IL-2, IL-13, IL-18 and TNF-α was lower in +CBT-NR compared to +CBT-R patients. Discussion: CBT seems to have specific additional effects on the immune systemof remissive IBD patients over and above what is seen under standard medical therapy whichmaintains remission. Innate and adaptive immune responses are both influenced by CBT.Patients who subsequently respond to CBT appear to be more immunologically reactive atbaseline than those who fail to respond, suggesting that immune pre-screening of patientsmight potentially select patients who will respond to CBT.

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The FFA2 Antagonist GLPG0974: A Promising Approach to Treat Neutrophil-Driven InflammationFrédéric P. Vanhoutte, Florence S. Namour, Sonia Dupont, Mathieu Pizzonero, Steve DeVos, Laurent Sanière, Annegret Van der Aa, Johan Beetens, Gerben van 't Klooster

Background: Free fatty acids (FFA) act as signalling molecules through several GPCRsincluding FFA2, a receptor activated by short chain fatty acids (SCFA). FFA2 is expressedon immune cells, enterocytes, entero-endocrine cells and adipocytes. FFA2 plays a majorrole in SCFA-induced neutrophil activation and migration. Studies in FFA2 knock-out micesuggest an important contribution to the control of inflammation. In IBD patients, FFA2expression in colon biopsies was shown to be upregulated and was reduced after successfultreatment with infliximab. Methods: Calcium flux and [35S]-GTPγS after acetate stimulationwere assessed in HEK293 cells, stably overexpressing FFA2. Neutrophil chemotaxis towardsFFA2 agonists was evaluated in a Transwell system. Acetate-induced activation of neutrophilsin human whole blood was evaluated by FACS analysis of CD11b activated epitope [AE]expression. The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) oforally administered GLPG0974 were evaluated in healthy volunteers after single dosing (SD)and multiple ascending dosing for 14 days (MAD). The PD was assessed by neutrophilactivation (CD11b[AE] expression) in whole blood upon ex vivo stimulation by acetate.Results: GLPG0974 is a potent and selective antagonist of human FFA2. In vitro, it inhibitsacetate-induced calcium flux in HEK293 cells (IC50: 11 nM) and human neutrophil migration(IC50: 43 nM). In human whole blood, GLPG0974 inhibits acetate-stimulated neutrophilactivation, as evidenced by downregulated CD11b [AE] exp (IC50: 483 nM). GLPG0974 isalso active against monkey FFA2, but not against rodent or dog FFA2. It is highly selectivefor FFA2 over the close homologues FFA1 and FFA3, other non-related GPCRs. In volunteers,single doses up to 250 mg and multiple doses up to 400 mg daily were safe and well-tolerated. GLPG0974 administered under fed conditions as capsules or oral solution, wasslowly absorbed with a median tmax of about 3 h and eliminated with a mean t1/2 of about5.5 h. The PK was dose proportional over the 50 to 400 mg daily dose range. GLPG0974substantially inhibited acetate-stimulated neutrophil activation in whole blood. In general,the inhibitory effect peaked at 2 h post dose and the activity was sustained for at least 12h after dosing. The PK/PD data showed a clear relationship between drug exposure and PDeffect. Conclusion: In humans, the potent FFA2 inhibitor GLPG0974 is safe, and showsgood PK properties and a dose-dependent inhibition of acetate-induced neutrophil activation.Inhibition of neutrophil migration into the gastro-intestinal tract may prevent neutrophil-induced tissue damage as in ulcerative colitis. A Proof-of-Concept study is ongoing toevaluate the safety and efficacy of GLPG0974 in patients with this condition.

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Photodynamic Diagnosis of Endoscopically Undetectable Dysplasia in PatientsWith Ulcerative Colitis by Visualization Following Oral 5-Aminolevulinic AcidSensitizationTetsuyoshi Iwasaki, Nobuhiko Komoike, Tomohiro Kato, Ryoichi Sawada, Daisuke Ide,Makoto Mitsunaga, Masayuki Saruta, Seiji Arihiro, Mika Matsuoka, Hisao Tajiri

[Background] An important issue in the clinical management of patients with long-standingulcerative colitis (UC) is the complication of colitis-associated cancer or dysplasia (CC/D).It is very difficult to detect CC/D with conventional colonoscopy (CE). Many endoscopicprocedures such as chromoendoscopy and target biopsy have been suggested for moreefficient detection of CC/D lesions, but reliable endoscopic detection methods still remainuncertain. Recently, photodynamic diagnosis (PDD) has been used clinically to detect theextent of neoplasms, especially in neurosurgical and urologic procedures. 5-aminolevulinicacid (5-ALA) is converted intracellularly into the sensitizer protoporphyrin IX (PpIX), whichaccumulates selectively in neoplastic tissue, allowing detection. As there are very few reportsregarding this use of 5-ALA for UC surveillance, its utility is still unclear and controversial.[Aim] The aim of this pilot study was to evaluate the efficacy of PDD for endoscopic detectionof dysplasia in patients with UC by visualization, using autofluorescent endoscopy (AFE)following sensitization by orally administered 5-ALA. [Method] Ten patients with pancolitisfor over ten years were enrolled at The Jikei University Hospital from October 2010 toSeptember 2012. Prior to this study, we confirmed that the 5-ALA metabolite PpIX wasdetected in vitro as strong fluorescence signals, using AFE (CF-FH260AZI, Olympus MedicalSystems, Tokyo, Japan). 5-ALA (20 mg/kg BW; Cosmo Bio, Tokyo, Japan) was administeredorally, and conventional colon lavage was undertaken. Endoscopic examination was per-formed five hours after oral 5-ALA administration. Each segment of large intestine was firstlyexamined by CE including chromoendoscopy and then reexamined by AFE. [Result] Noadverse side effects of 5-ALA were observed. For CE 81 lesions were suspected and biopsiedby CE, and we found out that 18 lesions were CC/D pathologically. During subsequentAFE, 22 lesions with strong fluorescence signals of characteristic shape were detected andbiopsied, and we found out that 14 lesions were CC/D on pathological examination. Positiveand negative predictive values of CE were 22% and 71%, on the other hand those of AFEwere 68% and 91%. [Conclusion] AFE after 5-ALA sensitization offers the possibility ofdetecting CC/D lesions by characteristic shape and color enhancement. Although the numberof patients enrolled in this study is very limited, our experience indicates that AFE is apromising method for detecting CC/D lesions during UC surveillance.

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