anti-TNF monotherapy does not impact responses relative to non-immunosuppressed con-trols. Booster vaccination with Tdap should ideally be administered prior to immunomodul-ator therapy.Response Rates to Pertussis and Tetanus Antigens by Group

Su2082

Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety of Amg 181, aFully Human Anti-α4β7 Antibody for Treating Inflammatory Bowel Diseases(IBD)Wei-Jian Pan, Barbara A. Sullivan, Christine M. Evangelista, David R. Doherty, Chi-Yan J.Tam, Sonal K. Patel, Peter J. Prince, Kai O. Reynhardt, William A. Rees, Hailing Hsu,Kefei Zhou, Wen Gu, Mark Yen, Christine A. Haller, Susanna Dodson, Zhigang Yu, LarryC. Wienkers, Dominique C. Borie

Background: To evaluate safety, PK/PD, and tolerability of single subcutaneous (SC) orintravenous (IV) doses of AMG 181 in healthy or ulcerative colitis (UC) subjects. Registeredat www.clinicaltrials.gov under ID NCT01290042 (on-going study sponsored by AmgenInc.). Methods: In this randomized, double-blinded, placebo-controlled, ascending singledose study, 68 healthy male subjects (18-44 yr, 56-121 kg) were randomized and adminis-tered single doses of AMG 181 or placebo (2:1 or 3:1 ratio) at dose levels of 0.7, 2.1, 7,21, 70 mg SC (or IV), 210 mg SC (or IV), and 420 mg IV. Eight UC subjects were randomizedto receive a single dose of 210 mg AMG 181 or placebo SC (3:1 ratio). Serum was collectedfor evaluation of PK and for the presence of anti-drug antibodies (ADA). Whole blood wascollected to assess α4β7 receptor occupancy (RO) and CD4 memory and naïve T cell countsusing a validated whole blood 6-color flow cytometric assay. PK and ADA samples wereassayed using validated electrochemiluminescent immunoassay (ECL) methods with a lowerlimit of quantification (LLOQ) of 10 ng/mL and a lower limit of reliable detection (LLRD)of 20 ng/mL, respectively. Population PK/PD modeling, with demography as covariates, wasconducted on AMG 181 concentration and RO data. The follow-up period was based onpredicted receptor occupancy, AMG 181 half-life and safety monitoring requirements.Results: The median time to Cmax (tmax) for AMG 181 was 2-10 days after SC dosing,with a mean bioavailability of 83%. While Cmax was dose-proportional at 21-210 mg SC,both Cmax and AUCinf were dose-proportional at 70-420 mg IV. AMG 181 clearance waslow (131 mL/day) and its distribution mostly limited within the central circulation (volumeof distribution: 4760 mL). AMG 181 had a linear elimination range half-life of 36 days,with terminal target-mediated disposition occurring below 1 μg/mL. The extent and durationof α4β7 RO increased with AMG 181 dose. The Emax model estimated E0, Emax, andEC50 values for RO were 0.0824, 0.946, and 1.18 ng/mL, respectively. An increase in CD4T cell counts in peripheral blood was not observed. All subjects tested negative for ADA.Preliminary population analyses revealed no demographic effects on AMG 181 PK/PD.Blinded safety data showed a 44% adverse event rate, with no treatment-related ≥Grade 3events, serious adverse events, deaths, or dose limiting toxicities. There were no abnormalitiesin ECGs or neurological exams. No subject discontinued the study due to an adverse event.Conclusion: AMG 181 has proven to be safe and well tolerated with desirable PK/PDproperties under fixed dose regimens. It is suitable for further testing in patients with IBD.

Su2083

One-Year Response and Remission Rates in Ulcerative Colitis Patients WithWeek 8 Response to Adalimumab: Subanalysis of Ultra 2William J. Sandborn, Geert R. D'Haens, Jean-Frederic Colombel, Gert A. Van Assche,Douglas C. Wolf, Martina Kron, Andreas Lazar, Anne Robinson, Jingdong Chao, RoopalThakkar

<p> Background: Physicians are unlikely to continue anti-TNF therapy for ulcerative colitis(UC) patients (pts) not exhibiting early therapeutic response. We evaluated Week (Wk) 52clinical remission and response rates in moderate to severe UC pts failing conventionaltherapy and achieving Wk 8 clinical response in ULTRA 2. <p> Methods: In the 52-wkULTRA 2 trial, pts were randomized 1:1 to adalimumab (ADA; 160/80 mg at Wk 0/2, 40mg every other wk [eow] thereafter) or placebo (PBO). Pts with inadequate response couldswitch to open-label (OL) ADA (40 mg eow, followed by 40 mg weekly) from Wk 12. Wk52 clinical remission (Mayo score ≤2; no subscore >1) and clinical response (Mayo scoredecrease of ≥3 points and ≥30% from baseline and decrease in rectal bleeding score [RBS]≥1 or absolute RBS of 0 or 1) rates were assessed in all PBO pts, in ADA pts achievingclinical response by full Mayo score, and in ADA pts achieving clinical response by partialMayo score (decrease of ≥2 points and ≥30% from baseline and above RBS criteria) at Wk8. Subgroup analyses by prior anti-TNF use were also performed. Non-responder imputation(NRI) was used for missing data or that collected on/after move to OL for PBO and ADA.ADA subgroups were also analyzed using modified NRI (mNRI); only missing data wereimputed as non-response/remission. Response and remission were compared between ADA(NRI or mNRI) and PBO (NRI only) groups. <p> Results: Significantly more ADA-treatedpts in each response group achieved Wk 52 remission or response as compared with PBOpts (Table; all comparisons P<0.01). A similar pattern of results was seen regardless of prioranti-TNF status (Table). <p> Conclusions: In moderate to severe UC pts in ULTRA 2,clinically meaningful long-term efficacy with ADA was seen at Wk 52 in pts with Wk 8 fullor partial Mayo score response.Wk 52 Results in ADA Week 8 Responders (by Full or Partial Mayo Score) and All PBO Pts

S-565 AGA Abstracts

aWk 8 responder per full Mayo score; bWk 8 responder per partial Mayo score; *P<0.01,ADA vs. PBO (CMH test for all, chi square test for anti-TNF subgroups)

Su2084

Efficacy of Certolizumab Pegol Induction and Maintenance Therapy inPatients With Crohn's Disease Not in Remission Following Active or PlaceboInductionWilliam J. Sandborn, Ziad H. Younes, Bosny Pierre-Louis, Geert R. D'Haens

Purpose To evaluate remission rates in patients with active Crohn's disease (CD) afterplacebo induction therapy or certolizumab pegol (CZP) induction or reinduction therapyfor 6 weeks and open-label CZP maintenance therapy for 20 weeks. Methods Patientscompleting the placebo-controlled CZP induction study (study 085, NCT00552058), andwith active disease (Crohn's Disease Activity Index 220-450), were eligible to enter an open-label study (study 088, NCT00552344) and receive open-label CZP 400 mg at Weeks 0,2, 4, and then every 4 weeks (q4w) thereafter. The Inflammatory Bowel Disease Questionnaire(IBDQ) and the CD Activity Index (CDAI) were used to measure remission rates. Remissionrates were analyzed from the baseline (Week 0) of the open-label study in patients whoreceived 6 weeks of induction therapy with CZP 400 mg or placebo in the CZP inductionstudy. Remission rates were calculated using the intention-to-treat population. Results Of439 patients who participated in the CZP induction study, 398 enrolled in the open-labelCZP study (intention-to-treat population). In the CZP induction study, 195 and 203 patientsreceived 6 weeks of placebo or CZP 400 mg, respectively. At baseline of the open-label CZPstudy (Week 0), 74% (144/195) and 60% (122/203) of patients did not achieve IBDQremission (IBDQ score ≥170 points) following 6 weeks of placebo or CZP 400 mg, respect-ively, in the CZP induction study. The mean IBDQ scores at Week 0 were 147 and 154among patients in the placebo and CZP 400 mg groups, respectively. Among patients notin remission at Week 0, IBDQ remission rates were 35% at Week 6 and 32% at Week 20for patients who received placebo induction, and 27% and 26%, respectively, for patientswho received CZP induction (Table). IBDQ remission rates for the total population in theopen-label CZP study at Weeks 6 and 20 were 45% and 42%, respectively, for patientswho received placebo induction, and 48% and 43%, respectively, for patients who receivedCZP induction (Table). Among patients not in remission at Week 0, the CDAI remissionrates (CD Activity Index score ≤150) at Week 6 were 35% (52/148) for patients receivingplacebo and 35% (48/138) for those receiving CZP 400 mg in the CZP induction study.Conclusions Induction or reinduction with open-label CZP 400 mg q4w captured remissionin a subset of patients with active CD following induction therapy with placebo or CZP 400mg. Remission rates with open-label CZP 400 mg q4w were similar to those reported inprevious clinical trials with CZP 400 mg. These data suggest that it may be useful to continueCZP 400 mg q4w treatment even if a patient has failed 6 weeks of CZP induction therapy.

Su2085

Association of Baseline C-Reactive Protein With Maintenance of Remission inAnti-TNF-Experienced Patients With Moderate to Severe Crohn's DiseaseTreated With AdalimumabWilliam J. Sandborn, Jean-Frederic Colombel, Geert R. D'Haens, Anne Robinson, Paul F.Pollack, Qian Zhou, Roopal Thakkar

Introduction: In the pivotal randomized placebo-controlled adalimumab (ADA) maintenancetrial (CHARM1), patients with elevated baseline C-reactive protein (CRP) who achievedclinical response after induction dosing demonstrated numerically higher rates of clinicalremission during maintenance therapy with weekly vs every other week (eow) ADA dosing.We previously reported that there was no difference in maintenance of remission betweendosing groups in the anti-TNF-naïve subgroup of CHARM patients with elevated baselineCRP.2We examined the effect of baseline CRP concentrations on themaintenance of remission

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swith weekly vs eow dosing of ADA in CHARM patients who had previously received anti-TNF treatment. Methods: In CHARM, all patients received 4-week induction with open-label ADA (80mg at week 0, 40mg at week 2). At week 4, all patients were randomized toreceive double-blind maintenance ADA (40mg weekly or eow) or placebo for 52 weeks. Inthis analysis, clinical remission (CDAI<150) at weeks 26 and 56 by baseline CRP (high:≥10mg/L, or low: <10mg/L) was determined (using non-responder imputation) for anti-TNF-experienced patients who achieved response at week 4 and were randomized to placebo,eow, or weekly ADA treatment groups. Results: 114 anti-TNF-experienced patients withhigh baseline CRP and 124 with low baseline CRP were included in the analysis. Baselinemedian CRP for each subgroup is shown in the Table. Remission rates for high CRP patientsrandomized to weekly dosing were approximately 2 times greater than for patients in theeow group (weeks 26 and 56, Table). By contrast, in patients with low baseline CRP,remission rates for ADA-treated patients in the weekly dosing group were similar to thoseof patients in the eow group at both time points. The incidence of adverse events wasgenerally similar among the subgroups. Conclusion: Weekly ADA dosing was associatedwith higher remission rates compared with eow dosing in anti-TNF-experienced patientswith elevated baseline CRP. These data and the previous analysis conducted in anti-TNF-naïve patients suggest that, in patients with moderately to severely active CD, dose escalationto manage loss of response may be most needed and achieve the most benefit in patientswho have been previously treated with anti-TNF agents and have elevated CRP at baseline.References: 1. Colombel JF, et al. Gastroenterology. 2007; 132:52. 2. Sandborn W, et al.UEGW. 2011; Abstract P0439.Baseline median CRP and percent of anti-TNF-experienced patients in clinical remission,by baseline CRP category

*P<0.05 vs. placebo; ***P<0.001 vs. placebo; †P<0.05 vs. eow

Su2086

A Phase Iia, Prospective, Randomized, Double-Blind, Placebo Controlled Trialof Green Tea Polyphenol Rich Extract (Polyphenon E®) in Mild to ModeratelyActive Ulcerative ColitisGerald W. Dryden, Allan P. Lam, Karen Beatty, Craig J. McClain

Inflammation in ulcerative colitis (UC) fails to respond to 5-aminosalicylic acid (5-ASA) inup to 30% of cases. Refractory cases require steroids, immunomodulators, or biologics toattain remission, with significant risk of infection. We have demonstrated green tea polyphen-ols (GTP) reduce inflammation in human immune cells by inactivating nuclear factor-κB(NF-κB). NF-κB activation promotes inflammatory cytokine expression that drives UC. Onthis basis, we initiated a clinical trial using Polyphenon E®, an encapsulted pharmaceuticalgrade extract of green tea enriched for (-)-epigallocatechin-3-gallate (EGCG), the most potentanti-inflammatory GTP. GTP are concentrated in the mucosa of the digestive tract. Wehypothesized that oral GTPwould suppress NF-κB activation and related cytokine productionto improve active UC. Objectives: Primary: assess safety and efficacy of GTP in patientswith UC per the UC Disease Activity Index (UCDAI), with response defined as decrease inDAI by >3 points at day 56 or an exit score of <3 (remission). Secondary: assess Qualityof Life (QOL) by Inflammatory Bowel Disease Questionnaire (IBDQ).Methods: Randomized,double-blinded, placebo controlled (review board approved) trial enrolling subjects ≥18years old, with a UCDAI ≥4 but ≤10 and an established diagnosis of UC for >3 months(confirmed by endoscopy). Twenty subjects were divided into two groups: cohort I (200mgEGCG BID + placebo) or cohort II (400mg EGCG BID). Controls received two identicalappearing placebo capsules BID. Subjects were randomized in a 4:1 ratio. Each cohortcontained eight treated subjects and two control subjects. Study drug was administered for56 days (+/- 5 days). Physical exam, lab analysis and UCDAI score (including endoscopy)were performed prior to drug administration and upon completion of medication on day56. IBDQ was performed on days 1, 14, 28, and 56. Results: Each cohort fully enrolled,with eight subjects receiving study drug (low vs. high dose Polyphenon E®) and two subjectsreceiving placebo. Three subjects dropped out prior to completion: two in the treatmentarm, one on placebo. In total, 10/16 treated subjects responded to therapy (62.5%, p=0.0382),while 8/16 (50%, p>0.05) achieved remission. No patients receiving placebo responded orremitted. There were no treatment group differences in subjects according to height, weight,UCDAI or baseline laboratory values (WBC, Hg, Hct, AST, ALT, and CRP). There were noserious adverse events or >grade 2 toxicity related to treatment. Conclusion: This first everclinical trial of GTP in the form of oral Polyphenon E® demonstrates convincing evidencefor a meaningful clinical benefit from the administration of this therapy, with no evidenceof significant side effects. These results indicate that larger controlled trials should beconducted to confirm GTP benefits.

S-566AGA Abstracts

Su2087

Effect of Long-Term Budesonide MMx 6 mg use on Bone Mineral Density inPatients With Ulcerative Colitis: Results From a Phase III, 12 Month Safetyand Extended use StudySimon Travis, Silvio Danese, E. David Ballard, Luigi Moro, Richard J. Jones, Robert Bagin,Therese Gautille, Michael Huang, Philip Yeung, Raul Harris-Collazo, William J. Sandborn

Background: Although systemic corticosteroids (SCS) are effective for the short-term induc-tion of remission in active UC, long term use leads to unacceptable side effects such as areduction in bone mineral density (BMD). Alternative agents with fewer SCS-related sideeffects are needed in UC. Budesonide, a non-systemic corticosteroid (NSCS) with high first-pass metabolism, combined with MMX® technology designed to deliver active drug to thecolon may be a viable therapeutic option. Budesonide MMX (B-MMX) 9 mg administeredonce daily is well tolerated and effective at inducing both clinical and endoscopic remissionwith symptom resolution in patients with mild-to-moderate UC after 8 weeks of therapy.In the current study, BMD was evaluated after long term therapy with B-MMX 6 mg over12 months. Materials and methods: Patients who were in strictly defined clinical andendoscopic remission after two Phase 3 studies or an Open Label study were randomized(1:1) to an extended use study with B-MMX 6mg QD or placebo (PBO). BMD was assessedat baseline and 12 months or the End of Study/Early Withdrawal Visit by dual-energy X-ray absorptiometry (DEXA) scan or alternative radiological methods if DEXA was not avail-able. Patients were required to receive therapy for at least 6 months to be included in theBMD evaluation. Results: Baseline BMD scans were obtained from 123 patients at the startof the long term study. 74 patients were eligible for inclusion in the BMD analysis (on drugfor 6 months) (N=39; PBO and N=35; B-MMX 6 mg). At study end, 66 patients had bothbaseline and end of study BMD scan for comparison. At study completion, normal BMDwas observed in 74% (PBO) and 77% (B-MMX 6 mg). BMD remained unchanged comparedto baseline in 77% (PBO) and 86% (B-MMX 6 mg). Worsening of BMD was observed in 3pts (7.7%) in PBO and 2 pts (5.7%) in B-MMX 6 mg. (Table). Overall, there were noclinically important differences between PBO and B-MMX 6 mg at the end of the study.There were no bone fractures reported by either group during the study. Conclusion: Inthis 12 month extended use study, there were no clinically meaningful differences betweenB-MMX 6 mg and PBO in bone mineral density. No bone fractures were reported duringthe study. The effect of extended use of B-MMX 6 mg on bone mineral density appears tobe comparable to PBO.Safety Analysis of Long Term Therapy up to 12 Months: Bone Mineral Density

Su2088

Safety Analysis of Budesonide MMx 6 mg Used for the Maintenance ofRemission in Patients With Ulcerative Colitis: Results From a Phase III, 12Month Safety and Extended use StudySimon Travis, Silvio Danese, E. David Ballard, Luigi Moro, Richard J. Jones, Robert Bagin,Therese Gautille, Michael Huang, Philip Yeung, Raul Harris-Collazo, William J. Sandborn

Background: Although systemic corticosteroids (SCS) are effective for the short-term induc-tion of remission in active UC, current guidelines (ACG 2010 and AGA 2006) advise againstSCS for maintaining remission because side effects are frequent and the risks associatedwith long term therapy outweigh the benefits. Alternative agents with fewer side effects areneeded. Budesonide, a non-systemic corticosteroid (NSCS) with high first-pass metabolismcombined with MMX® technology which is designed to deliver active drug to the colon,may be a viable therapeutic option. Budesonide MMX (B-MMX) 9 mg administered oncedaily is well tolerated and effective at inducing both clinical and endoscopic remission withsymptom resolution in patients with mild-to-moderate UC after 8 weeks of therapy. In thecurrent, the safety and tolerability of long term therapy was examined with B-MMX 6 mgover 12 months.Methods: The safety and tolerability of B-MMX 6 mg was evaluated througha placebo (PBO)-controlled 12 months extended use study in patients who were in clinical