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sMo1215

Serum Golimumab Exposure and the Incidence of Selected Safety Events inPatients With Ulcerative Colitis Following Treatment With Golimumab: AnExploratory Analysis of the PURSUIT Study DataOmoniyi J. Adedokun, Zhenhua Xu, Colleen W. Marano, Richard Strauss, HongyanZhang, Jewel Johanns, Honghui Zhou, Hugh M. Davis, Sam Liao, Jean-FredericColombel, Walter Reinisch, Brian G. Feagan, Paul J. Rutgeerts, Peter R. Gibson, WilliamSandborn

.Background: For anti-TNFα agents, it is unknown whether the incidence of safety eventscorrelates with systemic drug exposures in ulcerative colitis (UC). The relationships betweengolimumab (GLM) pharmacokinetic (PK) exposure metrics and selected safety events wereassessed using data from the PURSUIT GLM UC program. Methods: The relationshipsbetween systemic GLM exposure and the occurrence of selected safety events includinginfections, serious infections, and serious adverse events (SAE) through week 54 wereevaluated in patients who received placebo, GLM50 mg or GLM100 mg q4week doseregimens in the PURSUIT-Maintenance study. Empirical Bayesian PK parameter estimatesfrom a population PK model of GLM in UC patients were used to derive GLM exposuremetrics (cumulative AUC, Cmax, Cavg, and Ctrough), taking into account the actual doseseach patient received. Golimumab PK exposure metrics were categorized into quartiles andthe incidence of the selected safety events were compared across the quartile categories. Thedistributions of GLM PK exposure metrics were also compared between patients experiencingno selected safety event, 1 event, and more than 1 event. These analyses were performedfor all patients who were evaluable for PK, as well as for the subset of patients who remainedon their randomized GLM dose regimen through week 54 in the PURSUIT maintenancestudy. A total of 1227 patients were included in the PK/safety analysis dataset. Results: Fromthe analysis of the serum GLM AUC quartile categories, as systemic exposures to GLMincreased, there was no apparent trend in the rates of infections, serious infections, or SAEs(Figure 1). The distribution of serum GLM AUC in patients who experienced 1 or moresafety events were comparable to that in patients with no safety event. These findings wereconsistent when other GLM PK exposure metrics were assessed. Similar results were alsoobserved in the subset of patients randomized in the PURSUIT maintenance study whoremained on their assigned GLM regimen through week 54. Conclusions: Regardless of thePK exposure metric, no apparent correlation was observed between serum GLM exposureand the occurrence of infections, serious infections, or SAEs in UC patients treated with SCGLM 50mg or 100mg q4wks through 1 year. These findings are similar to those observedin rheumatology patients treated with SC GLM.

Mo1216

Tripeptide KDPT Accelerates Disease Remission in Patients With Mild toModerate Active Ulcerative ColitisTorsten Kucharzik, Gunter Lemmnitz, Christoph Abels, Christian Maaser

Background: KdPT is a tripeptide with broad anti-inflammatory activity. Pre-clinical dataindicated that KdPT is safe and efficacy was shown in different murine models of intestinalinflammation. KdPT given orally proved to be safe and well tolerated in a single and twomultiple ascending dose clinical studies. Methods: We performed a multi-centre, randomised,double-blind, placebo-controlled prospective phase II trial (2011-002462-20) to evaluateefficacy and safety of KdPT in patients with mild to moderate ulcerative colitis (UC). Asadd-on therapy to aminosalicylates, azathioprine, and/or corticosteroids placebo or KdPTin three different doses (20, 50, 100 mg BID) was administered . 168 patients were random-ized (ITT: n=162; PP: n= 116) in 31 investigational sites in 6 countries (D, I, PL, HU, CZ,SK). The primary objective was to determine time to response to KdPT, defined as timefrom Day 0 to earliest treatment visit at which sustained improvement in colitis activityindex (CAI) of ≥50% was determined. Improvement in CAI was to be ≥50% at Week 8,irrespective of any interim decline, for improvement to be classified as sustained. Due toan unusually high placebo rate from week 6 on assumptions for the statistical evaluationof the primary endpoint were violated, thus appropriate statistical tests were run to comparetreatment groups. Results: The primary endpoint for pooled KdPT (PP) approached signifi-cance using Log rank (Renyi family) test (p = 0.0525, one-sided) and showed statisticalsignificance for the Wilcoxon (Renyi family) test (p = 0.0368, one-sided). At Week 2 andWeek 4, remission rates were approximately twice as high for pooled KdPT compared toplacebo (2 weeks: p=0.0361; 4 weeks: p=0.0178). For 20 mg KdPT remission occurredearlier compared to 50 mg or 100 mg K(D)PT. CAI response rates lost significance at latertime points due to unexpected high placebo rates from week 6 on. Patients with active andmore severe disease (CAI ≥9 ; baseline medication : aminosalicylates + corticosteroids and/or azathioprine) showed earlier and more pronounced response to KdPT compared toplacebo (p=0.0156). KdPT was safe and tolerated well at the investigated doses with nodifference between placebo and KdPT groups. Conclusion: KdPT shows an early and statisti-cally significant pharmacological effect in patients with mild to moderately active UC whilebeing safe and well tolerated. Subgroups with active and more severe disease show markedor statistically significant differences between KdPT and placebo. Given as an add-on tobaseline therapy, KdPT accelerates disease remission and leads to an earlier response.

S-588AGA Abstracts

Mo1217

Effects of Continued Vedolizumab Therapy for Crohn's Disease in Week 6Induction Therapy NonrespondersWilliam J. Sandborn, Brian G. Feagan, Walter Reinisch, Michael D. Smyth, Jing Xu, AsitParikh, Irving Fox

Intro: In the placebo (PBO)-controlled GEMINI 2 study of vedolizumab (VDZ), an investiga-tional, gut-selective, humanized, anti-α4β7 integrin monoclonal antibody, approximately50% of patients with Crohn's disease (CD) had a clinical response to VDZ induction therapyat week 6. The current analysis evaluated the effects of continued VDZ therapy on rates ofclinical remission and Crohn's Disease Activity Index (CDAI)−100 response in patients withCD from the GEMINI 2 study who did not respond to VDZ induction therapy at week 6.Methods: During the 6-week induction trial of the 52-week GEMINI 2 study, patients withCD were randomly assigned to receive PBO or VDZ 300 mg (cohort 1) or received open-label VDZ (cohort 2) intravenously at weeks 0 and 2. At week 6, clinical response (≥70-point decrease in CDAI score from baseline) was assessed. During the maintenance trial,VDZ induction nonresponders were assigned to receive VDZ every 4 weeks (Q4W), and allPBO patients continued to receive PBO; the subset of week 6 PBO nonresponders was usedas a comparator. Proportions of week 6 nonresponders in clinical remission (CDAI score≤150 points) and of those with a CDAI-100 response (≥100-point decrease in CDAI scorefrom baseline) were assessed at weeks 10 and 14 (prespecified) and at week 52 (post hoc).Week 52 post hoc analyses were also performed for end points among week 6 nonresponderswho had a clinical response at week 10 or 14. Results: At baseline, mean CD durations(VDZ, 9.2 years; PBO, 8.2 years) and CDAI scores (VDZ, 323.4; PBO, 324.6) were similarfor the VDZ (cohorts 1 and 2; n=967) and PBO (cohort 1; n=148) groups; 59% and 47%of VDZ- and PBO-treated patients, respectively, had previous tumor necrosis factor antagonistfailure. Compared with PBO, continued VDZ generally led to numerically greater proportionsof week 6 nonresponders in clinical remission or with a CDAI-100 response at week 10,14, or 52 (Table). These between-treatment group differences generally increased over timefor both remission and CDAI-100 response and were more pronounced for CDAI-100response than for remission. Among week 6 nonresponders, proportions of patients withremission (41.3%) or a CDAI-100 response (54.5%) at week 52 were higher in week 14VDZ delayed responders (n=121) than the proportions (33.3% and 43.8%, respectively) inweek 10 VDZ delayed responders (n=96). Among PBO-treated patients, proportions ofpatients with remission or a CDAI-100 response were 16.7% and 25%, respectively, at week52 in week 14 responders (n=12), while the proportions were 16.7% and 16.7%, respectively,in week 10 responders (n=6); however, subgroup sizes were small. Concl: In patients withCD who did not respond to VDZ induction therapy at week 6, rates of clinical remissionand CDAI-100 response at weeks 10, 14, and 52 were higher with continued VDZ Q4Wtherapy than with PBO.

Mo1218

Long-Term Outcomes of Certolizumab Pegol for Crohn's Disease: 7 YearResults From the PRECiSE 3 StudyWilliam Sandborn, Scott D. Lee, Charles W. Randall, Alexandra Gutierrez, David A.Schwartz, Sumeet Ambarkhane, Cem Kayhan, Bosny Pierre-Louis, Gordana Kosutic,Stefan Schreiber, Gary R. Lichtenstein

Introduction: Crohn's disease (CD) is an incurable inflammatory condition that is oftentreated with anti-TNF agents such as certolizumab pegol (CZP). There are few clinical studieswith greater than 5 years of outcomes. We report the efficacy and safety outcomes forpatients (pts) receiving continuous CZP treatment during a 7-year interventional study.Methods: Pts with moderate to severe CD who completed a 26-week PRECiSE 1(P1) [1] orP2 [2] were eligible for inclusion in P3, an open-label extension (OLE) study that assessedCZP treatment, 400mg every 4 weeks; total study duration was 7 years. Those who completedthe OLE were assessed on up to 94 occasions and received up to 91 doses of study drug.Safety assessments included treatment-emergent adverse events (AEs) including opportunisticinfections (OI). Efficacy assessments included Harvey-Bradshaw Index (HBI), fecal calprotec-tin (FC), and C-reactive protein (CRP). Plasma levels of CZP and anti-CZP antibodies wereassessed up to 35 times. Pts who required defined rescue therapy were considered non-responders from that visit forward. Observed cases, last observation carried forward (LOCF)imputation, and non-responder imputation (NRI) were used. Results: In total, 595 ptsentered P3 (354 from P1; 241 from P2). At baseline of the qualifying studies, the mean(±SD) age was 38.1 (±11.9) years; 52% of pts were females; 95% were white; the median