Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases

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1 Accepted Manuscript Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases Brian G. Feagan, MD, Karen Lasch, MD, Trevor Lissoos, MBBCh, Charlie Cao, PhD, Abigail M. Wojtowicz, PhD, Javaria Mona Khalid, PhD, Jean-Frédéric Colombel, MD PII: S (18) DOI: /j.cgh Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 13 May 2018 Please cite this article as: Feagan BG, Lasch K, Lissoos T, Cao C, Wojtowicz AM, Khalid JM, Colombel J-F, Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases, Clinical Gastroenterology and Hepatology (2018), doi: /j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases Short title: Rapid response to vedolizumab in IBD Brian G. Feagan, MD, 1 Karen Lasch, MD, 2 Trevor Lissoos, MBBCh, 2 Charlie Cao, PhD, 2 Abigail M. Wojtowicz, PhD, 2 Javaria Mona Khalid, PhD, 3 Jean-Frédéric Colombel, MD 4 1 Robarts Research Institute, University of Western Ontario, London, Ontario, Canada 2 Takeda Pharmaceuticals U.S.A., Inc., Deerfield, IL, USA 3 Takeda Development Centre Europe, Ltd., London, UK 4 Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

3 Grant support: This study is supported by Takeda Pharmaceuticals U.S.A., Inc. Abbreviations: ANCOVA, analysis of covariance AP, abdominal pain BL, baseline BMI, body mass index CD, Crohn s disease CDAI, Crohn s disease activity index CI, confidence interval CRF, case report form CrI, credible interval CRP, C-reactive protein CS, corticosteroid Diff, difference EIM, extraintestinal manifestation HBI, Harvey-Bradshaw index IBD, inflammatory bowel disease IFX, infliximab IMM, immunomodulators IQR, interquartile range ITT, intent-to-treat IVRS, interactive voice response system LSF, loose stool frequency

4 MAdCAM-1, mucosal addressin cell adhesion molecule 1 MCS, Mayo Clinic score N/A, not applicable Non-Est, non-estimated OR, odds ratio PBO, placebo PK, pharmacokinetics PRO, patient-reported outcome RB, rectal bleeding RBS, rectal bleeding score SD, standard deviation SF, stool frequency SFS, stool frequency score SONIC, Study of Biologic and Immunomodulator Naïve Patients in CD TNF, tumor necrosis factor alpha UC, ulcerative colitis VDZ, vedolizumab VICTORY, VedolIzumab for Health OuTComes in InflammatORY Bowel Diseases Correspondence: Jean-Frédéric Colombel, MD Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA jean-frederic.colombel@mssm.edu

5 Phone: Fax: Disclosures: Brian G Feagan has received grant support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Roche, Genentech, J&J, Janssen, Millennium, Pfizer, Receptos, Tillotts, and UCB; and has served as a consultant or advisory board member for AbbVie, ActoGeniX, Akros, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corp, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, engene, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, GSK, Inception IBD Inc, Ironwood Pharmaceuticals, J&J, Janssen, Japan Tobacco, Kyowa Hakko Kirin Co Ltd, Lexicon, Lilly, Lycera Biotech, Merck, Mesoblast Ltd, Millennium, Nektar, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics & Diagnostics, Protagonist, Receptos, Salix, Shire, Sigmoid Pharma, Synergy Pharmaceuticals Inc, Takeda, Teva Pharmaceutical Industries Ltd, TiGenix, Tillotts, UCB, Vertex Pharmaceuticals, VHsquared Ltd, Warner Chilcott, Wyeth, Zealand Pharma, and Zyngenia. Jean-Frederic Colombel has received grant support from AbbVie, Janssen Pharmaceuticals, and Takeda; has served as a speaker for AbbVie, Amgen, and Ferring Pharmaceuticals; has served as a consultant for AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres Therapeutics, Shire, Takeda, and Theradiag; and is shareholder of Genfit and Intestinal Biotech Development. Karen Lasch, Trevor Lissoos, Charlie Cao, and Abigail M. Wojtowicz are employees of Takeda Pharmaceuticals U.S.A., Inc. Javaria Mona Khalid is an employee of Takeda Development Centre Europe, Ltd. Writing assistance: Medical writing assistance was provided by Reem Berro, PhD, of Syneos Health and supported by Takeda Pharmaceuticals U.S.A., Inc. Author contributions: 1. Acquisition of data (BGF, KL, TL, JMK, JFC) 2. Statistical analysis (CC) 3. Interpretation of data (all authors) 4. Critical revision of the manuscript for important intellectual content and final approval (all authors) Acknowledgments:

6 The authors thank Alexandra James, an employee of Takeda Development Centre Europe, Ltd., London, UK, for her assistance with statistical analysis and data interpretation.

7 Abstract: Background & Aims: Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn s disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists. Methods: We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (n=374) or CD (n=784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2). Results: In patients with UC (overall or naïve to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naïve to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naïve) achieved a composite score of rectal bleeding of 0 and stool frequency 1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naïve) of those receiving placebo. Among TNF antagonist-naïve patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of

8 abdominal pain 1 and loose stool frequency 3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo). Conclusion: In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks especially when given as first-line biologic therapy. KEY WORDS: GEMINI trials, IBD, time to response, patient-reported outcomes Summary: Vedolizumab is an antibody against α4β7 integrin that is used to treat patients with ulcerative colitis or Crohn s disease. In an analysis of data from 3 clinical trials, we found that vedolizumab rapidly (within 2 weeks) improved some patient-reported symptoms, through the first 6 weeks of treatment.

9 Introduction Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with a significant burden on patients quality of life. Diarrhea is a common symptom in both ulcerative colitis (UC) and Crohn s disease (CD). In addition, patients with UC often present with rectal bleeding (RB) and report abdominal pain (AP) in CD. 1, 2 Consequently, these important symptoms are regularly used as endpoints in clinical trials as a part of disease activity indices and to monitor disease activity in clinical practice. 3 Current therapy aims to resolve both relevant symptoms and underlying mucosal inflammation. 4 Patient-reported outcomes (PROs) have an increasingly important role in capturing symptomatic burden and have become required by regulatory agencies in assessing response to treatment and evaluation of claims for future product labeling. 4-6 Several studies have identified the resolution of RB and the normalization of bowel habit as primary PRO targets for UC therapy. 4, 5 In CD, Khanna et al recommended the resolution of AP and the normalization of bowel habit as the primary PROs for the evaluation of CD treatment efficacy in clinical trials. 7 Vedolizumab is a gut-selective humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to α 4 β 7 integrin expressed on the surface of lymphocytes, thereby blocking the binding of α 4 β 7 to its ligand MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expressed on the endothelial surface of venules in lymphoid tissue in the GI tract. The binding of vedolizumab to α 4 β 7 prevents the α 4 β 7 -expressing T lymphocytes from entering gut tissue, thus reducing inflammation. 8, 9 In the GEMINI trials, vedolizumab s efficacy as induction and maintenance therapy was demonstrated in moderately to severely active UC or CD patients who were naïve to, or had prior exposure to, tumor necrosis factor alpha (TNF) antagonists Clinical benefits of vedolizumab in UC patients were evident at week 6, with greater differences in efficacy

10 between vedolizumab and placebo observed in patients who were TNF antagonist-naïve compared with those who failed TNF antagonist treatment. 10, 13 Subgroup analyses of CD patients indicated that significantly higher remission and response rates were achieved in TNF antagonist-naïve patients treated with vedolizumab than those assigned to placebo at weeks 6 and 10. In patients who failed TNF antagonist treatment, a significant effect of vedolizumab induction on clinical remission was observed at week These data add to the growing evidence that second-generation biologics such as vedolizumab and ustekinumab have higher 12, 14, 15 efficacy in TNF antagonist-naïve patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage; hence the importance of evaluating the treatment effects of vedolizumab in biologic-naïve 16, 17 patients. It has been debated whether agents affecting lymphocyte trafficking may have a relatively slower onset of action, especially in CD. However, there are no published studies comparing the rapidity of onset of various classes of IBD drugs. The objective of this study was to investigate the time course of clinical response with vedolizumab, particularly when used as a first-line biologic. Therefore, we performed exploratory analyses of the GEMINI trial data to assess rapidity of onset and identify predictors of patient-reported symptom improvements with vedolizumab in patients with UC or CD. Methods Study Design The results are based on post hoc exploratory analyses of the phase 3, randomized, placebo-controlled trials GEMINI 1, GEMINI 2, and GEMINI 3. The design of the trials is reported

11 in detail elsewhere 10, 11, 18 and summarized in Figure S1. To summarize, eligible patients were aged 18 to 80 years and had UC for 6 months with a Mayo Clinic Score (MCS) of 6 to 12 points and endoscopic subscore of 2 in GEMINI 1, or had CD for 3 months and a Crohn s disease activity index (CDAI) score of 220 to 450 in GEMINI 2 and 3. Patients were randomized to induction treatment for 6 weeks (GEMINI 1 and 2) or 10 weeks (GEMINI 3) and received 300-mg intravenous vedolizumab or placebo at weeks 0 and 2 (GEMINI 1 and 2) or weeks 0, 2, and 6 (GEMINI 3). These patients are referred to as the induction intent-to-treat (ITT) population and are the focus of these analyses. Disease activity at entry into GEMINI and efficacy assessments throughout the studies were measured by MCS for UC and CDAI for CD. Patient-reported components of MCS were RB and stool frequency (SF) and those of CDAI were AP and loose SF (LSF). Patient-Reported Outcomes Mean percentage changes from baseline in patient-reported subscores were calculated for the overall population, TNF antagonist-naïve, and TNF antagonist-exposed patients at 2, 4, and 6 weeks. Percentages of UC patients who reached RB subscore=0 (elimination of bleeding) and SF subscore 1 (no more than 1 to 2 stools above normal) and of CD patients who achieved average daily composite score of AP 1 and LSF 3 (revised PRO-2 19 ) were determined at each timepoint (weeks 2, 4, and 6). Statistical Analyses The difference in adjusted percentage score change from baseline between vedolizumab and placebo was determined using an analysis of covariance (ANCOVA) model with treatment as a factor and baseline score as a covariate, and study as an additional factor for GEMINI 2 and 3. 95% confidence intervals (CIs) were calculated, and upper limit of 95% CI <0 was considered

12 statistically significant at a nominal significance level of 0.05, unless otherwise indicated. For the pooled GEMINI 2 and 3 analyses, the Cochran-Mantel-Haenszel method with study as a stratum was used to adjust for treatment differences in the proportion of CD patients who achieved average daily composite score of AP 1 and LSF 3. Univariate logistic regression analyses were performed to identify predictors of outcomes at week 2 (composite subscores of RB=0 and SF 1 for UC and AP 1 and LSF 3 for CD). P values 0.05 were considered statistically significant. A multivariate analysis was performed by fitting baseline variables from the univariate analyses with a P value of <0.05 using stepwise backward regression. For CD, study as a factor was included at each step of model building to adjust for potential study differences between GEMINI 2 and 3. Results Patient Baseline Characteristics A total of 374 UC (GEMINI 1) and 784 CD patients (GEMINI 2 and 3) were randomized for induction to receive vedolizumab or placebo, and these constituted the induction ITT population. TNF antagonist-naïve patients constituted 55% (n=206) and 36.5% (n=286) of the UC and CD populations, respectively. No statistical comparisons were made between subpopulations. However, a descriptive summary of baseline characteristics showed a few notable differences within the UC population (Table S1). Disease activity at baseline was similar across treatment groups with median MCS of 8.0 for vedolizumab vs 9.0 for placebo in the overall UC population, 8.0 for both vedolizumab and placebo in the TNF antagonist-naïve, and 9.0 for both vedolizumab and placebo in the TNF antagonist-exposed patients. Median disease duration was shorter in TNF antagonist-naïve (placebo: 3.4 years [y]; vedolizumab: 3.9 y) than TNF antagonist-exposed

13 patients (placebo: 5.3 y; vedolizumab: 5.0 y) (Table S1). In CD, median disease duration was shorter in TNF antagonist-naïve (placebo: 3.6 y; vedolizumab: 4.5 y) than the overall (placebo: 7.1 y; vedolizumab: 7.7 y) and TNF antagonist-exposed populations (placebo: 9.0; vedolizumab: 9.3). (Table S2). Symptom Improvement With Vedolizumab in UC Patients Numerically greater percentage decreases from baseline in RB subscore were observed with vedolizumab treatment than with placebo, reaching statistical significance at weeks 4 and 6 in both overall and TNF antagonist-naïve. No significant differences between vedolizumab and placebo were observed in TNF antagonist-exposed patients (Figure 1 A-C). In the overall population, statistically significant percentage decreases in SF subscore from baseline were observed with vedolizumab than with placebo at weeks 4 and 6 and at all timepoints in TNF antagonist-naïve patients (Figure 1 D, E). No significant differences between vedolizumab and placebo were observed in the TNF antagonist-exposed population (Figure 1 F). Significantly larger percentages of patients achieved a composite score of RB=0 and SF 1 with vedolizumab than placebo at all timepoints in the overall and TNF antagonist-naïve populations (Figure 2 A, B). No significant differences between vedolizumab and placebo were observed in the TNF antagonist-exposed population (Figure 2 C). Symptom Improvement With Vedolizumab in CD Patients Percentage score decrease from baseline was evaluated in the pooled GEMINI 2 and 3 populations. GEMINI 2 was composed of 50% TNF antagonist-naïve patients while GEMINI 3 consisted of predominantly TNF antagonist-failure population (failure: 76%; naïve: 24%) (Table S3). Significantly greater percentage decreases in AP subscore from baseline were observed

14 with vedolizumab than placebo as of week 4 in the overall GEMINI 2 and 3 combined (Figure 3 A). In TNF antagonist-naïve patients, there was a significantly greater decrease in the AP subscore with vedolizumab than placebo as of week 4 (Figure 3B). No significant differences were observed in the TNF antagonist-exposed population (Figure 3C). Greater percentage decreases in LSF were observed with vedolizumab than placebo, reaching statistical significance as of week 2 in all populations (Figure 3 D-F). A combined score, calculated by adding the AP and LSF subscores, showed a similar trend with significantly greater percentage decreases with vedolizumab than placebo at all timepoints in all populations (Figure 4 A-C). Overall, differences in percentage subscore reduction between vedolizumab and placebo were greater in the TNF antagonist-naïve patients than in the overall and TNF antagonistexposed populations. Notably, differences in the percentage decrease from baseline in the AP subscore among the TNF antagonist-naïve patients at week 2 (-7.2), week 4 (-18.7), and week 6 (-17.7) were about 2 times as high as in the overall population (-3.8, -6.4, and -6.9, respectively) (Figure 3 A, B). Significantly larger percentages of patients achieved an average daily composite score of AP 1 and LSF 3 with vedolizumab than placebo at weeks 2 and 4 in the TNF antagonist-naïve group and only at week 4 in the overall population, but not in the TNF antagonist-exposed group (Figure 5). Predictors of Symptomatic Improvement in UC and CD at Week 2 Univariate analyses of UC outcome predictors identified disease severity, baseline partial and complete MCS, and baseline SF subscore as significant variables (P 0.05) for achieving the composite score of RB subscore=0 and SF subscore 1 (Table S4). In multivariate analyses,

15 baseline complete MCS remained significant and lower baseline MCS was associated with achieving RB subscore=0 and SF subscore 1 (Table S6). In CD, univariate analyses of outcome predictors identified male sex, CD duration of <2 or <5 years, no prior bowel surgery, no previous exposure or failure to TNF antagonists, corticosteroid use, lower baseline CDAI, HBI, and LSF scores as significant predictors for achieving the composite score of AP 1 and LSF 3 (Table S5). A multivariate analysis confirmed a CD duration of <5 years, corticosteroid use, and lower baseline CDAI score as significant predictors of week 2 outcome (Table S6).

16 Discussion These exploratory, post hoc analyses indicated that vedolizumab was effective at reducing patient-reported symptoms as of week 2 in patients with UC or CD, with continued improvement throughout the first 6 weeks of treatment. More specifically, 40.8% of TNF antagonist-naïve UC patients achieved both elimination of RB (RB subscore=0) and reduction in SF (SF subscore 1) at week 6 with vedolizumab compared with 13.2% with placebo. In CD, greater percentage decreases from baseline in combined AP and LSF score were observed with vedolizumab (32.0%) than placebo (16.0%) in the TNF antagonist-naïve patients after 6 weeks. The efficacy of vedolizumab for inducing response and remission was demonstrated in the GEMINI trials, whereby clinical benefits were more likely to be achieved at week 6 in patients treated with vedolizumab than those assigned to placebo. The rapid onset of vedolizumab s action reported here suggests that symptomatic improvements may precede observed benefits by objective measures of disease activity. To assist with clinical interpretation of these data, we explored changes in complete MCS and CDAI that corresponded with the percentage change from baseline in the individual symptomatic improvements. At week 6, the change in RB subscore (overall: ~50%; TNF antagonist-naïve: ~60%) and SF subscore (overall: 25%; TNF antagonist-naïve: ~37%) were associated with an approximate reduction of and points in complete MCS in the overall and TNF antagonist-naïve GEMINI 1 populations, respectively. In GEMINI 2 and 3, a change in AP subscore of 25.4%% and LSF subscore of 25.2% corresponded to an approximate 80-point reduction in CDAI score in the overall population. In TNF antagonist-naïve populations, changes of 32.8% and 30.9% in AP and LSF subscores, respectively, corresponded to an approximate 98.6-point reduction in CDAI score.

17 Although there is no published evidence to establish a correlation between early patientreported symptomatic improvement and long-term treatment benefits, several studies have demonstrated that PROs are responsive to treatment effects. Specifically, in a post hoc analysis of two independent studies in UC, the combination score of RB=0 and SF 1 (defined as PRO2) was able to differentiate a treatment effect between active drug and placebo and was significantly associated, alone or in combination with endoscopy, with clinical response. 5 In addition, symptom scores generally correlated well with endoscopic scores in UC, but some patients still exhibited persistent symptoms even after endoscopic healing. 16 Similarly in CD, 2- or 3-item PROs consisting of SF and RB, or SF, RB, and general well-being, respectively, were responsive to change in disease activity and indicated similar treatment effects as CDAI-based outcomes. 7 On the other hand, in a post hoc analysis of the Study of Biologic and Immunomodulator Naïve Patients in CD (SONIC) trial, clinical symptoms as scored by CDAI did not correlate with objective measures of inflammation such as mucosal lesions and CRP levels 20, highlighting the need to further assess the relationship between symptoms and disease activity, particularly in CD. In a real-world setting, symptom-based clinical response to vedolizumab at week 4 was found to be an independent predictor of long-term mucosal healing (up to 12 months) for UC and CD. 21 In general, reductions from baseline in symptom scores with vedolizumab versus placebo were observed in the overall ITT UC or CD population, but were greater in TNF antagonist-naïve patients. These observations are consistent with published clinical trial and real-world data supporting the efficacy of vedolizumab in TNF antagonist-naïve patients at week 6 and beyond. In a post hoc analysis of GEMINI 1 and GEMINI 2 data, TNF antagonist-naïve vedolizumabtreated UC and CD patients had greater differences versus placebo at week 6 than patients who

18 had previous TNF antagonist failure, specifically in clinical response and remission in UC and CD and mucosal healing in UC. 13, 18 A German real-world study observed that vedolizumab was significantly more effective at inducing clinical remission (partial MCS 1 with RB=0) at week 54 in TNF-naïve than in TNF-exposed patients with UC (55% vs 18%, P=0.02). 22 A network metaanalysis of 5 studies provides further evidence for the benefits of vedolizumab maintenance therapy over other biologics among TNF antagonist-naïve UC patients 23, including significantly greater odds for achieving durable clinical response, clinical remission, and mucosal healing. Specifically, vedolizumab was associated with higher odds of achieving durable clinical response than adalimumab (OR: 3.96; 95% credible interval [CrI]: ), infliximab (IFX) (OR: 3.18; 95% CrI: ), and golimumab (OR: 2.33; 95% CrI: ). Data from the VICTORY consortium, the largest cohort of IBD patients on vedolizumab in a real-world clinical setting, reported a reduction in vedolizumab effectiveness when used after TNF antagonists, with an incremental reduction in effectiveness based on the number of prior TNF antagonists used. Vedolizumab s benefits on corticosteroid use and IBD-related hospitalization in TNF antagonistnaïve patients were also demonstrated in a real-world setting. 25 Overall, our results in addition to published evidence indicate that vedolizumab could be considered as a viable first-line biologic option for UC and CD patients who are TNF antagonist treatment naïve. Previous studies have evaluated the predictors of response to vedolizumab at later time points (54 weeks and beyond) 14, 26 ; however, this is the first evaluation of predictors of early symptomatic response. In fact, multivariate regression analyses in this study indicated that baseline disease activity (MCS and CDAI scores in UC and CD patients, respectively) was a 14, 24 significant predictor of symptomatic improvements at week 2. In addition, CD duration and CS use were significant predictors of CD outcome.

19 Overall, our observations here are inconsistent with the current notion that anti-integrin therapies have a relatively slow onset of action. In fact, etrolizumab, an anti-integrin therapy still in development, has recently been shown induce symptom improvement as of week 4 in a phase 3 study in UC. 27 Our study demonstrated early symptomatic improvement with vedolizumab, achieved as of week 2, particularly in patients naïve to anti-tnf therapies, and thus has important implications on the optimal positioning of vedolizumab in treatment algorithms. However, for patients who show a modest initial improvement, continued treatment and assessment through week 14 is recommended. 28

20 Figure legends Figure 1. Rectal bleeding and stool frequency subscores in patients with UC. a Adjusted % change from BL mean, where adjustment is for BL subscore and treatment b Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. BL, baseline; CI, confidence interval; ITT, intent-to-treat; PBO, placebo; RBS, rectal bleeding subscore; SE, standard error; SFS, stool frequency subscore; TNF, tumor necrosis factor alpha; UC, ulcerative colitis; VDZ, vedolizumab. Figure 2. Proportion of patients with UC who achieved the composite score RBS=0 and SFS 1. a Lower 95% CI limits >0 indicate statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. CI, confidence interval; PBO, placebo; RBS, rectal bleeding subscore; SFS, stool frequency subscore; TNF, tumor necrosis factor alpha; UC, ulcerative colitis; VDZ, vedolizumab. Figure 3. Abdominal pain and loose stool frequency subscores in patients with CD. a Adjusted % change from BL mean, where adjustment is for BL subscore and treatment. b Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. APS, abdominal pain subscore; BL, baseline; CD, Crohn s disease; CI, confidence interval; ITT, intent-to-treat; LSFS, loose stool frequency subscore; PBO, placebo; SE, standard error; tumor necrosis factor alpha; VDZ, vedolizumab. Figure 4: Combined score of abdominal pain and loose stool frequency in patients with CD. a Adjusted % change from BL mean, where adjustment is for BL subscore and treatment. b Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. APS, abdominal pain subscore; BL, baseline; CD, Crohn s disease; CI, confidence interval; LSFS, loose stool frequency subscore; PBO, placebo; SE, standard error; TNF, tumor necrosis factor alpha; VDZ, vedolizumab.

21 Figure 5. Proportion of patients with CD (GEMINI 2 and 3) who achieved the average daily composite score of AP 1 and LSF 3. a Lower 95% CI limits >0 indicate statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. APS, abdominal pain subscore; CD, Crohn s disease; CI, confidence interval; LSFS, loose stool frequency subscore; PBO, placebo; TNF, tumor necrosis factor alpha; VDZ, vedolizumab.

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29 Feagan et al. 1 Supplemental material Detailed figure legend Figure 1. Rectal bleeding and stool frequency subscores in patients with UC. Percentage change from baseline in RB subscore in the overall ITT (A), TNF antagonist-naïve (B), and TNF antagonist-exposed (C) populations and in SF subscore in the overall ITT (D), TNF antagonist-naïve (E), and TNF antagonist-exposed (F) populations after vedolizumab or placebo administration. a Data points represent adjusted % change from BL mean, where adjustment is for subscore BL value and treatment. Error bars represent standard error. b Difference adjusted % change [VDZ - PBO]=adjusted mean % change from BL for VDZ adjusted mean % change from BL for PBO. Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS nonsignificance. Patients with baseline RBS=0 or SFS=0 were excluded from this analysis. Of note, the number of patients varies per study population at weeks 2, 4, and 6 and is reported below the x-axis. BL, baseline; CI, confidence interval; ITT, intent-to-treat; PBO, placebo; RBS, rectal bleeding subscore; SFS, stool frequency subscore; TNF, tumor necrosis factor alpha; UC, ulcerative colitis; VDZ, vedolizumab. Figure 2. Proportion of patients with UC who achieved the composite score RBS=0 and SFS 1 in the overall ITT (A), TNF antagonistnaïve (B), and TNF antagonist-exposed (C) populations. a Difference adjusted % change [VDZ PBO]=% of VDZ patients who achieved the indicated subscore % of PBO patients who achieved the indicated subscore. Lower 95% CI limits >0 indicate statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. CI, confidence interval; PBO, placebo; RBS, rectal bleeding subscore; SFS, stool frequency subscore; TNF, tumor necrosis factor alpha; UC, ulcerative colitis; VDZ, vedolizumab. 1

30 Feagan et al. 2 Figure 3. Abdominal pain subscores in patients with CD. Percentage change from baseline in AP subscore in overall ITT (A), TNF antagonistnaïve (B), and TNF antagonist-exposed (C) populations and percentage change from baseline in LSF subscore in overall ITT (D), TNF antagonistnaïve (E), and TNF antagonist-exposed (F) populations after vedolizumab or placebo administration. a Data points represent adjusted % change from BL mean, where adjustment is for subscore BL value and treatment. Error bars represent standard error. b Difference adjusted % change [VDZ PBO]=% =adjusted mean % change from BL for VDZ adjusted mean % change from BL for PBO. Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS nonsignificance. Patients with baseline APS=0 or LSFS=0 were excluded from this analysis. APS, abdominal pain subscore; BL, baseline; CD, Crohn s disease; CI, confidence interval; ITT, intent-to-treat; LSFS, loose stool frequency subscore; PBO, placebo; SE, standard error; tumor necrosis factor alpha; VDZ, vedolizumab. Figure 4: Combined score of abdominal pain and loose stool frequency in patients with CD. Percentage change from baseline in AP and LSF subscores in the overall ITT (A), TNF antagonist-naïve (B), and TNF antagonist-exposed (C) populations after vedolizumab or placebo administration. a Data points represent adjusted % change from BL mean, where adjustment is for subscore BL value and treatment. Error bars represent standard error. b Difference adjusted % change [VDZ PBO]=adjusted mean % change from BL for VDZ adjusted mean % change from BL for PBO. Upper limit of 95% CI <0 indicates statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS nonsignificance. Patients with baseline APS=0 and LSFS=0 were excluded from this analysis. APS, abdominal pain subscore; BL, baseline; CD, Crohn s disease; CI, confidence interval; LSFS, loose stool frequency subscore; PBO, placebo; SE, standard error; TNF, tumor necrosis factor alpha; VDZ, vedolizumab. 2

31 Feagan et al. 3 Figure 5. Proportion of patients with CD (GEMINI 2 and 3) who achieved the average daily composite score of AP 1 and LSF 3 in the overall ITT (A), TNF antagonist-naïve (B), and TNF antagonist-exposed (C) populations. a Difference adjusted % change [VDZ PBO]=% of VDZ patients who achieved the indicated subscore % of PBO patients who achieved the indicated subscore. Lower 95% CI limits >0 indicate statistical significance at a nominal significance level of Asterisk (*) indicates statistical significance and NS non-significance. APS, abdominal pain subscore; CD, Crohn s disease; CI, confidence interval; LSFS, loose stool frequency subscore; PBO, placebo; TNF, tumor necrosis factor alpha; VDZ, vedolizumab. 3

32 Feagan et al. 4 Tables Table S1. Baseline Characteristics of Patients With UC Characteristic Age (years), median (min, max) Placebo n=149 Overall TNF antagonist-naïve a TNF antagonist-exposed Vedolizumab n= (19, 76) 39.4 (18, 73) Placebo n=76 Vedolizumab n= (19, 65) 38.9 (18, 73) Placebo n=73 Vedolizumab n= (19, 76) 40.4 (19, 73) Sex (male), n (%) 92 (62) 132 (59) 47 (62) 69 (53) 45 (62) 63 (66) Weight (kg), median (min, max) 71.1 (40, 125) 72.0 (33, 118) 70.9 (40, 125) 67.4 (33, 118) 71.8 (47, 111) 77.3 (38, 113) Current smoker, n (%) 11 (7) 12 (5) 7 (9) 7 (5) 4 (5) 5 (5) Duration of disease (years), median (min, max) 4.5 (0.5, 38.5) 4.6 (0.5, 25.8) 3.4 (0.5, 37.4) 3.9 (0.5, 25.8) 5.3 (0.7, 38.5) 5.0 (0.5, 21.6) Complete Mayo Clinic Score, median (min, max) 8.0 (3, 12) 9.0 (5, 12) 8.0 (4, 12) 8.0 (5, 12) 9.0 (3, 12) 9.0 (5, 12) Disease localization b, n (%) Proctosigmoiditis 22 (15) 25 (11) 10 (13) 14 (11) 12 (16) 11 (12) Left-sided colitis 59 (40) 92 (41) 35 (46) 66 (51) 24 (33) 26 (27) Extensive colitis 18 (12) 25 (11) 7 (9) 14 (11) 11 (15) 11 (12) Pancolitis 50 (34) 83 (37) 24 (32) 36 (28) 26 (36) 47 (49) History of EIMs, n (%) 44 (30) 74 (33) N/A N/A N/A N/A EIMs, n (%) N/A N/A 17 (22) 39 (30) 27 (37) 35 (37) Concomitant medications (yes), n (%) CS only 58 (39) 79 (35) 28 (37) 42 (32) 30 (41) 37 (39) IMM only 18 (12) 28 (12) 10 (13) 24 (18) 8 (11) 4 (4) 4

33 Feagan et al. 5 CS and IMM 26 (17) 47 (21) 16 (21) 31 (24) 10 (14) 16 (17) No CS and IMM 47 (32) 71 (32) 22 (29) 33 (25) 25 (34) 38 (40) Type of TNF antagonist failure, n (%) c 1 Failure 63 (42) 82 (36) N/A N/A 58 (82) 80 (84) Inadequate response d 29 (46) 44 (54) N/A N/A 26 (45) 43 (54) Loss of response e 26 (41) 32 (39) N/A N/A 24 (41) 32 (40) Intolerance f 8 (13) 6 (7) N/A N/A 8 (14) 5 (6) CRF, case report form; CS, corticosteroid; EIM, extraintestinal manifestation; IMM, immunomodulator; IVRS, interactive voice response system; N/A, not applicable (or not available for EIMs); TNF, tumor necrosis factor alpha; UC, ulcerative colitis. a TNF antagonist exposure status was derived from data captured on the IVRS at screening and enrollment. b Disease localization was reported by the investigator per CRF options of proctosigmoiditis, left-sided colitis, extensive colitis, or pancolitis. c Prior TNF antagonist failure was defined by data recorded on the CRF at week 0. Each patient was counted only once according to his or her worst outcome. Inadequate response was considered worse than lost response; lost response was considered worse than intolerance. d Included in this category were patients who did not have an initial response. e Loss of response indicates that the patient had a response initially but subsequently did not have a response. f Intolerance is defined as occurrence of treatment-related toxicity. 5

34 Feagan et al. 6 Table S2. Baseline Characteristics of Patients With CD (GEMINI 2 and 3) Characteristics Overall TNF antagonist-naïve a TNF antagonist-exposed Placebo Vedolizumab Placebo Vedolizumab Placebo Vedolizumab n=355 n=429 Age (years), median (min, max) 35.8 (19, 77) 36.0 (18, 77) 34.0 (19, 75) 34.2 (18, 66) 36.5 (19, 77) 36.9 (19, 77) Sex (male), n (%) 158 (45) 196 (46) 66 (52) 82 (51) 92 (40) 114 (42) Weight (kg), median (min, max) 66.0 (32, 147) 66.0 (30, 167) 67.0 (32, 147) 63.0 (30, 167) 65.4 (37, 128) 68.0 (40, 144) Current smoker, n (%) 92 (26) 119 (28) 29 (23) 47 (29) 63 (28) 72 (27) Disease duration (years), median (min, max) 7.1 (0.3, 42.9) 7.7 (0.3, 43.6) 3.6 (0.3, 29.2) 4.5 (0.3, 43.6) 9.0 (0.6, 42.9) 9.3 (0.5, 42.8) Disease localization, n (%) Ileum only 50 (14) 70 (16) 23 (18) 35 (22) 27 (12) 35 (13) Colon only 95 (27) 110 (26) 40 (32) 40 (25) 55 (24) 70 (26) Ileum and colon 210 (59) 249 (58) 63 (50) 85 (53) 147 (64) 164 (61) CDAI score, median (min, max) (155, 584) (132, 524) n= (155, 584) n= (132, 500) n= (166, 564) n= (142, 524) Prior surgery for CD, n (%) 143 (40) 190 (44) 25 (20) 58 (36) 118 (52) 132 (49) History of fistulizing disease, n (%) 133 (37) 161 (38) 26 (21) 55 (34) 107 (47) 106 (39) Draining fistulae, n (%) 48 (14) 63 (15) 18 (14) 26 (16) 30 (13) 37 (14) History of EIMs, n (%) 297 (84) 343 (80) 92 (73) 118 (74) 205 (90) 225 (84) EIMs, n (%) 237 (67) 249 (58) 77 (61) 98 (61) 160 (70) 151 (56) Concomitant medications, n (%) CS only 117 (33) 140 (33) 32 (25) 43 (27) 85 (37) 97 (36) IMM only 58 (16) 71 (17) 28 (22) 32 (20) 30 (13) 39 (14) CS and IMM 62 (17) 75 (17) 28 (22) 35 (22) 34 (15) 40 (15) No CS and IMM 118 (33) 143 (33) 38 (30) 50 (31) 80 (35) 93 (35) 6

35 Feagan et al. 7 Type of TNF antagonist failure, n (%) b 1 Failure 226 (64) 260 (61) N/A N/A 221 (97) 254 (95) Inadequate response c 110 (49) 122 (47) N/A N/A 106 (48) 117 (46) Loss of response d 91 (40) 111 (43) N/A N/A 91 (41) 110 (43) Intolerance e 25 (11) 27 (10) N/A N/A 24 (11) 27 (11) CD, Crohn s disease; CDAI, Crohn s disease activity index; CRF, case report form; CS, corticosteroid; EIM, extraintestinal manifestation; IMM, immunomodulator; IVRS, interactive voice response system; N/A, not applicable; TNF, tumor necrosis factor alpha. a TNF antagonist-naïve patients were classified by data captured on the IVRS at screening and enrollment. b Prior TNF antagonist failure was defined by data recorded on the CRF at week 0. Each patient was counted only once according to his or her worst outcome. Inadequate response was considered worse than lost response; lost response was considered worse than intolerance. c Included in this category were patients who did not have an initial response. d Loss of response indicates that the patient had a response initially but subsequently did not have a response. e Intolerance is defined as occurrence of treatment-related toxicity. 7

36 Feagan et al. 8 Table S3. Baseline Characteristics of Patients With CD Characteristics Overall (GEMINI 2) Overall (GEMINI 2 and 3) Placebo Vedolizumab Placebo Vedolizumab n=148 n=220 n=355 n=429 Age (years), median (min, max) 36.7 (19, 75) 34.8 (18, 77) 35.8 (19, 77) 36.0 (18, 77) Sex (male), n (%) 69 (47) 105 (48) 158 (45) 196 (46) Weight (kg), median (min, max) 66.0 (32, 130) 65.2 (30, 167) 66.0 (32, 147) 66.0 (30, 167) Current smoker, n (%) 34 (23) 54 (25) 92 (26) 119 (28) Disease duration (years), median (min, max) 6.1 (0.3, 42.0) 7.1 (0.5, 43.6) 7.1 (0.3, 42.9) 7.7 (0.3, 43.6) Disease localization, n (%) Ileum only 21 (14) 37 (17) 50 (14) 70 (16) Colon only 43 (29) 62 (28) 95 (27) 110 (26) Ileum and colon 84 (57) 121 (55) 210 (59) 249 (58) CDAI score, median (min, max) (155, 584) (132, 500) (155, 584) (132, 524) Prior surgery for CD, n (%) 54 (36) 98 (45) 143 (40) 190 (44) History of fistulizing disease, n (%) 56 (38) 90 (41) 133 (37) 161 (38) Draining fistulae, n (%) 23 (16) 38 (17) 48 (14) 63 (15) History of EIMs, n (%) 123 (83) 177 (80) 297 (84) 343 (80) EIMs, n (%) 107 (72) 133 (60) 237 (67) 249 (58) Concomitant medications, n (%) CS only 45 (30) 67 (30) 117 (33) 140 (33) IMM only 25 (17) 37 (17) 58 (16) 71 (17) CS and IMM 26 (18) 38 (17) 62 (17) 75 (17) No CS and IMM 52 (35) 78 (35) 118 (33) 143 (33) Type of TNF antagonist failure, n (%) a 8

37 Feagan et al. 9 1 Failure 70 (47) 105 (48) 226 (64) 260 (61) Inadequate response b 41 (59) 56 (53) 110 (49) 122 (47) Loss of response c 22 (31) 40 (38) 91 (40) 111 (43) Intolerance d 7 (10) 9 (9) 25 (11) 27 (10) CD, Crohn s disease; CDAI, Crohn s disease activity index; CRF, case report form; CS, corticosteroid; EIM, extraintestinal manifestation; IMM, immunomodulator; IVRS, interactive voice response system; N/A, not applicable; TNF, tumor necrosis factor alpha. a Prior TNF antagonist failure was defined by data recorded on the CRF at week 0. Each patient was counted only once according to his or her worst outcome. Inadequate response was considered worse than lost response; lost response was considered worse than intolerance. b Included in this category were patients who did not have an initial response. c Loss of response indicates that the patient had a response initially but subsequently did not have a response. d Intolerance is defined as occurrence of treatment-related toxicity. 9

38 Table S4. Predictors of Week 2 Outcomes in UC RBS=0 AND SFS 1 Variable OR estimates a P value Age (at first dose) Sex (female vs male) Smoker (current/previous smoker vs non-smoker) UC duration UC duration ( 2 y vs <2 y) UC duration ( 5 y vs <5 y) Prior hospitalization (no vs yes) EIM (no vs yes) Disease severity based on Complete Mayo Clinic Score (<10 vs 10) * Previous bowel surgery (no vs yes) < Previous TNF antagonist exposure (no vs yes) TNF antagonist failure (no vs yes) CS (no vs yes) IMM (no vs yes) Baseline fecal calprotectin Baseline Partial Mayo Clinic Score <0.0001* Baseline Complete Mayo Clinic Score <0.0001* Baseline albumin BMI Race (non-white vs white) Ethnicity (other vs non-hispanic/latino) b Region (Rest of world vs N America) c Baseline endoscopy (moderate vs severe) Baseline stool frequency 1 vs Baseline stool frequency 2 vs Baseline stool frequency 3 vs <0.0001* Baseline rectal bleeding 1 vs Baseline rectal bleeding 2 vs Baseline rectal bleeding 3 vs 0 < Baseline stool frequency (non-severe vs severe) <0.0001* Baseline rectal bleeding (non-severe vs severe) Non-Est Pancolitis Left-sided colitis Extensive colitis Proctosigmoiditis BMI, body mass index; CS, corticosteroid; IMM, immunomodulator; EIM, extraintestinal manifestation; Non-Est, non-estimated; OR, odds ratio; RBS, rectal bleeding score; SFS, stool frequency score; TNF, tumor necrosis factor alpha; UC, ulcerative colitis. a OR estimates are based on a logistic regression model with achieving RBS=0 or SFS 1 or both as the response variable. b Other race includes American Indian or Alaskan Native, Asian, Black, and Native Hawaiian or Other Pacific Islander. c Rest of world includes Western/Northern Europe, Central Europe, Eastern Europe, and Africa/Asia/Australia. *P value 0.05 is considered statistically significant. 10