BACKGROUND:This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) versus ustekinumab (UST) in patients with moderate to severe Crohn's disease (CD) with prior inadequate response or intolerance to ≥ 1 anti-tumor necrosis factor (TNF) therapy. METHODS:SEQUENCE (NCT04524611) was an open-label, multicenter, randomized, efficacy assessment-blinded study. Patients were randomized 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, then a subcutaneous [SC] 360 mg maintenance dose every 8 weeks [Q8w] starting at week 12) or UST (single weight-based IV induction dose, then a SC 90 mg maintenance dose Q8w starting at week 8) up to week 48. Patients tapered corticosteroids beginning at week 2. Achievement of clinical, endoscopic, and quality of life outcomes without concomitant use of steroids ("corticosteroid-free") and safety were assessed. RESULTS:In patients taking corticosteroids at baseline, response rate differences by the week 24 and 48 timepoints with RZB versus UST were 10.5% and 25.4% (P ≤ .01) for corticosteroid-free clinical remission per CD activity index and 20.4% (P ≤ .001) and 29.2% (P ≤ .01) per stool frequency/abdominal pain score, and 23.0% and 20.2% (both P ≤ .01) for corticosteroid-free endoscopic remission. Similar results were also observed for additional corticosteroid-free endpoints, including endoscopic, composite (clinical + endoscopic), and quality of life outcomes. Numerically higher exposure-adjusted event rates of serious infections and hypersensitivity with RZB and UST were observed with corticosteroid use. CONCLUSION:In patients with CD refractory to anti-TNF therapy, higher rates of corticosteroid-free clinical, endoscopic, and quality of life outcomes were achieved with RZB versus UST. Both treatments were well-tolerated. CLINICAL TRIAL REGISTRATION NUMBER:NCT04524611.

Abstract Background Corticosteroid (CS) dependency and/or resistance occurs in approximately 50% of patients with Crohn’s disease (CD).1 In SEQUENCE, risankizumab (RZB; interleukin [IL]-23 inhibitor) demonstrated superiority over ustekinumab (UST; IL-12/IL-23 inhibitor) for the ranked secondary endpoints of CS-free clinical remission and CS-free endoscopic remission at week 48. In this post hoc analysis, we evaluate the CS-sparing effects of RZB and UST over 48 weeks in patients taking CS at baseline (BL). Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study in adults with moderately to severely active CD who previously failed ≥ 1 anti-tumor necrosis factor (TNF) therapy. Patients in the primary efficacy analysis were randomised 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, followed by a subcutaneous [SC] 360 mg maintenance dose every 8 weeks starting at week 12) or UST (single weight-based IV induction dose, followed by a SC 90 mg maintenance dose every 8 weeks starting at week 8) up to week 48. A mandatory CS taper started at week 2. CS-free outcomes (clinical remission or endoscopic remission and no CS at the assessed visit) were evaluated among patients taking CS at BL. Nominal P values were reported. Results The primary efficacy analysis included 520 patients (RZB, n = 255; UST, n = 265), and 24.8% (129/520) of patients were taking CS at BL. Demographics and disease characteristics were generally similar between treatment groups and between patients with and without CS use at BL. The mean (SD) daily prednisone-equivalent dose at BL was 21.4 (12.9) mg (RZB) and 19.5 (10.7) mg (UST), respectively. By week 8, more patients treated with RZB vs UST discontinued CS (75.9% vs 59.2%; nominal P < .05). Although a similar proportion of patients in either treatment group discontinued CS at week 24, more patients treated with RZB vs UST discontinued CS at week 48 (86.2% vs 57.7%; nominal P < .001). Of the patients taking CS at BL, RZB vs UST treatment resulted in higher rates of CS-free clinical remission (week 24: RZB, 44.8% vs UST, 33.8%; week 48: RZB, 56.9% vs UST, 31.0%) and CS-free endoscopic remission (week 24: RZB, 34.5% vs UST, 11.3%; week 48: RZB, 32.8% vs UST, 12.7%) (Table 1). Most patients who achieved CS-free outcomes at week 48 were CS-free for 90 days before week 48. Conclusion In patients with CD who previously failed anti-TNF therapy, RZB was more effective than UST for discontinuing CS use and achieving CS-free clinical and endoscopic remission. References: 1. Lichtenstein G., et al. Am J Gastroenterol. 2018;113:481−517

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI < 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

Due to exacerbated inflammation and recurring tissue injury patients with Inflammatory Bowel Disease (IBD) are at higher risk of developing colorectal cancer (CRC). Although, PMN infiltration of the intestinal mucosa is a hallmark of IBD, and is associated with tissue injury, the contribution of PMNs to CRC and more so to IBD associated CRC is not known. We recently showed that PMNs can acutely exacerbate tissue injury and promote genomic instability by promoting miR-23a and miR-155-dependent accumulation of double-strand breaks (DSBs) and inhibition of DSB-repair by homologous recombination (HR). We now demonstrate that in chronic gut inflammation and recurring epithelial injury, as seen in IBD, via similar miRNA-dependent mechanism, PMNs alter DNA damage responses (DDR) to promote CRC progression. In murine model of Colitis-associated CRC (Azoxymethane, AOM/Dextran sodium sulfate, DSS) and human CRC xenografts, intratumoral PMNs intriguingly, functional dualism, suppressing tumor onset, but promoting tumor cell survival and growth in progressive tumors. The observed PMN effects were mediated by persistent suppression of HR-mediated DSB repair. HR suppression by PMNs, initially resulted in elevated replication stress and increased tumor cell apoptosis, however, longer term, altered DDR transcriptional profile and facilitated the upregulation of DSB repair by non-homologous end-joining (NHEJ). NHEJ upregulation enhanced CRC progression and tumor cell survival. PMN depletion, CRSPER-mediated deletion of miR-155 responsive sequence in RAD51 (preserves HR activity) or inhibition of NHEJ by small molecule inhibitors increased tumor cell death and diminished tumor development. Collectively, our data define a novel link between PMN-mediated mucosal injury and colon carcinogenesis.

To evaluate endoscopic healing in the ustekinumab (UST) induction (UNITI-1&2) & maintenance (IM-UNITI) phase 3 studies. Substudy patients (pts) had colonoscopies at baseline (UNITI Wk0), then 8 & 52 weeks later (IM-UNITI Wk44). Video-endoscopies were centrally read by a single blinded reader for ulcerations & SES-CD. In UNITI, pts received one IV dose (UST 130mg, UST ~6mg/kg, or PBO). Pts with clinical response [CR] (CDAI drop≥100) in UNITI were re-randomized to subcutaneous (SC) PBO or UST 90mg (q12w or q8w) [primary randomized IM-UNITI population]. Non-randomized pts were added to the pooled IM-UNITI population: UST IV non-responders - SC UST 90mg, then SC UST 90mg q8w if in CR 8wks later; PBO IV non-responders - UST IV 130mg, then SC UST 90mg q12w if in CR 8wks later; PBO induction responders - PBO throughout. Pts required SES-CD ≥3 at UNITI Wk0 to be included. Primary outcome: Change in SES-CD at UNITI Wk8 (combined UST vs PBO). IM-UNITI Wk44 efficacy was evaluated for both the IM-UNITI populations. At wk8, UST reduced SES-CD significantly more vs PBO. Results were similar across UST doses, studies, & other endpoints (Table 1a). At IM-UNITI Wk44, in the primary randomized IM-UNITI population trends favoured UST vs PBO maintenance (especially UST 90mg q8w) but small sample sizes (UST n=46; PBO n=24) limited conclusions. In the post-hoc pooled IM-UNITI population (Table 1b), trends supporting UST maintenance were favourable, especially 90mg q8w. The endoscopy substudy primary endpoint was met: One IV UST dose significantly reduced SES-CD vs PBO, as early as Wk8. More pts receiving UST maintenance achieved wk44 endpoints vs PBO. These data support efficacy of UST in inducing & maintaining endoscopic healing in CD. (Table 1a) Week 8 Results from UNITI-1/2 (Table 1a) Week 8 Results from UNITI-1/2 (Table 1b) IM-UNITI Week 44 Results *P ˂0.05 §Primary endpoint 1SES-CD reduction ≥3 from UNITI BL 2SES-CD reduction ≥50% from UNITI BL 3SES-CD ≤2 4No ulcerations (Table 1b) IM-UNITI Week 44 Results *P ˂0.05 §Primary endpoint 1SES-CD reduction ≥3 from UNITI BL 2SES-CD reduction ≥50% from UNITI BL 3SES-CD ≤2 4No ulcerations Janssen Research & Development, LLC

溃疡性结肠炎(ulcerative colitis,UC)是一种消化道炎症性疾病,病变主要位于结直肠.UC好发于青年人,发达国家的人群患病率较高.UC表现为结直肠弥漫性、连续性浅表炎症,以及相应的组织学改变.下消化道内镜或影像检查可以明确诊断.目前尚未发现UC的明确病因,其发病机制与遗传易感个体的结肠内环境变化有关,具有慢性、终身、易复发的病程特点.

Background: Histological remission (HR) has been reported as a positive prognostic indicator of clinical activity in ulcerative colitis (UC). The TOUCHSTONE open-label extension (OLE) is an opportunity to examine the impact of histologic remission on UC activity during a long-term evaluation of efficacy and safety of ozanimod 1 mg. TOUCHSTONE was a randomized, double-blind, placebo-controlled phase 2 trial designed to assess the efficacy and safety of ozanimod 0.5 mg and 1 mg versus placebo during induction and maintenance in patients with moderate to severe UC [1], and established that ozanimod induced and maintained clinical response, clinical remission (CR), endoscopic mucosal healing, and HR through weeks 8 and 32. Methods: A total of 197 patients were randomized (1:1:1) and treated with daily ozanimod at 0.5 mg, 1 mg, or placebo in TOUCHSTONE. Of the initial 197 patients randomized, 170 (86%) entered OLE and received daily ozanimod 1 mg, and 131 (77%) and 105 (62%) completed assessments at weeks 44 and 80. In this analysis, HR was defined as a Geboes score <2 and CR was defined as rectal bleeding score =0 and stool frequency score ≤1. Results: Of the patients who entered OLE, 27% showed histologic remission at the time of OLE entry and 34% were in CR. Clinical remission increased to 62% at OLE week 32, with 62%, and 55% in CR at OLE weeks 44 and 80. At OLE weeks 44 and 80, CR was seen in 83% and 80% of those in HR at OLE entry compared to 55% and 46% of those not in HR at OLE entry. The proportion of patients in CR increased throughout OLE while receiving 1 mg of ozanimod, regardless of prior treatment in the TOUCHSTONE study or HR status at OLE entry. The highest rates of CR were seen in patients in HR at OLE entry who had received ozanimod for 32 weeks prior to OLE entry, with CR rates at OLE weeks 4 and 8, with over 90% in CR. The lowest CR rates were seen in patients naïve to ozanimod and not in HR at OLE entry, with CR increasing from 13% at entry to 50% at OLE week 8, reaching a peak of 56% at OLE week 32. Overall, treatment with ozanimod for 32 to 36 weeks resulted in CR in 80% of patients. Most common adverse events seen in OLE were UC flare, back pain, URTI, anemia, and nasopharyngitis. Transient asymptomatic elevations in ALT or AST >3× ULN were seen in 3% of patients. Conclusions: Histological remission is predictive of CR in patients with UC receiving ozanimod 1 mg in OLE. All patients, whether naïve to or having received ozanimod in TOUCHSTONE, showed additional improvements in CR upon continued treatment with ozanimod 1 mg in OLE. Patients naïve to ozanimod had a rapid improvement in CR over the first 8 weeks of treatment with ozanimod 1 mg in OLE. References: [1] Sandborn WJ, Feagan BG, Wolf DC, et al. (2016), Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med, 1754–62

sex, body mass index, kinds and durations of anti-thrombotic agents, underlying diseases, and mucoprotective agent use. Conclusion: Risk of tentative lower GI bleeding is relatively high in chronic anti-thrombotic agent users. We should pay attention to the risk of lower GI bleeding and need to perform regular blood tests in patients taking anti-thrombotic agents chronically. Am J Gastroenterol 2017; 112:S319–S428; doi:10.1038/ajg.2017.303

Background:Interleukins 12&23 are implicated in the pathophysiology of Crohn's disease (CD). These pro-inflammatory cytokines are blocked by ustekinumab (UST). In a previous Phase 2b study (CERTIFI),1 UST IV induction followed by SC maintenance was shown effective in moderate-severe CD refractory to anti-TNF therapy. This Phase 3 study examined the efficacy and safety of IV UST induction in these patients. Methods:Patients with moderate-severely active CD (CDAI 220–450) who previously failed or were intolerant to at least 1 TNF-antagonist were randomized (1:1:1) at Week (Wk) 0 to a single dose of IV placebo (PBO), UST 130 mg, or weight-based tiered UST dosing approximating 6 mg/kg (260mg [weight ⩽55 kg], 390mg [weight >55 kg and ⩽85 kg], 520mg [weight >85 kg]). The primary endpoint was clinical response at Wk6, defined as reduction from baseline in the CDAI score of >100 points; patients with baseline CDAI score >220 to <248 points were considered in clinical response if a CDAI score of <150 was present. At Wk8, patients either transitioned to the IM-UNITI maintenance study or were followed to Wk20. Results:The 741 randomized patients had a history of TNF-antagonist failure, with baseline median CDAI of 317, CRP of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥2 anti-TNFs with 29.1%, 69.4%, and 36.4% of patients, respectively, satisfying protocol criteria for primary non-response, secondary non-response, or intolerance to at least one TNF antagonist. Statistical significance was demonstrated for the primary and all 4 major secondary endpoints at both IV doses. Clinical response at Wk6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups versus 21.5% in PBO (P = 0.003 and 0.002, respectively). Clinical remission (CDAI <150) at Wk8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group versus 7.3% on PBO (P < 0.001, P = 0.003, respectively). Clinical response at Wk8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups, versus 20.2% on PBO (each P ⩽ 0.001). Proportion of patients with 70pt CDAI response at Wk6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups versus 30.4% in PBO (P = 0.002 and <0.001, respectively) and at the first post-baseline Wk3 visit, 40.6% in ∼6 mg/kg and 38.4% in the 130 mg UST groups versus 27.1% in PBO (P = 0.001 and P = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, IBDQ, CRP, fecal lactoferrin and calprotectin versus IV PBO. Proportions of patients with AEs, SAEs, and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated patients through Wk20. Conclusions:In a population of moderate-severe CD patients refractory to one or more prior TNF-antagonists, IV UST induced clinical response and remission and was well-tolerated throughout induction, confirming the previous positive induction data from the Phase 2b CERTIFI study.

Introduction In the Ph2b CERTIFI study, a single intravenous (IV) UST induction dose was effective & safe in CD pts previously failing anti-TNFs,1 but efficacy in pts only failing conventional therapy is unknown. We evaluated 2 IV UST induction dose regimens in a CD population not refractory to anti-TNFs. Methods Pts with moderate-severely active CD (CDAI 220–450) who failed conventional therapy but were not refractory to anti-TNFs were randomised to a single dose of IV PBO, UST 130 mg, or weight-based tiered UST dosing ~6 mg/kg. Primary endpoint was clinical response at Wk6 (reduction in CDAI score of ≥100 pts). At Wk8, pts transitioned to IM-UNITI maintenance study or had safety follow-up through Wk20. Results Of 628 pts randomised, median disease duration was 6.4 yrs; baseline (BL) mean CDAI was 303; 39% & 35% were receiving steroids & immunomodulators, respectively at BL; 69% were naïve to anti-TNFs. At Wk6, 55.5% & 51.7% in ~6 mg/kg & 130 mg UST grps were in clinical response vs 28.7% PBO (p < 0.001). At Wk8, 40.2% & 30.6% of pts in ~6 mg/kg & 130 mg UST grps were in clinical remission vs 19.6% PBO (p ≤ 0.009). Both UST doses showed significant improvements vs PBO in CDAI, IBDQ, CRP, & faecal lactoferrin & calprotectin. Proportions of AEs, SAEs, & infections were similar in UST & PBO grps. No malignancies, deaths, opportunistic infections or TB occurred in UST-treated pts. Conclusion IV UST induced clinical response & remission in pts with moderate-severe CD not previously failing anti-TNFs & was well-tolerated through induction. Reference 1 Sandborn WJ, et al. N Engl J Med 2012;367:1519–1528. Disclosure of Interest B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Patent holder; Member Scientific Advisory board, Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; Member, Board of Directors Officer – Robarts Clinical Trials Inc, C. Gasink Shareholder of: Janssen, Employee of: Janssen, Y. Lang Shareholder of: Janssen, Employee of: Janssen, J. Friedman Shareholder of: Janssen, Employee of: Janssen, J. Johanns Shareholder of: Janssen, Employee of: Janssen, L.-L. Gao Shareholder of: Janssen, Employee of: Janssen, B. Sands Grant/research support from: Janssen, Consultant for: Janssen, S. Hanauer Grant/research support from: Janssen, Consultant for: Janssen, Conflict with: Lecturer for Janssen, P. Rutgeerts Grant/research support from: J&J, Merck, UCB, AbbVie, Consultant for: J&J, Merck, UCB, AbbVie, Millenium/Takeda, Genentech/Hoffman LaRoche, Medimmune/AstraZeneca/Amgen, Merck/Serono, Bristol Myers Squibb, Robarts, Tillotts Pharma, Conflict with: Lectures for J&J, Merck, AbbVie, S. Targan Grant/research support from: Cedars-Sinai Medical Centre, Consultant for: Janssen, NuMedii, Inc., Conflict with: Advisory board for the Seaver Foundation; Scientific Advisory Board Member Symbiotix, S. Ghosh Grant/research support from: Abbvie, Conflict with: International Steering Committees: Janssen, Abbvie, Pfizer, Receptos, BMS, Aerpio; Advisory Committees: Takeda, Abbvie, Janssen, Pfizer, Allergan, W. de Villiers Conflict with: member of steering committee, active participant as investigator, J.-F. Colombel Consultant for: Pfizer, Takeda, Protagonist Therapies, Celgene, Genentech, Second Genome, Vertex, Amgen, Merck Sharp Dohme, Janssen, Nestle, AbbVie, Tigenix, Receptos, Conflict with: Speaker for AbbVie, Ferring, Shire, Takeda, Z. Tulassay: None Declared, U. Seidler Conflict with: Local continuing medical education seminars for MSD, W. Sandborn Grant/research support from: Receptos, Exact Sciences, Amgen, the American College of Gastroenterology, Broad Foundation, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners, Conflict with: Personal fees from Receptos, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, Nutrition Science Partners, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and the University of Western Ontario (owner of Robarts Clinical Trials); non-financial support from Receptos

Introduction In the Ph2b CERTIFI study, a single intravenous (IV) UST induction dose was effective & safe in CD pts previously failing anti-TNFs,1 but efficacy in pts only failing conventional therapy is unknown. We evaluated 2 IV UST induction dose regimens in a CD population not refractory to anti-TNFs. Methods Pts with moderate-severely active CD (CDAI 220–450) who failed conventional therapy but were not refractory to anti-TNFs were randomised to a single dose of IV PBO, UST 130 mg, or weight-based tiered UST dosing ~6 mg/kg. Primary endpoint was clinical response at Wk6 (reduction in CDAI score of ≥100 pts). At Wk8, pts transitioned to IM-UNITI maintenance study or had safety follow-up through Wk20. Results Of 628 pts randomised, median disease duration was 6.4 yrs; baseline (BL) mean CDAI was 303; 39% & 35% were receiving steroids & immunomodulators, respectively at BL; 69% were naïve to anti-TNFs. At Wk6, 55.5% & 51.7% in ~6 mg/kg & 130 mg UST grps were in clinical response vs 28.7% PBO (p < 0.001). At Wk8, 40.2% & 30.6% of pts in ~6 mg/kg & 130 mg UST grps were in clinical remission vs 19.6% PBO (p ≤ 0.009). Both UST doses showed significant improvements vs PBO in CDAI, IBDQ, CRP, & faecal lactoferrin & calprotectin. Proportions of AEs, SAEs, & infections were similar in UST & PBO grps. No malignancies, deaths, opportunistic infections or TB occurred in UST-treated pts.Abstract OC-007 Table 1 PBO(n = 209) UST 130 mg(n = 209) UST ~6 mg/kgcc (n = 209) Clinical Responsea Wk 3 45 (21.5) 68 (32.5)p = 0.010 81 (38.8)p < 0.001 *Wk 6 60 (28.7) 108 (51.7)Delta =23%p < 0.001 116 (55.5)Delta =26.8%p < 0.001 Wk 8 67 (32.1) 99 (47.4)p < 0.001 121 (57.9)p < 0.001 Clinical Remissionb Wk 3 24 (11.5) 33 (15.8)p = 0.199 48 (23.0)p = 0.002 Wk 6 37 (17.7) 60 (28.7)p = 0.007 73 (34.9)p < 0.001 Wk 8 41 (19.6) 64 (30.6)Delta =11.0%p = 0.009 84 (40.2)Delta =20.6%p < 0.001 N (%); a ≥ 100 pt reduction in CDAI; bCDAI <150; cweight-range based UST doses ~6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 kg and ≤85 kg), 520 mg (weight >85 kg); *primary endpoint Conclusion IV UST induced clinical response & remission in pts with moderate-severe CD not previously failing anti-TNFs & was well-tolerated through induction. Reference 1 Sandborn WJ, et al. N Engl J Med 2012;367:1519–1528. Disclosure of Interest B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Patent holder; Member Scientific Advisory board, Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; Member, Board of Directors Officer – Robarts Clinical Trials Inc, C. Gasink Shareholder of: Janssen, Employee of: Janssen, Y. Lang Shareholder of: Janssen, Employee of: Janssen, J. Friedman Shareholder of: Janssen, Employee of: Janssen, J. Johanns Shareholder of: Janssen, Employee of: Janssen, L.-L. Gao Shareholder of: Janssen, Employee of: Janssen, B. Sands Grant/research support from: Janssen, Consultant for: Janssen, S. Hanauer Grant/research support from: Janssen, Consultant for: Janssen, Conflict with: Lecturer for Janssen, P. Rutgeerts Grant/research support from: J&J, Merck, UCB, AbbVie, Consultant for: J&J, Merck, UCB, AbbVie, Millenium/Takeda, Genentech/Hoffman LaRoche, Medimmune/AstraZeneca/Amgen, Merck/Serono, Bristol Myers Squibb, Robarts, Tillotts Pharma, Conflict with: Lectures for J&J, Merck, AbbVie, S. Targan Grant/research support from: Cedars-Sinai Medical Centre, Consultant for: Janssen, NuMedii, Inc., Conflict with: Advisory board for the Seaver Foundation; Scientific Advisory Board Member Symbiotix, S. Ghosh Grant/research support from: Abbvie, Conflict with: International Steering Committees: Janssen, Abbvie, Pfizer, Receptos, BMS, Aerpio; Advisory Committees: Takeda, Abbvie, Janssen, Pfizer, Allergan, W. de Villiers Conflict with: member of steering committee, active participant as investigator, J.-F. Colombel Consultant for: Pfizer, Takeda, Protagonist Therapies, Celgene, Genentech, Second Genome, Vertex, Amgen, Merck Sharp Dohme, Janssen, Nestle, AbbVie, Tigenix, Receptos, Conflict with: Speaker for AbbVie, Ferring, Shire, Takeda, Z. Tulassay: None Declared, U. Seidler Conflict with: Local continuing medical education seminars for MSD, W. Sandborn Grant/research support from: Receptos, Exact Sciences, Amgen, the American College of Gastroenterology, Broad Foundation, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners, Conflict with: Personal fees from Receptos, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, Nutrition Science Partners, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and the University of Western Ontario (owner of Robarts Clinical Trials); non-financial support from Receptos

legend N2D N1D 2LPEG N2D vs. 2LPEG N1D vs. 2LPEG EFFICACY Primary analysis set, n1⁄4 275 Primary analysis set, n1⁄4 275 Primary analysis set, n1⁄4 272 Primary endpoint: Patients with successful overall bowel cleansing efficacy (HCS) [n] 253 (92.0%) 245 (89.1%) 238 (87.5%) -4.00%* [0.055] -6.91%* [0.328] Supportive secondary endpoint: Patients with successful overall bowel cleansing efficacy (BBPS) [n] 249 (90.5%) 243 (88.4%) 232 (85.3%) n.a. n.a. Primary endpoint: Excellent plus Good cleansing rate in colon ascendens (primary analysis set) [n] 87 (31.6%) 93 (33.8%) 41 (15.1%) 8.11%* [50.001] 10.32%* [50.001] Key secondary endpoint: Adenoma detection rate, colon ascendens 11.6% 11.6% 8.1% -4.80%; 12.00%** [0.106] -4.80%; 12.00%** [0.106] Key secondary endpoint: Adenoma detection rate, overall colon 26.6% 27.6% 26.8% -8.47%; 8.02%** [0.569] -7.65%; 9.11%** [0.455] Key secondary endpoint: Polyp detection rate, colon ascendens 23.3% 18.6% 16.2% -1.41%; 15.47%** [0.024] -6.12%; 10.82%** [0.268] Key secondary endpoint: Polyp detection rate, overall colon 44.0% 45.1% 44.5% -8.85%; 8.00%** [0.579] –7.78%; 9.09%** [0.478] Compliance rates (min 75% of both doses taken) [n] 235 (85.5%) 233 (84.7%) 245 (90.1%) n.a. n.a. SAFETY Safety set, n1⁄4 262 Safety set, n1⁄4 269 Safety set, n1⁄4 263 All treatment-emergent adverse events [n] 77 89 53 n.a. n.a. Patients with any related treatment-emergent adverse event [n] 30 (11.5%) 40 (14.9%) 20 (7.6%) n.a. n.a. *1⁄4 97.5% 1-sided CI; **1⁄4 95% 2-sided CI; n.a.1⁄4 not applicable. United European Gastroenterology Journal 4(5S) A219

Introduction In a Ph2b study(CERTIFI),1 UST intravenous(IV) induction followed by subcutaneous(SC) maintenance was effective in moderate-severe CD refractory to anti-TNF therapy. This Ph3 study examined efficacy&safety of IV UST induction in these pts. Methods Pts with moderate-severe CD(CDAI 220–450) who previously failed/were intolerant to ≥1 TNF-antagonist were randomised 1:1:1 at Wk0 to a single dose of IV PBO, UST 130 mg, or weight-based tiered UST dosing ~6 mg/kg. Primary endpoint was clinical response at Wk6(baseline [BL] CDAI score reduced by ≥100); pts with BL CDAI ≥220 to ≤248 were considered in clinical response if CDAI score of <150 was present. At Wk8, pts transitioned to the IM-UNITI maintenance study or were followed to Wk20. Results The 741 randomised pts had history of TNF-antagonist failure, with BL median CDAI = 317, CRP = 9.9 mg/L, and prior disease duration of 10.1 yrs. Of these, 51% had previously failed ≥2 anti-TNFs with 29.1%, 69.4%, and 36.4% of pts, respectively. Clinical response at Wk6 was observed in 33.7%/34.3% of the ~6 mg/kg/130 mg UST grps vs 21.5% on PBO(p = 0.003, p = 0.002, respectively). Clinical remission(CDAI < 150) at Wk8 was seen in 20.9%/15.9% vs 7.3% on PBO(p < 0.001, p = 0.003, respectively). Clinical response at Wk8 was seen in 37.8%/33.5% vs 20.2% on PBO(each p ≤ 0.001). Proportion of pts with 70 pt CDAI response at Wk6 was 43.8%/46.1% vs 30.4% on PBO(p = 0.002, p < 0.001, respectively) and at first post-BL Wk3 visit, 40.6%/38.4% vs 27.1% on PBO(p = 0.001, p = 0.009, respectively). Both IV UST induction doses resulted in significant improvements in CDAI, IBDQ, CRP, faecal lactoferrin and calprotectin vs PBO. Rates of AEs, SAEs, and infections were similar in the UST&PBO grps. One opportunistic infection(listeria meningitis) was reported in the ~6 mg/kg UST grp. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated pts through Wk20. Conclusion In a population of moderate-severe CD pts refractory to ≥1 prior TNF-antagonists, IV UST induced clinical response and remission and was well-tolerated throughout induction, confirming the previous positive induction data from CERTIFI. Reference 1 Sandborn WJ, et al. N Engl J Med 2012;367:1519–1528. Disclosure of Interest P. Rutgeerts Consultant for: J&J, Merck, UCB, AbbVie, Millenium/Takeda, Genentech/Hoffman LaRoche, Medimmune/AstraZeneca/Amgen, Merck/Serono, Bristol Myers Squibb, Robarts, Tillotts Pharma, Conflict with: Lectures for J&J, Merck, AbbVie, C. Gasink Shareholder of: Janssen, Employee of: Janssen, M. Blank Employee of: Janssen, Y. Lang Shareholder of: Janssen, Employee of: Janssen, J. Johanns Shareholder of: Janssen, Employee of: Janssen, L.-L. Gao Shareholder of: Janssen, Employee of: Janssen, B. Sands Grant/research support from: Janssen, Consultant for: Janssen, S. Hanauer Grant/research support from: Janssen, Consultant for: Janssen, Conflict with: Lecturer for Janssen, B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Patent holder; Member Scientific Advisory board, Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; Member, Board of Directors Officer – Robarts Clinical Trials Inc, S. Targan Grant/research support from: Cedars-Sinai Medical Centre, Consultant for: Janssen, NuMedii, Inc., Conflict with: Advisory board for the Seaver Foundation; Scientific Advisory Board Member Symbiotix, S. Ghosh Grant/research support from: Abbvie, Conflict with: International Steering Committees: Janssen, Abbvie, Pfizer, Receptos, BMS, Aerpio; Advisory Committees: Takeda, Abbvie, Janssen, Pfizer, Allergan, W. de Villiers Conflict with: member of steering committee, active participant as investigator, J.-F. Colombel Consultant for: Pfizer, Takeda, Protagonist Therapies, Celgene, Genentech, Second Genome, Vertex, Amgen, Merck Sharp Dohme, Janssen, Nestle, AbbVie, Tigenix, Receptos, Conflict with: Speaker for AbbVie, Ferring, Shire, Takeda, S. Lee Grant/research support from: AbbVie Pharmaceuticals UCB Pharma Janssen Pharmaceuticals, Inc. Salix Pharmaceuticals Takeda Pharmaceuticals, Inc. Celgene Pharmaceuticals, Inc. Amgen Pharmaceuticals, Inc. Pfizer Pharmaceuticals, Inc., Consultant for: UCB Pharma Robarts Mesoblast Cornerstones Janssen Pharmaceuticals, Inc. Takeda Pharmaceuticals, Inc., P. Desreumaux Grant/research support from: 1. Ferring, St Prex, Suisse 2. Ferring, Danemark 3. Giuliani SpA, Milano, Italy 4. Lesaffre, Marcq en Baroeul, France 5. Roquette, Lestrem, France 6. Sanofi-Synthelabo, Paris, France 7. UCB Pharma, Paris, France 8. Yoplait, Paris, France 9. Omega Pharma, Belgium, Consultant for: 1. Biofortis, Nantes, France 2. Ferring, St Prex, Suisse 3. Giuliani SpA, Milano, Italy 4. Roquette, Lestrem, France 5. UCB Pharma, Paris, France 6. Txcell, Nice, France 7. Lesaffre, Marcq en Baroeul, France 8. MSD, France 9. Abbott, France 10. Norgine, France 11. Genfit, France 12. OmegaPharma International 13. Ppm, Switzerland 14. Kitozyme, Belgium 15. LFB, France, Conflict with: Lecture fees: 1. Ferring, Paris, France 2. Ferring, London, UK 3. Shire Pharmaceuticals, USA 4. UCB Pharma, Paris, France 5. MSD, France 6. Norgine, France 7. Abbott, France 8. Pileje, France, E. Loftus Jr Grant/research support from: Takeda, UCB, Janssen, AbbVie, Genentech, Celgene, Amgen, Pfizer, Gilead, Receptos, Robarts Clinical Trials, Consultant for: Takeda, UCB, Janssen, AbbVie, Genentech, Celgene, Theradiag, Seres Therapeutics, Sun Pharmaceuticals, Bristol-Myers Squibb, S. Vermeire Grant/research support from: Abbvie, MSD, Takeda, Consultant for: Abbvie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, Janssen, Conflict with: Lectures: Abbie, MSD, Takeda, Ferring, Falk Pharma, Hospira, Tillotts, W. Sandborn Grant/research support from: Receptos, Exact Sciences, Amgen, the American College of Gastroenterology, Broad Foundation, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners, Conflict with: Personal fees from Receptos, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, Nutrition Science Partners, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and the University of Western Ontario (owner of Robarts Clinical Trials); non-financial support from Receptos

Introduction Single dose intravenous (IV) UST induced response and remission in CD pts refractory to TNF antagonists (UNITI-1) and failing conventional therapies (UNITI-2). The objective of this study (IM-UNITI) was to evaluate safety and efficacy of 2 subcutaneous (SC) UST regimens as maintenance therapy. Methods Moderate-severe CD pts (n = 388 for primary study population) who achieved clinical response at Wk8 in 1 of 2 UST IV induction studies were randomly assigned to receive SC injections of PBO or UST 90 mg every 8 wks (q8w) or every 12 wks (q12w). The primary endpoint was clinical remission at Wk44. Results A significantly greater proportion of pts in the UST grps were in clinical remission at Wk44 compared with PBO (53.1% & 48.8% in the q8w & q12w grps vs 35.9% PBO; p = 0.005 & p = 0.040, respectively). The treatment effect difference for q8w vs PBO (17.2%, [95%CI: 5.32%, 29.71%]) was numerically higher than the q12w grp (13.0%, [95%CI: 1.05%, 24.87%]. Primary, major, and other secondary endpoints in notable subsets are in Table 1 below. Similar proportions of pts with AEs were seen across treatment grps (81.7% & 80.3% for q8w & q12w vs 83.5% PBO). The proportions of pts with SAEs were 9.9%, 12.2%, and 15.0% among q8w, q12w, and PBO grps. Serious infections occurred in 2.3%, 5.3%, and 2.3% of pts in q8w, q12w, and PBO grps. Among the primary population, no deaths or major adverse cardiovascular events were reported, and 2 pts reported malignancies (1 basal cell carcinoma each in PBO and q8w grps). Conclusion UST 90 mg q8w and q12w maintained clinical response and remission among pts with moderate-severe CD induced into clinical response with IV UST, with a favourable safety profile through Wk44. The q8w regimen more consistently demonstrated efficacy than the q12w regimen across the range of endpoints. Disclosure of Interest W. Sandborn Grant/research support from: Receptos, Exact Sciences, Amgen, the American College of Gastroenterology, Broad Foundation, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners, Conflict with: Personal fees from Receptos, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, Nutrition Science Partners, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and the University of Western Ontario (owner of Robarts Clinical Trials); non-financial support from Receptos, B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Patent holder; Member Scientific Advisory board, Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; Member, Board of Directors Officer – Robarts Clinical Trials Inc, C. Gasink Shareholder of: Janssen, Employee of: Janssen, D. Jacobstein Employee of: Janssen, L.-L. Gao Shareholder of: Janssen, Employee of: Janssen, J. Johanns Shareholder of: Janssen, Employee of: Janssen, B. Sands Grant/research support from: Janssen, Consultant for: Janssen, S. Hanauer Grant/research support from: Janssen, Consultant for: Janssen, Conflict with: Lecturer for Janssen, S. Targan Grant/research support from: Cedars-Sinai Medical Centre, Consultant for: Janssen, NuMedii, Inc., Conflict with: Advisory Board for Seaver Foundation; Scientific Advisory Board Member Symbiotix, S. Ghosh Grant/research support from: Abbvie, Conflict with: International Steering Committees: Janssen, Abbvie, Pfizer, Receptos, BMS, Aerpio; Advisory Committees: Takeda, Abbvie, Janssen, Pfizer, Allergan, W. de Villiers Conflict with: member of steering committee, active participant as investigator, J.-F. Colombel Consultant for: Pfizer, Takeda, Protagonist Therapies, Celgene, Genentech, Second Genome, Vertex, Amgen, Merck Sharp Dohme, Janssen, Nestle, AbbVie, Tigenix, Receptos, Conflict with: Speaker for AbbVie, Ferring, Shire, Takeda, S. Lee Grant/research support from: AbbVie Pharmaceuticals UCB Pharma Janssen Pharmaceuticals, Inc. Salix Pharmaceuticals Takeda Pharmaceuticals, Inc. Celgene Pharmaceuticals, Inc. Amgen Pharmaceuticals, Inc. Pfizer Pharmaceuticals, Inc., Consultant for: UCB Pharma Robarts Mesoblast Cornerstones Janssen Pharmaceuticals, Inc. Takeda Pharmaceuticals, Inc., L. Dieleman Grant/research support from: Canadian Institutes of Health and Research (CIHR) and Alberta Innovates Biosolutions, Consultant for: Janssen, Abbvie and Shire, S. Katz Grant/research support from: Abbott, Amgen, BMS, Centocor, Hutchison, Millennium, Pfizer, Receptos, Salix, Sanofi, Speaker bureau with: Abbvie, UCB, Actavis, P. Rutgeerts Grant/research support from: J&J, Merck, UCB, AbbVie, Consultant for: J&J, Merck, UCB, AbbVie, Millenium/Takeda, Genentech/Hoffman LaRoche, Medimmune/AstraZeneca/Amgen, Merck/Serono, Bristol-Myers Squibb, Robarts, Tillots Pharma, Conflict with: Lectures for J&J, Merck, AbbVie

Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.

Objective The aim of this study was to assess the impact of the evolving role of the addition of chemotherapy to postoperative radiotherapy on oncological outcomes and toxicity in patients with early-stage cervical cancer after radical hysterectomy. Methods Retrospective cohort study of patients with stage IB1–IIB FIGO 2009 cervical cancer treated from November 1999 to May 2015 by primary surgery and radiotherapy (46–50.4 Gy in 1.8–2.0 Gy fractions) with or without concurrent cisplatin (40 mg/m2, 5–6 weekly cycles) with or without a brachytherapy boost. Chemotherapy was allocated depending on the risk factors for recurrence. Incidences of all outcomes were calculated using Kaplan–Meier’s methodology and compared by log-rank tests. Risk factors for recurrence and survival were identified using Cox’s proportional hazards models. Results A total of 154 patients were included, median follow-up was 9.6 years (IQR: 6.1–12.8). Five-year pelvic recurrence-free survival was 75.3%; 74.7% in patients with high-risk factors treated with radiotherapy; and 77.3% in those treated with chemoradiation (P=0.43). Distant metastasis-free survival at 5 years was 63.4%; 63.6% in high-risk patients after radiotherapy; and 57.1% after chemoradiation (P=0.36). Five-year overall survival was 63.9%: 66.8% and 51.6% after radiotherapy and after chemoradiation in patients with high-risk factors (P=0.37), respectively. Large tumor size was a risk factor for vaginal and pelvic recurrence, ≥2 involved lymph nodes was a significant risk factor for para-aortic recurrence and death. Mild treatment-related late toxicity was observed in 53.9% of the patients. Five-year severe (grade 3–5) late rectal, bladder, bowel, and vaginal toxicities were, respectively, 1.3%, 0%, 3.4%, and 0.9%. Any late severe toxicity was observed in 5.5% of patients treated with radiotherapy and in 15.3% of those treated with chemoradiation (P=0.07). Conclusion Postoperative (chemo)radiation for early-stage cervical cancer patients with risk factors for recurrence yields adequate pelvic tumor control, but overall survival is limited due to distant metastasis.