Late breaking abstracts

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United European Gastroenterology JournalVolume 6, Issue 10 p. 1586-1597 Late breaking abstractOpen Access Late breaking abstracts First published: 01 December 2018 https://doi.org/10.1177/2050640618812015AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Monday, October 22, 201814:00–15:30 Clinical trials in IBD – Room C____ LB01 SAFETY AND EFFICACY OF USTEKINUMAB INDUCTION THERAPY IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 UNIFI STUDY B.E. Sands1, W.J. Sandborn2, R. Panaccione3, C. O'Brien4, H. Zhang4, J. Johanns4, L. Peyrin-Biroulet5, G. van Assche6, S. Danese7, S. Targan8, M.T. Abreu9, T. Hisamatsu10, P. Szapary4, C.W. Marano4 1Icahn School of Medicine at Mount Sinai, New York, United States 2University of California San Diego, La Jolla, United States 3University of Calgary, Calgary, Canada 4Janssen Research & Development, LLC, Spring House, United States 5Nancy University Hospital, Department of Gastroenterology, Vandoeuvre les Nancy, France 6University of Leuven, Louvain, Belgium 7Humanitas Research Hospital, Inflammatory Bowel Diseases Center, Milano, Italy 8Cedars Sinai Medical Center, Los Angeles, United States 9University of Miami Miller School of Medicine, Miami, United States 10Kyorin University, Tokyo, Japan Contact E-Mail Address: bruce.sands@mssm.edu Introduction: The purpose of this study was to evaluate the safety and efficacy of intravenous (IV) ustekinumab (UST) induction therapy in patients with moderately to severely active ulcerative colitis (UC) who demonstrated an inadequate response to or were unable to tolerate conventional (ie, corticosteroids, immunomodulators) or biologic therapies (ie, 1 or more TNF blockers or vedolizumab). Aims and Methods: UNIFI was a Phase 3 randomized, double-blind, placebo-controlled study in which patients were randomized 1:1:1 at Week (Wk) 0 to receive a single IV induction dose of UST 130 mg or a dose approximating UST 6 mg/kg [∼6 mg/kg]: 260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], or 520 mg [weight >85 kg]) or placebo (PBO). At Wk 8, patients were evaluated for clinical remission, endoscopic healing, clinical response, change from baseline in the IBDQ score, and mucosal healing (an endpoint that includes both endoscopic healing and histologic healing). Results: Nine hundred sixty-one patients, of which about 50% had failed biologic therapy and 16.6% had failed both anti-TNF and vedolizumab, were randomized to treatment in the primary analysis population; 941 patients (98%) completed through Wk 8. Baseline demographics, UC disease characteristics and concomitant UC medications were generally similar among treatment groups. Significantly (p < 0.001) higher proportions of patients receiving UST IV 130 mg and ∼6 mg/kg achieved clinical remission, endoscopic healing, clinical response, and mucosal healing at Wk 8 and significant improvement from baseline in IBDQ was achieved (Table 1) compared to PBO. Significant (p < 0.05) decreases in median levels of fecal biomarkers (calprotectin and lactoferrin) were also observed at Wk 8. Similar proportions of patients reported adverse events (41.4%, 50.0%, and 48.0%), serious adverse events (3.7%, 3.1%, and 6.6%), infections (15.9%, 15.3%, and 15.0%) and serious infections (0.6%, 0.3%, and 1.3%) in the UST IV 130 mg, ∼6 mg/kg and PBO groups, respectively. No malignancies, opportunistic infections or tuberculosis were reported through Wk 8. One death from esophageal varices hemorrhage was reported for a patient with no known history of cirrhosis in the UST ∼6 mg/kg group prior to Wk 8. Conclusion: A single IV dose of UST resulted in significant improvements in clinical, endoscopic and health-related quality of life outcomes at Wk 8 compared to PBO in patients with moderate-severe UC who had previously failed conventional or biologic therapy. The therapy was well tolerated through induction. Abstract No: LB01 PBO IV UST IV 130 mg UST IV ∼ 6 mg/kg Number of randomized patients 319 320 322 Patients in clinical remissiona (%) 17 (5.3%) 50 (15.6%)* 50 (15.5%)* Patients with endoscopic healingb (%) 44 (13.8%) 84 (26.3%)* 87 (27.0%)* Patients in clinical responsec (%) 100 (31.3%) 164 (51.3%)* 199 (61.8%)* Change from baseline in IBDQ: N, Median (IQ range) 317, 10.0 (−2.0; 34.0) 316, 31.5 (7.5; 53.5)* 321, 31.0 (11.0; 56.0)* Mucosal healingd: N, Patients with mucosal healing (%) 316, 28 (8.9%) 316, 64 (20.3%)* 315, 58 (18.4%)* aA Mayo score ≤2 points, with no individual subscore >1. bMayo endoscopy subscore of 0 or 1. cA decrease from induction baseline in the Mayo score by ≥30% and ≥3 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. dCombined endoscopic healing (Mayo endoscopy subscore of 0 or 1) and histologic healing (defined as 0-<5% neutrophils in epithelium, no crypt destruction, and no erosions or ulcerations or granulations). *p < 0.001 [Primary and other multiplicity-controlled endpoints at Week 8] Disclosure: This study was supported by Janssen Research & Development, LLC LB02 PTG-100, AN ORAL GUT-RESTRICTED PEPTIDE α4β7 ANTAGONIST, INDUCES CLINICAL AND HISTOLOGIC REMISSION IN PATIENTS WITH MODERATE TO SEVERELY ACTIVE ULCERATIVE COLITIS W.J. Sandborn1, B. Bressler2, S. Lee3, R. Bhandari4, B. Kanwar5, L. Tozzi5, R. Shames5, G. D'Haens6, J.-F. Colombel7, S. Schreiber8, S. Danese9, R.K. Pai10, B.G. Feagan11 1University of California – San Diego, La Jolla, California, United States 2University of British Columbia, Vancouver, Canada 3University of Washington Dept. of Gastroenterology, Seattle, United States 4Delta Research Partners, Monroe, United States 5Protagonist Therapeutics, Newark, United States 6AMC Amsterdam Inflammatory Bowel Disease Centre – Academic Medical Center, AMC Amsterdam Inflammator, Academic Medical Center, Amsterdam, Netherlands 7Icahn School of Medicine at Mount Sinai, Gastroenterology, USA, United States 8Universität Kiel UKSH Medizinische Abt. I – UKSH, Universität Kiel UKSH Medizinische Abt. I; Kiel/DE, UKSH, Kiel, Germany 9Humanitas Research Hospital, Inflammatory Bowel Diseases Center, Rozzano, Italy 10Mayo Clinic, Scottsdale, United States 11Robarts Clinical Trials Inc., Gastroenterology, London, Canada Contact E-Mail Address: wsandborn@ucsd.edu Introduction: PTG-100 is an oral, gut-restricted peptide antagonist of the α4β7 integrin. We conducted a Phase 2b randomized, double-blind, placebo-controlled induction study of PTG-100 in patients with moderate to severely active ulcerative colitis which planned to enroll up to 240 patients. A pre-specified futility assessment was conducted by an independent DMC after the first 65 patients were randomized and completed treatment on one of three active arms (150 mg, 300 mg, 900 mg once daily) or placebo followed by 12 weeks of treatment. Futility was based on rates of clinical remission (Mayo endoscopic subscore of 0/1, rectal bleeding subscore of 0, and stool frequency subscore of 0/1 with at least a 1-point reduction from baseline) at week 12. The trial was determined by the DMC to be futile due to an abnormally high placebo remission rate (4/17 = 24%). A systematic error was noted on central read endoscopy, and the entire data set (n = 83) was re-read by an independent CRO, Robarts Clinical Trials, to determine if further development of PTG-100 is warranted. Aims and Methods: Robarts re-read all endoscopies in a blinded manner with a single reader paradigm using 2 readers with a high inter-reader correlation coefficient (κ = 0.92). Baseline and week 12 biopsies were also centrally read in a blinded manner to determine rates of histologic remission as defined by the Robarts histopathologic index (RHI) overall score ≤ 3 amongst patients who had a baseline score > 3. Results: PTG-100 exhibited a dose-dependent increase in clinical remission, endoscopic response, and histologic remission with maximal efficacy at the 900 mg dose (See Table). Given the course of events, these efficacy results will ultimately require confirmation in subsequent trials. PTG-100 was well tolerated, with low rates of adverse events, serious adverse events, and discontinuations. Conclusion: Clinical Remission Endoscopic Response Histologic Remission PTG-100 (150 mg QD) 2/22 (9.1%) 2/22 (9.1%) 2/13 (15%) PTG-100 (300 mg QD) 2/21 (9.5%) 3/21 (14.3%) 2/9 (22%) PTG-100 (900 mg QD) 3/19 (15.8%) 3/19 (15.8%) 7/16 (44%) Placebo 1/21 (4.8%) 1/21 (4.8%) 0/13 (0%) [Results of Efficacy] 1. An oral gut-restricted approach to α4β7 integrin antagonism may be effective in ulcerative colitis. 2. Histologic remission (e.g., mucosal healing) was achieved in a dose dependent manner with PTG-100. 3. These data support future development and PTG-100 is expected to advance to a larger induction and maintenance study in ulcerative colitis. Disclosure: Nothing to disclose LB03 EFFICACY AND SAFETY OF A NEW VEDOLIZUMAB SUBCUTANEOUS FORMULATION FOR ULCERATIVE COLITIS: RESULTS OF THE VISIBLE 1 PHASE 3 TRIAL W.J. Sandborn1, F. Baert2, S. Danese3, Ž. Krznarić4, G. D'haens5, T. Kobayashi6, X. Yao7, J. Chen7, K. Kisfalvi7, S. Vermeire8 1University of California San Diego, Division of Gastroenterology, La Jolla, United States 2University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium 3Humanitas University, Gastrointestinal Immunopathology, Milan, Italy 4Clinical Hospital Centre Zagreb, Division of Gastroenterology and Hepatology, Zagreb, Croatia 5Academic Medical Centre, Dept. of Gastroenterology, Amsterdam, Netherlands 6Kitasato University Kitasato Institute Hospital, Center for Advanced IBD Research and Treatment, Tokyo, Japan 7Takeda Development Center Americas Inc., Cambridge, United States 8University Hospitals Leuven, Department of Clinical and Experimental Medicine, Leuven, Belgium Contact E-Mail Address: wsandborn@ucsd.edu Introduction: Vedolizumab, a gut-selective, humanised, monoclonal α4β7 integrin antibody, is available as an intravenous (IV) formulation to adult patients (pts) with moderately to severely active ulcerative colitis (UC) or Crohn's disease. We present the first phase 3 results on a new subcutaneous (SC) formulation for maintenance treatment in UC. Aims and Methods: A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial (VISIBLE 1; NCT02611830; EudraCT 2015-000480-14) assessed vedolizumab SC as maintenance treatment in adult pts with active UC. An open-label induction with vedolizumab IV (300 mg) was administered at Weeks (Wks) 0 and 2, with disease evaluation at Wk 6. Pts with a clinical response at Wk 6 (complete Mayo score reduction of ≥3 points and ≥30% from Baseline [Wk 0] plus reduction in rectal bleeding subscore of ≥1 point or absolute subscore of ≤1 point) were randomised (2:1:1) to receive vedolizumab SC (108 mg every 2 wks), or vedolizumab IV (300 mg every 8 wks), or placebo for up to 52 wks. The primary objective was to assess clinical remission (defined as complete Mayo score of ≤2 points and no individual subscore >1 point) with vedolizumab SC vs placebo at Wk 52. Between-group treatment effects were compared using the Cochran-Mantel-Haenszel test with stratification by study randomisation factors (concomitant corticosteroid use, Wk 6 remission status, and prior anti-tumour necrosis factor alpha [anti-TNFα] failure or immunomodulator use). Results: A total of 383 pts received open-label vedolizumab IV induction. Of those, 216 (56.4%) experienced clinical response at Wk 6 and entered the maintenance phase. At Wk 52, 46.2% of pts on vedolizumab SC vs 14.3% on placebo were in clinical remission (p < 0.001) (Table 1). Similarly, 42.6% of vedolizumab IV pts were in clinical remission at Wk 52. Further, vedolizumab SC was significantly superior to placebo for the key secondary endpoints mucosal healing and durable clinical response (both p < 0.001; Table 1). The efficacy results on vedolizumab SC were consistent with those on vedolizumab IV. Subgroup analysis showed clinical remission rates were significantly higher with vedolizumab SC vs placebo in both anti-TNFα-naïve pts (vedolizumab 53.7% vs placebo 18.9%, p < 0.001) and anti-TNFα-failure pts (vedolizumab 33.3% vs placebo 5.3%, p = 0.023). Injection-site reactions were mild (9.4% in vedolizumab SC vs 0 in placebo pts), none leading to discontinuation. Adverse event rates, including severe adverse events and infections, were similar in the vedolizumab SC and IV groups. The rate of anti-vedolizumab antibodies (AVAs) in the vedolizumab SC group was 5.7% (consistent with 5.6% for vedolizumab IV). Abstract No: LB03 Table 1. Primary and Secondary Outcomes, Week 52, Maintenance-Phase ITT Population (N = 216) 52-Week Endpoint PBOa,b (n = 56) VDZ SC (108 mg) Q2Wa,c (n = 106) VDZ IV (300 mg) Q8Wa,d (n = 54) VDZ SC vs PBO P Value Primary Endpoint: Clinical remission, % (95% CI)e 14.3 (6.4–26.2) 46.2 (36.5–56.2) 42.6 (29.2–56.8) <0.001 Secondary Endpoints: Mucosal healing, % (95% CI)f 21.4 (11.6–34.4) 56.6 (46.6–66.2) 53.7 (39.6–67.4) <0.001 Durable clinical response, % (95% CI)g 28.6 (17.3–42.2) 64.2 (54.3–73.2) 72.2 (58.4–83.5) <0.001 Durable clinical remission, % (95% CI)h 5.4 (1.1–14.9) 15.1 (8.9–23.4) 16.7 (7.9–29.3) 0.076 Corticosteroid-free remission, % (95% CI)i 8.3 (1.0–27.0) 28.9 (16.4–44.3) 28.6 (11.3–52.2) 0.067 CI, confidence interval; ITT, intent-to-treat; IV, intravenous; PBO, placebo; Q2W, every 2 weeks; Q8W, every 8 weeks; SC, subcutaneous; VDZ, vedolizumab. All patients received open-label VDZ IV induction treatment (300 mg VDZ IV at Week 0 and Week 2). Patients who achieved clinical response were randomised into treatments for the maintenance phase. Clinical response was defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. Statistical significance was calculated only between placebo and VDZ SC arms. a Maintenance treatment was initiated at Week 6 after the open-label induction phase. The last IV injection (VDZ or PBO) was administered at Week 46, and the last SC injection (VDZ or PBO) was administered at Week 50. b PBO IV Q8W and PBO SC Q2W. c VDZ SC Q2W and PBO IV Q8W. d VDZ IV Q8W and PBO SC Q2W. e Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. f Mucosal healing is defined as Mayo endoscopic subscore of ≤1 point. g Durable clinical response is defined as clinical response at Weeks 6 and 52. h Durable clinical remission is defined as clinical remission at Weeks 6 and 52. i Corticosteroid-free remission is defined as patients using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. PBO: n = 24, VDZ SC: n = 45, VDZ IV: n = 21. Conclusion: Vedolizumab SC 108 mg every 2 wks was efficacious, generally safe and well-tolerated as maintenance therapy in UC pts following induction with vedolizumab IV 300 mg. The new SC formulation of vedolizumab showed an efficacy and safety profile similar to that of the currently available IV formulation and consistent with that previously reported for vedolizumab IV.1 Disclosure: WJS-research grants: Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, Celgene/Receptos; consulting fees from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Conatus, Cosmo, Escalier Biosciences, Ferring, Genentech, Gilead, Janssen, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis Nutrition Science Partners, Oppilan Pharma, Otsuka, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust or HART), Salix, Shire, Seres Therapeutics, Sigmoid Biotechnologies, Takeda, Tigenix, Tillotts Pharma, UCB Pharma, Vivelix; stock options: Ritter Pharmaceuticals, Oppilan Pharma, Escalier Biosciences, Precision IBD, Progenity. FB-Department research grants: AbbVie, Chiesi, Ipsen, MSD, Roche. Speaker and consultancy fees: AbbVie, Celgene, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Vifor. SD-Lecture fee (s): AbbVie, Ferring, Hospira, Johnson and Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim; Consultancy: AbbVie, Ferring, Hospira, Johnson and Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim. ŽK-Lecture fee (s): AbbVie, Hospira, Johnson and Johnson, MSD, Oktal Pharma. GD-Financial support for research: AbbVie, Buhlmann Laboratories, Ferring, DrFALK Pharma, Johnson and Johnson, GlaxoSmithKline, Medtronics, Millennium/Takeda, MSD, Photopill, Prometheus laboratories, Robarts Clinical Trials, Setpoint; Lecture fee (s): AbbVie, Biogen, Ferring, DrFALK Pharma, Johnson and Johnson, Giuliani, Millennium/Takeda, MSD, Norgine, Otsuka, Shire, Tillotts, UCB, Vifor; Consultancy: AbbVie, Ablynx, Actogenix, Amakem, Amgen, AM Pharma, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Cosmo, Elan, Ferring, Celgene/Receptos, Celltrion, Johnson and Johnson, Engene, Galapagos, Gilead, GlaxoSmithKline, Immunic Therapeutics, Lycera, Medimetrics, Medtronics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Otsuka, Hospira/Pfizer, PDL, Prometheus Laboratories, Protagonist, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, TEVA, Tigenix, Tillotts, Topivert, UCB, Versant, Vifor; Directorship (s): Robarts Clinical Trials TK-Lecture fees: Mitsubishi Tanabe Pharma, Pfizer, Eisai, Kyorin Pharmaceutical, AbbVie, Janssen, JIMRO, Ajinomoto Pharma, EA Pharma, Astellas Pharma, Mochida Pharmaceutical, Asahi Kasei Medical, Takeda, Gilead Sciences, Celltrion, Nippon Kayaku, Alfresa Pharma; Advisory/consultancy fees: Janssen, Pfizer, Kyorin Pharmaceutical, Mochida Pharmaceutical, Takeda, Eli Lilly, Ferring Pharmaceutical, Nippon Kayaku, Thermo Fisher Scientific, Covidien Japan; and Research grant from EA Pharma, Thermo Fisher Scientific, Alfresa Pharma, and Nippon Kayaku. XY, JC and KK-Employees of Takeda Pharmaceutical Company, Ltd. SV-Financial support for research: MSD, AbbVie, Takeda, Pfizer; Lecture fee (s): MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Genentech/Roche; Consultancy: MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Genentech/Roche, Celgene, Mundipharma, Celltrion, SecondGenome, Prometheus. Reference 1Feagan BG, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8): 699– 710. LB04 PREDICTING CLINICAL RESPONSE TO VEDOLIZUMAB THERAPY IN CROHN'S DISEASE WITH MUCOSAL BIOMARKER OF INNATE IMMUNE ACTIVATION M. Osterman1, I. Gordon2, M. Ciorba3, S.C. Glover4, B.P. Abraham5, E. Davis6, F. Khan7, K. Young6, X. Guo8, E. Yee9, F. Allard9, B. Claggett10, B. Shen7, J. Liu6 1University of Pennsylvania, Medicine, Philadelphia, United States 2Cleveland Clinic Foundation, Pathology, Cleveland, United States 3Washington University School of Medicine, St. Louis, United States 4University of Florida, Medicine, Gainesville, United States 5Baylor College of Medicine, Houston, United States 6University of Arkansas for Medical Sciences, Medicine, Little Rock, United States 7Cleveland Clinic Foundation, Gastroenterology, Cleveland, United States 8Third Affiliated Hospital of Xi'an Jiaotong University, Gastroenterology, Xi'an, China 9University of Arkansas for Medical Sciences, Pathology, Little Rock, United States 10Brigham and Women's Hospital, Harvard Medical School, Cardiovascular Medicine, Cambridge, United States Contact E-Mail Address: jjliu@uams.edu Introduction: Mucosal barrier dysfunction to luminal microbes plays a crucial role in the development of intestinal inflammation in Crohn's disease (CD). Recently, intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was proposed as a possible cause of this barrier defect. We hypothesize that small bowel IEC pyroptosis, as a marker of mucosal barrier dysfunction, may have predictive value for clinical response and help to guide the selection of biologic therapy in CD patients. Vedolizumab is an anti-integrin monoclonal antibody approved for treatment of ulcerative colitis and CD. Aims and Methods: The aim of this multi-centered study was to determine the predictive value of pre-treatment ileal biopsy IEC pyroptosis for clinical response to vedolizumab in CD. CD patients aged 18 to 78 years from five American IBD centers who had pre-vedolizumab ileal biopsies obtained during colonoscopy were enrolled. Clinical response, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from pre-treatment baseline, and clinical remission, defined as HBI < 5, was determined at ≥6 months after therapy by chart review. Biopsy samples were sectioned and stained for IEC pyroptosis using the Maximus Barrier Assay kit (Maximus Diagnostics LLC). Samples with at least 10 intact villi per patient were analyzed by blinded pathologists for quantitation of mucosal innate immune activation. The primary outcome was clinical response rate to vedolizumab stratified by pre-treatment mucosal IEC pyroptosis, using 18 positive cells/1000 IECs as a cut-point. Binary and continuous outcomes were compared using chi-squared and t-tests, respectively. Results: A total of 78 CD patients were enrolled and 5 were excluded from further analysis due to inadequate intestinal biopsy samples for IEC pyroptosis quantification. In the remaining 73 patients (39 M, 34 F), the median age was 47 (19, 78) years; 43 (59%) had clinical response to vedolizumab therapy, and 25 (34%) were in clinical remission. There were no significant differences in baseline patient characteristics, disease characteristics, previous anti-TNF exposure, and concomitant medication use between responders and non-responders. The clinical response rate in patients with IEC pyroptosis below the critical cut-point of 18 positive cells / 1000 IECs was significantly higher compared to those above: 74% (28/38) vs. 43% (15/35), odds ratio 3.7 (1.4, 10.0), p = 0.009. IEC pyroptosis in responders and non-responders were 16.8 ± 11.8 vs. 24.5 ± 11.6 positive cells / 1000 IECs, respectively (p = 0.007). The probability of response to vedolizumab therapy was inversely related to the level of mucosal IEC pyroptosis, with IEC pyroptosis of >39 positive cells / 1000 IECs associated with a clinical response rate of 17% (1/6), while a level of < 13 positive cells / 1000 IECs was associated with a 90% (18/20) clinical response. Conclusion: In this multi-centered study, we found that pre-treatment IEC pyroptosis on ileal biopsy was predictive of clinical response to vedolizmab in Crohn´s patients. Disclosure: Dr. Liu and Dr. Davis are holders of a patent on the method of detecting barrier dysfunction using mucosal innate immune activation in IBD. LB05 THE INTESTINALLY RESTRICTED, ORALLY ADMINISTERED, PAN-JAK INHIBITOR TD-1473 DEMONSTRATES FAVORABLE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND SIGNAL FOR CLINICAL ACTIVITY IN SUBJECTS WITH MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS W.J. Sandborn1, R. Bhandari2, J. Leighton3, R. Ganeshappa4, D. Nguyen5, B. Ferslew5, A. Olmsted5, R. Graham5, J. Panés6 1University of California San Diego, San Diego, United States 2Delta Research Partners, Monroe, United States 3Mayo Clinic Phoenix, Medicine, Phoenix, United States 4Pinnacle Clinical Research, San Antonio, United States 5Theravance Biopharma, South San Francisco, United States 6Hospital Clínic Barcelona Dept. of Gastroenterology – Dept. of Gastroenterology, Hospital Clínic Bar, Dept. of Gastroenterology, Barcelona, Spain Contact E-Mail Address: jpanes@clinic.ub.es Introduction: A need exists for effective and safe oral therapeutic options for moderate to severe ulcerative colitis (UC). TD-1473 is an orally administered and intestinally restricted pan-Janus kinase (JAK) inhibitor that was well tolerated by healthy volunteers when administered up to 300 mg once daily for 14 days with very low systemic exposure. Aims and Methods: To assess the safety, tolerability, and pharmacokinetics (PK) of TD-1473 in subjects with moderately-to-severely active UC. In this double-blind placebo-controlled multicenter phase 1b study, 40 subjects were enrolled and administered placebo (n = 9), 20 mg (n = 10), 80 mg (n = 10), or 270 mg (n = 11) TD-1473 once daily for 28 days after meeting eligibility criteria (including Mayo rectal bleeding subscore of ≥ 1, stool frequency subscore of ≥ 1, and centrally read endoscopic subscore of ≥ 2). Safety, PK, clinical outcomes, and biomarkers were evaluated. Results: The mean age was 44 years with 65% of subjects being male and a median disease duration of 3.1 years. The baseline mean total Mayo Score ranged from 8.2 (80 mg) to 9.6 (20 mg), with an overall mean of 8.9. All subjects completed dosing, except for one subject at 20 mg who stopped taking TD-1473 at Day 5 due to lack of efficacy. Two serious treatment-emergent adverse events consisted of hospitalization for UC exacerbation (20 mg and 80 mg). No cases of serious or opportunistic infection or signals for abnormalities in hematologic or chemistry laboratory parameters were observed. Plasma exposures were low and consistent with those observed previously in healthy subjects. Colonic tissue concentrations of TD-1473 were higher than plasma and in the range needed for JAK inhibition. There were trends for higher rates of mucosal healing and improvement by ≥ 1 point in rectal bleeding and endoscopy, relative to placebo. C-reactive protein (CRP) decreased relative to placebo at all dose levels. Fecal calprotectin decreased in subjects treated with 80 mg and 270 mg. High variability was observed for CRP and fecal calprotectin at all dose levels. Conclusion: TD-1473 was generally well tolerated over 4 weeks with evidence of intestinal restriction, low systemic exposure, and signals for clinical and biomarker activity in subjects with moderately-to-severely active UC. Abstract No: LB05 TD-1473 Dose Subjects with Improvement in Rectal Bleeding Subscore by ≥ 1 point (n, %) Subjects with Improvement in Endoscopy Subscore by ≥ 1 point (n, %) Subjects with Mucosal Healing* Serum CRP (Placebo Adjusted Change from Baseline; %, 95% CI) Fecal Calprotectin (Placebo Adjusted Change from Baseline; %, 95% CI) GI Tissue TD-1473 Concentration** (nM) Plasma TD-1473 Concentration: Ctrough (nM) Plasma TD-1473 Concentration: Cmax (nM) Placebo (n = 9) 4 (44%) 0 (0%) 0 (0%) NA NA NA NA NA 20 mg (n = 10) 3 (30%) 2 (20%) 2 (20%) −61 (−84, −1) +62 (−76, +987) 10 NC 0.350 80 mg (n = 10) 7 (70%) 3 (30%) 2 (20%) −57 (−83, +6) −31 (−89, +344) 162 0.202 5.66 270 mg (n = 11) 8 (73%) 2 (18%) 1 (9%) −70 (−88, −28) −26 (−88, +351) 108 1.74 30.1 *: mucosal healing: endoscopic subscore ≤ 1 point **: JAK1-3 and TYK2 T-cell stimulation IC50s 32-158 nM; Beattie DT. TD-1473, a Novel, Potent, and Orally Administered, GI-targeted, Pan-Janus Kinase (JAK) Inhibitor. Poster presented at: The European Crohn's and Colitis Organisation meeting; 16-19 March 2016; Amsterdam, The Netherlands ***: Ctrough and Cmax values provided to indicate range of plasma exposures over 24 hour treatment period NA: not applicable NC: not calculated because concentrations were below limit of detection [Key Efficacy, biomarker and PK results in subjects with moderately- to severely-active UC after 28 days of treatment with TD-1473 or placebo] Disclosure: William Sandborn: consulting fees from Abbvie, Akros Pharma, Allergan, Ambrx Inc., Amgen, Ardelyx, Arena Pharmaceuticals, Atlantic Pharmaceuticals, Avaxia, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Conatus, Cosmo Technologies, Escalier Biosciences, Ferring, Ferring Research Institute, Forward Pharma, Galapagos, Genentech, Gilead Sciences, Immune Pharmaceuticals, Index Pharmaceuticals, Janssen, Kyowa Hakko Kirin Pharma, Lilly, Medimmune, Mesoblast, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Palatin, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust or HART), Salix, Seattle Genetics, Seres Therapeutics, Shire, Sigmoid Biotechnologies, Takeda, Theradiag, Theravance, Tigenix, Tillotts Pharma, UCB Pharma, Vascular Biogenics, Vivelix; research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly, Celgene/Receptos; payments for lectures/speakers bureau from Abbvie, Janssen, Takeda; and holds stock/stock options in Escalier Biosciences, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals. Julian Panes: Consulting fees from Abbvie, Arena, Boehringer Ingelheim, Celgene, GoodGut, GSK, Janssen, MSD, Nestlé, Oppilan, Pfizer, Takeda, Theravance, and TiGenix; unrestricted research grants from Abbvie and MSD. Raj Bhandari: nothing to disclose. Jonathan Leighton: consulting fees from Medtronic; research funds from Pfizer, Shire, and Medtronic. Ravi Ganeshappa: nothing to disclose. Brian Fersl