Search

Background Upadacitinib (UPA), an oral, reversible JAK inhibitor, demonstrated superior efficacy compared to placebo (PBO) in patients with moderate to severe Crohn’s disease (CD) in 2 multicentre, phase 3 induction (U-EXCEL and U-EXCEED), and 1 maintenance (U-ENDURE) trial.1-3 This sub-analysis assessed endoscopic outcomes in patients with or without a history of biologic failure (inadequate response or intolerance) among those receiving UPA treatment. Methods Eligible patients had average daily stool frequency [SF] ≥4 and/or abdominal pain score [APS]≥2, plus a Simple Endoscopic Score for CD (excluding the presence of narrowing component) ≥6 [≥4 for isolated ileal disease]). Patients received UPA 45 mg once daily (QD; UPA45) or PBO (2:1) for 12 weeks (wks). Patients that achieved SF/APS clinical response after 12 weeks of treatment with UPA45 (≥ 30% decrease in daily very soft/liquid SF and/or ≥ 30% decrease in daily abdominal pain APS with neither worse than baseline) were re-randomized (1:1:1) to UPA 30 mg QD (UPA30), UPA15 mg QD (UPA15) or PBO for 52 wks of maintenance. Endoscopic response\ remission were evaluated by central reading at wk 12 induction and wk 52 maintenance. Adverse events (AEs) were assessed through wk 52. Statistical significance in comparisons was not assessed due to an inability to control for type I error in subgroup analysis. Results Baseline characteristics/demographics were similar across treatment groups. In the pooled induction population (U-EXCEED+U-EXCEL), 72.0% UPA45 and 71.5% PBO patients had history of prior biologic failure. In U-ENDURE, 73.4% UPA15, 75.6% UPA30, and 76.4% PBO patients had history of prior biologic failure. In patients without or with biologic failure, UPA demonstrated higher rates for endoscopic response compared to PBO at wk 12 (52.0%, 35.7% UPA45 vs 16.2%, 5.3% PBO, Figure 1A) and wk 52 (Figure 1B). Similarly, in patients without or with a history of biologic failure, UPA exhibited higher rates of endoscopic remission at wk 12 (36.0%, 19.6% UPA45 vs. 10.1%, 2.8% PBO, Figure 1A) and wk 52 (Figure 1B). Differences from PBO were found in endoscopic response or remission in patients that remained in response/remission from the entry of maintenance to wk 52 for either dose, regardless of prior history of biologic failure (Figure 1C). UPA treatment was well-tolerated, with no new safety risks observed compared to the known safety profile of UPA (Tables 1-2). Conclusion Upadacitinib achieved clinically meaningful endoscopic outcomes, which were maintained up to 1 year, irrespective of a patient’s prior biologic treatment, with an acceptable safety profile.

Background The once-daily, oral, Janus kinase 1 preferential inhibitor filgotinib (FIL) is approved for the treatment of moderately to severely active rheumatoid arthritis (RA) and ulcerative colitis (UC) in the UK, the EU and Japan.1 To further understand the safety profile of FIL across indications, we evaluated the risk of major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) in patients treated with FIL 200 mg (FIL200) or FIL 100 mg (FIL100). Methods An integrated analysis was conducted with RA data from five phase 2/3 trials and two long-term extension (LTE) trials of FIL, and UC data from two phase 2/3 trials and one LTE trial of FIL (herein termed ‘overall’ data). Subgroup analyses by age and cardiovascular (CV) risk factors (excluding age) were conducted. Real-world data were extracted from a systematic literature review. Exposure-adjusted incidence rates (EAIRs) or incidence rates per 100 patient-years of exposure and 95% confidence intervals (CIs) were estimated for MACEs and VTEs. For clinical trial data, MACEs and VTEs included positively adjudicated events only. Results In pooled data, baseline characteristics were generally similar across treatment arms for RA and UC (Tables 1 and 2). In the RA data, MACE EAIRs were 0.29 and 0.41 for the overall FIL200 and FIL100 arms, respectively (Figure 1). MACE IRs were 0.45–0.77 for the general RA population. Higher MACE EAIRs were reported in the subgroup of patients with RA aged ≥65 years vs In the UC data, MACE rates were 0.29, 0.35 and 0.87 in the overall FIL200 and FIL100 arms and in the general UC population, respectively (Figure 2). VTE rates were 0.08, 0.18 and 0.39 in the overall FIL200 and FIL100 arms and in the general UC population, respectively. For both MACE and VTE EAIRs, wide CIs were reported in patients with UC aged ≥65 years and in those with CV risk, owing to low numbers of events and/or patients in these subgroups. Conclusion No association was identified between FIL200 treatment and an increased risk of MACEs or VTEs compared with the general RA or UC population. Patients aged ≥65 years or with CV risk had slightly higher rates of MACEs and VTEs than those in other subgroups; however, overlapping CIs suggested no real difference. Further work should examine real-world data from FIL-treated patients and longer follow-up. 1. https://www.ema.europa.eu/en/medicines/human/EPAR/jyseleca

Background The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms on patients with moderate to severe UC and Crohn’s disease and to investigate gaps in communication with healthcare professionals (HCPs) in the United States (US), Europe (EUR), and Japan. Purpose This report focuses on patients with moderate to severe UC and HCPs from the US and EUR. Method Online, quantitative, cross-sectional surveys of patients with UC and HCPs were conducted in the US and EUR (France, Germany, Italy, Spain, and UK). HCP surveys included physicians and non-physician HCPs responsible for making prescribing decisions. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Data collected included perspectives on the experience of patients with UC. Result(s) A total of 200 US (62% male, mean age 40.4 years) and 556 EUR patients (57% male, mean age 38.9 years), and 200 US and 503 EUR HCPs completed the survey. According to US and EUR patients, the top 3 symptoms currently (past month) experienced were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). Blood in stool was reported as currently experienced by 27% and 24% of US and EUR patients, respectively. Among patients currently experiencing bowel urgency, 47% of US and 27% of EUR patients discuss this symptom at every appointment. Among those who do not discuss bowel urgency at every appointment, 74% and 75% of US and EUR patients would like to discuss this symptom more frequently with their HCP. A total of 30% and 43% of US and EUR patients that ever experienced bowel urgency were not comfortable reporting it to their HCP, with 62% and 58% of these US and EUR patients feeling embarrassed talking about this symptom (Table). HCPs in both the US and EUR ranked diarrhoea (74% and 65%), blood in stool (69% and 65%) and increased stool frequency (38% and 34%) as the top 3 symptoms most reported by patients. According to US and EUR HCPs, the top 4 symptoms proactively discussed in routine appointments were blood in stool (93% and 94%), diarrhoea (90% and 91%), increased stool frequency (82% and 82%) and bowel urgency (76% and 82%). Among HCPs who did not proactively discuss bowel urgency, 47% of US and 40% of EUR HCPs expect patients to bring this up if it is an issue. Image Conclusion(s) Communication gaps were similar between US and EUR patients and HCPs. Bowel urgency is the second-most reported symptom by patients with moderate to severe UC. However, this symptom is not among the HCP-perceived top 3 most reported symptoms. Although a substantial proportion of patients reported a desire to discuss bowel urgency more frequently with their HCP, some patients reported feeling embarrassed talking about it. Many HCPs who do not proactively discuss this symptom expect patients to bring this up. A communication gap was identified and highlights the under-appreciation of bowel urgency as an important symptom of UC. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest S. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, A. Bleakman Employee of: Eli Lilly and Company, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared

Background The unmet need in Crohn’s disease (CD) exists for new medications with an optimized risk-benefit ratio with avoidance of systemic side effects. This Phase 2 study evaluated the efficacy and safety of the oral, once-daily, gut-selective pan-Janus kinase inhibitor izencitinib as an induction therapy for CD. Methods This trial was a multicentre, randomized, double-blind, Phase 2 study of adults with moderately-to-severely active CD (≥220 and ≤ 450 CDAI with SES-CD score of ≥6 [or ≥4 if isolated ileal disease]) who were corticosteroid-dependent or had demonstrated failure to aminosalicylates, corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomised 2:3:3 to receive placebo or izencitinib, 80, or 200 mg once daily for 12 weeks. The primary endpoint was change in CDAI score from baseline to week 12 and was analysed using a mixed-model repeated measures analysis. Change from baseline in SES-CD was analysed with an analysis of covariance model and binary endpoints were analyzed using a stratified Cochran-Mantel-Haenszel chi-square test. Results 159 and 145 patients were included in the safety and modified ITT populations, respectively. At week 12, the LS mean change in CDAI was -105.6 (SE: 12.7) and -117.9 (12.4) points for patients randomized to izencitinib 80 and 200 mg, respectively, vs -104.86 (SE: 15.496) for those randomized to placebo. There were no improvements observed in change from baseline in SES-CD. There were non-significant numerical improvements in clinical and endoscopic response between placebo and the highest dose 200mg. No improvements were observed in CDAI-based clinical remission or PRO2 (SF/AP)-based remission at any dose of izencitinib relative to placebo. As expected, plasma izencitinib exposure was low. Serious adverse events (AEs; n = 13) were well balanced among the treatment groups and not considered related to study treatment; no deaths were observed. Exacerbation of Crohn’s Disease, headache, rash, abdominal pain and nausea were the most common treatment-emergent AEs observed with izencitinib treatment. No clinically important changes in laboratory values, electrocardiography parameters, or vital signs were noted in patients treated with izencitinib compared with placebo, and no drug-related AEs of special interest were observed. Conclusion In patients with moderately-to-severely active Crohn’s Disease, izencitinib treatment for 12 weeks did not demonstrate a statistically significant reduction in CDAI or endoscopic severity. Izencitinib at both doses was well tolerated without a new safety signal.

Background Bowel urgency is increasingly being recognized as an impactful symptom in patients with ulcerative colitis (UC)1. However, limited information is available regarding its potential association with other patient reported outcomes. We assessed the association of bowel urgency clinically meaningful improvement (CMI) or bowel urgency remission with Inflammatory Bowel Disease Questionnaire (IBDQ) scores whilst adjusting for the potential confounding effects of stool frequency (SF) and rectal bleeding (RB) remission using data from LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) phase 3 trials. Methods Bowel urgency severity was assessed by the Urgency Numeric Rating Scale (UNRS) (0=no urgency to 10=worst possible urgency). Bowel urgency CMI was defined as ≥3-point decrease in UNRS compared to baseline and bowel urgency remission was defined as UNRS of 0 or 1.2 IBDQ scores (range: 32–224) were calculated; higher scores indicate better quality of life. Mediation analyses were performed to examine the relative association between direct effects of bowel urgency CMI and bowel urgency remission (separate predictors) and IBDQ scores while adjusting for the potential confounding effects of SF remission and RB remission (mediators). Analyses were treatment agnostic and combined patients from mirikizumab and placebo groups from LUCENT-1 (N=1162) and LUCENT-2 (N=544) trials at Week (W) 12 and 40 (W52 of continuous treatment). Results At W12 and W52, bowel urgency remission directly accounted for 44.8% and 32.5% improvement in IBDQ total score, respectively; 22.7% and 39.1% of improvement was mediated by RB remission and 32.5% and 28.4% by SF remission, respectively. At W12, bowel urgency remission resulted in the largest proportion of improvement in each of the IBDQ domain subscores, whereas at W52, RB remission had a greater confounding effect (Fig. 1A). At W12 and W52, bowel urgency CMI accounted for 70% and 57.3% improvement in IBDQ total score, respectively; 12.8% and 25.6% of effects were mediated by RB remission and 17.2% and 17.1% by SF remission, respectively (Fig. 1B). Bowel urgency CMI accounted for the largest proportion of association with improvement in each of the IBDQ domain subscores at both W12 and W52. Conclusion Improvements in IBDQ scores were primarily ascribed to bowel urgency remission and bowel urgency CMI relative to RB remission and SF remission, particularly at W12, in patients with moderately-to-severely active UC. These findings suggest that bowel urgency is a critical and independent symptom that considerably impacts patients’ quality of life. References

Background Bowel urgency is increasingly recognized as a common and impactful symptom in patients with Ulcerative Colitis (UC).1 However, there are limited data exploring the relationship of bowel urgency with work productivity. We examined the relative association of bowel urgency clinically meaningful improvement (CMI) and bowel urgency remission with Work Productivity and Activity Impairment (WPAI) scores in the presence of rectal bleeding (RB) remission and stool frequency (SF) remission as potential confounding variables using data from LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) phase 3 trials. Methods Bowel urgency severity was assessed using the Urgency Numeric Rating Scale (UNRS; 0=no urgency to 10=worst possible urgency). Bowel urgency CMI is a ≥3-point decrease and bowel urgency remission is a UNRS score of 0 or 1.2 WPAI scores (absenteeism, presenteeism, and work productivity loss in employed patients, and activity impairment in all patients) were measured using a 6-item questionnaire; higher scores indicate greater impairment and less productivity. Mediation analyses were performed to separately examine the relative association between the direct effect of bowel urgency CMI and bowel urgency remission (predictor) and WPAI scores while adjusting for the potential confounding effects of RB remission and SF remission (mediator). Analyses were treatment agnostic and combined patients from mirikizumab and placebo groups from LUCENT-1 (N=1162) and LUCENT-2 (N=544) trials. Results At week (W)12 and W52, the direct effect of bowel urgency remission accounted for 43%–49% and 27%–57% of the improvement in all WPAI domain scores except absenteeism, respectively. The association values greater than 100% at W12 and W52 (153% and 148%, respectively) reflect the critical importance of SF remission in the improvement of absenteeism score (Table 1). Bowel urgency CMI resulted in the largest proportion of improvement in WPAI domain scores (except absenteeism) at W12 (71%–74%) and W52 (66%–78%). Bowel urgency CMI accounted for 68% and 239% of the improvement in absenteeism scores at W12 and W52, respectively. At W52, 750% of the effect was mediated by RB remission (Table 2). Conclusion Improvement in work productivity and regular activities were primarily ascribed to bowel urgency remission or bowel urgency CMI relative to RB remission and SF remission in patients with moderately-to-severely active UC. These findings suggest that bowel urgency is a critical and independent symptom that considerably impacts patients’ productivity. Reference: 1Dubinsky MC, et al. Crohn's & Colitis 360. Volume 4, Issue 3, July 2022;7(4):3. 2Dubinsky MC, et al. J Patient Rep Outcomes. 2022;6(1):114.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Although ≈30% of UC patients initially present with isolated proctitis, most phase 3 trials of systemic therapies in UC excluded this subgroup. We report the efficacy and safety of etrasimod in subjects with isolated proctitis enrolled in the ELEVATE UC programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-week induction period. Both trials allowed inclusion of subjects with isolated proctitis ( Results This analysis included 64 pooled subjects with isolated proctitis at week 12 (42 etrasimod, 22 PBO) and 36 subjects from UC 52 at week 52 (27 etrasimod, 9 PBO). Greater proportions (P Conclusion Efficacy and safety of etrasimod in subjects with isolated proctitis was consistent with the overall population of the ELEVATE programme.1 The analysis was performed on a small dataset and should be interpreted with caution but informs on the efficacy of etrasimod in a subpopulation of UC subjects commonly excluded from drug development trials. Reference: 1. Sandborn WJ, et al. Presented at: DDW 2022; May 24, 2022. Abstract 968a.

Background Clinical trials with advanced therapies typically document the efficacy of induction and maintenance therapies as landmark endpoints. In ulcerative colitis (UC), independent assessments of clinical remission, endoscopic improvement, inflammatory biomarker, and histologic response are used, while little is known about the individual patient benefit. Disease control (DC) as a composite of symptomatic, biochemical, and morphologic remission becomes important to achieve for patients. By analysing their symptom trajectories towards the new outcome DC, distinct subpopulations of the seemingly uniform therapy response phenotype in UC can be identified. In a prospective cohort, we investigate UC patients using symptoms (i.e., partial Mayo Clinical Score (PCMS)) to detect different trajectories that may lead to DC. Methods 231 UC patients from Kiel Campus of University Hospital Schleswig-Holstein receiving first time induction and maintenance therapy with anti-TNF, anti-IL-12/23, anti-Integrin or JAK inhibitors (JAKi) between 2010-2022 were enrolled. Patients were assigned by clinical choice to their therapy and received standard care: Symptoms were assessed by PCMS with laboratory investigations at each visit (every 4-12 weeks) and endoscopies (at week 0, 14, 52) were evaluated using Mayo endoscopic score (eMayo) and histology assessment with Nancy index (NI). We defined DC at week 52 (DC52) as the combination of eMayo =0, NI =0-1, PMCS =0-1, C-reactive protein Results 24.2% (56) of patients achieved DC52, while 25.6% (59) reached week 52 without DC and 50.2% (116) changed therapy within 52 weeks due to inefficacy. We identified an early separation of PMCS trajectories between DC52 (2.07, ±0.27SEM) vs. non-DC52 (3.49, ±0.27SEM) already 6 weeks after induction (p 3 (40.24% vs. 16.92%; sensitivity 0.79, specificity 0.60) were associated with higher rates of DC52 vs. non-DC52. Linking DC52 with prospective outcomes, we observed higher rates of clinical remission (75.00% vs. 27.12%) and DC at week 104 (57.14% vs. 20.34%) in DC52 vs. non-DC52. Conclusion In this real-world cohort, DC52 was characterized by early drop of PMCS and a higher likelihood of DC until week 104. While our results await replication, the observation of discrete super-response trajectories leading to DC could give rise to algorithmic trials investigating early change of therapy for patients not joining an ideal trajectory as early as week 6.

Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

OBJECTIVE: The clinical management of the interrelationship between diabetes and periodontitis is a challenge for all parties involved in health care. For this reason, this project aims to provide subsidies for the implementation of routines that increase the partnership between endocrinologists, periodontists, and other health professionals in the patient care team. MATERIAL AND METHODS: The Brazilian Society of Periodontology – SOBRAPE and the Brazilian Society of Endocrinology and Metabolism – SBEM appointed specific committees to develop joint guidelines addressing the interrelationship between diabetes and periodontitis. Results: Guidelines were developed for patients, physicians, dentists, and teams working in the Unified Health System. CONCLUSION: The application of the guidelines can provide a complete approach to patients with diabetes and periodontitis, with a consequent improvement in quality of life, and an improvement in medical parameters, with possible cost reduction for all medical and dental activities.

Background Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks. Aims FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB Methods Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time. Results Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P Conclusions In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated. Funding Agencies AbbVie

Background The inflammatory bowel disease questionnaire (IBDQ) is a measure of health-related quality of life (QoL), with higher scores indicating greater QoL. In a prior phase 2 study (NCT02589665), mirikizumab, an anti-IL23p19 antibody, demonstrated efficacy and improvement in IBDQ scores in participants with moderately to severely active ulcerative colitis (UC). Purpose This analysis evaluated effect of mirikizumab (miri) vs placebo (PBO) on IBDQ scores in patients (pts) with moderately to severely active ulcerative colitis (UC) who had failed prior conventional or biologic therapy in a Phase 3, double-blind, 12-week (W) induction study (LUCENT-1) followed by a 40W maintenance study (LUCENT-2) for a total of 52W continuous therapy. Method Pts (N=1162) in LUCENT-1 were randomized 3:1 to receive 300mg miri or PBO intravenously once every four weeks (Q4W). 544 pts who achieved Modified Mayo Score Clinical Response to miri by W12 of induction were rerandomized 2:1 in LUCENT-2 to subcutaneous miri 200mg or PBO Q4W in maintenance period. Randomization was stratified by previous biologic therapy failure, baseline corticosteroid use, and region. LUCENT-1 stratification included baseline (BL) disease activity, and LUCENT-2 included LUCENT-1 clinical remission status. The least squares mean change from BL in IBDQ scores at W12 of induction and W40 of maintenance was determined using analysis of covariance models. BL was W0 of therapy and stratification factors and BL scores were used as covariates. The Minimal Clinically Important Difference (MCID) was defined as an improvement of ≥16 points in total IBDQ score (IBDQ response) and IBDQ remission as a total score ≥170 points. IBDQ response and remission were calculated using non-responder imputations. Treatments were compared using the common risk difference (risk diff). Result(s) Miri treatment resulted in significantly greater improvement from BL in IBDQ total and domain scores vs PBO at both W12 of induction and W40 of maintenance (52W treatment) (Table). The proportions of pts who achieved an IBDQ response was significantly greater for miri treated pts vs PBO at W12 (risk diff =17.1[95%CI:10.7, 23.5]) and W40 (29.5 [21.0, 37.9]). Significantly greater proportions of pts receiving miri achieved IBDQ remission at W12 (18.1 [11.8, 24.4]) and W40 (28.5 [20.1, 37.0]) vs PBO (all evaluations and timepoints: p Image Conclusion(s) Pts reported significantly greater improvements in IBDQ scores at induction and maintenance with miri compared to PBO. Over 75% of pts achieved a clinically meaningful improvement in QoL, as measured by IBDQ response, at the end of the 52 weeks of miri treatment. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest B. Sands Consultant of: Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Eli Lilly and Company, Enthera, Evommune, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutic, MRM Health, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio, B. Feagan Shareholder of: Gossamer Bio, Consultant of: AbbVie, AdMIRx, AgomAb Therapeutics, Akebia Therapeutics, Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avir Pharma, Azora Therapeutics, Boehringer Ingelheim, Boston Scientific, Celgene/Bristol Myers Squibb, Connect BioPharma, Cytoki Pharma, Disc Medicine, Ecor1 Capital, Eli Lilly and Company, Equillium, Everest Clinical Research, F. Hoffmann-La Roche, Ferring Pharmaceuticals, Galapagos NV, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Gossamer Bio, HotSpot Therapeutics, Imhotex, ImmuNext, InDex Pharmaceuticals, Intact Therapeutics, Janssen, Japan Tobacco, Kaleido Biosciences, Leadiant Biosciences, Millennium Pharmaceuticals, MiroBio, Morphic Therapeutics, Mylan, Novartis, OM Pharma, Origo Biopharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, PTM Therapeutics, Q32 Bio, Rebiotix, RedHill, Biopharma, Redx Pharma, Sandoz, Sanofi, Seres Therapeutics, Surrozen, Takeda, Teva, Thelium Therapeutics, Theravance Biopharma, TiGenix, Tillotts Pharma AG, UCB Pharma, VHsquared, Viatris, Ysios Capital, and Zealand Pharma, T. Gibble Employee of: Eli Lilly and Company, K. Traxler Employee of: Eli Lilly and Company, N. Morris Employee of: Eli Lilly and Company, X. Li Employee of: Eli Lilly and Company, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, V. Jairath Consultant of: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Shire, Takeda, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics, A. Armuzzi Consultant of: AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and TiGenix, J. Jones: None Declared

Background Moderate to severe ulcerative colitis (UC) exerts a significant burden on patients’ lives. Patients with UC report that bowel urgency has a substantial negative impact on their quality of life and psychosocial functioning, however, this symptom is missing from most disease activity indices. Purpose The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms, including bowel urgency, on the lives of patients (pts) with moderate to severe UC and Crohn’s disease in the United States (US), Europe (EUR), and Japan. These data focus on pts in the US and EUR. Method Online, quantitative, cross-sectional surveys of pts with moderate to severe UC were conducted in the US and EUR (France, Germany, Italy, Spain, and UK). Data included pt perspectives on their UC symptoms and the impact on their daily lives. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Descriptive statistics summarise the data. Result(s) 200 US pts (62% male, mean age 40.4 years) and 556 EUR pts (57% male, mean age 38.9 years) completed the survey, with 77% and 54% currently receiving advanced therapies (biologic or novel oral therapy), respectively. The top 3 symptoms currently (past month) experienced by US and EUR pts were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). In past 3 months, pts who have ever experienced bowel urgency or urge incontinence reported bowel urgency (93% US, 89% EUR) and urge incontinence (86% US, 71% EUR) at least once a month (Table). 69% and 65% of all US and EUR pts, respectively, reported wearing a diaper/pad/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. For pts receiving advanced therapies, similar patterns were observed. Among both US and EUR pts, the most common UC-related reasons for declining participation in social events were bowel urgency (43% and 30%) and fear of urge incontinence (40% and 32%). Similarly, the most common reasons for declining participation in work/school and sports/physical exercise were bowel urgency and fear of urge incontinence. Image Conclusion(s) Bowel urgency, which was the second-most frequently reported symptom, has an extensive impact on the lives of pts with moderate to severe UC. In this younger pt population, including pts receiving advanced therapies, almost two thirds of US and EUR pts reported wearing diapers/pads/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. Both US and EUR pts reported bowel urgency and fear of urge incontinence as the top reasons for declining participation in social events, work/school, and sports/physical exercise. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, A. Bleakman Employee of: Eli Lilly and Company, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, J. Jones: None Declared

Background Ulcerative colitis (UC) can result in a high prevalence of bowel movement urgency (BU), significantly reducing patient quality of life. Purpose Early BU improvement association with later clinical endpoint improvements was examined in moderately-to-severely active UC patients (pts) treated with mirikizumab (miri). Method BU was evaluated in Phase 3 randomized placebo (PBO)-controlled 12-week induction (LUCENT-1, NCT03518086) and 40-week maintenance (LUCENT-2, NCT03524092) trials with miri. Pts received IV miri 300mg or PBO during induction. Week (W)12 miri responders were rerandomized at LUCENT-2 baseline (BL) to subcutaneous miri 200mg or PBO. BU was measured with 11-point Urgency Numeric Rating Scale (UNRS) from 0 (no urgency) to 10 (worst possible). Pts’ UNRS scores were an average from 7 consecutive days prior to visit. Association of pts with BU Clinically Meaningful Improvement (CMI) or BU remission between BL and W4 with the proportion of pts achieving clinical response, and clinical, endoscopic, or symptomatic remission at end of W12 was assessed. For pts who achieved clinical response at W12, the analyses were repeated for the end of maintenance based on W12 BU status. Logistic regression models with treatment, urgency (BU CMI or BU Remission), treatment-by-urgency group interaction, and stratification factors were fitted to examine the association between early urgency improvement and later clinical endpoints. Result(s) Treatment-by-urgency group interactions were not statistically significant across clinical outcomes for induction and maintenance. For induction, treatment and urgency status were statistically significant. Pts experiencing BU CMI or BU remission at W4 were consistently more likely to achieve clinical response, and clinical, endoscopic, or symptomatic remission at W12 for both treatment groups. For remission, only treatment main effect was statistically significant. Among miri induction clinical responders (an enriched population), BU CMI or BU Remission at end of induction (W12) was not associated with later maintenance efficacy outcomes (W52). Miri-treated pts achieved higher rates of clinical response, and clinical, endoscopic, or symptomatic remission at W52 than with PBO regardless of BU CMI or BU Remission at W12 (Table). Image Conclusion(s) Early BU Improvement, CMI or Remission, was associated with better clinical outcomes during induction for miri and PBO pts, showing BU is a sensitive predictor of early clinical outcomes. Among miri induction responders, miri consistently provided better maintenance of response and remission rates than PBO. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest D. Clemow Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, T. Hibi Grant / Research support from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, S. Vermeire Consultant of: AbbVie, Arena Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, ProDigest, Progenity, Prometheus Therapeutics and Diagnostics, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance Biopharma, and Tillots Pharma AG, Speakers bureau of: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Janssen, Pfizer, Robarts Clinical Trials, and Takeda, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, L. Peyrin-Biroulet Grant / Research support from: AbbVie, Fresenius Kabi, Merck Sharp & Dohme, and Takeda, Consultant of: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillots Pharma AG, Viatris, and Vifor Pharma, M. Watanabe Grant / Research support from: AbbVie, Alfresa Pharma, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical, Consultant of: AbbVie, Boehringer Ingelheim, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Nippon, and Takeda, Speakers bureau of: EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Janssen, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Japan, Takeda, and Zeria Pharmaceutical, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared

Background: Chemosensory dysfunction (CD) has been reported as a common symptom of SARS-CoV-2 infection, but it is not well understood whether and for how long changes of smell, taste and chemesthesis persist in infected individuals. Methodology: Unselected adult residents of the German federal state of Schleswig-Holstein with Polymerase Chain Reaction (PCR)-test-confirmed SARS-CoV-2 infection were invited to participate in this large cross-sectional study. Data on the medical history and subjective chemosensory function of participants were obtained through questionnaires and visual analogue scales (VAS). Olfactory function (OF) was objectified with the Sniffin’ Sticks test (SST), including threshold (T), discrimination (D) and identification (I) test as well as summarized TDI score, and compared to that in healthy controls. Gustatory function (GF) was evaluated with the suprathreshold taste strips (TS) test, and trigeminal function was tested with an ampoule containing ammonia. Results: Between November 2020 and June 2021, 667 infected individuals (mean age: 48.2 years) were examined 9.1 months, on average, after positive PCR testing. Of these, 45.6% had persisting subjective olfactory dysfunction (OD), 36.2% had subjective gustatory dysfunction (GD). Tested OD, tested GD and impaired trigeminal function were observed in 34.6%, 7.3% and 1.8% of participants, respectively. The mean TDI score of participants was significantly lower compared to healthy subjects. Significant associations were observed between subjective OD and GD, and between tested OD and GD. Conclusion: Nine months after SARS-CoV-2 infection, OD prevalence is significantly increased among infected members of the general population. Therefore, OD should be included in the list of symptoms collectively defining Long-COVID.

To date, a plethora of tools for molecular biology have been developed on the basis of the CRISPR-Cas system. Almost all use the class 2 systems since here the setup is the simplest with only one protein and one guide RNA, allowing for easy transfer to and expression in other organisms. However, the CRISPR-Cas components harnessed for applications are derived from mesophilic bacteria and are not optimal for use in extremophilic archaea.Here, we describe the application of an endogenous CRISPR-Cas system as a tool for silencing gene expression in a halophilic archaeon. Haloferax volcanii has a CRISPR-Cas system of subtype I-B, which can be easily used to repress the transcription of endogenous genes, allowing to study the effects of their depletion. This article gives a step-by-step introduction on how to use the implemented system for any gene of interest in Haloferax volcanii. The concept of CRISPRi described here for Haloferax can be transferred to any other archaeon, that is genetically tractable and has an endogenous CRISPR-Cas I systems.

Background With a growing prevalence of inflammatory bowel disease (IBD) in elderly patients, there is a clinical requirement to understand the impact of treatment in this population.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. This post hoc analysis of data collected in the phase 2b/3 SELECTION programme evaluated the efficacy and safety of FIL in patients with ulcerative colitis (UC) stratified by age. Methods The SELECTION programme includes two Induction Studies, a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC were randomized 2:2:1 to receive FIL 200 mg or 100 mg or placebo once daily for 11 weeks. Responders at week 10 were re-randomized 2:1 to continue assigned FIL treatment or placebo from week 11–58. In LTE, patients with disease worsening and those completing week 58 continued assigned treatment before receiving open-label FIL. We assessed the efficacy and safety of FIL at any dose in the overall cohort of SELECTION and LTE, stratified into five age groups: Results Baseline disease activity and previous and concomitant treatments were comparable across age groups in each treatment arm. While there were fewer patients in the ≥60 years group, patient distribution was similar in all other age groups. FIL induced clinical (~16%) and pMCS (~36%) remission in similar proportions of patients across all age groups at week 10 (Figure 1). At week 58, pMCS remission was achieved in ~53% of FIL-treated patients across age groups (Figure 2). In LTE, the proportion of FIL-treated patients in pMCS remission generally increased with time and remained similar across all age groups (Figure 3). FIL-treated patients aged ≥60 years had higher EAIRs of any AE, infections, herpes zoster, malignancies, NMSC and MACE than younger patients (Table). One thromboembolic event occurred in a FIL-treated patient aged Conclusion These findings suggest FIL is efficacious in inducing and maintaining symptomatic remission and could have an acceptable safety profile in adults with UC of all ages, including ≥60 years old. Age-related increases in incidences of certain AEs might be expected in patients with IBD; however, the number of patients ≥60 years limits comparison of these data with reported rates. Reference 1Zammarchi et al. BMC Gastroenterol 2020;20;147

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety, and tolerability of etrasimod in subjects with moderately to severely active Crohn’s disease (CD). Here, we report the induction data from the first substudy (Substudy A). Methods Substudy A was a phase 2, randomised, double-blind study using a 14-week induction period followed by a 52-week extension period. Adults (18-80 years) with moderately to severely active CD and an inadequate response, loss of response to, or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to once-daily etrasimod 2 mg or 3 mg. Subjects were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI Results Of 83 subjects randomised to etrasimod 2 mg or 3 mg, respectively, 32/42 (76.2%) and 36/41 (87.8%) completed week 14 (Table 1). Overall, 21.4% and 9.8% of subjects in the 2-mg and 3-mg groups, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at week 14 (Figure 1). Most treatment-emergent AEs were mild or moderate, with more AEs reported in the 3-mg vs 2-mg group. The incidence of serious AEs (4.8% and 2.4%) and AEs leading to discontinuation (4.8% and 7.3%) was low in the 2-mg and 3-mg groups, respectively (Table 2). Two subjects in the 3-mg group experienced second degree atrioventricular block type 1 TEAEs (during 2-mg titration). Conclusion Data from this substudy of subjects with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 mg and 3 mg. However, the small sample size and lack of placebo arm limit the ability to draw conclusions about efficacy including comparison between the 2-mg vs 3-mg groups. Both doses were well tolerated and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.

Background To gain insight into vedolizumab (VEDO) use as a first-line biologic in Crohn′s disease (CD), this comparative, two-arm prospective real-world-evidence (RWE) study with propensity score (PS) adjustment aimed to assess, within the maintenance phase, the 2-year comparative effectiveness and persistence of VEDO vs anti-TNF therapy in biologic-naïve CD patients. Methods Between 2017-2020, 1200 consecutively enrolled biologic-naïve and biologic-experienced patients with ulcerative colitis (UC) and CD were prospectively included in the VEDOIBD study from 45 IBD-experienced centres across Germany. 260 biologic-naïve CD patients starting a new therapy with VEDO or anti-TNF were included in this RWE comparison of VEDO vs anti-TNF. The Kaplan-Meier curve was used to summarize the treatment persistence from the start of therapy through week-104. The primary outcome was two-year clinical remission (HBI ≤ 4). Patients were analysed on a modified intent-to-treat basis (mITT; switchers considered as outcome failure). To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used to evaluate the effectiveness. The results were reported as odds ratio (OR) and 95% confidence interval (CI). Results 63 VEDO and 197 anti-TNF (ADA: 58.4%, IFX: 41.6%) biologic-naïve CD-patients were evaluated. Two years after treatment initiation approximately 83% of VEDO patients were still in continuous treatment vs only 56% of anti-TNF patients (Fig. 1). In the mITT analysis (Fig. 2), there was a significantly higher clinical remission rate with VEDO when compared to anti-TNF after two years (VEDO: 64.2% vs anti-TNF: 44.7%), and a higher steroid-free remission (VEDO: 62.5% vs anti-TNF: 41.6%). Both differences were statistically significant (p Conclusion Compared to previous RCTs, this prospective two-year RWE study comparing VEDO with anti-TNF showed that, in biologic-naïve CD patients, remission rates at two years with VEDO were remarkably higher than with anti-TNF. Given the favourable side effect profile of VEDO, these findings may aid physicians’ decision-making on the choice of VEDO as a first-line biologic for CD.

Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for the treatment of moderately to severely active ulcerative colitis (UC). ELEVATE UC 52 and ELEVATE UC 12 were two phase 3 studies that demonstrated efficacy and safety of etrasimod in patients with UC in which several patient-reported outcomes were collected. Health-related quality of life (HRQoL) was assessed in a post hoc analysis of the ELEVATE programme with the validated Inflammatory Bowel Disease Questionnaire (IBDQ).1 Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Patients in the full analysis set with modified Mayo Scores 5-9 with a completed 32-item IBDQ questionnaire at baseline, week 12 (both trials) and week 52 (ELEVATE UC 52 only) were included in this analysis. Least squares mean (LSM) change from baseline for IBDQ total score and IBDQ domain scores were compared between etrasimod and PBO arms in both trials at each time point (data as observed), along with the proportion of patients who achieved IBDQ remission (IBDQ total score ≥170; nonresponder imputation). Results At baseline, a total of 237 and 191 etrasimod-treated patients and 112 and 96 PBO-treated patients completed the IBDQ for ELEVATE UC 52 and ELEVATE UC 12, respectively. LSM change from baseline in IBDQ total scores for etrasimod vs PBO were 42.8 vs 27.4 (difference [95% CI] 15.4 [6.5, 24.4]; P Conclusion Patients treated with etrasimod demonstrated greater improvement from baseline in total and all 4 domain scores of the IBDQ at the end of the 12-week induction phase and 52-week maintenance phase in comparison with PBO. These findings demonstrate the benefits of etrasimod on disease-specific HRQoL and support the clinical findings from the ELEVATE programme. Reference: 1. Chen XL, et al. Health Qual Life Outcomes. 2017;15:1-13.

Background Observational real-world evidence (RWE) studies on the effectiveness and safety of ustekinumab (UST) in ulcerative colitis (UC) are required in addition to RCTs, which are usually confined to selected patients and thus may not represent distinct treatment patterns and everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted in UC patients starting a newly initiated biologics therapy with a follow-up period of 3 years. The aim of the present analysis was to investigate the induction phase effectiveness of UST vs anti-TNF vs vedolizumab (VEDO) in UC in terms of clinical and steroid-free remission. Methods Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres across Germany. After exclusion of small molecules and missing outcomes, the final sample consisted of 317 patients. Response modified (reduction of partial Mayo score (pMayo) by ≥ 3 points from baseline to week-16 and a reduction of at least 30% or reaching remission at week-16), clinical remission (pMayo ≤ 1 plus a bleeding subscore=0), and steroid-free remission (pMayo ≤ 1, bleeding subscore=0 and no systemic use of steroids or oral budesonide during the last 8 weeks) were considered as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Health-related quality of life was assessed by using the self-reported visual analogue scale (EQ-VAS) of the EQ-5D. Changes in EQ-VAS from baseline to week-16 were assessed with a linear model. Results 101 UST (bio-naïve: 6), 106 anti-TNF (ADA: 24.5%, IFX: 65.1%, GOL: 10.4%) (bio-naïve: 70) and 110 VEDO (bio-naïve: 73) UC-patients were included. PS adjustment removed systematic differences between the three groups (UST/anti-TNF/VEDO: 44.9/43.8/48.1% males, 6.7/9.9/5.5% smokers, 7.9/12.5/9.3% EIM). The effectiveness of UST in terms of response, clinical and steroid-free remission was comparable to that of anti-TNF and VEDO at week 16 (Tab. 1). We observed a significant increase in EQ-VAS within all three groups (Tab. 2). The increase in the UST group was significantly higher than in the VEDO group and numerically higher than in the anti-TNF group. Conclusion In this prospective RUN-UC study, with propensity score weighted groups, UST showed similar induction phase effectiveness in comparison with anti-TNF and VEDO. Quality of life was significantly improved in the UST group vs VEDO and was numerically higher than anti-TNF after the induction phase.

Background CT-P13 SC is the only subcutaneous (SC) formulation of infliximab (IFX) approved to treat Crohn’s disease (CD) or ulcerative colitis (UC). The primary CT-P13 SC study reported no increased risk of immunogenicity (anti-drug antibody [ADA]/neutralising antibody [NAb] positivity) with CT-P13 SC vs. intravenous (IV) in CD or UC patients (pts) despite a numerical trend for lower ADA/NAb positivity with SC dosing.1 It is unclear whether high trough levels (Ctrough) during IFX dosing may account for these observations. Methods This post hoc analysis of part 2 of the randomised, parallel-group CT-P13 SC study (NCT02883452) evaluated predictors of immunogenicity in CD or UC pts treated with CT-P13. The relationship of Week (W) 22 and 30 ADA and NAb positivity rates with W22 CT-P13 Ctrough, under stable dosing, was examined. The optimal threshold of Ctrough for predicting ADA positivity was estimated by receiver operating characteristic (ROC) methodology using W22 data. A generalised linear regression model identified predictive factors for ADA and NAb positivity at W22 and W30. The proportion of pts with Ctrough levels equal to or above the calculated predictive threshold, and ADA/NAb positivity rates, were determined by treatment arm. Results The analysis included 131 pts randomised at W6 to receive CT-P13 SC (n=66) or CT-P13 IV (n=65) as maintenance treatment. Of 113 pts with both Ctrough and immunogenicity data available at W22, 60 were ADA negative, and 53 were ADA positive. At W22, median Ctrough levels were significantly higher in the ADA-negative vs. ADA-positive group (16.95 vs. 3.44 μg/mL, p ROC analysis showed that a Ctrough threshold of 4.695 μg/mL optimally predicted ADA positivity with 66.2% sensitivity and 77.3% specificity (area under the ROC curve, 0.766 [95% confidence interval, 0.664–0.869]; Fig. 2). Concomitant medication use and W22 Ctrough ≥4.695 μg/mL were significantly associated with lower rates of ADA and NAb positivity at W22 and were significant predictors of lower rates of ADA and NAb positivity at W30 (Fig. 3). At W22, a higher proportion of pts had Ctrough ≥4.695 μg/mL in the SC vs. IV arm (96.5% vs. 25.0%, p Conclusion Ctrough level predicted ADA and NAb positivity in CD or UC pts, with levels ≥4.695 μg/mL significantly associated with lower rates of positivity, providing initial evidence on high zone tolerance of IFX. Reference: 1. Schreiber S et al. Gastroenterology 2021;160:2340–2353.

Background In this two-arm prospective real-world-evidence (RWE) study with propensity score adjustment, we aimed to analyse the persistence of biologic therapy in biologic-naïve ulcerative colitis (UC) patients and to compare the 2-year effectiveness of vedolizumab (VEDO) and anti-TNF. Methods Between 2017 and 2020, 1200 consecutively enrolled biologic-naïve and biologic-experienced patients with UC and CD (Crohn’s disease) were prospectively included in the VEDOIBD study from 45 IBD-experienced centres across Germany. After the exclusion of biologic-experienced patients, CD, and missing outcomes, the final sample consisted of 314 biologic-naïve UC patients with 2-year follow-up data. In this mITT analysis switching was considered as outcome failure, and clinical remission and (steroid-free) remission rates (pMayo ≤1 plus a bleeding subscore=0 - and no systemic use of steroids or oral budesonide at two years) at two years were predefined as outcomes. To reduce the effect of confounders, propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Results The two-year maintenance phase effectiveness of 182 VEDO and 132 anti-TNF (ADA: 25.8%; IFX: 58.3%; GOL 15.9%) biologic-naïve UC patients were analysed in this prospective RWE-comparison of VEDO vs anti-TNF. Significantly more patients switched to another biologic in the anti-TNF group when compared to the VEDO group up to 2 years (54% vs 29%; p Conclusion As shown previously, in the induction phase, there is comparable effectiveness for VEDO and anti-TNF, although the remission rates are relatively low and similar to the range reported in RCTs. Over one year, the effectiveness tends to improve in favour of VEDO, potentially due to better treatment persistence. After two years, the clinical remission rate in the VEDO group is statistically significantly higher than in the anti-TNF group. The higher treatment persistence of VEDO vs anti-TNF and the higher effectiveness may suggest VEDO as a first-line biologics therapy option in UC patients.

Background CT-P13 subcutaneous (SC) infliximab formulation was developed to provide patients with a convenient option for treatment. Previous studies have shown efficacy and safety of CT-P13 SC comparable to CT-P13 intravenous (IV) in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate superiority of CT-P13 SC over placebo in maintenance therapy after induction therapy of CT-P13 IV in patients with ulcerative colitis (UC). Methods Patients with moderately to severely active UC (modified Mayo score 5 to 9 with endoscopic subscore of ≥ 2 points) were enrolled LIBERTY-UC (NCT04205643) and treated with open label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point, were randomised in a 2:1 ratio to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC arms every 2 weeks up to Week 54. The primary endpoint was clinical remission at Week 54. The key secondary endpoints of clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission were assessed at Week 54. Safety was evaluated up to Week 54. Results A total of 548 patients were enrolled. Among them, 438 patients (79.9%) responded to CT-P13 IV induction dosing and were randomised (294 in CT-P13 SC arm and 144 in placebo arm, respectively) at Week 10. The rate of clinical remission at Week 54 was significantly greater in CT P13 SC (43.2%) compared to placebo (20.8%) (P The safety profile during maintenance phase was generally comparable between CT-P13 SC and placebo arms (table 2). No deaths were reported. Conclusion CT-P13 SC was more effective than placebo for clinical remission, clinical response, endoscopic histologic mucosal improvement, and corticosteroid-free remission at Week 54 in patients with moderately to severely active UC. No new safety concerns were identified. These results demonstrate that the CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to patient with moderately to severely active UC. 1 Schreiber et al., 2021. Gastroenterology 2021;160:2340–23 2 Westhovens et al., 2020. Rheumatology 2020;00:1

Background Since April 2020, vedolizumab (VEDO) has been available for use in IBD in intravenous (iv) and subcutaneous (sc) formulations. Due to limited data on real-world use and effectiveness, the objectives of this real-world evidence (RWE), observational, prospective study are to observe (1) the time point of conversion to VEDO sc, (2) the 6-month remission rate with VEDO sc. using data from the VEDOIBD study. Methods Between 2017-2020, 1200 consecutively enrolled patients with ulcerative colitis (UC) and Crohn’s disease (CD) were prospectively included in the VEDOIBD study from 45 IBD-experienced centers across Germany. Additionally, 74 VEDO-naïve patients were included with the goal of conversion to VEDO sc after an iv-induction period with VEDO (VEDO iv week 0, 2, 6). Effectiveness was measured by clinical remission (HBI ≤ 4) at month 6. Results A total of 180 IBD patients with a running VEDO iv therapy were converted to VEDO sc during the entire study, with at least one 6-month visit from 119 patients (UC: n=67; CD: n=52). Characteristics are shown in Table 1. 87 IBD patients (73.1%) were still receiving VEDO sc after 6 months. 32 IBD patients (26.9%) stopped VEDO sc therapy within the first 6 months. The majority of patients returned to treatment with VEDO iv (37.9%) and the others switched to other biologics: 24.1% ustekinumab, 34.5% anti-TNF (Figure 1). At the time of conversion to sc, 92 patients (77.3%) were in remission (UC: 75%; CD: 84.6%). Of those, 88% remained in remission at 6 months (UC: 89.6%; CD: 86.4%). 45.8% of patients not in remission at the time of conversion to VEDO sc were in remission at 6 months (UC: 50%; CD: 37.5%). Of the 74 patients with planned conversion to VEDO sc, 52 patients (70.3%) received VEDO sc as planned previously: 11.5% within the first 2 weeks, 42.3% after week 6, 19.2% after week 14, and 26.8% after six months or later. Conclusion IBD patients with a conversion from VEDO iv to VEDO sc show high effectiveness after 6 months; conversion usually was carried out between 6 and 14 weeks. Based on these data, VEDO sc is shown to be an effective alternative to VEDO iv in RWE and should therefore be considered an important option in treatment planning and discussion with patients.