bluuebunny/crossref_metadata_2025 huggingface dataset:
P519 Mirikizumab pharmacokinetics and exposure-response relationships in patients with moderately to severely active ulcerative colitis: results from randomised phase 2 and phase 3 induction and maintenance trials
Authors: Friedrich S , Chua L , Zhang X C
Published: January 2023

Background

Mirikizumab (MIRI) is a p19-targeted anti–interleukin-23 developed for ulcerative colitis (UC), and has demonstrated efficacy in Phase 2 (AMAC, NCT02589665) and Phase 3 (LUCENT-1, NCT03518086; LUCENT-2, NCT03524092) trials in patients with moderately to severely active UC. We characterised MIRI pharmacokinetics (PK) and the exposure-response (E-R) relationship between MIRI exposure and clinical outcomes in these 3 trials.

Methods

Patients received 12-week MIRI induction (50, 200 or 600 mg [AMAC] or 300 mg [LUCENT-1] intravenous [IV] every 4 weeks [Q4W]), and induction responders then received MIRI maintenance (200 mg subcutaneous [SC] Q4W or every 12 weeks for 92 weeks in AMAC; 200 mg SC Q4W for 40 weeks in LUCENT-2). Serum PK parameters were analysed by non-linear mixed-effects modelling, and covariate effects on MIRI exposure were evaluated using simulation-based estimations. Relationships between MIRI exposure and clinical remission, clinical response, endoscopic remission and symptomatic remission, based on the Mayo scoring system, were assessed using logistic regression models.

Results

MIRI PK (clearance, 0.022 L/hr (95% CI 0.02,0.03); volume of distribution for central and peripheral compartments, 3.11 L (95% CI 3.07, 3.15) and 1.69 L (95% CI 1.03, 2.57); half-life, 9.5 days) were best described by a 2-compartment model with first-order absorption. Clearance increased with body weight and decreased with albumin concentration, and bioavailability decreased with body mass index, but impacts of covariates were small relative to random variability. MIRI SC bioavailability was 48%. Modelling of E-R relationships during MIRI induction in AMAC revealed statistically significant positive associations of MIRI exposure with clinical response and with change in Modified Mayo Score. Maximum effect was predicted at 300 mg, with no significant improvement at higher doses. Steep positive relationships between exposure and efficacy in LUCENT-1 were not explained by patient covariates, and analyses suggest confounding by unknown variables. MIRI exposure during maintenance was not a significant predictor of efficacy in AMAC and LUCENT-2.

Conclusion

MIRI PK characteristics were typical of an immunoglobulin G monoclonal antibody. The MIRI E-R relationship revealed an apparent lack of sensitivity of efficacy to individual patient exposures at the dose levels studied in Phase 3. Overall, the PK and E-R data suggest that dose adjustments due to patient factors are not justified.
P522 Kono-S anastomosis reduces endoscopic and surgical post-operative recurrence in Crohn’s disease. The SuPREMe-CD Trial Update.
Authors: Luglio G , Rispo A , Tropeano F P , Giglio M C , Cricrì M , Imperatore N , De Sire R , Guarino A D , Bucci L , Castiglione F , De Palma G D
Published: January 2023

Background

Recently, a new antimesenteric, functional, end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence (ER) and surgical recurrence (SR) rate in Crohn’s disease (CD). This trial aimed to provide randomized controlled data comparing Kono-S anastomosis and conventional stapled ileocolic side-to-side anastomosis.

Methods

Randomized controlled trial (RCT) at a tertiary referral centre. The primary endpoint is ER rate (Rutgeerts score ≥ i2) after 6 months and surgical recurrence at 60 months. Secondary endpoints are clinical recurrence (CR) rate after 24 and 36 months, and SR after 24 and 36 months. Statistics was performed by using standard analyses. Furthermore, a sample size able to consent the detection of a reduction >30% in total endoscopic recurrence (when assuming a 60% to 65% ER expected rate in the control group and a 30% in the case group) was calculated; to allow a 10% drop-out of patients, 36 patients per group were needed (72 patients in the entire population).

Results

A total of 119 CD patients were included in the study. In all, 51 ileocolic CD patients were randomized in the Kono group and 68 in the conventional side-to-side group.

At 6 months, 17 (33.3%) patients in the Kono group and 51 (75%) patients in the conventional group presented an ER (Rutgeerts score≥i2) at colonoscopy (p<0.001). A severe post-operative ER (Rutgeerts score≥i3) was found in 8 (15.7%) patients in the Kono group versus 23 (33.8%) patients in the conventional group (p=0.03).

At 24 months, CR rate was 19.6% in the Kono group versus 30.9% in the conventional group (p=0.2), while SR rate was 0% in the Kono group versus 4.4% (3 patients) in the standard group (p=0.2).

At 36 months, CR rate was 19.6% in the Kono-s group versus 33.8% in the conventional group (p=0.1). At 36 months, no patients (0%) in the Kono group experienced SR, while 6 patients (8.8%) in the conventional group did (p=0.03).

Furthermore, when considering a median follow-up of 54 (42-60) months at interim analysis of SR, the difference between the two groups was confirmed to be significant (0% vs 8.8%; p=0.02).

Conclusion

This is the first RCT comparing Kono-S anastomosis and conventional side-to-side anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and surgical recurrence rates, no safety issues, and a favourable trend for lower clinical recurrence rate in patients who underwent Kono-S anastomosis compared to the conventional side-to-side anastomosis.
P525 Real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis: a systematic review and meta-analysis
Authors: Taxonera C , Olivares D , Olga N L G , Alba C
Published: January 2023

Background

Knowledge of the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC) is relevant to confirm the benefit observed in clinical trials. The aim of this systematic review was to summarize reported evidence on the real-world outcomes of ustekinumab for UC and to conduct a meta-analysis of effectiveness and safety data.

Methods

A systematic search was conducted in electronic databases PubMed, Web of Science, EMBASE, and Science Direct, and conference proceedings until 15 September 2022 for real-world studies evaluating ustekinumab for UC. A random-effects meta-analysis model was used to calculate the pooled rates of clinical and safety outcomes. We evaluated the outcomes at week 8, week 12 to 16, month 6, and month 12. Need for colectomy and adverse events (AE) were reported as percentages and incidence rates (IRs) per 100 patients-year (PY) of exposure.

Results

Of the 254 citations identified, 19 studies were included with 3786 patients. Sixteen studies reported prior exposure to biologics or JAK inhibitors and included 1003 patients, of whom 92.3% were previously treated with any biologic, 61.1% with both anti-TNF and vedolizumab, and 16.4% with any biologic and tofacitinib (Figure 1). Remission was achieved in 45.4% of patients at week 8 (95% confidence interval 30.1-60.6%), 43.8% (38.4-49.2%) at weeks 12 to 16, 44.6% (35.9-53.3%) at month 6, and 50.6% (36.3-64.8%) at month 12 (Figure 2). Response was achieved in 61.2%, 59.4%, 65.2%, and 76.8% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively (Figure 3). Corticosteroid-free remission was achieved in 18.7%, 36.8%, 34.5%, and 39% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Endoscopic improvement was achieved in 29.9%, 24.3% %, and 58.2% of patients at weeks 12 to 16, month 6, and month 12, respectively. Almost 30% of the patients needed dose escalation, which was effective in 40% of these patients. The pooled rate of persistence with ustekinumab was 76.9% and 73.3% at month 9 and month 12, respectively. The IRs of colectomy, AE, serious AE, and serious infections were 5.1, 7.9, 1 and 0.5 per 100 PY, respectively (Figure 4).

Conclusion

The results of this systematic review and meta-analysis of real-world studies confirm the effectiveness of ustekinumab in a highly treatment-refractory population of patients with active moderate-to-severe UC. The acceptable safety data presented here support the positive long-term benefit-risk profile of ustekinumab in the treatment of UC. These real-world effectiveness and safety results were consistent with clinical trials and provide a broader perspective that can be used to aid treatment decisions in a more heterogeneous clinical setting.
P539 Patient Preferences for Inflammatory Bowel Disease Treatments: Development of a European Preference Survey using a Discrete Choice Experiment
Authors: Schoefs E , Vermeire S , Ferrante M , Sabino J , Verstockt B , Avedano L , De Rocchis M S , Sajak-Szczerba M , Saldaña R , Straetemans N , Vandebroek M , Huys I , Janssens R
Published: January 2023

Background

There is a growing consensus across stakeholders on the value of patient preference (PP) studies, as recognized by the European Medicines Agency and the European Network for Health Technology Assessment. This study aimed to develop a PP survey to quantitatively evaluate which characteristics are most important to inflammatory bowel disease (IBD) patients, so that the results can inform the medicinal product life cycle (MPLC).

Methods

Following the PREFER recommendations, a four-step approach was followed to develop the PP survey: 1) stated preference method selection, 2) attribute and level development, 3) survey implementation, and 4) survey piloting. Throughout the different steps of the survey development, an advisory board (AB) consisting out of patients, patient organizations, gastroenterologists, IBD nurses, and statisticians were consulted.

Results

First, a discrete choice experiment (DCE) was chosen as the preferred elicitation method because it allows to reach the objectives of the survey, namely to: 1) quantify the relative importance of different attributes, 2) elicit the trade-offs patients make, and 3) measure preference heterogeneity. Second, a scoping literature review of IBD clinical trials, available IBD treatments, and previously published preference studies was performed. Discussions on these characteristics with patients (n=11) during focus group discussions (FGDs) using the nominal group technique revealed the following patient prioritized characteristics: prevent surgery, long-term clinical remission, improved quality of life, occurrence of urgency, and improved labor rate. Based upon the results of the FGDs, a preliminary list of possible attributes for inclusion in the DCE was refined during AB meetings. This list was iteratively adapted until consensus was found on 14 attributes, their levels, and corresponding explanations (Figure 1).

Third, the DCE survey was designed to include these 14 attributes using partial profiles next to measures about sociodemographic variables, health literacy, and treatment experience. Fourth, piloting the study with IBD patients (n=4) revealed that the survey was comprehensible, had a good flow, and contained graphics that supported the content. Only minor text edits were needed.

Conclusion

It is key to develop a PP survey in partnership with patients and other members of the AB. This survey will be rolled out across Europe in 11 different languages and will increase understanding of which treatment aspects are most important to IBD patients. These aspects should be included in drug development and evaluation so that the MPLC can be more patient-centered and future treatments will target aspects that are most important to IBD patients themselves.
P543 Induction and maintenance of mucosal healing in Crohn’s disease with ustekinumab in clinical practice – Results of a nationwide, prospective, multicenter study in Germany (MUCUS)
Authors: Baumgart D C , Stallmach A , Schubert A , Howaldt S , von Arnim U , Ochsenkühn T , Stein J , Lügering A , Schmidt D , Schulz M , Fischer A
Published: January 2023

Background

Ustekinumab (UST) is a fully human IgG1k monoclonal antibody to human IL-12/23p40 approved in several jurisdictions for the treatment of adult patients with moderately to severely active Crohn’s disease (CD). UST’s impact on induction and maintenance of mucosal healing, fistula healing and extraintestinal manifestations were not fully elucidated in the registration trial program.

Methods

In this prospective, multicenter study (EudraCT number: 2017-005151-83) across all care levels in Germany, we evaluated the real-world effectiveness of UST prescribed within its German label to achieve the primary endpoint of combined clinical (Harvey Bradshaw Index (HBI) score reduction ≥ 3 points from baseline) and endoscopic (50% reduction of the simple Endoscopic Score for Crohn Disease (SES-CD) from baseline) response in week 52 and a variety of secondary endpoints including mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic segment and endoscopic remission defined as an SES-CD score of 0 – 2.

Results

We recruited 52 CD patients (female n=28, bionaive n=13, bioexposed n=39). See Table 1 for baseline demographics and pertinent history details. At week 52, 50% (n=12/24) of patients achieved the primary endpoint [50% (n=3/6) in the bionaive, 45.5% (n=5/11) bioexposed to one and 57.1% (n=4/7) bioexposed to multiple biologics cohorts, respectively], 58.3% (n=14/24) of patients achieved endoscopic response [50% (n=3/6) in the bionaive, 54.5% (n=6/11) bioexposed to one and 71.4% (n=5/7) bioexposed to multiple biologics cohorts, respectively], 33.3% (n=8/24) of patients achieved endoscopic remission [50% (n=3/6) in the bionaive, 27.3% (n=3/11) bioexposed to one and 28.6% (n=2/7) bioexposed to multiple biologics cohorts, respectively], 45.8% (n=11/24) of patients achieved mucosal healing [50% (n=3/6) in the bionaive, 36.4% (n=4/11) bioexposed to one and 57.1% (n=4/7) bioexposed to multiple biologics cohorts, respectively]. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event (TEAE), in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to discontinuation of UST, but no very severe events or deaths (Table 2).

Conclusion

UST reliably induces endoscopic response and mucosal healing in both bionaive and bioexperienced CD patients in routine clinical practice. The limited samples size is a direct result from the Covid-19 pandemic. No new safety signals were recorded.
P549 One-Year Comparison of Clinical and Endoscopic Outcomes of Tofacitinib Versus Vedolizumab for Ulcerative Colitis After Anti-Tumor Necrosis Factor Failure: A Real-World Cohort Study in the United States
Authors: Dalal R , Sharma P , Bains K , Pruce J , Allegretti J
Published: January 2023

Background

Tofacitinib (tofa) is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We compared 52 week real-world outcomes of tofa vs vedolizumab (vedo) for UC after anti-TNF failure.

Methods

In this retrospective cohort study, adults initiated tofa or vedo after failure of ≥1 anti-TNF between 5/1/18 and 4/1/21 at a large U.S. medical center. Vedo patients were frequency matched to tofa patients 2:1 by age and sex. The primary outcome was steroid-free clinical remission at 12 and 52 (+/- 4) weeks (SFCR 12 and 52, simple clinical colitis activity index [SCCAI] ≤2 or provider assessment and no use of oral/IV steroids for ≥30 days). The secondary outcome was endoscopic response (ER) within 52 weeks (decrease in Mayo endoscopic subscore [MES] by ≥1 point). Other outcomes within 52 weeks: endoscopic remission (MES=0), biochemical response/remission (improvement by 25%/normalization of C-reactive protein), drug discontinuation for non-response (NR), improvement in arthralgia, UC hospitalization, and adverse events (AEs). Multivariable logistic regression was performed for primary/secondary outcomes adjusting for UC duration, number of prior anti-TNFs, steroid/immunomodulator use, albumin, Montreal disease extent >E1, MES = 3, and UC hospitalization within 12 months.

Results

136 vedo patients were matched to 68 tofa patients. Tofa patients had more anti-TNF exposures, higher CRP and SCCAI, and most had prior vedolizumab exposure (Table 1). 54% of tofa vs 46% of vedo patients achieved SFCR 12 and 59% vs 45% achieved SFCR 52. Within 52 weeks, 74% tofa vs 55% vedo had ER, 30% vs 27% had endoscopic remission, 55% vs 50% had improvement in arthralgia, 71% vs 59% had biochemical response, 46% vs 32% had biochemical remission, 5% vs 13% had UC hospitalization, 30% vs 29% discontinued treatment for NR, and 0% vs 2% discontinued treatment due to AEs (vedo group only: perforated diverticulitis, nausea, and oral pain) (Figure 1). During available follow-up (not limited to 52 weeks), the most common AEs (reported among >1% of total cohort) included rash (0% tofa vs 4% vedo), C. difficileinfection (1% vs 2%), shingles (2% vs 1%), COVID-19 (1% vs 2%), other infection (2% vs 4%), and elevated liver enzymes (1% vs 2%) (Figure 2). After multivariable logistic regression, tofa was associated with a non-significantly higher odds of SFCR 12 (OR 1.66, 95% CI 0.77-3.62) and significantly higher odds of SFCR 52 (OR 2.15, 95% CI 1.01-4.61) and ER within 52 weeks (aOR 3.42, 95% CI 1.08-10.80) vs vedo.

Conclusion

Tofa was associated with higher odds of SFCR 52 and ER vs vedo for UC. AEs were consistent with known safety profiles. Due to limited sample sizes, larger cohort studies are needed.
P558 Etrasimod for the treatment of ulcerative colitis: analysis of infection rates from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials
Authors: Regueiro M , Siegmund B , Yarur A , Steinwurz F , Gecse K B , Goetsch M , Bhattacharjee A , Wu J , Green J , McDonnell A , Crosby C , Lazin K , Ferreira Branquinho D , Modesto I , Abreu M T
Published: January 2023

Background

Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. 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). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme.

Methods

Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: 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). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (≥ CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections.

Results

From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received ≥1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subject-years of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41; PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR<0.01; PBO: 0.8%, EAIR=0.02); these were localised and nonserious. One opportunistic infection was reported in each arm (etrasimod: subject withdrew from the study on day 20, the AE of Cytomegalovirus infection [Grade 2] was reported on day 36; PBO: tuberculosis [Grade 2]). Overall, 3 cases of infection led to discontinuation: 2 in the etrasimod arm (both mild) and 1 in the PBO arm (Table 2). No subject with an absolute lymphocyte count <0.2×109/L subsequently reported a serious/severe or opportunistic infection. There were no deaths.

Conclusion

In these trials, etrasimod-treated subjects reported no increase in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.
P561 Risk of stoma formation in patients with Crohn’s perianal fistulas over a two decades period. A cohort study from a tertiary referral center.
Authors: Bislenghi G , Baldi C , Ferrante M , Sabino J , Verstockt B , Wolthuis A , Vermeire S , D'Hoore A
Published: January 2023

Background

Optimal management of perianal Crohn’s disease (pCD) consists of combined medical (preferentially anti-TNF) and surgical treatment. However, it is still unclear if this has improved outcomes. This study aimed to described outcome and prognosis of pCD patients at a referral center over almost two decades.

Methods

All pCD patients referred for active perianal fistulas between 2000-2018 at our center were considered eligible for this retrospective study. Patients were divided into two groups according to the date of pCD diagnosis: period A (2000-2006) and period B (2006-2018). The complement of Kaplan-Meier estimates were used to visualize the time since pCD diagnosis until temporary and definitive fecal diversion. Clinically important outcomes such as need for temporary or permanent fecal diversion, and factors associated to these outcomes were evaluated by Cox regressions models.

Results

A total of 336 patients with active pCD were identified. The mean interval between the diagnosis of CD and the perineal fistulizing disease was 4.9 years (+-7.64). Mean follow up was 10.83 years (SD ± 4.5). The two groups were similar for demographic and clinical characteristics, except for the cumulative exposure to biologicals prior to pCD diagnosis [27.8% vs 46.9% in period A and B, respectively (p<0.001)]. (Table 1) The risk for temporary and definitive fecal diversion was higher for group B, at 5- [temporary stoma: 10.8 CI (6.7%-17.3%) vs 27.3% CI (21.1%-34.9%), p<0.001; definitive stoma: 0.7% CI (0.1%-4.8%) vs 13.1% CI (8.7%-19.5%), p=0.002] and 10-years follow-up [temporary stoma: 23.3% CI (17%-31.5%) vs 39.0% CI (31.1%-48.1%), p<0.001; definitive stoma: 11.7% CI (7.2%-18.7%) vs 19.9% CI (13.9-28.0%), p=0.002], respectively. (Figure 1 and Figure 2). At multivariate analysis, the presence of extraintestinal manifestations [HR 2.55 CI (1.40-4.62)], B2 stricturing disease [HR 4.43 CI (1.46-13.4)], B3 penetrating disease [HR 7.10 CI (2.37-21.27)], and diagnosis of pCD diagnosis after 2006 (period B) [HR 2.20 CI (1.16-4.17)], were independent risk factors for need for permanent ileostomy. (Table 2)

Conclusion

This retrospective analysis spanning almost twenty years shows that prognosis of CD patients affected by anal fistulas remains poor and has not much changed over time, despite the introduction of biologicals and new surgical techniques. The observed increase in definitive fecal diversion in more recent years can be partially explained by referral bias and/or a more aggressive clinical management of the most severe cases. Extraintestinal manifestations and synchronous complicated luminal disease increased the risk of definitive stoma in the long-term.
P562 Real world effectiveness and safety of ozanimod: One-year follow-up from a large tertiary center
Authors: Cohen N A , Choi D , Garcia N , Choi N , Picker E , Krugliak-Cleveland N , Cohen R , Dalal S , Sakuraba A , Pekow J , Rubin D
Published: January 2023

Background

Ozanimod is a first in class sphingosine-1-phosphate receptor modulator approved by the FDA for moderately-to-severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. We provide one-year follow up results of our patient cohort treated with ozanimod.

Methods

This prospective, observational cohort study includes consecutive patients who initiated ozanimod at our center. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical response was defined as a decrease in ≥3 points in SCCAI from baseline with only patients with clinically active disease included in the analysis, and clinical remission was defined as an SCCAI score of ≤ 2.

Results

47 patients have initiated ozanimod therapy at our center: 45 patients with ulcerative colitis (UC), 1 patient with Crohn’s colitis and 1 patient with lymphocytic colitis. Only patients with UC were included in the effectiveness analysis. Demographics are in Table 1: in the UC cohort, the mean age was 40.6 ±16.6 years, mean disease duration was 9.6 ±9.2 years, 26 (58%) were male, 23 (51%) had extensive colitis, and 34 (76%) had previous advanced therapy exposure. 19 had baseline endoscopy with a mean Mayo endoscopic score of 2.6 ±0.5. Clinical response, remission, and corticosteroid free remission (CSFR) rates at weeks 2, 4, 10, 24, and 52 are in Figure 1. At week 10, follow-up was available for 41 patients: 18 patients (55%) achieved clinical response, 24 (59%) clinical remission, and 22 (54%) achieved CSFR. At week 52, follow-up was available for 30 patients: 5 (17%) achieved clinical response, 5 (17%) clinical remission, and 4 (13%) achieved CSFR. There were no significant differences between advanced therapy naïve and experienced patients, including when stratified by the number of previous advanced therapies or prior use of vedolizumab (Figures 2A+B and 3). Patients with a > 75% reduction in absolute lymphocytes had numerically greater induction clinical response and remission rates (80% vs 54%, p=0.4 and 75% vs 53%, p=0.4, respectively). 13 patients experienced adverse events (AEs): hypertension (n=2), transient nausea (n=2), fatigue (n=3), dry skin (n=2), transient liver enzyme elevation (n=2) and transient headache (n=3). Two AEs required discontinuation – hypertensive crisis in a patient with a prior dx of hypertension, and fatigue. There were no episodes of symptomatic bradycardia.

Conclusion

We present one-year real world follow-up of ozanimod in a largely treatment-refractory cohort of patients with UC, and describe modest one-year effectiveness and a safety profile that is not different from that described in the clinical trials.
P563 Monitoring of vedolizumab drug levels in a treat to target strategy for moderate-severe IBD (MOVE-IBD)
Authors: Logan H , Rimmer K , Doecke J , Patrick D
Published: January 2023

Background

Vedolizumab is an effective drug in moderate-severe ulcerative colitis (UC) and Crohn’s disease (CD). A previous link between drug exposure and clinical response has been suggested in the literature making therapeutic drug monitoring (TDM) for vedolizumab an attractive idea to try and optimize patient outcomes. Recent data from the ENTERPRET induction study in UC presented at Digestive Diseases 2022 suggest no advantage to dose optimizing based on vedolizumab levels. Thus, there is discordance in the literature regarding the clinical relevance of vedolizumab drug levels. We aimed to clarify the utility of proactive TDM of vedolizumab trough levels in our cohort of maintenance vedolizumab patients using objective markers of disease activity in a treat to target strategy.

Methods

A single-centre retrospective cross sectional cohort study using proactive TDM was performed on 84 patients with moderate to severe IBD on vedolizumab maintenance therapy. All patients were receiving standard vedolizumab dosing of 300 mg every eight weeks. A vedolizumab trough drug level was paired with clinical and objective markers of disease activity. The two endpoints examined were steroid free clinical remission and objective remission. Objective remission targets were individualized for each patient using a treat to target strategy and benchmarked against a baseline abnormal test. Steroid free clinical remission was defined in Crohn’s disease as a Crohn’s disease activity index (CDAI) of < 150 and in ulcerative colitis as a partial MAYO score of < 1 in a patient off steroids. Objective remission was defined as faecal calprotectin < 150 ug/g, normal bowel wall thickness on intestinal ultrasound or magnetic resonance imaging without associated features of inflammation or absence of ulceration on colonoscopy or sigmoidoscopy within 3 months of the vedolizumab level.

Results

Median trough vedolizumab levels for patients were numerically higher but not statistically different in patients who had achieved steroid free clinical remission (13.3 ug/ml vs 8.89 ug/ml p = 0.544) or objective remission (15.22 ug/ml vs 10.28 ug/ml p = 0.139). See Figures 1. In addition, quartile analysis showed no statistically significant difference between quartiles of vedolizumab levels and clinical or objective remission (p = 0.822).

Conclusion

Trough serum vedolizumab levels in our real-life cohort of maintenance moderate severe IBD patients were not associated with clinical or objective remission. Caution should be applied to basing treatment decisions off vedolizumab maintenance levels until more data becomes available to support its routine use in clinical practice.
P564 vedolizumab versus infliximab and adalimumab in the real-world persistence in Ulcerative Colitis and Crohn’s disease – a meta-analysis
Authors: Yiu T H , Leong R , Ko Y , Pudipeddi A
Published: January 2023

Background

In Ulcerative Colitis (UC), vedolizumab demonstrated increased efficacy over adalimumab in the VARSITY study. However, the real-world effectiveness of vedolizumab against adalimumab, infliximab and in UC and Crohn’s disease (CD) is not well-known. Drug persistence measures the duration of time from initiation to discontinuation of a therapy, is a surrogate marker that combines therapeutic efficacy, safety, and tolerability. This meta-analysis compared drug persistence of vedolizumab versus anti TNF alpha inhibitors (TNFi) adalimumab and infliximab in UC and CD.

Methods

Systematic review and meta-analysis were conducted with observational studies identified in electronic database – EMBASE and PubMed search from inception of 2017 to July 2022 and abstracts screened from recent gastroenterology conference – Digestive disease week 2022 San Diego. 6 observational studies evaluating persistence of vedolizumab versus TNFi (infliximab and adalimumab) among participants aged >18 years with diagnosis of IBD met inclusion criteria and were included.

Results

Overall, 1 year persistence of vedolizumab is 71.2% in UC and 76% in CD, significantly higher than infliximab (56.4% in UC, 53.7% in CD) and adalimumab (53.7% in UC, 55.6% in CD). (Table 1) Head-to-head comparison shows RR of 1.15 (95% CI of 1.12 – 1.19), favouring vedolizumab.

2-years persistence was pooled from 4 studies. Vedolizumab had a 2-years persistence of 66% in UC and 61% in CD, which also shows superiority to both infliximab (49.7% for UC, 59.1% for CD) and adalimumab (31.4% for UC and 56% for CD). (Table 2) Meta-analysis with head-to-head comparison continue to show a statistically significant difference in 2 years persistence of vedolizumab versus TNFi (RR of 1.12, 95% CI 1.01 – 1.25).

For UC patients, vedolizumab shows superiority over both adalimumab and infliximab with a RR of 1.41 (95% CI 1.14 – 1.74) and 1.15 (95% CI 1.06 – 1.25) respectively and RR of 1.23 (CI 1.14 – 1.33) when adalimumab and infliximab combined.

For CD, vedolizumab has a slightly higher 1-year persistence over TNFi combined (RR 1.10 95% CI 1.02 – 1.19) but fails to show any statistically significant difference from adalimumab (RR 1.07 95% CI 0.86 – 1.32) and infliximab (RR 0.55 95% CI 0.07 – 4.35) individually.

Vedolizumab has a higher 1-year persistence in bio-naïve subgroup (RR 1.14 95% CI 1.07 – 1.22) but fails to show statistically significant advantage in bio-experienced group (RR 1.04 95% CI 0.80 – 1.35) when compare with TNFi.

Conclusion

Vedolizumab achieved a higher overall 1- and 2-years persistence compared to adalimumab and infliximab in both CD and UC but mainly in bio-naïve subjects. The benefit of vedolizumab over TNFi was more evident in UC than CD.
P578 Exploring duration of corticosteroid withdrawal in definitions of corticosteroid-free remission endpoints in ustekinumab clinical trials: results from the IM-UNITI, UNIFI, and SEAVUE trials
Authors: Panés J , Panaccione R , Sands B , Gasink C , Marano C , Ma T , Hoops T
Published: January 2023

Background

Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC).

Methods

In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI<150 in IM-UNITI and SEAVUE and a Mayo score ≤2 with no individual subscore >1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE.

Results

The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2).

Conclusion

In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition.

References:

1) Ma C, Hanzel J, Panaccione R, et al. CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease. Gastroenterol 2022;4:950-64.
P584 Efficacy, safety, and tolerability of AMT-101, a gut selective oral IL-10 fusion, in the Phase 2 FILLMORE trial of patients with chronic pouchitis
Authors: Jairath V , Bressler B , Silverberg M S , Lee L Y , Lugo K A , Mayoral Monibas R , Annamalai T , Whitney J A , Weng E Y , Kanwar B , Danese S , Feagan B
Published: January 2023

Background

Chronic pouchitis can occur in up to half of patients within 10 years of ileal pouch-anal anastomosis (IPAA) after proctocolectomy for ulcerative colitis (UC). There is a large unmet need for medical treatments.

Methods

This was a phase 2, randomized double-blind, parallel-group, 2 active-arm trial of the combined phase 2/3 trial in adults (18-75 years) with a prior history of UC with proctocolectomy and subsequent IPAA, who presented with chronic or recurrent pouchitis. The trial was conducted in US, Canada, and Western Europe. Approximately 20 patients were planned to be randomized 1:1 to either 3 mg or 10 mg AMT-101 doses administered once daily, orally, for 12 weeks. The key efficacy endpoints were: 1) the proportion of patients with symptomatic improvement, as measured by stool frequency response, and 2) the proportion of patients with histologic healing, as measured by Geboes scores. Histology and endoscopy were centrally read.

Results

22 patients were randomized to receive AMT-101 3 mg (n=10) or 10 mg (n=12). The mean (SD) baseline absolute stool frequency was 13.4 (4.5). Overall, 36.4% (8/22) of patients achieved stool frequency response, defined as either a reduction of ≥ 3 stools and a ≥ 30% reduction in number of stools from baseline, or a return to post-IPAA number of stools or lower, at Week 12. 40% (4/10) and 33% (4/12) of patients dosed with 3 mg or 10 mg, respectively, achieved stool frequency response at Week 12. Rapidity of stool frequency response was demonstrated as early as Week 2 in both arms and was substantially maintained through Week 12.

Patients had a median (IQR) baseline Geboes score of 5.1 (3.2 to 5.2), representing severe pouchitis with ulceration and tissue destruction. Across both arms, 22.7% (5/22) [20.0% (3 mg) and 25.0% (10 mg)] of patients met the histologic healing response of Geboes score ≤ 3.1, an objective assessment of disease improvement. Endoscopic assessments (SES-CD, ≥50% reduction) were also performed, with modest improvements [10% (3 mg) and 8.3% (10 mg)] at Week 12.

There was no systemic AMT-101 PK (by design) nor anti-drug antibodies detected. Translational analysis revealed IL-10 biological responses in both arms. In tissue, IHC results showed increases in anti-inflammatory FOXP3+ (Tregs) and CD163+ (M2-macrophages) cells in the lamina propria.

Treatment emergent adverse events were mostly mild to moderate, with only one treatment-unrelated serious adverse event.

Conclusion

AMT-101 3 mg and 10 mg both appeared to be safe and generally well tolerated. PK and translational data confirmed AMT-101’s gut-restricted profile over the 12-week treatment with tissue-level PD effects and no systemic exposure. The AMT-101 3 mg dose is advancing into a Phase 3 trial for chronic pouchitis.
P586 Vedolizumab in Mild to Moderate Crohn’s Disease Patients Naïve to Biological Therapy: a Multicentric Observational Study
Authors: Dotti A Z , Vilela E G , Chebli J M F , Chebli L A , Magro D O , Steinwurz F , Argollo M , Carvalho N S , Parente J M L , Parra R S , Perin R L , Flores C , Morsoletto E M , Ferreira S D C , Ludvig J C , Kaiser Jr R L , Queiroz N S F , Faria M A G , Nicollelli G M , Andrade A R , Kotze P G
Published: January 2023

Background

Vedolizumab, a human monoclonal antibody that blocks integrin α4-β7, was approved for the management of Inflammatory Bowel Diseases. In real-world experience the number of patients using vedolizumab as first-line biological therapy was low, mainly in Crohn′s Disease (CD). This study aimed to evaluate the efficacy of vedolizumab exclusively in CD patients who were naïve to previous biologics, with mild to moderate disease. Additionally, we aimed to analyze the safety profile of vedolizumab, rates of mucosal healing, need for abdominal surgery and drug discontinuation over time in this specific population.

Methods

We performed a retrospective multicentric cohort study with patients with mild to moderate CD treated with VDZ who were naïve to previous biologics agents. These patients had clinical activity scores (Harvey-Bradshaw Index [HBI]) measured at baseline and weeks 12, 26, 52 as well as at the last follow-up. Clinical response was defined as a reduction ≥3 in HBI whereas clinical remission as HBI ≤4. Mucosal healing was defined as the complete absence of ulcers in control colonoscopies. Kaplan-Meier survival analysis was used to assess the persistence with vedolizumab over time.

Results

From a total of 72 patients (6 excluded) 53% (35/66) reached clinical remission at week 12. This percentage increased to 71.9% (46/64) at week 26, 88.1% (52/59) at week 52 and 81.8% (54/66) at the last follow-up visit. Clinical response was achieved in 72.7% (48/66), 92.2% (59/64), 95,1% (58/61) and 83.3% (55/66) in the same periods, respectively. Mucosal healing was achieved in 62.3% (33/57) of patients. Vedolizumab was well-tolerated and most adverse events were minor; 89.3% remained on vedolizumab after 52 weeks. During vedolizumab treatment, 3/66 patients underwent surgery.

Conclusion

Vedolizumab was effective in the management of patients with mild to moderate CD as first biological agent, with a remission rate of 88.1% after one year. Mucosal healing was observed in 62.3% of patients and major abdominal surgery was needed in only 4.5% of patients. This is one of the first international studies focused on the use of vedolizumab as a first-line biological treatment option in clinical practice in mild to moderate CD.
P599 Similar efficacy of mesalazine in adult and elderly patients: post-hoc analysis of randomised non-inferiority trial of 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis
Authors: Safroneeva E , Gerstner O , Laoun R
Published: January 2023

Background

Ulcerative colitis (UC) incidence has bimodal age distribution with a peak in the second to fourth decade and a second smaller peak in the sixth to eighth decade. We assessed the difference in rates of clinical and endoscopic response and remission in adult (≤60 years of age) and elderly (>60 years of age) mild-to-moderate (Mayo Clinic Score ≥5) UC patients treated with mesalazine.

Methods

We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 817 UC patients treated with mesalazine for 8 and additional 38 weeks in a double-blind and open label study, respectively (D’Haens et al. Aliment Pharmacol Ther.2017;46:292–302). The differences between groups were analysed using Wilcoxon rank sum or chi-square test with continuity correction. P-value of <0.05 was considered to be statistically significant.

Results

Elderly patients had longer disease duration, higher body mass index, higher number of co-morbiditities and concomitant medications recorded prior and during the trial, when compared with adults participating in the study (Table 1). These patients also had higher baseline Mayo endoscopic score (2.38±0.486 standard deviation [SD] in elderly vs. 2.26±0.439 SD in adult patients; p-value=0.0077). No difference in rates of combined clinical and endoscopic remission, clinical remission and response, endoscopic remission and response were observed at week 8 and 38 (Table 2).

Conclusion

We observed similar rates of clinical and endoscopic response and remission in adult and elderly mild-to-moderate UC patients treated with mesalazine for 8 and 38 weeks.
P600 Democratic deliberation to assess Veteran preferences for biosimilar medication switching for the treatment of Inflammatory Bowel Disease in a resource-conscious setting.
Authors: Ryan K , Hou J K , Baker J , Krenz C , De Vries R , Waljee A K
Published: January 2023

Background

Optimizing care while being resource-conscious, the Veterans Health Administration (VHA) must develop equitable policies incorporating Veterans’ values and beliefs. Switching patients with Inflammatory Bowel Disease (IBD) from biologic medications (originators) to less expensive biosimilars offers opportunities to explore potential policies. Unlike originators, the FDA did not require disease-specific randomized controlled trials for approval of biosimilars, raising provider and patient concerns about the safety of switching to these medications. Deliberative democratic (DD) methods allow us to assess Veteran views of switching programs, a necessary step in creating equitable policies.

Methods

We carried out two 2-day sessions with Veterans from the Ann Arbor VA (n=17) and Houston VA (n=12). Deliberation began with education about IBD, the use of biologics (including biosimilars), and related implementation challenges. Participants engaged in facilitated small group discussions to 1) identify Veterans views about biosimilar switching and Veteran preferences about switching, and 2) evaluate five approaches for switching: (a) “status quo”–switching policies vary by VHA facility, (b) “sickest last”–Veterans with severe IBD are switched last, (c) “opt-out”–Veterans may opt-out of switching, (d) “next appointment”–Veterans are switched at follow-up, and (e) “lottery”–patients are switched based on random selection. Participants ranked options (1=most preferred, 5=least preferred) and proposed modifications to these approaches. Participants completed pre- and post-DD session surveys. Transcripts were analysed using qualitative methods.

Results

Participant demographics are in Table 1. Most Veterans sessions preferred the “sickest last” (mean rank: 1.8, standard deviation: 0.9) or “opt-out” (2.4,1.4) approaches over the “status quo” (3.1,1.0) or “lottery” (4.6,0.9); preferences did not significantly change after deliberation (Figure 1). Preferences reflected Veterans’ concerns about the risk of switching to biosimilars for the most vulnerable Veterans and their strong preference for transparency around biosimilar switching. Participants emphasized the importance of informed choice, prioritizing based on health status, personalization, and shared decision-making.

Conclusion

DD methods are effective for soliciting Veterans' opinions and preferences for health policies. Veterans favoured policies that provided information and control, promoted shared decision-making, and reduced risk to vulnerable patients. Incorporating patient preferences and insights is critical when implementing health policies in the VHA and other resource-limited settings.