Sa1118 Withdrawing or Continuing Maintenance Treatment With Thiopurines in Patients With Crohn's Disease in Sustained Clinical Remission: A Lifetime Risk-Benefit Analysis

Abstract Background The exposure–efficacy relationship and immunogenicity rates of the new vedolizumab subcutaneous (SC) formulation have been established for maintenance treatment of ulcerative colitis (UC).1 Here, we report vedolizumab SC exposure–efficacy and immunogenicity in Crohn’s disease (CD). Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of vedolizumab SC (108 mg every 2 weeks) as maintenance treatment in patients with moderately to severely active CD. Following intravenous (IV) vedolizumab (300 mg Week 0 and 2) induction, patients with a clinical response at Week 6 (≥70-point decrease in CD activity index [CDAI] from Week 0) were randomised to blinded maintenance treatment and included in the analyses. Vedolizumab serum concentrations were measured prior to dosing using an enzyme-linked immunosorbent assay. Immunogenicity was assessed with a drug-tolerant electrochemiluminescence assay. Predicted vedolizumab trough concentrations at Week 52 were grouped by quartiles (Q), and Week 52 efficacy outcome rates calculated for each Q. Missing efficacy outcome data were imputed as failures. Efficacy outcomes were clinical remission (CDAI ≤150) and enhanced clinical response (≥100-point decrease in CDAI from Week 0 at Week 52). Results Following vedolizumab IV induction (N = 644), patients with a clinical response were randomised and received vedolizumab SC (N = 275) or placebo (N = 134) as maintenance treatment. At Week 52, patients on vedolizumab SC maintenance had a positive exposure–efficacy relationship for clinical remission (Q1: 37.7%; Q4: 50.7%) and enhanced clinical response (Q1: 37.7%; Q4: 53.6%; Figures 1 and 2). Overall, 7/275 (2.5%) patients on vedolizumab SC (following vedolizumab IV induction) developed anti-vedolizumab antibodies (AVAs): 3/7 patients were persistently AVA positive and 4/7 had neutralising antibodies. Five of 7 AVA-positive patients on vedolizumab SC did not achieve clinical remission and enhanced clinical response at Week 52; 2 of those patients were persistently AVA-positive. Immunogenicity was not associated with injection-site reactions or hypersensitivity reactions. Conclusion These preliminary results suggest a trend for higher vedolizumab SC serum concentrations with greater efficacy in CD, but the association was less pronounced than was reported in UC. (1) The AVA rate was similar to what was observed in prior vedolizumab IV studies. (2) In this study, vedolizumab immunogenicity appeared to be associated with clinical outcome. References

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T1197 A Risk-Benefit Analysis of Adalimumab vs. Standard of Care in Patients with Crohn's Disease

Gastroenterology ◽

10.1016/s0016-5085(08)62355-0 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-505

Author(s):

Edward V. Loftus ◽

Jean-Frédéric Colombel ◽

Scott J. Johnson ◽

Eric Wu ◽

Jingdong Chao ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Standard Of Care ◽

Benefit Analysis ◽

Risk Benefit Analysis

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OP23 Efficacy and safety of vedolizumab SC in patients with moderately to severely active Crohn’s disease: Results of the VISIBLE 2 study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.022 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S020-S021

Author(s):

S Vermeire ◽

W Sandborn ◽

F Baert ◽

S Danese ◽

T Kobayashi ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Response ◽

Clinical Remission ◽

Maintenance Treatment ◽

Activity Index ◽

Study Drug ◽

Open Label ◽

Phase 3 ◽

Double Blind

Abstract Background Vedolizumab (VDZ) is a gut-selective, humanised, monoclonal α 4β 7 integrin antibody for the treatment of patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). VDZ is currently an intravenous (IV) therapy; a subcutaneous (SC) formulation is under development to provide patients with an alternative route of administration for maintenance treatment for UC and CD. Here we present the first data from the phase 3 study of VDZ SC maintenance treatment in CD. Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a randomised, double-blind, placebo (PBO)-controlled phase 3 trial of VDZ SC as maintenance treatment in adults with moderately to severely active CD. Patients (n = 644) received open-label VDZ 300mg IV induction therapy at Weeks 0 and 2. At Week 6, clinical responders (defined as patients with a ≥70-point decrease in CD Activity Index [CDAI] from baseline) were randomly assigned to receive vedolizumab SC (108 mg every 2 weeks [Q2W]), or placebo (Q2W) for up to 52 weeks. The primary endpoint was clinical remission at Week 52 (defined as CDAI score ≤150). Rank-ordered secondary endpoints were enhanced clinical response at Week 52 (a drop of ≥100 in CDAI score), corticosteroid (CS)-free clinical remission at Week 52, and clinical remission at Week 52 in anti-tumour necrosis factor (TNF)-naïve patients. Finally, VDZ immunogenicity and predefined adverse events of special interest were assessed. Results Patients who responded to VDZ IV induction at Week 6 (n = 409) were randomised to VDZ SC (n = 275) or PBO (n = 134) maintenance and received at least 1 dose of study drug; 61% and 53%, respectively, were previously exposed to anti-TNF therapy. At Week 52, 48.0% of patients on VDZ SC vs. 34.3% on PBO were in clinical remission (p = 0.008, Figure). Enhanced clinical response at Week 52 was reached by 52.0% vs. 44.8% of patients on VDZ SC vs. PBO, respectively (p = 0.167). Among patients on concomitant CS at baseline (VDZ SC, n = 95; PBO, n = 44), 45.3% receiving VDZ SC vs. 18.2% receiving PBO achieved CS-free clinical remission at Week 52. Of anti-TNF-naïve patients (VDZ SC, n = 107; PBO, n = 63), 48.6% vs. 42.9% were in clinical remission at Week 52 in the VDZ SC and PBO arms, respectively. Injection-site reactions were reported for <3% of patients treated with VDZ SC. Serious infections, malignancy, and liver injury were ≤5% for both arms. Anti-VDZ antibodies were detected in 7 (2.5%) patients treated with VDZ SC arm; 4 of 7 patients developed neutralising antibodies. No new safety signals were observed. Conclusion Among VDZ IV induction responders, significantly more patients on maintenance VDZ SC than PBO achieved clinical remission at Week 52. The safety findings with VDZ SC remain in line with the known safety profile of VDZ IV in patients with CD.

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Mucosal healing of ileal lesions is associated with long-term clinical remission after infliximab maintenance treatment in patients with Crohn's disease

Digestive Endoscopy ◽

10.1111/den.12313 ◽

2014 ◽

Vol 27 (1) ◽

pp. 73-81 ◽

Cited By ~ 16

Author(s):

Takahiro Beppu ◽

Yoichiro Ono ◽

Toshiyuki Matsui ◽

Fumihito Hirai ◽

Yutaka Yano ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Remission ◽

Maintenance Treatment ◽

Mucosal Healing

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P823 DNA methylation profiles accurately predict vedolizumab response and remain stable during induction and maintenance treatment in Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.951 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S639-S640

Author(s):

V Joustra ◽

I Hageman ◽

A Li Yim ◽

K Gecse ◽

M Lowenberg ◽

...

Keyword(s):

Dna Methylation ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Peripheral Blood ◽

Clinical Remission ◽

Maintenance Treatment ◽

Treatment Selection ◽

Response To Treatment ◽

Gene Promoters ◽

Dna Methylome

Abstract Background While the use of biologicals has revolutionised the treatment of Crohn’s disease (CD) in recent decades, many patients fail to respond or lose response over time. Predictors for treatment selection and/or success are lacking. Vedolizumab (VDZ) induces corticosteroid-free clinical remission in 29% and endoscopic remission in 36% of patients after 6 months. Accumulating evidence suggests that the epigenome, mainly DNA-methylation, is associated with certain CD phenotypes. Here, we investigated whether the DNA methylome of peripheral blood (PB) obtained from CD patients treated with VDZ was associated with clinical and endoscopic response or non-response to treatment. Methods We prospectively recruited CD patients scheduled to start VDZ treatment at regular dosage and who underwent baseline endoscopy. PB was collected prior to treatment (T1) and at a median of 14 weeks (T2) into treatment. Additionally, a third PB sample was collected after a median of 79 weeks (T3) into treatment for 10 CD patients. DNA methylation was measured using the Illumina Infinium Methylation EPIC BeadChip. After a median 27 weeks of treatment, patients were characterised as responders (R) or non-responders (NR) based on endoscopic changes (R= ≥50% reduction in SES-CD score) combined with either steroid-free clinical remission (≥3 point drop in HBI, no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein and faecal calprotectin). Results We analysed data of 16 R and 14 NR patients, 53% of which were female with a median age of 37. No significant differences in age, sex or smoking were observed between R and NR. All patients had measurable serum VDZ concentration at the second endoscopy. To identify response-associated biomarkers, we performed elastic net regression through repeated cross-validation. We identified 38 differentially methylated probes (DMPs) associated with response (Figure a), 7 of which were located in gene promoters. Performance-wise the DMPs displayed a sensitivity of 0.86 and a specificity of 0.8 in predicting response (Figure b). Notably, the degree of methylation for the response-associated DMPs did not change after 14 weeks of treatment (n = 30), or even after 79 weeks (n = 10). Conclusion Here, we show that the DNA methylome in peripheral blood is associated with response to VDZ. As the difference in methylation remained stable during induction and maintenance treatment with VDZ, inflammation did not appear to affect the response-associated DMPs. Our observations provide evidence towards the establishment of epigenetic marks with predictive biomarker capabilities, paving the road towards personalised treatment selection in CD.

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P560 Clinical outcomes of vedolizumab maintenance treatment for Korean patients with inflammatory bowel disease who failed anti-TNF therapy: A KASID prospective multicenter cohort study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.681 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S523-S524

Author(s):

K Oh ◽

J Kim ◽

N Kim ◽

H Yoon ◽

K M Lee ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Events ◽

Clinical Remission ◽

Maintenance Treatment ◽

Multivariable Analysis ◽

Real Life ◽

Life Effectiveness ◽

The Real ◽

Korean Patients

Abstract Background We investigated the real-life effectiveness and safety of vedolizumab maintenance treatment among Korean patients with Crohn’s disease (CD) or ulcerative colitis (UC) who previously failed anti-tumour necrosis factor (anti-TNF) therapy. Methods Adult patients with CD or UC who have previously failed anti-TNF therapy and received vedolizumab were prospectively enrolled from 16 hospitals in Korea. The primary outcome was clinical remission at week 54. Clinical remission was defined as a Crohn’s disease activity index (CDAI) <150 and a partial Mayo score ≤2 with a combined rectal bleeding and stool frequency subscore ≤1. We also analyzed factors associated with clinical remission at week 54. Results Between August 2017 to July 2020, a total of 165 patients (81 with CD and 84 with UC) received vedolizumab therapy, of whom 154 patients (93.3%) (75 with CD and 79 with UC) received vedolizumab maintenance therapy (Table 1). Clinical remission and response rates at week 54 were 22.2% and 24.1% among patients with CD and 41.4% and 45.7% among patients with UC, respectively (Figure 1A and 1B). Among 70 patients with UC with baseline Mayo endoscopic subscore ≥2, endoscopic remission (Mayo endoscopic subscore ≤1) at week 54 was observed in 19 patients (27.1%). Out of 50 patients with CD with ulcers in baseline endoscopy, 2 patients (4%) showed a disappearance of ulcers at week 54 (Figure 1C). In the multivariable analysis, age at baseline (adjusted odds ration [aOR] 1.065, 95% confidence interval [CI] 1.003–1.131, P=0.041) and Mayo endoscopic subscore at baseline (aOR 0.141, 95% CI 0.026–0.746, P=0.021) were significantly associated with clinical remission at week 54 among patients with UC (Table 2). No factors were found to be associated with clinical remission at week 54 among patients with CD. Among patients who experienced one or more adverse events (n=134, 81.2%), serious adverse events occurred in 82 patients (49.7%) (Table 3). Disease exacerbation was the most common adverse events (n=89, 53.9%). Conclusion The real-life effectiveness of vedolizumab maintenance treatment for Korean patients with UC who failed anti-TNF therapy was generally similar with the outcomes reported from the previous Western studies. A substantial proportion of patients with CD experienced a loss of response during the first year of treatment. Less severe disease at baseline was associated with clinical remission at 1 year of vedolizumab therapy among patients with UC.

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P084 DEEP REMISSION WITH DOUBLE BIOLOGIC THERAPY: A SUCCESSFUL CASE OF COMBINATION USTEKINUMAB AND VEDOLIZUMAB FOR SEVERE REFRACTORY CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.182 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S72-S72

Author(s):

Ahmed Elmoursi ◽

Courtney Perry ◽

Terrence Barrett

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Combination Therapy ◽

Clinical Remission ◽

Biologic Therapy ◽

Case Reports ◽

Sigmoid Resection ◽

Safety And Efficacy ◽

Ileal Stricture

Abstract Background Stricturing Crohn’s disease (CD) constitutes a severe phenotype often associated with a high degree of morbidity (3). Surgical resection is first-line therapy for symptomatic strictures, but most patients relapse without subsequent medical therapy (4–5). Biologics are the mainstay for inducing and maintaining remission, but some cases are refractory despite maximum dosage of therapy. Reports of dual biological therapy (DBT) in refractory, stricturing CD are sparse, and prior case reports document only clinical remission (1). To contribute further knowledge regarding the use of DBT in stricturing CD, we present the case of a refractory CD patient who achieved deep remission with ustekinumab and vedolizumab. Case Presentation A 35 year old non-smoking, Caucasian male was referred to our clinic in 2014 for refractory CD complicated by multiple strictures. Prior to establishing care with us, he received two jejunal resections and a sigmoid resection. Previously failed therapies included azathioprine with infliximab, adalimumab, and certolizumab. He continued to progress under our care despite combination methotrexate/certolizumab, as well as methotrexate/golimumab. He underwent proctocolectomy with end ileostomy in 2015 and initiated vedolizumab q8weeks post-operatively. He reoccurred in 2018, when he presented with an ulcerated ileal stricture. He was switched from vedolizumab to ustekinumab q8weeks and placed on prednisone, but continued to progress, developing significant hematochezia requiring hospitalization and blood transfusions. Ileoscopy performed during hospital admission confirmed severe, ulcerating disease in the ileum with stricture. Ustekinumab dosing was increased to q4weeks, azathioprine was initiated, and he underwent stricturoplasty. Follow-up ileoscopy three months later revealed two ulcers in the neo- TI (Figure 1). Vedolizumab q8weeks was initiated in addition to ustekinumab q4weeks and azathioprine 125mg. After four months on this regimen the patient felt better, but follow-up ileoscopy showed two persistent ulcers in the neo-TI. Vedolizumab dosing interval was increased to q4weeks. After four months, subsequent ileoscopy demonstrated normal neo-TI (Figure 2). Histologic evaluation of biopsies confirmed deep remission of crohn’s disease. No adverse side effects have occurred with maximum doses of both ustekinumab and vedolizumab combination therapy. Discussion This case supports both the safety and efficacy of ustekinumab and vedolizumab dual biologic therapy for treatment of severe, refractory Crohn’s disease. While there are reports of DBT inducing clinical remission, this case supports efficacy for vedolizumab and ustekinumab combination therapy to induce deep histologic remission. Large practical clinical trials are needed to better investigate the safety and efficacy of DBT with vedolizumab and ustekinumab, but our case suggests this combination may be a safe and efficacious therapy for refractory CD patients.

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P089 REAL-WORLD EXPERIENCE: CLINICAL AND ENDOSCOPIC EFFECTIVENESS OF STANDARD VEDOLIZUMAB DOSING AND MODIFIED MAINTENANCE DOSING IN PATIENTS WITH MODERATE-SEVERE CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.187 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S75-S75

Author(s):

Scott D Lee ◽

Anand Singla ◽

Caitlin Kerwin ◽

Kindra Clark-Snustad

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Events ◽

Real World ◽

Clinical Remission ◽

Mucosal Healing ◽

Clinical Disease ◽

Endoscopic Remission ◽

Starting Dose

Abstract Background Vedolizumab (VDZ) is an effective treatment for Crohn’s disease (CD); however, inadequate and loss of response is common. Pivotal VDZ trials evaluated alternative dosing intervals, demonstrating numeric but not statistical superiority in efficacy as compared to FDA-approved dosing. The safety and effectiveness of FDA-approved and modified-dosing schedules in a real-world population are unknown. We aimed to evaluate clinical and endoscopic effectiveness & safety of standard and modified maintenance VDZ dosing in a real world cohort. Methods We retrospectively reviewed CD patients (pts) treated with >3 months VDZ, assessing Harvey Bradshaw Index (HBI), Simple Endoscopic Score for Crohn’s disease (SESCD), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), C-reactive protein (CRP), albumin and hematocrit prior to and following standard VDZ dosing, and prior to and following modified VDZ maintenance dosing. We measured duration on therapy and adverse events. Results We identified 226 eligible pts, mean age 41.5 years, 55.3% female, median disease duration 10 years, 88.9% with prior biologic exposure. Mean duration on VDZ was 28.3 months. Standard VDZ dosing: 61.5% of pts with active clinical disease and adequate follow up data achieved clinical response after 3–12 months; 41.0% had clinical remission. 51.9% of pts with active endoscopic disease and adequate follow up data achieved mucosal improvement; 42.3% had endoscopic remission; 26.0% had mucosal healing after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized CRP after 3–12 months. Modified maintenance dosing: 72 non-remitters to standard VDZ dosing received modified VDZ maintenance dosing. 51.5% of pts with active clinical disease prior to starting dose modification and adequate follow up data achieved clinical response after 3–12 months of modified maintenance dosing; 42.4% had clinical remission. 22.2% of pts with SESCD ≥3 prior to starting dose modification achieved mucosal improvement after 3–24 months; 22.2% had mucosal healing. 26.7% of pts with SESCD ≥4 prior to starting modified dosing had endoscopic remission after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized their CRP after 3–12 months. Safety: 82.7% of pts reported ≥1 adverse events, most commonly infection and worsening CD symptoms. Discussion Standard VDZ dosing resulted in clinical and endoscopic improvement in pts with moderate-severe CD, with prior exposure to multiple advanced therapies. For non-remitters to standard dosing, modified VDZ maintenance dosing improved clinical disease activity in ∼50% of pts and improved endoscopic disease activity in ∼20% of pts, suggesting that for pts who did not achieve remission with standard VDZ dosing, modified VDZ dosing may result in clinical and endoscopic improvement.

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