Vermeire, Séverine

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.

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of UC. Safety and efficacy of tofacitinib were demonstrated in Phase (P)2/3 induction studies, a 52-week, P3 maintenance study, and are being further investigated in an ongoing, open-label, long-term extension (OLE) study.1,2 Here, we provide an updated analysis of age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical programme.3 Methods Proportions of AEs and serious AEs (SAEs), and incidence rates (IRs; unique patients with events per 100 patient-years) for AEs of special interest (AESIs), were determined for two cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily [BID] in the maintenance study) and the Overall Cohort (all tofacitinib 5 or 10 mg BID-treated patients in the P2/P3/OLE studies; as of May 2019), stratified by age. Multivariable Cox proportional hazards regression analyses were performed to assess whether older age was associated with increased risk of AESIs in the Overall Cohort. Results In the Maintenance Cohort, IRs of AEs and SAEs were generally similar between treatment groups, with no age-related trend in the proportions of AEs in tofacitinib-treated patients. AESIs were infrequent in both treatment groups; however, herpes zoster (HZ; non-serious and serious) IRs were numerically higher in the ≥40 to <50 and ≥50 years age groups for patients treated with tofacitinib 10 mg BID vs. placebo and tofacitinib 10 vs. 5 mg BID. In the Overall Cohort, IR of serious infections was generally similar between age groups, while IRs of opportunistic infections (OIs) and HZ (non-serious and serious), malignancy (excl. non-melanoma skin cancer [NMSC]), NMSC and major adverse cardiovascular events increased with increasing age. The IRs of HZ and NMSC were significantly greater in patients ≥50 years compared with patients <30 years, and in patients ≥30 to <40 years for NMSC. In multivariate analyses, older age was identified as a significant predictor of malignancy (excl. NMSC), NMSC and HZ. Conclusion In the Overall Cohort, there was a trend for an increase in the rates of OIs, HZ, malignancy (excl. NMSC) and NMSC with increasing age. In multivariate analyses, older age was associated with increased risk of malignancy (excl. NMSC), NMSC and HZ. The results of this analysis are generally consistent with previous studies suggesting older age may be associated with an increased risk of certain AESIs in patients with UC, and in some instances in the general population.4 References

BACKGROUND: Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody approved for moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Although VDZ efficacy and safety are well established, there are limited publications on longer-term (>3 years) treatment persistence. This study evaluated VDZ treatment persistence for up to 5 years in a GEMINI long-term safety (LTS) VDZ de novo cohort. METHODS: All patients in GEMINI LTS (NCT00790933) were treated with VDZ every 4 weeks. A post hoc analysis of data from patients not previously treated with VDZ before Week 0 of GEMINI LTS (de novo cohort) was conducted, with VDZ treatment persistence assessed using Kaplan-Meier survival analysis. Treatment discontinuations due to adverse events (AEs) or lack of efficacy were considered for the analysis; discontinuations due to protocol deviation, patient withdrawal, or loss to follow-up were censored. Treatment persistence analyses were further stratified by Week 12 treatment response (primary response/nonresponder), prior anti-tumor necrosis factor (anti-TNF) failure (Yes/No), type of anti-TNF failure (primary/secondary nonresponse), and concomitant therapy (corticosteroids, 5-aminosalicylates, immunomodulators, or their combinations) at baseline (Yes/No); a log-rank test assessed statistical differences between subgroups. RESULTS: The GEMINI LTS de novo cohort included 421 patients (UC 190; CD 231) with a mean disease duration of 8.7 (UC) and 10.6 (CD) years, 6.0 mean partial Mayo score (UC) and 11.1 mean Harvey-Bradshaw Index; 61% of patients with UC and 74% with CD had prior anti-TNF failure. Up to 5 years follow-up, 276 patients (66%) total discontinued VDZ: 16% with UC and 17% with CD due to AEs, and 24% with UC and 33% with CD due to lack of efficacy. Survival probabilities for VDZ treatment persistence at 54 months were 53% for UC and 41% for CD. These VDZ 54-month survival probabilities were higher in patients with VDZ treatment response at Week 12 vs without (UC, 60% vs 26%, respectively, P < 0.0001; CD, 42% vs 35%, respectively, P = 0.001) and in patients without prior anti-TNF failure vs with (UC, 63% vs 47%, respectively, P = 0.046; CD, 47% vs 42%, respectively, P = 0.016). Among patients with baseline anti-TNF failure, survival probabilities for VDZ treatment persistence at 54 months were higher in UC patients who were secondary nonresponders vs those who were primary nonresponders (65% vs 15%, respectively, P < 0.0001); this difference was not observed in CD patients (44% vs 40%, respectively, P = 0.573). There were no differences in survival probabilities of continuing VDZ at 54 months among patients with UC or CD who initiated VDZ therapy with vs without any concomitant medications. CONCLUSION(S): More than half of patients with UC and 4 of every 10 patients with CD persisted on VDZ for 54 months. Treatment persistence rates in UC and CD cohorts were significantly higher in Week 12 responders and patients without prior anti-TNF failure, whereas there were no differences in persistence rates with baseline use of concomitant medications. Vedolizumab discontinuation rates due to AEs were low. These findings from GEMINI LTS support the longer-term effectiveness and safety of VDZ in patients with moderately to severely active UC and CD.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn’s disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

SummaryBackgroundReliable tools for patient selection are critical for clinical drug trials.AimTo evaluate a consensus‐based, standardised magnetic resonance enterography (MRE) protocol for selecting patients for inclusion in Crohn's disease (CD) multicenter clinical trials.MethodsThis study recruited 20 patients [Crohn's Disease Activity Index (CDAI) scores: <150 (n = 8); 150–220 (n = 4); 220–450 (n = 8)], to undergo ileocolonoscopy and two MREs (with and without colonic contrast) within a 14‐day period. Procedures were scored centrally using, Magnetic Resonance Index of Activity (MaRIA), and both Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simplified Endoscopic Score (SES‐CD).Results37 MREs were acquired. Both MREs were evaluable in 16 patients for calculation of test–retest and inter‐reader reliability scores. The MaRIA scores for the terminal ileum had excellent test–retest and inter‐reader reliability, with correlations >0.9. The proximal ileum showed strong within‐reader agreement (0.90–0.96), and fair between‐reader agreement (0.59–0.72). MRE procedures were tolerable. MaRIA scores correlated with CDEIS and SES‐CD (0.63 and 0.71), but not with CDAI (0.34). MRE identified 3 patients with intra‐abdominal complications, who would otherwise have been included in clinical trials. Furthermore, both MRE and ileocolonoscopy identified active bowel wall inflammation in 2 patients with CDAI <150, and none in 1 patient with CDAI > 220. Data quality was good/excellent in 85% of scans, and fair or better in 96%.ConclusionsMagnetic resonance enterography of high‐quality and reproducibility was feasible in a global multi‐ centre setting, with evidence for improved selectivity over CDAI and ileocolonoscopy in identifying appropriate CD patients for inclusion in therapeutic intervention trials.