M Smyth

Long-term Efficacy of Vedolizumab for Ulcerative Colitis

Background and Aims The GEMINI long-term safety [LTS] study is a continuing phase 3 trial investigating the safety and efficacy of vedolizumab, an α4β7 integrin antagonist for ulcerative colitis [UC] and Crohns disease. We provide an interim analysis of efficacy in patients with UC. Methods Patients from the C13004 and GEMINI 1 studies and a cohort of vedolizumab-naïve patients received open-label vedolizumab every 4 weeks. Interim data were collected from May 22, 2009 to June 27, 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life [HRQL] were assessed for up to 152 weeks of cumulative treatment in the efficacy population. Results As of June 27, 2013, 63% of the efficacy population [n = 532/845] were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88% [n = 120/136] were in remission after 104 weeks of exposure (96% [n = 70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI 1 [n = 32] before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41% and 28%, respectively, after 52 weeks, an increase from 19% and 6%, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior tumour necrosis factor-antagonist exposure. Durable benefits on HRQL were also observed. Conclusions Patients with UC experienced clinical and HRQL improvements with continued vedolizumab treatment. Increased dosing frequency to every 4 weeks was beneficial in patients who had loss of response to 8-weekly dosing.

Long-term Efficacy of Vedolizumab for Crohn’s Disease

Background and Aims Vedolizumab is a gut-selective α4β7 integrin antagonist therapy for ulcerative colitis and Crohns disease. The GEMINI long-term safety [LTS] trial is an ongoing open-label study investigating the safety of vedolizumab. We present interim exploratory analyses of efficacy in patients with Crohns disease. Methods Patients from the C13004, GEMINI 2 and GEMINI 3 studies and vedolizumab-naïve patients could enrol in GEMINI LTS and received vedolizumab every 4 weeks. Data were collected from May 22, 2009 to June 27, 2013. Outcomes of clinical response and remission, defined by the Harvey-Bradshaw Index, and health-related quality of life [HRQL] were assessed for up to 152 weeks of treatment in the efficacy population. Results Among patients with response at week 6 in GEMINI 2 who received vedolizumab continuously, 83% [n=100/120] and 89% [n=62/70] of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks [GEMINI 2] to every 4 weeks [GEMINI LTS] improved outcomes in patients who had withdrawn early from GEMINI 2, with 47% [n=27/57] experiencing clinical response and 32% [n=18/57] in remission at week 52 of GEMINI LTS [up from 39% and 4% before the dose increase]. Similar improvements were observed regardless of prior tumour necrosis factor [TNF] antagonist exposure. Long-term benefits of HRQL were also observed. Conclusions The clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. Increased dosing frequency might improve outcomes in patients who lose response to conventional 8-weekly dosing.

Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease

Background and Aims A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohns disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Methods Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. Results Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. Conclusions Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.

Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists

BACKGROUND & AIMS: The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin &agr;4&bgr;7, were demonstrated in multicenter, phase 3, randomized, placebo‐controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohns disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti–tumor necrosis factor‐&agr; (TNF) antagonists. METHODS: We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations. RESULTS: At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4–40.4; RR, 2.0; 95% CI, 1.3–3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8–33.5; RR, 1.9; 95% CI, 1.1–3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9–41.1; RR, 2.5; 95% CI, 1.5–4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8–46.1; RR, 6.6; 95% CI, 1.7–26.5). No differences in adverse events were observed among groups. CONCLUSIONS: Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.

Systematic review with network meta-analysis: Comparative efficacy of biologics in the treatment of moderately to severely active ulcerative colitis

Background Biological therapies are increasingly used to treat ulcerative colitis (UC). Aim To compare the efficacy of biologics in adults with moderately-to-severely active UC, stratified by prior exposure to anti-tumour necrosis factor (anti-TNF) therapy. Methods A systematic literature review was undertaken to identify studies of biologics approved for UC. Network meta-analysis was conducted for endpoints at induction and maintenance. Results Seven studies were included in the meta-analysis of induction treatment for anti-TNF therapy-naïve patients. All biologics were more effective than placebo in inducing clinical response, clinical remission, and mucosal healing. Infliximab demonstrated a statistically significant improvement over adalimumab in clinical response (odds ratio [OR] [95% credible interval (CrI)]: 2.19 [1.35–3.55]), clinical remission (OR [95% CrI]: 2.81 [1.49–5.49]), and mucosal healing (OR [95% CrI]: 2.23 [1.21–4.14]); there were no other significant differences between biologics for induction efficacy. Five studies were included in the meta-analysis of maintenance treatment, two studies rerandomised responder patients at end of induction, and three followed the same patients ‘straight through’. To account for design differences, the number of responders at end of induction was assumed to be equivalent to the number rerandomised. Vedolizumab showed significantly different durable clinical response from comparators (OR [95% CrI] infliximab 3.18 [1.14–9.20], golimumab 2.33 [1.04–5.41], and adalimumab 3.96 [1.67–9.84]). In anti-TNF therapy-experienced patients, only vedolizumab and adalimumab could be compared. At induction, no significant differences in efficacy were seen. During maintenance, vedolizumab showed significantly improved rates of mucosal healing versus adalimumab (OR [95% CrI]: 6.72 [1.36–41.0]). Conclusions This study expands the understanding of comparative efficacies of biologic treatments for UC, encompassing outcomes and populations not previously studied. All biologic treatments were effective for UC during induction. Vedolizumab demonstrated possible clinical benefits in the maintenance setting versus all comparators, irrespective of prior anti-TNF exposure and after adjusting for differences in study design.

P497 Efficacy of continued vedolizumab therapy in patients with Crohn's disease who did not respond to vedolizumab induction therapy at week 6

The authors regret that an inaccuracy in the published abstract has been brought to their attention and is described …

P501 Effects of continued vedolizumab therapy for ulcerative colitis in week 6 induction therapy nonresponders

Background: Vedolizumab (VDZ), a gut-selective, humanized, anti-α4β7 integrin monoclonal antibody, was evaluated for the treatment of ulcerative colitis (UC) in the 52-week GEMINI 1 trial. In this study, 47.1% of patients had a clinical response to VDZ induction therapy at week 6. Here the efficacy of continuing VDZ therapy is evaluated in week 6 nonresponders to VDZ induction therapy. Methods: GEMINI 1 participants were randomly assigned to receive placebo (PBO) or VDZ 300 mg (cohort 1) or assigned to receive open-label VDZ (cohort 2) intravenously at weeks 0 and 2. Patients who did not respond to VDZ induction therapy at week 6 received open-label VDZ every 4 weeks (Q4W) during maintenance, whereas all PBO patients continued on PBO. Clinical response (reduction in partial Mayo Clinic score [MCS] of ≥2 points and decrease of ≥25% from the baseline score, with an accompanying reduction in rectal bleeding subscore of ≥1 point or a rectal bleeding subscore of 0 or 1) and clinical remission (partial MCS of ≤2 points and no subscore >1 point) were assessed in week 6 nonresponders at weeks 10 and 14 (prespecified) and at week 52 (post hoc). Week 52 post hoc analyses were also performed for mucosal healing (Mayo Clinic scale endoscopic subscore of 0 or 1) in week 6 nonresponders and for efficacy end points in week 6 nonresponders who had clinical response at week 10 or 14. Results: At baseline, the median duration of UC in VDZ week 6 nonresponders (4.6 years) was comparable to week 6 responders. Baseline UC activity (ie, complete MCS) was higher in VDZ week 6 nonresponders (median, 9.0) than inweek 6 responders (median, 8.0), whichwas attributable mainly to a greater proportion of patients withMCS of 9 to 12 (56% of week 6 nonresponders, 42% of week 6 responders). Rate of previous tumor necrosis factor antagonist failure was higher among week 6 nonresponders (51%) than among week 6 responders (32%). Proportions of week 6 nonresponders who had clinical response, clinical remission, or mucosal healing at weeks 10, 14, and 52 were numerically greater with VDZ than with PBO (Table). These differences were most pronounced at week 52. For both VDZ and PBO, the proportions of week 6 nonresponders who had clinical response, clinical remission, or mucosal healing at week 52 were similar between those who responded at week 10 and those who responded at week 14; the small numbers of PBO-treated patients in these subgroups are a limitation of this analysis. Conclusions: Patients with UC who did not have a clinical response to VDZ induction therapy at week 6 and continued VDZ Q4W had higher rates of clinical response and remission at weeks 10, 14, and 52 and of mucosal healing at week 52 than did those who received PBO.

Cost-effectiveness of vedolizumab compared with infliximab, adalimumab, and golimumab in patients with ulcerative colitis in the United Kingdom

ObjectiveTo examine the clinical and economic impact of vedolizumab compared with infliximab, adalimumab, and golimumab in the treatment of moderately to severely active ulcerative colitis (UC) in the United Kingdom (UK).MethodsA decision analytic model in Microsoft Excel was used to compare vedolizumab with other biologic treatments (infliximab, adalimumab, and golimumab) for the treatment of biologic-naïve patients with UC in the UK. Efficacy data were obtained from a network meta-analysis using placebo as the common comparator. Other inputs (e.g., unit costs, adverse-event disutilities, probability of surgery, mortality) were obtained from published literature. Costs were presented in 2012/2013 British pounds. Outcomes included quality-adjusted life-years (QALYs). Costs and outcomes were discounted by 3.5% per year. Incremental cost-effectiveness ratios were presented for vedolizumab compared with other biologics. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty.ResultsThe model predicted that anti-tumour necrosis factor-naïve patients on vedolizumab would accrue more QALY than patients on other biologics. The incremental results suggest that vedolizumab is a cost-effective treatment compared with adalimumab (incremental cost-effectiveness ratio of £22,735/QALY) and dominant compared with infliximab and golimumab. Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. However, vedolizumab is cost-effective irrespective of variation in any of the input parameters.ConclusionsOur model predicted that treatment with vedolizumab improves QALY, increases time in remission and response, and is a cost-effective treatment option compared with all other biologics for biologic-naïve patients with moderately to severely active UC.

Indicators of suboptimal tumor necrosis factor antagonist therapy in inflammatory bowel disease

BACKGROUND Inflammatory bowel disease (IBD) is refractory to treatment in one-half of patients. AIMS To evaluate the occurrence of suboptimal therapy among patients with IBD treated with tumor necrosis factor antagonists (anti-TNFs). METHODS A multinational chart review in Europe and Canada was conducted among IBD patients diagnosed with ulcerative colitis (UC) or Crohns disease (CD) who initiated anti-TNF therapy between 2009 and 2013. The primary endpoint was the cumulative incidence of suboptimal therapy during a two-year follow-up period, defined by the presence of the following indicators: dose escalation, discontinuation, switching, non-biologic therapy escalation, or surgery. RESULTS The study included 1195 anti-TNF initiators (538 UC and 657 CD). The majority of patients (64% of UC and 58% of CD) had at least one indicator of suboptimal therapy. The median time to suboptimal therapy indicator was 12.5 and 17.5 months for UC and CD patients, respectively. Among the 111 UC and 174 CD anti-TNF switchers, 51% and 56% had an indicator of suboptimal therapy, respectively. The median time to suboptimal therapy indicator with the second anti-TNF was 14.3 and 13.0 months for UC and CD patients, respectively. CONCLUSION The majority of IBD patients showed suboptimal therapy with current anti-TNFs.

PTH-084 Cost-Effectiveness of Vedolizumab Compared with Infliximab, Adalimumab, and Golimumab for Treatment of Moderately-to-Severely Active Ulcerative Colitis in The United Kingdom

Introduction The objective of this analysis was to examine the clinical and economic impact of vedolizumab (VDZ) compared with infliximab (IFX), adalimumab (ADA), and golimumab (GOL) in the treatment of moderately to severely active ulcerative colitis (UC) in the UK (UK). Methods A Markov decision analytic model in Microsoft Excel was used to compare VDZ with IFX, ADA, and GOL for the treatment of UC patients in the UK. Due to a lack of data in comparable patient populations, this analysis was conducted in anti-tumour necrosis factor (TNF)-naïve patients only. Efficacy data were obtained from a network meta-analysis of Phase III clinical trials, using placebo as the common comparator. Other inputs (e.g., unit costs, adverse event disutilities, probability of surgery, mortality) were obtained from published literature. Costs are presented in 2014 British pounds. Outcomes included quality-adjusted life-years (QALY), time spent in clinical response, and time spent in clinical remission. Time horizons included 10 year (base case) and lifetime (scenario) horizons, with costs and outcomes discounted by 3.5% per year. Incremental cost-effectiveness ratios (ICER) were presented for VDZ compared with other biologics. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty. Results Over the base-case (10 year) time horizon, the model predicted that anti-TNF-naïve patients on VDZ accrued more QALY than patients on other biologics: 5.898 QALY vs 5.818, 5.760, and 5.790 QALY for IFX, ADA, and GOL, respectively. The incremental results over a 10 year horizon suggests that VDZ is a cost-effective treatment compared with ADA (ICER of £6,634/QALY), and VDZ is dominant compared with IFX and GOL. Patients on VDZ spent more time in clinical response (2.93 years vs 2.55 years for ADA, IFX and GOL) and clinical remission (1.38 years vs 1.08, 0.99, and 1.04 years for IFX, ADA and GOL respectively). VDZ was found to be dominant compared with all other biologics over a lifetime horizon. Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. However, VDZ remained cost-effective irrespective of variation in any of the input parameters. Conclusion Our model predicted that treatment with VDZ improves QALY, increases time in remission and response, and is a cost-effective treatment option for anti-TNF-naïve patients with moderately to severely active UC compared with all other biologics tested. VDZ may also be a cost-saving treatment strategy as well. Disclosure of Interest M. Wilson Conflict with: Employee of RTI Health Solutions, a company hired to conduct the study by Takeda Pharmaceuticals, M. Kerrigan Conflict with: Employee of PHMR Ltd, a company hired to conduct the study by Takeda Pharmaceuticals, M. Smyth Employee of: Takeda Development Centre Europe Ltd, London, UK, H. Chevrou-Severac Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, A. Bergman Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, R. Selby Employee of: Takeda UK Ltd., Bucks, UK